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Safety and Tolerability Profile of Second-Line Anti-Tuberculosis Medications

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Abstract

Tuberculosis (TB) remains a major public health problem, representing the second leading cause of death from infectious diseases globally, despite being nearly 100 % curable. Multidrug-resistant (MDR)-TB, a form of TB resistant to isoniazid and rifampicin (rifampin), two of the key first-line TB drugs, is becoming increasingly common. MDR-TB is treated with a combination of drugs that are less effective but more toxic than isoniazid and rifampicin. These drugs include fluoroquinolones, aminoglycosides, ethionamide, cycloserine, aminosalicyclic acid, linezolid and clofazimine among others. Minor adverse effects are quite common and they can be easily managed with symptomatic treatment. However, some adverse effects can be life-threatening, e.g. nephrotoxicity due to aminoglycosides, cardiotoxicity due to fluoroquinolones, gastrointestinal toxicity due to ethionamide or para-aminosalicylic acid, central nervous system toxicity due to cycloserine, etc. Baseline evaluation may help to identify patients who are at increased risk for adverse effects. Regular clinical and laboratory evaluation during treatment is very important to prevent adverse effects from becoming serious. Timely and intensive monitoring for, and management of adverse effects caused by, second-line drugs are essential components of drug-resistant TB control programmes; poor management of adverse effects increases the risk of non-adherence or irregular adherence to treatment, and may result in death or permanent morbidity. Treating physicians should have a thorough knowledge of the adverse effects associated with the use of second-line anti-TB drugs, and routinely monitor the occurrence of adverse drug reactions. In this review, we have compiled safety and tolerability information regarding second-line anti-TB drugs in both adults and children.

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References

  1. World Health Organisation. Global tuberculosis report, 2010. Geneva: WHO; 2010.

    Google Scholar 

  2. Crofton J. Global challenge of TB. Lancet. 1994;344(8922):609.

    CAS  PubMed  Google Scholar 

  3. Crofton J, Chaulet P, Maher D. Guidelines for the management of drug-resistant tuberculosis. WHO/TB/96.210 (Rev 1). Geneva: WHO; 1997.

    Google Scholar 

  4. Fox W, Mitchison DA. Short course chemotherapy for pulmonary tuberculosis. Am Rev Respir Dis. 1975;111:845–8.

    CAS  PubMed  Google Scholar 

  5. Hooper DC, Strahilevitz J. Quinolones. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone; 2010. p. 487–510.

    Google Scholar 

  6. Leibovitz E. The use of fluoroquinolones in children. Curr Opin Pediatr. 2006;18(1):64–70.

    PubMed  Google Scholar 

  7. Hayakawa I, Atarashi S, Yokohama S, Imamura M, Sakano K, Furukawa M. Synthesis and antibacterial activities of optically active ofloxacin. Antimicrob Agents Chemother. 1986;29(1):163–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  8. Fu KP, Lafredo SC, Foleno B, Isaacson DM, Barrett JF, Tobia AJ, et al. In vitro and in vivo antibacterial activities of levofloxacin (l-ofloxacin), an optically active ofloxacin. Antimicrob Agents Chemother. 1992;36(4):860–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Neu HC, Chin NX. In vitro activity of S-Ofloxacin. Antimicrob Agents Chemother. 1989;33(7):1105–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  10. Une T, Fujimoto T, Sato K, Osada Y. In vitro activity of DR-3355, an optically active ofloxacin. Antimicrob Agents Chemother. 1988;32(9):1336–40.

    PubMed Central  CAS  PubMed  Google Scholar 

  11. Moxifloxacin. Tuberculosis (Edinb). 2008;88 (2):127–131.

  12. Hampel B, Hullmann R, Schmidt H. Ciprofloxacin in pediatrics: worldwide clinical experience based on compassionate use–safety report. Pediatr Infect Dis J. 1997;16(1):127–9 (discussion 60–2).

    CAS  PubMed  Google Scholar 

  13. Yew WW, Chau CH, Wen KH. Pseudomembranous colitis in a patient treated with ofloxacin for tuberculosis. Tuber Lung Dis. 1996;77(5):484.

    CAS  PubMed  Google Scholar 

  14. Pépin J, Saheb N, Coulombe M-A, Alary M-E, Corriveau M-P, Authier S, et al. Emergence of fluoroquinolones as the predominant risk factor for Clostridium difficile–associated diarrhea: a cohort study during an epidemic in Quebec. Clin Infect Dis. 2005;41(9):1254–60.

    PubMed  Google Scholar 

  15. Ettehad D, Schaaf HS, Seddon JA, Cooke GS, Ford N. Treatment outcomes for children with multidrug-resistant tuberculosis: a systematic review and meta-analysis. Lancet Infect Dis. 2012;12(6):449–56.

    PubMed  Google Scholar 

  16. Tome AM, Filipe A. Quinolones: review of psychiatric and neurological adverse reactions. Drug Saf. 2011;34(6):465–88.

    CAS  PubMed  Google Scholar 

  17. Kushner JM, Peckman HJ, Snyder CR. Seizures associated with fluoroquinolones. Ann Pharmacother. 2001;35(10):1194–8.

    CAS  PubMed  Google Scholar 

  18. Liu HH. Safety profile of the fluoroquinolones: focus on levofloxacin. Drug Saf. 2010;33(5):353–69.

    CAS  PubMed  Google Scholar 

  19. Kass JS, Shandera WX. Nervous system effects of antituberculosis therapy. CNS Drugs. 2010;24(8):655–67.

    CAS  PubMed  Google Scholar 

  20. Walton GD, Hon JK, Mulpur TG. Ofloxacin-induced seizure. Ann Pharmacother. 1997;31(12):1475–7.

    CAS  PubMed  Google Scholar 

  21. Christie MJ, Wong K, Ting RH, Tam PY, Sikaneta TG. Generalized seizure and toxic epidermal necrolysis following levofloxacin exposure. Ann Pharmacother. 2005;39(5):953–5.

    PubMed  Google Scholar 

  22. Bellon A, Perez-Garcia G, Coverdale JH, Chacko RC. Seizures associated with levofloxacin: case presentation and literature review. Eur J Clin Pharmacol. 2009;65(10):959–62.

    CAS  PubMed  Google Scholar 

  23. Jo M, Tachi N, Shinoda M. Convulsions from excessive dosage of nalidixic acid: a case report. Brain Dev. 1979;1(4):327–9.

    CAS  PubMed  Google Scholar 

  24. Islam MA, Sreedharan T. Convulsions, hyperglycemia, and glycosuria from overdose of nalidixic acid. JAMA. 1965;21(192):1100–1.

    Google Scholar 

  25. Upton C. Sleep disturbance in children treated with ofloxacin. BMJ. 1994;309(6966):1411.

    PubMed Central  CAS  PubMed  Google Scholar 

  26. Seddon J, Hesseling A, Finlayson L, Schaaf HS. Toxicity and tolerability of multidrug-resistant tuberculosis preventive treatment in children [abstract no. PC-646-17]. In: 43rd World Conference on Lung Health of the International Union Against Tuberculosis and Lung Disease (The Union): Kuala Lumpur; 2012.

  27. Falagas ME, Rafailidis PI, Rosmarakis ES. Arrhythmias associated with fluoroquinolone therapy. Int J Antimicrob Agents. 2007;29(4):374–9.

    CAS  PubMed  Google Scholar 

  28. Makaryus AN, Byrns K, Makaryus MN, Natarajan U, Singer C, Goldner B. Effect of ciprofloxacin and levofloxacin on the QT interval: is this a significant “clinical” event? South Med J. 2006;99(1):52–6.

    PubMed  Google Scholar 

  29. Kang J, Wang L, Chen X-L, Triggle DJ, Rampe D. Interactions of a series of fluoroquinolone antibacterial drugs with the human cardiac K+ channel HERG. Mol Pharmacol. 2001;59(1):122–6.

    CAS  PubMed  Google Scholar 

  30. Tsikouris JP, Peeters MJ, Cox CD, Meyerrose GE, Seifert CF. Effects of three fluoroquinolones on QT analysis after standard treatment courses. Ann Noninvasive Electrocardiol. 2006;11(1):52–6.

    PubMed  Google Scholar 

  31. Noel GJ, Natarajan J, Chien S, Hunt TL, Goodman DB, Abels R. Effects of three fluoroquinolones on QT interval in healthy adults after single doses. Clin Pharmacol Ther. 2003;73(4):292–303.

    CAS  PubMed  Google Scholar 

  32. Noel GJ, Goodman DB, Chien S, Solanki B, Padmanabhan M, Natarajan J. Measuring the effects of supratherapeutic doses of levofloxacin on healthy volunteers using four methods of QT correction and periodic and continuous ECG recordings. J Clin Pharmacol. 2004;44(5):464–73.

    CAS  PubMed  Google Scholar 

  33. Frothingham R. Rates of Torsades de pointes associated with ciprofloxacin, ofloxacin, levofloxacin, gatifloxacin, and moxifloxacin. Pharmacotherapy. 2001;21(12):1468–72.

    CAS  PubMed  Google Scholar 

  34. Lapi F, Wilchesky M, Kezouh A, Benisty JI, Ernst P, Suissa S. Fluoroquinolones and the risk of serious arrhythmia: a population-based study. Clin Infect Dis. 2012;55(11):1457–65.

    CAS  PubMed  Google Scholar 

  35. Demolis J-L, Kubitza D, Tenneze L, Funck-Brentano C. Effect of a single oral dose of moxifloxacin (400 and 800 mg) on ventricular repolarization in healthy subjects. Clin Pharmacol Ther. 2000;68(6):658–66.

    CAS  PubMed  Google Scholar 

  36. Osborn LA, Skipper B, Arellano I, MacKerrow SD, Crawford MH. Results of resting and ambulatory electrocardiograms in patients with hypothyroidism and after return to euthyroid status. Heart Dis. 1999;1(1):8–11.

    CAS  PubMed  Google Scholar 

  37. Bakiner O, Ertorer ME, Haydardedeoglu FE, Bozkirli E, Tutuncu NB, Demirag NG. Subclinical hypothyroidism is characterized by increased QT interval dispersion among women. Med Princ Pract. 2008;17(5):390–4.

    CAS  PubMed  Google Scholar 

  38. Unal O, Erturk E, Ozkan H, Kiyici S, Guclu M, Ersoy C, et al. Effect of levothyroxine treatment on QT dispersion in patients with subclinical hypothyroidism. Endocr Pract. 2007;13(7):711–5.

    PubMed  Google Scholar 

  39. Kweon KH, Park BH, Cho CG. The effects of l-thyroxine treatment on QT dispersion in primary hypothyroidism. J Korean Med Sci. 2007;22(1):114–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Murphy ME, Singh KP, Laurenzi M, Brown M, Gillespie SH. Managing malaria in tuberculosis patients on fluoroquinolone-containing regimens: assessing the risk of QT prolongation. Int J Tuberc Lung Dis. 2012;16(2):144–9 (i–iii).

    CAS  PubMed  Google Scholar 

  41. Burkhardt JE, Walterspiel JN, Schaad UB. Quinolone-induced arthropathy in animals versus children. Clin Infect Dis. 1997;25(5):1196–204.

    CAS  PubMed  Google Scholar 

  42. Grady R. Safety profile of quinolone antibiotics in the pediatric population. Pediatr Infect Dis J. 2003;22(12):1128–32.

    PubMed  Google Scholar 

  43. Schaad UB. Fluoroquinolone antibiotics in infants and children. Infect Dis Clin N Am. 2005;19(3):617–28.

    Google Scholar 

  44. Schaad UB. Use of quinolones in pediatrics. Eur J Clin Microbiol Infect Dis. 1991;10(4):355–60.

    CAS  PubMed  Google Scholar 

  45. Jafri HS, McCracken GH Jr. Fluoroquinolones in paediatrics. Drugs. 1999;58(Suppl 2):43–8.

    CAS  PubMed  Google Scholar 

  46. Alghasham AA, Nahata MC. Clinical use of fluoroquinolones in children. Ann Pharmacother. 2000;34(3):347–59 (quiz 413–4).

    CAS  PubMed  Google Scholar 

  47. Adefurin A, Sammons H, Jacqz-Aigrain E, Choonara I. Ciprofloxacin safety in paediatrics: a systematic review. Arch Dis Child. 2011;96(9):874–80.

    PubMed Central  PubMed  Google Scholar 

  48. Noel GJ, Bradley JS, Kauffman RE, Duffy CM, Gerbino PG, Arguedas A, et al. Comparative safety profile of levofloxacin in 2,523 children with a focus on four specific musculoskeletal disorders. Pediatr Infect Dis J. 2007;26(10):879–91.

    PubMed  Google Scholar 

  49. Li F, Nandy P, Chien S, Noel GJ, Tornoe CW. Pharmacometrics-based dose selection of levofloxacin as a treatment for postexposure inhalational anthrax in children. Antimicrob Agents Chemother. 2010;54(1):375–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  50. Yee CL, Duffy C, Gerbino PG, Stryker S, Noel GJ. Tendon or joint disorders in children after treatment with fluoroquinolones or azithromycin. Pediatr Infect Dis J. 2002;21(6):525–9.

    PubMed  Google Scholar 

  51. Goldman JA, Kearns GL. Fluoroquinolone use in paediatrics: focus on safety and place in therapy. 18th Expert Committee on the Selection and Use of Essential Medicines. World Health Organization; 2011. http://www.who.int/selection_medicines/committees/expert/18/applications/fluoroquinolone_review.pdf. Accessed 18 Sept 2012.

  52. Bradley JS, Kauffman RE, Balis DA, Duffy CM, Gerbino PG, Maldonado SD, Noel GJ. Assessment of musculo-skeletal toxicity five years after therapy with levofloxacin. Paediatr. 2014;134(1):e146–53.

    Google Scholar 

  53. Tumbanatham A, Vinodkumar S. Ofloxacin induced arthropathy in patients with multi-drug resistance tuberculosis. J Assoc Physicians India. 2000;48(6):647–8.

    CAS  PubMed  Google Scholar 

  54. Arora VK, Tumbanatham A. Severe arthropathy with ofloxacin in two cases of MDR tuberculosis. Int J Tuberc Lung Dis. 1998;2(11):941–3.

    CAS  PubMed  Google Scholar 

  55. Wong HY, Chau CH, Yew WW. Moxifloxacin-induced arthropathy. Int J Tuberc Lung Dis. 2007;11(1):117.

    CAS  PubMed  Google Scholar 

  56. Friedrich LV, Dougherty R. Fatal hypoglycemia associated with levofloxacin. Pharmacotherapy. 2004;24(12):1807–12.

    PubMed  Google Scholar 

  57. Saigal S, Agarwal SR, Nandeesh HP, Sarin SK. Safety of an ofloxacin-based antitubercular regimen for the treatment of tuberculosis in patients with underlying chronic liver disease: a preliminary report. J Gastroenterol Hepatol. 2001;16(9):1028–32.

    CAS  PubMed  Google Scholar 

  58. Yew WW, Lee J, Wong PC, Kwan SY. Tolerance of ofloxacin in the treatment of pulmonary tuberculosis in presence of hepatic dysfunction. Int J Clin Pharmacol Res. 1992;12(4):173–8.

    CAS  PubMed  Google Scholar 

  59. Ho CC, Chen YC, Hu FC, Yu CJ, Yang PC, Luh KT. Safety of fluoroquinolone use in patients with hepatotoxicity induced by anti-tuberculosis regimens. Clin Infect Dis. 2009;48(11):1526–33.

    CAS  PubMed  Google Scholar 

  60. Roberts CH, Smith C, Breen R, Gadhok R, Murphy M, Aryee A, et al. Hepatotoxicity in the treatment of tuberculosis using moxifloxacin-containing regimens. Int J Tuberc Lung Dis. 2011;15(9):1275–6.

    PubMed  Google Scholar 

  61. World Health Organization. Guidelines for the programmatic management of drug-resistant tuberculosis: emergency update 2008. 2008. http://whqlibdoc.who.int/publications/2008/9789241547581_eng.pdf.

  62. Gilbert DN, Leggett JE. Aminoglycosides. In: Mandell GL, Bennett JE, Dolin R, editors. Mandell, Douglas, and Bennett’s principles and practice of infectious diseases. 7th ed. Philadelphia: Churchill Livingstone; 2010. p. 359–84.

    Google Scholar 

  63. Amikacin. Tuberculosis. 2008;88(2):87–8.

  64. Kawaguchi H. Discovery, chemistry, and activity of amikacin. J Infect Dis. 1976;134:S242–8.

    CAS  PubMed  Google Scholar 

  65. Capreomycin. Tuberculosis (Edinb). 2008;88(2):89–91.

  66. Evaluation of a new antituberculous agent. Capreomycin sulfate (capastat sulfate). JAMA. 1973;223(2):179–80.

  67. Bycroft BW, Cameron D, Croft LR, Hassanali-Walji A, Johnson AW, Webb T. Total structure of capreomycin IB, a tuberculostatic peptide antibiotic. Nature. 1971;231(5301):301–2.

    CAS  PubMed  Google Scholar 

  68. Dauby N, Payen MC. Amikacin-induced hypomagnesaemic tetany complicating multidrug-resistant tuberculosis treatment. Int J Tuberc Lung Dis. 2010;14(5):657–8.

    PubMed  Google Scholar 

  69. Lemos AC, Matos ED. Multidrug–resistant tuberculosis. Braz J Infect Dis. 2013;17(2):239–46.

    PubMed  Google Scholar 

  70. Mingeot-Leclercq MP, Tulkens PM. Aminoglycosides: nephrotoxicity. Antimicrob Agents Chemother. 1999;43(5):1003–12.

    PubMed Central  CAS  PubMed  Google Scholar 

  71. Rybak MJ, Abate BJ, Kang SL, Ruffing MJ, Lerner SA, Drusano GL. Prospective evaluation of the effect of an aminoglycoside dosing regimen on rates of observed nephrotoxicity and ototoxicity. Antimicrob Agents Chemother. 1999;43(7):1549–55.

    PubMed Central  CAS  PubMed  Google Scholar 

  72. Shin SS, Pasechnikov AD, Gelmanova IY, Peremitin GG, Strelis AK, Mishustin S, et al. Adverse reactions among patients being treated for MDR-TB in Tomsk, Russia. Int J Tuberc Lung Dis. 2007;11(12):1314–20.

    CAS  PubMed  Google Scholar 

  73. de Jager P, van Altena R. Hearing loss and nephrotoxicity in long-term aminoglycoside treatment in patients with tuberculosis. Int J Tuberc Lung Dis. 2002;6(7):622–7.

    PubMed  Google Scholar 

  74. Shin S, Furin J, Alcantara F, Hyson A, Joseph K, Sanchez E, et al. Hypokalemia among patients receiving treatment for multidrug-resistant tuberculosis. Chest. 2004;125(3):974–80.

    PubMed  Google Scholar 

  75. Keating MJ, Sethi MR, Bodey GP, Samaan NA. Hypocalcemia with hypoparathyroidism and renal tubular dysfunction associated with aminoglycoside therapy. Cancer. 1977;39(4):1410–4.

    CAS  PubMed  Google Scholar 

  76. Holmes AM, Hesling CM, Wilson TM. Capreomycin-induced serum electrolyte abnormalities. Thorax. 1970;25(5):608–11.

    PubMed Central  CAS  PubMed  Google Scholar 

  77. Hesling CM. Treatment with capreomycin, with special reference to toxic effects. Tubercle. 1969;50(Suppl):39–41.

    PubMed  Google Scholar 

  78. Dheda K, Shean K, Zumla A, Badri M, Streicher EM, Page-Shipp L, et al. Early treatment outcomes and HIV status of patients with extensively drug-resistant tuberculosis in South Africa: a retrospective cohort study. Lancet. 2010;375(9728):1798–807.

    PubMed  Google Scholar 

  79. Huth ME, Ricci AJ, Cheng AG. Mechanisms of aminoglycoside ototoxicity and targets of hair cell protection. Int J Otolaryng. 2011;2011:1–19.

  80. Bardien S, Human H, Harris T, Hefke G, Veikondis R, Schaaf HS, et al. A rapid method for detection of five known mutations associated with aminoglycoside-induced deafness. BMC Med Genet. 2009;10:2.

    PubMed Central  PubMed  Google Scholar 

  81. Human H, Hagen CM, de Jong G, Harris T, Lombard D, Christiansen M, et al. Investigation of mitochondrial sequence variants associated with aminoglycoside-induced ototoxicity in South African TB patients on aminoglycosides. Biochem Biophys Res Commun. 2010;393(4):751–6.

    CAS  PubMed  Google Scholar 

  82. Xing G, Chen Z, Cao X. Mitochondrial rRNA and tRNA and hearing function. Cell Res. 2007;17(3):227–39.

    CAS  PubMed  Google Scholar 

  83. O’Donnell EP, Scarsi KK, Scheetz MH, Postelnick MJ, Cullina J, Jain M. Risk factors for aminoglycoside ototoxicity in adult cystic fibrosis patients. Int J Antimicrob Agents. 2010;36(1):94–5.

    PubMed  Google Scholar 

  84. Gatell JM, Ferran F, Araujo V, Bonet M, Soriano E, Traserra J, et al. Univariate and multivariate analyses of risk factors predisposing to auditory toxicity in patients receiving aminoglycosides. Antimicrob Agents Chemother. 1987;31(9):1383–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  85. Tran Ba Huy P, Deffrennes D. Aminoglycoside ototoxicity: influence of dosage regimen on drug uptake and correlation between membrane binding and some clinical features. Acta Otolaryngol. 1988;105(5–6):511–5.

    CAS  PubMed  Google Scholar 

  86. Pettorossi VE, Ferraresi A, Errico P, Draicchio F, Dionisotti S. The impact of different dosing regimens of the aminoglycosides netilmicin and amikacin on vestibulotoxicity in the guinea pig. Eur Arch Otorhinolaryngol. 1990;247(5):277–82.

    CAS  PubMed  Google Scholar 

  87. Takumida M, Nishida I, Nikaido M, Hirakawa K, Harada Y, Bagger-Sjoback D. Effect of dosing schedule on aminoglycoside ototoxicity: comparative cochlear ototoxicity of amikacin and isepamicin. J Otorhinolaryngol Relat Spec. 1990;52(6):341–9.

    CAS  Google Scholar 

  88. Peloquin CA, Berning SE, Nitta AT, Simone PM, Goble M, Huitt GA, et al. Aminoglycoside toxicity: daily versus thrice-weekly dosing for treatment of mycobacterial diseases. Clin Infect Dis. 2004;38(11):1538–44.

    CAS  PubMed  Google Scholar 

  89. Seddon JA, Godfrey-Faussett P, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in patients on treatment for drug-resistant tuberculosis. Eur Respir J. 2012;40(5):1277–86.

    PubMed  Google Scholar 

  90. Harris T, Bardien S, Schaaf HS, Petersen L, De Jong G, Fagan JJ. Aminoglycoside-induced hearing loss in HIV-positive and HIV-negative multidrug-resistant tuberculosis patients. S Afr Med J. 2012;102(6):363–6.

    PubMed  Google Scholar 

  91. Seddon JA, Thee S, Jacobs K, Ebrahim A, Hesseling AC, Schaaf HS. Hearing loss in children treated for multidrug-resistant tuberculosis. J Infect. 2013;66(4):320–9.

    PubMed  Google Scholar 

  92. Drobac PC, Mukherjee JS, Joseph JK, Mitnick C, Furin JJ, del Castillo H, et al. Community-based therapy for children with multidrug-resistant tuberculosis. Pediatrics. 2006;117(6):2022–9.

    PubMed  Google Scholar 

  93. Fairlie L, Beylis NC, Reubenson G, Moore DP, Madhi SA. High prevalence of childhood multi-drug resistant tuberculosis in Johannesburg, South Africa: a cross sectional study. BMC Infect Dis. 2011;11:28.

    PubMed Central  PubMed  Google Scholar 

  94. Rist N, Grumbach F, Libermann D. Experiments on the antituberculous activity of alpha-ethylthioisonicotinamide. Am Rev Tuberc. 1959;79(1):1–5.

    CAS  PubMed  Google Scholar 

  95. Ethionamide. Tuberculosis. 2008;88(2):106–8.

  96. Wang F, Langley R, Gulten G, Dover LG, Besra GS, Jacobs WR Jr, et al. Mechanism of thioamide drug action against tuberculosis and leprosy. J Exp Med. 2007;204(1):73–8.

    PubMed Central  CAS  PubMed  Google Scholar 

  97. Banerjee A, Dubnau E, Quemard A, Balasubramanian V, Um KS, Wilson T, et al. inhA, a gene encoding a target for isoniazid and ethionamide in Mycobacterium tuberculosis. Science. 1994;263(5144):227–30.

    CAS  PubMed  Google Scholar 

  98. Kass I. Chemotherapy regimens used in retreatment of pulmonary tuberculosis. Observations on the efficacy of combinations of kanamycin, ethionamide and either cycloserine or pyrazinamide. Tubercle. 1965;46:151–65.

    CAS  PubMed  Google Scholar 

  99. Seddon JA, Furin JJ, Gale M, Del Castillo Barrientos H, Hurtado RM, Amanullah F, et al. Caring for children with drug-resistant tuberculosis: practice-based recommendations. Am J Respir Crit Care Med. 2012;186(10):953–64.

    CAS  PubMed  Google Scholar 

  100. Lee HW, Kim DW, Park JH, Kim SD, Lim MS, Phapale PB, et al. Pharmacokinetics of prothionamide in patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2009;13(9):1161–6.

    CAS  PubMed  Google Scholar 

  101. A comparison of the toxicity of prothionamide and ethionamide: a report from the research committee of the British Tuberculosis Association. Tubercle. 1968;49(2):125–35.

  102. Comparison of the clinical usefulness of ethionamide and prothionamide in initial treatment of tuberculosis: tenth series of controlled trials. Tubercle. 1968;49(3):281–90.

  103. Drucker D, Eggo MC, Salit IE, Burrow GN. Ethionamide-induced goitrous hypothyroidism. Ann Intern Med. 1984;100(6):837–9.

    CAS  PubMed  Google Scholar 

  104. Soumakis SA, Berg D, Harris HW. Hypothyroidism in a patient receiving treatment for multidrug-resistant tuberculosis. Clin Infect Dis. 1998;27(4):910–1.

    CAS  PubMed  Google Scholar 

  105. McDonnell ME, Braverman LE, Bernardo J. Hypothyroidism due to ethionamide. N Engl J Med. 2005;352(26):2757–9.

    CAS  PubMed  Google Scholar 

  106. Thee S, Zollner EW, Willemse M, Hesseling AC, Magdorf K, Schaaf HS. Abnormal thyroid function tests in children on ethionamide treatment. Int J Tuberc Lung Dis. 2011;15(9):1191–3 (i).

    CAS  PubMed  Google Scholar 

  107. Satti H, Mafukidze A, Jooste PL, McLaughlin MM, Farmer PE, Seung KJ. High rate of hypothyroidism among patients treated for multidrug-resistant tuberculosis in Lesotho. Int J Tuberc Lung Dis. 2012;16(4):468–72.

    CAS  PubMed  Google Scholar 

  108. Gupta J, Breen RAM, Milburn HJ. Drug-induced hypothyroidism in patients receiving treatment for multidrug-resistant tuberculosis in the UK [correspondence]. Int J Tuberc Lung Dis. 2012;16(9):1278.

    CAS  PubMed  Google Scholar 

  109. Modongo C, Zetola NM. Prevalence of hypothyroidism among MDR-TB patients in Botswana [correspondence]. Int J Tuberc Lung Dis. 2012;16(11):1561–2.

    PubMed Central  PubMed  Google Scholar 

  110. Dutta BS, Hassan G, Waseem Q, Saheer S, Singh A. Ethionamide-induced hypothyroidism. Int J Tuberc Lung Dis. 2012;16(1):141.

    PubMed  Google Scholar 

  111. Hollinrake K. Acute hepatic necrosis associated with ethionamide. Br J Dis Chest. 1968;62(3):151–4.

    CAS  PubMed  Google Scholar 

  112. Swash M, Roberts AH, Murnaghan DJ. Reversible pellagra-like encephalopathy with ethionamide and cycloserine. Tubercle. 1972;53(2):132–6.

    CAS  PubMed  Google Scholar 

  113. Narang RK. Acute psychotic reaction probably caused by ethionamide. Tubercle. 1972;53(2):137–8.

    CAS  PubMed  Google Scholar 

  114. Lansdown FS, Beran M, Litwak T. Psychotoxic reaction during ethionamide therapy. Am Rev Respir Dis. 1967;95(6):1053–5.

    CAS  PubMed  Google Scholar 

  115. Sharma PK, Bansal R. Gynecomastia caused by ethionamide. Indian J Pharmacol. 2012;44(5):654–5.

    PubMed Central  PubMed  Google Scholar 

  116. Dixit R, George J, Sharma AK, Chhabra N, Jangir SK, Mishra V. Ethionamide-induced gynecomastia. J Pharmacol Pharmacother. 2012;3(2):196–9.

    PubMed Central  CAS  PubMed  Google Scholar 

  117. Ticholov K, Dobrev P. Severe hypoglycemic manifestations in tuberculous diabetes treated with ethionamide. Tuberkulosearzt. 1963;17:439–46.

    CAS  PubMed  Google Scholar 

  118. Prothionamide. Tuberculosis. 2008;88(2):139–40.

  119. Cycloserine. Tuberculosis (Edinb). 2008;88(2):100–1.

  120. Chen JM, Uplekar S, Gordon SV, Cole ST. A point mutation in cycA partially contributes to the d-cycloserine resistance trait of Mycobacterium bovis BCG vaccine strains. PLoS One. 2012;7(8):e43467.

    PubMed Central  CAS  PubMed  Google Scholar 

  121. Bruning JB, Murillo AC, Chacon O, Barletta RG, Sacchettini JC. Structure of the Mycobacterium tuberculosis d-alanine: d-alanine ligase, a target of the antituberculosis drug d-cycloserine. Antimicrob Agents Chemother. 2011;55(1):291–301.

    PubMed Central  CAS  PubMed  Google Scholar 

  122. Halouska S, Chacon O, Fenton RJ, Zinniel DK, Barletta RG, Powers R. Use of NMR metabolomics to analyze the targets of d-cycloserine in mycobacteria: role of d-alanine racemase. J Proteome Res. 2007;6(12):4608–14.

    PubMed Central  CAS  PubMed  Google Scholar 

  123. Zitkova L, Tousek J. Pharmacokinetics of cycloserine and terizidone. A comparative study. Chemotherapy. 1974;20(1):18–28.

    CAS  PubMed  Google Scholar 

  124. Peloquin CA. Therapeutic drug monitoring in the treatment of tuberculosis. Drugs. 2002;62(15):2169–83.

    CAS  PubMed  Google Scholar 

  125. Kwon HM, Kim HK, Cho J, Hong YH, Nam H. Cycloserine-induced encephalopathy: evidence on brain MRI. Eur J Neurol. 2008;15(7):e60–1.

    PubMed  Google Scholar 

  126. Holmes CX, Martin GE, Fetterhoff KI. The role of the cycloserine (seromycin) blood level in the treatment of pulmonary tuberculosis and the prevention and control of cycloserine (seromycin) toxicity. Dis Chest. 1959;36:591–3.

    CAS  PubMed  Google Scholar 

  127. Donald PR. Cerebrospinal fluid concentrations of antituberculosis agents in adults and children. Tuberculosis (Edinb). 2010;90(5):279–92.

    CAS  PubMed  Google Scholar 

  128. Vega P, Sweetland A, Acha J, Castillo H, Guerra D, Smith Fawzi MC, et al. Psychiatric issues in the management of patients with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 2004;8(6):749–59.

    CAS  PubMed  Google Scholar 

  129. Shim JH, Kim TY, Kim HO, Kim CW. Cycloserine-induced lichenoid drug eruption. Dermatology. 1995;191(2):142–4.

    CAS  PubMed  Google Scholar 

  130. Akula SK, Aruna AS, Johnson JE, Anderson DS. Cycloserine-induced Stevens-Johnson syndrome in an AIDS patient with multidrug-resistant tuberculosis. Int J Tuberc Lung Dis. 1997;1(2):187–90.

    CAS  PubMed  Google Scholar 

  131. Vora A. Terizidone. J Assoc Physicians India. 2010;58:267–8.

    PubMed  Google Scholar 

  132. Weyer K. Annexure 2: DOTS-Plus for multidrug resistant tuberculosis patients in South Africa. Systematic evaluation of a standardised treatment regimen applied under tuberculosis control programme conditions. 2004. http://www.kznhealth.gov.za/chrp/National/TB?SA TB guidelines 2004.pdf. Accessed 12 Aug 2014.

  133. Steiner M. Newer and second-line drugs in the treatment of drug-resistant tuberculosis in children. Med Clin N Am. 1967;51(5):1153–67.

    CAS  PubMed  Google Scholar 

  134. Battaglia B, Kaufman I, Lyons HA, Marsh W. Toxicity of cycloserine combined with isoniazid in the treatment of tuberculosis in children. Am Rev Respir Dis. 1961;83:751–2.

    CAS  PubMed  Google Scholar 

  135. Schloss J, Ismail Z. Cycloserine and isoniazid in childhood tuberculous infections. Antibiotic Med Clin Ther. 1960;7:244–8.

    CAS  Google Scholar 

  136. Lehmann J. Para-aminosalicylic acid in the treatment of tuberculosis. Lancet. 1946;1(6384):15.

    CAS  PubMed  Google Scholar 

  137. Para-aminosalicylic acid. Tuberculosis. 2008;88(2):137–8.

  138. Ratledge C. Iron, mycobacteria and tuberculosis. Tuberculosis (Edinb). 2004;84(1–2):110–30.

    PubMed  Google Scholar 

  139. Durham NN, Hubbard JS. Mechanism of competitive inhibition of p-aminobenzoic acid oxidation by p-aminosalicylic acid. J Bacteriol. 1960;80:225–31.

    PubMed Central  CAS  PubMed  Google Scholar 

  140. Durham NN, Hubbard JS. Antagonism of the oxidative dissimilation of p-aminobenzoic acid by p-aminosalicylic acid. Nature. 1959;184(Suppl 18):1398.

    PubMed  Google Scholar 

  141. Lehmann J. The treatment of tuberculosis in Sweden with para-aminosalicylic acid; a review. Dis Chest. 1949;16(6):684–703.

    CAS  PubMed  Google Scholar 

  142. Woolley PB. The use of antrenyl in gastro-intestinal irritation due to PAS compounds. Br J Tuberc Dis Chest. 1957;51(4):382–4.

    CAS  PubMed  Google Scholar 

  143. Peloquin CA, Berning SE, Huitt GA, Childs JM, Singleton MD, James GT. Once-daily and twice-daily dosing of p-aminosalicylic acid granules. Am J Respir Crit Care Med. 1999;159(3):932–4.

    CAS  PubMed  Google Scholar 

  144. Hamilton RR. Effect of PAS on the thyroid gland. Br Med J. 1953;1(4800):29–30.

    PubMed Central  CAS  PubMed  Google Scholar 

  145. Balint JA, Fraser R, Hanno MG. Radio-iodine measurements of thyroid function during and after P.A.S. treatment of tuberculosis. Br Med J. 1954;1(4873):1234–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  146. Davies HT, Galbraith H-JB. Goitre and hypothyroidism developing during treatment with PAS. BMJ. 1953;1(4822):1261.

    PubMed Central  CAS  PubMed  Google Scholar 

  147. Komrower GM. Case of Myxoedema developing during p-aminosalicylic acid therapy. BMJ. 1951;2(4741):1193–4.

    PubMed Central  CAS  PubMed  Google Scholar 

  148. Macgregor AG, Somner AR. The anti-thyroid action of para-aminosalicylic acid. Lancet. 1954;267(6845):931–6.

    CAS  PubMed  Google Scholar 

  149. Macgregor AG, Somner AR. Iodide in goitre due to P.A.S. BMJ. 1954;1(4877):1494.

    PubMed Central  Google Scholar 

  150. Edwards DA, Rowlands EN, Trotter WR. The mechanism of the goitrogenic action of p-aminosalicylic acid. Lancet. 1954;267(6847):1051–2.

    CAS  PubMed  Google Scholar 

  151. Satti H, McLaughlin MM, Omotayo DB, Keshavjee S, Becerra MC, Mukherjee JS, et al. Outcomes of comprehensive care for children empirically treated for multidrug-resistant tuberculosis in a setting of high HIV prevalence. PLoS One. 2012;7(5):e37114.

    PubMed Central  CAS  PubMed  Google Scholar 

  152. Matsaniotis N, Jacobs J, Smith MH. Hypersensitivity reactions associated with sodium para-aminosalicylate therapy; four case reports and review of the literature. Pediatrics. 1958;21(5):781–92.

    CAS  PubMed  Google Scholar 

  153. Lynch MJ. Effect of para-amino-salicylic acid on prothrombin time. J Clin Pathol. 1950;3(2):114–7.

    PubMed Central  CAS  PubMed  Google Scholar 

  154. Ge QP, Wang QF, Duan HF, Wang J, Chu NH. Clinical analysis of prothionamide and para amino salicylic acid induced hepatotoxicity. Zhonghua Jie He He Hu Xi Za Zhi. 2013;36(10):737–40.

    PubMed  Google Scholar 

  155. Diekema DJ, Jones RN. Oxazolidinone antibiotics. Lancet. 2001;358(9297):1975–82.

    CAS  PubMed  Google Scholar 

  156. Shinabarger DL, Marotti KR, Murray RW, Lin AH, Melchior EP, Swaney SM, et al. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother. 1997;41(10):2132–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  157. Lin AH, Murray RW, Vidmar TJ, Marotti KR. The oxazolidinone eperezolid binds to the 50S ribosomal subunit and competes with binding of chloramphenicol and lincomycin. Antimicrob Agents Chemother. 1997;41(10):2127–31.

    PubMed Central  CAS  PubMed  Google Scholar 

  158. De Vriese AS, Coster RV, Smet J, Seneca S, Lovering A, Van Haute LL, et al. Linezolid-induced inhibition of mitochondrial protein synthesis. Clin Infect Dis. 2006;42(8):1111–7.

    PubMed  Google Scholar 

  159. Vinh DC, Rubinstein E. Linezolid: a review of safety and tolerability. J Infect. 2009;59(Suppl 1):S59–74.

    PubMed  Google Scholar 

  160. Garazzino S, Tovo PA. Clinical experience with linezolid in infants and children. J Antimicrob Chemother. 2011;66(Suppl 4):iv23–41.

    CAS  PubMed  Google Scholar 

  161. Chiappini E, Conti C, Galli L, de Martino M. Clinical efficacy and tolerability of linezolid in pediatric patients: a systematic review. Clin Ther. 2010;32(1):66–88.

    CAS  PubMed  Google Scholar 

  162. Saiman L, Goldfarb J, Kaplan SA, Wible K, Edge-Padbury B, Naberhuis-Stehouwer S, et al. Safety and tolerability of linezolid in children. Pediatr Infect Dis J. 2003;22(9 Suppl):S193–200.

    PubMed  Google Scholar 

  163. Gerson SL, Kaplan SL, Bruss JB, Le V, Arellano FM, Hafkin B, et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother. 2002;46(8):2723–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  164. Lee M, Lee J, Carroll MW, Choi H, Min S, Song T, et al. Linezolid for treatment of chronic extensively drug-resistant tuberculosis. N Engl J Med. 2012;367(16):1508–18.

    CAS  PubMed  Google Scholar 

  165. Meissner HC, Townsend T, Wenman W, Kaplan SL, Morfin MR, Edge-Padbury B, et al. Hematologic effects of linezolid in young children. Pediatr Infect Dis J. 2003;22(9 Suppl):S186–92.

    PubMed  Google Scholar 

  166. Bressler AM, Zimmer SM, Gilmore JL, Somani J. Peripheral neuropathy associated with prolonged use of linezolid. Lancet Infect Dis. 2004;4(8):528–31.

    PubMed  Google Scholar 

  167. Spellberg B, Yoo T, Bayer AS. Reversal of linezolid-associated cytopenias, but not peripheral neuropathy, by administration of vitamin B6. J Antimicrob Chemother. 2004;54(4):832–5.

    CAS  PubMed  Google Scholar 

  168. Nambiar S, Rellosa N, Wassel RT, Borders-Hemphill V, Bradley JS. Linezolid-associated peripheral and optic neuropathy in children. Pediatrics. 2011;127(6):e1528–32.

    PubMed  Google Scholar 

  169. Yogev R, Patterson LE, Kaplan SL, Adler S, Morfin MR, Martin A, et al. Linezolid for the treatment of complicated skin and skin structure infections in children. Pediatr Infect Dis J. 2003;22(9 Suppl):S172–7.

    PubMed  Google Scholar 

  170. Su E, Crowley K, Carcillo JA, Michaels MG. Linezolid and lactic acidosis: a role for lactate monitoring with long-term linezolid use in children. Pediatr Infect Dis J. 2011;30(9):804–6.

    PubMed Central  PubMed  Google Scholar 

  171. Rose PC, Hallbauer UM, Seddon JA, Hesseling AC, Schaaf HS. Linezolid-containing regimens for the treatment of drug-resistant tuberculosis in South African children. Int J Tuberc Lung Dis. 2012;16(12):1588–93.

    CAS  PubMed  Google Scholar 

  172. French G. Safety and tolerability of linezolid. J Antimicrob Chemother. 2003;51(Suppl 2):ii 45–53.

    CAS  Google Scholar 

  173. Reddy VM, O’Sullivan JF, Gangadharam PR. Antimycobacterial activities of riminophenazines. J Antimicrob Chemother. 1999;43(5):615–23.

    CAS  PubMed  Google Scholar 

  174. Clofazimine. Tuberculosis. 2008;88(2):96–9.

  175. World Health Organization. Chemotherapy of leprosy. Geneva: WHO; 1994. http://www.who.int/lep/resources/Chemotherapy.pdf. Accessed 10 Jan 2013.

  176. Yano T, Kassovska-Bratinova S, Teh JS, Winkler J, Sullivan K, Isaacs A, et al. Reduction of clofazimine by mycobacterial type 2 NADH:quinone oxidoreductase: a pathway for the generation of bactericidal levels of reactive oxygen species. J Biol Chem. 2011;286(12):10276–87.

    PubMed Central  CAS  PubMed  Google Scholar 

  177. Grant SS, Kaufmann BB, Chand NS, Haseley N, Hung DT. Eradication of bacterial persisters with antibiotic-generated hydroxyl radicals. Proc Natl Acad Sci. 2012;109(30):12147–52.

    PubMed Central  CAS  PubMed  Google Scholar 

  178. Ramu G, Iyer GG. Side effects of clofazimine therapy. Lepr India. 1976;48(4 Suppl):722–31.

    CAS  PubMed  Google Scholar 

  179. Hameed A, Beach FX, Kennedy RH, Barry RE. A case of clofazimine enteropathy. Int J Clin Pract. 1998;52(6):439–40.

    CAS  PubMed  Google Scholar 

  180. Singh H, Nel B, Dey V, Tiwari P, Dulhani N. Adverse effects of multi-drug therapy in leprosy, a two years’ experience (2006–2008) in tertiary health care centre in the tribal region of Chhattisgarh State (Bastar, Jagdalpur). Lepr Rev. 2011;82(1):17–24.

    PubMed  Google Scholar 

  181. Parizhskaya M, Youssef NN, Di Lorenzo C, Goyal RK. Clofazimine enteropathy in a pediatric bone marrow transplant recipient. J Pediatr. 2001;138(4):574–6.

    CAS  PubMed  Google Scholar 

  182. Balakrishnan S, Desikan KV, Ramu G. Quantitative estimation of clofazimine in tissue. Lepr India. 1976;48(4 Suppl):732–8.

    CAS  PubMed  Google Scholar 

  183. Revised National Tuberculosis Control Programme. DOTS-Plus guidelines, January 2010. http://www.tbcindia.nic.in. Accessed 12 Dec 2014.

  184. Orenstein EW, Basu S, Shah NS, Andrews JR, Friedland GH, et al. Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis. Lancet Infect Dis. 2009;9:153–61.

    PubMed  Google Scholar 

  185. Suarez PG, Floyd K, Portocarrero J, et al. Feasibility and cost-effectiveness of a standardized second line drugs treatment for chronic tuberculosis patients: national cohort study in Peru. Lancet. 2002;359:1980–9.

    PubMed  Google Scholar 

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No sources of funding were used to prepare this review. Geetha Ramachandran and Soumya Swaminathan have no conflicts of interest that are directly relevant to the content of this review.

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    Geetha Ramachandran & Soumya Swaminathan

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Ramachandran, G., Swaminathan, S. Safety and Tolerability Profile of Second-Line Anti-Tuberculosis Medications. Drug Saf 38, 253–269 (2015). https://doi.org/10.1007/s40264-015-0267-y

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