Doripenem Versus Meropenem For Empirical Antimicrobial Therapy In High Risk Febrile Neutropenic Patients With Hematological Malignancies: A Randomized, Controlled Trial
Authors: Fujisawa Yuka , Oyake Tatsuo , Mine Takahiro , Aoki Yusei , Tsukushi Yasuhiko , Sugawara Takeshi , Seguchi Masato , Hanamura Ichiro , Nakagawa Yasuaki , Murai Kazunori , Ito Shigeki , Ishida Yoji 
Published: October 2019

Background
Febrile neutropenia (FN) is often observed in the treatment of hematological malignancies including acute leukemia (AL). The pathogens of systemic infection are frequently unknown in FN patients. Carbapenem antibiotics are good candidates with a potent and broad antimicrobial activity against gram-positive and gram-negative bacteria including Pseudomonas aeruginosa. These antimicrobial agents are recommended to use early and sufficiently as empiric therapy for high-risk FN patients accompanied with profound neutropenia anticipated to > 7days. In the IDSA guideline published in 2010 on the use of antimicrobial agents in neutropenic patients, monotheapy with an anti-pseudomonal beta-lactam agent, such as cefepime (CFPM), meropenem (MEPM), imipenem-cilastatin (IPM) or piperacillin-tazobactam (TAZ/PIPC), is recommended as empiric therapy for high-risk FN patients. Several antimicrobial agents including MEPM, IPM or CFPM have been studied as empirical therapy for FN. However, limited data are available concerning the efficacy and safety of doripenem (DRPM), one of the carbapenem antibiotics, in FN with hematological malignancy.

Methods
We conducted a randomized, cooperative group, open-label trial comparing DRPM (1g, q8h IV) with MEPM (1g, q8h IV) as the first line empirical antimicrobial treatment for 165 hospitalized high-risk FN patients with AL (AML: n=90, APL: n=25, MDS-AML: n=13, ALL: n=35, ATL: n=2) during or after induction or consolidation chemotherapy (DRPM: n=83, MEPM: n=82). These study drugs were administered at least for 3 days without toxicity. The primary endpoint was response to treatment defined as complete defervescence by day 7 with improvement of infection-related symptoms and laboratory findings. We also evaluated the efficacy (resolution of fever by monotherapy at day 3 to 5, survival at day 30) and the safety of each drug, as a secondary endpoint.

Results
At the time of enrolment, there were no significant differences in the demographics or baseline characteristics, including as age, sex, body weight, underlying hematological malignancies, duration of initial antimicrobial therapy, median duration of severe neutropenia (neutrophil count < 100×106/L) and MASCC score, between the two groups. The response rate at day 7 was not significantly different between the two arms (DRPM: 75.8%, MEPM: 64.5% (p=0.14)). The resolution of fever by monotherapy at day 3 to 5 (DRPM: 58.6%, MEPM: 45.2% (p=0.10)), or survival at day 30 (DRPM: 97.6%, MEPM: 98.7% (p=0.33)) was not significantly different in the two groups. Adverse events were minimal in the two groups, and most of patients could continue the treatment by study drugs for 7days.

Conclusions
We could prove the non-inferiority of DRPM in comparison with MEPM for the initial treatment in FN patients with hematological malignancies. Both drugs were well tolerated as the first line empiric therapy for high-risk FN patients.

Disclosures:
No relevant conflicts of interest to declare.