Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

Abstract

f Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0-to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC 80 ). The tigecycline efficacy was 5.38 ؎ 2.35 log 10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log 10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC 80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC 80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC 80 and 46% for 1-log kill. For both the EC 80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was <0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment. Mycobacterium abscessus is, for all the correct reasons, considered an "antibiotic nightmare" (1). This pathogen primarily causes chronic pulmonary infections that are extremely difficult to cure owing to the extensive drug resistance intrinsic to this organism (2). Personalized treatment regimens based on in vitro drug susceptibility testing and aggressive surgical resection yielded "cure" rates of only 57% in one case series (3). Even then, over the years there is relapse and death among those who have been "cured." Thus, there has been a continued search for new drugs, with the hope to craft a new effective regimen. Tigecycline, the first developed glycylcycline, was designed to overcome mechanisms of resistance that are known for older tetracyclines, such as the active efflux and the ribosome protection mechanisms. It is considered a bacteriostatic antibiotic, sometimes bactericidal, with demonstrated broad in vitro effects on several Gram-positive and Gram-negative bacteria, including some rapidly growing mycobacteria (4-7). This broad antimicrobial spectrum, its large volume of distribution (Ն7 to 10 liters/kg), and the known intracellular accumulation represent a sound rationale for the clinical use of tigecycline (4, 5). Although tigecycline is FDA approved to be used for the treatment of complicated skin/soft tissue infections, complicated intra-abdominal infections, and community-acquired bacterial ...

New Insights in the Treatment of Nontuberculous Mycobacterial Pulmonary Disease

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