• Jeffrey R Strich, Ahmed Mishuk, Guoqing Diao, Alexander Lawandi, Willy Li, Cumhur Y Demirkale, Ahmed Babiker, Alex Mancera, Bruce J Swihart, Morgan Walker, Christina Yek, Maniraj Neupane, Nathaniel De Jonge, Sarah Warner, Sameer S Kadri, and National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative.
• Critical Care Medicine Department, Clinical Center, National Institutes of Health, Bethesda; and Critical Care Medicine Branch, National Heart, Lung, and Blood Institute, Bethesda, Maryland (J.R.S., A.Mishuk, C.Y.D., A.Mansera, B.J.S., M.W., C.Y., M.N., S.W., S.S.K.).
• Ann. Intern. Med. 2024 Apr 19.

BackgroundThe U.S. antibiotic market failure has threatened future innovation and supply. Understanding when and why clinicians underutilize recently approved gram-negative antibiotics might help prioritize the patient in future antibiotic development and potential market entry rewards.ObjectiveTo determine use patterns of recently U.S. Food and Drug Administration (FDA)-approved gram-negative antibiotics (ceftazidime-avibactam, ceftolozane-tazobactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-relebactam-cilastatin, and cefiderocol) and identify factors associated with their preferential use (over traditional generic agents) in patients with gram-negative infections due to pathogens displaying difficult-to-treat resistance (DTR; that is, resistance to all first-line antibiotics).DesignRetrospective cohort.Setting619 U.S. hospitals.ParticipantsAdult inpatients.MeasurementsQuarterly percentage change in antibiotic use was calculated using weighted linear regression. Machine learning selected candidate variables, and mixed models identified factors associated with new (vs. traditional) antibiotic use in DTR infections.ResultsBetween quarter 1 of 2016 and quarter 2 of 2021, ceftolozane-tazobactam (approved 2014) and ceftazidime-avibactam (2015) predominated new antibiotic usage whereas subsequently approved gram-negative antibiotics saw relatively sluggish uptake. Among gram-negative infection hospitalizations, 0.7% (2551 [2631 episodes] of 362 142) displayed DTR pathogens. Patients were treated exclusively using traditional agents in 1091 of 2631 DTR episodes (41.5%), including "reserve" antibiotics such as polymyxins, aminoglycosides, and tigecycline in 865 of 1091 episodes (79.3%). Patients with bacteremia and chronic diseases had greater adjusted probabilities and those with do-not-resuscitate status, acute liver failure, and Acinetobacter baumannii complex and other nonpseudomonal nonfermenter pathogens had lower adjusted probabilities of receiving newer (vs. traditional) antibiotics for DTR infections, respectively. Availability of susceptibility testing for new antibiotics increased probability of usage.LimitationResidual confounding.ConclusionDespite FDA approval of 7 next-generation gram-negative antibiotics between 2014 and 2019, clinicians still frequently treat resistant gram-negative infections with older, generic antibiotics with suboptimal safety-efficacy profiles. Future antibiotics with innovative mechanisms targeting untapped pathogen niches, widely available susceptibility testing, and evidence demonstrating improved outcomes in resistant infections might enhance utilization.Primary Funding SourceU.S. Food and Drug Administration; NIH Intramural Research Program.

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