Bakthavatchalam Y D, Kumar D T, Tayubi I A, Shankar B A, Babu P, Munusamy E, Thukkaram B, Ravi R, Doss C G P, Veeraraghavan B
Department of Clinical Microbiology, Christian Medical College, Vellore, Tamil Nadu, India.
Department of Integrative Biology, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
J Appl Microbiol. 2017 Sep;123(3):615-624. doi: 10.1111/jam.13522.
Recently, the cefixime-ofloxacin combination is approved by Drug Controller General of India to treat typhoid fever. We sought to evaluate the antimicrobial activity of cefixime-ofloxacin combination against Salmonella Typhi.
A total of 283 nonduplicate S. Typhi isolates collected during 2012-2014 were included in this study. Minimum inhibitory concentration (MIC) of cefixime and ofloxacin was determined by using broth microdilution method. Combinational testing was performed by using checkerboard assay. In checkerboard assay, synergistic activity was seen in 11% of isolates, while the majority of the isolate showed indifference and none of them showed antagonism. An in silico strategy, an alternative to the animal model, was carried out to understand drug interaction and toxicity. Molecular docking results elucidated that cefixime and ofloxacin are capable of inhibiting the cell wall synthesis and DNA replication, respectively. Computational ADMET analysis showed no toxicity and no drug-drug interaction between cefixime and ofloxacin.
Cefixime-ofloxacin combination could be effective against moderately susceptible fluoroquinolone S. Typhi but not fluoroquinolone-resistant isolates.
Cefixime-ofloxacin combination with no drug-drug interaction and nontoxic predicted through computational analysis did not show antagonism against S. Typhi in in vitro. Although this study showed no adverse effects with the cefixime-ofloxacin combination, further studies on pharmacokinetic and pharmacodynamic (PK-PD) parameters of cefixime and ofloxacin combination are warranted.
最近，头孢克肟-氧氟沙星联合用药已获印度药品总监批准用于治疗伤寒热。我们试图评估头孢克肟-氧氟沙星联合用药对伤寒沙门菌的抗菌活性。
本研究纳入了2012年至2014年期间收集的283株非重复伤寒沙门菌分离株。采用肉汤微量稀释法测定头孢克肟和氧氟沙星的最低抑菌浓度（MIC）。采用棋盘法进行联合检测。在棋盘法中，11%的分离株表现出协同活性，而大多数分离株表现为无相互作用，且无一表现出拮抗作用。为了解药物相互作用和毒性，采用了一种替代动物模型的计算机模拟策略。分子对接结果表明，头孢克肟和氧氟沙星分别能够抑制细胞壁合成和DNA复制。计算ADMET分析显示头孢克肟和氧氟沙星之间无毒性且无药物-药物相互作用。
头孢克肟-氧氟沙星联合用药可能对中度敏感的氟喹诺酮类伤寒沙门菌有效，但对耐氟喹诺酮类分离株无效。
通过计算分析预测，头孢克肟-氧氟沙星联合用药无药物-药物相互作用且无毒，在体外对伤寒沙门菌未表现出拮抗作用。尽管本研究显示头孢克肟-氧氟沙星联合用药无不良反应，但仍有必要进一步研究头孢克肟和氧氟沙星联合用药的药代动力学和药效学（PK-PD）参数。
