In vitro pharmacodynamics of human-simulated exposures of ampicillin/sulbactam, doripenem and tigecycline alone and in combination against multidrug-resistant Acinetobacter baumannii

Objectives: Multidrug resistance is common among Acinetobacter baumannii, limiting the available options used to treat infections caused by this organism. The objective of this study was to compare monotherapy and combination therapy with ampicillin/sulbactam, doripenem and tigecycline against multidrug-resistant A. baumannii using an in vitro pharmacodynamic model. Methods: Human free-drug concentration profiles of clinically relevant ampicillin/sulbactam, doripenem and tigecycline were simulated alone and in two-drug combinations against four clinical A. baumannii isolates (MICs: ampicillin/sulbactam, 4/2-64/32 mg/L; doripenem, 16 to >= 64 mg/L; and tigecycline, 1-4 mg/L) over 24 h. Microbiological response was measured as log(10) cfu/mL and the area under the bactericidal curve (AUBC). Results: Control strains grew to 7.11 +/- 0.13 log(10) cfu/mL. Except for ampicillin/sulbactam-containing regimens against the single ampicillin/sulbactam-susceptible isolate, all A. baumannii demonstrated regrowth to 24 h control levels against all mono and combination regimens. Using AUBC as an endpoint, the most active regimens were 9g of ampicillin/sulbactamevery 8h (3 hinfusion) + 2g of doripenemevery 8h (4 h infusion; 87.8 +/- 21.0), 9g of ampicillin/sulbactam every 8h (3h infusion) + 200 mg of tigecycline every 12h (30 min infusion; 100.6 +/- 33.0) and 9g of ampicillin/sulbactam every 8h (3h infusion) monotherapy (116.7 +/- 31.6), followed by 3g of ampicillin/sulbactam every 6h (30 min infusion) + 200 mg of tigecycline every 12h (30 min infusion; 134.0 +/- 31.5) and 2g of doripenem every 8h (4 h infusion) + 200 mg of tigecycline every 12h (30 min infusion; 142.7 +/- 16.9). Conclusions: Although specific combination regimens displayed additive activity at aggressive doses against these multidrug-resistant A. baumannii, none of the regimens could maintain cfu reductions against the more resistant isolates.