antibiotic choices
TRANSCRIPT
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Antibiotic Choices
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Outline
General Considerations:Host FactorsGeographic ConsiderationsMicrobial FactorsAntimicrobial FactorsAdjunctive ApproachesPharmacoeconomics
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Outline
Review of antibiotic classes:Beta-lactamsMacrolidesFluoroquinolonesAminoglycosidesLincosamidesTetracyclinesOthers: vancomycin, metronidazole,
chloramphenicol, linezolid
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Empiric Therapy
Often microbiologic diagnosis is not knownDecision regarding optimal empiric treatment based on: host factorsmicrobial factorsgeographic factorsantimicrobial factors
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Empiric Therapy
17 yr old previously healthy man with 2 day hx of fever, sore throat, cough.
Diagnostic possibilities? Can he wait or should be be treated? What would you treat him with?
17 yr old with HIV and 2 day hx of fever, sore throat, cough.
Diagnostic possibilities? Can he wait or should he be treated? What should he be treated with?
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Host Factors
Age
Immune adequacy
Underlying diseases
Renal/hepatic impairment
Presence of prosthetic materials
Ethnicity
Pregnancy
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Age
Can help to narrow the diagnosis with certain infections:Ex: Meningitis:
What bugs would you consider in neonate? In adult?
Ex: EBV infection In what age group would you consider this
diagnosis?
Ex: UTI: How does age affect your interpretation of laboratory
results?
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Immune Adequacy
Immune status important clue: Ex: Asplenic patients: at risk for encapsulated bacterial
infections Ex: HIV/AIDS patients: at risk for variety of opportunistic
infections Ex: Transplant patients: at risk for a variety of infections
depending on timeline etc.
Previous use of antibiotics: Prolonged broad spectrum Diarrhea
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Underlying Disease
Diabetes
Transplant
HIV
Cancer
Renal impairment
Autoimmune diseases
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Renal/Hepatic Impairment
Implications for treatment:Dose adjusting for renal impairmentAvoiding nephrotoxic drugsAvoiding hepatotoxic drugs
Implications for monitoring: If unavoidable
ensure good hyrdrationMonitor renal and liver function
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Presence of Prostheses
Implications for diagnosis:What bug is more pathogenic with artificial
joints/valves?
Implications for Treatment: Infected hardware needs to be removedAddition of rifampin in certain situations
(effective in treatment of prosthetic infections)
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Ethnicity
Consider diseases endemic in country of origin:Ex: TB in patients from TB endemic areas
as well as aboriginal patientsEx: Stronglyoides in patients from tropical
countries
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Geographic Factors
Need to know common microbial causes of infection in your area:
Ex: MRSA: 40% of S. aureus isolates in US but only 3% of isolates in Canada
Consider patient ethnicity
Travel history is important:Ex: fever in traveller returning from Sudan vs
fever in person who has never left Edmonton
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Pregnancy
Issues of antibiotic use in pregnancy have to be considered
Risks of transmission to baby:HIVGBSHSVSyphilis
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Microbial Factors
Probable organisms
Probable susceptibility patterns
Natural history of infections
Likelihood of obtaining good microbiologic data
Site of Infection
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Probable Organisms
Have to know most likely organisms for various common infections:CAPCellulitis Intra-abdominal infectionsEndocarditis
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Microbial Susceptibilities
Know general microbial susceptibilities as well as those which are geographicaly specific: S pneumoniae: 15% resistant to erythromycin, 3%
to penicillin P. aeruginosa: 30-40% resistant to ciprofloxacin,
20-25% to ceftazidime MRSA: account for 3-4% of S aureus isolates
*For Capital Health Region for 2004
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Natural History
Rapidly fatal vs slow growing:Ex: Meningococcemia – can be rapidly
fatal Ex: TB meningitis often more indolent
course
HIV
Hep C
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Likelihood of Obtaining Microbiologic Data
May be difficult to get specimen: Ex: brain abscess
If patient has been on antibiotics, it will affect culture results
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Antimicrobial Factors
Site of infection
Route of Administration
Bactericidal vs Bacteristatic
Combination vs single therapy
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Site of Infection
Susceptibility testing is geared to attainable serum levelsDoes not account for host factors or conditions that alter antimicrobial accessEx: diffusion into CSF is limited in many drugs Ex: abscesses:
Difficult to penetrate abscess wall High bacterial burden Low pH and low oxygen tension can affect antibiotic
activity
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Route of Administration
Many options exist:EnteralParenteralSmall particle aerosol IntrathecalTopical
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Enteral Administration
Must know oral bioavailability
Must be resistant to breakdown by gastric juicesSome drugs must be given with bufferSome require acidity for absorption
Other drugs cannot be given in high enough doses orally
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Bactericidal vs Bacteristatic
Cidal: B-lactams, aminoglycosides, quinolones
Static: tetracyclines. Macrolides, lincosamides
But there are exceptions:Chloramphenicol thought to be bacteriostatic is
cidal in H influenza, S pneumonia, N. menigitidis
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Combination Therapy
Three main reasons: Broader coverage: may be necessary for empiric
treatment of certain infections. Ex. Intra-abdominal sepsis
Synergistic activity: eg amp + gent for serious enterococcal infections
Prevent resistance: eg TB
Disadvantages: antagonism – theoretically should avoid combining
bacteriostatic and bactericidal agents Potential for increased toxicity
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Adjunctive Approaches
Shock and Sepsis: supportive care with fluids, possibly steroidsBacterial meningitis: steroidsDrainage and Debridement of abscessesRemoval of prosthetic materialsCorrection of trace nutrient deficienciesCorrection of protein calorie malnutritionAssisted organ function with ventilator, dialysis, vasopressors/ionotropes
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Monitoring Response to Therapy
Certain amount of gestaltMonitor infectious parameters: fever, WBC, ESR etc.Knowledge of natural historyImagingRepeat cultures useful in endocarditis, complicated UTI (ie normally sterile areas)
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Duration of Therapy
Very few studies to establish minimum durations of therapyEx. Viridans strep endocarditis:
5 days therapy: 80% failure 10 days: 50% 20 days: 2%
Duration usually based on anecdoteMost uncomplicated bacterial infections can be treated for –14 days4-6 weeks for endocarditis, osteo, 6-12 months: Mycobacterial diseases, endemic mycoses
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Pharmacoeconomics
Cost of illness includes:MedicationsProvider visitsAdministration of medicationsLoss of productivity
Cost is a tertiary consideration after effectiveness and safety
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Antibiotics: drugs for bugs
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Beta Lactams
Includes: Penicillins, cephalosporins, carbapenems, monobactams
Mechanism of Action: Inhibits cell wall synthesis by binding to PBP and
preventing formation of peptidoglycan cross linkage
Toxicity: Hypersensitivity reaction 10-20% X-reactivity with carbapenems 10% x-reactivity with 1st generation cephalosporins 1% x-reactivity with 3rd generation cephalosporins
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Beta-Lactams
Natural Penicillins: Pen G, Pen V, benzathine penicillin
Spectrum of activity: Viridans group strep, B-hemolytic strep, many Strep
pneumoniae Most N. menigiditis Staph spp Oral anaerobes L monocytogenes, Pasteurella multocida, Treponema
pallidum, Actinmyces israelii enterococcus (1/3) pen sensitive
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Aminopenicillins
Prototypes: Ampicillin, Amoxicillin
Covers:Strep sppDoes not cover enterococcus
Spectrum extended to include some GNB:
E. coli, Proteus mirabilis, Salmonella spp, Shigella, Moraxella, Hemophilus spp
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Penicillinase Resistant Penicillins
Protoype: Cloxacillin
Covers:Staph spp including MSSA, 2/3 of Staph epiStrep spp
No coverage for enterococcus
No coverage for gram negative organisms or anaerobes
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Carboxypenicillins
Prototype: Ticarcillin
Covers:Covers Stenotrophomonas, Pseudomonas
Problems with hypernatremia, hypokalemia, platelet dysfunction
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Ureidopenicillins
Prototype: PiperacillinCovers
Strep spp (less than earlier generations)EnterococcusAnaerobic organismsPseudomonasBroad Gram negative coverage
If tazobactam added – increases Staph coverage and anaerobic coverage
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Cephalosporins
Divided into 4 generations
Increasing gram negative coverage with less gram positive coverage with increasing generations
Enterococci are not covered by any of generations
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1st Generation
Prototype: Cefazolin
Covers:Staph spp (MSSA)Strep sppE. coli, Klebsiella, Proteus mirabilis
No anaerobic activity
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2nd Generation
Prototype: CefuoximeCovers:
Gram positives (Staph, Strep)H influenzaM catarrhalis
Cefoxitin:Some serratia coverageAnaerobic activityUsed for intra-abdominal infection and PID
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3rd Generation
Divided into two main groups: Ceftazidime:
Pseudomonas Good gram negative coverage Lose gram positive coverage (poor against Strep)
Ceftriaxone/cefotaxime: Reasonable Strep coverage, poor Staph coverage Good gram negative coverage Little anti-pseudomonal activity Little anaerobic activity Good CSF penetration Toxicity includes biliary sludge
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4th Generation
Prototype: Cefepime
Coverage:Maintains gram positive activity (Strep)PsuedomonasLower potential for resistance
Cefixime – oral version Good against gram negatives and StrepNo pseudomonal activity
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Carbapenems
Imipenem, Meropenem, ErtapenemImipenem/Meropenem:
Staph (MSSA), Strep Anaerobic activity Gram negatives (Legionella, Chlamydia, Mycoplasma, B
cepacia, Stenotrophomonas) Pseudomonas Enterococcus faecalis but not faecium
Ertapenem Allows once a day dosing Does not cover pseudomonas
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Monobactam
Prototype: AztreonamAerobic GNBPseudomonasNo gram positive or anaerobic coverage
Similar spectrum to aminoglycosides without renal toxicityCross reactivity to penicillin is rare but increases with ceftazidime
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Aminoglycosides
Includes: Gentamycin Tobramycin Amikacin Streptomycin
MOA: binds to 30S/50S ribosomal subunit inhibit protein synthesis
Toxicity: CN VIII - irreversible Renal toxicity – reversible Rarely hypersensitivity reactions
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Aminoglycosides
Covers:Aerobic GNB including pseudomonasMycobacteria Brucella, FranscicellaNocardiaSynergy with B-lactams (Enterococci,
Staphylococci)
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Fluoroquinolones
Includes: Ciprofloxacin Ofloxacin Levofloxacin Gatifloxicin Moxifloxacin
Mechanism of Action: DNA gyrase inhibitors
Toxicity: GI symptoms
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Fluoroquinolones
All cover: Mycoplasma, Legionella, Chlamydia Francisella, Rickettsia, Bartonella Atypical mycobacteria
Cipro: Good gram negative coverage Poor gram positive coverage N gonorrhea, H influenza Good for UTI, infectious diarrhea In combination for pseudomonas
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Fluoroquinolones
Ofloxacin: Better gram positive coverage (Strep but min staph
coverage) No pseudomonas activity
Levofloxacin: L-entomer of ofloxacin so identical coverage Used for LRTI
Gatifloxacin: Increased activity against strep No pseudomonas activity
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Fluoroquinolones
Moxifloxacin:Activity against Strep and StaphAnaerobic coverageNo pseudomonas activity
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Macrolides
Includes:ErythromycinClarithromycinAzithromycin
Mechanism of Action: Binds to ribosomal subunit Blocks protein synthesis
Toxicity: GI upset (especially with erythromycin)
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Erthromycin
Active against Strep spp
Also effective against: Legionella Mycoplasma Campylobacter Chlamydia N gonohhrea
Poor for H influenza
Used infrequently due to GI upset
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Clarithromycin
Active against:Strep including pneumoniaeMoraxella, Legionella, ChlamydiaAtypical mycobacteriaMore active against H influenza
Used in combination against H pylori
Less GI side effects
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Azithromycin
Active against:Mycoplasma, Legionella, ChlamydiaH influenzaStrep spp
Long half life
5 day course is adequate
Less GI side effects
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Clindamycin
Mechanism of Action: Blocks protein synthesis by binding to ribosomal subunits
Toxicity: Rash GI symptoms C diff colitis seen in 1-10%
No gram negative or enterococcus coverage
Covers Staph spp (MSSA), Strep spp and anaerobes
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Metronidazole
Mechanism not well understood
Covers: Most anaerobes except Peptostreptococci,
Actinmycetes, Proprionobacterium acnes Parasitic protozoa: Giardia lamblia, E. histolytica
Toxicity: Neutropenia Disulfuram reaction Potentiation of warfarin
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Tetracyclines
Includes: Tetracycline Doxycycline Minocycline
Mechanism of Action: Binds to 30S ribosomal subunit Blocks protein synthesis
Toxicity: Rash, Photosensitivity, impairs bone growth and stains
teeth of children, increased uremia
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Tetracyclines
Spectrum includes unusual organisms Rickettsia Chlamydia Mycoplasma Vibrio cholera Brucella Borreila burgdorferii
Minocycline: Active against stenotrophomonas and P acnes May be active against MRSA
Doxycycline: Used for prophylaxis against Plasmodium spp
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Glycopeptides
Prototype: Vancomycin
Mechanism of Action: Inhibits cell wall synthesis
Toxicity:Ototoxicity – rareCan induce histamine release – red man
syndrome
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Glycopeptides
Coverage:Gram positives: Staph (incl. MRSA), strep,
enterococcusGram positive anaerobesExceptions: VRE, Leuconostoc, Lactobacillis
Inferior to beta-lactams in terms of cure rates for beta-lactam sensitive organisms
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Sulfa drugs
Includes: TMP/SMX
Mechanism of Action:Folate reductase inhibitor
Toxicity:Hypersensitivity reactionsThrombocytopenia rash
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Sulfa
Coverage: Strep, Staph H influenza L monocytogenes Many GNG (E coli, Klebsiella) PCP Nocardia Isospora belli
Because of frequent allergic rxns, only used in special circumstances (eg PCP pneumonia)
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Chloramphenicol
Broad spectrum activity: GPC, GNB Menigitis organisms Rickettsia spp No activity against Klesiella, Eterobacter, Serratia,
Proteus, Pseudomonas
Toxicity: Dose related marrow toxicity Idiosyncratic aplastic anemia Gray syndrome – abdominal distention, cyanosis,
vasomotor collapse (seen in liver failure pts)
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Linezolid
Mechanism of Action: Binds to ribosomal subunit inhibiting protein synthesis
Oral drug
Active against: VRE, MRSA Enterococcus
No activity against gram negatives
Very expensive ($140/day) and currently not covered
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Questions