eskape pathogens antibacterial stewardship

Dr.T.V.Rao MD

Dr.T.V.Rao MD 1

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Antibiotics Advanced Medicine

� The discovery of potent and safe antimicrobial agents is arguably the single greatest health care advance in history. The availability of these agents rapidly reduced the morbidity and mortality associated with a host of formerly fatal diseases.

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Microbes follow the Darwin's Theory

� The widespread use of antibiotics has been associated with what we now know to be the predictable emergence of resistance.

� Early confidence that infections would eventually be conquered has given way to a greater appreciation of the genetic flexibility of common human pathogens

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ESKAPE AND CDC�According to the latest data from the Centers for Disease Control and Prevention (CDC), the six ESKAPE bacteria are responsible for two thirds of all health care-associated infections (HAIs)

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ESKAPE Pathogens of Highest Concern

� The most serious, life-threatening infections are caused by a group of drug-resistant bacteria that the

� Infectious Diseases Society of America (IDSA) has labeled the "ESKAPE" pathogens, because they effectively escape the effects of antibacterial drugs

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ESKAPE - Bacteria� ESKAPE bacteria—

Enterococcus faecium, Staphylococcus aureus, Klebsiella species, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species—are among the biggest threat of infectious diseases physicians face today,

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�� Enterococcus faecium(E), Staphylococcus aureus(S), Klebsiella pneumoniae(K), Acinetobacter baumannii(A), Pseudomonas aeruginosa(P), and Enterobacter spp. (also E. coli) (E)

� The late-stage clinical development pipeline remains unacceptably lean

� Some important molecules for problematic pathogens such as MRSA and E. faecium

� Few novel prospects for other ESKAPE pathogens, especially multidrug-resistant gram-negative bacilli, such as A. baumannii and P. aeruginosa)

Bad Bugs, No Drugs: No

New Drugs

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Why ESKAPE ARE THREAT

� The ESKAPE pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species) are responsible for a substantial percentage of nosocomial infections in the modern hospital and represent the vast majority of isolates whose resistance to antimicrobial agents presents serious therapeutic dilemmas for physician

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Why ESKAPE Microbes are a Global Concern

� The ESKAPE MICROBES are extraordinarily important, not only because they cause the lion’s share of nosocomial infections but also because they represent paradigms of pathogenesis, transmission, and resistance.

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ESKAPE Bacteria are Major Nosocomial Agents

�According to the latest data from the Centers for Disease Control and

Prevention (CDC), the six ESKAPE bacteria are responsible for two thirds of

all health care-associated infections (HAIs).

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�� Enterococci were responsible for one out of eight HAIs in

2006-2007. A 2004 study found about two thirds of E. faecium bloodstream infections were resistant to vancomycin, one of the most commonly used antibiotics to treat enterococcal infections. Some physicians are treating vancomycin-resistant E. faeciumwith the new antibiotics linezolid, daptomycin, and tigecycline, but these drugs have not been studied extensively for use against these infections. Furthermore, many patients cannot tolerate them.

Enterococcus species

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��With the advent of vancomycin-resistant E. faecium, which are intrinsically resistant to ampicillin and carbapenems, in the mid-1990s we encountered virtually untreatable organisms

�–However, enterococci have relatively low virulence, and treatment is not always required in mixed infections, unless also in blood; IV catheter infections may clear if the catheter is removed.

Enterococcus faecium (and faecalis)

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�� Synercid (synergistic combination of two streptogramins)

Bactericidal

� –Active against E. faecium but not E. faecalis

� –Side-effect of total-body tenderness

� –Rarely used

� •Linezolid (oxazolidinone)

� –Bacteriostatic Both po and IV

� –Occasional thrombocytopenia, esp. after 14 days (need to check plt counts at least weekly)

� –Emergence of resistant isolates

� –Increasingly important for MRSA

Newer Drugs Active Against VRE (and MRSA)

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�� Daptomycin (lipopeptide) � –Rapidly bactericidal (important for bacteremia's)� –IV only � –Binds to surfactant, so not effective in pneumonia � –Occasional elevations of creatine phosphokinase (CPK) and

associated muscle aches; seems not to be a serious problem � –Increasingly important for MRSA� •Tigecycline (glycylcycline; derivative of minocycline) � –Bacteriostatic � –IV only � –Active not only against Staph, Strep, and Enterococcus, but

also against Enterobacteriaceae

Newer Drugs Active Against VRE (and MRSA)

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��The prominent name among the ESKAPEbacteria, methicillin-resistant Staphylococcus aureus (MRSA) outbreaks have been reported among otherwise-healthy athletes, military recruits, school children, and others. MRSA caused an estimated 94,000 invasive infections—more than 19,000 of them fatal—in 2005, according to a recent study by CDC. MRSA is a serious and growing threat in hospitals and other health care facilities,

Staphylococcus aureus

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MRSA

�MRSA has drawn more attention from the pharmaceutical industry than any of the other ESKAPE bugs. Several new drugs are effective against these infections.

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�� 60-65% of SA are MR (both ICU and non-ICU) (DMC 2009) (for

presumptive treatment, must assume MR) � Vancomycin MIC –MICs have been generally rising� For vanco MIC >1 µg/ml, efficacy reduced, and even higher MICs

may be selected (hVISA) � Therefore, for MIC >1 (>50%), we use daptomycin (esp. for

bacteremia) (but not for pneumonia, in which case we use linezolid)� Other alternatives to vancomycin� TMP/SMX: IV/po; cidal; ~90% are S � –Clindamycin: IV/po; not reliably cidal; must check D-test; ~50%

Sensitive

� •We are losing vancomycin, but we have alternatives

Problems with MRSA in Treatments

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��These gram-negative bacteria cause infections in the urinary, biliary, and gastrointestinal tracts, and in trauma wounds. Klebsiella species and their gram-negative cousin E. coli together accounted for 18 percent of all HAIs in 2006-2007, and a growing proportion of these two carry resistance to a remarkable spectrum of antibiotics.

Klebsiella species

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��ESBL –Klebsiella pneumonia and E. coli (~8-10%)

�–>90% Sensitive to carbapenems, Cefotetan/cefoxitin, tigecycline

�KPC ß-lactamases (~1-3% Kleb pneumonia Resistant to carbapenems, as well as other ß-lactams)

Problems with

Enterobacteriaceae

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��Might appear susceptible to imipenem or meropenem, but with borderline MICs Usually ertapenem-resistant

�–Modified Hodge test to confirm�•Usually susceptible only to colistin, tigecycline, select aminoglycosides, and possibly TMP/SMX

�•Easily spread in hospitals (often requires cohorting of staff and patients to control)

KPC’s

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Acinetobacter baumannii

� Traditionally infects patients in ICU and Burn Units

� •Now being seen in general hospital population and nursing homes

� •Antimicrobial resistance is a major concern

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Acinetobacter baumannii:

� Drug resistance is a major problem in Acinetobacterinfections, which are responsible for about 3 percent of all HAIs,. Soldiers are returning from Iraq and Afghanistan with cases of highly resistant Acinetobacterwound infections. Strains have emerged that are resistant to all but the most toxic new generation of Antibiotics

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Pseudomonas aeruginosa

� The most commonly encountered multiresistant gram-negative pathogen

� Relatively low pathogenicity: mainly a problem in ICUs Burn Unit Patents from long-term care facilities Additional risk factors: Immunocompromised, debilitated, prior hospitalizations, prior antibiotic therapy, trauma outdoors with exposure to water/soil

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Pseudomonas aeruginosa:

�Pseudomonas is a particular problem for patients on respirators and those with cystic fibrosis. Eight percent of all HAIs are caused by P. aeruginosa, and one quarter of these are resistant to carbapenems, a class of antibiotics commonly used for these infections. There are no new drugs in development for these highly resistant infections.

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Enterobacter species:

� One in 20 HAIs is caused by this group of bacteria. Like Klebsiella, E. coli, and the other gram-negatives, Enterobacterspecies have developed broad-spectrum resistance to multiple classes of antibiotics. One drug, tigecycline, might work against these infections. There is no new antibiotics in the pipeline.

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��Clinical and media reports have documented the rapid rise of antibiotic-resistant and MDR bacterial infections, now a major global public health concern. Most hospital-acquired infections are resistant to at least one drug, and the incidence of multi-drug resistance is rising. The inability to rapidly get these infections under control results in nearly 100,000 deaths every year in the United States, many more in Developing World

The Challenge:Global Antibiotic Resistance

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��Antimicrobial stewardship is a key component of a

multifaceted approach to preventing emergence of antimicrobial resistance. Good antimicrobial stewardship involves selecting an appropriate drug and optimizing its dose and duration to cure an infection while minimizing toxicity and conditions for selection of resistant bacterial strains. Studies conducted over the years indicate that antibiotic use is unnecessary or inappropriate in as many as 50% of cases.

Antimicrobial Stewardship.

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�� The appropriate use of antimicrobials is an essential part

of patient safety.

� The frequency of inappropriate antimicrobial use is often used as a surrogate marker for the avoidable impact on antimicrobial resistance.

� The combination of antimicrobial stewardship and comprehensive infection control has been shown to limit the emergence and transmission of antimicrobial resistant bacteria.

Other Aspects of AntimicrobialStewardship

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ANTIMICROBIALSTEWARDSHIP GUIDELINES

� Current efforts to thwart the siege of MDROs and to address the lack of development of antimicrobial agents center on antimicrobial stewardship. In 2007, The Infectious Diseases Society of America (IDSA) published guidelines in conjunction with the Society for Healthcare Epidemiology of America to outline antimicrobial stewardship practices.

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Developing Antibiotic Stewardship -Committee Membership and Leadership

� Medical Staff- Active participation is critical to success

Includes Chief Medical Officer support, ID , Hospitalists, Intensivists, Pulmonary, ED, Community MDs and others as willing

� Pharmacy- Coordinates the efforts of the team, guideline development, education and tracking reports

� Infection Prevention & Control- Prevention Strategies, hand hygiene, precautions, medical staff-nursing laison

� Microbiology- Data trends, special testing expertise

� Quality & Organizational Development- Performance Improvement guidance; meeting guidance

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�� Infectious disease physician (Director or Co-director)

Clinical pharmacist with infectious disease training (Co-director or core member)

� Other members of the team

� – Microbiologist

� – Information system specialist

� – Infection control professional

� – Hospital epidemiologist

Core Members of the AntimicrobialStewardship Team

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Goals of Committee

� Assist providers in appropriate use of antimicrobial therapy with improved patient outcomes

� Slow the development of antimicrobial resistance

�Develop evidence- based appropriate use guidelines

� Educate providers and staff regarding guidelines

� Track resistance patterns and report back to medical and hospital staff

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��Antimicrobial stewardship is one method many

institutions are implementing to achieve this balance. Antimicrobial stewardship encompasses a wide range of services aimed at improving patient outcomes and minimizing the untoward effects of antimicrobial agents including side effects as well as induction of resistance. These programs have been shown to decrease both the development of resistance as well as expenditures on antimicrobial agents.

Need to Develop Antibiotic Stewardship in Developing Nations

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Antimicrobial Stewardship:Plan the programme to the Needs of your

Hospital on ……

� Restriction of the oximinocephalosporins

� – VRE� – C. difficile� – ESBLs� – AmpC hyperproduction� • Use vancomycin according to

HICPAC� guidelines� – VRE� – VISA� – VRSA

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Should Plan Matter on Judicious Use of Antibiotics

� Fluoroquinolones – judicious use

� – Elimination of ciprofloxacin

� • Association with MRSA

� • Association with C. difficile

� • Cost benefit with a single fluoroquinoloneformulary

� • Carbapenems – restriction

� –Metallo-beta-lactamases

� – Other carbapenemases (KPC 1 – 3, OXA)

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Why Participate in

Stewardship?� The primary goal of

stewardship is to…Optimize clinical outcomes while minimizing unintended consequences of antimicrobial use, including toxicity, the selection of pathogenic organisms, and emergence of resistance.

� Secondary goals…Reduce healthcare costs without adversely impacting quality of care.

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�� “Empiric therapy”: treatment prescribed before culture data and

other testing results are available� In most cases, empiric therapy should be narrowed at day 3-4 or

earlier

� –If cultures are negative, try to narrow regimen� –If cultures are positive, usually can focus regimen� Often, empiric antibiotics are continued due to inertia, complicated

clinical picture� Need automated reminders at day 3-4 for regimens including

multiple antibiotics –aggressive efforts to decrease number and duration of antibiotics

� Success might be stopping one agent out of 3, or limiting durations to 7 days instead of 14

Modifying Empiric Therapy

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Supplemental Elements to a Stewardship Program

� Education –e.g., Antibiotic rounds in the ICU

� Guidelines and clinical pathways

� Antimicrobial cycling� Antimicrobial order forms or

computer order entry� Combination therapy� Streamlining and de-escalation

of therapy

�Dose optimization� •Parenteral to oral

conversion

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��The Alliance for the Prudent Use of AntibioticsAlliance for the Prudent Use of AntibioticsAlliance for the Prudent Use of AntibioticsAlliance for the Prudent Use of Antibiotics

(APUA) is a non�profit organization founded in 1981 by Dr. Stuart B. Levy, Professor of Medicine at Dr. Stuart B. Levy, Professor of Medicine at Dr. Stuart B. Levy, Professor of Medicine at Dr. Stuart B. Levy, Professor of Medicine at Tufts University and headquartered in Boston, Tufts University and headquartered in Boston, Tufts University and headquartered in Boston, Tufts University and headquartered in Boston, Massachusetts Massachusetts Massachusetts Massachusetts APUA’s mission is to strengthen society’s defenses against infectious disease by promoting appropriate access and use to antimicrobial agents (antibiotics, antivirals, antimalarial etc.) and controlling antimicrobial resistance on a worldwide basis.

Alliance for the Prudent Use of Antibiotics

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Become a Member of Alliance for the Prudent Use of Antibiotics (APUA)

www.apua.org

�An international organization dedicated to curbing antibiotic resistance

�Chapters exist currently in several Asian countries: Australia, China, India, Nepal, Pakistan, Philippines, South Korea, Taiwan, Vietnam

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Research on Newer Antibiotics is a Priority

� "The difficulty in identifying novel antimicrobial agents with reliable activity against these pathogens argues for an augmentation of research in the basic and population science of resistance, as well as careful studies to identify optimal strategies for infection control and antimicrobial use.

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Infectious Diseases Society of America supports

Issues on antibiotic use

� IDSA support strengthening current approaches to antimicrobial resistance, to protect effectiveness of the drugs currently available. We must maximize hospital infection-control practices, to limit the spread of resistance

��No ESKAPE! New Drugs Against MRSA, Other

Superbugs Still Lacking IDA� Clinical Impact of Resistance and Control of Antibiotic Usage

Stephen A. Lerner, M.D. Professor of Medicine Division of Infectious Diseases Wayne State University School of Medicine Detroit, Michigan, USA

References

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�Programme Created by Dr.T.V.Rao MD for ‘ e ‘ learning resources for

Medical and Paramedical Students in the Developing World

� Email

� doctortvrao@gmail.com

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