Disclosure. Objectives. Evolution of β Lactamases. Extended Spectrum β Lactamases: The New Normal. Prevalence of ESBL Mystic Program

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1 47 th Annual Meeting August 2-4, 2013 Orlando, FL Extended Spectrum β Lactamases: The New Normal Disclosure I do have a vested interest in or affiliation with the following companies or organizations Triax [Speaking Honorarium] Christopher A Jankowski UF Health Jacksonville, FL 2 Objectives Prevalence of ESBL Mystic Program Upon completion of this activity, the participant should be able to: 1) Understand the difference between multiple drugresistant (MDR) organism terminology, including enzyme classifications. 2) Describe the prevalence and treatment options of community acquired extended spectrum beta lactamase [ESBL] producing organisms 3) Identify alternative antimicrobial agents for MDRpathogens 4) Describe an antimicrobial stewardship approach for combatting MDR pathogens 3 Europe Goosen H and Grabein B. Diagn Microbiol Infect Dis.2005; 53: United States Rates of ESBL Producing Organisms at UF Health Evolution of β Lactamases Wild Type Penicillins β lactamase (TEM 1, TEM 2, SHV 1) β lactam/β lactamase inhibitors; Cephalosporins AmpC; ESBL (TEM, SHV, CTX M) Carbapenems Carbapenemase (KPC, MBL,NDM 1) ESBL=extended-spectrum β-lactamase; KPC=Klebsiella pneumonia carbapenemase; MBL=metallo-β-lactamase; TEM-1,TEM-2, SHV-1, TEM, SHV, CTX-M=types of β-lactamases. Adapted from UF Health Antibiogram Data 5 Burgess DS, et al. Am J Health Syst Pharm. 2008;65:S4-S15. 1

2 Ambler Classification Common β Lactams Antibiotics A [serine] B [metallo] C [ampc] D [oxacillinase] Chromosomal Examples Klebsiella Stenotrophomonas maltophilia Plasmid Examples TEM, SHV, CTX M KPC IMP, VIM Associated Bacteria Enterobacteriaceae P. aeruginosa Acinetobacter Klebsiella [NDM1] Enterobacteriaceae CMY, FOX, LAT SPACE Bugs Aeromonas OXA Acinetobacter Penicillins Penicillin Methicillin Aminopenicillins Ampicillin Carboxypenicillin Ticarcillin Ureidopenicillin Piperacillin Cehalosporins 1 st : Cefazolin 2 nd : Cefuroxime 3 rd : Ceftriaxone 3 rd : Ceftazidime 4 th : Cefepime 5 th : Ceftaroline Cephamycins Cefoxitin Cefotetan Carbapenems Ertapenem Imipenem Meropenem Doripenem Monobactam Aztreonam Livermore DM. Clin. Microbiol. Rev. 1995; 8(4): Risk Factors for ESBL Infections or Colonization in Hospitalized Patients Healthcare Exposure Prolonged Hospital Stay Prolonged ICU Stay Resident in Long Term Care Gastrostomy Tracheostomy Endotracheal/NG Tube Indwelling Catheter Decubitus ulcer Exposure to Antibiotics Total antibiotic use Exposure to 3 rd generation cephalosporins Ciprofloxacin Trimethoprimsulfamethoxazole Survival Curve for Bloodstream Infections [BSI] due to ESBL E. coli and K. pneumoniae According to Definitive Antimicrobial Therapy Regimens 133 Patients with ESBL BSI 66: ESBL K. pneumoniae 67: ESBL E. coli Overall 30 day mortality rate = 25.6% [34/133] 30 day mortality rates Carbapenem: 12.9% [8/62] Ciprofloxacin: 10.3% [3/29] Other: 26.9% [7/26] Other= Cephalosporin or aminoglycoside 9 Hyle EP et al. Clin Infect Dis. 2005; 40: Kang C et al. Antimicrob. Agents Chemother. 2004;48: Cefepime for ESBL Bacteremia Cefepime for ESBL Bacteremia Patients with ESBL-bacteremia --5 year study period Mortality based on organism treated with cefepime E. coli [6/8] 75% K. pneumoniae [5/7] 71.4% E. cloacae [6/18] 33% Independently associated with 30-day mortality in multivariate analysis Definitive cefepime therapy Pitt bacteremia score 4 Rapidly fatal underlying disease Clinical Failure in [25/33] 75.8% of patients treated with cefepime Lee NY et al. Clin Infect Dis. 2013; 56: Lee NY et al. Clin Infect Dis. 2013; 56:

3 MIC data for E.coli Strains Producing Various CTX M Enzymes RRs of All Cause Mortality of Patients with ESBL Bacteraemia Treated Definitively with Carbapenems versus β Lactamase Inhibitor Combinations [BL/BLIs] β lactam CTX M 3 CTX M 15 CTX M 4 CTX M 5 CTX M 9 CTX M 16 CTX M 14 CTX M 18 CTX M 19 AMC PIP >512 > >128 >512 >512 >512 >512 >512 PZT CXT > CEF IMI AZT AMC :Amoxicillin clavulanic acid; PIP: Piperacillin; PZT: Piperacillin tazobactam; CXT: Cefotaxime; CEF: Cefepime; IMI: Imipenem; AZT: Aztreonam Bonnett, R. Antimicrob Agents Chemother. 2004; 48(1) Vardakas KZ et al. J. Antimicrob. Chemother. 2012; 67(12): β lactamase Inhibitor Combinations for Bloodstream Infections β lactamase Inhibitor Combinations for Bloodstream Infections II Post hoc analysis of patients with ESBL E. coli BSI CTX M 14 [ 50 cases, 48.5%] CTX M 15 & SHV 12 [19 cases, 18.4%] Empirical and Definitive Therapy analysis: Β lactam/β lactamase inhibitor [BLBLI] Piperacillin tazobactam 4500 mg IV Q 6 hours [PZT] Amoxicillin clavulanic acid 1200 mg IV Q 8 hours [AMC] Carbapenem Therapy Imipenem 500 mg Q 6 hours [IMI] Meropenem 1000 mg Q 8 hours [MER] Ertapenem 1000 mg Q 24 hour [ERT] Rodriguez-Bano J et al. Clin Infect Dis. 2012; 54: Empirical Cohort Definitive Cohort BLBLI [n=72] Carb [n=31] BLBLI [n=54] Carb [n=120] Mortality, # (%) Day 7 2 (2.8) 3 (9.7) 1 (1.9) 5 (4.2) Day 14 7 (9.7) 5 (16.1) 3 (5.6) 14 (11.7) Day 30 7 (9.7) 6 (19.4) 5 (9.3) 20 (16.7) Hospital stay after BSI, days Median (IRQ) 12 (8 28) 13 (9 25) 13 (8 22) 13 (10 25) CTX Menzyme 57 (80.3) 25 (86.2) 43 (82.7) 95 (81.2) Mortality by minimum inhibitory concentration [MIC] [From Empiric Therapy] Pip tazobactam 0/10 0/8 1/4 2/6 1/7 Amox Clavulanic acid 1/12 2/25 Rodriguez-Bano J et al. Clin Infect Dis. 2012; 54: Red= statistically significant Carb=Carbapenem BIBLI= B-lactam with B- lactamase Inhibitor 16 Rapid β lactamase Detection from Blood Samples Incidence of Community Associated ESBL E.coli in the United States Gram negative Organisms E. coli K. pneumoniae K. oxytoca Acinetobacter spp. Proteus spp. Citrobacter spp. Enterobacter spp. P. aeruginosa Shigella spp. CTX M OXA Resistance Markers KPC NDM Results < 2 hours Prospective, multicenter, observational study Community onset episodes outpatients Inpatients, within 48 hours of admission 5 Locations: New York, Pennsylvania, Michigan, Texas, Iowa Sept 2009 August % had CTX M enzyme 13,279 Unique E.Coli isolates Community Onset N=292 [1.9%] N= 523 ESBL [3.9%] Healthcareassociated N= 232 [1.7%] IMP VIM Nanosphere Verigene. Accessed 5/31/13 17 Doi Y et al. Clin Infect Dis. 2013;

4 Susceptibilities in Community Acquired CTX M ESBL E.coli PO Options Susceptible [%] Intermediate [%] Resistant [%] Nitrofurantoin TMP SMX Ciprofloxacin IV Options Susceptible [%] Intermediate [%] Resistant [%] AMS PZT Ertapenem Gentamicin Risk Factors for Community Acquired ESBL producing E. coli Infections Female sex 1 Recurrent UTI 1 Diabetes mellitus 2 Prostatic disease 2 Previous Antibiotics 3 Fluoroquinolones Β lactam antibiotics What is your institution s rate of treating asymptomatic bacteriuria? TMP-SMX: trimethoprim-sulfamethoxazole; AMS: Ampicillin-sulbactam; PZT: Piperacillin-tazobactam Doi Y et al. Clin Infect Dis. 2013; Meier S et al. Infection. 2011; 39: Yilmaz E et al. J Chemother. 2008; 2: Colodner R et al. J Antimicrob Chemother. 2006; 57: Antimicrobial Agents for ESBL Producing Organisms Standard Options Alternative Options Carbapenems [IV] Cephamycins [IV] Ertapenem Nitrofurantoin [PO] Imipenem/cilastatin Amoxicillin/Clavulanate [PO] Meropenem Fosfomycin [PO] Doripenem Fluroquinolones [IV/PO] Trimethoprimsulfamethoxazole [IV/PO] Aminoglycosides [IV] 21 Piperacillin/Tazobactam [IV]? Cefoxitin Ceftriaxone Stability of Cephamycins to ESBL β lactamases Wallick H and Hendlin D. Antimicrob. Agents Chemother. 1974: 5 (1): WHY 1.α-methoxy group in position 7 acts as steric shield 2.Urethane group is stable to metabolism compared to ester WHY NOT 1. Rare published literature utilizing cephamycins available in US for blood stream infections 2. Porin loss can lead to resistance 22 FOXICOLI Study Pending Nitrofurantoin Utility Conundrums Efficacy and Pharmacokinetic/Pharmacodynamic Parameters of Cefoxitin in Women With Acute Uncomplicated Pyelonephritis Due to Extended spectrum β lactamase Producing Escherichia Coli (FOXICOLI) Estimated Enrollment: 40 Study Start Date: March 2013 Estimated Study Completion Date: May 2015 Estimated Primary Completion Date: May 2015 Pros Approximately 40% of oral dose recovered in urine Low levels of resistance Bactericidal activity Inactivate or alter bacterial ribosomal proteins Cons Contraindicated in patients with CrCl < 60 ml/min?? Single dose study from 1968 Recent review suggests cutoff of CrCl <40 ml/min Only for lower urinary tract infections ClinicalTrials.gov. Accessed 5/22/13 23 Auer S et al. Antimicrob. Agents. Chemother. 2010; 54(9): Oplinger M and Andrews CO. Ann Pharmacother. 2013; 47:

5 Potential Utilization of Amoxicillin Clavulanate for ESBL E.coli Cystitis 17/18 [94%] MIC = 4 μg/ml 73 Patients with ESBL N=37 Treated with AMC 500 mg Q 8 h x 5 7 days 122 ESBL Cases Evaluated N=93 [76%] Susceptible to AMC 9/10 [90%] MIC = 8 μg/ml Rodriguez-Bano J et al. Arch Inter Med. 2008; 168: /4 [75%] MIC = 16 μg/ml 2/5 [40% MIC = 32 μg/ml 25 Fosfomycin for the treatment of ESBL E.coli Lower Urinary Tract Infections Affects cell wall synthesis enolpyruvate transferace inhibition Impairs adherence to urogenital mucosa High in vitro susceptibility rates on ESBL E.coli isolates Low resistance rates reported world wide Pullukcu H et al. International Journal of Antimicrobial Agents; ; Auer S et al. Antimicrob. Agents. Chemother. 2010; 54(9): Pullukcu et al. 52 adult symptomatic patients Sept July 2006 Received fosfomycin 3 g every 48 hours x 3 doses 94.3% clinical success 78.5% microbiological success 26 Fosfomycin Dosing & Considerations Treatment of Community Acquired ESBL Producing Organism UTI Oral Formulation Favorable PK: 37% bioavailable, 38% renally excreted Can be used in pregnant and penicillin allergic patients Can be utilized in patients with CrCl < 40 ml/min Minimal side effects [diarrhea, head ache] & interactions Pyelonephritis Suspected Use Carbapenem or Fluoroquinolone No ESBL Identified in Urine Culture Cystitis Suspected Is CrCL 40 ml/min? Asymptomatic bacteriuria: Does not require treatment unless 1. Pregnant 2. Undergoing urologic procedure Yes Infection CrCl 50 ml/min CrCl ml/min CrCl < 10 ml/min Uncomplicated 3 g oral x 1 dose 3 g oral x 1 dose 3 g oral x 1 dose Fosfomycin 3 grams Q 72 hours x 2 3 doses >95% Susceptible No Susceptible to CPO, AMC, TMP SMX Consider these agents Nitrofurantoin 100 mg BID x 5 days > 90% susceptible Complicated 3 g oral every 2 days for 7 21 days 3 g oral every 3 days for 7 21 days 3 g oral every 3 days for 7 21 days *In patients on HD, dose after HD session. Mix powder in ml of cool water until it dissolves Ciprofloxacin mg Q 12 hours < 50% Susceptible TMP SMX DS 1 tab Q 12 hours <50% Susceptible AMC 500 mg Q 8 hours Variable % TMP-SMX: trimethoprim-sulfamethoxazole; AMC: Amoxicillin clavulanate; CPO: ciprofloxacin Falagas ME. Lancet Infect Dis. 2010; 10: ASP Estimated Cost Savings Average cost of hospital day in Florida $1750 Average cost of PICC and estimated complications 2 $974 Number of urinary ESBLs treated via an ASP approach to justify an ASP Pharmacist Decrease in 1 IP day, $0 medication savings Assuming 100k salary th Annual Meeting August 2-4, 2013 Orlando, FL Extended Spectrum β Lactamases: The New Normal Christopher A Jankowski UF Health Jacksonville, FL 1. Becker s Hospital Review. Accessed 5/23/ Khachatryan A et al. Poster Presentation. K-239. ICAAC