Abstract
ABSTRACTCarbapenemase-producing Enterobacterales pose an increasing medical threat. Combination therapy is often used for severe infections; however, there is little evidence supporting the optimal selection of drugs. This study aimed to determine the in vitro effects of polymyxin B combinations against carbapenemase-producing Escherichia coli. The interactions of polymyxin B in combination with aztreonam, meropenem, minocycline or rifampin against 20 clinical isolates of NDM and OXA-48-group-producing E. coli were evaluated using time-lapse microscopy; 24-h samples were spotted on plates with and without 4× MIC polymyxin B for viable counts. Whole-genome sequencing was applied to identify resistance genes and mutations. Finally, potential associations between combination effects and bacterial genotypes were assessed using Fisher's exact test. Synergistic and bactericidal effects were observed with polymyxin B and minocycline against 11/20 strains and with polymyxin B and rifampin against 9/20 strains. The combinations of polymyxin B and aztreonam or meropenem showed synergy against 2/20 strains. Negligible resistance development against polymyxin B was detected. Synergy with polymyxin B and minocycline was associated with genes involved in efflux (presence of tet[B], wild-type soxR, and the marB mutation H44Q) and lipopolysaccharide synthesis (eptA C27Y, lpxB mutations, and lpxK L323S). Synergy with polymyxin B and rifampin was associated with sequence variations in arnT, which plays a role in lipid A modification. Polymyxin B in combination with minocycline or rifampin frequently showed positive interactions against NDM- and OXA-48-group-producing E. coli. Synergy was associated with genes encoding efflux and components of the bacterial outer membrane.
Highlights
The increasing prevalence of carbapenemase-producing Enterobacterales is an emerging threat worldwide
We evaluated the effects of polymyxin B in combination with aztreonam, meropenem, minocycline and rifampicin against 20 NDM- and OXA-48-producing E. coli in 24-h time-lapse microscopy experiments
All strains were intermediate to polymyxin B with MICs of 0.5 mg/L (Table 1)
Summary
The increasing prevalence of carbapenemase-producing Enterobacterales is an emerging threat worldwide. These bacteria are common causes of severe infections, such as sepsis, urinary tract infections and hospital-acquired pneumonia, and are difficult to treat due to their multidrug-resistant phenotypes [1,2,3]. Combination therapy is always recommended based on observational clinical data [6], evidence is still scarce on the optimal selection of companion drug. In vitro synergy against carbapenemase-producing Enterobacterales has been shown with polymyxins in combination with multiple other antibiotics (e.g., β-lactams, minocycline, rifampicin) [7,8,9,10]. The prevailing theory for the observed synergistic interactions is that the polymyxin-induced membrane disruption increases the membrane permeability, thereby facilitating entry of the second antibiotic. To date, the activity of antibiotic combinations cannot be predicted based on antibiotic susceptibility testing of single drugs or genetic characterization
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