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

Abstract

fThe 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 (EC 80 ) 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 EC 80 . 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 EC 80 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. Mycobacterium abscessus is a rapidly growing mycobacterium (RGM) responsible for about 80% of all pulmonary infections caused by RGM (1). It is one of the most drug-resistant microorganisms encountered in the clinic, far worse than extensively and totally drug-resistant Mycobacterium tuberculosis; this is a reason why it is considered the "new antibiotic nightmare" (2). The current treatment for M. abscessus diseases varies according to the infecting subspecies (3); in general, it involves a backbone of amikacin in combination with clarithromycin and either cefoxitin or imipenem early during therapy, followed by subsequent use of oral antibiotics, which is analogous to the initial and continuation phases of tuberculosis treatment (1). Unfortunately, at least half of the patients either fail this therapy, relapse, or die; there is no reliable antibiotic regimen that cures M. abscessus lung disease (1, 4). Several other regimens have been tried and found wanting. In such regimens and the standard regimen, the doses were chosen based on what has worked well in mundane Gramnegative bacilli. No formal antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) analyses have been performed with M. abscessus. Our time-kill assays in the past demonstrated that amikacin was the most active antibiotic compared to cefoxitin and clarithromycin (5)....

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

“…For the first time in the HFS model of pulmonary M. abscessus infection, a drug exhibited a considerable microbial kill below the stasis line, exceeding what has been previously observed for amikacin or moxifloxacin (12,13). This magnitude of the efficacy means that tigecycline could enter a regimen as the first truly bactericidal drug for M. abscessus.…”

“…The hollow-fiber system (HFS) model of pulmonary M. abscessus infection was previously developed and used to perform pharmacokinetic/pharmacodynamic (PK/PD) evaluation of amikacin and moxifloxacin (12,13). The peripheral compartments of 8 HFSs were each inoculated with 20 ml of 6 log 10 CFU/ml M. abscessus.…”

The epidemiology, pathogenesis, transmission, diagnosis, and management of multidrug-resistant, extensively drug-resistant, and incurable tuberculosis

“…This U-shaped relationship, first described in hollow-fibre models for isoniazid and pyrazinamide for M tuberculosis, has since been identified with other antibiotics in their relationships with other mycobacteria, including M abscessus. 432,433 For M tuberculosis, the relationship between exposure and the bacterial burden of the drug-resistant subpopulation forms a U-shaped curve early during therapy (figure 10). As drug exposure increases (eg, as C max /MIC increases) there is a progressive decrease in the size of the drug-resistant subpopulation, indicating suppression of acquired drug resistance.…”

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

“…We achieved an AUC 0 -24 /MIC of 5.3 mg · h/liter for clarithromycin, a percentage of time above the MIC of 100% for cefoxitin, and an fC max /MIC of 4.0 of amikacin, so that each drug was at optimal free-drug exposure (3). These exposures are actually better than those achieved in most patients with standard dosing, based on prior work (3,6,7,9).We sampled each system's peripheral compartment on days 0, 1, 2, 3, 5, 7, 10, 14, 21, and 28 of treatment, washed the cultures in saline to avoid antibiotic carryover, serially diluted the cultures, and cultured them on antibiotic-free Middlebrook 7H10 agar. The size of the resistant subpopulation was quantified by culturing on Middlebrook agar plates containing 3 times the MIC of each antibiotic.…”