In vivo efficacies of combinations of beta-lactams, beta-lactamase inhibitors, and rifampin against Acinetobacter baumannii in a mouse pneumonia model

Abstract

The effects of various regimens containing combinations of beta-lactams, beta-lactam inhibitor(s), and rifampin were assessed in a recently described mouse model of Acinetobacter baumannii pneumonia (M. L. Joly-Guillou, M. Wolff, J. J. Pocidalo, F. Walker, and C. Carbon, Antimicrob. Agents Chemother. 41:345-351, 1997). Two aspects of the therapeutic response were studied: the kinetics of the bactericidal effect (treatment was initiated 3 h after intratracheal inoculation, and bacterial counts were determined over a 24-h period) and survival (treatment was initiated 8 h after inoculation, and the cumulative mortality rate was assessed on day 5). Two clinical strains were used: a cephalosporinase-producing strain (SAN-94040) and a multiresistant strain (RCH-69). For SAN-94040 and RCH-69, MICs and MBCs (milligrams per liter) were as follows: ticarcillin, 32, 64, 256, and >256, respectively; ticarcillin-clavulanate, 32, 64, and 512, and >512, respectively; imipenem, 0.5, 0.5, 8, and 32, respectively; sulbactam, 0.5, 0.5, 8, and 8, respectively; and rifampin, 8, 8, 4, and 4, respectively. Against SAN-94040, four regimens, i.e., imipenem, sulbactam, imipenem-rifampin, and ticarcillin-clavulanate (at a 25/1 ratio)-sulbactam produced a true bactericidal effect (>/=3-log10 reduction of CFU/g of lung). The best survival rate (i.e., 93%) was obtained with the combination of ticarcillin-clavulanate-sulbactam, and regimens containing rifampin provided a survival rate of >/=65%. Against RCH-69, only regimens containing rifampin and the combination of imipenem-sulbactam had a true bactericidal effect. The best survival rates (>/=80%) were obtained with regimens containing rifampin and sulbactam. These results suggest that nonclassical combinations of beta-lactams, beta-lactamase inhibitors, and rifampin should be considered for the treatment of nosocomial pneumonia due to A. baumannii.

FIG. 1

Cumulative survival rates of treated and control mice challenged with 10⁸ CFU of A. baumannii SAN-94040 (a and b) or RCH-69 (c and d) per mouse. The treatment was initiated 8 h after intratracheal bacterial inoculation (five i.p. doses of β-lactams and one i.p. dose of rifampin). Symbols for monotherapy (a and c): ●, controls; ○, imipenem; □, sulbactam; ▵, ticarcillin; ▴, ticarcillin-clavulanate; ■, rifampin. Symbols for combinations (b and d): ○, rifampin-imipenem; □, rifampin-sulbactam; ▴, imipenem-sulbactam; ▵, ticarcillin-sulbactam; ▴, ticarcillin-clavulanate (25/1 ratio)-sulbactam; ■, rifampin-ticarcillin-clavulanate (25/1 ratio)-sulbactam. The number of mice in each group is indicated in parentheses.