Existing opportunities to increase the effectiveness of tuberculosis Treatment

  • Y.I. Feshchenko State Enterprise “National Institute for Phthisiology and Pulmonology named after F.G. Yanovskyi of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine
  • M.I. Gumeniuk State Enterprise “National Institute for Phthisiology and Pulmonology named after F.G. Yanovskyi of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine
  • O.Ya. Korolyuk Lviv national Danil Galitsky Medical University, Lviv, Ukraine


INTRODUCTION. According to the WHO, tuberculosis remains one of the 10 leading causes of death in the world. Certain features of the pathogen, peculiarities of treatment regimens and some individual characteristics of patients create barriers to the effective treatment of the disease.

MATERIALS AND METHODS. Retrospective analysis of literary sources - recommendations, scientific articles and statistical data.

RESULTS. A review of the literature data showed features of the pathogen, patient-related problems and possible omissions in treatment regimens, that may be the cause of treatment effectiveness lack and a risk factor for the emergence of drug resistance in M. tuberculosis. Insufficient efficacy of treatment was described in patients with low adherence to treatment with oral anti-TB drugs, the presence of comorbidities, with a low level of intestinal permeability of oral medications and in patients with severe forms of tuberculosis. All these patients had a high mortality rate when treated within standard regimens using oral medications.

CONCLUSIONS. To solve the problems of low TB treatment efficiency in these categories of patients, the necessary measures are aimed at maximizing the elimination of causes listed in the article in order to optimize treatment regimens in accordance with the patient’s characteristics and needs, taking into account the peculiarities of mycobacteria.

Keywords: mycobacterium, resistance, severe tuberculosis, malabsorption, intravenous anti-tuberculosis drugs.


World Health Organization (WHO), 2006. Global Tuberculosis Control: Surveillance, Planning, Financing. Geneva: WHO.

Global tuberculosis report 2017. Geneva: World Health Organization; 2017. Licence: CC BY-NCSA 3.0 IGO.

Saviola B. Mycobacterium tuberculosis adaptation to survival in a human host. In: Mahboub BH, Vats MG, ed. Tuberculosis: current issues in diagnosis and management. In Tech; 2013: 3–18.

Tuberculous granulomas are hypoxic in guinea pigs, rabbits, and nonhuman primates. / Via LE, Lin PL, Ray SM, [et al.] // Infect Immun. – 2008. – Vol. 76(6). – P. 2333-2340.

Cole S. Т. Mycobacterium tuberculosis: drug-resistance mechanisms // Trends Microbiol. – 1994. – Vol. 2(10). – P. 411-416; Musser J. M. Antimicrobial agent resistance in mycobacteria: molecular genetic insights // Clin. Microbiol. Rev. – 1995. – Vol. 8(4). – P. 496-514.

L. Nguyen. Antibiotic resistance mechanisms in M. tuberculosis: an update. // Arch Toxicol. – 2016. – Vol. 90(7). – P. 1585-1604.

Starke J. R. Drug‐resistance in tuberculosis: Mechanisms and prevention // Pediatr. Pulmonol. – 1997. – Vol. 16. – P. 154-156.

Rattan A., Kalia A., Ahmad N. Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives. // Emerg. Infect. Dis. – 1998. – Vol. 4(2). – P. 195-209; Riska P. F., Jacobs W. R., Alland D. Molecular determinants of drug resistance in tuberculosis. // Intern. J. Tubercul. Lung Dis. – 2000. – Vol. 4(2). – P. S4-S10.

March F., Garriga X., Rodrigues P., et al. Acquired drug resistance in Mycobacterium tuberculosis isolates recovered from compliant patients with human immunodeficiency virus-associated tuberculosis // Intern. J. Tubercul. Lung Dis. – 1997. –V. 25. – P. 1044–104; Rattan A., Kalia A., Ahmad N. Multidrug-resistant Mycobacterium tuberculosis: molecular perspectives. // Emerg. Infect. Dis. – 1998. – Vol. 4(2). – P. 195-209.

Surveillance of anti-tuberculosis drug resistance in the world: an updated analysis, 2007–2010 / M. Zignol, W. van Gemert, D. Falzon [et al.] // Bulletin of the World Health Organization. – 2012. – Vol. 90. – P. 111-119D.

Migliori GB, De Iaco G, Besozzi G, et al. First tuberculosis cases in Italy resistant to all tested drugs. // Euro Surveillance. – 2007. – Vol. 12(5). – E070517.1; Udwadia ZF, Amala RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. // Clin Infect Dis. – 2012. – Vol. 54. – P. 579-581; Parida SK, Axelsson-Robertson R, Rao MV, et al. Totally drug-resistant tuberculosis and adjunct therapies. // J. Intern. Med. – 2015. – Vol. 277. – P. 388–405.

The causes of death among patients with tuberculosis. / L. Simonovska, M. Trajcevska, V. Mitreski, I. Simonovska // European Respiratory Journal. – 2015. – Vol. 46. – P. A2713.

Disseminated Tuberculosis. A 10-Year Experience in a Medical Center. / J.Y. Wang, P.R. Hsueh, S.K. Wang [et al.] // Medicine (Baltimore). – 2007. – Vol. 86. – P. 39-46; Ribeiro S, Trabulo D, Cardoso C, Oliveira A, Cremers I. Disseminated Tuberculosis in an Immunocompetent Patient: The Answer is in the Liver. // GE Port J Gastroenterol. – 2015. – Vol. 23(4). – P. 208-213.

Sharma SK, Mohan A, Sharma A, Mitra DK. Miliary tuberculosis: new insights into an old disease. // Lancet Infect. Dis. – 2005. – Vol. 5. – P. 415-430.

Talavera W., Miranda R., Lessnau K.K.L., Klapholz A. Extrapulmonary tuberculosis. // In: Friedman LN, ed. Tuberculosis: Current Concepts and Treatment 2nd ed. Boca Raton, Fla.: CRC Press; 2001. – 518 р.

Wang JY, Hsueh PR, Lee LN, [et al.]. Mycobacterium tuberculosis inducing disseminated intravascular coagulation. // Thromb. Haemost. – 2005. – Vol. 93. – P. 729-734.

A 10-Year Experience in a Medical Center. / J.Y. Wang, P.R. Hsueh, S.K. Wang [et al.] // Medicine (Baltimore). – 2007. – Vol. 86. – P. 39-46.

Long R, O’Connor R, Palayew M, Hershfield E, Manfreda J. Disseminated tuberculosis with and without a miliary pattern on chest radiograph: a clinical-pathologic-radiologic correlation. // Int. J. Tuberc. Lung Dis. 1997. – Vol.1. – P. 52-58; A 10-Year Experience in a Medical Center. / J.Y. Wang, P.R. Hsueh, S.K. Wang [et al.] // Medicine (Baltimore). – 2007. – Vol. 86. – P. 39-46.

Shaw J.E., Pasipanodya J.G., Gumbo T. Meningeal tuberculosis: high long-term mortality despite standard therapy. // Medicine (Baltimore). – 2010. – Vol. 89(3). – P. 189-195.

Nelson LJ, Schneider E, Wells CD, Moore M. Epidemiology of childhood tuberculosis in the United States, 1993-2001: the need for continued vigilance. // Pediatrics. – 2004. – Vol. 114(2). – P. 333-341.

Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. / Ruslami R., Ganiem A.R., Dian S. [et al.] // Lancet Infect Dis. – 2013. – Vol. 13(1). – P. 27-35.

The American-European consensus conference on ARDS: Definitions, mechanisms relevant outcomes, and clinical trial coordination. / Bernard G., Artigas A., Carlet J., [et al.] // Am J Respir Crit Care Med. – 1994. – Vol. 149. – P. 818-824; Tuberculosis in the intensive care unit: a prospective observational study. / C.A. Balkema, E.M. Irusen, J.J. Taljaard, C.F.N. Koegelenberg // Int J Tuberc Lung Dis. – 2014. – Vol. 18(7). – P. 824-830.

Characteristics and outcome of patients with active pulmonary tuberculosis requiring intensive care. / Erbes R, Oettel K, Raffenberg M, [et al.] // Eur Respir J. – 2006. – Vol. 27. – P. 1223-1228; Mortality among patients with tuberculosis requiring intensive care: a retrospective cohort study. / Silva DR, Menegotto DM, Schulz LF, Gazzana MB, Dalcin PT // BMC Infect Dis – 2010. – Vol. 10:54. [http://dx.doi.org/10.1186/1471-2334-10-54].

The pharmacokinetics of enteral antituberculosis drugs in patients requiring intensive care. / Koegelenberg C. Nortje A., Lalla U. [et al.] // South African Medical Journal. – 2013. – Vol. 103(6). – P. 394-398.

Dian, Sofiati & Yunivita, Vycke & Ganiem, Ahmad Rizal & Pramaesya, Tiara & Chaidir, Lidya & Wahyudi, K & H. Achmad, T & Colbers, Angela & te Brake, Lindsey & Van Crevel, Reinout & Ruslami, Rovina & Aarnoutse, R. (2018). A double-blinded randomised placebo-controlled phase II trial to evaluate high dose rifampicin for tuberculous meningitis: a dose finding study. Antimicrobial Agents and Chemotherapy. 62. 10.1128/AAC.01014-18.

Kimerling ME, Phillips P, Patterson P, et al. Low serum antimycobacterial drug levels in non-HIV-infected tuberculosis patients. // Chest. – 1998. – Vol.5. – P. 1178-1183.

Isoniazid, rifampin, ethambutol, and pyrazinamide pharmacokinetics and treatment outcomes among a predominantly HIV-infected cohort of adults with tuberculosis from Botswana. / Chideya S., Winston C.A., Peloquin C.A.[et al.] // Clin Infect Dis. – 2009. – Vol. 48. – P. 1685-1694.

McIlleron H, Wash P, Burger A, Norman J, Folb PI, Smith P. Determinants of rifampicin, isoniazid, pyrazinamide and ethambutol pharmacokinetics in a cohort of tuberculosis patients. // Antimicrob Agents Chemother. – 2006. – Vol. 50. – P. 1170-1177.

Intestinal permeability and malabsorption of rifampin and isoniazid in active pulmonary tuberculosis. / Pinheiro V.G., Ramos L.M., Monteiro H.S. [et al.] // Braz J Infect Dis. – 2006. – Vol. 10(6). – P.374-379.

Serum concentrations of rifampin, isoniazid, and intestinal absorption, permeability in patients with multidrug resistant tuberculosis. / Barroso E.C., Pinheiro V.G., Facanha M.C. [et al.] //Am J Trop Med Hyg. – 2009. – Vol. 81(2). – P. 322-329.

Malabsorption of antimycobacterial drugs as a cause of treatment failure in tuberculosis. / Bento J., Duarte R., Brito M.C., [et al.] // BMJ Case Reports. – 2010.

Sahai J, Gallicano K, Swick L, et al. Reduced plasma concentrations of antituberculosis drugs in patients with HIV infection. // Ann Intern Med. – 1997. – Vol. 127. – P. 289-293; 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. – Vol. 48. – P. 4473-4475.

Mehta JB, Shantaveerapa H, Byrd RP Jr, et al. Utility of rifampin blood levels in the treatment and follow-up of active pulmonary tuberculosis in patients who were slow to respond to routine directly observed therapy. // Chest. – 2001. – Vol. 120. – P. 1520-1524.

McIlleron H, Wash P, Burger A. [et al.]. Determinants of rifampin, isoniazid, pyrazinamide, and ethambutol pharmacokinetics in a cohort of tuberculosis patients. // Antimicrob Agents Chemother. – 2006. – Vol. 50. – P. 1170-1177.

Intestinal tuberculosis in a celiac disease patient. S. Singh, S. Khichy, D. Bhangale, S. P. Aggarwal // Indian J Tuberc. – 2010. – Vol. 57. – P. 216-219.

Peloquin C.A. Therapeutic drug monitoring in the treatment of tuberculosis. // Drugs. – 2002. – Vol. 62. – P. 2169-2183.

Perri G.D., Bonora S. Which agents should we use for treatment of multidrug–resistant Mycobacterium tuberculosis? // J. Antimicrob. Chemother. – 2004. – Vol. 54. – P. 593-602; Raviglione M.C., Smith I.M. XDR tuberculosis–implications for global public health. // N Engl J Med. – 2007. – Vol.356. – P. 656-659.

Impact of food intake on the pharmacokinetics of first-line antituberculosis drugs in Taiwanese tuberculosis patients. / H.-C. Lin, M.-C. Yu, H.-J. Liu, K.-J. Bai // Journal of the Formosan Medical Association. – 2014. – Vol. 113(5). – P. 291-297.

Pharmacokinetics of rifampicin under fasting conditions, with food, and with antacids. / Peloquin CA, Namdar R, Singleton MD, Nix DE. // Chest. – 1999. – Vol. 115. – P. 12-18.

Nuermberger E., Grosset J. Pharmacokinetic and pharmacodynamic issues in the treatment of mycobacterial infections. // Eur J Clin Microbiol Infect Dis. – 2004. – Vol. 23. – P. 243-255.

Concentration-dependent Mycobacterium tuberculosis killing and prevention of resistance by rifampin. / Gumbo T, Louie A, Deziel MR, Liu W, Parsons LM, et al. // Antimicrob Agents Chemother. – 2007. – Vol. 51. – P. 3781-3788.

Protein Binding of First-Line Antituberculosis Drugs. / Alghamdi W.A., Al-Shaer M.H., Peloquin C.A. // Antimicrob Agents Chemother. – 2018. – Vol. 62.

Severe isoniazid-associated liver injuries among persons being treated for latent tuberculosis infection – United States, 2004-2008 / Centers for Disease Control and Prevention (CDC). // MMWR Morb. Mortal. Wkly Rep. – 2010 – Vol. 59(8). – P. 224-229.

Clinical Case of Using Intravenous Forms of Anti-Tuberculosis Drugs to Improve the Treatment Efficiency of Tuberculosis in Patients with Malabsorption Syndrome. / Kuzhko MM, Butov DO, Hulchuk NM, Avramchuk OV, Protsyk LM, et al. // J Pulm Respir Med. – 2015. – Vol. 5. – P. 269. doi:10.4172/2161-105X.1000269.

Karpin N.L. Efferent therapy in the treatment of patients with pulmonary tuberculosis drug resistant mycobacteria. // Tuberculosis and Lung Disease. – 2010. – Vol. 3. – P. 28-33.

Mishin V. Yu. The effectiveness of the treatment of patients with destructive pulmonary tuberculosis with parenteral and oral administration of anti-TB drugs. // Pulmonology. – 2011. – Vol. 1. – P. 55-59.

Boff DF, Goldani LZ. Initial combination of injectable and oral anti-tuberculosis agents for the treatment of severe disseminated tuberculosis. // Trop Doct. – 2013. – Vol. 43. – P. 148-150.

Treatment of Tuberculosis / American Thoracic Society, CDC, and Infectious Diseases Society of America // MMWR recommendations and reports - 2003. – Vol. 53(RR11). – P. 1-7.

Target regimen profiles for TB treatment: candidates: rifampicin-susceptible, rifampicin-resistant and pan-TB treatment regimens. / World Health Organization, 2016 – Geneva, – 41 p.

Intermittent intravenous chemotherapy of primarily detected patients with destructive pulmonary tuberculosis: Guidelines / Authored and complied by: Ursov I.G. et al. – Novosibirsk, 1979. – 19 p.

Frieden T. Toman’s Tuberculosis. Case detection, treatment, and monitoring – questions and answers/ T. Frieden, M. Espinal. – edited by T. Frieden. – 2nd ed. – Geneva, 2004. – 387p.

How to Cite
Feshchenko, Y., Gumeniuk, M., & Korolyuk, O. (2018). Existing opportunities to increase the effectiveness of tuberculosis Treatment. Infusion & Chemotherapy, (1), 6-12. https://doi.org/10.32902/2663-0338-2018-18-1-6-12

Author Biography

Y.I. Feshchenko, State Enterprise “National Institute for Phthisiology and Pulmonology named after F.G. Yanovskyi of the National Academy of Medical Sciences of Ukraine”, Kyiv, Ukraine

Director of National Institute of phtisiology and pulmonology named after F.G. Yanovskii National Academy of Medical sciences of Ukraine. President of Civic Union “Communicable diseases intensive care association”.
Academician of NAMS of Ukraine, professor.
03038, Ukraine, Kyiv, 10, M. Amosova str. info@incure.info