The increasing emergence of penicillin-resistant (P') 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 pr 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 pr 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 pr 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 Pr 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 pr S. pneumoniae strain in this model. The microbiological activity and pharmacodynamic and pharmacokinetic properties of CRO (time during which concentrations exceed the MIC for the test pathogen [AtMIC], .8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: AtMIC, <2 h; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.

Azithromycin is a new acid-stable 15-membered-ring macrolide that exhibits an extended half-life and exceHlent tissue distribution, including distribution in the lung. We compared its in vivo activity with that of erythromycin using two models of Streptococcus pneumoniae pneumonia, namely, a model of acute infection in Swiss mice and a model of subacute infection in CS7BL/6j mice. Female mice were infected by oral delivery into the trachea of 105 CFU of a virulent serotype 3 strain of S. pneumoniae (P 4241). Prophylactic and therapeutic treatments were given orally (p.o.) or subcutaneously (s.c.) by various regimens. In the model of subacute infection, a single dose of azithromycin, 25 mg/kg, given p.o. 7 h before infection protected 92% of the mice, while erythromycin was completely ineffective. In the model of acute infection, a single dose of azithromycin, 50 mg/kg, given s.c. 24 h prior to challenge protected 80% of the mice, whereas only 35% of the mice survived with erythromycin, 50 mg/kg, 1 h before challenge. Therapy, which was studied exclusively in the model of subacute infection, was initiated 48 h postinfection. Two doses of 12.5 mg/kg given p.o. 12 h apart resulted in 80% survival of mice treated with azithromycin versus 7% survival of mice treated with erythromycin. Pulmonary clearance of bacteria was consistent with the survival rates. Two doses (25 mg/kg) of azithromycin given s.c. at 48 and 65 h after infection led to complete clearance of bacteria from the lungs and blood, whereas erythromycin-treated mice remained bacteremic. The pharmacokinetics of azithromycin account for its superior efficacy against S. pneumoniae pneumonia relative to the efficacy of erythromycin.

The efficacy of temafloxacin against Streptococcus pneumoniae in an experimental murine pneumonia model was compared with that of ofloxacin and ciprofloxacin. Erythromycin and amoxicillin were used as reference agents. Subcutaneous administration of antibiotics every 12 h for 3 days was initiated at various times after infection. The cumulative survival rates of mice treated with temafloxacin at 50 mg/kg were 100%, 92%, 81%, and 50% with treatment beginning 18, 48, 72, and 96 h after infection, respectively. The activity of temafloxacin at 50 mg/kg was not significantly different from that of erythromycin and amoxicillin but was superior to that of ofloxacin and ciprofloxacin. The maximum cumulative survival rates of mice treated with ofloxacin and ciprofloxacin at 100 mg/kg were 67% and 50%, respectively, with treatment beginning 18 h after infection. Treatment with ofloxacin and ciprofloxacin at 50 mg/kg 18 h after infection did not significantly increase survival rates compared with those of untreated controls.