Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models
Antistaphylococcal Activity of WCK 771, a Tricyclic Fluoroquinolone, in Animal Infection Models
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WCK 771（一种三环氟喹诺酮）在动物感染模型中的抗葡萄球菌活性
DOI：
10.1128/aac.48.12.4754-4761.2004
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发表时间：
2004
影响因子：
4.9
通讯作者：
P. Appelbaum
中科院分区：
文献类型：
--
作者：
Mahesh V Patel;N. J. de Souza;S. Gupte;M. Jafri;S. Bhagwat;Y. Chugh;H. F. Khorakiwala;M. Jacobs;P. Appelbaum
摘要WCK 771是S-（-）-那氟沙星的精氨酸盐，在葡萄球菌感染的动物模型和体外进行了评价。WCK 771对302株甲氧西林敏感株的半数抑菌浓度（MIC_（50））和MIC_（90）分别为0.03和0.03 μg/ml;对198株甲氧西林耐药株的MIC_（50）和MIC_（90）分别为0.5和1.0 μg/ml。所有甲氧西林敏感葡萄球菌均对喹诺酮类药物敏感，几乎所有耐甲氧西林葡萄球菌均对喹诺酮类药物耐药。WCK 771的效力高于阿托沙星、曲伐沙星、左氧氟沙星和环丙沙星，且效力与克林沙星相当。只有WCK 771和克林伐他汀对万古霉素中间体金黄色葡萄球菌菌株表现出较强的效力（MIC = 1 μg/ml）。WCK 771不是诺拉泵的底物，这从利血平对MIC的作用缺乏以及对外排阳性和阴性葡萄球菌引起的感染的相似保护剂量中可以看出。WCK 771通过口服和皮下途径对腹腔感染喹诺酮敏感的甲氧西林敏感的S.金黄色葡萄球菌（MSSA）菌株。对于由喹诺酮耐药的甲氧西林耐药的S。对于金黄色葡萄球菌（MRSA）菌株，皮下给药的WCK 771的活性上级曲伐沙星和司帕沙星，50%有效剂量范围为27.8至46.8 mg/kg体重。在由一种MSSA和两种MRSA菌株引起的感染的小鼠蜂窝织炎模型中，WCK 771的活性上级于利奈沙星、万古霉素和利奈唑胺，MSSA菌株的有效剂量为2.5和5 mg/kg，MRSA菌株的有效剂量高10倍。与万古霉素和利奈唑胺一样，WCK 771以50 mg/kg剂量皮下给药4次时，可根除小鼠肝脏、脾脏、肾脏和肺中的MRSA。这些研究证明了WCK 771经口和胃肠外给药治疗小鼠各种葡萄球菌感染的有效性，包括由喹诺酮耐药菌株引起的感染。
ABSTRACT WCK 771, the arginine salt of S-(−)-nadifloxacin, was evaluated in animal models of staphylococcal infection and in vitro. For 302 methicillin-susceptible strains the MIC at which 50% of isolates are inhibited (MIC50) and the MIC90 of WCK 771 were 0.03 and 0.03 μg/ml, respectively, and for 198 methicillin-resistant strains the MIC50 and the MIC90 were 0.5 and 1.0 μg/ml, respectively. All methicillin-susceptible staphylococci were quinolone susceptible, and almost all methicillin-resistant staphylococci were quinolone resistant. WCK 771 was more potent than moxifloxacin, trovafloxacin, levofloxacin, and ciprofloxacin and had potency comparable to that of clinafloxacin. Only WCK 771 and clinafloxacin demonstrated strong potencies against vancomycin-intermediate Staphylococcus aureus strains (MICs = 1 μg/ml). WCK 771 is not a substrate of the NorA pump, as evident from the lack of an effect of reserpine on the MICs and similar protective doses against infections caused by efflux-positive and -negative staphylococci. WCK 771 was effective by both the oral and the subcutaneous routes in mice infected intraperitoneally with quinolone-susceptible methicillin-susceptible S. aureus (MSSA) strains. For infections caused by quinolone-resistant methicillin-resistant S. aureus (MRSA) strains, the activity of WCK 771 administered subcutaneously was superior to those of trovafloxacin and sparfloxacin, with a 50% effective dose range of 27.8 to 46.8 mg/kg of body weight. The activity of WCK 771 was superior to those of moxifloxacin, vancomycin, and linezolid in a mouse cellulitis model of infection caused by one MSSA and two MRSA strains, with effective doses of 2.5 and 5 mg/kg for the MSSA strain and 10-fold higher effective doses for MRSA strains. WCK 771, like vancomycin and linezolid, eradicated MRSA from mouse liver, spleen, kidney, and lung when it was administered subcutaneously at a dose of 50 mg/kg for four doses. These studies have demonstrated the effectiveness of WCK 771, administered orally and parenterally, for the treatment of diverse staphylococcal infections in mice, including those caused by quinolone-resistant strains.