Mortality rates in patients with difficult-to-treat resistant (DTR), Gram-negative infections remain high despite increased use of newer antibiotics with greater efficacy and corresponding susceptibility testing, according to findings of a recent large retrospective cohort study.1
"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," declare lead author Morgan Walker, MD, Clinical Epidemiology Section, Critical Care Medicine Department, National Institutes of Health (NIH), Bethesda, MD, and colleagues.
In accompanying commentary,2 Sarah Kabbani, MD, MSC and Clifford McDonald, MD, Division of Healthcare Quality Promotion, National Center for Emerging and Zoonotic Infectious Diseases, Centers for Disease Control and Prevention (CDC), Atlanta, GA, agree that clinical outcomes are poorer than would be expected from the development of several novel agents with improved safety profiles and optimized pharmacodynamic and pharmacokinetic properties.
"However, despite this progress, important challenges remain regarding how these antibiotics are integrated into clinical practice," Kabbani and McDonald observe.
The study encompassed the period between January 2016 and August 2023, identifying 9,384 adult inpatient encounters at 262 hospitals with microbiologic evidence of a DTR Gram-negative infection.The clinical cultures grew Pseudomonas aeruginosa, Acinetobacer baumannii, or specified Enterobacterales species; with each reported as resistant, or of intermediate susceptibility to all fluoroquinolones and ß-lactam antibiotics.
Patients in the cohort had received at least 3 consecutive days of DTR-active antibiotic, starting 2 days before culture collection until 2 days after the first susceptibility test report. The antibiotics characterized as new DTR-active were ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, omadacycline, and cefiderocol.
Walker and colleagues reported that although the proportion of encounters with a newer antibiotic increased from 4% in 2016 to 15% in 2023, most (84%) continued to receive in-vitro discordant initial antibiotic therapy, even in 2023. Over that period, there was no change in the average marginal effect (average percentage change per year) for adjusted mortality 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]).
Distinguishing between bloodstream and non-bloodstream infections, the investigators found the marginal effect for adjusted mortality remained generally unchanged for most pathogen and site combinations, with the exception of P aeruginosa blood stream infections which did decrease (-4.5% [-8.2 to -0.60]).
The investigators suspect several factors for the mortality decreasing in from P aeruginosa bloodstream infections while remaining unchanged with other DNR infections.The reliance on antibiotics such as polymyxins and aminoglycosides to treat A baumannii carry an increased risk of toxicities, for example, which could contribute to poorer outcomes.
What You Need to Know
Even with increased availability and use of newer agents (eg, ceftolozane-tazobactam, cefiderocol), overall mortality rates for difficult-to-treat Gram-negative infections have not meaningfully improved from 2016–2023. This suggests that drug innovation alone has not translated into better real-world outcomes.
A striking 84% of patients still received in-vitro discordant initial antibiotic therapy—even in 2023. This mismatch between the pathogen and the initial treatment likely contributes significantly to poor outcomes and highlights gaps in early decision-making and diagnostics.
Experts emphasize that improving outcomes will require better integration of tools and strategies, including rapid diagnostics, antimicrobial stewardship to ensure timely appropriate therapy, and exploration of non-antibiotic or host-directed treatments.
Walker and colleagues offer several suggestions for reducing mortality rates for DTR Gram-negative infections, including increasing development and implementation of rapid diagnostic testing for resistant pathogens; broadening the assessment of clinical efficacy in trials of new agents beyond noninferiority, including mortality endpoints; and increasing research into nonantimicrobial and host-directed therapies. The latter, they note, could target the immune dysregulation that can occur in these critically ill patients.
To these suggestions, Kabbani and McDonald add a call for stewardship programs that improve timely initiation of appropriate antibiotics."Concerns regarding cost and resistance could lead clinicians to reserve these drugs to preserve their effectiveness, inadvertently delaying appropriate empirical therapy for patients at high risk," they caution.
References
1. Walker MK, Yek C, Sarzynski S, et al. Survival trends on patients with difficult-to-treat, antibiotic-resistant, Gram-negative infections in the era of next-generation antibiotics in the USA: A retrospective cohort study. Lancet Infect Dis. 2026; online March 25. https://doi.org/10.1016/S1473-3099(26)00020-4.
2. Kabbani S, McDonald CL. Treatment of multidrug-resistant Gram-negative infections: A stewardship imperative. Lancet Infect Dis. 2026; online March 25. https://doi.org/10.1016/S1473-3099(26)00113-1.
