Abstract
Few effective therapeutic options are available for treating severe infections caused by extensively drug-resistant Acinetobacter baumannii (XDR-AB). Using a murine thigh-infection model, we examined the in vivo efficacy of colistin in combination with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against 12 XDR-AB strains. Colistin, tigecycline, rifampin, and sulbactam monotherapy significantly decreased bacterial counts in murine thigh infections compared with those observed in control mice receiving no treatment. Colistin was the most effective agent tested, displaying bactericidal activity against 91.7% of strains at 48 h post-treatment. With strains showing a relatively low minimum inhibitory concentration (MIC) for meropenem (MIC ≤ 32 mg/L), combination therapy with colistin plus meropenem caused synergistic inhibition at both 24 h and 48 h post-treatment. However, when the meropenem MIC was ≥64 mg/L, meropenem did not significantly alter the efficacy of colistin. The addition of rifampin and fusidic acid significantly improved the efficacy of colistin, showing a synergistic effect in 100% and 58.3% of strains after 24 h of treatment, respectively, while the addition of tigecycline, fosfomycin, or sulbactam did not show obvious synergistic activity. No clear differences in activities were observed between colistin-rifampin and colistin-fusidic acid combination therapy with most strains. Overall, our in vivo study showed that administering colistin in combination with rifampin or fusidic acid is more efficacious in treating XDR-AB infections than other combinations. The colistin-meropenem combination may be another appropriate option if the MIC is ≤32 mg/L. Further clinical studies are urgently needed to confirm the relevance of these findings.
Highlights
Acinetobacter baumannii is a non-fermentative Gram-negative coccobacillus, whose natural reservoir remains to be determined [1]
To establish the potential use of combination therapy with colistin in clinical situations, we developed a murine thigh-infection model and employed this model to examine the in vivo efficacy of colistin combined with meropenem, tigecycline, fosfomycin, fusidic acid, rifampin, or sulbactam against XDR-AB
All strains were resistant to meropenem and susceptible to colistin, based on breakpoints determined using the Clinical and Laboratory Standard Institute (CLSI) guidelines (Table 2)
Summary
Acinetobacter baumannii is a non-fermentative Gram-negative coccobacillus, whose natural reservoir remains to be determined [1]. It has emerged as one of the most significant nosocomial pathogens in health-care settings. An “old drug” that was abandoned in the 1960s because of it severe nephrotoxicity, has been reintroduced in clinical settings. It exhibits rapid and concentration-dependent bactericidal activity by destroying the outer membrane of Gram-negative bacteria [5]. Many physicians prefer to prescribe combination therapy to treat XDR-AB infections, especially considering the synergistic effects observed between colistin and other antibiotics, which have been proven in various in vitro studies [8]
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