In vitro activity of tigecycline in combination with various antimicrobials against multidrug resistant Acinetobacter baumannii

Abstract

Background: Infections sustained by multidrug-resistant (MDR) and pan-resistant Acinetobacter baumannii have become a challenging problem in Intensive Care Units. Tigecycline provided new hope for the treatment of MDR A. baumannii infections, but isolates showing reduced susceptibility have emerged in many countries, further limiting the therapeutic options. Empirical combination therapy has become a common practice to treat patients infected with MDR A. baumannii, in spite of the limited microbiological and clinical evidence supporting its efficacy. Here, the in vitro interaction of tigecycline with seven commonly used anti-Acinetobacter drugs has been assessed.

Methods: Twenty-two MDR A. baumannii isolates from Intensive Care Unit (ICU) patients and two reference strains for the European clonal lineages I and II (including 3, 15 and 6 isolates that were resistant, intermediate and susceptible to tigecycline, respectively) were tested. Antimicrobial agents were: tigecycline, levofloxacin, piperacillin-tazobactam, amikacin, imipenem, rifampicin, ampicillin-sulbactam, and colistin. MICs were determined by the broth microdilution method. Antibiotic interactions were determined by chequerboard and time-kill assays. Only antibiotic combinations showing synergism or antagonism in both chequerboard and time-kill assays were accepted as authentic synergistic or antagonistic interactions, respectively.

Results: Considering all antimicrobials in combination with tigecycline, chequerboard analysis showed 5.9% synergy, 85.7% indifference, and 8.3% antagonism. Tigecycline showed synergism with levofloxacin (4 strains; 16.6%), amikacin (2 strains; 8.3%), imipenem (2 strains; 8.3%) and colistin (2 strains; 8.3%). Antagonism was observed for the tigecycline/piperacillin-tazobactam combination (8 strains; 33.3%). Synergism was detected only among tigecycline non-susceptible strains. Time-kill assays confirmed the synergistic interaction between tigecycline and levofloxacin, amikacin, imipenem and colistin for 5 of 7 selected isolates. No antagonism was confirmed by time-kill assays.

Conclusion: This study demonstrates the in vitro synergistic activity of tigecycline in combination with colistin, levofloxacin, amikacin and imipenem against five tigecycline non-susceptible A. baumannii strains, opening the way to a more rationale clinical assessment of novel combination therapies to combat infections caused by MDR and pan-resistant A. baumannii.

Figure 1

Time-kill kinetics for confirmed synergistic interactions. (A) TIG/LVX, study code 5; (B) TIG/LVX, study code 11; (C) TIG/AMK, study code 71, (D) TIG/IPM, study code 80; (E) TIG/CS, study code 75; (F) Comparison of quantitative change in CFU/ml, relative to the most active constituent, for the synergistic interactions. The drug concentrations are as follows: TIG/LVX, 0.25 and 4 mg/L, respectively (study codes 5 and 11); TIG/AMK, 1 and 64 mg/L, respectively (study code 71); TIG/IPM, 0.5 and 16 mg/L, respectively (study code 80); TIG/CS, 2 and 0.25 mg/L, respectively (study code 75). The dotted line denotes the threshold value to define synergy. Panels show one representative experiment of three replicates.