Contact Information: Michael Satlin, MD Piperacillin-tazobactam, Carbapenems, and Levofloxacin for Clearance of Carbapenem- New York-Presbyterian/Weill Cornell 1300 York Avenue, A-421 New York, NY 10021 Phone: 212-746-6320 resistant Klebsiella pneumoniae from the Urine Fax: 212-746-8972 [email protected] Michael J. Satlin MD1, Christine J. Kubin PharmD BCPS2, Jill S. Blumenthal MD2, Andrew B. Cohen MD DPhil2, E. Yoko Furuya MD MS3, Stephen J. Wilson MD MPH1, Stephen G. Jenkins PhD1, David P. Calfee MD MS1 1Weill Cornell Medical College, New York, NY, 2New York-Presbyterian Hospital, New York, NY, 3Columbia University College of Physicians and Surgeons, New York, NY

Abstract Objective Characteristics of Cases Stratified by Cohort* Multivariate Analysis*: Factors Associated with Microbiologic Clearance (using backward, stepwise logistic regression) Background: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is an To assess whether beta-lactams and fluoroquinolones achieve greater Baseline Variables PT CM LX None P increasingly common cause of urinary tract infection (UTI). Treatment rates of microbiologic clearance of CRKP bacteriuria than cases not (n=26) (n=9) (n=11) (n=70) Variable Odds Ratio P options with in vitro activity against CRKP are limited. Beta-lactams and treated with gram-negative antimicrobial agents. Age (years) 72 63 66 69 0.68 Antimicrobial therapy fluoroquinolones, antimicrobials to which CRKP typically demonstrate in Male sex 31% 44% 45% 43% 0.71 No gram-negative antimicrobial 1.00 Reference vitro resistance, are highly concentrated in the urinary tract. Use of these Methods Baseline serum Cr (mg/dL) 0.9 1.4 1.0 1.4 0.17 Piperacillin-tazobactam 13.8 (2.41-79.4) 0.003 agents for the treatment of CRKP UTI has not been evaluated. Urinary tract abnormality 8% 56% 27% 21% 0.02 Carbapenem 1.12 (0.08-15.3) 0.93 Methods: We conducted a retrospective cohort study of CRKP Study Design: Retrospective cohort study 5 bacteriuria (≥ 104 CFU/mL) at New York-Presbyterian Hospital from Colony count > 10 CFU/mL 74% 56% 91% 61% 0.19 Levofloxacin 0.24 (0.03-1.76) 0.16 2005-2010. Cases were included if (1) only one beta-lactam or Study Population: Cases of CRKP bacteriuria (≥ 104 CFU/mL) at New Pyuria (> 5 wbc/hpf) 81% 75% 100% 64% 0.046 Charlson Comorbidity Index score 1.36 (1.04-1.78) 0.03 fluoroquinolone was initiated within 7 days after the index culture; (2) York-Presbyterian Hospital between 2005-2010 that received: Catheter-associated 60% 67% 64% 44% 0.32 Pyuria 0.29 (0.09-0.90) 0.01 the CRKP isolate was resistant in vitro to the agent administered; (3) a 1. One beta-lactam or fluoroquinolone that was initiated within 7 Fever (temperature ≥ 38.0ºC) 50% 33% 27% 14% 0.003 Fever 5.94 (1.51-23.3) 0.01 days after the index culture OR 3 follow-up urine culture was performed 3-21 days after antimicrobial WBC (x 10 /µL) 13.7 11.8 9.2 9.5 0.008 WBC 0.89 (0.81-0.97) 0.13 initiation; (4) ≥ 3 days of the antimicrobial was given between the index 2. No gram-negative antimicrobial therapy before the follow-up urine Intensive care unit 23% 13% 33% 12% 0.27 and follow-up cultures. We constructed a control cohort of cases that culture (Untreated cohort) Urinary catheter retention 0.21 (0.05-0.93) 0.04 Charlson Comorbidity Index 3 4 3 3 0.73 Input from infectious diseases 0.31 (0.10-0.97) 0.04 did not receive an antimicrobial with intrinsic gram-negative activity. score Definition of carbapenem resistance: Isolates that met any of the * The primary outcome was microbiologic clearance, defined as the Mortality Prediction Model III 13 8 7 9 0.29 Variables included in the final model: antimicrobial therapy, Charlson Comorbidity Index absence of CRKP on follow-up culture. We assessed microbiologic following criteria: score (% mortality) score, urinary tract abnormality, pyuria, fever, WBC, urinary catheter retention, input from 1. Resistant to ertapenem, imipenem, or meropenem by VITEK® 2 infectious diseases, receipt of antimicrobial on day of follow-up culture clearance rates of the three inactive agents most commonly used among Treatment Variables or Etest (using 2010 CLSI breakpoints) eligible cases and compared these rates to that of the control cohort. We Antimicrobial Dosing and Microbiologic Clearance* constructed a logistic regression model to estimate the odds of 2. Detection of carbapenemase by Modified Hodge test Catheter management n=12 n=4 n=6 n=27 0.36 microbiologic clearance with each agent compared to controls after Catheter retained 67% 25% 67% 41% 0.33 Antimicrobial Dose N No. with clearance (%) adjusting for covariates. Eligibility Criteria: Days of antimicrobial until 4 6 4 N/A 0.33 Piperacillin-tazobactam 4.5 gm. IV q6h 1 1 (100%) Results: Piperacillin-tazobactam (PT; n=26), carbapenems (CM; n=9) • Age ≥ 13 years follow-up culture 4.5 gm. IV q8h 12 9 (75%) and levofloxacin (LX; n=11) were the most commonly used agents • Results of an appropriate follow-up urine culture were available Receipt of antimicrobial on 62% 89% 45% N/A 0.17 4.5 gm. IV q12h 2 2 (100%) among eligible cases. The clearance rate among cases that received PT (see below) day of follow-up culture Carbapenem 500 mg IV q6h or q8h 3 0 (0%) was significantly greater than that of control cases (85% vs. 36%, P < • Beta-lactam and fluoroquinolone cohorts: *Data are median values for continuous variables and % for dichotomous variables Levofloxacin 750 mg daily 2 2 (100%) 0.001), whereas clearance rates among recipients of CM (54%) and LX • Agent tested resistant in vitro to the CRKP isolate based on a 250-500 mg daily 4 0% Microbiologic Clearance Rate by Cohort (27%) did not significantly differ from that of controls. In multivariate documented MIC 100% *Dosing assessed only in patients with creatinine clearance ≥ 50 mL/min analysis, recipients of PT were more likely to achieve clearance (OR • Only one antimicrobial agent was administered between the index culture and follow-up culture 9.5; 95% CI 3.0-30.0, P < 0.001), even after adjusting for covariates P < 0.001 Minimum Inhibitory Concentration (MIC) and Microbiologic such as urinary tract abnormality and catheter removal. • Receipt of at least 3 days of the agent before the follow-up 90% P values compare clearance 85% rate of antimicrobial cohort to Clearance Conclusions: PT use was associated with a high rate of microbiologic culture that of the untreated cohort clearance of CRKP bacteriuria. Prospective studies are warranted to 80% Antimicrobial Method MIC (µg/mL) N No. with clearance (%) assess whether PT is an effective treatment option for CRKP UTI. Primary Outcome: Microbiologic clearance: A follow-up urine culture Piperacillin- Vitek2 ≥ 128 26 22 (85%) that did not yield CRKP. tazobactam st 70% Introduction • Follow-up urine culture: the 1 urine culture 3-21 days after Carbapenem Etest 4-8 4 2 (50%) antimicrobial initiation (beta-lactam and fluoroquinolone cohorts) P = 0.16 Etest 16-32 5 3 (60%) • K.pneumoniae is a leading cause of healthcare-associated, catheter- or index bacteriuria (untreated cohort) 60% associated urinary tract infections (UTI).1 54% Levofloxacin Vitek2 ≥ 8 11 3 (27%) • 21% of K. pneumoniae isolates from New York hospitals reported to Results 50% the CDC in 2006-2007 were carbapenem-resistant.1 Conclusions • Carbapenem-resistant K. pneumoniae (CRKP) has been identified in Antimicrobial agents that were most frequently administered 2 40% • Despite testing resistant in vitro, piperacillin-tazobactam may be effective at least 36 U.S. states and in many countries. among eligible cases P = 0.54 36% • CRKP are typically susceptible in vitro to the following agents3, each in eradicating CRKP from the urinary tract. of which are suboptimal for the treatment of UTI: • Prospective studies that include urinary tract antimicrobial concentrations, Pip-tazo (PT) 26 30% 27% 1. Polymyxins (colistin and polymyxin B): nephrotoxicity accurate in vitro resistance testing, standardized treatment regimens, and 2. Tigecycline: low urinary tract concentrations4 standardized clinical and microbiologic follow-up are warranted to assess Imipenem: 6 20% the role of piperacillin-tazobactam and carbapenems in the treatment of 3. Aminoglycosides: nephrotoxicity Carbapenem (CM) 9 • Beta-lactams and fluoroquinolones are highly concentrated in the Meropenem: 3 CRKP UTI. 10% urinary tract. References: • Perhaps beta-lactams and fluoroquinolones are effective in treating Levofloxacin (LX) 11 1. Hidron AI et al. Infect Control Hosp Epidemiol 2008;29:996-1011. CRKP UTI because their urinary tract concentrations exceed the 0% 2. Gupta N et al. Clin Infect Dis 2011;53(1):60-7. 3. Castanheira M et al. Antimicrob Agents Chemother 2008;52:570-3. minimum inhibitory concentration (MIC) of the CRKP isolate. No other beta-lactam or fluoroquinolone was used in > 5 eligible cases Pip-tazo Carbapenem Levofloxacin Untreated 4. Rello J et al. J Chemother 2005;17 Suppl 1:12-22.