Pharmacological and Pharmaceutical Chemistry Perspectives on Optimizing Drug Combinations in Multidrug-Resistant Tuberculosis Patients

Iffat Ullah; Abdul Rauf; Pooja Chapagai

doi:10.62497/irabcs.157

Authors

Iffat Ullah Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences Prince of Songkla University Author https://orcid.org/0009-0004-4968-9184
Abdul Rauf Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand Author https://orcid.org/0009-0006-5348-9438
Pooja Chapagai Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand Author https://orcid.org/0009-0007-9862-8240

DOI:

https://doi.org/10.62497/irabcs.157

Keywords:

MDR-TB, pharmacology, pharmaceutical chemistry, drug combinations, therapeutic drug monitoring, treatment outcomes

Abstract

Background: Multidrug-resistant tuberculosis (MDR-TB) poses a major global health challenge, requiring optimized drug combinations to improve outcomes.

Objective: To evaluate pharmacological and pharmaceutical chemistry perspectives in optimizing MDR-TB regimens, focusing on therapeutic effectiveness, resistance reduction, and clinical outcomes.

Methodology: A prospective observational study was conducted at Bumrungrad International Hospital, Thailand, in collaboration with Prince of Songkla University from January 2022 to December 2023. A total of 406 confirmed MDR-TB patients were enrolled. Data included demographics, comorbidities, therapeutic drug monitoring, pharmaceutical chemistry profiling, in vitro drug–drug interaction assays, and clinical outcomes. Statistical analyses included chi-square, t-tests, and multivariate logistic regression.

Results: Of 406 patients, 243 (59.85%) were male and 163 (40.15%) female. Diabetes mellitus (21.92%) and HIV co-infection (6.65%) were significantly associated with poor outcomes (p < 0.001). Therapeutic drug monitoring showed optimal levofloxacin and bedaquiline levels in 73.40% and 79.80% of patients, respectively, both significantly linked to treatment success (p = 0.020 and p = 0.010). In vitro assays revealed synergy for levofloxacin–linezolid (62.81%) and linezolid–bedaquiline (57.14%). At six months, sputum culture conversion reached 84.00%, with overall treatment success in 78.82% (320/406). Early culture conversion (AOR 3.24, p < 0.001), absence of diabetes (AOR 2.11, p = 0.001), and adequate levofloxacin exposure (AOR 1.89, p = 0.004) were independent predictors of success. Adverse drug reactions occurred in 220 patients (54.19%), mostly gastrointestinal (21.18%) and neuropathy (12.81%), but only 3.45% required permanent drug withdrawal.

Conclusion: Integrating pharmacological monitoring and pharmaceutical chemistry insights enhances regimen optimization and improves MDR-TB treatment outcomes.

Downloads

Download data is not yet available.

Author Biographies

Iffat Ullah, Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences Prince of Songkla University

Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences Prince of Songkla University, Hat Yai, 90110, Thailand
Abdul Rauf , Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand

Affiliation: Department of Pharmaceutical Chemistry, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand
Pooja Chapagai, Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand

Department of Clinical Pharmacy, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat Yai, 90110, Thailand

References

Jain A, Mondal R. Extensively drug-resistant tuberculosis: current challenges and threats. FEMS Immunology & Medical Microbiology. 2008 Jul 1;53(2):145-50. https://doi.org/10.1111/j.1574-695X.2008.00400.x.

Lange C, Chesov D, Heyckendorf J, Leung CC, Udwadia Z, Dheda K. Drug‐resistant tuberculosis: an update on disease burden, diagnosis and treatment. Respirology. 2018 Jul;23(7):656-73. https://doi.org/10.1111/resp.13304.

Souza LL, Santos FL, Crispim JD, Fiorati RC, Dias S, Bruce AT, Alves YM, Ramos AC, Berra TZ, da Costa FB, Alves LS. Causes of multidrug-resistant tuberculosis from the perspectives of health providers: challenges and strategies for adherence to treatment during the COVID-19 pandemic in Brazil. BMC Health Services Research. 2021 Oct 1;21(1):1033. https://doi.org/10.1186/s12913-021-07057-0.

Allué-Guardia A, García JI, Torrelles JB. Evolution of drug-resistant Mycobacterium tuberculosis strains and their adaptation to the human lung environment. Frontiers in microbiology. 2021 Feb 4;12:612675. https://doi.org/10.3389/fmicb.2021.612675.

Gajic I, Tomic N, Lukovic B, Jovicevic M, Kekic D, Petrovic M, Jankovic M, Trudic A, Mitic Culafic D, Milenkovic M, Opavski N. A comprehensive overview of antibacterial agents for combating Multidrug-Resistant bacteria: the current landscape, development, future opportunities, and challenges. Antibiotics. 2025 Feb 21;14(3):221. https://doi.org/10.3390/antibiotics14030221.

Yew WW. Clinically significant interactions with drugs used in the treatment of tuberculosis. Drug safety. 2002 Feb;25(2):111-3. https://doi.org/10.2165/00002018-200225020-00005.

Lakshminarayana SB, Huat TB, Ho PC, Manjunatha UH, Dartois V, Dick T, Rao SP. Comprehensive physicochemical, pharmacokinetic and activity profiling of anti-TB agents. Journal of Antimicrobial Chemotherapy. 2015 Mar 1;70(3):857-67. https://doi.org/10.1093/jac/dku457.

Kerantzas CA, Jacobs Jr WR. Origins of combination therapy for tuberculosis: lessons for future antimicrobial development and application. MBio. 2017 May 3;8(2):10-128. https://doi.org/10.1128/mbio.01586-16.

Nair A, Greeny A, Nandan A, Sah RK, Jose A, Dyawanapelly S, Junnuthula V, KV A, Sadanandan P. Advanced drug delivery and therapeutic strategies for tuberculosis treatment. Journal of Nanobiotechnology. 2023 Nov 9;21(1):414. https://doi.org/10.1186/s12951-023-02156-y.

Alsultan A, Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis: an update. Drugs. 2014 Jun;74(8):839-54. https://doi.org/10.1007/s40265-014-0222-8.

Verbeeck RK, Günther G, Kibuule D, Hunter C, Rennie TW. Optimizing treatment outcome of first-line anti-tuberculosis drugs: the role of therapeutic drug monitoring. European journal of clinical pharmacology. 2016 Aug;72(8):905-16. https://doi.org/10.1007/s00228-016-2083-4.

Sadiq IZ, Usman A, Muhammad A, Ahmad KH. Sample size calculation in biomedical, clinical and biological sciences research. Journal of Umm Al-Qura University for Applied Sciences. 2025 Mar;11(1):133-41. https://doi.org/10.1007/s43994-024-00153-x.

Magee MJ, Kempker RR, Kipiani M, Tukvadze N, Howards PP, Narayan KV, Blumberg HM. Diabetes mellitus, smoking status, and rate of sputum culture conversion in patients with multidrug-resistant tuberculosis: a cohort study from the country of Georgia. PloS one. 2014 Apr 15;9(4):e94890. https://doi.org/10.1371/journal.pone.0094890.

Salindri AD, Kipiani M, Kempker RR, Gandhi NR, Darchia L, Tukvadze N, Blumberg HM, Magee MJ. Diabetes reduces the rate of sputum culture conversion in patients with newly diagnosed multidrug-resistant tuberculosis. InOpen forum infectious diseases 2016 May 1 (Vol. 3, No. 3, p. ofw126). Oxford University Press. https://doi.org/10.1093/ofid/ofw126.

Pooranagangadevi N, Padmapriyadarsini C. Treatment of tuberculosis and the drug interactions associated with HIV-TB co-infection treatment. Frontiers in Tropical Diseases. 2022 May 13;3:834013. https://doi.org/10.3389/fitd.2022.834013.

Lyons MA. Pharmacodynamics and bactericidal activity of bedaquiline in pulmonary tuberculosis. Antimicrobial Agents and Chemotherapy. 2022 Feb 15;66(2):e01636-21. https://doi.org/10.1128/aac.01636-21.

Al-Shaer MH, Alghamdi WA, Alsultan A, An G, Ahmed S, Alkabab Y, Banu S, Barbakadze K, Houpt E, Kipiani M, Mikiashvili L. Fluoroquinolones in drug-resistant tuberculosis: culture conversion and pharmacokinetic/pharmacodynamic target attainment to guide dose selection. Antimicrobial agents and chemotherapy. 2019 Jul;63(7):10-128. https://doi.org/10.1128/aac.00279-19.

Eimer J, Fréchet-Jachym M, Le Dû D, Caumes E, El-Helali N, Marigot-Outtandy D, Mechai F, Peytavin G, Pourcher V, Rioux C, Yazdanpanah Y. Association between increased linezolid plasma concentrations and the development of severe toxicity in multidrug-resistant tuberculosis treatment. Clinical Infectious Diseases. 2023 Feb 1;76(3):e947-56. https://doi.org/10.1093/cid/ciac485.

Cholo MC, Mothiba MT, Fourie B, Anderson R. Mechanisms of action and therapeutic efficacies of the lipophilic antimycobacterial agents clofazimine and bedaquiline. Journal of Antimicrobial Chemotherapy. 2016 Oct 20:dkw426. https://doi.org/10.1093/jac/dkw426.

Zou L, Liu M, Wang Y, Lu J, Pang Y. Determination of in vitro synergy between linezolid and other antimicrobial agents against Mycobacterium tuberculosis isolates. Tuberculosis. 2015 Dec 1;95(6):839-42. https://doi.org/10.1016/j.tube.2015.07.003.

Abebe M, Atnafu A, Tilahun M, Sero N, Neway S, Alemu M, Tesfaye G, Mihret A, Bobosha K, Wan C. Determinants of sputum culture conversion time in multidrug-resistant tuberculosis patients in ALERT comprehensive specialized hospital, Addis Ababa, Ethiopia: A retrospective cohort study. Plos one. 2024 May 31;19(5):e0304507. https://doi.org/10.1371/journal.pone.0304507

Ramachandran G, Swaminathan S. Safety and tolerability profile of second-line anti-tuberculosis medications. Drug safety. 2015 Mar;38(3):253-69. https://doi.org/10.1007/s40264-015-0267-y.