Replacing rifampicin with minocycline increases the activity of the treatment regimen for Mycobacterium avium complex pulmonary disease in a dynamic hollow-fibre system

Int J Antimicrob Agents. 2024 Dec 27:107423. doi: 10.1016/j.ijantimicag.2024.107423. Online ahead of print.

Abstract

Mycobacterium avium complex bacteria cause chronic pulmonary disease (MAC-PD) in susceptible patients [1]. The recommended treatment regimen (rifampicin, ethambutol and azithromycin) achieves 65% cure rates but with considerable toxicity and drug-drug interactions [2,3]. Minocycline proved active in monotherapy experiments using the hollow-fibre model [4]. We compared the efficacy of the recommended regimen with a minocycline, ethambutol, and azithromycin regimen using this model. Epithelial lining fluid pharmacokinetic profiles of the recommended regimen and minocycline, ethambutol, azithromycin regimen were simulated. THP-1 cells infected with M. avium ATCC 700898 were exposed to these regimens for 21 days. Pharmacokinetic profiles were determined at day 0 and day 21. The pharmacodynamic effect was measured by determining bacterial densities at days 0, 3, 7, 14 and 21 for intra- and extracellular fractions. Emergence of macrolide-resistance was monitored by inoculating azithromycin-containing agar, MIC measurements and resistance mutation analysis. The minocycline-containing regimen exhibited a 1.5 log10 CFU/ml lower bacterial burden than the recommended regimen at day 7, though both regimens lost effectiveness over time. Treatment failure in both arms was not linked to the emergence macrolide-resistance. Pharmacokinetic profiles simulated in the model matched those in MAC-PD patients. Replacing rifampicin with minocycline increased the antimycobacterial activity of the MAC-PD treatment regimen in the hollow-fibre model, without jeopardizing the prevention of macrolide-resistance. This promising minocycline-containing regimen is a candidate for inclusion in clinical trials.

Keywords: Antibiotics; Hollow-fibre infection model; Mycobacteriology; PK/PD; Pharmacokinetics.