Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial.

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem–cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem–cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem–cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem–cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem–cilastatin compared with cefepime were −5.9% (95% confidence interval (CI): −20.1–8.4), −0.7% (95% CI: −14.6–13.3), and 5.7% (95% CI: −8.1–19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3–5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤100 × 106/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3–5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem–cilastatin compared with cefepime (clinical trial number: UMIN000000462).