Re-evaluating trimethoprim-sulfamethoxazole treatment in A. baumannii
Acinetobacter baumannii frequently causes drug resistant infections that are hard to treat, and resistance to last-line therapies is rising. The synergistic combination of trimethoprim-sulfamethoxazole has been highlighted as a potentially viable option for treating carbapenem- or polymyxin- resistant infections. However, clinical performance is inconsistent. This study investigated potentially contributing factors: (1) strain-specific variability in TMP-SMX drug interactions, and (ii) the suitability of the current fixed-dose treatment ratio (1 TMP : 20 SMX). Method: Interaction profiles were determined for a diverse panel of A. baumannii using broth microdilution chequerboard assays. Mutants were used to assess the contributions of resistance genes on interaction type in A. baumannii. MIC and FIC analyses were used to assess suitability of the fixed ratio and compare it to other ratios. Results TMP-SMX interactions were generally synergistic, but additivity was observed in strains carrying sul or dfr resistance genes. Mutant analyses confirmed that the drug interaction could be shifted from synergistic to additive and vice versa based on the presence or absence of dfrA7 or sul2 genes. Efflux pump activity also contributed, with distinct roles across strains. Importantly, the standard 1:20 (TMP:SMX) ratio was not synergistic in most isolates. Alternative ratios, (4:1 and 20:1) produced stronger synergy across nearly all strains tested. Conclusions TMP-SMX can interact both additively and synergistically in A. baumannii depending on the presence or absence of antifolate resistance genes, and the current fixed dosing ratio is sub-optimal against this organism.  These findings provide a foundation for improving TMP-SMX therapy against A. baumannii and underscore the value of dissecting genetic determinants of drug interactions and revisiting dosing for drug combinations, an approach that is applicable to other pathogens and drug pairs, particularly in the context of rising antimicrobial resistance.
Acinetobacter baumannii frequently causes drug resistant infections that are hard to treat, and resistance to last-line therapies is rising. The synergistic combination of trimethoprim-sulfamethoxazole has been highlighted as a potentially viable option for treating carbapenem- or polymyxin- resistant infections. However, clinical performance is inconsistent. This study investigated potentially contributing factors: (1) strain-specific variability in TMP-SMX drug interactions, and (ii) the suitability of the current fixed-dose treatment ratio (1 TMP : 20 SMX). Method: Interaction profiles were determined for a diverse panel of A. baumannii using broth microdilution chequerboard assays. Mutants were used to assess the contributions of resistance genes on interaction type in A. baumannii. MIC and FIC analyses were used to assess suitability of the fixed ratio and compare it to other ratios. Results TMP-SMX interactions were generally synergistic, but additivity was observed in strains carrying sul or dfr resistance genes. Mutant analyses confirmed that the drug interaction could be shifted from synergistic to additive and vice versa based on the presence or absence of dfrA7 or sul2 genes. Efflux pump activity also contributed, with distinct roles across strains. Importantly, the standard 1:20 (TMP:SMX) ratio was not synergistic in most isolates. Alternative ratios, (4:1 and 20:1) produced stronger synergy across nearly all strains tested. Conclusions TMP-SMX can interact both additively and synergistically in A. baumannii depending on the presence or absence of antifolate resistance genes, and the current fixed dosing ratio is sub-optimal against this organism.  These findings provide a foundation for improving TMP-SMX therapy against A. baumannii and underscore the value of dissecting genetic determinants of drug interactions and revisiting dosing for drug combinations, an approach that is applicable to other pathogens and drug pairs, particularly in the context of rising antimicrobial resistance.
Macquarie University