The Lancet Infectious Diseases | Survival trends in patients with difficult-to-treat, antibiotic-resistant, Gram-negative infections in the era of next-generation antibiotics in the USA
Morgan K Walker, Christina Yek, Sadia Sarzynski, Sarah Warner, Prof Anthony D Harris, Jonathan D Baghdadi, et al.
DOI: 10.1016/S1473-3099(26)00020-4
Background
Difficult-to-treat resistant (DTR) Gram-negative infections show resistance to all first-line antibiotics (ie, β-lactams and fluoroquinolones) and have a 40% greater mortality rate than susceptible infections. New antibiotics with improved safety and efficacy and in-vitro activity against DTR infections are now available; however, their influence on patient outcomes remains unclear. This study aimed to evaluate whether and why mortality in patients with DTR infections has changed since the introduction of these newer antibiotics in the USA.
Methods
In this retrospective cohort study in the USA, adult patients (aged ≥18 years) with DTR Gram-negative infections were identified using the PINC-AI Healthcare Database. DTR infection was defined as microbiological evidence of DTR Enterobacterales, Pseudomonas aeruginosa, or Acinetobacter baumannii, along with receipt of at least 3 consecutive days of antibiotic therapy. The study characterised the proportion of inpatient encounters receiving newer DTR-active antibiotics, traditional DTR-active antibiotics, and non-DTR-active antibiotics. A generalised linear mixed model with marginal predictions was used to assess changes in in-hospital mortality (death or discharge to hospice), adjusting for patient-related, treatment-related, hospital-related, and COVID-19 pandemic-related factors. A three-way interaction term for time (year), pathogen, and infection site (bloodstream vs non-bloodstream) was included.
Results
Between Jan 1, 2016, and Aug 31, 2023, 8,319,398 adult inpatient encounters were recorded, of which 9,384 (0.11%) had evidence of a DTR organism, and 5,065 (54.0%) met inclusion criteria. The prescription and availability of newer antibiotics and corresponding susceptibility tests increased substantially over time. Use of newer antibiotics as initial therapy increased from 4% in 2016 to 15% in 2023; however, most patients (84% in 2023) still received in-vitro discordant initial therapy. There was no change in adjusted mortality over time for Enterobacterales (0.1% per year), P aeruginosa (−0.7%), or A baumannii (−0.4%) infections. When stratified by infection site, mortality remained unchanged for most groups, except for a decrease in P aeruginosa bloodstream infections (−4.5%).
Fig. 1 Flow diagram
Fig. 2 Proportion of patient encounters receiving different antibiotic types from day −1 to day +5 relative to culture collection
Fig. 3 Distribution of antibiotic administrations between 2016 and 2023 among patients with DTR Gram-negative infections
Fig. 4 Adjusted predicted probability of mortality between 2016 and 2023 using marginal predictions conditional on pathogen type (A–C) and on pathogen type and infection site (D–F)
Conclusion
Despite increased availability of newer antibiotics, mortality remains high and the use of in-vitro discordant initial therapy persists among patients with DTR infections in US hospitals. Prompt recognition of pathogens and resistance phenotypes may be crucial for reducing mortality. The observed decrease in mortality for P aeruginosa bloodstream infections should be interpreted cautiously due to the small sample size.
Reference
Walker, M.K., Yek, C., Sarzynski, S., Warner, S., Harris, A.D., Baghdadi, J.D., Goodman, K.E., Powers, J.H., Klompas, M., Rhee, C., Swihart, B. and Kadri, S.S. (2026). Survival trends in patients with difficult-to-treat, antibiotic-resistant, Gram-negative infections in the era of next-generation antibiotics in the USA: a retrospective cohort study. The Lancet Infectious Diseases. doi:https://doi.org/10.1016/s1473-3099(26)00020-4.
