ESBLs and Epidemiologically Important Gram-negative Bacteria

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1 ESBLs and Epidemiologically Important Gram-negative Bacteria Anthony Harris, MD, MPH Department of Epidemiology and Preventive Medicine University of Maryland

2 The introduction of antibacterial drug therapy in the 1940s led to a dramatic reduction in illness. The emergence of drug- resistant bacteria is reversing the trend

3 The current antibiotic crisis differs from those in the past because several different organisms are involved and because there are no immediate solutions on the horizon Barbara E. Murray, NEJM 330;1229.

4 The prevalence of antimicrobial- resistant human pathogens is rapidly increasing, but the discovery and development of new antimicrobial drugs have slowed dramatically Robert Moellering,, NEJM 1996;335:1445

5 Citywide clonal Outbreak of multiresistant Acinetobacter baumannii and Pseudomonas aeruginosa in Brooklyn, NY: the preantibiotic Era Has Returned Arch Intern Med Jul 8;162(13):

6 Outline of talk Mechanisms of resistance E. coli Klebsiella Pseudomonas Acinetobacter Stenotrophomonas Reasons for spread of resistance Methods to reduce resistance

8 Mechanisms of Resistance Decreased permeability of the outer membrane important for Pseudomonas aeruginosa Alteration of the target site important for penicillin-resistant Streptococcus pneumoniae Production of a bacterial enzyme

9 B-lactamase Production Encoded within a chromosome inducible important for Citrobacter, Enterobacter, Serratia, Pseudomonas Acquired on a plasmid or transposon usually produced all the time (noninducible) potentially transferable to other bacteria

10 Plasmid-mediated B lactamases First described: TEM-1, TEM-2, and SHV-1 resistance to penicillins 1st generation cephalosporins 2nd generation cephalosporins easily inhibited by clavulinic acid, sulbactam or tazobactam Now, more than 200 B lactamases have been documented (

11 Extended Spectrum B lactamases (ESBL) Discovered in 1983 in Europe plasmid mediated B lactamase leads to diminished sensitivity to cefotaxime, ceftazadime and aztreonam Increasing importance: US ICU s demonstrate 10% of Klebsiella and 3% of E. coli produce ESBL

12 ESBL Most common in Klebsiella oxytoca, Klebsiella pneumoniae, and E. coli Plasmids can be transferred to other bacterial species Risk factors for acquisition: antibiotics comorbid illnesses severity of illness

13 Microbiologic Diagnosis of ESBLs Be concerned if R to ceftaz and S to cefotaxime Screen using ceftazidime misses 20% Cefpodoxime as a screen may be overly sensitive Confirmatory tests (NCCLS) discs compared to discs with B-lactamase inhibitors (ceftaz vs ceftaz/clavulanate or cefotaxime vs cefotaxime/clavulanate)

14 1a) Ceftazidime 30 ug 1b) Ceftazidime/clavulanic acid 30/10ug 2a) Cefotaxime 30 ug 2b) Cefotaxime/clavulanic acid 30/10 ug

15 Method Phenotypic Confirmatory Test Medium Mueller Hinton Agar Antimicrobial Disk Concentration Inoculum Incubation length Ceftazidime 30 µg Ceftazidime/clavulanic acid 30/10 µg And Cefotaxime 30 µg Cefotaxime/clavulanic acid 30/10 µg Standard disk diffusion recommendations hrs Results A >5 mm increase in a zone diameter for either antimicrobial agent tested in combination with clavulanic acid versus its zone when tested alone=esbl

16 Treatment of ESBL Infections Do not treat ESBL s with third generation cephalosporins Cefepime may be a viable alternative Antibiotics of choice include carbapenems B-lactam/B-lactamase inhibitor antibiotics quinolones

17 E. coli Most common pathogen of nosocomial infections Sites of nosocomial infection surgical site infections blood stream infections urinary tract infections Common pathogen in ICU s

19 Klebsiella Common isolate 5% of nosocomial infection site isolates 8% of hospital-acquired UTI and pneumonia Sites of nosocomial infection surgical site infections pneumonia UTI

20 Pseudomonas Common isolate 9% of nosocomial infection site isolates most common cause of nosocomial gramnegative pneumonia Sites of nosocomial infection bacteremia surgical site infections pneumonia

21 Antibiotic Options for Pseudomonas Due to mechanism of resistance, resistance can evolve Hence, repeat cultures Role of double antibiotic coverage practiced by many but documentation of effectiveness poor

22 Antibiotic Options for Pseudomonas At University of Maryland (2002): 83% susceptible to cefepime 54% susceptible to gatifloxacin 86% susceptible to imipenem 86% susceptible to piperacillin/tazobactam

23 Pseudomonas bacteremia Combination Therapy: Fact or Fiction

24 Monotherapy

25 Combination Therapy

26 Authors Year Combination beneficial Hilf et al Y 1986 Bodey et al N Chatzinikolao N u et al 1995 Vidal et al N 1994 Kuikka et al N

27 Conclusions of Bacteremia Data: Minimal to no effect of combination therapy on cure of infection or mortality Instituting effective treatment up-front is what is important Patients with pseudomonas pneumonia as primary source have poorer outcome

28 Acinetobacter gram-negative coccobacillus often a colonizer emerging as a nosocomial pathogen Acinetobacter baumannii is the most common Outbreak of imipenem-resistant Acinetobacter in New York Difficult to eradicate colonized state

29 Acinetobacter most common site of isolation is respiratory hospital outbreaks occur with Acinetobacter most are related to contaminated respiratory equipment resistance mechanisms are not clearly understood carbapenems are the antibiotic of choice

30 Stenotrophomonas Often a colonizer Emerged over the past several years as a cause of infection Sites of infection bacteremia respiratory tract infections skin and soft tissue infections

31 Stenotrophomonas Patients at risk: cancer receiving broad-spectrum antibiotics Major concern is its limited antibiotic susceptibility resistance to imipenem approaches 100% antibiotic of choice: trimethoprim/sulfa other choices: ticarcillin/clavulanate, cefepime

32 KEY POINTS TO REMEMBER Plasmid mediated resistance (e.g. ESBL) is non-inducible: evolving sensitivities unlikely Worry about ESBL for Klebsiella and E. coli chromosomal resistance is inducible and common for Pseudomonas, Citrobacter, Serratia, Enterobacter: evolving sensitivities do occur

33 KEY POINTS TO REMEMBER Stenotrophomonas and Acinetobacter are emerging pathogens Both have extremely limited sensitivities For Stenotrophomonas, use trimethoprim-sulfa For Acinetobacter, use imipenem

34 Spread of Resistance Reasons for spread of resistant bacteria excessive antibiotic use overcrowding poor hygiene and failure of infection control practices

35 Handwashing is the single most important means of preventing the spread of infection CDC

37 Nosocomial Transmission and Antibiotic Pressure Antibiotic Use A Patient A with antibiotic resistant organism B C Transmission Patient B without antibiotic resistant organism D

38 Association Between Antibiotic Use and Resistance: Changes in antibiotic use are paralleled by changes in the prevalence of resistance Antimicrobial resistance is more prevalent in nosocomial bacterial strains than in community-acquired strains Patients with resistant strains are more likely to have received antimicrobials McGowan, Rev Infect Dise 1983;5:1033.

39 Do Certain Antibiotics Lead to Emergence of Resistance? Answer is likely yes but as to specific ones it is uncertain due to poor study design variable and incorrect control group selection lack of statistical control for confounding and collinearity of antibiotics lack of adjustment for length of stay lack of adjustment for severity of illness

40 As much as possible and consistent with first-rate medical care, we must starve these bacteria of the lifeblood that promotes their persistence- the unrelenting selective pressure exerted by overuse of antibitoics Lou Rice, CID 2000;31:762.

41 Then What Antibiotic Recommendations Should I Be Making? Limit duration of antibiotics Limit unnecessary use of broadspectrum agents Controversial issues: Two agents versus one Cycling of antibiotics Importance of dosing frequency of antibiotics and their effect on resistance

42 How To Prevent Resistance Improve handwashing compliance Find novel ways to decrease patient-topatient transmission Limit duration of antibiotics

43 How To Prevent Resistance Limit unnecessary use of broadspectrum agents IN GENERAL, LIMIT THE USE OF ANTIBIOTICS BOTH IN THE HOSPITAL AND OUTSIDE THE HOSPITAL

46 References: A good general review of resistance Kaye KS. Pathogens resistant to antimicrobial agents. Epidemiology, molecular mechanisms, and clinical management. Infect Dis Clin North Am Jun;14(2):293. Detailed review of ESBL s Jacoby GA. Extendedspectrum beta-lactamases and other enzymes providing resistance to oxyimino-beta-lactams. Infect Dis Clin North Am Dec;11(4):875. Most up-to-date but most detailed Bush K. New B- lactamases in Gram-Negative Bacteria. Clin Infect Dis. 2001;32:1085.

47 References A good review of ESBL s Bradford, P. A Extendedspectrum ß-lactamases in the 21st century: characterization, epidemiology, and detection of this important resistance threat. Clin. Microbiol. Rev. 14: Recent article on Acinetobacter Urban C. et al. Considerations in control and treatment of nosocomial infections due to multidrug-resistant Acinetobacter baumannii. Clin Infect Dis May 15;36(10): Pharmacodynamic article Craig WA. Does the dose matter. Clin Infect Dis Sep 15;33 Suppl 3:S233-7.

48 References A good review of Pseudomonas resistance mechanisms. Livermore DM. Multiple mechanisms of antimicrobial resistance in Pseudomonas aeruginosa: our worst nightmare? Clin Infect Dis. 2002;34:

Management of Extended Spectrum Beta- Lactamase (ESBL) Producing Enterobacteriaceae in health care settings

Management of Extended Spectrum Beta- Lactamase (ESBL) Producing Enterobacteriaceae in health care settings Dr. Mary Vearncombe PIDAC-IPC February 2012 Objectives: To provide an overview of the RP/AP Annex