Kaushik Amit, Makkar Nayani, Pandey Pooja, Parrish Nicole, Singh Urvashi, Lamichhane Gyanu
Taskforce to Study Resistance Emergence & Antimicrobial Development Technology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA.
Department of Microbiology, All India Institute of Medical Sciences, New Delhi, India.
Antimicrob Agents Chemother. 2015 Oct;59(10):6561-7. doi: 10.1128/AAC.01158-15. Epub 2015 Aug 10.
An effective regimen for treatment of tuberculosis (TB) is comprised of multiple drugs that inhibit a range of essential cellular activities in Mycobacterium tuberculosis. The effectiveness of a regimen is further enhanced if constituent drugs act with synergy. Here, we report that faropenem (a penem) or biapenem, doripenem, or meropenem (carbapenems), which belong to the β-lactam class of antibiotics, and rifampin, one of the drugs that forms the backbone of TB treatment, act with synergy when combined. One of the reasons (carba)penems are seldom used for treatment of TB is the high dosage levels required, often at the therapeutic limits. The synergistic combination of rifampin and these (carba)penems indicates that (carba)penems can be administered at dosages that are therapeutically relevant. The combination of faropenem and rifampin also limits the frequency of resistant mutants, as we were unable to obtain spontaneous mutants in the presence of these two drugs. The combinations of rifampin and (carba)penems were effective not only against drug-sensitive Mycobacterium tuberculosis but also against drug-resistant clinical isolates that are otherwise resistant to rifampin. A combination of doripenem or biapenem and rifampin also exhibited synergistic activity against Mycobacterium abscessus. Although the MICs of these three drugs alone against M. abscessus are too high to be of clinical relevance, their concentrations in combinations are therapeutically relevant; therefore, they warrant further evaluation for clinical utility to treat Mycobacterium abscessus infection, especially in cystic fibrosis patients.
一种有效的结核病（TB）治疗方案由多种药物组成，这些药物可抑制结核分枝杆菌一系列基本的细胞活动。如果组成药物具有协同作用，方案的有效性会进一步提高。在此，我们报告，属于β-内酰胺类抗生素的法罗培南（一种青霉烯类）或比阿培南、多立培南或美罗培南（碳青霉烯类），与作为结核病治疗基础药物之一的利福平联合使用时具有协同作用。碳青霉烯类药物很少用于结核病治疗的原因之一是所需剂量水平高，常常处于治疗极限。利福平和这些碳青霉烯类药物的协同组合表明，碳青霉烯类药物可以以治疗相关剂量给药。法罗培南和利福平的组合还限制了耐药突变体的出现频率，因为在这两种药物存在的情况下我们无法获得自发突变体。利福平和碳青霉烯类药物的组合不仅对药物敏感的结核分枝杆菌有效，而且对原本对利福平耐药的耐药临床分离株也有效。多立培南或比阿培南与利福平的组合对脓肿分枝杆菌也表现出协同活性。尽管这三种药物单独对脓肿分枝杆菌的最低抑菌浓度过高，无临床相关性，但它们在组合中的浓度具有治疗相关性；因此，它们值得进一步评估其治疗脓肿分枝杆菌感染的临床效用，尤其是在囊性纤维化患者中。
