[Pharmacodynamic basis for the use of amoxicillin-clavulanic acid in respiratory infections due to Streptococcus pneumoniae: In vitro studies in an experimental model].

Amoxicillin-clavulanic acid is a first choice treatment for respiratory tract infections caused by Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis. In a previous study we observed its high efficacy against penicillin-susceptible and intermediate-resistant strains of S. pneumoniae. We aimed to study the efficacy of this antibiotic against three strains of S. pneumoniae (susceptible, intermediate and resistant to penicillin) in a mouse model of pneumonia, and to determine the influence of the time of starting treatment and the in vitro postantibiotic effect. We also determined the serum levels of the antimicrobial agent in the mice, and correlated the pharmacodynamic parameters (Cmax/MIC, AUC/MIC and T>MIC) with the survival rate to establish the best predictor of efficacy. MICs with amoxicillin-clavulanic acid were 0. 03 mg/l, 0.25 mg/l and 2 mg/l for the penicillin-susceptible, -intermediate and -resistant strains, respectively. The ED90 were approximately 5 mg/kg for susceptible strains, 25 mg/kg for the intermediate and 50 mg/kg for the resistant strains. We observed a lower survival rate (approximately 55%) when the treatment began 31 h after infection than when it began 5 h (100%) and 19 h (approximately 90-100%) afterwards. Serum levels were dose dependent and the correlation with the pharmacodynamic parameters showed a significant association between survival and the T>MIC (r = 0.946). In vitro postantibiotic effects with 1, 4 and 10 times the MIC were 0.96 to 1.69 h for susceptible strains, 0.38 to 1.23 h for intermediate, and 1.52 to 2. 20 h for resistant strains. These results show the high efficacy of this antibiotic combination against strains with variable susceptibility to penicillin, with this activity being related mainly to the T>MIC of the microorganism. The postantibiotic effect would prolong the effect of the antibiotic in the dosing interval. These parameters and antimicrobial effects are important in terms of the clinical application of this antimicrobial agent.