In vitro time-kill studies of antimicrobial agents against blood isolates of imipenem-resistant Acinetobacter baumannii, including colistin- or tigecycline-resistant isolates

Abstract

The emergence of colistin or tigecycline resistance as well as imipenem resistance in Acinetobacter baumannii poses a great therapeutic challenge. The bactericidal and synergistic effects of several combinations of antimicrobial agents against imipenem-, colistin-or tigecyclineresistant A. baumannii isolates were investigated by in vitro time-kill experiments. Six imipenemresistant A. baumannii blood isolates were examined in this study, including colistin-and tigecycline-susceptible, colistin-resistant but tigecycline-susceptible, and colistin-susceptible but tigecycline-resistant isolates. Time-kill studies were performed using five antimicrobial agents singly or in combinations (imipenem plus colistin, imipenem plus ampicillin-sulbactam, colistin plus rifampicin, colistin plus tigecycline, and tigecycline plus rifampicin) at concentrations of 0.5¾ and 1¾ their MICs. Only imipenem was consistently effective as a single agent against all six A. baumannii isolates. Although the effectiveness of combinations of 0.5¾ MIC antimicrobial agents was inconsistent, combination regimens using 1¾ MIC of the antimicrobial agents displayed excellent bactericidal activities against all six A. baumannii isolates. Among the combinations of 0.5¾ MIC antimicrobial agents, the combination of colistin and tigecycline showed synergistic or bactericidal effects against four of the isolates. This in vitro time-kill analysis suggests that antimicrobial combinations are effective for killing imipenem-resistant A. baumannii isolates, even if they are simultaneously resistant to either colistin or tigecycline. However, the finding that the combinations of 0.5¾ MIC antimicrobial agents were effective on only some isolates may warrant further investigation of the doses of combination agents needed to kill resistant A. baumannii.

Investigation of Colistin Heteroresistance and Some Factors Affecting Heteroresistance in Carbapenem-Resistant A. baumannii Strains

“…In an in vitro study in 2010, Ozbek and Senturk [31] reported the synergistic effect of Col+Tig against meropenem resistant ABC. In a study in 2012, Peck et al [32] reported that this combination was synergistic and had bactericidal effects even at 0.5x MIC antibiotic concentration. Therefore, we also assume that tigecycline may be another combination alternative.…”

“…Several in vitro studies reported synergistic effects between diverse drugs for the treatment of Acinetobacter [26,[29][30][31][32]37] . However, more in vivo studies about these combinations are needed to provide high grade of evidence.…”

Is there a future for tigecycline?

“…In vitro interaction synergy studies against KPC or carbapenem-resistant Acinetobacter spp. have revealed promising effects of tigecycline in combination [14,15]. Despite the demonstration of an adequate activity against Acinetobacter species of clinical significance [14], the question regarding whether tigecycline constitutes an effective option against resistant Acinetobacter spp.…”

In Vitro Pharmacodynamics of Polymyxin B and Tigecycline Alone and in Combination against Carbapenem-Resistant Acinetobacter baumannii

“…Most synergy studies against A. baumannii, however, are conducted in vitro by applying time-kill or checkerboard methodology, where only specific fixed concentrations of antibiotics are studied. Using this methodology, numerous studies have observed synergistic interactions between polymyxins and various other antibiotic classes, including carbapenems, tigecycline, rifampin, and most recently, vancomycin (15)(16)(17)(18)(19)(20)(21)(22). These time-kill and checkerboard experiments, however, ignore the contribution of human pharmacokinetics and the dynamic effects of varied drug concentrations over the duration of the experiment.…”