EXTENDED-SPECTRUM BETA-LACTAMASES EMERGING GRAM-NEGATIVE ORGANISMS

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1 EXTENDED-SPECTRUM BETA-LACTAMASES EMERGING GRAM-NEGATIVE ORGANISMS David J. Feola, Pharm.D., Ph.D. Assistant Professor University of Kentucky College of Pharmacy

2 Disclosures Research Funding Pfizer

3 Objectives 1. Distinguish between the characteristics of ESBLs and other mechanisms of antimicrobial resistance, and understand their epidemiology and impact 2. Discuss the detection, reporting, infection control practices, and antimicrobial stewardship strategies to minimize the impact of ESBL-producing organisms 3. Review the treatment options for infections caused by ESBL-producing bacteria, with an emphasis upon what is known about the efficacy and clinical experience of each

4 Antimicrobial Resistance We have a problem Emergence of resistance Collateral damage Mechanism overview

5 Modern Healthcare, August 7, 2006, page 36 Protesting infections from MRSA

6 Hospital Acquired Infections State of Pennsylvania Heath Care Cost Containment Counsel Mortality Length of Stay Average Charge Readmission Rate Without infection 1.8% 4.9 days $37, % With HAI 9.4% 21.6 days $306, % Patients/consumers can use this report as an aid in making decisions about where to seek treatment PA Health Care Cost Containment Council, February

7 A Disturbing Trend Sulfa, BL, AG, Chloramphenicol TCN, MAC, Vanc, RIF, FQ, TMP No new classes. Modification of existing agents. LZD, DAP, TIG CPT; DAL; New Entities Limited PCN-resistant S. aureus MRSA VRE VISA in 7 states MDR Pseudomonas and Acinetobacter, metallo-beta-lactamases, carbapenemases LZD-R S. aureus VRSA Over half of companies END antimicrobial research and development

8 The Critical Balance Importance of appropriate empiric therapy Mortality increases when initial therapy is inappropriate Effect of broad-spectrum therapy on resistance Resistance increases when broad-spectrum agents are needed; Resistance has a negative impact on outcomes Collateral damage

9 Antimicrobial Use and Resistance Changes in use parallel changes in resistance Resistance higher in healthcare-associated infections Patients with resistant infections more likely to have received prior antimicrobials Hospital areas of highest resistance associated with highest antimicrobial use Increased duration of therapy increase likeliness of colonization with resistant organisms Shales DM et al. CID 1997;25:

10 Example: Oximinocephalosporins Cefotaxime, ceftazidime, ceftriaxone cause Extended-spectrum beta-lactamase production Selection of stably de-repressed isolates in SPACE bacteria Selection of VRE Contribution to MRSA emergence Increased cases of Clostridium difficile associated diarrhea/colitis Dancer SJ. J Antimicrobial Chemother 2001; 48:

11 Perilous Cycle: KPC Example Resistant Pathogen ESBL-producing E. coli, K. pneumo, SPACE KPC Antimicrobial Resistance ESBL production Carbapenemase development Infection Unknown pathogen ESBL-producing bacteria KPC-producing infection Antimicrobial Use Oximinocephalosporins Carbapenems?????

12 Selection for Resistant Strains Resistant Strains Rare Antimicrobial Exposure Resistant Strains Dominant

13 Emergence of Resistance Susceptible Bacteria Resistant Bacteria Resistance Gene Transfer New Resistant Bacteria

14 Mechanism Classes Mechanism Drug modification/degradation Decreased bacterial permeability Affected Agents β-lactams, FQ, AGL, TCN, macrolides, linezolid, clindamycin Sulfa, AGL, TCN, daptomycin, carbapenems Alteration of target site Efflux pumps β-lactams, FQ, TCN, vancomycin, linezolid, clindamycin, macrolides FQ, AGL, TCN, macrolides, carbapenems

15 ESBL Emerging Resistance Epidemiology New enzymes Patient impact Risk factors

16 β-lactamases More than 800 have been described More than 200 are ESBLs Classified by: Plasmid vs. chromosomally mediated Genes located on plasmids can spread Constitutive vs. inducible production Expression relates to β-lactam exposure Bush K. Clin Infect Dis ;32: Livermore DM. Clin Microbiol Inf ;14:S

17 β-lactam Hydrolysis Sites of β-lactamase Hydrolysis Dever LA et al. Arch Intern Med ;151:

18 TEM and SHV β-lactamases TEM-1, TEM-2, SHV-1 Most common plasmid-mediated β-lactamases in Gram-negative bacteria Drove the development of Extended-spectrum cephalosporins: resist hydrolysis β-lactamase inhibitors: protect parent β-lactam compound Carbapenems: enzymes cannot bind Livermore DM. Clin Microbiol Inf ;14:S Rice LB. Pharmacotherapy ;19:120S-128S. 128S.

19 TEM and SHV β-lactamases Extended spectrum beta-lactamases (ESBL) Mutants of classical enzymes Hydrolyze most extended-spectrum cephalosporins and aztreonam Carbapenems are spared Inhibited by clavulanic acid Organisms that produce ESBLs Klebsiella, E. coli, other Enterobacteriaceae and nonfermenting Gram-negative bacteria Livermore DM. Clin Microbiol Inf ;14:S Livermore DM et al. J Antimicrob Chemother. 2001;48(suppl):59-64.

20 Molecular Basis of ESBLs Amino acid position Ceftazidime Enzyme MIC (µg/ml) TEM-1 <0.12 Glu Arg Glu TEM Glu Ser Glu TEM Glu Ser Lys TEM-26 >256 Lys Ser Glu Modified from Rice LB. Pharmacotherapy ;19:120S-128S. 128S.

21 Emergence of CTX-M Enzymes Distribution of CTX-M-15-producing E. coli Pitout JD. Drugs. 2010;70:

22 Results of CTX-M Emergence Increasing spectrum and prevalence of resistance complicate management Fluoroquinolones and trimethoprim-sulfamethoxazole resistance limit outpatient options Extended-spectrum cephalosporin resistance limits options in the hospital Results Delays in appropriate therapy Higher costs Increased use of last resort antimicrobials Johnson JR, et al. Clin Infect Dis. 2010;51:

23 AmpC β-lactamases Different from ESBLs Not inhibited by β-lactamase inhibitors Differing susceptibilities Usually chromosomally encoded Generally confers resistance to First-, second-, and third-generation cephalosporins and aztreonam Broad-spectrum penicillins associated with β-lactamase inhibitors Pfaller MA, Segreti J. Clin Infect Dis. 2006;42(suppl 4):S153-S163. Jones RN. Diagn Microbiol Infect Dis. 1998;31:

24 Chromosomal, Inducible AmpCs Produced by the SPACE Bacteria Serratia marcescens Pseudomonas aeruginosa Acinetobacter species Citrobacter species Enterobacter species β-lactamase under the control of the ampc gene (turn on) and repressor gene (turn off) Mutation is loss of the repressor gene terminology is the isolate becomes stably de-repressed Bush, K. Clin Infect Dis 2001; 32:

25 Stable De-repression Selection During Therapy Resistant Strain Resistant Strain Rare Dominant Selection of stable derepressed mutants: susceptible when tested, then resistance 3 days later

26 Carbapenemases Two categories: serine β-lactamases and metallo-β-lactamases (MBL) Can be chromosomally encoded or plasmid encoded Bacteria that produce Pseudomonas aeruginosa Acinetobacter baumannii Klebsiella oxytoca Escherichia coli Enterobacter cloacae Serratia marcescens Klebsiella pneumoniae Citrobacter freundii Proteus mirabolis Livermore DM, Woodford N. Trends Microbiol. 2006;14: Bonomo RA, Szabo D. Clin Infect Dis. 2006;43(suppl 2):S49-S56.

27 KPC Carbapenemase Outbreak 602 K. pneumoniae isolates collected during a NYC, citywide surveillance study 45% had ESBLs Of the ESBL-producing isolates, 3.3% carried KPC-2 Two hospitals experienced the rapid spread of carbapenem-resistant isolates involving 58 patients Overall 14-day mortality in bacteremic patients was 47% Bratu S, et al. J Antimicrobial Chemother 2005;56:

28 Risk Factors and Significance Risk factors for KPC colonization Increasing severity of illness Prior fluoroquinolone, cephalosporin, carbapenem use ICU admission Spread among Enterobacteriaceae, Pseudomonas spp. and Acinetobacter spp. reported Outcomes study, K. pneumoniae infection mortality KPC-producing: 32.1% Carbapenem susceptible: 9.9% Patel G, et al. Infect Control Hosp Epidemiol. 2008;29: Gasink LB, et al. Infect Control Hosp Epidemiol. 2009;30: Kwak YG, et al. Microb Drug Resist. 2005;11:

29 New ESBL Gene (bla NDM-1 ) Patient traveled from Sweden to India for surgical procedure Developed a decubital ulcer, returned to Sweden Treated with amox/clav, amikacin, and gatifloxacin K. pneumoniae isolated from urine culture ESBL-producing carbapenem resistant E. coli isolate from wound Producing the MBL, designated NF-NDM-1 Yong D, et al. Antimicrob Agents Chemother. 2009;53: Rolain JM, et al. Clin Microbiol Infect. 2010;16:

30 Clinical Outcome: Mortality K. pneumoniae ESBL Pos ESBL Neg Bacteremia 1 52% (n=48) 29% (n=99) P=0.007 A. baumannii Imipenem Resistant Imipenem Susceptible Bacteremia % (n=40) 27.5% (n=40) P<0.05 P. aeruginosa Multidrug Resistant Not Multidrug Resistant Bacteremia 3 21% (n=82) 12% (n=82) P=0.08 Enterobacter spp. Imipenem Resistant Imipenem Susceptible Multiple sources 4 11% (n=33) 3% (n=33) P= Tumbarello M, et al. Antimicrob Agents Chemother. 2006;50: Kwon KT, et al. J Antimicrob Chemother. 2007;59: Aloush V, et al. Antimicrob Agents Chemother. 2006;50: Marchaim D, et al. Antimicrob Agents Chemother. 2008;52:

31 ESBL Production and Outcomes Non-urinary tract isolates of Klebsiella, E. coli Length of stay 21 days vs. 11 days (P=0.006) Clinical success 48% vs. 86% (P=0.027) Lee, et al. Inf Cont Hosp Epi 2006;27:

32 ESBL Impact: Bacteremia Study Mortality contribution in Enterobacteriaceae bacteremia OR P-value ESBL Inappropriate therapy ESBL (inappropriate therapy excluded) Inappropriate therapy (ESBL excluded) <0.001 Marchaim D, et al. Antimicrob Agents Chemother. 2010;54:

33 Management of ESBL s Detection Reporting Infection control Stewardship

34 Laboratory Detection Problem No simple marker for presence of ESBL ESBLs give variable MICs to the extended-spectrum cephalosporins Revised breakpoint for resistance should predict ESBL production ( 16 µg/ml) Present susceptibility break points for ceftazidime (revised 2010) Susceptible < 4 mcg/ml Intermediate 8 mcg/ml Resistant > 16 mcg/ml Livermore DM. Clin Microbiol Inf ;14:S

35 Recommended ESBL Detection ESBL screening If MIC 2 µg/ml to ceftazidime, cefotaxime, or ceftriaxone, then must do an: ESBL confirmatory test 3 two-fold concentration decrease in an MIC for an antimicrobial agent tested in combination with clavulanic acid or > 5 mm increase in ceftazidime/clavulanic acid zone diameter CLSI no longer recommends for individual patient care, only for epidemiological evaluations

36 Laboratory Detection of ESBLs Etest ESBL Prescribing Information; AB Biodisk.

37 Lab Detection Enzyme Organism Examples Inhibitors Detection ESBL K. pneumoniae E. coli P. mirabilis Clavulanic acid Tazobactam Sulbactam Screen: 3 rd ceph Confirm: 3 rd ceph + clavulanate AmpC K. pneumoniae Cloxacillin Screen: R to cefoxitin (plasmid) E. coli Boronic acid Confirm: Cefotetan + boronic acid MBL KPC P. aeruginosa Acinetobacter spp K. pneumoniae E. coli Metal chelation Clavulanic acid Tazobactam Boronic acid Screen: R to carbapenem Confirm: Carbapenem + EDTA Screen: Ertapenem Confirm: Refer to reference lab Pitout JDD. Expert Rev Anti Infect. 2008;6:

38 Antimicrobial Stewardship Infection control plus antimicrobial management Appropriate antimicrobial selection, dosing, route, and duration System selection of antimicrobials that cause the System selection of antimicrobials that cause the least collateral damage MRSA ESBLs Clostridium difficille Stable derepression Metallo-beta-lactamases and other carbapenemases VRE

39 Active Core Strategies Prospective audit with intervention and feedback to reduce inappropriate antimicrobial use Formulary restriction and pre-authorization leading to reductions in antimicrobial use and cost NOTE neither of these strategies are mutually exclusive

40 Formulary Restriction: Example Grams per 1000 Patient Days Year Third-Generation Cephalosporins Cefepime Ceftazidime-Resistant K Pneumoniae % Ceftazidime-R Resistant K Pneumoniae e Isolates After initiation of formulary restriction Third-generation cephalosporins use decreased Cefepime use remained stable Rates of ceftazidime-resistant Klebsiella pneumoniae decreased Martin CA et al. Am J Health Syst Pharm. 2005;62:

41 Antimicrobial Treatment Timely Any delay in initiation potentially lethal Appropriate All isolated pathogens are susceptible to 1 of the administered antibiotics Consider policies that limit use of cephalosporins and fluoroquinolones Dose agents consistent with PK/PD parameters Timely streamlining based on clinical response and microbiological data Prompt discontinuation when practical

42 Treatment Duration Prolonged antibiotics courses have long been considered the solution to, instead of the cause of, resistance CDC Get Smart Website Complete the prescribed course of treatment, even if you are feeling better. Example: CAP Guidelines 2000: We are not aware of any controlled trials that have specifically addressed the question of how long pneumonia should be treated 2007: Patients with CAP should be treated for a minimum of 5 days, should be afebrile for 48-72h, and should have no more than 1 sign of CAP-associated clinical instability before discontinuation of therapy. Rice LB. CID 2008;46: (accessed Mar 29, 2011) Mandel LA et al. CID 2007;44(Suppl 2):S27-72.

43 Treatment of ESBL Producers Drugs of choice Outcomes data Susceptibilities Future directions

44 Treatment: ESBL-Producers No longer nosocomial infections only Carbapenems the treatment of choice for serious infections Resistance to other antimicrobials (eg, aminoglycosides, fluoroquinolones, trimethoprim, sulfonamides, tetracyclines, and chloramphenicol) often present in ESBL producers Potential for selection of carbapenem-resistant variants reported Hunter PA, et al. J Antimicrob Chemother. 2010;65(suppl 1):i3-i17. Pitout JDD. Drugs. 2010;70:

45 Treatment: ESBL-Producers Carbapenems: current drugs of choice for serious infections Cefepime: more stability but reports of treatment failures Resistance to other antimicrobials often present in ESBL producers Paterson DL, et al. CID 2004; 39: Marchaim D, et al. Antimicrob Agents Chemother. 2010;54:

46 Carbapenem Clinical Data K. pneumoniae bacteremia Prospective study, 12 hospitals over 2 years 85 ESBL-producing isolates Carbapenems significantly lowered 14-day mortality rate Enterobacteriaceae ventilator-associated pneumonia Prospective, 20 patients with ESBL-producing strains Ertapenem clinical success rate of 80% K. pneumoniae bloodstream infection Clinical case series 35 cases caused by TEM-52-producing strains Success: imipenem/cilastatin 80% vs. ciprofloxacin 28% Endimiani A et al. CID 2004;38(2): Bassetti M et al. JAC 2007;60(2):433-5 Paterson DL et al. CID 2004;39(1):31-7

47 Susceptibilities Agent Nonsusceptibility (%) Piperacillin/tazobactam 0-53 Amoxicillin/clavulanate Gentamicin 9-67 Tobramycin Amikacin 5-27 Ciprofloxacin Sulfamethoxazole-trimethoprim Nitrofurantoin 6-29 Fosfomycin 1-9 Tigecycline 0-1 Pitout JDD. Drugs 2010;70(3):

48 Cefepime Active against some ESBL producers RCT comparison of imipenem vs. cefepime Prospective, multicenter, nosocomial pneumonia in ICU Subgroup analysis, ESBL-producers Cefepime: 4 of 13 patients failed therapy Imipenem/cilastatin: 0 of 10 patients failed therapy All isolates tested susceptible to cefepime Zanetti G et al. AAC 2003;47(11): Ramphal R et al. CID 2006;42 Suppl 4:S164-72

49 β-lactam/inhibitor Combinations Several studies support their use to reduce incidence of ESBL-producing bacteria vs. cephalosporins Pip/tazo efficacy in a limited number of studies All infections, 48 cases, 21-day success rate of 28% ESBL-producing E. coli, 43 cases, lower mortality when receiving either pip/tazo or a carbapenem vs. a cephalosporin or fluoroquinolone (9% vs. 35%) Amox/clavulanate in 37 patients with cystitis Cure rate 84% Efficacy tied to MIC to the combination Tumbarello M et al. AAC 2006;50(2): Gavin PJ et al. AAC 2006;50(6): Rodriguez-Bano J et al. Arch Int Med 2008;168(17):

50 Tigecycline Excellent in vitro activity against ESBL-producing strains (especially CTX-M producers) Success shown in animal infection models Successful case studies of its use published Morosini MI et al. AAC 2006;50(8):2695-9

51 Other Agents Aminoglycosides ESBL producers often resistant CTX-M-15 often carries AGL-modifying enzyme E. coli and K. pneumoniae bacteremia study 36 infections caused by ESBL-producing strains 7 of 15 patients treated with AGL had sufficient response Fluoroquinolones High rates of resistance May be an option if strains test susceptible Kim YK et al. AAC 2002;46(5): Pitout JD. Expert Rev Infect Ther 2008;6(5):

52 Other Agents Fosfomycin, nitrofurantoin Limited data Restricted to use against urinary tract infections Temocillin, colistin In vitro activity Clinical data not available Combination therapy currently being studied Pitout JDD. Drugs. 2010;70:

53 Treatment: Carbapenemase Producers Data limited to case series Review of 15 papers, total of 55 patient cases Polymyxins Good only when used in synergy Polymyxin B + rifampin Polymyxin B + imipenem Tigecycline Majority of cases report positive outcomes Aminoglycosides Majority of cases report positive outcomes Hirsch EB et al. JAC 2010;65(6):

54 Conclusions Antimicrobial stewardship practices effective in limiting emergence and spread of ESBL-producing organisms Emergence associated with use of 3 rd generation cephalosporins, fluoroquinolones, and carbapenems Must spare the use of carbapenems when possible Treatment options limited dire need for clinical experience trials to be published