Hospital uptake of newer antibiotics to treat multidrug-resistant gram-negative bacteria was low over a 5-year period, according to a retrospective cohort study.
Fully 41.5% of episodes of difficult-to-treat resistant (DTR) gram-negative infections were treated exclusively with older, generic agents, which were largely ones with suboptimal safety-efficacy profiles, Sameer Kadri, MD, of the National Institutes of Health Clinical Center in Bethesda, Maryland, and colleagues, reported in the Annals of Internal Medicine. The findings were also presented at the American College of Physicians meeting in Boston.
Use of new antibiotics gradually increased across the study period from January 2016 to June 2021, but gains were uneven across agents. The most commonly used next-generation antibiotics during that time frame were ceftolozane-tazobactam (Zerbaxa) and ceftazidime-avibactam (Avycaz).
Other more recently approved antibiotics -- cefiderocol (Fetroja), eravacycline (Fetroja), imipenem-cilastatin-relebactam (Recarbrio), and meropenem-vaborbactam (Vabomere) -- had more sluggish uptake, Kadri and colleagues wrote. And not even a single hospital used plazomicin (Zemdri) after its FDA approval in 2018 for complicated gram-negative urinary tract infections.
"The two most used 'new' antibiotics, ceftazidime-avibactam and ceftolozane-tazobactam, are themselves a decade old and have largely occupied the carbapenem-resistant Enterobacterales and multidrug-resistant [Pseudomonas] aeruginosa niches," the authors wrote. "On the other hand, the five subsequently approved gram-negative antibiotics with partially overlapping pathogen spectrums were markedly underutilized."
Of concern, 79.3% of DTR gram-negative infections were treated with traditional agents known to have suboptimal safety or efficacy, such as polymyxins, aminoglycosides, tigecycline, and chloramphenicol.
"Given the high mortality risk associated with DTR infections, such treatment gaps could risk patient lives," Kadri's group wrote.
They suggested policy change: "Few overall treatment opportunities in the U.S. market and sluggish utilization trajectories for recently approved antibiotics observed in our study reinforce the need for pull incentives," such as subscription models for new antibiotics piloted in the United Kingdom, they suggested, pointing to the PASTEUR bill as a potential solution to provide that funding.
"Why are these next-generation antibiotics not being used more often?" wrote Jessica Howard-Anderson, MD, of Emory University School of Medicine in Atlanta, and Helen Boucher, MD, of Tufts Medical Center in Boston. "Antimicrobial stewardship is frequently cited -- however, this represents a fundamental misunderstanding of stewardship, which aims to use the right drug, for the right patient, at the right time," they wrote in an accompanying editorial.
Cost may be one factor, the editorialists posited. Mean wholesale price for a day's dosage averaged across the seven new antibiotics noted in the study was $1,036.69 versus $173.41 for traditional agents.
Another factor may be that clinical trials that evaluated the new antibiotics did not always enroll patients that would need the drugs in practice, Howard-Anderson and Boucher wrote. "Clinicians are therefore left wondering whether these new antibiotics are applicable to their patients."
The study analyzed inpatient admissions from a large retrospective administrative database. Between January 2019 and June 2021, 362,142 inpatient encounters occurred across 299 hospitals that indicated one or more cultures with a gram-negative organism. Of these, 0.7% (2,551) were hospitalizations for DTR gram-negative infections. Overall, the DTR infection prevalence among hospitalized patients was 72.7 episodes per 10,000 inpatient encounters.
P. aeruginosa was the most common DTR pathogen, occurring in 48.2% of infections, followed by Acinetobacter baumannii complex (22%). Enterobacterales species accounted for 23% of infections and other gram-negative pathogens accounted for the remaining 6.8%. Of DTR infections, 42.9% were respiratory tract infections and 8.36% were bloodstream infections.
Several patient factors were associated with increased probability of being one of the 58.8% who were treated with newer, next-generation antibiotics. DTR bloodstream infection was a big factor, with newer agents used for about 72% of these compared with 57% of non-bloodstream infections. Patients presenting with do-not-resuscitate status, acute liver failure, and with pathogenic A. baumannii complex or infections caused by other non-pseudomonal non-fermenters were less likely to receive newer antibiotics.
However, age, gender, race/ethnicity, and ICU admissions were not associated with the probability of receiving newer versus traditional antibiotics, nor were mechanical ventilation or presentation at the hospital with neurologic, renal, or respiratory failure.
Of 299 study hospitals, 107 did not prescribe any of the newer antibiotics for DTR infections over the study period. However, only 3.9% of all DTR episodes occurred in the non-prescribing hospitals, most of which were relatively small, with fewer than 100 beds.
Researchers also found that geographical region mattered. For example, in the Midwest, the marginally adjusted probability of hospitals using newer antibiotics was about 61% versus 34% in the Western states. Also, hospitals that reported susceptibility of the infection to newer agents were more likely to use those agents (60% vs 54% for those with no reporting of susceptibility to the agents). However, urban location, teaching status, and technological or bed capacity did not appear to affect patients' probability of receiving newer antibiotics.
Hospital bed capacity was "the strongest factor associated with nonuse" of newer agents: hospitals with fewer than 100 beds had a 28% probability of using new antibiotics, whereas those with 300 or more beds had a 95% probability of using new antibiotics. In particular, smaller rural hospitals and smaller urban hospitals with low baseline prevalence of antibiotic resistance were less likely to use newer antibiotics.
At baseline, the median age of patients with DTR gram-negative infections was 61 years, 58.5% were men, and 49.1% were non-Hispanic whites. The median Elixhauser Comorbidity Index was 5. About one-third of patients were admitted to the ICU, 22.2% required mechanical ventilation, and 17.6% needed vasopressors. Approximately one in five patients with DTR gram-negative infections died. Mortality was higher in patients with DTR bloodstream infections (32%) compared with a 20% mortality rate among those without bloodstream infections.
"The study did have limitations," Howard-Anderson and Boucher cautioned, noting that "medical records were not reviewed to determine the rationale for antibiotic therapy or to determine if the antibiotic was intended to treat the DTR pathogen."
Also, the study didn't cover a period recent enough to have seen the full effects of Infectious Diseases Society of America guidelines on antimicrobial resistance first published in September 2020, they added.
Disclosures
The study was funded by the FDA Center for Drug Evaluation and Research.
Kadri reported no ties to industry. One study served on a clinical advisory board for Beckman Coulter.
Howard-Anderson and Boucher reported no relationships with industry.
Primary Source
Annals of Internal Medicine
Source Reference: Strich JR, et al "Assessing clinician utilization of next-generation antibiotics against resistant gram-negative infections in U.S. hospitals" Ann Intern Med 2024; DOI: 10.7326/M23-2309.
Secondary Source
Annals of Internal Medicine
Source Reference: Howard-Anderson J, Boucher HW "New antibiotics for resistant infections: What happens after approval?" Ann Intern Med 2024; DOI: 10.7326/M24-0192.
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