Efficacy of rifampin and its combinations with imipenem , sulbactam , and colistin 1 in experimental models caused by imipenem - resistant Acinetobacter baumannii . 2 3

32 Background 33 There are currently no defined optimal therapies available for multidrug-resistant 34 (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, 35 imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in 36 experimental pneumonia and meningitis models. 37 Methods 38 The bactericidal in vitro activity of rifampin, imipenem, sulbactam, colistin, and 39 their combinations were tested using time-kill curves. Murine pneumonia and rabbit 40 meningitis models were performed using the A. baummnnii strain Ab1327 (with MICs 41 for rifampin, imipenem, sulbactam, and colistin of 4, 32, 32, and 0.5 mg/l, respectively). 42 Mice were treated with the four antimicrobials and their combinations. For the 43 meningitis model, the efficacy of colistin, rifampin and its combinations with imipenem, 44 sulbactam, or colistin, and of imipenem plus sulbactam were assayed. 45 Results 46 In the pneumonia model, compared to the control group, rifampin alone or plus 47 imipenem, sulbactam or colistin, colistin, and imipenem plus sulbactam significantly 48 reduced lung bacterial concentrations (10.6±0.27 vs. 3.05±1.91, 2.07±1.82, 2.41±1.37, 49 3.4±3.07, 6.82±3.4, and 4.22±2.72 log10 CFU/g, respectively), increased sterile blood 50 cultures (0% vs. 78.6%, 100%, 93.3%, 93.8%, 73.3%, and 50%), and improved survival 51 (0% vs. 71.4%, 60%, 46.7%, 43.8%, 40%, and 85.7%). In the meningitis model rifampin 52 alone or plus colistin reduced cerebrospinal fluid (CSF) bacterial counts (-2.6 and -4.4 53