IN-VIVO EFFICACY OF A BROAD-SPECTRUM CEPHALOSPORIN, CEFTRIAXONE, AGAINST PENICILLIN-SUSCEPTIBLE AND PENICILLIN-RESISTANT STRAINS OF STREPTOCOCCUS-PNEUMONIAE IN A MOUSE PNEUMONIA MODEL

The increasing emergence of penicillin-resistant (P-r) strains of Streptococcus pneumoniae could pose a therapeutic problem in the next few years. Ceftriaxone (CRO), a broad-spectrum cephalosporin, exhibits a smaller increase in MICs against P-r S. pneumoniae strains than amoxicillin (AMO) (usually referred as to the ''gold standard'' therapy for pneumococcal infections). Therefore, we compared their respective efficacies in a leukopenic Swiss mouse model of pneumococcal pneumonia. Infection was induced with two serotype 19 strains: a penicillin-susceptible (PS) strain (MICs of <0.01 for penicillin, 0.03 for AMO, and 0.03 for CRO) and a P-r strain (MICs of 4 for penicillin, 2 for AMO, and 0.5 for CRO). Untreated mice died within 2 or 3 days. Against the PS strain, the minimal protective dose (two subcutaneous injections at 12-h intervals for 3 days) for both CRO and AMO was 5 mg/kg of body weight (87% survivors). Ten-fold-increased doses of CRO (50 mg/kg) gave similar protection (75% survivors) against the P-r strain, whereas 20- and 40-fold-increased doses of AMO protected 0 and 34% of the animals, respectively, against the PS strain. CRO had a marked and prolonged antibacterial effect in the lungs (2.7-log-unit reduction of CFU in 24 h after a single 50-mg/kg injection) against the P-r strain in comparison with AMO. A standard dosage of 50 mg of CRO per kg in mice resulted in peak levels in serum and protein binding comparable to those observed with 1 g given intravenously in humans. This dosage remained effective against a highly P-r S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC far the test pathogen [Delta tMIC], greater than or equal to 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: Delta tMIC, <2 h; peak/MIC ratio, <25) against the highly P-r S. pneumoniae strain used in this study.