Efficacy of Ertapenem for Treatment of Bloodstream Infections Caused by Extended-Spectrum-␤-Lactamase-Producing Enterobacteriaceae Vicki L. Collins,a Dror Marchaim,a Jason M. Pogue,b Judy Moshos,a Suchitha Bheemreddy,a Bharath Sunkara,a Alex Shallal,a Neelu Chugh,a Sara Eiseler,a Pragati Bhargava,a Christopher Blunden,a Paul R. Lephart,c Babar Irfan Memon,a Kayoko Hayakawa,a Odaliz Abreu-Lanfranco,a Teena Chopra,a L. Silvia Munoz-Price,d Yehuda Carmeli,e and Keith S. Kayea Division of Infectious Diseases,a Department of Pharmacy Services,b and Department of Clinical Microbiology,c Detroit Medical Center, Wayne State University, Detroit, Michigan, USA; Division of Infectious Diseases, Department of Medicine and Department of Public Health and Epidemiology, University of Miami, Miami, Florida, USAd; and Division of Epidemiology, Tel-Aviv Sourasky Medical Center, Tel-Aviv, Israele Ertapenem is active against extended-spectrum-␤-lactamase (ESBL)-producing Enterobacteriaceae organisms but inactive against Pseudomonas aeruginosa and Acinetobacter baumannii. Due to a lack of therapeutic data for ertapenem in the treatment of ESBL bloodstream infections (BSIs), group 2 carbapenems (e.g., imipenem or meropenem) are often preferred for treatment of ESBL-producing Enterobacteriaceae, although their antipseudomonal activity is unnecessary. From 2005 to 2010, 261 patients with ESBL BSIs were analyzed. Outcomes were equivalent between patients treated with ertapenem and those treated with group .(0.18 ؍ carbapenems (mortality rates of 6% and 18%, respectively; P 2 xtended-spectrum-␤-lactamase (ESBL)-producing Entero- stay (LOS), deterioration in functional status (18), discharge to Ebacteriaceae organisms are recognized as an imminent threat a long-term care facility (LTCF) after being admitted from to public health (7, 26). No prospective, randomized, controlled home, additional hospitalization in the 6 months following trials have been conducted analyzing the preferred therapeutic discharge, and additional isolations of the same organism in management of ESBL-producing Enterobacteriaceae infections. the 3 months following the culture date (i.e., “bacteriologic Few small retrospective trials have demonstrated the relative su- failures”). Bacteria were identified to the species level, and sus- periority of carbapenems over other agents (4, 8, 12, 14, 17, 19, 21, ceptibilities to predefined antimicrobials were determined 24, 31). The carbapenems that were studied were group 2 carbap- based on an automated broth microdilution system (Micro- enems (e.g., imipenem and meropenem). Ertapenem is a group 1 Scan; Siemens AG, Germany) and in accordance with the CLSI carbapenem with no appreciable activity versus Pseudomonas criteria (9). For representative isolates, a positive ESBL test aeruginosa and Acinetobacter baumannii (13). Unfortunately, from the automated system was confirmed with disc diffusion there are limited data pertaining to the efficacy of ertapenem for tests (9). All analyses were performed using IBM SPSS 19 the treatment of serious invasive infections, such as bloodstream (2011). Logistic regression was used for multivariate analyses. infections (BSIs), that are due to ESBL-producing Enterobacteria- Variables chosen for the model were based on clinical impor- ceae (2, 3, 6, 10, 13, 22, 23, 27–30). Due to a lack of data, many tance and the results of bivariate analyses between relevant clinicians rely on group 2 carbapenems for treatment of severe groups (variables with a P value of Յ0.05). Variables with a P ESBL infections. A recent, commonly cited expert opinion review value of Յ0.05 were included in the final model and were ad- article did not even mention ertapenem as an option for the treat- justed for confounds. A propensity score analysis was con- ment of BSIs due to ESBL-producing Enterobacteriaceae (25). This ducted to establish the likelihood of receiving ertapenem and study aimed to compare the efficacies of group 1 carbapenems and incorporated into outcome models. group 2 carbapenems for the treatment of BSIs due to ESBL-pro- The study cohort included 261 unique patients with BSIs due ducing Enterobacteriaceae. to ESBL-producing Enterobacteriaceae (Table 1). The majority of A retrospective cohort study from 1 January 2005 to 30 June patients were elderly (53.6%), and 71% had a permanent device 2010 pertaining to outcomes of ESBL-producing Escherichia coli present for at least 48 h prior to ESBL-producing Enterobacteria- and Klebsiella pneumoniae BSIs was conducted at the Detroit ceae isolation. Most BSIs were from a urinary source (n ϭ 108 Medical Center (DMC) health system after institutional review [41.4%]), and 51 (19.5%) were primary BSIs. Rates of resistance board approvals. Only unique adult (Ͼ18 years old) patient epi- to other antimicrobial agents were high. No resistance to group 2 sodes were included. BSIs were defined according to CDC and carbapenems was noted, but two cases (9.5%) were resistant to systemic inflammatory response syndrome (SIRS) criteria (11, 15). Polymicrobial infectious episodes were excluded. The time to initiation of appropriate therapy was captured in hours. Empir- Received 12 October 2011 Returned for modification 6 November 2011 ical regimens (antimicrobials administered from 48 h before to Accepted 15 January 2012 71 h after the culture) and consolidative regimens (antimicro- Published ahead of print 30 January 2012 bials administered 72 h to 14 days following the culture) were Address correspondence to Dror Marchaim, [email protected]. reviewed. Only drugs for which Ն2 doses were administered Copyright © 2012, American Society for Microbiology. All Rights Reserved. were included as treatment agents. Outcomes captured in- doi:10.1128/AAC.05913-11 cluded in-hospital and 3-month mortality, length of hospital 0066-4804/12/$12.00 Antimicrobial Agents and Chemotherapy p. 2173–2177 aac.asm.org 2173 Collins et al. TABLE 1 Characteristics of patients with bloodstream infections due to TABLE 1 (Continued) ESBL-producing Enterobacteriaceaea Parameter and characteristic Value (%)b b Parameter and characteristic Value (%) Empirical therapy Demographic information Penicillinsc 42 (16.1) Age (yr) (mean Ϯ SD) 65.5 Ϯ 16.1 Cephalosporins 157 (60.2) Elderly (Ն65 years) 140 (53.6) Monobactam 14 (5.4) Female 124 (47.5) Ertapenem 28 (12.6) African American 202 (78.6) Group 2 carbapenems 106 (42.5) Fluoroquinolones 27 (10.3) Source of bloodstream infection Glycopeptides 122 (46.7) Central line associated 52 (19.9) Tetracyclines 18 (6.9) Urinary tract infection 108 (41.4) Polymyxins 5 (1.9) Pneumonia 33 (12.6) Aminoglycosides 41 (15.8) Intra-abdominal 24 (9.2) TMP-SMX 8 (3.1) Skin and soft-tissues, surgical sites, joints, and bones 31 (11.9) Daptomycin 7 (2.7) Linezolid 14 (5.4) Infection strain Macrolides 9 (3.4) Klebsiella pneumoniae 128 (49) Clindamycin 8 (3.1) Escherichia coli 133 (51) Metronidazole 40 (15.4) Rifampin 4 (1.5) Median MIC (IQR) Ertapenem 0.12 (0.06–0.5) Main therapy Piperacillin-tazobactam 11 (4.2) Drug resistance Cephalosporins 29 (11.2) Ertapenem 2 (9.5) Cefepime 13 (5) Colistin 0 (0) Ertapenem 72 (27.8) Tigecycline 0 (0) Group 2 carbapenems 132 (51) Cefepime 252 (96.6) Fluoroquinolones 10 (3.9) Gentamicin 167 (64) Tetracyclines 12 (4.6) Tobramycin 207 (79.3) Polymyxins 8 (3.1) Ciprofloxacin 203 (79.3) Aminoglycosides 26 (10) TMP-SMX 165 (65.3) TMP-SMX 13 (5) Status at admission Outcomes Dependent functional status 161 (61.7) In-hospital mortality 69 (26.4) Rapidly fatal McCabe score 60 (23.0) 90-day mortality 85 (38.3) Diabetes mellitus 129 (49.4) Functional status deterioration compared to 80 (41.2) Chronic renal disease 65 (24.9) preinfection status Pulmonary disease 70 (26.8) Discharged to LTCF after being admitted from 40 (18.0) Congestive heart failure 101 (38.7) home Neurologic disease 84 (32.2) Additional hospitalizations within 6 months of 126 (49.8) Dementia 70 (26.8) isolation Malignancy 56 (21.5) Invasive procedures within 3 months of isolation 117 (45.3) AIDS 4 (1.5) Bacteriological failured 106 (40.6) Median Charlson’s weighted index comorbidity 4 (0–12) Median total LOS (days) (IQR) 14 (7–24.75) score (range) Median LOS after isolation excluding those who 10 (7–16.5) Median Charlson’s combined condition score 6 (0–17) died early (days) (IQR) (range) a Charlson’s 10-year survival probability (%) and 2 (0–98) Data are from patients at the Detroit Medical Center between January 2005 and July 2010. IQR, interquartile range; TMP-SMX, trimethoprim-sulfamethoxazole; LTCF, median (range) long-term care facility; LTAC, long-term acute care facility; LOS, length of hospital stay; Major immunosuppressive state 55 (21.1) ICU, intensive-care unit; ESBL, extended-spectrum ␤-lactamase. b Values in parentheses are percentages unless otherwise noted. The percentages are Exposure to health care setting calculated with the missing data excluded. Admitted from LTCF 141 (54.0) c Including ␤-lactam/␤-lactamase inhibitor combinations. Regular visits to hemodialysis unit 65 (24.9) d Additional isolations of the same type of ESBL-producing bacteria in the 3 months ICU stay 3 months prior to ESBL isolation 120 (46) following index isolation. Severity of illness indices at time of ESBL isolation Impaired consciousness 163 (62.5) ertapenem (9). Sixty-nine patients died in the hospital (26.4%), Severe sepsis/septic shock/multiorgan failure 80 (30.8) and 85 patients died within 90 days (38.3%). In multivariate anal- Antimicrobial therapy ysis, in-hospital mortality was significantly lower among patients