Abstract
Purpose
Patients with pulmonary tuberculosis (PTB) who fail therapy or develop a relapse are initiated on a retreatment regimen. These patients are at high risk for adverse outcomes. This study aimed to assess the relationship between plasma levels of anti-tubercular drugs and therapy outcome in patients on retreatment.
Methods
Pharmacokinetics of retreatment regimen drugs [isoniazid (INH), rifampicin (RIF), pyrazinamide (PZA), ethambutol (EMB), and streptomycin (STM)] were compared between cured and not-cured patients using liquid chromatography-tandem mass spectrometry (LC-MS/MS) in 134 patients with PTB on a retreatment regimen.
Results
Of 134 patients, 108 were cured, 17 developed multi-drug resistant TB (MDR-TB), and 9 remained smear-positive after completion of the retreatment (8 months). Two-hour plasma levels (C2hr) at Day 0 were lower in ‘not cured’ subjects than ‘cured’ subjects and reflected the drug levels achieved later in the duration of retreatment. Notably, in the 26 ‘not cured’ subjects, C2hr plasma levels after the first dose at Day 0 were significantly low (INH: 0.86 vs. 2.94 mg/L, p ≤ 0.002, RIF: 0.56 vs. 2.55 mg/L, p ≤ 0.003, PZA: 1.85 vs. 26.58 mg/L, p ≤ 0.001 and EMB: 0.72 vs. 1.53 mg/L, p ≤ 0.010).
Conclusion
Therapeutic failure in patients with PTB on a retreatment regimen is associated with lower plasma drug levels. Therapeutic drug monitoring would prove useful for obtaining a favorable clinical outcome. C2hr levels on Day 0 reflected drug levels achieved later and could be a good predictor of patient outcome.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
There was no role of the funding agency in the study design, data collection, analysis, interpretation of data, or writing of the manuscript. The corresponding author has full access to all the data in the study and had final responsibility for the decision to submit the manuscript for publication.
Code availability
Not applicable.
References
Aarnoutse R (2011) Chapter 18: pharmacogenetics of antituberculosis drugs. Antituberculosis chemotherapy. Karger, Basel
Barakat MT, Scott J, Hughes JM, Walport M, Calam J et al (1996) Grand Rounds-Hammersmith hospital. Persistent fever in pulmonary tuberculosis. BMJ 313(7071):1543–1545
Boman G, Ringberger VA (1974) Binding of rifampicin by human plasma proteins. Eur J Clin Pharmacol 7(5):369–373
Burhan E, Ruesen C, Ruslami R, Ginanjar A, Mangunnegoro H et al (2013) Isoniazid, rifampin, and pyrazinamide plasma concentrations in relation to treatment response in Indonesian pulmonary tuberculosis patients. Antimicrob Agents Chemother 57(8):3614–3619
Chideya S, Winston CA, Peloquin CA, Bradford WZ, Hopewell PC et al (2009) Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. Clin Infect Dis 48(12):1685–1694
Cohen DB, Davies G, Malwafu W, Mangochi H, Joekes E et al (2019) Poor outcomes in recurrent tuberculosis: more than just drug resistance? PLoS ONE 14(5):e0215855
Hall RG, Leff RD, Gumbo T (2009) Treatment of active pulmonary tuberculosis in adults: current standards and recent advances. Insights from the society of infectious diseases pharmacists. Pharmacotherapy 29(12):1468–1481
Heysell SK, Moore JL, Keller SJ, Houpt ER (2010) Therapeutic drug monitoring for slow response to tuberculosis treatment in a state control program, Virginia, USA. Emerg Infect Dis 16(10):1546–1553
Hoagland DT, Liu J, Lee RB, Lee RE (2016) New agents for the treatment of drug-resistant mycobacterium tuberculosis. Adv Drug Deliv Rev 102(July):55–72
Johnston JC, Campbell JR, Menzies D (2017) Effect of intermittency on treatment outcomes in pulmonary tuberculosis: an updated systematic review and metaanalysis. Clin Infect Dis 64(9):1211–1220
Jones-López EC, Ayakaka I, Levin J, Reilly N, Mumbowa F et al (2011) Effectiveness of the standard WHO recommended retreatment regimen (category II) for tuberculosis in Kampala, Uganda: a prospective cohort study. PLoS Med 8(3):15
Kimerling ME, Phillips P, Patterson P, Hall M, Robinson CA et al (1998) Low serum antimycobacterial drug levels in non-hiv-infected tuberculosis patients. Chest 113(5):1178–1183
Lambert M-L, Hasker E, Van Deun A, Roberfroid D, Boelaert M et al (2003) Recurrence in tuberculosis: relapse or reinfection? Lancet Infect Dis 3(5):282–287
Loos U, Musch E, Jensen JC, Mikus G, Schwabe HK et al (1985) Pharmacokinetics of oral and intravenous rifampicin during chronic administration. Klin Wochenschr 63(23):1205–1211
Loos U, Musch E, Jensen JC, Schwabe HK, Eichelbaum M (1987) Influence of the enzyme induction by rifampicin on its presystemic metabolism. Pharmacol Ther 33(1):201–204
Meyer UA, Zanger UM (1997) Molecular mechanisms of genetic polymorphisms of drug metabolism. Annu Rev Pharmacol Toxicol 37:269–296
Motta I, Calcagno A, Baietto L, Bigliano P, Costa C et al (2017) Pharmacokinetics of first-line antitubercular drugs in plasma and PBMCs. Br J Clin Pharmacol 83(5):1146–1148
Mukherjee A, Velpandian T, Singla M, Kanhiya K, Kabra SK et al (2016) Pharmacokinetics of isoniazid, rifampicin, pyrazinamide, and ethambutol in HIV-infected Indian Children. Int J Tuberc Lung Dis 20(5):666–672
Nahid P, Dorman SE, Alipanah N, Barry PM, Brozek JL et al (2016) Official American Thoracic Society/Centers for Disease Control and Prevention/Infectious Diseases Society of America Clinical practice guidelines: treatment of drug-susceptible tuberculosis. Clin Infect Dis 63(7):e147–e195
Niward K, Davies Forsman L, Bruchfeld J, Chryssanthou E, Carlström O et al (2018) Distribution of plasma concentrations of first-line anti-TB drugs and individual MICs: a prospective cohort study in a low endemic setting. J Antimicrob Chemother 73(10):2838–2845
NTEP (formerly National Tuberculosis Elimination Programme) (2005) “Technical and Operational Guidelines for TB Control in India.” Currently RNTCP, Revised National T B Control Program 2012–2017. Ministry of Health and Family Welfare, Directorate General of Health Services, New Delhi. Accessed from https://tbcindia.gov.in/showfile.php?lid=3197
Pasipanodya JG, McIlleron H, Burger A, Wash PA, Smith P et al (2013) Serum drug concentrations predictive of pulmonary tuberculosis outcomes. J Infect Dis 208(9):1464–1473
Peloquin CA (1997) Using therapeutic drug monitoring to dose the antimycobacterial drugs. Clin Chest Med 18(1):79–87
Peloquin CA (2001) Pharmacological issues in the treatment of tuberculosis. Ann N Y Acad Sci 953:157–164
Peloquin CA (2002) Therapeutic drug monitoring in the treatment of tuberculosis. Drugs 62(15):2169–2183
RNTCP, Revised National T B Control Program. (2009) “Training Manual for Mycobacterium Tuberculosis Culture & Drug Susceptibility Testing.” Ministry of Health and Family Welfare, New Delhi 110011. Accessed from https://tbcindia.gov.in/WriteReadData/l892s/6995271860Training%20manual%20M%20tuberculosis%20C%20DST.pdf
Saktiawati AMI, Harkema M, Setyawan A, Subronto YW, Sumardi Y et al (2019) Optimal sampling strategies for therapeutic drug monitoring of first-line tuberculosis drugs in patients with tuberculosis. Clin Pharmacokinet 58(11):1445–1454
Singh UB, Pandey P, Mehta G, Bhatnagar AK, Mohan A et al (2016) Genotypic, phenotypic and clinical validation of GeneXpert in extra-pulmonary and pulmonary tuberculosis in India. PLoS ONE 11(2):e0149258
Sisodia RS, Wares DF, Sahu S, Chauhan LS, Zignol M (2006) Source of retreatment cases under the revised national TB control programme in Rajasthan, India, 2003. Int J Tuberc Lung Dis 10(12):1373–1379
Srivastava S, Pasipanodya JG, Meek C, Leff R, Gumbo T (2011) Multidrug-resistant tuberculosis not due to noncompliance but to between-patient pharmacokinetic variability. J Infect Dis 204(12):1951–1959
World Health Organization (2010) Treatment of tuberculosis: guidelines, 4th edn. World Health Organization, Geneva
World Health Organization (2013) Definitions and reporting framework for tuberculosis—2013 revision: updated December 2014 and January 2020. World Health Organization. Accessed from https://apps.who.int/iris/handle/10665/79199
Zheng X, Bao Z, Forsman LD, Hu Y, Ren W et al (2020) Drug exposure and minimum inhibitory concentration predict pulmonary tuberculosis treatment response. Clin Infect Dis. https://doi.org/10.1093/cid/ciaa1569
Zuur MA, Bolhuis MS, Anthony R, den Hertog A, van der Laan T et al (2016) Current status and opportunities for therapeutic drug monitoring in the treatment of tuberculosis. Expert Opin Drug Metab Toxicol 12(5):509–521
Acknowledgements
We thank our patients for participating in this study. We would like to thank Mr. Ashish Datt Upadhayay, Statistical Assistant, Department of Biostatistics, AIIMS, New Delhi for the ROC curve analysis and DST-FIST for providing a liquid chromatography-coupled tandem mass spectroscopy facility for this study. We would also like to thank Editage (www.editage.com) for English language editing.
Funding
This work was supported by the Indian Council of Medical Research (ICMR Grant No. 5/8/5/10/2012-ECD-I). Dr. Anant Mohan received research support from ICMR as above. No funds, grants, or other support were received during the preparation of this manuscript.
Author information
Authors and Affiliations
Contributions
AM, AB, TV, RG, and UBS—conceptualization of the study, acquisition of funds, supervision, and validation of methodology, data curation. UKD, TG, and SK—investigation of study, methodology, data curation, formal analysis, and validation. SK and UBS took the lead in writing the original manuscript. All authors discussed the results and contributed to the final manuscript.
Corresponding author
Ethics declarations
Conflict of interest
All authors (A. Mohan, A. Bhatnagar, T. Gupta, D. Ujjalkumar, S. Kanswal, T. Velpandian, R. Guleria, U.B. Singh) have no relevant financial or non-financial interests to disclose. The authors report no competing interests.
Ethical approval
This study was conducted at the All India Institute of Medical Sciences (AIIMS), New Delhi, India from 2012-to 2014. The questionnaire and methodology for this study were approved by the Institutional Ethics Committee, AIIMS (IEC/NP-251/2012&RP-22/2012), and adhere to the tenets of the Declaration of Helsinki.
Consent to participate
Written informed consent was obtained from all individual participants included in the study at the time of enrolment.
Consent for publication
The authors affirm that all human participants provided informed consent for the publication of the study results. There is no identifying information about participants in this article.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
Mohan, A., Bhatnagar, A., Gupta, T. et al. Early pharmacokinetic evaluation of anti-tubercular treatment as a good indicator of treatment success in pulmonary tuberculosis patients on a retreatment regimen. J. Pharm. Investig. 52, 489–499 (2022). https://doi.org/10.1007/s40005-022-00577-9
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s40005-022-00577-9