Assessing Clinician Utilization of Next-Generation Antibiotics Against Resistant Gram-Negative Infections in U.S. Hospitals : A Retrospective Cohort Study

Abstract

Background: The 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.

Objective: To 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).

Design: Retrospective cohort.

Setting: 619 U.S. hospitals.

Participants: Adult inpatients.

Measurements: Quarterly 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.

Results: Between 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.

Limitation: Residual confounding.

Conclusion: Despite 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 source: U.S. Food and Drug Administration; NIH Intramural Research Program.

Figure 1.. Trends in the use of DTR-active gram-negative antibiotics: 619 U.S. hospitals, January 2016 to June 2021.

DTR = difficult-to-treat resistance; Q1 = quarter 1; Q2 = quarter 2; Q3 = quarter 3; Q4 = quarter 4. Top and Middle. Raw quarterly trends of traditional gram-negative antibiotics with suboptimal safety–efficacy and new antibiotics, respectively. Bottom. Estimates of mean change in antibiotic use hospitalizations per 10 000 hospitalizations per quarter (points) and 95% CIs (horizontal lines) were obtained by weighted linear regression. Initial U.S. Food and Drug Administration (FDA) approval dates are displayed for each new agent. Ceftolozane–tazobactam trends were truncated in the model [bottom] for the period of nationwide shortage but retained for visualization in the middle panel. Note: No usage was identified for plazomicin, and infrequent usage of chloramphenicol precluded reporting of trends. Ceftolozane–tazobactam (approved 19 December 2014) and ceftazidime–avibactam (approved 25 February 2015) trends shown post-Q12016 (top) but modeled as commencing at zero use at time of FDA approval (middle).

Figure 1.. Trends in the use of DTR-active gram-negative antibiotics: 619 U.S. hospitals, January 2016 to June 2021.

DTR = difficult-to-treat resistance; Q1 = quarter 1; Q2 = quarter 2; Q3 = quarter 3; Q4 = quarter 4. Top and Middle. Raw quarterly trends of traditional gram-negative antibiotics with suboptimal safety–efficacy and new antibiotics, respectively. Bottom. Estimates of mean change in antibiotic use hospitalizations per 10 000 hospitalizations per quarter (points) and 95% CIs (horizontal lines) were obtained by weighted linear regression. Initial U.S. Food and Drug Administration (FDA) approval dates are displayed for each new agent. Ceftolozane–tazobactam trends were truncated in the model [bottom] for the period of nationwide shortage but retained for visualization in the middle panel. Note: No usage was identified for plazomicin, and infrequent usage of chloramphenicol precluded reporting of trends. Ceftolozane–tazobactam (approved 19 December 2014) and ceftazidime–avibactam (approved 25 February 2015) trends shown post-Q12016 (top) but modeled as commencing at zero use at time of FDA approval (middle).

Figure 2.. Cohort selection diagram.

DTR = difficult-to-treat resistance.

Figure 3.. Distribution of new versus traditional antibiotic use across key DTR pathogens.

Horizontal stacked bars display the proportional distribution of traditional (gray sections) and new (sections colored by agent) agent use among the 3 most common difficult-to-treat resistance (DTR) gram-negative taxa. Use of fosfomycin, trimethoprim–sulfamethoxazole, and nitrofurantoin is limited to genitourinary site infections.

Figure 4.. Interhospital variation in preference for new antibiotics adjusted for patient- and hospital-level factors.

Estimates represent odds ratios of new antibiotics use at individual hospitals compared with a hospital at median usage, arranged from lowest to highest. Horizontal bars represent corresponding 95% prediction intervals.