ESKAPE Pathogens Antibiotic Stewardship


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ESKAPE from pathogens ? Antimicrobial Stewardship:

E S K A P E from pathogens ? Antimicrobial Stewardship Dr.T.V.Rao MD Dr.T.V.Rao MD 1

Antibiotics Advanced Medicine:

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 . Dr.T.V.Rao MD 2

Microbes follow the Darwin's Theory:

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 Dr.T.V.Rao MD 3


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) Dr.T.V.Rao MD 4

ESKAPE Pathogens of Highest Concern:

Dr.T.V.Rao MD 5 ESKAPE Pathogens of Highest Con cern 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

ESKAPE - Bacteria:

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, Dr.T.V.Rao MD 6

Bad Bugs, No Drugs: No New Drugs:

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 Dr.T.V.Rao MD 7


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 Dr.T.V.Rao MD 8

Why ESKAPE Microbes are a Global Concern:

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. Dr.T.V.Rao MD 9

ESKAPE Bacteria:

ESKAPE Bacteria Dr.T.V.Rao MD 10

ESKAPE Bacteria are Major Nosocomial Agents:

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). Dr.T.V.Rao MD 11

Enterococcus species:

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. faecium with 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 Dr.T.V.Rao MD 12

Enterococcus faecium (and faecalis):

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 ) Dr.T.V.Rao MD 13

Newer Drugs Active Against VRE (and MRSA):

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) Dr.T.V.Rao MD 14

Newer Drugs Active Against VRE (and MRSA) :

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) Dr.T.V.Rao MD 15

Staphylococcus aureus:

The prominent name among the ESKAPE bacteria, 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 Dr.T.V.Rao MD 16


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. Dr.T.V.Rao MD 17

Problems with MRSA in Treatments:

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 Dr.T.V.Rao MD 18

Klebsiella species:

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 Dr.T.V.Rao MD 19

Problems with Enterobacteriaceae:

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 Enterobacteriace ae Dr.T.V.Rao MD 20

KPC’s :

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 Dr.T.V.Rao MD 21

Acinetobacter baumannii:

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 Dr.T.V.Rao MD 22

Acinetobacter baumannii::

Acinetobacter baumannii : Drug resistance is a major problem in Acinetobacter infections, which are responsible for about 3 percent of all HAIs,. Soldiers are returning from Iraq and Afghanistan with cases of highly resistant Acinetobacter wound infections. Strains have emerged that are resistant to all but the most toxic new generation of Antibiotics Dr.T.V.Rao MD 23

Pseudomonas aeruginosa:

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: I mmunocompromised , debilitated, prior hospitalizations, prior antibiotic therapy, trauma outdoors with exposure to water/soil Dr.T.V.Rao MD 24

Pseudomonas aeruginosa::

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. Dr.T.V.Rao MD 25

Enterobacter species::

Enterobacter species: One in 20 HAIs is caused by this group of bacteria. Like Klebsiella , E. coli , and the other gram-negatives, Enterobacter species 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. Dr.T.V.Rao MD 26

The Challenge: Global Antibiotic Resistance:

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 Dr.T.V.Rao MD 27

Antimicrobial Stewardship:

Dr.T.V.Rao MD 28 Antimicrobial Stewardship

Antimicrobial Stewardship. :

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 . Dr.T.V.Rao MD 29

Other Aspects of Antimicrobial Stewardship:

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 Antimicrobial Stewardship Dr.T.V.Rao MD 30


ANTIMICROBIAL STEWARDSHIP 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. Dr.T.V.Rao MD 31

Developing Antibiotic Stewardship - Committee Membership and Leadership:

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 expert ise Quality & Organizational Development- Performance Improvement guidance; meeting guidance Dr.T.V.Rao MD 32

Core Members of the Antimicrobial Stewardship Team:

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 Antimicrobial Stewardship Team Dr.T.V.Rao MD 33

Goals of Committee:

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 Dr.T.V.Rao MD 34

Need to Develop Antibiotic Stewardship in Developing Nations:

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 Dr.T.V.Rao MD 35

Antimicrobial Stewardship: Plan the programme to the Needs of your Hospital on ……:

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 Dr.T.V.Rao MD 36

Should Plan Matter on Judicious Use of Antibiotics:

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) Dr.T.V.Rao MD 37

Why Participate in Stewardship?:

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. Dr.T.V.Rao MD 38

Modifying Empiric Therapy:

“ 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 Dr.T.V.Rao MD 39

Supplemental Elements to a Stewardship Program:

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 Dr.T.V.Rao MD 40

Alliance for the Prudent Use of Antibiotics :

The Alliance for the Prudent Use of Antibiotics (APUA) is a non-profit organization founded in 1981 by Dr. Stuart B. Levy, Professor of Medicine at Tufts University and headquartered in Boston, 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 Dr.T.V.Rao MD 41

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

Become a Member of Alliance for the Prudent Use of Antibiotics (APUA ) 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 Dr.T.V.Rao MD 42

Research on Newer Antibiotics is a Priority:

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. Dr.T.V.Rao MD 43

Infectious Diseases Society of America supports Issues on antibiotic use:

Dr.T.V.Rao MD 44 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

References :

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 Dr.T.V.Rao MD 45

Slide 46:

Programme Created by Dr.T.V.Rao MD for ‘ e ‘ learning resources for Medical and Paramedical Students in the Developing World Email Dr.T.V.Rao MD 46

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