BACTERICIDAL ACTIVITIES OF CEFPROZIL, PENICILLIN, CEFACLOR, CEFIXIME,AND LORACARBEF AGAINST PENICILLIN-SUSCEPTIBLE AND PENICILLIN-RESISTANT STREPTOCOCCUS-PNEUMONIAE IN AN IN-VITRO PHARMACODYNAMIC INFECTION MODEL

We examined the bactericidal activities of penicillin, cefprozil, cefi xime, cefaclor, and loracarbef against three clinical isolates of Stre ptococcus pneumoniae which were susceptible, moderately susceptible, a nd resistant to penicillin. An in vitro two-compartment glass infectio n model was used to simulate human pharmacokinetics in the presence of bacteria. Also, changes in organism susceptibility and development of resistant subpopulations were evaluated. Simulated pediatric dosage r egimens and target peak concentrations in the central compartment were as follows: penicillin V-potassium, 26 mg/kg of body weight every 6 h (q6h) and 14 mu g/ml; cefaclor, 13.4 mg/kg q8h and 16 mu g/ml; loraca rbef, 15 mg/kg q12h and 19 mu g/ml; cefprozil, 15 mg/kg q12h and 11 mu g/ml; and cefixime, 8mg/kg q24h and 4 mu g/ml. Targeted half-lives of each agent were 1 h for penicillin, cefaclor, and loracarbef; 1.3 h f or cefprozil; and 3.5 h for cefixime. Growth controls were performed a t two different pump rates, 0.8 and 2.0 ml/min (half-lives = 3.5 and 1 h, respectively). Each isolate demonstrated autolysis at the lower ra te which was attributed to a decreased supply of fresh nutrients avail able to the organisms in the infection compartment. Against the suscep tible isolate, the time to 99.9% killing was statistically significant between penicillin V-potassium and both cefaclor and cefixime (P < 0. 029). Loracarbef never achieved a 99.9% reduction in the inoculum. At 48 h penicillin, cefprozil, and cefaclor were equivalent in extent of killing. Against the intermediately resistant isolate, cefprozil was s uperior to all other regimens with respect to rate of killing (P < 0.0 13) and extent of killing at 24 h (P < 0.0003). At 48 h penicillin, ce fprozil, and cefaclor were equivalent in extent of killing. All of the regimens exhibited inferior activity against this penicillin-resistan t isolate. A 99.9% kill was never obtained with any of the regimens, n or was there an appreciable decrease in the colony counts. In conclusi on, it appears that cefprozil, penicillin, and cefaclor are effective therapies against sensitive and even intermediately sensitive isolates of S. pneumoniae. However, none of the oral therapies appear to be of any benefit against penicillin-resistant isolates. The in vitro model may be an effective tool in evaluating other multiple-dose therapies against this fastidious organism, since the continual supply of fresh medium maintains the viability of S. pneumoniae with minimal stationar y-phase autolysis.