Summary
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 are now available with improved safety and efficacy and with in-vitro activity against DTR infections; however, their influence on the outcomes of patients with DTR infections remains unclear. We 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 a DTR Gram-negative infection, defined as microbiological evidence of DTR Enterobacterales, Pseudomonas aeruginosa, or Acinetobacter baumannii and receipt of at least 3 consecutive days of any antibiotic therapy, were identified from hospitals reporting microbiology data in the PINC-AI Healthcare Database. We characterised the proportion of inpatient encounters receiving newer DTR-active antibiotics, traditional DTR-active antibiotics, and non-DTR-active antibiotics. We used a generalised linear mixed model with marginal predictions to examine changes in in-hospital mortality, defined as death or discharge to hospice, over the study period when adjusting for patient-related and treatment-related factors (including receipt of a new antibiotic and receipt of in-vitro discordant initial therapy), hospital-related factors (including the availability of newer antibiotics and corresponding susceptibility testing), and COVID-19 pandemic-related factors. A three-way interaction term for time (year), pathogen, and infection site (ie, bloodstream and non-bloodstream) was included given the expected differences in mortality.
Findings
Between Jan 1, 2016, and Aug 31, 2023, 8 319 398 adult inpatient encounters with available microbiology data were recorded from 471 hospitals, of which 9384 (0.11%) encounters had microbiological evidence of an eligible DTR organism. 5065 (54·0%) of these 9384 encounters, from 262 hospitals, met the inclusion criteria for DTR Gram-negative infections and were included in the study. Among this cohort, the prescription of newer antibiotics, as well as the availability of newer antibiotics and their corresponding susceptibility tests, increased substantially from 2016 to 2023. Although the proportion of encounters in which the patient received a newer antibiotic as initial therapy increased from 4% (21 of 589) in 2016 to 15% (34 of 234) in 2023, in most cases (196 [84%] of 234) patients continued to receive in-vitro discordant initial antibiotic therapy, even in 2023. We observed no change in the average marginal effect (the average percentage change per year) for adjusted mortality between 2016 and 2023 for Enterobacterales (0.1% [95% CI −1.1 to 1.4]), P aeruginosa (−0.7% [−1.7 to 0.3]), or A baumannii (−0.4% [−1.8 to 0.9]) infections. When dichotomised into bloodstream and non-bloodstream infections, the marginal effect for adjusted mortality remained unchanged over time for most pathogen and site combinations, with the exception of P aeruginosa bloodstream infections, for which a decrease was observed (−4.5% [−8.2 to −0.60]).
Interpretation
Despite the availability of newer antibiotic agents, the estimated mortality and ongoing use of in-vitro discordant initial antibiotics remains unacceptably high among patients with DTR infections in US hospitals. Prompt recognition of both the pathogen and resistance phenotype could be a crucial component in reducing mortality. Although notable, the decrease over time in adjusted mortality for P aeruginosa bloodstream infections should be considered hypothesis-generating because the cohort of patients with such infections was small.
Funding
US National Institutes of Health (NIH) Clinical Center; US National Cancer Institute; the Intramural Research Program of the US National Heart, Lung, and Blood Institute; the US National Institute of Allergy and Infectious Diseases; and the US Food and Drug Administration.
Research in context
Evidence before this study
Difficult-to-treat resistance is a resistance phenotype describing Gram-negative pathogens that show resistance to all first-line, safe and effective traditional antibiotic options (ie, β-lactams [including carbapenems] and fluoroquinolones). As a result, difficult-to-treat resistant (DTR) infections are associated with high mortality, of which they are a better predictor than susceptible infections. Several new antibiotics have been introduced into the US market since 2014 and could provide more treatment options to patients with antimicrobial-resistant (AMR) infections such as DTR infections, for whom no safe and effective treatment exists. Evidence supporting a reduction in mortality after treatment with these new antibiotics, specifically in patients with AMR infections, is scarce. Understanding the population-level change in mortality following the implementation of these new antibiotic therapies could inform current priorities in therapeutic and diagnostic development to improve outcomes in this high-risk patient population. We searched PubMed from database inception to Dec 16, 2025, for studies with the Medical Subject Headings Major Topics “Bacterial Infections/mortality” AND “Drug Resistance, bacterial”, with no language restrictions. This search returned 426 publications. 34 articles evaluated trends in bacterial resistance over time and associated mortality among drug-resistant bacterial infections, of which 13 examined only Gram-positive bacterial infections and eight examined a period before the introduction of any of the newer antibiotics (ie, before 2014). Mortality estimates over time in the remaining 13 publications considered only discrete phenotypes for which alternative effective treatment options might exist, did not characterise the use of newer antibiotics within the study population, and did not adjust for relevant COVID-19 pandemic-related factors that are likely to affect the interpretation of mortality trends since 2020.
Added value of this study
This study leverages an administrative and clinical database to identify, to our knowledge, the largest cohort to date of hospitalised patients with DTR Gram-negative infections in the USA. We evaluate adjusted mortality trends in patients with DTR infections after the real-world introduction of six new antibiotics (ceftolozane–tazobactam, ceftazidime–avibactam, meropenem–vaborbactam, imipenem–relebactam, eravacycline, and cefiderocol) with broad spectra of activity and variable side-effect profiles. Trends in mortality were examined using a generalised linear mixed model adjusted for relevant patient-related, hospital-related, and COVID-19 pandemic-related covariates. The estimated probability of mortality across DTR Enterobacterales, Pseudomonas aeruginosa, and Acinetobacter baumannii infections did not change from 2016 to 2023. When dichotomised into bloodstream and non-bloodstream infections, we identified a 4.5% annual reduction in the adjusted mortality for P aeruginosa bloodstream infections, albeit the sample size for this population was small (n=87). The trends in adjusted mortality for all other pathogen and infection-site combinations remained unchanged. These findings occurred in the setting of persistent and frequent use of in-vitro discordant initial empirical therapy despite a substantial increase in access to and use of newer antibiotic options.
Implications of all the available evidence
Our results underscore the importance of better understanding why survival has not improved across all DTR Gram-negative infections despite the availability of newer, safe, and effective broad-spectrum antibiotic options. The development and real-world implementation of improved rapid diagnostic platforms for early detection of resistant phenotypes could improve patient outcomes. Comparative trials of new antibiotics with increased representation of patients with highly resistant bacterial infections, namely DTR infections, could elucidate the true clinical benefit of newer antibiotics in their respective target populations. Exploration of additional non-antibiotic, host-directed therapies could address the immune dysregulation that might contribute to poor patient outcomes, even among those who die with susceptible infections.
Source:
Link: https://www.thelancet.com/journals/laninf/article/PIIS1473-3099(26)00020-4/fulltext?rss=yes
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