By Richard R. Watkins, MD, MS, FACP, FIDSA, FISAC
Professor of Medicine, Northeast Ohio Medical University, Rootstown, OH
SYNOPSIS: A retrospective cohort study on adult inpatients with difficult-to-treat resistant pathogens found clinicians used older, generic antibiotics with suboptimal safety profiles in almost 80% of cases.
SOURCE: Strich JR, Mishuk A, Diao G, et al. Assessing clinician utilization of next-generation antibiotics against resistant gram-negative infections in U.S. hospitals: A retrospective cohort study. Ann Intern Med 2024;177:559-572.
The ongoing spread of antibiotic resistance in gram-negative pathogens threatens to derail the spectacular advances of modern medicine. The pharmaceutical industry has responded by bringing to market eight antibiotics in the last 10 years that are active against multidrug-resistant gram-negative bacteria. However, the use of these agents by clinicians has been low. Strich and colleagues sought to determine inpatient use patterns for newer gram-negative antibiotics as well as the factors associated with their selection over older alternatives.
The study was a retrospective cohort analysis that included data from 619 hospitals collected between January 2016 and June 2021. The investigators classified gram-negative pathogens as “difficult-to-treat resistance” (DTR) if they were resistant to penicillins, cephalosporins, carbapenems, traditional beta-lactam/beta-lactamase inhibitors like piperacillin-tazobactam, and fluoroquinolones. A linear model was constructed to assess patient and hospital factors associated with the preferred use of any newer antibiotic over a traditional one. The newer antibiotics were ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, plazomicin, eravacycline, imipenem-cilastatin-relebactam, and cefiderocol. Because sulbactam-durlobactam was approved in 2023, it was not included in the analysis.
Ceftolozane-tazobactam and ceftazidime-avibactam had the greatest increase in use overall. The use for the four subsequently approved antibiotics was stagnant. No use of plazomicin was found. This is not surprising since the company that developed plazomicin, Achaogen, went bankrupt almost immediately following Food and Drug Administration approval of the drug, which now is available in single uses from a specialty pharmacy. There were 2,222 patients with a DTR infection. The median age was 61 years, 58% were men, 33% were admitted to the intensive care unit, 22% required mechanical ventilation, and 18% received vasopressors. Overall mortality was 21% (469/2,222) and mortality for patients with a DTR bloodstream infection (BSI) was 32%. The most common DTR pathogen was Pseudomonas aeruginosa (48%), followed by Enterobacterales (23%) and Acinetobacter baumanii (22%). Lactose nonfermentors other than P. aeruginosa made up the remaining 7%.
The mean daily average wholesale price for the seven newer agents was $1,036, compared to $173 for 11 traditional agents. Seventy-three percent of DTR Enterobacterales and 68% of P. aeruginosa infections received new antibiotics compared to just 32% of DTR A. baumanii infections. BSIs were associated with the highest frequency of newer agent use (all > 50%) compared to other sites regardless of the causative pathogen.
Patient factors associated with a lower probability of receiving a newer antibiotic were having a do-not-resuscitate status on admission and acute liver failure. Hospitals that reported susceptibility against one or more newer agents had a higher probability for newer agent use compared to hospitals that did not (60% vs. 54%, respectively). At 107 of the 299 hospitals, no use of the newer agents was reported during the study time frame. Hospitals with fewer than 100 beds had a 28% probability of using newer agents compared to 95% among hospitals with 300 or more beds. This was the strongest characteristic associated with nonuse in the study. Finally, urban and rural hospitals with a low baseline level of antibiotic resistance also had a lower tendency to use the newer antibiotics.
COMMENTARY
Bringing new antibiotics to the clinic is a complicated and costly process. Even when a new agent gains approval, financial success remains uncertain. Indeed, the unfortunate example of plazomicin, in which the pharmaceutical company that developed it had to declare bankruptcy a year later, underscores how risky it can be for companies to invest in novel antibiotics. The findings reported by Strich and colleagues certainly will not allay the fears of scientists and pharmaceutical executives involved in antibiotic development. One small glimmer of hope is that reporting antibiotic susceptibility results for the newer agents was associated with increased use. Thus, making both rapid diagnostic testing and susceptibility testing more widely available may be one strategy to increase newer antibiotic usage.
Most often, the goal of antibiotic stewardship is to save the hospital money, rather than choosing the most effective and safe therapy for an individual patient. What Strich and colleagues termed traditional agents are known to have suboptimal efficacy and/or safety (e.g., polymyxins). For example, colistin use declined dramatically in the 1970s after other safer agents were developed. It saw a resurgence in use around 2016 as a result of the ongoing spread of multidrug-resistant A. baumanii, for which therapeutic options were very limited. Yet, colistin and other traditional agents are less costly than the newer antibiotics, which leads to their continued use in clinical practice. While there are no easy solutions, all clinicians must act ethically and responsibly by strongly advocating for the best therapy for their patients.
The study has a few limitations worth mentioning. First, the end of the study overlapped with the COVID-19 pandemic, which is known to have affected antibiotic prescribing. Second, medical records were not reviewed to determine the rationale for antibiotic selection. Third, because it was a retrospective cohort study, it may have been affected by unmeasured confounding variables. Finally, the hospitals included in the study were not located in all regions of the United States, thus limiting the generalizability of the results.
Despite the approval of newer antibiotics, they are not being fully used by clinicians even when they are available. While there is some evidence that newer antibiotics are superior to traditional ones for treating gram-
negative DTR infections, further randomized clinical trials are necessary to confirm these findings and to increase awareness of the benefits of the newer agents.1
REFERENCE
- van Duin D, Lok JJ, Earley M, et al. Colistin versus ceftazidime-avibactam in the treatment of infections due to carbapenem-resistant Enterobacteriaceae. Clin Infect Dis 2018;66:163-171.
