Failure of the Amikacin, Cefoxitin, and Clarithromycin Combination Regimen for Treating Pulmonary Mycobacterium abscessus Infection

Abstract

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of -0.09 (95% confidence interval, -0.04 to 0.03) log10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed.

FIG 1

Efficacy of standard combination regimen against M. abscessus and resistance emergence during 1 month of treatment. (a) The initial very slow decline, slower than the doubling time of the bacteria, was reversed after 14 days, and all treated systems started to grow. (b) Changes in bacterial burden and the emergence of acquired drug resistance with time during repetitive sampling in nontreated controls. Total M. abscessus population in untreated control (solid line) and amikacin- or cefoxitin-resistant subpopulation (dashed lines) over the course of 28 days. The amikacin- and cefoxitin-resistant proportion was stable in the untreated control. (c) Changes in bacterial burden and the emergence of acquired drug resistance with time during repetitive sampling in systems treated with standard therapy. Starting with no CFU per milliliter resistant to 3 times the cefoxitin MIC, there developed a higher cefoxitin-resistant subpopulation of M. abscessus in the systems exposed to standard therapy, coincident with cessation of effect of the triple regimen.