Difficult-to-treat resistance, not carbapenem non-susceptibility, is associated with 30-day mortality in respiratory gram-negative bacilli: a 12-year surveillance cohort

Abstract

Objectives Antimicrobial resistance in respiratory gram-negative bacilli (GNB) is rising in Saudi Arabia, yet the clinical impact of difficult-to-treat resistance (DTR) remains poorly defined. We characterized temporal trends in organism distribution, non-susceptibility phenotypes, and their association with 30-day in-hospital mortality. Methods Retrospective cohort of hospitalized patients aged ≥12 years with culture-positive respiratory GNB at a referral hospital in southern Saudi Arabia (January 2013–August 2024). Non-susceptibility phenotypes were fluoroquinolone (FQ-NS), extended-spectrum cephalosporin (ESC-NS), carbapenem non-susceptibility, and DTR. Trends were assessed with segmented binomial regression, mortality with modified Poisson regression. Results Among 6,999 isolate-episodes from 3,808 patients, Enterobacterales (57.2%) increased while non-fermenting GNB declined (AAPC, −2.5%). Carbapenem non-susceptibility rose among Enterobacterales (AAPC, + 5.4%), driven by Klebsiella pneumoniae . DTR was 37.6%, rising in Enterobacterales (AAPC, + 12.1%) but declining in Acinetobacter baumannii . Thirty-day mortality was 27.9%. DTR was associated with mortality in Enterobacterales (aRR, 1.34; 95% CI, 1.16–1.55) and non-fermenting GNB (aRR, 1.28; 95% CI, 1.12–1.46); carbapenem non-susceptibility without DTR was not. Mortality rose as active first-line agents decreased ( P -trend<.001). Conclusions Respiratory GNB epidemiology is shifting toward Enterobacterales with rising resistance. DTR, not carbapenem non-susceptibility alone, was consistently associated with 30-day mortality and provides a meaningful framework for risk stratification and resistance-centered surveillance.