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

Abstract

In a hollow-fiber model, we mimicked the drug exposures achieved in the lungs of humans treated with standard amikacin, clarithromycin, and cefoxitin combination therapy for Mycobacterium abscessus infection. At optimal dosing, a kill rate of ؊0.09 (95% confidence interval, ؊0.04 to 0.03) log 10 CFU per ml/day was achieved over the first 14 days, after which there was regrowth due to acquired drug resistance. Thus, the standard regimen quickly failed. A new regimen is needed. Clinicians treat Mycobacterium abscessus pulmonary disease with a combination of amikacin, clarithromycin, and cefoxitin for 1 to 2 months, followed by an oral maintenance regimen, usually with a fluoroquinolone, based on the recommendations of experts (1). However, the use of this approach "cures" only 50% even with adjunctive surgery, most of whom relapse or die (2). We have developed a hollow-fiber model of M. abscessus (HFS-M. abscessus) and evaluated the effect of monotherapy of amikacin and moxifloxacin in the system. Each drug failed dramatically, and acquired drug resistance (ADR) developed (3, 4). Since these drugs are given as combination therapy in patients, they could still work in combination. Here, we evaluated the performance of the standard combination regimen of amikacin, cefoxitin, and clarithromycin in the HFS-M. abscessus to determine potential synergy, and even more importantly, whether the combination therapy could prevent ADR.Antibiotics were purchased from the Baylor University Medical Center Pharmacy (Dallas, TX) and from Sigma-Aldrich (St. Louis, MO). Antibiotics were dissolved in water-methanol (clarithromycin), sterile filtered, and diluted to the desired concentrations in Middlebrook 7H9 broth (here broth; Remel, Lenexa, KS). Stock solutions of M. abscessus ATCC 19977 (ATCC, Manassas, VA) were grown to logarithmic-growth phase in the broth. MICs were measured using broth microdilution (5). The amikacin, cefoxitin, and clarithromycin MICs were 32, 16, and 8 mg/liter, respectively.The peripheral compartments of six HFS-M. abscessus systems were inoculated with 20 ml of 6.0 log 10 CFU/ml M. abscessus, as previously described (3). Three systems were immediately treated with a combination of amikacin, cefoxitin, and clarithromycin, while three replicate systems were nontreated controls. Amikacin, cefoxitin, and clarithromycin were administered via syringe pumps for 28 days, as in patients. We mimicked free-drug area under the concentration-time curve from 0 to 24 h (fAUC 0 -24 ), peak concentration (fC max ), and time to maximum concentration achieved in the lungs of humans treated with amikacin and clarithromycin administered once daily, at 1,000 mg, and cefoxitin administered at 2 g four times a day (6, 7). Different half-lives in each HFS-M. abscessus system were achieved, as described by us in the past (8). Antibiotic concentrations achieved in all the systems were validated by sampling from the central compartment of each system at seven time points over 24 h postdose, after which concentrations were assayed in ...

The Diverse Cellular and Animal Models to Decipher the Physiopathological Traits of Mycobacterium abscessus Infection

“…This includes the ability to persist within granulomatous structures and to generate pulmonary caseous lesions (Tomashefski et al, 1996; Medjahed et al, 2010). Alarming is the natural resistance of Mabs to most antitubercular drugs, making these infections particularly long, difficult to treat and associated with a significant therapeutic failure rate (Ferro et al, 2016). Mabs manifests as either a smooth (S) or a rough (R) colony morphotype that can result in different clinical outcomes.…”

Moxifloxacin efficacy againstMycobacterium abscessus in vivousing zebrafish model

“…This situation is worsened by the fact that antibio-therapy against M. abscessus is often unsuccessful and/or poorly tolerated by patients. M. abscessus is notorious for being intrinsically resistant to most antibiotics [7], thus rendering these infections particularly complicated, difficult to treat, and associated with a high rate of therapeutic failure [30].…”

Preclinical Pharmacokinetic and Pharmacodynamic Data To Support Cefoxitin Nebulization for the Treatment of Mycobacterium abscessus

“…Since, according to Lavollay et al (17) and Greendyke and Byrd (21), FOX is supposed to possess bacteriostatic activity against M. abscessus, a growth inhibition PD model was selected with a single homogenous bacterial population. This model provided reasonably good data fitting (see the supplemental material), but noticeably, using the same strain (CIP 104536), Ferro et al have identified a FOX-resistant subpopulation, preexistent at time zero (22), suggesting that the PK/PD model with a single homogenous bacterial population is not appropriate. However, our initial data set, with regrowth observed at only one FOX concentration, was probably not sufficiently informative to support the superiority of two subpopulations (S and R) versus one population PD model.…”