Moxifloxacin's Limited Efficacy in the Hollow-Fiber Model of Mycobacterium abscessus Disease

Abstract

Current regimens used to treat pulmonary Mycobacterium abscessus disease have limited efficacy. There is an urgent need for new drugs and optimized combinations and doses. We performed hollow-fiber-system studies in which M. abscessus was exposed to moxifloxacin lung concentration-time profiles similar to human doses of between 0 and 800 mg/day. The minimum bactericidal concentration and MIC were 8 and 2 mg/liter, respectively, in our M. abscessus strain, suggesting bactericidal activity. Measurement of the moxifloxacin concentrations in each hollow-fiber system revealed an elimination rate constant (kel) of 0.11 ± 0.05 h(-1) (mean ± standard deviation) (half-life of 9.8 h). Inhibitory sigmoid maximal effect (Emax) modeling revealed that the highest Emax was 3.15 ± 1.84 log10 CFU/ml on day 3, and the exposure mediating 50% of Emax (EC50) was a 0- to 24-h area under the concentration time curve (AUC0-24)-to-MIC ratio of 41.99 ± 31.78 (r(2) = 0.99). The EC80 was an AUC0-24/MIC ratio of 102.11. However, no moxifloxacin concentration killed the bacteria to burdens below the starting inoculum. There was regrowth beyond day 3 in all doses, with replacement by a resistant subpopulation that had an MIC of >32 mg/liter by the end of the experiment. A quadratic function best described the relationship between the AUC0-24/MIC ratio and the moxifloxacin-resistant subpopulation. Monte Carlo simulations of 10,000 patients revealed that the 400- to 800-mg/day doses would achieve or exceed the EC80 in ≤12.5% of patients. The moxifloxacin susceptibility breakpoint was 0.25 mg/liter, which means that almost all M. abscessus clinical strains are moxifloxacin resistant by these criteria. While moxifloxacin's efficacy against M. abscessus was poor, formal combination therapy studies with moxifloxacin are still recommended.

FIG 1

Moxifloxacin exposure-effect against M. abscessus in the HFS. None of the moxifloxacin exposures evaluated attained killing below the starting inoculum of 6.0 log₁₀ CFU/ml at any point during the study. Regrowth was observed after day 3 in all systems.

FIG 2

Moxifloxacin exposure versus M. abscessus burden. Inhibitory sigmoid E_max curves are shown for the first 3 days, prior to replacement of microbial population by drug-resistant subpopulation. The highest E_max was encountered on day 3, but not even that produced kill below the stasis level.

FIG 3

Changes in total and moxifloxacin-resistant subpopulations with time. Total M. abscessus population (solid lines) and moxifloxacin-resistant subpopulation (hatched lines) over the course of 21 days of treatment with different moxifloxacin AUC_0–24/MIC exposures. (A) Control and three lower exposures. While the drug-resistant subpopulation increased with time, especially beyond day 10, it had not completely replaced the total population in these lower doses, with the highest dose among these lower doses associated with the largest moxifloxacin-resistant subpopulation. (B) At the three highest exposures, the total population had been completely replaced by the moxifloxacin-resistant subpopulation by day 14. (C) The relationship between moxifloxacin AUC/MIC and size of subresistant subpopulation is described by systems of evolving U-shaped curves. At day 1 it was a straight line, then it switched to an inverted U-shaped curve that was more pronounced by day 21.

FIG 4

Probability of target attainment of three different moxifloxacin doses in 10,000 patients. Target attainment probability at each MIC fell to 0% after the 0.25-mg/liter MIC for a dose of 400 mg and to just above 60% for 600 mg. The target attainment probability for a dose of 800 mg a day plummeted after the 0.5-mg/liter MIC. Since the proportion of clinical isolates with an MIC of >0.25 mg/liter is large (and 0% of these achieve the EC₈₀), the fraction of all patients who will achieve the EC₈₀ is very small.

FIG 5

Moxifloxacin MIC distribution in three different practice locations. The MIC distribution from South Korea was used for the Monte Carlo simulations; the other two settings are used as comparators. Notably, the MIC distributions from the Netherlands and from Texas, United States, show most isolates to be resistant to moxifloxacin.