Moine P, Vallée E, Azoulay-Dupuis E, Bourget P, Bédos J P, Bauchet J, Pocidalo J J
Institut National de la Santé et de la Recherche Médicale Unité 13, Paris, France.
Antimicrob Agents Chemother. 1994 Sep;38(9):1953-8. doi: 10.1128/AAC.38.9.1953.
The increasing emergence of penicillin-resistant (Pr) 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 [delta t MIC], > or less than 8 h; and peak/MIC ratio, >90 for free active drug) accounted for its efficacy relative to AMO (50 mg/kg: delta t MIC, <2; peak/MIC ratio, <25) against the highly Pr S. pneumoniae strain used in this study.
肺炎链球菌青霉素耐药（Pr）菌株的不断出现可能在未来几年引发治疗难题。头孢曲松（CRO）是一种广谱头孢菌素，相较于阿莫西林（AMO）（通常被视为肺炎球菌感染的“金标准”疗法），它对Pr肺炎链球菌菌株的最低抑菌浓度（MIC）升高幅度较小。因此，我们在白细胞减少的瑞士小鼠肺炎模型中比较了它们各自的疗效。用两种19型菌株诱发感染：一种青霉素敏感（Ps）菌株（青霉素MIC<0.01，AMO MIC为0.03，CRO MIC为0.03）和一种Pr菌株（青霉素MIC为4，AMO MIC为2，CRO MIC为0.5）。未治疗的小鼠在2或3天内死亡。对于Ps菌株，CRO和AMO的最小保护剂量（每12小时皮下注射一次，共3天）均为5mg/kg体重（存活率87%）。CRO剂量增加10倍（50mg/kg）对Pr菌株提供了相似的保护（存活率75%），而AMO剂量增加20倍和40倍分别仅保护0%和34%的动物免受Pr菌株感染。与AMO相比，CRO对Pr菌株在肺部具有显著且持久的抗菌作用（单次注射50mg/kg后24小时内CFU减少2.7个对数单位）。小鼠中每千克50mg CRO的标准剂量导致血清中的峰值水平和蛋白结合情况与人类静脉注射1g时观察到的相当。该剂量在该模型中对高度Pr肺炎链球菌菌株仍然有效。CRO的微生物活性以及药效动力学和药代动力学特性（浓度超过测试病原体MIC的时间[Δt MIC]，>或<8小时；以及峰浓度/MIC比值，游离活性药物>90）解释了其相对于AMO（50mg/kg：Δt MIC，<2；峰浓度/MIC比值，<25）对本研究中使用的高度Pr肺炎链球菌菌株的疗效。
