title: Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial.
abstract: 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 × 10(6)/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).
authors.affiliation: Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan. Electronic address: nakane@med.osaka-cu.ac.jp.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Nakane
authors.affiliation: Department of Oncology, Hematology, and Infectious Diseases, Fukuoka University School of Medicine, Fukuoka, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Tamura
authors.affiliation: Hematology, Graduate School of Medicine, Osaka City University, Osaka, Japan.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Hino
authors.affiliation: Hematology Division, Rinku General Medical Center, Osaka, Japan.
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Tamaki
authors.affiliation: Hematologic Oncology, Shikoku Cancer Center, Ehime, Japan.
authors.forename: Isao
authors.initials: I
authors.lastname: Yoshida
authors.affiliation: Department of Hematology and Immunology, Kanazawa Medical University, Japan.
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Fukushima
authors.affiliation: Department of Hematology, Rheumatology, and Nephrology, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Youichi
authors.initials: Y
authors.lastname: Tatsumi
authors.affiliation: Department of Hematology, Japanese Red Cross Medical Center, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Hematology/Oncology, Wakayama Medical University, Wakayama, Japan.
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hatanaka
authors.affiliation: Department of Oncology/Hematology, Shimane University Hospital, Shimane, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Internal Medicine, Tokyo Metropolitan Bokutoh Hospital, Tokyo, Japan.
authors.forename: Nobu
authors.initials: N
authors.lastname: Akiyama
authors.affiliation: Department of Hematology, Okayama University School of Medicine, Okayama, Japan.
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
authors.affiliation: First Department of Internal Medicine, Tokyo Medical University, Tokyo, Japan.
authors.forename: Kazuma
authors.initials: K
authors.lastname: Ohyashiki
authors.affiliation: NTT Medical Center Tokyo, Tokyo, Japan.
authors.forename: Akio
authors.initials: A
authors.lastname: Urabe
authors.affiliation: Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Masaoka
authors.affiliation: Department of Internal Medicine, Kinki University School of Medicine, Osaka, Japan.
authors.forename: Akihisa
authors.initials: A
authors.lastname: Kanamaru
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents / Q000008:administration & dosage* / Q000009:adverse effects; D000077723:Cefepime; D002511:Cephalosporins / Q000008:administration & dosage* / Q000009:adverse effects; D064146:Chemotherapy-Induced Febrile Neutropenia / Q000188:drug therapy* / Q000382:microbiology; D015377:Cilastatin / Q000008:administration & dosage* / Q000009:adverse effects; D000077728:Cilastatin, Imipenem Drug Combination; D004338:Drug Combinations; D006801:Humans; D015378:Imipenem / Q000008:administration & dosage* / Q000009:adverse effects; D008297:Male; D000077731:Meropenem; D008875:Middle Aged; D011446:Prospective Studies; D013845:Thienamycins / Q000008:administration & dosage* / Q000009:adverse effects; D055815:Young Adult; D000097586:Cefozopran
chemical_list: D000900:Anti-Bacterial Agents; D000077723:Cefepime; D002511:Cephalosporins; D015377:Cilastatin; D000077728:Cilastatin, Imipenem Drug Combination; D004338:Drug Combinations; D015378:Imipenem; D000077731:Meropenem; D013845:Thienamycins; D000097586:Cefozopran
keywords: Cefepime; Cefozopran; Febrile neutropenia; Meropenem and imipenem–cilastatin; Randomized trial