Why is There Limited Use of Novel, Gram-Negative Antibiotics?

In recent years there has been the FDA approval of novel gram-negative antibiotics, but they have not seen the adoption of use that might be associated with the introduction of newer therapies that can help treat difficult infections.

A new study confirms the limited usage of these antibiotics at hundreds of hospitals through a large database. The results were reported at IDWeek 2023.

“At 619 hospitals, while colistin use declined between 2016Q1 and 2021Q2, post-approval use grew variably for each novel agent); compared to the first novel anti–Klebsiella pneumoniae carbapenemase (KPC) agent ceftazidime-avibactam (approved 2015), usage was relatively sluggish for subsequently approved anti-KPC-agents meropenem-vaborbactam and imipenem-cilastatin-relebactam and zero for plazomicin,” the investigators wrote. “At 302 microbiology reporting hospitals, 44.4% of 2830 overall difficult-to-treat resistance (DTR) cases including 70.2% of 627 DTR-A baumannii cases received only older/reserve agents.”

“[Antibiotics] that have overlapping spectrums are not really being utilized that much—so that was the first key observation,” 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 said. “The other finding that is worth noting is we looked in the subset of patients who have difficult to treat gram negative infections…So it's a practical bedside definition for a clinician saying, ‘do I have one safe and effective drug to treat this patient and if not, it's difficult to treat.’ This also seems to be the unique niche that potentially a novel agent may come to the market and might be used by clinicians, because there are no other good options. And so we said, 'this seems like an appropriate population within this population.'”

“Nearly half the patients in US hospitals with DTR-GNIs are still receiving targeted therapy with older/reserve agents. While the value of novel agents is indicated by clinicians preferring them over older/reserve agents in sicker patients, future agents with distinctly novel mechanisms and activity against DTR-A baumannii are needed to bridge the utilization gap,” the investigators wrote.

Kadri says that medical providers appear to go the route of prescribing well-established antibiotics and even using ones that could be potentially toxic like colistin and aminoglycosides.

“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.”

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.”

Click here for more coverage of IDWeek 2023.

REFERENCE

Strich J, Mishuk A, et al. Why has Utilization of Novel Gram-negative Antibiotics been Sluggish in U.S. Hospitals? A Retrospective Cohort Study to Inform Future Antibiotic Development and Market Entry Rewards. Presented at: IDWeek 2023. October 11-14, 2023; Boston, MA. Abstract 1110.