Azoulay-Dupuis E, Bédos J P, Mohler J, Schmitt-Hoffmann A, Schleimer M, Shapiro S
INSERM, Faculté de Médecine Xavier Bichat, Paris, France.
Antimicrob Agents Chemother. 2004 Apr;48(4):1105-11. doi: 10.1128/AAC.48.4.1105-1111.2004.
BAL5788 is a water-soluble prodrug of BAL9141, a new broad-spectrum cephalosporin with high levels of in vitro activity against methicillin- and vancomycin-resistant staphylococci and penicillin-resistant streptococci. In plasma BAL5788 is rapidly converted to BAL9141. We studied the activity of BAL5788 in a mouse model of acute pneumococcal pneumonia. Leukopenic female Swiss albino mice were challenged intratracheally with 10(7) CFU of clinical Streptococcus pneumoniae strains P-52181 (Pen(s) Cro(s) Ctx(s)), P-15986 (Pen(r) Cro(s) Ctx(s)), P-40422 (Pen(r) Cro(r) Ctx(r)), and P-40984 (Pen(r) Cro(r) Ctx(r)). Infected mice received subcutaneous (s.c.) injections of BAL5788 or ceftriaxone starting 3 h after pneumococcal challenge. Uninfected nonleukopenic mice received single s.c. doses of BAL5788 to determine the BAL9141 concentration-time profiles in serum and lungs. Untreated control mice died within 5 days postinfection. Ten-day cumulative survival rates for infected mice receiving BAL5788 (total daily doses of BAL9141 equivalents, 2.1 to 75 mg/kg of body weight) ranged from 57 to 100%, whereas with ceftriaxone (total daily doses, 10 to 400 mg/kg), the survival rates varied between 13 and 100%. In mice infected with P-15986, the survival rates achieved with BAL5788 (BAL9141 equivalent, 8.4 mg/kg) and those achieved with ceftriaxone (50 mg/kg) were significantly different (93 versus 13%; P < 0.0001) in favor of BAL5788; the outcomes of the trials with all other strains were not significantly different between the two antibiotics, but markedly lower doses of BAL5788 than ceftriaxone were required to obtain similar survival rates. Pharmacokinetic data showed that BAL9141 was effective against the four pneumococcal strains tested at very low values of the time above the MIC (T > MIC), which ranged from 9 to 18% of the dosing interval, whereas the values of T > MICs for ceftriaxone ranged from 30 to 50% of the dosing interval.
BAL5788是BAL9141的水溶性前体药物，BAL9141是一种新型广谱头孢菌素，对耐甲氧西林和耐万古霉素的葡萄球菌以及耐青霉素的链球菌具有高水平的体外活性。在血浆中，BAL5788迅速转化为BAL9141。我们在急性肺炎球菌肺炎小鼠模型中研究了BAL5788的活性。用临床肺炎链球菌菌株P - 52181（青霉素敏感、头孢菌素敏感、环丙沙星敏感）、P - 15986（青霉素耐药、头孢菌素敏感、环丙沙星敏感）、P - 40422（青霉素耐药、头孢菌素耐药、环丙沙星耐药）和P - 40984（青霉素耐药、头孢菌素耐药、环丙沙星耐药）的10⁷CFU经气管内攻击白细胞减少的雌性瑞士白化小鼠。感染小鼠在肺炎球菌攻击后3小时开始皮下注射BAL5788或头孢曲松。未感染的非白细胞减少小鼠接受单次皮下注射BAL5788，以确定血清和肺中BAL9141的浓度 - 时间曲线。未治疗的对照小鼠在感染后5天内死亡。接受BAL5788（BAL9141等效物的每日总剂量，2.1至75mg/kg体重）的感染小鼠的10天累积生存率在57%至100%之间，而使用头孢曲松（每日总剂量，10至400mg/kg）时，生存率在13%至100%之间变化。在用P - 15986感染的小鼠中，BAL5788（BAL9141等效物，8.4mg/kg）和头孢曲松（50mg/kg）所达到的生存率有显著差异（93%对13%；P<0.0001），有利于BAL5788；对于所有其他菌株的试验结果，两种抗生素之间没有显著差异，但获得相似生存率所需的BAL5788剂量明显低于头孢曲松。药代动力学数据表明，BAL9141在高于最低抑菌浓度（T>MIC）的时间值非常低时（占给药间隔的9%至18%）对四种测试的肺炎球菌菌株有效，而头孢曲松的T>MIC值占给药间隔的30%至50%。
