Methicillin-resistant Staphylococcus aureus (MRSA) is the most detected drug-resistant organism in Japan. MRSA is sometimes one of the normal flora on the skin and in the nasal cavity. It can cause severe infections, such as pneumonia and bloodstream infections in immunocompromised patients. In bloodstream infections, MRSA is the most detected drug-resistant bacteria. However, in recent years, its detection rate has declined due to infection control and appropriate use of antimicrobial agents. In the past ten years, however, community-acquired MRSA (CA-MRSA) has emerged as a global problem, and USA-300, which produces panton valentine leukocidin (PVL) and causes severe conditions as necrotizing pneumonia, has been reported in North America. In Japan, however, the proportion of PVL-positive CA-MRSA is low, and CA-MRSA may be sensitive to antibacterial agents other than beta-lactams. MRSA bloodstream infections have a high mortality rate, and some studies have shown the benefit of combination therapy with anti-MRSA agents and other agents.

Therefore, combination therapy of anti-MRSA agents with sensitive antimicrobial agents may be a treatment option for bloodstream infections caused by CA-MRSA. However, from the viewpoint of the appropriate use of antimicrobial agents, it is desirable to confirm that the drugs used in combination with anti-MRSA agents are sensitive to the detected MRSA before use. At present, the use of mass spectrometry (MALDI-TOF/MS) and fully automated genetic testing has made it possible to identify MRSA more rapidly than the conventional method of culture testing. However, there is also the problem that it is not possible to detect drug resistance genes comprehensively. Recently, with the advent of next-generation sequencing, whole-genome sequencing (WGS) can be performed more quickly and easily than before. WGS data can be used not only for the comprehensive detection of drug resistance genes but also for identifying genotypes and pathogenic factors, making it a useful microbiological test. However, there are many issues to be solved before implementing WGS as a routine microbiological test. Therefore, it is important to conduct various verifications, such as detection of drug-resistant genes by WGS and comparison with drug susceptibility tests.

In June 2015, febrile neutropenia was approved as an additional indication for tazobactam/piperacillin (ZOSYN®).A special drug use-results survey was performed between February 2016 and February 2019 to investigate the clinical safety and efficacy of this drug in patients with febrile neutropenia who had non-hematopoietic malignant tumors. A total of 220 patients from 101 institutions nationwide who were at least 15 years old at the beginning of administration were enrolled in the study, and safety and efficacy assessments were performed on 201 and 199 patients, respectively.

Among the 201 patients, adverse drug reactions (ADRs) were found in 19 patients (19 cases), with an incidence rate of ADRs being 9.5% (19/201 patients).ADRs occurring in two or more patients included diarrhea (8 patients, 4.0%) and blood creatinine increased (2 patients, 1.0%).Lung disorder as a serious ADR was found in one patient. All other ADRs were non- serious. Grade 3 ADRs included hypertension (one patient), lung disorder (one patient), and transaminase increased (one patient);all other ADRs were of Grade 2 or less. Hypertension as an ADR not expected from the “Precautions” section of the package insert occurred in one patient. All cases of ADRs recovered or improved.

There were no ADRs specific to patients with febrile neutropenia who had non- hematopoietic malignant tumors in comparison to those reported in the previous clinical studies, including a clinical study on ZOSYN® performed prior to approval of febrile neutropenia as an additional indication for this drug and a special drug use-results survey of patients with previously approved indications. Thus, no new safety concerns were identified.

Among the 185 patients in whom the clinical efficacy was assessed, the response rate was 95.7% (177/185 patients), which was consistent with the results of previous clinical studies and special drug use-results surveys.

This study revealed the favorable safety and efficacy of ZOSYN® in patients with febrile neutropenia who had non-hematopoietic malignant tumors, indicating that the drug is a useful empiric treatment for febrile neutropenia, as is recommended by Practical Guideline of Febrile Neutropenia.