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

Abstract

There are currently no defined optimal therapies available for multidrug-resistant (MDR) Acinetobacter baumannii infections. We evaluated the efficacy of rifampin, imipenem, sulbactam, colistin, and their combinations against MDR A. baumannii in experimental pneumonia and meningitis models. The bactericidal in vitro activities of rifampin, imipenem, sulbactam, colistin, and their combinations were tested using time-kill curves. Murine pneumonia and rabbit meningitis models were evaluated using the A. baummnnii strain Ab1327 (with MICs for rifampin, imipenem, sulbactam, and colistin of 4, 32, 32, and 0.5 mg/liter, respectively). Mice were treated with the four antimicrobials and their combinations. For the meningitis model, the efficacies of colistin, rifampin and its combinations with imipenem, sulbactam, or colistin, and of imipenem plus sulbactam were assayed. In the pneumonia model, compared to the control group, (i) rifampin alone, (ii) rifampin along with imipenem, sulbactam, or colistin, (iii) colistin, or (iv) imipenem plus sulbactam significantly reduced lung bacterial concentrations (10.6 +/- 0.27 [controls] versus 3.05 +/- 1.91, 2.07 +/- 1.82, 2.41 +/- 1.37, 3.4 +/- 3.07, 6.82 +/- 3.4, and 4.22 +/- 2.72 log(10) CFU/g, respectively [means +/- standard deviations]), increased sterile blood cultures (0% versus 78.6%, 100%, 93.3%, 93.8%, 73.3%, and 50%), and improved survival (0% versus 71.4%, 60%, 46.7%, 43.8%, 40%, and 85.7%). In the meningitis model rifampin alone or rifampin plus colistin reduced cerebrospinal fluid bacterial counts (-2.6 and -4.4 log(10) CFU/ml). Rifampin in monotherapy or with imipenem, sulbactam, or colistin showed efficacy against MDR A. baumannii in experimental models of pneumonia and meningitis. Imipenem or sulbactam may be appropriate for combined treatment when using rifampin.

FIG. 1.

Time-kill curves for imipenem (IPM), sulbactam (SUL), rifampin (RIF), and colistin (CST), at 1× the MIC, alone and in combination against strains Ab506, Ab940, Ab1327, and Ab1417. Symbols for the monotherapies: control, vertical ellipse; imipenem, full diamond; sulbactam, full circle; colistin, square; rifampin, full triangle. For the combinations: imipenem plus sulbactam, inverted triangle; rifampin plus imipenem, cross; rifampin plus sulbactam, open diamond; rifampin plus colistin, horizontal line.

FIG. 2.

Concentrations of rifampin and colistin in serum and CSF obtained from infected rabbits after the administration of a single dose of 25 mg/kg and 12 mg/kg, respectively. Filled triangles, serum levels; filled squares, CSF levels. *, MIC of the antimicrobial against the Ab1327 strain.