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

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.

[Assessment of the invasiveness of rapidly-growing nonpigmented mycobacteria with the fibroblast microcolony assay]. / Evaluación de la capacidad invasiva de las micobacterias no pigmentadas de crecimiento rápido mediante el estudio de la morfología de las microcolonias en fibroblastos.

OBJECTIVE: The invasive capacity of rapidly-growing nonpigmented mycobacteria strains was evaluated by means of a fibroblast microcolony assay and related to the colony phenotype on Middlebrook 7H11 and to the clinical significance of the isolates. METHODS: Twenty-nine strains [Mycobacterium chelonae (8), M. fortuitum (6), M. peregrinum (5), M. abscessus (5), M. mucogenicum (4) and M. septicum (1)], proceeding from a bacterial collection and clinical isolates, were evaluated. The smooth or rough phenotype of the colonies was assessed in Middlebrook 7H11 medium. Intracellular invasiveness was determined by the fibroblast-microcolony assay described by Shepard. Quantitative culture characteristics were compared with Student's t-test, and qualitative characteristics with Fisher's exact test. RESULTS: No significant differences were found between colonies with different phenotypes or strains having a different clinical significance, except for two strains of Mycobacterium chelonae isolated from cases of catheter-related bacteremia, which showed elongated microcolonies. M. fortuitum and M. peregrinum strains showed larger microcolonies than M. chelonae, M. abscessus and M. mucogenicum, and displayed a fluffy appearance, while the latter two strains showed rounded colonies. CONCLUSION: Very few strains of mycobacteria had invasive capacity and the majority of strains isolated from human infections do not show this characteristic; hence this trait is not essential for mycobacteria to cause infection in humans.

[Manifestations, diagnosis and treatment of non-tuberculous mycobacterial infections in patients with HIV infection]. / Manifestations, diagnostic et traitement des infections mycobactériennes non tuberculeuses chez les patients porteurs du VIH.

The most frequent bacterial infections in patients infected with HIV and suffering from AIDS are non-tuberculous mycobacterial infections. Their incidence is increasing all the more as the survival of profoundly immunocompromised patients is prolonged. There are unknown factors as regards the precise origin of these infections and as to the exact epidemiology of atypical mycobacteria. It is known that 95 per cent of atypical mycobacterial infections are due to M. avium. If the pathophysiology of the infection (involving the intervention of cytokines and also factors in relation to the virulence of the germ) is imperfectly understood, the atypical mycobacteria are an independent cause of mortality in advanced stages of the disease. The clinical picture is that of a low grade fever with weight loss and a deterioration in the general physical state. There are subtle physical signs such as a fall in the functional capacity accompanied by weight loss and an unexplained anaemia these should also suggest a diagnosis. More rarely the infection will be localised. The clinical diagnosis will be confirmed by bacteriology which has been aided by recent progress in molecular biology. With the arrival of the newer macrolides it has been shown that treatment prolongs survival in a significant manner. Current recommendations consist of a treatment with a combined regime including a minimum of Clarithyromycin and Ethambutol. The place for polychemotherapy remains to be determined in particular the role for Rifabutine and Amikacine. Immunomodulation by interferon-gamma or GCSF are also under review. The duration of treatment and the necessity of long term suppressive treatment is the object of randomised studies. Prophylaxis is currently recommended for patients with CD4 < 75/mm3. The role of Rifabutine and the new macrolides remains to be determined. Finally, in a large European study the objective is to compare prophylaxis to systematic bacteriological surveillance both as regards efficacy, tolerance, and in terms of pharmaco-economics.