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dc.contributor.authorMcCallum, Andrew D
dc.contributor.authorPertinez, Henry E
dc.contributor.authorChirambo, Aaron P
dc.contributor.authorSheha, Irene
dc.contributor.authorChasweka, Madalitso
dc.contributor.authorMalamba, Rose
dc.contributor.authorShani, Doris
dc.contributor.authorChitani, Alex
dc.contributor.authorMallewa, Jane E
dc.contributor.authorMeghji, Jamilah Z
dc.contributor.authorGhany, Jehan F
dc.contributor.authorCorbett, Elizabeth L
dc.contributor.authorGordon, Stephen B
dc.contributor.authorDavies, Geraint R
dc.contributor.authorKhoo, Saye H
dc.contributor.authorSloan, Derek J
dc.contributor.authorMwandumba, Henry C
dc.date.accessioned2022-05-13T16:30:10Z
dc.date.available2022-05-13T16:30:10Z
dc.date.issued2022-05-03
dc.identifier.citationMcCallum , A D , Pertinez , H E , Chirambo , A P , Sheha , I , Chasweka , M , Malamba , R , Shani , D , Chitani , A , Mallewa , J E , Meghji , J Z , Ghany , J F , Corbett , E L , Gordon , S B , Davies , G R , Khoo , S H , Sloan , D J & Mwandumba , H C 2022 , ' High intrapulmonary rifampicin and isoniazid concentrations are associated with rapid sputum bacillary clearance in patients with pulmonary tuberculosis ' , Clinical Infectious Diseases , vol. Advance Article , ciac228 . https://doi.org/10.1093/cid/ciac228en
dc.identifier.issn1058-4838
dc.identifier.otherPURE: 278755341
dc.identifier.otherPURE UUID: e756a31a-e850-40aa-841f-2e49880c13c9
dc.identifier.otherJisc: 211559
dc.identifier.otherORCID: /0000-0002-7888-5449/work/113061055
dc.identifier.urihttp://hdl.handle.net/10023/25371
dc.descriptionThis work was supported by a Wellcome Trust Clinical PhD Fellowship [grant number 105392/B/14/Z to A.D.M. and L69AGB to JM]. ELC was supported by Wellcome [200901/Z/16/Z]. The Malawi-Liverpool-Wellcome Clinical Research Programme is supported by a strategic award from the Wellcome Trust [206545/Z/17/Z]. We also acknowledge infrastructural support for bioanalysis from the Liverpool Biomedical Research Centre funded by Liverpool Health Partners.en
dc.description.abstractBackground Intrapulmonary pharmacokinetics may better explain response to tuberculosis (TB) treatment than plasma pharmacokinetics. We explored these relationships by modelling 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 to 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 (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% HIV co-infected), 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%) unfavourable 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.
dc.format.extent9
dc.language.isoeng
dc.relation.ispartofClinical Infectious Diseasesen
dc.rightsCopyright © The Author(s) 2022. Published by Oxford University Press for the Infectious Diseases Society of America. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. https://doi.org/10.1093/cid/ciac228.en
dc.subjectAntibioticsen
dc.subjectAntitubercularen
dc.subjectTuberculosisen
dc.subjectPharmacokineticsen
dc.subjectPharmacodynamicsen
dc.subjectQR Microbiologyen
dc.subjectRB Pathologyen
dc.subjectNDASen
dc.subject.lccQRen
dc.subject.lccRBen
dc.titleHigh intrapulmonary rifampicin and isoniazid concentrations are associated with rapid sputum bacillary clearance in patients with pulmonary tuberculosisen
dc.typeJournal articleen
dc.description.versionPublisher PDFen
dc.contributor.institutionUniversity of St Andrews. Infection and Global Health Divisionen
dc.contributor.institutionUniversity of St Andrews. School of Medicineen
dc.identifier.doihttps://doi.org/10.1093/cid/ciac228
dc.description.statusPeer revieweden


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