Mine Y, Watanabe Y, Sakamoto H, Hatano K, Kuno K, Higashi Y, Kamimura T, Matsumoto Y, Tawara S, Matsumoto F
Product Development Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
J Antibiot (Tokyo). 1993 Jan;46(1):71-87. doi: 10.7164/antibiotics.46.71.
FK037 is a new parenteral cephalosporin, which offers some advantages over the commercially available parenteral cephalosporins. It demonstrated potent broad-spectrum activity against clinical isolates of Gram-positive bacteria including methicillin-resistant staphylococci, and Gram-negative bacteria including Pseudomonas aeruginosa. Against clinical isolates of aerobic Gram-positive bacteria, FK037, like cefpirome, demonstrated more potent activity than ceftazidime, cefoperazone and ceftizoxime. It is noteworthy that FK037, on the basis of the MIC90s, was the most active of all the cephalosporins tested against methicillin-resistant Staphylococcus aureus (MRSA). It was similar in activity to cefpirome against methicillin-sensitive S. aureus (MSSA). Against clinical isolates of aerobic Gram-negative bacteria, FK037, like cefpirome, was superior to cefoperazone, similar to ceftazidime and inferior to ceftizoxime in activity. Against P. aeruginosa, FK037 was superior to cefoperazone, similar or slightly superior to cefpirome and inferior to ceftazidime in activity. However, FK037 exhibited significant activity against Citrobacter and Enterobacter which were highly resistant to ceftazidime, cefoperazone and ceftizoxime. FK037 had an advantage in that its bactericidal activity against S. aureus, Escherichia coli and P. aeruginosa at sub-MICs (1/2 or 1/4 the MIC) was much stronger than those of cefpirome and ceftazidime. Moreover, it exhibited potent bactericidal activity against MSSA, MRSA and P. aeruginosa in a pharmacokinetic in vitro model simulating human plasma concentrations after intravenous dosage of 0.125, 1.0 and 1.0 g, respectively. FK037 inhibited essential penicillin-binding proteins (PBPs), 1, 2 and 3 of S. aureus with a 50% inhibitory concentration (I50) of 0.58 micrograms/ml or lower. Of essential PBPs 3, 1a and 1b of E. coli and P. aeruginosa, FK037 inhibited PBP 3 at the lowest I50 (0.03 and 0.04 micrograms/ml, respectively) and PBPs 1a and 1b with I50 values of 2.7 micrograms/ml or lower. FK037, like cefpirome, was highly stable to hydrolysis by various beta-lactamases except Ic cephalosporinase from Bacteroides fragilis, and had extremely low affinity for beta-lactamases. Therefore, FK037 was more potent than ceftazidime in activity against beta-lactamase-producing bacteria except P. aeruginosa and Serratia marcescens. The ability of FK037 to penetrate the outer membrane of E. coli was slightly higher than that of ceftazidime, but slightly lower than that of cefpirome.
FK037是一种新型肠胃外注射用头孢菌素，与市售的肠胃外注射用头孢菌素相比具有一些优势。它对包括耐甲氧西林葡萄球菌在内的革兰氏阳性菌临床分离株以及包括铜绿假单胞菌在内的革兰氏阴性菌临床分离株显示出强大的广谱活性。对于需氧革兰氏阳性菌临床分离株，FK037与头孢匹罗一样，显示出比头孢他啶、头孢哌酮和头孢唑肟更强的活性。值得注意的是，基于MIC90s，FK037是所有测试头孢菌素中对耐甲氧西林金黄色葡萄球菌（MRSA）活性最强的。它对甲氧西林敏感金黄色葡萄球菌（MSSA）的活性与头孢匹罗相似。对于需氧革兰氏阴性菌临床分离株，FK037与头孢匹罗一样，活性优于头孢哌酮，与头孢他啶相似，低于头孢唑肟。对于铜绿假单胞菌，FK037活性优于头孢哌酮，与头孢匹罗相似或略强，低于头孢他啶。然而，FK037对头孢他啶、头孢哌酮和头孢唑肟高度耐药的柠檬酸杆菌和肠杆菌显示出显著活性。FK037的优势在于其在亚MIC（1/2或1/4 MIC）时对金黄色葡萄球菌、大肠杆菌和铜绿假单胞菌的杀菌活性比头孢匹罗和头孢他啶强得多。此外，在分别模拟静脉注射0.125、1.0和1.0 g后人体血浆浓度的药代动力学体外模型中，它对MSSA、MRSA和铜绿假单胞菌表现出强大的杀菌活性。FK037抑制金黄色葡萄球菌的必需青霉素结合蛋白（PBPs）1、2和3，50%抑制浓度（I50）为0.58微克/毫升或更低。对于大肠杆菌和铜绿假单胞菌的必需PBPs 3、1a和1b，FK037以最低的I50（分别为0.03和0.04微克/毫升）抑制PBP 3，并以2.7微克/毫升或更低的I50值抑制PBPs 1a和1b。FK037与头孢匹罗一样，除了脆弱拟杆菌的Ic头孢菌素酶外，对各种β-内酰胺酶的水解高度稳定，并且对β-内酰胺酶的亲和力极低。因此，除铜绿假单胞菌和粘质沙雷氏菌外，FK037对产β-内酰胺酶细菌的活性比头孢他啶更强。FK037穿透大肠杆菌外膜的能力略高于头孢他啶，但略低于头孢匹罗。
