antibiotic history
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Antibiotics ndash mechanism of resistance ndash
related history [MRSA VRE VISA ESBLS]
By DrRaghu prakash reddy
A statue of the Hindu God Brahma Hinduism believes in the divine origin of Ayurveda
1495 Europeans Mercury ------gt syphilis(Treponema pallidum)
1630 Europeans Quinine (bark of cinchona) -----gt malaria (Plasmodium spp)
Ignaacutec Semmelweis (1818-1865)ndash assistant in midwifery ofAllgemeines Krankenhaus(Vienna) in 1846ndash noted that up to 15 women diedfrom childbed puerperal feverafter physician-assisted deliveryndash by contrast mortality was low indeliveries performed by midwives
History of infection control
bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality
ndash he wrote a bunch of letters to the establishmentoutlining his discovery
ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket
History of infection control
bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds
ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo
ndash gloves were originally introduced toprevent dermatitis from antiseptics
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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-
A statue of the Hindu God Brahma Hinduism believes in the divine origin of Ayurveda
1495 Europeans Mercury ------gt syphilis(Treponema pallidum)
1630 Europeans Quinine (bark of cinchona) -----gt malaria (Plasmodium spp)
Ignaacutec Semmelweis (1818-1865)ndash assistant in midwifery ofAllgemeines Krankenhaus(Vienna) in 1846ndash noted that up to 15 women diedfrom childbed puerperal feverafter physician-assisted deliveryndash by contrast mortality was low indeliveries performed by midwives
History of infection control
bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality
ndash he wrote a bunch of letters to the establishmentoutlining his discovery
ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket
History of infection control
bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds
ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo
ndash gloves were originally introduced toprevent dermatitis from antiseptics
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
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- Slide 3
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- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
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-
Ignaacutec Semmelweis (1818-1865)ndash assistant in midwifery ofAllgemeines Krankenhaus(Vienna) in 1846ndash noted that up to 15 women diedfrom childbed puerperal feverafter physician-assisted deliveryndash by contrast mortality was low indeliveries performed by midwives
History of infection control
bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality
ndash he wrote a bunch of letters to the establishmentoutlining his discovery
ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket
History of infection control
bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds
ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo
ndash gloves were originally introduced toprevent dermatitis from antiseptics
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 16
- Slide 17
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- Slide 19
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- Slide 23
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- Slide 27
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- Slide 29
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
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- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
History of infection control
bullIgnaacutec Semmelweisndash discovered that physician handwashing with carbolicacid prior to delivery dramatically reduced mortality
ndash he wrote a bunch of letters to the establishmentoutlining his discovery
ndash he was declared a lunatic and institutionalizedndash died from blood poisoning 10 d after receiving afinger cut while forced into a straightjacket
History of infection control
bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds
ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo
ndash gloves were originally introduced toprevent dermatitis from antiseptics
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
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- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
History of infection control
bull Joseph Lister (1827-1912)ndash English surgeonndash knew of Louis Pasteurs germ theoryndash reasoned that if airborne microbes could sour milk and rot meat they may also infect wounds
ndash in the 1860s he introduced disinfection of operating theatres using carbolic acid spray Listerian antisepsisldquo
ndash gloves were originally introduced toprevent dermatitis from antiseptics
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 7
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
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-
History of Antibiotics
1877 Louis Pasteur Inhibition of some microbes by others anthrax
1908 Gelmo Synthesized sulfanilamide (1st sulfonamide)
1908-10 Paul Ehrlich Selective stains Synthesized arsenic compound arsphenamine (Nobel Prize) (606 Salvarsan) -----gt syphilis (T pallidum) Coined terms magic bullet chemotherapy chemical knife) Further progress delayed by physician hesitancy
1913 Eisenberg Studied bactericidal properties of azo dyes with sulfonamide grouping
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 13
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- Slide 16
- Slide 17
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- Slide 19
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- Slide 23
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- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Asepsis
bull Antisepsis vs asepsis
ndash aseptic techniques introduced in early 1900s
ndash focused on preventing microbes from getting to the patient rather than fumigating everything
ndash surgeons used gloves gowns masks filtered air etc in combination with disinfection
ndash asepsis continued as the primary means of infection control into the 1950s
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Selman Waksman suggests the word antibiotic (coined in 1889 by P Vuillemin) after Dr J E Flynn the editor of Biological Abstracts asked him
to suggest a term for chemical substances including compounds and preparations that are produced by microbes and have antimicrobial
properties
Although there is no journal citation Waksman recalled the incident in his book The Antibiotic Era Because the word was accepted quickly and the
meaning became confused Waksman published a comprehensive definition in 1947
an antibiotic is a chemical substance produced by microbes that inhibits the growth of and even destroys other microbes (and is active in dilute
solutions) was added later
The word antibiotic came from the word antibiosis a term coined in 1889 by Louis Pasteurs pupil Paul Vuillemin which means a process by which life could be used to destroy life
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 17
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- Slide 19
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- Slide 23
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- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Brief History of Antibiotics
bull 1928- Penicillin discovered by Fleming
bull 1932- Sulfonamide antimicrobial activity discovered Erlichbull
bull 1943- Drug companies begin mass production of penicillin
bull 1948- Cephalosporins precursor sent to Oxford for synthesis
bull 1952- Erythromycin derived from Streptomyces erythreus
bull 1956- Vancomycin introduced for penicillin resistant staphylococcus
bull 1962- Quinolone antibiotics first discovered
bull 1970s- Linezolide discovered but not pursued
bull 1980s- Fluorinated Quinolones introduced making then clinically useful
bull 2000- Linezolide introduced into clinical practice
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Antibiotic natural source first description as anti-infective drug
discoverer
sulfanilamide (prontosil 1932
1941
GDomagk
penicillin Penicillium notatum AFleming Florey Chain
streptomycin Streptomyces griseus 1944 SAWaksman
cephalosporin Cephalosporium acremonium 1945 GBrotzu
bacitracin Bacillus subtilis 1945
BAJohnson
chloramphenicol Streptomyces venezuellae 1947 IEhrlich
polymyxin Bacillus polymyxa 1947 CGAinsworth
chlortetracyclin Streptomyces aureofaciens 1948 BMDuggar
neomycin Streptomyces fradiae 1949
SAWaksman
oxytetracyclin Streptomyces rimosus 1950 ACFinlay
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
The End of Infectious Disease
bullIn 1967 US Surgeon General William H Stewart told a White House gathering of health officers that ldquoit was time to close the book on infectious diseasesrdquoand shift all national attention (and dollars) to what he termed lsquothe New Dimensionsrsquoof health chronic diseasesrdquo
bullIn the US deaths from infectious disease dropped by 82 annually from 1938 to 1952 and by 23 annually thereafter until 1980
bullNew antibiotics were being discovered on a yearly basis to replace any that had lost effectiveness
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
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- Slide 7
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- Slide 10
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- Slide 16
- Slide 17
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- Slide 19
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- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
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- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
The End of Infectious DiseasebullFrom 1981 to 1995 deaths from infectious disease increased by 48 annually
bullIn 1998 WHO estimated that over 13 million deaths worldwide were caused by infectious disease almost a quarter of the total deaths in that period That percentage was up to 26 in 2001
bullIn 1995 the annual in-hospital costs associated with resistance of 6 bacterial species to a single antibiotic were estimated to be $13 billion
bull37 new human pathogens have been identified in the last 30 years
bull12 of known human pathogens have been recognized as emerging or reemerging health threats
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
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- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
The End of Infectious Disease
bullSince 1967ndashLegionnairersquos diseasendashToxic shock syndromendashAIDSndashLymediseasendashWest Nile encephalitisndashSARS ndashAvian FlubullChronic diseases associated with pathogensndashPeptic ulcers (Helicobacter pylori)ndashLiver cancer (Hepatitis B and C)ndashLymearthritis (Borreliaburgdorferi)
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 29
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- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
It is not difficult to make microbes resistant to penicillin in thelaboratory by exposing them to concentrations not sufficient to killthem and the same thing has occasionally happened in the bodyhellipmdashAlexander Fleming 1945
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 10
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
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-
The greatest possibility of evil in self-medication is the useof too small doses so that instead of clearing up infectionthe microbes are educated to resist penicillin and a host ofpenicillin-fast organisms is bread out which can be passedto other individuals and from them to other until they reachsomeone who gets a septicemia or a pneumonia whichpenicillin cannot save Sir Alexander Flemming
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Howard Florey
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Basic Classes of Antibiotics
bullAlthough a large number of antibiotics exist they fall into only a few classes with an even more limited number of targets
ndashβ-lactams (penicillins) ndashcell wall biosynthesis
ndashGlycopeptides (vancomycin) ndashcell wall biosynthesis
ndashAminoglycosides (gentamycin) ndashprotein synthesis
ndashMacrolides (erythromycin) ndashprotein synthesis
ndashQuinolones (ciprofloxacin) ndashnucleic acid synthesis
ndashSulfonamides (sulfamethoxazole) ndashfolic acid metabolism
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
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- Slide 30
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- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
The four main mechanisms of antibacterial action
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 7
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- Slide 30
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
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- Slide 57
- Slide 58
- Slide 59
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- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Lipid Carrier Cycle
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Historical Aspects
bull 1941 Albert Alexander first recepient of penicillinbull 1942 first resistant isolates of Staph aureus reportedbull 1960 Methicillin introducedbull 1964 first MRSA reportedbull 1980s MRSA became major nosocomial infection
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Historical aspectsbull 1980s ndashESBL producing GN bacteriabull 1990 Vancomycin resistant Enterococci emergedbull 2000 VISA (intermediate level resistance)bull 2002-VRSA (high level resistance)bull 2002- Linezolid resistant enterococci and Staphylococci reported
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
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- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Evolution of b-LactamasePlasmid-Mediated TEM and SHV Enzymes
AmpicillinThird-GenerationCephalosporins
1963
1965
TEM-1E coliS paratyphi
1970s
TEM-1Reported in28 Gram-NegativeSpecies
1980s1983
ESBLinUnitedStates
1987
ESBL inEurope
2000
gt120 ESBLsWorldwide
How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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How Do Bacteria Develop Resistance
Presence of antibiotics provides selection pressure for spontaneous mutants (1 in 106) with increased resistance1048708 High population density rarr efficient gene transfer1048708 Short generation time rarr rapid evolution
How Does it work
Inactivating enzymes1048708 Alter antibiotic target1048708 Pump antibiotics out of the cell
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
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- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
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- Slide 49
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-
What does not destroy me makes me strongermdashNietzsche 1899
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
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- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
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-
Whats MRSA And What Can Be Done About It
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
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-
Mechanisms of Antibiotic Resistance
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Horizontal Gene Transfer
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 10
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- Slide 14
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- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
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- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Resistance to Antibiotics
bullBacteria (and viruses) are very resourceful creatures and they have developed resistance mechanisms to essentially every antibiotic that has been developed
bullMoreover increased use of antibiotics results in increased resistance (the paradox of antibiotics)
bullThe basic resistance mechanisms are quite simple
1Modify the antibiotic
2Modify the target of the antibiotic
3Destroy the antibiotic
4Make it more difficult for the antibiotic to get into the cell
5Actively remove the antibiotic from the cell
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
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- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Active efflux of antibiotics
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
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- Slide 19
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- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Efflux pump is a less potentand less common cause ofresistance
Efflux pumpPmrA
Mutation of bacterial genesfor binding sites causesresistancegyrA parC (parE gyrB)
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
- Slide 18
- Slide 19
- Slide 20
- Slide 21
- Slide 22
- Slide 23
- Slide 24
- Slide 25
- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Antibiotic Efflux Pumps
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
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- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Alteration of the Drug Target SiteVancomycin
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
- Slide 9
- Slide 10
- Slide 11
- Slide 12
- Slide 13
- Slide 14
- Slide 15
- Slide 16
- Slide 17
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- Slide 19
- Slide 20
- Slide 21
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- Slide 23
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- Slide 26
- Slide 27
- Slide 28
- Slide 29
- Slide 30
- Slide 31
- Slide 32
- Slide 33
- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
- Slide 51
- Slide 52
- Slide 53
- Slide 54
- Slide 55
- Slide 56
- Slide 57
- Slide 58
- Slide 59
- Slide 60
- Slide 61
- Slide 62
- Slide 63
- Slide 64
-
Genetic basisGenetic selection underlies all resistanceSome single amino acid substitution bymutation (ESBL) are rapid and some needmultiple genes to cause resistance (VRE)
bull Mutationsbull Plasmidsbull Transposonsbull Integrons
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
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- Active efflux of antibiotics
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-
Beta Lactamases
bull Classified based on Prim structure
ndash Class A (Serine residue)ndash Class B (metallo-enzyme)ndash Class C (Serine residue)ndash Class D (Serine residue)
bull Class AampD - plasmid mediated
bull Class BampC - encoded by chromosomal genes
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
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- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
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- Slide 64
-
Beta Lactamasesbull Major defence of GNB against B lactams
bull Hundreds have co-evolved with newer drugs
bull Spread from Staphylococci to H Influenzae and N gonorrhoeae
bull With over-use of new B lactams in last 2 decades ldquonewrdquo Extended spectrum beta lactamases(ESBLs) carbapenemases
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
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- Slide 40
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- Slide 42
- Active efflux of antibiotics
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-
bull TEM type ESBLbull SHV type ESBLbull CTX type ESBLbull OXA type ESBLbull Plasmid mediated Amp C enzymesbull Carbapenemases
New Beta lactamases
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Active efflux of antibiotics
- Slide 44
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-
Epidemiology of the Transmissionof Antibiotic-Resistant Bacteria
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
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- Active efflux of antibiotics
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-
Antibiotics in Agriculture Antibiotics in poultry
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
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- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
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- Slide 46
- Slide 47
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- Slide 49
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- Slide 62
- Slide 63
- Slide 64
-
AntibioticsSubject Antimicrobial (Pounds)Human 3000000
Beef 3700000
Swine 1030000
Chicken 10500000
Total in animals 24500000
The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
- Slide 1
- Slide 2
- Slide 3
- Slide 4
- Slide 5
- Slide 6
- Slide 7
- Slide 8
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- Slide 34
- Slide 35
- Slide 36
- Slide 37
- Slide 38
- Slide 39
- Slide 40
- Slide 41
- Slide 42
- Active efflux of antibiotics
- Slide 44
- Slide 45
- Slide 46
- Slide 47
- Slide 48
- Slide 49
- Slide 50
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The Dramatic Rise in Plasmid-MediatedMBL and Other Carbapenemasesbull The quiet before the stormbull Only 1 publication of a transferable MBL in P aeruginosa in 1993bull 2005 ndash The presence of transferable MBLs in 28 countriesbull 2005 ICAAC ndash 31 abstracts on carbapenemasesMBLsbull 2005 ICAAC ndash major scientific symposium The Expanding World ofCarbapenemasesbull They have arrived in the United Statesbull Government industry and academics working as one seems to bethe required path to regain our previous advantage over infestingmicrobes ndash promote antimicrobial prescription disciplineWalsh TR et al Clin Micro Reviews 200518306-325 Jones RN et al Diagn Microbiol Infect Dis20055177-84 ICAAC 2005 Symposium 113 (C1) December 16 2005
The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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The History of Medicine
2000 BCmdashHere eat this root1000 ADmdashThat root is heathen Here say this prayer1850 ADmdashThat prayer is superstition Here drink this potion1920 ADmdashThat potion is snake oil Here swallow this pill1945 ADmdashThat pill is ineffective Here take this penicillin1955 ADmdashOopshellipbugs mutated Here take this tetracycline1960ndash1999mdash39 more ldquooopsrdquoHere take this more powerful antibiotic2000 ADmdashThe bugs have won Here eat this rootmdashAnonymous (WHO 2000)
What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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What Is Antimicrobial Stewardship
bull A marriage of infection control and antimicrobial managementbull Mandatory infection control compliancebull Selection of antimicrobials from each class of drugs that doesthe least collateral damagebull Collateral damage issues includendash MRSAndash ESBLsndash C difficilendash Stable derepressionndash MBLs and other carbapenemasesndash VREbull Appropriate de-escalation when culture results are availableDellit TH et al Clin Infect Dis 200744159-177
IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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IDSA Guidelines ndash Definition ofAntimicrobial Stewardship
bull Antimicrobial stewardship is an activity that promotes
ndash The appropriate selection of antimicrobials
ndash The appropriate dosing of antimicrobials
ndash The appropriate route and duration of antimicrobial therapy
The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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The Primary Goal ofAntimicrobial Stewardship
bull The primary goal of antimicrobial stewardship is to
ndash Optimize clinical outcomes while minimizing unintendedconsequences of antimicrobial use
bull Unintended consequences include the followingndash Toxicity
ndash The selection of pathogenic organisms such as C difficile
ndash The emergence of resistant pathogens
Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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Antimicrobial StewardshipSuggested Starting Points
bull Obtain baseline informationndash Antimicrobial usage and expenditures
ndash Institutional susceptibilities
ndash Recurrent problems
bull Strategiesndash Baseline create collaborative antibiotic guidelines (participation and buy-in from as many doctors as possible)
ndash Low-hanging fruit IV to per os switches dosing streamlining antimicrobials based on culture results
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- Active efflux of antibiotics
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