In Vitro Activity of Gemifloxacin (SB-265805, LB20304a) against Legionella pneumophila and Its Pharmacokinetics in Guinea Pigs with L. pneumophila Pneumonia

The activity of gemifloxacin against intracellular Legionella pneumophila and for the treatment of guinea pigs with L. pneumophila pneumonia was studied. Gemifloxacin, azithromycin, and levofloxacin (1 μg/ml) reduced bacterial counts of two L. pneumophila strains grown in guinea pig alveolar macrophages by 2 to 3 log(10) units. Gemifloxacin and levofloxacin had roughly equivalent intracellular activities. In contrast, erythromycin had static activity only. Therapy studies of gemifloxacin, azithromycin, and levofloxacin were performed in guinea pigs with L. pneumophila pneumonia. When gemifloxacin (10 mg/kg) was given by the intraperitoneal (i.p.) route to infected guinea pigs, mean peak levels in plasma were 1.3 μg/ml at 0.5 h and 1.2 μg/ml at 1 h postinjection. The terminal half-life phase of elimination from plasma was 1.3 h, and the area under the concentration-time curve from 0 to 24 h (AUC(0–24)) was 2.1 μg · h/ml. For the same drug dose, mean levels in lungs were 3.4 μg/g at both 0.5 and 1 h, with a half-life of 1.5 h and an AUC(0–24) of 6.0 μg · h/ml. All 15 L. pneumophila-infected guinea pigs treated with gemifloxacin (10 mg/kg/dose given i.p. once daily) for 2 days survived for 9 days after antimicrobial therapy, as did 13 of 14 guinea pigs treated with the same dose of gemifloxacin given for 5 days. All 12 azithromycin-treated animals (15 mg/kg/dose given i.p. once daily for 2 days) survived, as did 11 of 12 animals treated with levofloxacin (10 mg/kg/dose given i.p. once daily for 5 days). None of 12 animals treated with saline survived. Gemifloxacin is effective against L. pneumophila in infected macrophages and in a guinea pig model of Legionnaires' disease, even with an abbreviated course of therapy. These data support studies of the clinical effectiveness of gemifloxacin for the treatment of Legionnaires' disease.

本研究考察了吉米沙星（gemifloxacin）对抗细胞内嗜肺军团菌（Legionella pneumophila）的活性，以及其用于治疗嗜肺军团菌肺炎豚鼠的效果。吉米沙星、阿奇霉素（azithromycin）与左氧氟沙星（levofloxacin）在1 μg/ml浓度下，可使豚鼠肺泡巨噬细胞（alveolar macrophages）内培养的两株嗜肺军团菌的菌落数降低2~3个log₁₀单位。吉米沙星与左氧氟沙星的细胞内活性大致相当；而红霉素（erythromycin）仅具有抑菌活性。我们对嗜肺军团菌肺炎豚鼠开展了吉米沙星、阿奇霉素与左氧氟沙星的治疗实验。当以腹腔内（intraperitoneal, i.p.）给药方式给予感染豚鼠10 mg/kg剂量的吉米沙星时，给药后0.5 h血浆平均峰浓度为1.3 μg/ml，1 h时为1.2 μg/ml；血浆消除的终末半衰期为1.3 h，0~24 h浓度-时间曲线下面积（area under the concentration-time curve, AUC₀–24）为2.1 μg·h/ml。以相同给药剂量，给药后0.5 h与1 h时肺组织平均药物浓度均为3.4 μg/g，半衰期为1.5 h，AUC₀–24为6.0 μg·h/ml。接受每日1次腹腔内给药、剂量为10 mg/kg的吉米沙星、疗程2天的15只嗜肺军团菌感染豚鼠，在抗菌治疗后均存活至第9天；接受相同剂量吉米沙星、疗程5天的14只豚鼠中，有13只存活。接受阿奇霉素治疗（每日1次腹腔内给药，15 mg/kg/剂，疗程2天）的12只动物全部存活；接受左氧氟沙星治疗（每日1次腹腔内给药，10 mg/kg/剂，疗程5天）的12只动物中有11只存活。而接受生理盐水治疗的12只动物无一存活。吉米沙星对感染巨噬细胞内的嗜肺军团菌以及军团菌病（Legionnaires' disease）豚鼠模型均具有治疗效果，即便缩短疗程亦可见效。上述数据支持开展吉米沙星治疗军团菌病的临床有效性研究。