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

Ferro, Beatriz E.; Srivastava, Shashikant; Deshpande, Devyani; Pasipanodya, Jotam G.; Soolingen, Dick van; Mouton, Johan W.; Ingen, Jakko van; Gumbo, Tawanda

doi:10.1128/aac.02821-15

Cited by 24 publications

(18 citation statements)

References 49 publications

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“…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.…”

Section: Discussionmentioning

confidence: 82%

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Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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f Mycobacterium abscessus causes chronic pulmonary infections that are extremely difficult to cure. The currently recommended combination therapy is associated with high failure rates and relapse. Tigecycline has been explored in salvage regimens, with a response rate of 43% in those who received at least a month of therapy. We performed a dose-response study in a hollow-fiber system model of pulmonary M. abscessus infection in which we recapitulated tigecycline human pulmonary concentration-time profiles of 8 different doses for 21 days. We identified the maximal kill or efficacy in CFU per milliliter and the ratio of the 0-to 24-h area under the concentration-time curve to MIC (AUC/MIC) associated with 80% efficacy (EC 80 ). The tigecycline efficacy was 5.38 ؎ 2.35 log 10 CFU/ml, and the drug achieved the unprecedented feat of a bacterial level of 1.0 log 10 CFU/ml below the pretreatment inoculum (1-log kill) of M. abscessus in the hollow-fiber system. The EC 80 AUC/MIC ratio was 36.65, while that for a 1-log kill was 44.6. Monte Carlo experiments with 10,000 patients were used to identify the clinical dose best able to achieve the EC 80 or 1-log kill. The standard dose of 100 mg/day had a cumulative fraction of response of 51% for the EC 80 and 46% for 1-log kill. For both the EC 80 target and 1-log kill, the optimal tigecycline clinical dose was identified as 200 mg/day. The susceptibility breakpoint was <0.5 mg/liter. Tigecycline is the most active single agent evaluated to date, and we propose that 200 mg/day be examined as the backbone of new combination therapy regimens to replace current treatment. Mycobacterium abscessus is, for all the correct reasons, considered an "antibiotic nightmare" (1). This pathogen primarily causes chronic pulmonary infections that are extremely difficult to cure owing to the extensive drug resistance intrinsic to this organism (2). Personalized treatment regimens based on in vitro drug susceptibility testing and aggressive surgical resection yielded "cure" rates of only 57% in one case series (3). Even then, over the years there is relapse and death among those who have been "cured." Thus, there has been a continued search for new drugs, with the hope to craft a new effective regimen. Tigecycline, the first developed glycylcycline, was designed to overcome mechanisms of resistance that are known for older tetracyclines, such as the active efflux and the ribosome protection mechanisms. It is considered a bacteriostatic antibiotic, sometimes bactericidal, with demonstrated broad in vitro effects on several Gram-positive and Gram-negative bacteria, including some rapidly growing mycobacteria (4-7). This broad antimicrobial spectrum, its large volume of distribution (Ն7 to 10 liters/kg), and the known intracellular accumulation represent a sound rationale for the clinical use of tigecycline (4, 5). Although tigecycline is FDA approved to be used for the treatment of complicated skin/soft tissue infections, complicated intra-abdominal infections, and community-acquired bacterial ...

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Section: Discussionmentioning

confidence: 82%

“…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.…”

Section: Methodsmentioning

confidence: 99%

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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“…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.…”

Section: The Lancet Respiratory Medicine Commissionmentioning

confidence: 99%

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

Dheda

Gumbo

Maartens

et al. 2017

The Lancet Respiratory Medicine

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“…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.…”

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confidence: 99%

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

Ferro

Srivastava

Deshpande

et al. 2016

Antimicrob Agents Chemother

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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 ...

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

Cited by 24 publications

References 49 publications

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

Tigecycline Is Highly Efficacious against Mycobacterium abscessus Pulmonary Disease

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

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

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