Efficacies of Cefotaxime and Ceftriaxone in a Mouse Model of Pneumonia Induced by Two Penicillin- and Cephalosporin- Resistant Strains ofStreptococcus pneumoniae

Wepreviouslydemonstratedtheefficacyofceftriaxone(CRO),at50mg/kgofbodyweightevery12h,against a highly penicillin-resistant (MIC, 4 mg/ml)Streptococcus pneumoniaestrain with low-level resistance to CRO (MIC, 0.5 mg/ml) in a leukopenic-mouse pneumonia model (P. Moine, E. Vallee, E. Azoulay-Dupuis, P. Bourget, J.-P. Bedos, J. Bauchet, and J.-J. Pocidalo, Antimicrob. Agents Chemother. 38:1953-1958, 1994). In the present study, we assessed the activity of CRO versus those of cefotaxime (CTX) and amoxicillin (AMO) against two highly penicillin- and cephalosporin-resistantS. pneumoniaestrains (P40422 and P40984) (MICs of 2 and 8 for penicillin, 2 and 4 for AMO, and 4 and 8 for CRO or CTX, respectively). Against both strains, agreaterthanan80%cumulativesurvivalratewasobservedwithCROatadoseof100or200mg/kgevery12h (dose/MIC ratio, 25). With CTX, a high dosage of 400 mg/kg (dose/MIC ratio, 100 or 50) administered every 8 h (TID) was needed to protect 66 and 75% of the animals, respectively, with no statistically significant differences versus CRO. Against the P40422 strain, CRO (100 mg/kg) produced the greatest bactericidal effect, fromthe8thtothe24thhourafterasingleinjection(1.8-log-unitreductionover24h),andthefastestbacterial pulmonary clearance during treatment; with CTX, only multiple injections at a high dosage, i.e., 400 mg/kg TID, demonstrated a significant bactericidal effect. AMO in a high dosage, 400 mg/kg (dose/MIC ratio, 200) TID, showed good activity only against the P40422 strain. Despite the identical MICs of CTX and CRO, the longertime(3.6to4.6h)thatserumCROconcentrationsremainedabovetheMICsforthepathogensatadose of 100 mg/kg resulted in greater efficacy versus CTX against highly penicillin- and cephalosporin-resistantS. pneumoniaestrains.