Cefepime versus Imipenem-Cilastatin for Treatment of Nosocomial Pneumonia in Intensive Care Unit Patients: a Multicenter, Evaluator-Blind, Prospective, Randomized Study

Abstract

In a randomized, evaluator-blind, multicenter trial, we compared cefepime (2 g three times a day) with imipenem-cilastatin (500 mg four times a day) for the treatment of nosocomial pneumonia in 281 intensive care unit patients from 13 centers in six European countries. Of 209 patients eligible for per-protocol analysis of efficacy, favorable clinical responses were achieved in 76 of 108 (70%) patients treated with cefepime and 75 of 101 (74%) patients treated with imipenem-cilastatin. The 95% confidence interval (CI) for the difference between these response rates (؊16 to 8%) failed to exclude the predefined lower limit for noninferiority of ؊15%. In addition, therapy of pneumonia caused by an organism producing an extendedspectrum ␤-lactamase (ESBL) failed in 4 of 13 patients in the cefepime group but in none of 10 patients in the imipenem group. However, the clinical efficacies of both treatments appeared to be similar in a secondary intent-to-treat analysis (95% CI for difference, ؊9 to 14%) and a multivariate analysis (95% CI for odds ratio, 0.47 to 1.75). Furthermore, the all-cause 30-day mortality rates were 28 of 108 (26%) patients in the cefepime group and 19 of 101 (19%) patients in the imipenem group (P ‫؍‬ 0.25). Rates of documented or presumed microbiological eradication of the causative organism were similar with cefepime (61%) and imipenem-cilastatin (54%) (95% CI, ؊23 to 8%). Primary or secondary resistance of Pseudomonas aeruginosa was detected in 19% of the patients treated with cefepime and 44% of the patients treated with imipenem-cilastatin (P ‫؍‬ 0.05). Adverse events were reported in 71 of 138 (51%) and 62 of 141 (44%) patients eligible for safety analysis in the cefepime and imipenem groups, respectively (P ‫؍‬ 0.23). Although the primary end point for this study does not exclude the possibility that cefepime was inferior to imipenem, some secondary analyses showed that the two regimens had comparable clinical and microbiological efficacies. Cefepime appeared to be less active against organisms producing an ESBL, but primary and secondary resistance to imipenem was more common for P. aeruginosa. Selection of a single agent for therapy of nosocomial pneumonia should be guided by local resistance patterns.

The continuing challenge of ESBLs

“…route) to be substantially better than cefepime (2g q8h by i.v. route) for treatment of nosocomial pneumonia among ICU-patients [84]. These results suggest that cefepime is not the optimal therapy in the treatment of ESBL-producing enterobacteria, particularly during serious infections (e.g., bacteremia and pneumonia).…”

The Use of Noncarbapenem β-Lactams for the Treatment of Extended-Spectrum β-Lactamase Infections

“…Results of observational studies comparing the activity of cefepime and carbapenems for invasive ESBL infections have been conflicting with some studies showing no difference [39,40] and others suggesting cefepime therapy is inferior [38,41,42] (Table 4). Lee and colleagues conducted an observational study including 17 patients with ESBL bacteremia receiving cefepime therapy and 161 patients receiving carbapenem therapy [42].…”

Consensus Guidelines for the Prevention and Treatment of Catheter-Related Infections and Peritonitis in Pediatric Patients Receiving Peritoneal Dialysis: 2012 Update

“…Furthermore, patients infected with ESBL-producing gram-negative bacteria have been found to experience more treatment failures and lethal outcomes than do patients with non-ESBL-producing E. coli. For that reason, cefepime, which can be used to treat infections secondary to certain ESBL-producing organisms (for example, those caused by AmpC enzyme-producing species such as Citrobacter and Enterobacter), has been prioritized over ceftazidime for empiric therapy in the present guidelines; however, carbapenems are recommended as the first choice for post-empiric antibiotic therapy of infections secondary to ESBL-producing bacteria, because those agents have generally shown superior clinical results in severe nosocomial infections (228). Alternatively, fluoroquinolones such as ciprofloxacin can be used-unless the antibiogram indicates resistance to multiple antibiotic classes.…”