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High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis

McCallum, Andrew, Pertinez, Henry E, Chirambo, Aaron P, Sheha, Irene, Chasweka, Madalitso, Malamba, Rose, Shani, Doris, Chitani, Alex, Mallewa, Jane E, Meghji, Jamilah ORCID: https://orcid.org/0000-0002-4693-8884, Ghany, Jehan F, Corbett, Elizabeth L, Gordon, Stephen ORCID: https://orcid.org/0000-0001-6576-1116, Davies, Geraint R, Khoo, Saye H, Sloan, Derek J and Mwandumba, Henry ORCID: https://orcid.org/0000-0003-4470-3608 (2022) 'High Intrapulmonary Rifampicin and Isoniazid Concentrations Are Associated With Rapid Sputum Bacillary Clearance in Patients With Pulmonary Tuberculosis'. Clinical Infectious Diseases. (In Press)

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Abstract

Background
Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modeling bacillary clearance in sputum in adult patients on first-line treatment in Malawi.
Methods
Bacillary elimination rates (BER) were estimated using linear mixed-effects modelling of serial time-to-positivity in mycobacterial growth indicator tubes for sputum collected during the intensive phase of treatment (weeks 0–8) for microbiologically confirmed TB. Population pharmacokinetic models used plasma and intrapulmonary drug levels at 8 and 16 weeks. Pharmacokinetic-pharmacodynamic relationships were investigated using individual-level measures of drug exposure (area-under-the-concentration-time-curve [AUC] and Cmax) for rifampicin, isoniazid, pyrazinamide, and ethambutol, in plasma, epithelial lining fluid, and alveolar cells as covariates in the bacillary elimination models.
Results
Among 157 participants (58% human immunodeficiency virus [HIV] coinfected), drug exposure in plasma or alveolar cells was not associated with sputum bacillary clearance. Higher peak concentrations (Cmax) or exposure (AUC) to rifampicin or isoniazid in epithelial lining fluid was associated with more rapid bacillary elimination and shorter time to sputum negativity. More extensive disease on baseline chest radiograph was associated with slower bacillary elimination. Clinical outcome was captured in 133 participants, with 15 (11%) unfavorable outcomes recorded (recurrent TB, failed treatment, or death). No relationship between BER and late clinical outcome was identified. Conclusions
Greater intrapulmonary drug exposure to rifampicin or isoniazid in the epithelial lining fluid was associated with more rapid bacillary clearance. Higher doses of rifampicin and isoniazid may result in sustained high intrapulmonary drug exposure, rapid bacillary clearance, shorter treatment duration and better treatment outcomes.

Item Type: Article
Subjects: QV Pharmacology > QV 38 Drug action.
QY Clinical Pathology > Diagnostic Tests > QY 120 Sputum
WF Respiratory System > Tuberculosis > WF 200 Tuberculosis (General)
WF Respiratory System > Tuberculosis > WF 300 Pulmonary tuberculosis
WF Respiratory System > Tuberculosis > WF 360 Drug therapy
Faculty: Department: Clinical Sciences & International Health > Clinical Sciences Department
Digital Object Identifer (DOI): https://doi.org/10.1093/cid/ciac228
SWORD Depositor: JISC Pubrouter
Depositing User: JISC Pubrouter
Date Deposited: 21 Jul 2022 10:56
Last Modified: 21 Jul 2022 10:56
URI: https://archive.lstmed.ac.uk/id/eprint/20402

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