Clinicians are Choosing Older, Generic Antibiotics Over Newer Ones for Gram-Negative Infections

Utilization of some next-generation antibiotics, including meropenem–vaborbactam, eravacycline, imipenem–cilastatin–relebactam, and cefiderocol was considered lowed in terms of prescribing practices.

Clinicians in US hospitals treated more than 40% of patients battling highly resistant, gram-negative infections exclusively with older, generic antimicrobials.

This data comes from a large retrospective cohort study published in the Annals of Internal Medicine, and investigators found that despite the FDA approval for 7 new gram-negative antibiotics between 2014 and 2019, found the preference was older, generic antimicrobials. Additionally, nearly 80% of the time these older agents are already known to be highly toxic or sub-optimally effective.¹

In a previous interview with Contagion, Sameer S. Kadri, MD, MS, FIDSA, intensivist and head, Clinical Epidemiology Section, Critical Care Medicine Department, National Institutes of Health Clinical Center, and coauthor of the study, explained why some providers might be more comfortable prescribing well-established antibiotics and even using ones that could be potentially toxic like colistin and aminoglycosides.²

“I think there was a degree of comfort level with some of the older agents, even though they were toxic, when there was no agent available as an alternative. Now that there are agents available, I think, there is evidence in the form of trials that have led to the approval of these novel agents,” Kadri said. “But you know, there's not that much representation of patients with highly-resistant pathogens in some of those trials, and that does result in a little bit of uneasiness around whether the evidence is generalizable to the patients with highly-resistant pathogens.”²

Kadri says one of the key takeaways to overcoming this reticence of clinicians for these newer agents is susceptibility testing.

“I think an important factor is that hospitals that opted for testing susceptibility against these novel agents tended to [have] greater use of these novel agents,” Kadri said. “It's a reminder that there needs to be wider implementation of susceptibility testing capabilities across the country against novel agents that are released, so that clinicians like myself feel confident that the drug that we're using in our patients actually works.”²

Study Parameters and Results
Investigators looked at 619 hospitals with data collected between January 2016 and June 2021. Investigators reviewed prescribing trends from a large administrative database to determine inpatient use patterns of recently approved gram-negative antibiotics.

Specifically, they looked at ceftazidime–avibactam, ceftolozane–tazobactam, meropenem–vaborbactam, plazomicin, eravacycline, imipenem–relebactam–cilastatin, and cefiderocol. Of that group, the investigators reported that ceftolozane–tazobactam and ceftazidime–avibactam, the 2 first “next-generation” b-lactam/b-lactamase inhibitor antibiotics approved by the FDA, had the largest increase in use between 2016 and 2019.¹

However, utilization of other next-generation antibiotics, including meropenem–vaborbactam, eravacycline, imipenem–cilastatin–relebactam, and cefiderocol was much lower, with no documented use of plazomicin (the manufacturer of which latter filed for bankruptcy).¹

Clinical Considerations Around Stewardship
One of the ongoing considerations is balancing the approval of new antimicrobials vs stewardship, especially as the latter’s overarching goal is to elongate the life of individual antibiotics and to reduce antimicrobial resistance (AMR).

An accompanying editorial in the journal discussed this very issue and provided a reminder of the scope and concern of antimicrobial resistance beginning with an estimated 1.2 million deaths globally per year caused by AMR. The authors pointed to the time it takes to get an antibiotic to market—10 to 15 years and can cost up to a $1 billion.³

They point out that it is important to ensure that new antibiotics are not only being developed but also effectively used.

“Continued efforts to raise awareness, innovation in pathogen-specific trials, regularly updated AMR guidance, patient-centered end points, and rapid susceptibility testing will be key to appropriate and optimal use of these new antibiotics,” the authors concluded.³

References
1. Strich J, Mishuk A, Diao G, et al. National Institutes of Health Antimicrobial Resistance Outcomes Research Initiative. Assessing Clinician Utilzation of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals: A Retrospective Cohort Study. Ann Intern Med. [Epub 19 April 2024]. doi:10.7326/M23-2309

2. Parkinson J. Why is There Limited Use of Novel, Gram-Negative Antibiotics? Contagion. October 16, 2023. Accessed April 25, 2024.
https://www.contagionlive.com/view/why-is-there-limited-use-of-novel-gram-negative-antibiotics-

3. Howard-Anderson J, Boucher H. New Antibiotics for Resistant Infections: What Happens After Approval?. Ann Intern Med. [Epub 19 April 2024]. doi:10.7326/M24-0192