https://doi.org/10.4081/monaldi.2024.3036
Study of risk factors and clinical management of patients with clinical non-response due to low plasma levels of anti-tubercular drugs
Submitted: April 28, 2024
Accepted: May 3, 2024
Published: July 23, 2024
Accepted: May 3, 2024
Abstract Views: 353
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
This study was carried out to assess the role of therapeutic drug monitoring of crucial first-line anti-tubercular drugs: rifampicin (R) and isoniazid (H) among 75 non-responding proven drug-sensitive tuberculosis patients on treatment followed by intervention in field conditions. The intervention was done in the form of either an increase in the dosage of R and H in patients with minimally low drug levels or a modification of the regimen in a certain group of patients with significantly low drug levels by augmenting it with three or four second-line drugs in addition to standard first-line drugs. This study also aimed to determine the relationship between the measured plasma concentration of anti-tubercular drugs and various demographic, microbiological, radiological, and malabsorption factors and the presence of co-morbidities affecting them. The study also focused on the clinical impact of the intervention for low plasma levels of anti-TB drugs on TB treatment outcomes. In our study overall, 85.5% of patients had low levels of any drug. In 85.3% of patients, R levels were low, and in 39.1%, H levels were low. On univariate analysis, low body mass index (BMI), hypoalbuminemia, bilateral disease on chest X-rays, and the presence of cavities were found to be significantly associated with low drug levels, while none of the factors were independently significantly associated. Low BMI, pulmonary tuberculosis and disseminated tuberculosis, far-advanced disease and bilateral disease on chest X-ray, presence of cavities, and only low R levels were associated with unfavorable outcomes, with none of the factors found to be significant on multivariate analysis. In our study, it was seen that the treatment outcome was favorable in 59.6% of patients in whom this intervention was done by augmenting the treatment regimen with three/four second-line drugs along with increasing the dose of R and H. To conclude, various factors may be associated with low plasma levels of anti-tubercular drugs. If such patients show clinical non-response after >6 months of treatment and have significantly low drug levels, with an absence of drug resistance, their treatment regimen may need augmentation with three/four second-line drugs along with an increase in the dose of R and H, which may lead to a favorable outcome.
WHO. Global tuberculosis report 2023. Available from: https://www.who.int/teams/global-tuberculosis-programme/tb-reports/global-tuberculosis-report-2023. Accessed on: 01/11/2023.
Peloquin CA. Pharmacological issues in the treatment of tuberculosis. Ann N Y Acad Sci 2001;953:157-64.
DOI: https://doi.org/10.1111/j.1749-6632.2001.tb11374.x
Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 2002;62:2169-83.
DOI: https://doi.org/10.2165/00003495-200262150-00001
Metwally AS, El-Sheikh SMA, Galal AAA. The impact of diabetes mellitus on the pharmacokinetics of rifampicin among tuberculosis patients: a systematic review and meta-analysis study. Diabetes Metab Syndr 2022;16:102410.
DOI: https://doi.org/10.1016/j.dsx.2022.102410
Alffenaar JWC, Stocker SL, Forsman LD, et al. Clinical standards for the dosing and management of TB drugs. Int J Tuberc Lung Dis 2022;26:483-99.
DOI: https://doi.org/10.5588/ijtld.22.0188
Heysell SK, Moore JL, Keller SJ, Houpt ER. Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis 2010;16:1546-53.
DOI: https://doi.org/10.3201/eid1610.100374
National Tuberculosis Association. Diagnostic standards and classification of tuberculosis. 1961.
Song SH, Jun SH, Park KU, et al. Simultaneous determination of first-line anti-tuberculosis drugs and their major metabolic ratios by liquid chromatography/tandem mass spectrometry. Rapid Commun Mass Spectrom 2007;21:1331-8.
DOI: https://doi.org/10.1002/rcm.2961
Tostmann A, Mtabho CM, Semvua HH, vet al. Pharmacokinetics of first-line tuberculosis drugs in Tanzanian patients. Antimicrob Agents Chemother 2013;57:3208-13.
DOI: https://doi.org/10.1128/AAC.02599-12
Weiner M, Benator D, Burman W, et al. Association between acquired rifamycin resistance and the pharmacokinetics of rifabutin and isoniazid among patients with HIV and tuberculosis. Clin Infect Dis 2005;40:1481-91.
DOI: https://doi.org/10.1086/429321
Weiner M, Burman W, Vernon A, et al. Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine. Am J Respir Crit Care Med 2003;167:1341-7.
DOI: https://doi.org/10.1164/rccm.200208-951OC
Chideya S, Winston CA, Peloquin CA, et al. Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis 2009;48:1685-94.
DOI: https://doi.org/10.1086/599040
Tappero JW, Bradford WZ, Agerton TB, et al. Serum concentrations of antimycobacterial drugs in patients with pulmonary tuberculosis in Botswana. Clin Infect Dis 2005;41:461-9.
DOI: https://doi.org/10.1086/431984
Ray J, Gardiner I, Marriott D. Managing antituberculosis drug therapy by therapeutic drug monitoring of rifampicin and isoniazid. Intern Med J 2003;33:229-34.
DOI: https://doi.org/10.1046/j.1445-5994.2003.00390.x
van Crevel R, Alisjahbana B, de Lange WCM, et al. Low plasma concentrations of rifampicin in tuberculosis patients in Indonesia. Int J Tuberc Lung Dis 2002;6:497-502.
DOI: https://doi.org/10.5588/09640569513002
Seneadza NAH, Antwi S, Yang H, et al. Effect of malnutrition on the pharmacokinetics of anti-TB drugs in Ghanaian children. Int J Tuberc Lung Dis 2021;25:36-42.
DOI: https://doi.org/10.5588/ijtld.20.0301
Peloquin CA, MacPhee AA, Berning SE. Malabsorption of antimycobacterial medications. N Engl J Med 1993;329:1122-3.
DOI: https://doi.org/10.1056/NEJM199310073291513
Kimerling ME, Phillips P, Patterson P, et al. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. Chest 1998;113:1178-83.
DOI: https://doi.org/10.1378/chest.113.5.1178
Gurumurthy P, Ramachandran G, Hemanth Kumar AK, et al. Decreased bioavailability of rifampin and other antituberculosis drugs in patients with advanced human immunodeficiency virus disease. Antimicrob Agents Chemother 2004;48:4473-5.
DOI: https://doi.org/10.1128/AAC.48.11.4473-4475.2004
Choudhri SH, Hawken M, Gathua S, et al. Pharmacokinetics of antimycobacterial drugs in patients with tuberculosis, AIDS, and diarrhea. Clin Infect Dis 1997;25:104-11.
DOI: https://doi.org/10.1086/514513
Babalik A, Ulus IH, Bakirci N, Kuyucu T, Arpag H, Dagyildizi L, et al. Plasma concentrations of isoniazid and rifampin are decreased in adult pulmonary tuberculosis patients with diabetes mellitus. Antimicrob Agents Chemother. 2013 Nov;57(11):5740–2.
Ministry of Health and Family Welfare. Nikshay Poshan Yojana: central TB division. Available from: https://tbcindia.gov.in/index1.php?lang=1&level=1&sublinkid=5275&lid=3385. Accessed on: 12/10/2020.
Requena-Méndez A, Davies G, Waterhouse D, et al. Effects of dosage, comorbidities, and food on isoniazid pharmacokinetics in Peruvian tuberculosis patients. Antimicrob Agents Chemother 2014;58:7164-70.
DOI: https://doi.org/10.1128/AAC.03258-14
Chang MJ, Chae JW, Yun HY, et al. Effects of type 2 diabetes mellitus on the population pharmacokinetics of rifampin in tuberculosis patients. Tuberculosis (Edinb) 2015;95:54-9.
DOI: https://doi.org/10.1016/j.tube.2014.10.013
Nijland HMJ, Ruslami R, Stalenhoef JE, et al. Exposure to rifampicin is strongly reduced in patients with tuberculosis and type 2 diabetes. Clin Infect Dis 2006;43:848-54.
DOI: https://doi.org/10.1086/507543
Ruslami R, Nijland HMJ, Adhiarta IGN, et al. Pharmacokinetics of antituberculosis drugs in pulmonary tuberculosis patients with type 2 diabetes. Antimicrob Agents Chemother 2010;54:1068-74.
DOI: https://doi.org/10.1128/AAC.00447-09
Requena-Méndez A, Davies G, Ardrey A, et al. Pharmacokinetics of rifampin in Peruvian tuberculosis patients with and without comorbid diabetes or HIV. Antimicrob Agents Chemother 2012;56:2357-63.
DOI: https://doi.org/10.1128/AAC.06059-11
Babalik A, Ulus IH, Bakirci N, et al. Plasma concentrations of isoniazid and rifampin are decreased in adult pulmonary tuberculosis patients with diabetes mellitus. Antimicrob Agents Chemother 2013;57:5740-2.
DOI: https://doi.org/10.1128/AAC.01345-13
Verbeeck RK, Günther G, Kibuule D, et al. Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring. Eur J Clin Pharmacol 2016;72:905-16.
DOI: https://doi.org/10.1007/s00228-016-2083-4
Prahl JB, Johansen IS, Cohen AS, et al. Clinical significance of 2 h plasma concentrations of first-line anti-tuberculosis drugs: a prospective observational study. J Antimicrob Chemother 2014;69:2841-7.
DOI: https://doi.org/10.1093/jac/dku210
Srivastava S, Pasipanodya JG, Meek C, et al. Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis 2011;204:1951-9.
DOI: https://doi.org/10.1093/infdis/jir658
Van Tongeren L, Nolan S, Cook VJ, et al. Therapeutic drug monitoring in the treatment of tuberculosis: a retrospective analysis. Int J Tuberc Lung Dis 2013;17:221-4.
DOI: https://doi.org/10.5588/ijtld.12.0279
Ramachandran G, Agibothu Kupparam HK, et al. Factors influencing tuberculosis treatment outcome in adult patients treated with thrice-weekly regimens in India. Antimicrob Agents Chemother 2017;61:e02464-16.
DOI: https://doi.org/10.1128/AAC.02464-16
Perumal R, Naidoo K, Naidoo A, et al. A systematic review and meta-analysis of first-line tuberculosis drug concentrations and treatment outcomes. Int J Tuberc Lung Dis 2020;24:48-64.
DOI: https://doi.org/10.5588/ijtld.19.0025
Park JS, Lee JY, Lee YJ, et al. Serum levels of antituberculosis drugs and their effect on tuberculosis treatment outcome. Antimicrob Agents Chemother 2016;60:92-8.
DOI: https://doi.org/10.1128/AAC.00693-15
Pasipanodya JG, McIlleron H, Burger A, et al. Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis 2013;208:1464-73.
DOI: https://doi.org/10.1093/infdis/jit352
Ethics Approval
Research and ethical approval (office letter no. NITRD/RC/2024/2521, letter no. NITRD/EC/2024/7497 respectively) has been obtained from Institutional Research and Ethical Committee.How to Cite
Singla, Rupak, Amitesh Gupta, Vikas Kumar, Chandrasekaran Padmapriyadarsini, Devika Tayal, Shweta Anand, Abhishek Faye, AK Hemanth Kumar, and Madhumita Paul Choudhary. 2024. “Study of Risk Factors and Clinical Management of Patients With Clinical Non-Response Due to Low Plasma Levels of Anti-Tubercular Drugs”. Monaldi Archives for Chest Disease, July. https://doi.org/10.4081/monaldi.2024.3036.
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