Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases | 2021
Standard therapy of Mycobacterium avium complex pulmonary disease shows limited efficacy in an open source hollow fiber system that simulates human plasma and epithelial lining fluid pharmacokinetics.
Abstract
OBJECTIVES\nMycobacterium avium complex (MAC) bacteria can cause chronic pulmonary disease (PD). Current treatment regimens of azithromycin, ethambutol and rifampicin have culture conversion rates of around 65%. Dynamic, pre-clinical models to assess the efficacy of treatment regimens are important to guide clinical trial development. The hollow fiber system (HFS) has been applied but reports lack experimental details.\n\n\nMETHODS\nWe simulated the human pharmacokinetics of azithromycin, ethambutol and rifampicin both in plasma and epithelial lining fluid (ELF) in a hollow fiber system (HFS), exposing THP-1 cells infected with M. avium to the triple-drug regimen for 3\xa0weeks. We accounted for drug-drug interactions and protein-binding and provide all laboratory protocols. We differentiated the effects on the intracellular and extracellular mycobacterial population.\n\n\nRESULTS\nThe antibiotic concentrations in the HFS accurately reflected the time to peak concentration (Tmax), the peak concentration (Cmax), and half-life of azithromycin, rifampicin and ethambutol in plasma and ELF reported in literature. We find that plasma drug concentrations fail to hold the MAC bacterial load static (ΔLog10 CFU/mlControl:Regimen = 0.66 ± 0.76 and 0.45 ± 0.28 at 3 and 21\xa0days); ELF concentrations do hold the bacterial load static for 3\xa0days and inhibit bacterial growth for the duration of the experiment (ΔLog10 CFU/mlControl:Regimen = 1.1 ± 0.1 and 1.64 ± 0.59 at 3 and 21\xa0days).\n\n\nCONCLUSIONS\nIn our model, the current therapy against MAC is ineffective, even when accounting for antibiotic accumulation at the site of infection and intracellularly. New treatment regimens need to be developed and be compared to currently recommended regimens in dynamic models prior to clinical evaluation. With the publication of all protocols we aim to open this technology to new users.