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7/27/2013

47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL Disclosure

• I do have a vested interest in or affiliation with Extended‐Spectrum β‐Lactamases: the following companies or organizations The New Normal – Triax [Speaking Honorarium]

Christopher A Jankowski UF Health Jacksonville, FL

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Prevalence of ESBL Objectives Mystic Program 1997‐2004 • Upon completion of this activity, the participant should be able to: Europe United States 1) Understand the difference between multiple drug‐ 1997-2004 1997-2004 resistant (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 MDR‐ pathogens 4) Describe an antimicrobial stewardship approach for combatting MDR‐pathogens 3 4 Goosen H and Grabein B. Diagn Microbiol Infect Dis.2005; 53: 257-264

Rates of ESBL‐Producing Organisms at Evolution of β‐Lactamases UF Health 2009‐2012 Wild‐Type

β‐lactamase (TEM‐1, TEM‐2, SHV‐1) β‐lactam/β‐lactamase inhibitors;

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.

5 Adapted from UF Health 2009-2012 Antibiogram Data Burgess DS, et al. Am J Health Syst Pharm. 2008;65:S4-S15.

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Ambler Classification Common β‐Lactams

Chromosomal Plasmid Associated Bacteria Penicillins Cehalosporins Examples Examples 1st: Klebsiella TEM, SHV, Enterobacteriaceae 2nd: CTX‐M A [serine] KPC 3rd: Stenotrophomonas IMP, VIM P. aeruginosa ‐‐ 3rd: [metallo] maltophilia Acinetobacter B Klebsiella [NDM1] Carboxypenicillin 4th: ‐‐ 5th: Ceftaroline Enterobacteriaceae CMY, FOX, LAT SPACE Bugs C [ampC] ‐‐ Aeromonas OXA Acinetobacter D [oxacillinase]

7 8 Livermore DM. Clin. Microbiol. Rev. 1995; 8(4):557-584

Risk Factors for ESBL Infections or Survival Curve for Bloodstream Infections [BSI] due to ESBL‐E. coli and K. pneumoniae According to Definitive Antimicrobial Therapy Colonization in Hospitalized Patients Regimens

Healthcare Exposure Exposure to Antibiotics 133 Patients with ESBL‐BSI • Prolonged Hospital Stay • Total use •66: ESBL‐K. pneumoniae •67: ESBL‐E. coli • Prolonged ICU Stay • Exposure to • Resident in Long Term – 3rd‐generation Care cephalosporins Overall 30‐day mortality rate = • Gastrostomy – Ciprofloxacin 25.6% [34/133] • Tracheostomy – Trimethoprim‐ • Endotracheal/NG Tube sulfamethoxazole 30‐day mortality rates • Indwelling Catheter : 12.9% [8/62] Ciprofloxacin: 10.3% [3/29] Other: 26.9% [7/26] • Decubitus ulcer Other= or aminoglycoside

9 Hyle EP et al. Clin Infect Dis. 2005; 40: 1317-1324 Kang C et al. Antimicrob. Agents Chemother. 2004;48:4574-4581

Cefepime for ESBL‐Bacteremia Cefepime for ESBL‐Bacteremia

Patients with ESBL-bacteremia Independently associated with --5 year study period 30-day mortality in multivariate analysis Mortality based on organism treated with cefepime •Definitive cefepime therapy • E. coli [6/8] 75% •Pitt bacteremia score ≥ 4 • K. pneumoniae [5/7] 71.4% •Rapidly fatal underlying disease • E. cloacae [6/18] 33%

Clinical Failure in [25/33] 75.8% of patients treated with cefepime

Lee NY et al. Clin Infect Dis. 2013; 56: 488-495 11 Lee NY et al. Clin Infect Dis. 2013; 56: 488-495 12

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MIC data for E.coli Strains Producing RRs of All‐Cause Mortality of Patients with ESBL‐Bacteraemia Treated Definitively with Carbapenems versus β‐Lactamase Various CTX‐M Enzymes Inhibitor Combinations [BL/BLIs]

β‐lactam CTX‐M‐3CTX‐M‐15 CTX‐M‐4CTX‐M‐5CTX‐M‐9CTX‐M‐16 CTX‐M‐14 CTX‐M‐18 CTX‐M‐19 AMC 128 32 8 32 888128 128 PIP >512 >512 128 >128 >512 >512 >512 >512 >512 PZT 2421222168 CXT 512 512 512 >128 16 16 16 64 4 CEF 128 64 ‐‐‐‐0.5 16 4 IMI 0.25 0.25 ‐ 0.5 ‐‐‐0.25 0.25 AZT 128 64 32 128 4 8 4 64 4 AMC :‐; PIP: Piperacillin; PZT: Piperacillin‐; CXT: ; CEF: Cefepime; IMI: Imipenem; AZT: Aztreonam

Bonnett, R. Antimicrob Agents Chemother. 2004; 48(1). 1-14 13 Vardakas KZ et al. J. Antimicrob. Chemother. 2012; 67(12): 2793-2803

β‐lactamase Inhibitor Combinations for β‐lactamase Inhibitor Combinations for Bloodstream Infections Bloodstream Infections II

Empirical Cohort Definitive Cohort • Post hoc analysis of patients with ESBL‐E. coli BSI BLBLI [n=72] Carb [n=31] BLBLI [n=54] Carb [n=120] – CTX‐M‐14 [ 50 cases, 48.5%] Mortality, # (%) – CTX‐M‐15 & SHV‐12 [19 cases, 18.4%] • 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) • Empirical and Definitive Therapy analysis: • Day 30 7 (9.7) 6 (19.4) 5 (9.3) 20 (16.7) – Β‐lactam/β‐lactamase inhibitor [BLBLI] Hospital stay 12 (8‐28) 13 (9‐25) 13 (8‐22) 13 (10‐25) • Piperacillin‐tazobactam 4500 mg IV Q 6 hours [PZT] after BSI, days • Amoxicillin‐clavulanic acid 1200 mg IV Q 8 hours [AMC] Median (IRQ) – Carbapenem Therapy CTX‐Menzyme 57 (80.3) 25 (86.2) 43 (82.7) 95 (81.2) • Imipenem 500 mg Q 6 hours [IMI] Mortality by minimum inhibitory concentration [MIC] Red= statistically significant • Meropenem 1000 mg Q 8 hours [MER] Carb=Carbapenem [From Empiric Therapy] ≤12 4 816 BIBLI= B-lactam with B- • Ertapenem 1000 mg Q 24 hour [ERT] lactamase Inhibitor Pip‐tazobactam 0/10 0/8 1/4 2/6 1/7 Amox‐Clavulanic acid ‐‐1/12 2/25 ‐ 15 16 Rodriguez-Bano J et al. Clin Infect Dis. 2012; 54: 167-174 Rodriguez-Bano J et al. Clin Infect Dis. 2012; 54: 167-174

Rapid β‐lactamase Detection from Blood Incidence of Community‐Associated Samples ESBL‐E.coli in the United States Gram‐negative Organisms • Prospective, multicenter, observational study 13,279 Unique E. coli K. pneumoniae K. oxytoca – Community‐onset episodes E.Coli isolates • outpatients Acinetobacter spp. Proteus spp. Citrobacter spp. • Inpatients, within 48 hours of admission N= 523 ESBL Enterobacter spp. P. aeruginosa Shigella spp. Results < 2 – 5 Locations: New York, [3.9%] hours Pennsylvania, Michigan, Texas, Iowa Resistance Markers – Sept 2009 – August 2010 CTX‐MKPC • 91.3% had CTX‐M enzyme Community Healthcare‐ Onset associated OXA NDM N=292 [1.9%] N= 232 [1.7%]

IMP VIM

17 18 Nanosphere Verigene. http://www.nanosphere.us/product/gram-negative-blood-culture . Doi Y et al. Clin Infect Dis. 2013; 56. 641-648 Accessed 5/31/13

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Susceptibilities in Community‐ Risk Factors for Community‐Acquired Acquired CTX‐M ESBL‐E.coli ESBL‐producing E. coli Infections PO Options Susceptible [%] Intermediate [%] Resistant [%] • Female sex1 Nitrofurantoin 98.1 1.9 0 1 TMP‐SMX 31.7 0 68.3 • Recurrent UTI Ciprofloxacin 11.5 1.0 87.5 • Diabetes mellitus2 • Prostatic disease2 IV Options Susceptible [%] Intermediate [%] Resistant [%] • Previous Antibiotics3 AMS 30.8 54.8 14.4 PZT 100 0 0 – Fluoroquinolones What is your institution’s rate of Ertapenem 99.0 1.0 0 – Β‐lactam antibiotics treating asymptomatic bacteriuria? Gentamicin 59.6 1.0 39.4

TMP-SMX: trimethoprim-sulfamethoxazole; AMS: Ampicillin-; PZT: Piperacillin-tazobactam

1. Meier S et al. Infection. 2011; 39: 333-340 2. Yilmaz E et al. J Chemother. 2008; 2: 581-585 20 Doi Y et al. Clin Infect Dis. 2013; 56. 641-648 19 3. Colodner R et al. J Antimicrob Chemother. 2006; 57:780-783

Antimicrobial Agents for ESBL‐ Stability of Cephamycins to Producing Organisms ESBL‐β‐lactamases Standard Options Alternative Options WHY 1.α-methoxy group in • Carbapenems [IV] • Cephamycins [IV] position 7 acts as steric shield – Ertapenem • Nitrofurantoin [PO] Cefoxitin 2.Urethane group is – Imipenem/cilastatin stable to metabolism • Amoxicillin/Clavulanate [PO] compared to ester – Meropenem • [PO] WHY NOT – Doripenem 1. Rare published literature utilizing • Fluroquinolones [IV/PO] cephamycins available in US for blood stream • Trimethoprim‐ infections sulfamethoxazole [IV/PO] 2. Porin loss can lead to Ceftriaxone resistance • Aminoglycosides [IV] • Piperacillin/Tazobactam [IV]? 21 Wallick H and Hendlin D. Antimicrob. Agents Chemother. 1974: 5 (1): 25-32 22

FOXICOLI Study Pending Nitrofurantoin Utility Conundrums

• Efficacy and Pharmacokinetic/Pharmacodynamic Parameters Pros Cons of Cefoxitin in Women With Acute Uncomplicated • Approximately 40% of • Contraindicated in Pyelonephritis Due to Extended‐spectrum β‐lactamase Producing Escherichia Coli (FOXICOLI) oral dose recovered in patients with CrCl < 60 urine mL/min?? – Single dose study from • Estimated Enrollment: 40 • Low levels of resistance 1968 • Study Start Date: March 2013 • Bactericidal activity – Recent review suggests • Estimated Study Completion Date: May 2015 – Inactivate or alter cutoff of CrCl <40 mL/min • Estimated Primary Completion Date: May 2015 bacterial ribosomal proteins • Only for lower urinary tract infections

Auer S et al. Antimicrob. Agents. Chemother. 2010; 54(9): 4006-4008 24 23 Oplinger M and Andrews CO. Ann Pharmacother. 2013; 47: 106-111 ClinicalTrials.gov. www.clinicaltrials.gov: Accessed 5/22/13

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Potential Utilization of Fosfomycin for the treatment of ESBL‐ Amoxicillin‐Clavulanate for ESBL‐E.coli Cystitis E.coli Lower Urinary Tract Infections

122 ESBL Cases • Affects • Pullukcu et al. Evaluated synthesis – 52 adult symptomatic N=93 [76%] Susceptible to AMC – enolpyruvate transferace patients inhibition • Sept. 2004 –July 2006 – Impairs adherence to • Received fosfomycin 3 g 73 Patients with ESBL every 48 hours x 3 doses urogenital mucosa cystitis – 94.3% clinical success N=37 • High in‐vitro – 78.5% microbiological Treated with AMC 500 mg Q 8 h x 5‐7 days susceptibility rates on success Clinical Cure Clinical Cure Clinical Cure Clinical Cure ESBL‐E.coli isolates 17/18 [94%] 9/10 [90%] 3/4 [75%] 2/5 [40% MIC = 4 μg/mL MIC = 8 μg/mL MIC = 16 μg/mL MIC = 32 μg/mL • Low resistance rates reported world wide

Rodriguez-Bano J et al. Arch Inter Med. 2008; 168: 1897-1902 25 Pullukcu H et al. International Journal of Antimicrobial Agents; 2007. 29; 62-65 26 Auer S et al. Antimicrob. Agents. Chemother. 2010; 54(9): 4006-4008

Treatment of Community‐Acquired Fosfomycin Dosing & Considerations ESBL‐Producing Organism UTI

Asymptomatic bacteriuria: ESBL Identified in Does not require treatment unless • Oral Formulation Urine Culture 1. Pregnant 2. Undergoing urologic procedure • Favorable PK: 37% bioavailable, 38% renally excreted Pyelonephritis Cystitis Suspected • Can be used in pregnant and penicillin allergic patients Suspected • Can be utilized in patients with CrCl < 40 mL/min Use Carbapenem or Is CrCL ≥ 40 mL/min? Fluoroquinolone • Minimal side effects [diarrhea, head ache] & interactions No Yes No Fosfomycin Infection CrCl ≥ 50 ml/min CrCl 10‐50 ml/min CrCl < 10 ml/min Nitrofurantoin 3 grams Q 72 hours 100 mg BID x 5 days Uncomplicated 3 g oral x 1 dose 3 g oral x 1 dose 3 g oral x 1 dose x 2‐3 doses Susceptible to CPO, AMC, TMP‐SMX > 90% susceptible cystitis >95% Susceptible Consider these agents Complicated 3 g oral every 2 days 3 g oral every 3 days 3 g oral every 3 cystitis for 7‐21 days for 7‐21 days days for 7‐21 days Ciprofloxacin TMP‐SMX DS AMC 500‐750 mg Q 12 *In patients on HD, dose after HD session. Mix powder in 90‐120 ml of cool water hours 1 tab Q 12 hours 500 mg Q 8 hours until it dissolves < 50% Susceptible <50% Susceptible Variable %

TMP-SMX: trimethoprim-sulfamethoxazole; AMC: Amoxicillin clavulanate; CPO: ciprofloxacin 27 28 Falagas ME. Lancet Infect Dis. 2010; 10: 43-50

47th Annual Meeting ҉ August 2-4, 2013 ҉ Orlando, FL ASP Estimated Cost Savings

• Average cost of hospital day in Florida 20101 – $1750 Extended‐Spectrum β‐Lactamases: • Average cost of PICC and estimated complications2 The New Normal – $974 • Number of urinary ESBLs treated via an ASP approach to justify an ASP Pharmacist Christopher A Jankowski – Decrease in 1 IP day, $0 medication savings UF Health – Assuming 100k salary Jacksonville, FL –37

1. Becker’s Hospital Review. http://www.beckershospitalreview.com/lists/average-cost-per-inpatient-day-across-50-states-in-2010.html Accessed 5/23/13 29 2. Khachatryan A et al. Poster Presentation. K-239. ICAAC 2012

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