Combination therapy: a way to limit emergence of resistance?

The ability of antibiotic combinations to limit the emergence of resistance during therapy was evaluated in a murine model. Peritonitis was produced by injecting a mixture containing 10(8) colony-forming units of bacteria and sterilized talcum into the peritoneum. Two hours later, a single antibiotic dose was administered subcutaneously. The next day, peritoneal bacterial populations were analyzed on Szybalski's gradients. Acquired resistance was recorded when there was at least a fourfold increase in minimum inhibitory concentrations compared with untreated animals. No resistance emerged after amikacin monotherapy (15 mg/kg); however, resistance was frequently observed after monotherapy with ceftriaxone (50 mg/kg) or pefloxacin (25 mg/kg). Resistance to ceftriaxone and pefloxacin emerged, respectively, in 15 percent and 83 percent of animals with Klebsiella pneumoniae, 71 percent and 54 percent with Enterobacter cloacae, 0 percent and 83 percent with Serratia marcescens, 25 percent and 100 percent with Pseudomonas aeruginosa, and 0 percent with both Escherichia coli and Staphylococcus aureus. In mice with K. pneumoniae or E. cloacae infections, any dual combination of amikacin, pefloxacin, and ceftriaxone produced less acquired resistance than did monotherapy. In these animals, the combination of ceftriaxone and pefloxacin abolished all resistance, whereas the combinations of amikacin plus ceftriaxone or amikacin plus pefloxacin reduced the frequency of resistance by more than half. In animals with P. aeruginosa or S. marcescens infections, resistance to pefloxacin diminished or disappeared after treatment with the combinations of pefloxacin plus ceftriaxone or pefloxacin plus amikacin. However, combinations with ceftriaxone resulted in more frequent resistance to ceftriaxone than did ceftriaxone alone. This was the case in P. aeruginosa infections treated with ceftriaxone plus amikacin (p less than 0.01), and in S. marcescens infections treated with ceftriaxone plus pefloxacin (p less than 0.05). Despite these certain notable exceptions, our data confirm that in most cases combination therapy does limit the emergence of resistance.