Amikacin Pharmacokinetics/Pharmacodynamics in a Novel Hollow-Fiber Mycobacterium abscessus Disease Model

Abstract

The treatment of pulmonary Mycobacterium abscessus disease is associated with very high failure rates and easily acquired drug resistance. Amikacin is the key drug in treatment regimens, but the optimal doses are unknown. No good preclinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments to determine these optimal doses. We developed a hollow-fiber system model of M. abscessus disease and studied amikacin exposure effects and dose scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak concentration-to-MIC ratios; the peak/MIC ratio associated with 80% of maximal kill (EC80) was 3.20. However, on the day of the most extensive microbial kill, the bacillary burden did not fall below the starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus infection and examined the probability that patients treated with one of 6 doses from 750 mg to 4,000 mg would achieve or exceed the EC80. We also examined these doses for the ability to achieve a cumulative area under the concentration-time curve of 82,232 mg · h/liter × days, which is associated with ototoxicity. The standard amikacin doses of 750 to 1,500 mg a day achieved the EC80 in ≤ 21% of the patients, while a dose of 4 g/day achieved this in 70% of the patients but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8 to 16 mg/liter. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. It is urgent that different antibiotics be tested using our preclinical model and new regimens developed.

FIG 1

Amikacin concentration-effect response in test tubes. The graph shows impressive microbial kill after 3 days of incubation in test tubes. Surprisingly, the pattern of microbial kill, characterized by maxing out at 2 to 4 times the MIC, would be more consistent with time-dependent killing instead of concentration-dependent killing.

FIG 2

Changes in bacterial burden and amikacin-resistant subpopulation with time. (A to D) The total M. abscessus population (solid lines) and amikacin-resistant subpopulation (dashed lines) over the course of 14 days of exposure to different C_max/MIC exposures are shown. There was a higher amikacin-resistant subpopulation of M. abscessus as the C_max/MIC increased, so that at higher C_max/MIC ratios (C and D), the total population had been completely replaced by the amikacin-resistant subpopulation by day 14.

FIG 3

Amikacin exposure effect in the hollow-fiber system. The results are shown up to day 7, at which point the drug-resistant subpopulation had begun to replace the total population in some systems. This is reflected by the increase in E_max each day until day 5, after which it began to decline. At the maximal microbial kill, the bacterial burden barely fell below the stasis line, suggesting that in fact amikacin is not bactericidal in the hollow-fiber system.

FIG 4

Amikacin-resistant subpopulation evolution with duration of treatment. The curves for each day are piecewise for the U-shaped relationship between exposure versus size of the drug-resistant subpopulation. With increasing time, the baseline amikacin-resistant subpopulation in the absence of drug exposure grows so that curves start at a different y intercept on each day. For days 1 and 2, the curve shape is an inverted U curve; at day 3, it is a straight line, and then it switches to an upright “U.” However, by day 14, the right side of the curve has straightened out, which means that there was no amikacin C_max/MIC ratio high enough to reduce the size of the drug-resistant subpopulation, and the curve is no longer a “U.”

FIG 5

Probability target attainment of different amikacin doses in 10,000 patients. (A) At doses of 750 mg and 1,000 mg, which are standard doses, there was very poor target attainment at the most commonly encountered MICs. The target attainment fell below 90% at the 8 mg/liter MIC. (B) At doses of 1,500 mg to 2,000 mg, <90% of the patients achieved the target C_max/MIC after the MIC of 8 mg/liter. At a dose of 15 mg/kg of body weight, patients weighing up 100 kg would have 1,500 mg as normal dose, while the 2,000-mg dose is higher than currently administered. (C) Doses of 3,000 mg and 4,000 mg would better attain target concentrations, but even at these high doses, target attainment falls below 90% at an MIC of 32 mg/liter. (D) Probability of ototoxicity in 10,000 patients exposed to different amikacin concentrations for different durations of therapy, indicating a rapid increase in the odds of attaining toxic cumulative AUCs (cAUC) with just 2 months of therapy for doses of ≥2,000 mg.