Drug concentration at the site of disease in children with pulmonary tuberculosis

Abstract

Background Current TB treatment for children is not optimized to provide adequate drug levels in TB lesions. Dose optimization of first-line antituberculosis drugs to increase exposure at the site of disease could facilitate more optimal treatment and future treatment-shortening strategies across the disease spectrum in children with pulmonary TB. Objectives To determine the concentrations of first-line antituberculosis drugs at the site of disease in children with intrathoracic TB. Methods We quantified drug concentrations in tissue samples from 13 children, median age 8.6 months, with complicated forms of pulmonary TB requiring bronchoscopy or transthoracic surgical lymph node decompression in a tertiary hospital in Cape Town, South Africa. Pharmacokinetic models were used to describe drug penetration characteristics and to simulate concentration profiles for bronchoalveolar lavage, homogenized lymph nodes, and cellular and necrotic lymph node lesions. Results Isoniazid, rifampicin and pyrazinamide showed lower penetration in most lymph node areas compared with plasma, while ethambutol accumulated in tissue. None of the drugs studied was able to reach target concentration in necrotic lesions. Conclusions Despite similar penetration characteristics compared with adults, low plasma exposures in children led to low site of disease exposures for all drugs except for isoniazid.

Aerosolization of viable Mycobacterium tuberculosis bacilli by tuberculosis clinic attendees independent of sputum-Xpert Ultra status

“…7 ). This is unlikely to be due to poor penetration of drugs since BAL sampling of patients on treatment demonstrate sterilizing concentrations of the standard TB drugs in PLF ( 48 – 51 ). Alternatively, this aerosolized Mtb population may exhibit phenotypic drug tolerance with clearance from this compartment primarily driven by innate immune processes.…”