Infectious Disease

Ferro, B. E., S. Srivastava, D. Deshpande, C. M. Sherman, J. G. Pasipanodya, D. van Soolingen, J. W. Mouton, J. van Ingen and T. Gumbo (2015). “Cuddling Nightmare Bacteria: Amikacin Pharmacokinetics / Pharmacodynamics in a Novel Hollow Fiber Mycobacterium abscessus Disease Model.” Antimicrobial Agents and Chemotherapy.

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The treatment of pulmonary Mycobacterium abscessus disease treatment is associated with very high failure rates and ease of acquired drug resistance. Amikacin is the key drug in treatment regimens, but optimal doses are unknown. No good pre-clinical model exists to perform formal pharmacokinetics/pharmacodynamics experiments for this. We developed a hollow fiber system model of M. abscessus disease and studied amikacin exposure-effect and dose-scheduling. We mimicked amikacin human pulmonary pharmacokinetics. Both amikacin microbial kill and acquired drug resistance were linked to the peak to minimum inhibitory concentration (MIC) ratios; the peak/MIC associated with 80% of maximal kill (EC80) was 3.20. However, on day of the most extensive microbial kill, the bacillary burden did not fall below starting inoculum. We performed Monte Carlo simulations of 10,000 patients with pulmonary M. abscessus 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 of achieve a cumulative area under the concentration time curve of 82,232 mg*h/L x days that is associated with ototoxicity. The standard amikacin doses of 750-1,500 mg a day achieved EC80 in </=21%, while 4 grams/day achieved this in 70%, but at the cost of high rates of ototoxicity within a month or two. The susceptibility breakpoint was an MIC of 8-16 mg/L. Thus, amikacin, as currently dosed, has limited efficacy against M. abscessus. Different antibiotics should be urgently tested in our pre-clinical model and new regimens developed.