Reduction strategies for inpatient oral third-generation cephalosporins at a cancer center: An interrupted time-series analysis

PLOS ONE RESEARCH ARTICLE Reduction strategies for inpatient oral thirdgeneration cephalosporins at a cancer center: An interrupted time-series analysis Naoya Itoh ID1,2*, Takanori Kawabata3, Nana Akazawa ID2, Daichi Kawamura2, Hiromi Murakami2, Yuichi Ishibana2, Eiichi N. Kodama ID4, Norio Ohmagari1,5,6 a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 1 Collaborative Chairs Emerging and Reemerging Infectious Diseases, National Center for Global Health and Medicine, Graduate School of Medicine, Tohoku University, Miyagi, Japan, 2 Division of Infectious Diseases, Aichi Cancer Center Hospital, Nagoya, Japan, 3 Department of Data Science, National Cerebral and Cardiovascular Center, Suita, Japan, 4 Division of Infectious Diseases, International Research Institute of Disaster Science, and Graduate School of Medicine, Tohoku University and Tohoku Medical Megabank Organization, Sendai, Japan, 5 AMR Clinical Reference Center, Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan, 6 Disease Control and Prevention Center, National Center for Global Health and Medicine, Tokyo, Japan * Abstract OPEN ACCESS Citation: Itoh N, Kawabata T, Akazawa N, Kawamura D, Murakami H, Ishibana Y, et al. (2023) Reduction strategies for inpatient oral thirdgeneration cephalosporins at a cancer center: An interrupted time-series analysis. PLoS ONE 18(2): e0281518. https://doi.org/10.1371/journal. pone.0281518 Editor: Iddya Karunasagar, Nitte University, INDIA Received: September 28, 2022 Accepted: January 24, 2023 Published: February 9, 2023 Peer Review History: PLOS recognizes the benefits of transparency in the peer review process; therefore, we enable the publication of all of the content of peer review and author responses alongside final, published articles. The editorial history of this article is available here: https://doi.org/10.1371/journal.pone.0281518 Copyright: © 2023 Itoh et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Oral third-generation cephalosporins (3GCs) are not recommended for use owing to their low bioavailability and the risk of emergence of resistant microorganisms with overuse. A standardized and effective method for reducing their use is lacking. Here, in a 60-month, single-institution, interrupted time-series analysis, which was retrospectively conducted between April 1, 2017, and March 31, 2022, we evaluated the effectiveness of a four-phase intervention to reduce the use of 3GCs in patients at a cancer center: Phase 1 (pre-intervention), Phase 2 (review of clinical pathways), Phase 3 (establishment of infectious disease consultation service and implementation of antimicrobial stewardship program), and Phase 4 (educational lecture and pop-up displays for oral antimicrobials at the time of ordering). Although no significant changes were observed in Phases 3 and 4, the first intervention resulted in a significant decrease in the trend and level of days of therapy (DOT) for 3GCs. The level for cephalexin DOT and the trend for sulfamethoxazole-trimethoprim DOT increased in Phase 4, and the trend for amoxicillin and amoxicillin-clavulanate DOT increased in Phase 3. Macrolide DOT showed a decreasing trend in Phases 2 and 4 and decreasing and increased levels in Phases 3 and 4, respectively; no change was observed for quinolones. Actual and adjusted purchase costs of 3GCs decreased significantly during all study periods, while those for oral antimicrobials decreased in Phase 2, and actual purchase costs increased in Phases 3 and 4. No significant reduction in resistant organisms, length of hospital stay, or mortality was observed. This is the first study on the effects of oral 3GC reduction strategies in patients with cancer. We conclude that even facilities that substantially use antimicrobials can efficiently reduce the use of 3GCs. Data Availability Statement: All relevant data are within the manuscript and its Supporting Information files. PLOS ONE | https://doi.org/10.1371/journal.pone.0281518 February 9, 2023 1 / 17 PLOS ONE Funding: This work was supported by grants from the National Academic Research Grant Funds [JSPS KAKENHI: 22K10547] and the Aichi Cancer Research Foundation. The funder had no role in the study design, data collection, analysis, or manuscript preparation. Competing interests: The authors have declared that no competing interests exist. Impact of antimicrobial stewardship programs in reducing 3GC overuse Introduction The spread of drug-resistant bacteria is a serious global health threat [1]. In Japan, as in other countries, there is concern about the relationship between inappropriate use of antimicrobial agents and antimicrobial resistance [2]. Patients with cancer often receive multiple antimicrobial treatments following chemotherapy or surgery owing to the progression of the underlying disease or complications, resulting in substantial antimicrobial use [3, 4]. In patients with cancer, appropriate diagnosis and management of infections are often challenging because patients often present with subtle or atypical symptoms, and inappropriate antimicrobial use is frequent [3–5]. Therefore, there is an urgent need to address the increasing number of antimicrobial-resistant bacteria and prevent their occurrence in patients with cancer. A survey conducted from 2009 to 2013 in Japan reported that oral antimicrobial consumption accounted for 92.6% of the total antimicrobial consumption [6]. The consumption of oral third-generation cephalosporins (3GCs), macrolides, and fluoroquinolones was specifically higher in Japan than in the United States and European countries [6–8]. Japan announced the National Action Plan (NAP) for antimicrobial resistance in April 2016, with the specific goal of reducing the use of antimicrobials by 2020 [2]. In addition to total antimicrobial use, one of the targets established in the NAP was a 50% reduction in the use of oral 3GCs by 2020; however, the reduction rate of 3GCs in Japan at the time was only 36.39% [9]. Oral 3GCs are not widely recommended owing to several reasons. First, the selective pressure from the extensive use of oral antimicrobials in Japan, including 3GCs, may have led to the emergence of resistant bacteria [6]. Inappropriate use of oral 3GCs has been implicated as a cause for the higher proportion of β-lactamase-nonproducing ampicillin-resistant Haemophilus influenzae (BLNAR) and penicillin-resistant Streptococcus pneumoniae (PRSP) in Japan compared with that in European countries and the United States [2, 10–13]. In addition, extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae counts are increasing in Japan [14, 15], and Hosokawa et al. reported that the use of oral 3GCs is responsible for the increase in ESBL-producing Escheri (...truncated)