Divergent Organism-Specific Trajectories of Multidrug Resistance Across the COVID-19 Pandemic: An Interrupted Time-Series Study in a Mexican Tertiary Hospital, 2017–Early 2026

Background/Objectives: Whether the COVID-19 pandemic uniformly increased antimicrobial resistance (AMR) is contested, and aggregate analyses may mask organism-specific patterns. The objective of the study was to characterize changes in the level and slope of monthly multidrug-resistant (MDR), possible extensively drug-resistant (pXDR), possible pandrug-resistant (pPDR), vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA) positivity at a Mexican tertiary-care hospital, and to assess heterogeneity by organism, antimicrobial class, specimen type, and hospital service. Methods: Retrospective interrupted time-series of deduplicated bacterial isolates (October 2017 to January 2026), analyzed by segmented regression across pre-pandemic, pandemic, and post-peak phases. Results: Cohort-wide MDR positivity had been declining before 2020 and rose abruptly at pandemic onset (level shift +6.81 percentage points, p = 0.0092) with a simultaneous slope reversal, reaching 24.27 percentage points above the extrapolated pre-pandemic trend by February 2022 (95% CI 14.26–34.28, p < 0.0001). The decline resumed after the pandemic peak, but the two slope changes did not offset one another (joint p = 0.0064). pXDR and pPDR moved in the same direction (+8.93, p = 0.0233; +15.40, p = 0.0113). VRE showed no significant departure, whereas MRSA declined in every phase yet departed significantly from its extrapolated trajectory (+23.68, p = 0.0040). Among species, Escherichia coli showed the largest departure from its counterfactual (+48.82 percentage points, p < 0.0001) and Klebsiella pneumoniae had the largest abrupt level rise (+14.46 percentage points, p = 0.0055), while S. aureus declined in every phase despite an abrupt rise in level at pandemic onset. At the class level, carbapenem and third-/fourth-generation cephalosporin non-susceptibility rose at pandemic onset and returned to baseline afterwards (19.1% to 28.0% to 18.7%, and 51.7% to 59.4% to 52.5%; all q < 0.001), whereas fluoroquinolone non-susceptibility rose and did not revert, climbing further in E. coli (61.5% to 65.2% to 72.7%, q = 0.0012) and plateauing at an elevated level in K. pneumoniae (37.6% to 46.5% to 49.3%, q = 0.1919 post-peak). Conclusions: Resistance trajectories across pandemic-related phases were divergent and, for the Gram-negative organisms, incompletely reversed, with the highest burden of advanced resistance in high-intensity settings. Organism-resolved surveillance and sustained stewardship are needed.