Needs assessment for novel Gram-negative antibiotics in US hospitals: a retrospective cohort study.
Journallancet infectious diseases24.446Date
2020 Jun 04
5 months ago
Research Support, U.S. Gov't, P.H.S.
Research Support, N.I.H., Intramural
Journal Article
2020-10 / 20 : 1172-1181
Strich JR 1, Warner S 2, Lai YL 3, Demirkale CY 2, Powers JH 4, Danner RL 2, Kadri SS 2
  • 2. Critical Care Medicine Department, National Institutes of Health Clinical Center, Bethesda, MD, USA.
  • 3. Epidemiology Unit, Division of Intramural Research, National Institute of Allergy and Infectious Disease, Frederick, MD, USA.
  • 4. Clinical Research Directorate/Clinical Monitoring Research, Leidos Biomedical Research, National Cancer Institute Campus, Frederick, MD, USA.
Anti-Bacterial Agents
Cohort Studies
Disease Outbreaks
Gram-Negative Bacteria
Gram-Negative Bacterial Infections
Microbial Sensitivity Tests
Needs Assessment
Retrospective Studies
United States
BACKGROUND: Evidence-based needs assessments for novel antibiotics against highly-resistant Gram-negative infections (GNIs) are scarce. We aimed to use real-world data from an electronic health record repository to identify treatment opportunities in US hospitals for GNIs resistant to all first-line drugs.
METHODS: For this retrospective cohort study, population estimates with an unmet need for novel Gram-negative antibiotics were quantified using the Cerner Health Facts database (2009-15), aggregating episodes of infection in US hospitals with pathogens displaying difficult-to-treat resistance (DTR; resistance to carbapenems, other β-lactams, and fluoroquinolones) and episodes involving empirical coverage with reserve drugs (colistin or polymyxin B and aminoglycosides). Episodes displaying extended-spectrum cephalosporin resistance (ECR) were also estimated. Episodes were multiplied by site-specific and fixed 14-day treatment durations for conservative and liberal days-of-therapy (DOT) estimates and stratified by site and taxon. Hospital type-specific DOT rates were reliability adjusted to account for random variation; cluster analyses quantified contribution from outbreaks.
FINDINGS: Across 2 996 271 inpatient encounters and 134 hospitals, there were 1352 DTR-GNI episodes, 1765 episodes involving empirical therapy with colistin or polymyxin B, and 16 632 episodes involving aminoglycosides. Collectively, these yielded 39·0 (conservative estimate) to 138·2 (liberal estimate) DOT per 10 000 encounters for a novel DTR-GNI-targeted drug, whereas greater treatment opportunities were identified for ECR (six times greater) and β-lactam susceptible GNIs (70 times greater). The most common DTR-GNI site and pathogen was lower respiratory (14·3 [43·3%] of 33 DOT per 10 000 encounters) and Pseudomonas aeruginosa (522 [38·1%] of 1371 episodes), whereas Enterobacteriaceae urinary-tract infections dominated the ECR or carbapenem-sparing niche (59·0% [5589 of 9535 episodes]) equating to 210·7 DOT per 10 000 encounters. DTR Stenotrophomonas maltophilia, Burkholderia spp, and Achromobacter spp represented less than 1 DOT per 10 000 encounters each. The estimated need for DTR-GNI-targeted antibiotics saw minor contributions by outbreaks and varied from 0·5 to 73·1 DOT per 10 000 encounters by hospital type.
INTERPRETATION: Suspected or documented GNIs with no or suboptimal treatment options are relatively infrequent. Non-revenue-based strategies and innovative trial designs are probably essential to the development of antibiotics with improved effectiveness for these GNIs.
FUNDING: Center for Drug Evaluation and Research, US Food and Drug Administration; Intramural Research Program, National Institutes of Health Clinical Center and the National Institute of Allergy and Infectious Diseases and the National Cancer Institute.
Lancet Infect Dislancet infectious diseases
LocationUnited States

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