A Prospective Randomized Crossover Comparison Between Piperacillin/Tazobactam and Meropenem As Empirical Antibiotic Therapy for Febrile Neutropenia in Children with Hematological and Malignant Disorders
Authors: Sano Hirozumi , Kobayashi Ryoji , Suzuki Daisuke , Hori Daiki , Kobayashi Kunihiko 
Published: November 2019

Abstract
Background
Febrile neutropenia (FN) remains an important cause of morbidity and mortality in pediatric cancer patients. Although monotherapy using broad spectrum antibiotics is now a standard of care, there is currently no consensus on optimal agents. Carbapenems are effective and widely used in the treatment of FN; however, they have several disadvantages such as the risk of the emergence of drug-resistant bacteria. The usefulness of intravenous immunoglobulin (IVIG) for FN remains unclear. This randomized crossover study was designed to assess whether piperacillin/tazobactam (PIPC/TAZ) is as effective as meropenem (MEPM). We also evaluated the effectiveness of IVIG in combination with switched antibiotics as a second-line therapy.
METHODS
Febrile and neutropenic patients treated with conventional or high-dose chemotherapy at the Department of Pediatrics, Sapporo Hokuyu Hospital between April 2012 and March 2016 were included. As a first-line treatment, FN cases were randomized for treatment with either PIPC/TAZ (337.5 mg/kg/day in 3 portions, 1-hour DIV, maximum 13.5 g/day; arm PM) or MEPM (120 mg/kg/day in 3 portions, 1-hour DIV maximum 3 g/day, arm MP). Success was defined as (1) fever and clinical signs of infection resolving within 120 hours of the initiation of antibiotic therapy; and (2) no recurrence of infection/fever after the end of the treatment. Failure was defined as the persistence of fever and infectious signs more than 120 hours after the initiation of antibiotic therapy, a required change in the initial antibiotic therapy, or deterioration/death due to infection. FN cases judged as failures were registered for a second-line treatment, in which antibiotics were switched to another antibiotic (MEPM (arm PM) or PIPC/TAZ (arm MP)), and further randomized to be treated with or without IVIG at 100 mg/kg/day (maximum 5 g/day) for 3 consecutive days. The effects of the second-line therapy were evaluated 72 hours after its initiation. The Institutional Review Board of the hospital approved our project, and written informed consent was obtained from all patients or their parents.
RESULTS A total of 434 febrile episodes in 105 patients (42 females and 63 males) with a median age of 8 years (range, 0-25) were enrolled for the first-line therapy. During the study period, 26 patients underwent hematopoietic stem cell transplantation (HSCT). Blood cultures were positive in 47 out of 434 episodes (10.8%) and the leading cause of bacteremia was a-streptococcus (25.5%). Regarding responses to the first-line treatment, success rates between the PIPC/TAZ and MEPM groups were similar (62.4% vs 65.9%, P=0.484), even if patients were restricted to those with bacteremia (26.1% vs 37.5%, P=0.534). Mortality rates did not significantly differ between the two groups (0.8% vs 0%, P=0.500). A total of 144 febrile episodes in 71 patients (29 females and 42 males) with a median age of 11 years (range, 0-25) were enrolled for the second-line therapy. During the study period, 20 patients underwent HSCT. Success rates did not significantly differ between cases treated with PIPC/TAZ (switched from MEPM, with and without IVIG; arm MP) and with MEPM (switched from PIPC/TAZ, with and without IVIG; arm PM) (55.3% vs 44.3%, P=0.936). Cases treated with IVIG had slightly better success rates than those without IVIG (58.7% vs 41.9%, P= 0.064). When cases were restricted to those with IgG <500 mg/dl at the beginning of the second-line therapy, success rates were significantly better in cases with IVIG than in those without (81.8% vs 38.5%, P=0.047). No significant differences were observed in total success rates between arm PM (PIPC/TAZ followed by MEPM) and arm MP (MEPM followed by PIPC/TAZ) (57.7% vs 63.4%, P=0.174). The rates of adverse events in the first- and second-line therapies were not significantly different between the two groups.
DISCUSSION
This study demonstrated that PIPC/TAZ and MEPM were effective and safe as empirical therapies for FN. Therefore, we concluded that these agents are equally effective. Large numbers of cases with treatment failure after MEPM may be rescued by PIPC/TAZ and vice versa. Carbapenems are now more widely used in the treatment of FN; however, this may increase the prevalence of drug-resistant bacteria, and, thus, the use of PIPC/TAZ for neutropenic children is favorable. In addition, the concomitant use of IVIG needs to be considered for patients with low serum IgG values.

Disclosures
No relevant conflicts of interest to declare.