Abstract
Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa We evaluated the interactions of polymyxin B in combination with amikacin, aztreonam, cefepime, chloramphenicol, ciprofloxacin, fosfomycin, linezolid, meropenem, minocycline, rifampin, temocillin, thiamphenicol, or trimethoprim by automated time-lapse microscopy using predefined cutoff values indicating inhibition of growth (≤106 CFU/ml) at 24 h. Promising combinations were subsequently evaluated in static time-kill experiments. All strains were intermediate or resistant to polymyxin B, antipseudomonal β-lactams, ciprofloxacin, and amikacin. Genes encoding β-lactamases (e.g., blaPAO and blaOXA-50) and mutations associated with permeability and efflux were detected in all strains. In the time-lapse microscopy experiments, positive interactions were found with 39 of 52 antibiotic combination/bacterial strain setups. Enhanced activity was found against all four strains with polymyxin B used in combination with aztreonam, cefepime, fosfomycin, minocycline, thiamphenicol, and trimethoprim. Time-kill experiments showed additive or synergistic activity with 27 of the 39 tested polymyxin B combinations, most frequently with aztreonam, cefepime, and meropenem. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa Further study is needed to explore the clinical utility of these combinations.
Highlights
Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking
We screened the antibacterial effects of polymyxin B and 13 other antibiotics, alone and in combination, against four clinical strains of MDR P. aeruginosa using automated time-lapse microscopy
All strains were multidrug resistant, displaying nonsusceptibility to antipseudomonal -lactam antibiotics, amikacin, and ciprofloxacin according to EUCAST definitions [13], and intermediate to polymyxin B (MICs, Յ1 mg/liter), according to CLSI clinical breakpoints (Table 1) [15]
Summary
Antibiotic combination therapy is used for severe infections caused by multidrug-resistant (MDR) Gram-negative bacteria, yet data regarding which combinations are most effective are lacking. This study aimed to evaluate the in vitro efficacy of polymyxin B in combination with 13 other antibiotics against four clinical strains of MDR Pseudomonas aeruginosa. Positive interactions were frequently found with the tested combinations, against strains that harbored several resistance mechanisms to the single drugs, and with antibiotics that are normally not active against P. aeruginosa. Because clinical evidence on antibiotic combination therapy for MDR Pseudomonas aeruginosa is lacking and difficult to assemble [10], in vitro data are important to identify promising regimens and provide a better understanding of the mechanisms of synergistic interaction. We screened the antibacterial effects of polymyxin B and 13 other antibiotics, alone and in combination, against four clinical strains of MDR P. aeruginosa using automated time-lapse microscopy. (The results of this study were in part presented at the 27th European Congress of Clinical Microbiology and Infectious Diseases [ECCMID] in Vienna, Austria, and at the 28th ECCMID in Madrid, Spain.)
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