Worldwide experience with the use of doripenem against extended-spectrum-beta-lactamase-producing and ciprofloxacin-resistant Enterobacteriaceae: analysis of six phase 3 clinical studies

Abstract

The worldwide increase in fluoroquinolone-resistant and extended-spectrum beta-lactamase (ESBL)-producing Enterobacteriaceae pathogens has led to doripenem and other carbapenems assuming a greater role in the treatment of serious infections. We analyzed data from 6 phase 3 multinational doripenem clinical trials on ciprofloxacin-resistant Enterobacteriaceae isolates consisting of all genera (CIPRE) and ESBL-producing Enterobacteriaceae isolates consisting of Escherichia coli, Klebsiella spp., and Proteus spp. with ceftazidime MICs of >or=2 microg/ml (ESBLE) for prevalence by geographic region and disease type, in vitro activities of doripenem and comparator agents, and clinical or microbiologic outcomes in doripenem- and comparator-treated patients across disease types (complicated intra-abdominal infection [cIAI], complicated urinary tract infection [cUTI], and nosocomial pneumonia [NP]). Of 1,830 baseline Enterobacteriaceae isolates, 88 (4.8%) were ESBLE and 238 (13.0%) were CIPRE. The incidence of ESBLE was greatest in Europe (7.8%); that of CIPRE was higher in South America (15.9%) and Europe (14.4%). ESBLE incidence was highest in NP (12.9%) cases; that of CIPRE was higher in cUTI (18.3%) and NP (14.9%) cases. Against ESBLE and CIPRE, carbapenems appeared more active than other antibiotic classes. Among carbapenems, doripenem and meropenem were most potent. Doripenem had low MIC(90)s for CIPRE (0.5 microg/ml) and ESBLE (0.25 microg/ml). Doripenem and comparators were highly clinically effective in infections caused by Enterobacteriaceae, irrespective of their ESBL statuses. The overall cure rates were the same for doripenem (82%; 564/685) and the comparators (82%; 535/652) and similar for ESBLE (73% [16/22] versus 72% [21/29]) and CIPRE (68% [47/69] versus 52% [33/64]). These findings indicate that doripenem is an important therapeutic option for treating serious infections caused by ESBLE and CIPRE.

Trial registration: ClinicalTrials.gov NCT00210938 NCT00210990 NCT00211003 NCT00211016 NCT00229021 NCT00229060.

FIG. 1.

MIC distributions of ESBLE (top panel) and CIPRE (bottom panel) for doripenem and comparator agents. ESBLE, extended-spectrum β-lactamase-producing Enterobacteriaceae isolates; CIPRE, ciprofloxacin-resistant Enterobacteriaceae isolates.