Pharmacodynamic assessment of cefprozil against Streptococcus pneumoniae: Implications for breakpoint determinations

Cefprozil, an oral semissynthetic cephalosporin, is commonly utilized in th e treatment of respiratory-tract infections in children. While this agent h as provided acceptable clinical success over a number of years, this study was undertaken to better define its pharmacodynamic profile against Strepto coccus pneumoniae. Nineteen clinical isolates of S. pneumoniae were utilize d in the neutropenic murine thigh infection model. To simulate the pharmaco kinetic profile of cefprozil in children, the renal function of mice was im paired with uranyl nitrate, and a commercially available cefprozil suspensi on (6 mg/kg of body weight) was administered orally every 12 h, Mice were i nfected with 10(6) to 10(7) CFU per thigh, and therapy was initiated 2 h la ter. At 0 and 24 h postinfection, thighs were harvested to determine bacter ial density. Survival was assessed during 96 h of therapy. The magnitude of bacterial kill ranged from 0.5 to 4.4 log(10) CFU per thigh over 24 h, and the extent of microbial eradication was dependent on the MIC. Killing of m ore than 2.6 log(10) CFU per thigh was observed with MICs of less than or e qual to 3 mu g/ml, while either minimal killing or growth was detected with MICs of greater than or equal to 4 mu g/ml. Mortality in untreated control animals was 100%. Animals infected with strains for which the MICs were le ss than or equal to 2 mu g/ml survived the infection, whereas MICs exceedin g 2 mu g/ml resulted in substantial mortality. These studies demonstrate th e effectiveness of cefprozil against isolates of the pneumococcus for which the MICs are less than or equal to 2 mu g/ml using a drug exposure typical ly observed in children. These data support a susceptibility breakpoint of less than or equal to 2 mu g/ml for cefprozil.