Continuing Education Activity

Antitubercular medications: rifampin, isoniazid, pyrazinamide, and ethambutol are FDA approved to treat Mycobacterium tuberculosis infections. Antitubercular medications are a group of drugs used to treat tuberculosis. Tuberculosis (TB) is a disease caused by Mycobacterium tuberculosis (M-TB), an acid-fast aerobic bacteria that can grow on gram stain as either gram-positive or gram-negative. This review will outline the indications, contraindications, and other aspects of these drugs.

Objectives:

• Identify the mechanism of action of antitubercular therapy.
• Describe the potential adverse effects of antitubercular therapy.
• Review the risk factors for developing drug resistance to antitubercular therapy.
• Summarize interprofessional team strategies for improving care coordination and communication to advance antitubercular therapy and improve outcomes.

Indications

Tuberculosis is a disease that results from infection with the bacteria Mycobacterium tuberculosis. It most commonly affects the lungs but can also affect other areas of the body. The infection can be active or latent, with approximately 10% of latent infections progressing to active status. The disease is spread by droplets from speaking, coughing, and sneezing. In the past, the disease was colloquially known by the name consumption. Diagnosis is via chest X-ray, microbacterial cultures, and tuberculin skin test.[1]

Anti-tubercular medications: rifampin, isoniazid, pyrazinamide, and ethambutol are FDA-approved for the treatment of Mycobacterium tuberculosis infections.[2] The combination and duration on which medications to use for therapy rely on whether the patient has active or latent disease.[3] A feared complication of tuberculosis therapy is multi-drug-resistant tuberculosis(MDR-TB). MDR-TB is distinguished from its resistance to first-line medications isoniazid and rifampin.[4] Therapy for MDR-TB is steadily advancing, and suggestions are continually changing.[5] Second-line drugs that are in common use for MDR-TB are kanamycin, capreomycin, and amikacin via injections.[5] Fluoroquinolones such as levofloxacin, moxifloxacin, and gatifloxacin are also among the common second-line agents used when drug resistance develops to the first-line agents.[6][7] Drugs that have recently received FDA approval for multi-drug resistance TB are pretomanid, used in sequence with bedaquiline and linezolid.[5][8][9][10] A more dangerous and uncommon type of MDR-TB is extensively multi-drug resistant tuberculosis(XDR-TB). This infection characteristically shows the resistance to first-line medications rifampin and isoniazid, one second-line aminoglycoside, and either of the fluoroquinolones.[11][12] 

First Line

• Rifampin
• Isoniazid
• Pyrazinamide
• Ethambutol

Second Line

• Kanamycin (discontinued use in the USA)
• Streptomycin
• Capreomycin
• Amikacin
• Levofloxacin
• Moxifloxacin
• Gatifloxacin

MDR-TB

• Bedaquiline
• Delamanid
• Linezolid
• Pretomanid

The information presented in this overview article is high level; for more details on each specific agent, the reader is instructed to seek the Statpearls articles on the individual agents.

Mechanism of Action

Rifampin

Rifampin exerts its effects by reversibly inhibiting DNA-dependent RNA polymerase, which further inhibits bacterial protein synthesis and transcription.[13][14][15]

Isoniazid

Isoniazid is a pro-drug that is converted to its active form metabolite by catalase-peroxidase and exerts its action by further inhibiting the biosynthesis of mycolic acid.[4][16]

Pyrazinamide

Pyrazinamide's mechanism of action remains unknown and not fully understood.[17] Pyrazinamide is converted to its active form pyrazinoic acid and exerts its effect by inhibiting trans-translation and possibly coenzyme A synthesis needed for the bacteria to survive.[18]

Ethambutol

Ethambutol inhibits the enzyme arabinosyltransferases and prevents the biosynthesis of the mycobacterial cell wall.[19]

Aminoglycosides (Streptomycin, Kanamycin, Amikacin)

Aminoglycosides exert their action by binding to the 30S subunit of ribosomes and inhibiting the protein synthesis of the mycobacteria.[20][21]

Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin)

Fluoroquinolones exert their effects by inhibiting DNA gyrase and topoisomerase IV, further inhibiting DNA synthesis within the bacteria.[22]

Administration

Active Tuberculosis

During active disease, there are two phases for treatment: the initiation phase and the continuation phase.[23][5] The initiation phase consists of two months of rifampin, isoniazid, pyrazinamide, and ethambutol therapy.[5] This regimen is administered orally daily for eight weeks for a total of 56 doses.  Once completed, isoniazid and rifampin are continued for an additional four-month for the continuation phase.[2][5] This regimen is administered orally daily for 18 weeks for a total of 126 doses. For patients that cannot tolerate ethambutol, streptomycin can be substituted.[2]

Rifampin [24]

10 mg/kg /day

The maximum dose: 600mg

Isoniazid [24]

5 mg/kg/day

The maximum dose: 300mg

Pyrazinamide [24]

25 mg/kg/day

Dosages are adjusted according to weight

Ethambutol [24]

15 to 20 mg/kg/day

Dosages are adjusted according to weightSecond-line agents such as kanamycin, capreomycin, amikacin are administered as an injection, and fluoroquinolones such as moxifloxacin, gatifloxacin, and levofloxacin are administered orally. These agents are options when resistance to first-line medication develops.[25]

Latent Tuberculosis

The most typical and used treatment for latent tuberculosis is isoniazid therapy for a duration of nine months.[3] This regimen is administered orally daily for nine months for a total of 270 doses. A three-month combination of isoniazid and rifampin or a fourth-month duration of rifampin monotherapy are also possibilities.[3] Isoniazid monotherapy can have an effect of greater than 90% on the latent disease if taken upon completion of the full nine-month duration.[26] Pyridoxine (vitamin B6) use is advised alongside isoniazid therapy, as isoniazid use individually can cause peripheral neuropathy secondary to vitamin B6 deficiency.

Isoniazid [24]

5 mg/kg/day

The maximum dose: 300mg

Vitamin B6 [23]

10 to 25 mg/day

Anti-tubercular medications should be taken in the daytime one hour before consuming any meals.[2]

Adverse Effects

Rifampin [5] [27] [28] [24]

• Hepatotoxicity
• Thrombocytopenia
• Neutropenia
• Orange/Red discoloration of bodily fluids
• CYP450 Inducer

Isoniazid [26] [29]

• Hepatotoxicity
• Vitamin B6 deficiency
• Peripheral Neuropathy

Pyrazinamide [27] [30]

• Hepatotoxicity
• Hyperuricemia
• Arthralgia

Ethambutol [31]

• Optic neuropathy
• Hepatotoxicity

Aminoglycosides (Streptomycin, Kanamycin, Amikacin) [23][32]

• Ototoxicity
• Nephrotoxicity

Fluoroquinolones (Levofloxacin, Moxifloxacin, Gatifloxacin) [33]

• Tendonitis
• Tendon rupture
• Arthropathy

Contraindications

Pregnancy: During pregnancy, all anti-tubercular medications are useful for treatment except for aminoglycosides.[23] Aminoglycosides such as streptomycin, amikacin, and kanamycin may exhibit ototoxic effects on the developing fetus and are contraindicated during pregnancy.[23]

In the USA, pyrazinamide use is avoided during pregnancy because it is a possible teratogen.

Monitoring

Liver function tests should be monitored routinely as rifampin, isoniazid, pyrazinamide, and ethambutol all may exert hepatotoxic effects.[27] A CBC is also required to regularly monitor patients taking rifampin, as it can lead to thrombocytopenia and neutropenia.[27] Rifampin also exerts its effects by inducing cytochrome P450(CYP450), which may cause unwanted drug interactions of medications that are metabolized by the CYP450 system and decrease their clinical efficacy.[28] Isoniazid can cause pyridoxine deficiency that may lead to peripheral neuropathy in patients.[29] The patient can supplement vitamin B6 to prevent this from happening.[29] Pyrazinamide can increase uric acid concentrations and precipitate acute gout flare-ups in predisposed individuals.[34] The recommendation is to monitor uric acid concentrations routinely for patients managed with pyrazinamide.[35]

Toxicity

All first-line anti-tubercular medications, rifampin, isoniazid, pyrazinamide, and ethambutol, can exert hepatotoxic effects.[27][36] A continual rise in liver functions test should prompt discontinuation of treatment.[27] Aminoglycoside-induced nephrotoxicity is reversible when stopping the medication.[37] Renal toxicity depends on the patient if any underlying renal disease is present and on the dose of the medication being administered. Renal insufficiency is avoidable in most patients.[37]

Enhancing Healthcare Team Outcomes

Rifampin, isoniazid, pyrazinamide, and ethambutol are first-line antitubercular medications, which are FDA-approved and indicated for the treatment of Mycobacterium tuberculosis infections. The care for patients suffering from tuberculosis prompts critical care from an interprofessional team of healthcare professionals as the preventable infectious disease can lead to medication resistance and mortality. These healthcare professionals include a primary care clinician, an infectious disease specialist, a nurse, and a pharmacist. The primary care physicians and specialists should educate the patients about the consequences of non-adherence to pharmacotherapy for the full duration and how resistance to treatment can further develop into MDR-TB and cause mortality.

Primary care clinicians should routinely monitor labs, as all four agents are hepatotoxic drugs. Counseling and careful monitoring should be conducted during pregnancy, as some second-line medications are teratogenic. Clinicians should be up to date with the newly FDA-approved MDR-TB and their effects in the event drug resistance develops. Interprofessional communication between all team members is key to building patient rapport and developing a therapeutic alliance, so the patients adhere to therapy adequately to eradicate the bacteria and prevent further spread. This interprofessional approach with open communication channels between team members will drive better patient outcomes with fewer adverse events. [Level 5]

Review Questions

• Access free multiple choice questions on this topic.
• Comment on this article.

References

1.

Alzayer Z, Al Nasser Y. StatPearls [Internet]. StatPearls Publishing; Treasure Island (FL): Jan 2, 2023. Primary Lung Tuberculosis. [PubMed: 33620814]

2.

Ben Amar J, Dhahri B, Aouina H, Azzabi S, Baccar MA, El Gharbi L, Bouacha H. [Treatment of tuberculosis]. Rev Pneumol Clin. 2015 Apr-Jun;71(2-3):122-9. [PubMed: 25434510]

3.

Parekh MJ, Schluger NW. Treatment of latent tuberculosis infection. Ther Adv Respir Dis. 2013 Dec;7(6):351-6. [PubMed: 24056289]

4.

Unissa AN, Subbian S, Hanna LE, Selvakumar N. Overview on mechanisms of isoniazid action and resistance in Mycobacterium tuberculosis. Infect Genet Evol. 2016 Nov;45:474-492. [PubMed: 27612406]

5.

Bloom BR, Atun R, Cohen T, Dye C, Fraser H, Gomez GB, Knight G, Murray M, Nardell E, Rubin E, Salomon J, Vassall A, Volchenkov G, White R, Wilson D, Yadav P. Tuberculosis. In: Holmes KK, Bertozzi S, Bloom BR, Jha P, editors. Major Infectious Diseases. 3rd ed. The International Bank for Reconstruction and Development / The World Bank; Washington (DC): Nov 03, 2017. [PubMed: 30212088]

6.

Berning SE. The role of fluoroquinolones in tuberculosis today. Drugs. 2001;61(1):9-18. [PubMed: 11217874]

7.

Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR, Marra F. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs. 2007;67(14):2077-99. [PubMed: 17883288]

8.

Mase S, Chorba T, Parks S, Belanger A, Dworkin F, Seaworth B, Warkentin J, Barry P, Shah N. Bedaquiline for the Treatment of Multidrug-resistant Tuberculosis in the United States. Clin Infect Dis. 2020 Aug 14;71(4):1010-1016. [PMC free article: PMC7350275] [PubMed: 31556947]

9.

Andrei S, Droc G, Stefan G. FDA approved antibacterial drugs: 2018-2019. Discoveries (Craiova). 2019 Dec 31;7(4):e102. [PMC free article: PMC7086080] [PubMed: 32309620]

10.

Riccardi N, Del Puente F, Magnè F, Taramasso L, Di Biagio A. Bedaquiline: A New Hope for Shorter and Better Anti-Tuberculosis Regimens. Recent Pat Antiinfect Drug Discov. 2018;13(1):3-11. [PubMed: 28625141]

11.

Chang KC, Yew WW. Management of difficult multidrug-resistant tuberculosis and extensively drug-resistant tuberculosis: update 2012. Respirology. 2013 Jan;18(1):8-21. [PubMed: 22943408]

12.

Dheda K, Chang KC, Guglielmetti L, Furin J, Schaaf HS, Chesov D, Esmail A, Lange C. Clinical management of adults and children with multidrug-resistant and extensively drug-resistant tuberculosis. Clin Microbiol Infect. 2017 Mar;23(3):131-140. [PubMed: 27756712]

13.

White RJ, Lancini GC, Silvestri LG. Mechanism of action of rifampin on Mycobacterium smegmatis. J Bacteriol. 1971 Nov;108(2):737-41. [PMC free article: PMC247133] [PubMed: 4942761]

14.

Wehrli W, Staehelin M. Actions of the rifamycins. Bacteriol Rev. 1971 Sep;35(3):290-309. [PMC free article: PMC378391] [PubMed: 5001420]

15.

Nakamura Y, Yura T. Effects of rifampicin on synthesis and functional activity of DNA-dependent RNA polymerase in Escherichia coli. Mol Gen Genet. 1976 Jun 15;145(3):227-37. [PubMed: 781514]

16.

De La Iglesia AI, Morbidoni HR. [Mechanisms of action of and resistance to rifampicin and isoniazid in Mycobacterium tuberculosis: new information on old friends]. Rev Argent Microbiol. 2006 Apr-Jun;38(2):97-109. [PubMed: 17037259]

17.

Dillon NA, Peterson ND, Feaga HA, Keiler KC, Baughn AD. Anti-tubercular Activity of Pyrazinamide is Independent of trans-Translation and RpsA. Sci Rep. 2017 Jul 21;7(1):6135. [PMC free article: PMC5522395] [PubMed: 28733601]

18.

Zhang Y, Shi W, Zhang W, Mitchison D. Mechanisms of Pyrazinamide Action and Resistance. Microbiol Spectr. 2013;2(4):1-12. [PMC free article: PMC4268777] [PubMed: 25530919]

19.

Goude R, Amin AG, Chatterjee D, Parish T. The arabinosyltransferase EmbC is inhibited by ethambutol in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2009 Oct;53(10):4138-46. [PMC free article: PMC2764220] [PubMed: 19596878]

20.

Vianna JF, S Bezerra K, I N Oliveira J, Albuquerque EL, Fulco UL. Binding energies of the drugs capreomycin and streptomycin in complex with tuberculosis bacterial ribosome subunits. Phys Chem Chem Phys. 2019 Sep 21;21(35):19192-19200. [PubMed: 31436279]

21.

Prokhorova I, Altman RB, Djumagulov M, Shrestha JP, Urzhumtsev A, Ferguson A, Chang CT, Yusupov M, Blanchard SC, Yusupova G. Aminoglycoside interactions and impacts on the eukaryotic ribosome. Proc Natl Acad Sci U S A. 2017 Dec 19;114(51):E10899-E10908. [PMC free article: PMC5754804] [PubMed: 29208708]

22.

Luan G, Drlica K. Fluoroquinolone-Gyrase-DNA Cleaved Complexes. Methods Mol Biol. 2018;1703:269-281. [PubMed: 29177748]

23.

API Consensus Expert Committee. API TB Consensus Guidelines 2006: Management of pulmonary tuberculosis, extra-pulmonary tuberculosis and tuberculosis in special situations. J Assoc Physicians India. 2006 Mar;54:219-34. [PubMed: 16800350]

24.

Boeree MJ, Heinrich N, Aarnoutse R, Diacon AH, Dawson R, Rehal S, Kibiki GS, Churchyard G, Sanne I, Ntinginya NE, Minja LT, Hunt RD, Charalambous S, Hanekom M, Semvua HH, Mpagama SG, Manyama C, Mtafya B, Reither K, Wallis RS, Venter A, Narunsky K, Mekota A, Henne S, Colbers A, van Balen GP, Gillespie SH, Phillips PPJ, Hoelscher M., PanACEA consortium. High-dose rifampicin, moxifloxacin, and SQ109 for treating tuberculosis: a multi-arm, multi-stage randomised controlled trial. Lancet Infect Dis. 2017 Jan;17(1):39-49. [PMC free article: PMC5159618] [PubMed: 28100438]

25.

Fan YL, Wu JB, Cheng XW, Zhang FZ, Feng LS. Fluoroquinolone derivatives and their anti-tubercular activities. Eur J Med Chem. 2018 Feb 25;146:554-563. [PubMed: 29407980]

26.

Lobue P, Menzies D. Treatment of latent tuberculosis infection: An update. Respirology. 2010 May;15(4):603-22. [PubMed: 20409026]

27.

Schonell M, Dorken E, Grzybowski S. Rifampin. Can Med Assoc J. 1972 Apr 08;106(7):783-6. [PMC free article: PMC1940515] [PubMed: 4622757]

28.

Baciewicz AM, Chrisman CR, Finch CK, Self TH. Update on rifampin, rifabutin, and rifapentine drug interactions. Curr Med Res Opin. 2013 Jan;29(1):1-12. [PubMed: 23136913]

29.

Snider DE. Pyridoxine supplementation during isoniazid therapy. Tubercle. 1980 Dec;61(4):191-6. [PubMed: 6269259]

30.

Pham AQ, Doan A, Andersen M. Pyrazinamide-induced hyperuricemia. P T. 2014 Oct;39(10):695-715. [PMC free article: PMC4189695] [PubMed: 25336865]

31.

Chamberlain PD, Sadaka A, Berry S, Lee AG. Ethambutol optic neuropathy. Curr Opin Ophthalmol. 2017 Nov;28(6):545-551. [PubMed: 28759559]

32.

Wargo KA, Edwards JD. Aminoglycoside-induced nephrotoxicity. J Pharm Pract. 2014 Dec;27(6):573-7. [PubMed: 25199523]

33.

Stephenson AL, Wu W, Cortes D, Rochon PA. Tendon Injury and Fluoroquinolone Use: A Systematic Review. Drug Saf. 2013 Sep;36(9):709-21. [PubMed: 23888427]

34.

Inoue T, Ikeda N, Kurasawa T, Sato A, Nakatani K, Ikeda T, Yoshimatsu H. [Hyperuricemia and arthralgia during pyrazinamide treatment]. Nihon Kokyuki Gakkai Zasshi. 1999 Feb;37(2):115-8. [PubMed: 10214039]

35.

Şişmanlar T, Aslan AT, Budakoğlu I. Is Hyperuricemia Overlooked when Treating Pediatric Tuberculosis Patients with Pyrazinamide? J Trop Pediatr. 2015 Oct;61(5):351-6. [PubMed: 26136257]

36.

Cao J, Mi Y, Shi C, Bian Y, Huang C, Ye Z, Liu L, Miao L. First-line anti-tuberculosis drugs induce hepatotoxicity: A novel mechanism based on a urinary metabolomics platform. Biochem Biophys Res Commun. 2018 Mar 04;497(2):485-491. [PubMed: 29454961]

37.

Fabrizii V, Thalhammer F, Hörl WH. [Aminoglycoside-induced nephrotoxicity]. Wien Klin Wochenschr. 1997 Nov 14;109(21):830-5. [PubMed: 9454436]

Disclosure: Inderbir Padda declares no relevant financial relationships with ineligible companies.

Disclosure: Kona Muralidhara Reddy declares no relevant financial relationships with ineligible companies.