In Vitro Activities of Various Antimicrobials Alone and in Combination with Tigecycline against Carbapenem-Intermediate or -Resistant Acinetobacter baumannii

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Abstract
The activities of tigecycline alone and in combination with other antimicrobials are not well defined for carbapenem-intermediate or -resistant Acinetobacter baumannii (CIRA). Pharmacodynamic activity is even less well defined when clinically achievable serum concentrations are considered. Antimicrobial susceptibility testing of clinical CIRA isolates from 2001 to 2005 was performed by broth or agar dilution, as appropriate. Tigecycline concentrations were serially increased in time-kill studies with a representative of the most prevalent carbapenem-resistant clone (strain AA557; imipenem MIC, 64 mg/liter). The in vitro susceptibility of the strain was tested by time-kill studies in duplicate against the average free serum steady-state concentrations of tigecycline alone and in combination with various antimicrobials. Ninety-three CIRA isolates were tested and were found to have the following antimicrobial susceptibility profiles: tigecycline, MIC(50) of 1 mg/liter and MIC(90) of 2 mg/liter; minocycline, MIC(50) of 0.5 mg/liter and MIC(90) of 8 mg/liter; doxycycline, MIC(50) of 2 mg/liter and MIC(90) of > or =32 mg/liter; ampicillin-sulbactam, MIC(50) of 48 mg/liter and MIC(90) of 96 mg/liter; ciprofloxacin, MIC(50) of > or =16 mg/liter and MIC(90) of > or =16 mg/liter; rifampin, MIC(50) of 4 mg/liter and MIC(90) of 8 mg/liter; polymyxin B, MIC(50) of 1 mg/liter and MIC(90) of 1 mg/liter; amikacin, MIC(50) of 32 mg/liter and MIC(90) of > or =32 mg/liter; meropenem, MIC(50) of 16 mg/liter and MIC(90) of > or =128 mg/liter; and imipenem, MIC(50) of 4 mg/liter and MIC(90) of 64 mg/liter. Among the tetracyclines, the isolates were more susceptible to tigecycline than minocycline and doxycycline, according to FDA breakpoints (95%, 88%, and 71% of the isolates were susceptible to tigecycline, minocycline, and doxycycline, respectively). Concentration escalation studies with tigecycline revealed a maximal killing effect near the MIC, with no additional extent or rate of killing at concentrations 2x to 4x the MIC for tigecycline. Time-kill studies demonstrated indifference for tigecycline in combination with the antimicrobials tested. Polymyxin B, minocycline, and tigecycline are the most active antimicrobials in vitro against CIRA. Concentration escalation studies demonstrate that tigecycline may need to approach concentrations higher than those currently achieved in the bloodstream to adequately treat CIRA bloodstream infections. Future studies should evaluate these findings in vivo.

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