Moxifloxacin’s limited efficacy in the hollow-fiber model of mycobacterium abscessus disease.
Tawanda Gumbo M.D.
Ferro, B. E., S. Srivastava, D. Deshpande, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2016). “Moxifloxacin’s limited efficacy in the hollow-fiber model of mycobacterium abscessus disease.” Antimicrob Agents Chemother Apr 11 [Epub ahead of print].
Current regimens used to treat pulmonaryMycobacterium abscessusdisease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow fiber system studies in whichM. abscessuswas exposed to moxifloxacin lung concentration-time profiles similar to human doses between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter in ourM. abscessusstrain, suggesting bactericidal activity. Measurement of moxifloxacin concentrations in each hollow fiber system revealed an elimination rate (kel) of 0.11+/-0.05 hr-1(half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emaxwas 3.15+/-1.84 log10CFU/ml on day 3, and the exposure mediating 50% of Emax(EC50) was a 0-24 hour area under the concentration time curve (AUC0-24) to MIC ratio of 41.99+/-31.78 (r2=0.99). The EC80was an AUC0-24/MIC of 102.11. However no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was re-growth beyond day 3 in all doses, with replacement by resistant subpopulation that had an MIC >32 mg/liter by the end of experiment. A quadratic function best described the relationship between AUC0-24/MIC and moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400-800 mg/day doses would achieve or exceed the EC80in /=12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means almost allM. abscessusclinical strains were moxifloxacin-resistant by these criteria. While moxifloxacin’s efficacy againstM. abscessuswas poor, formal combination therapy studies with moxifloxacin are still recommended.