Antimycobacterial Agents

Antimycobacterial agents represent a diverse group of compounds that have activity against mycobacterial infections, including tuberculosis, leprosy and Mycobacterium avium complex (MAC) disease. The 1st-line agents for tuberculosis are rifampin, isoniazid, pyrazinamide, and ethambutol. The drugs vary in their mechanisms of action: rifampin inhibits RNA synthesis, isoniazid inhibits mycolic acid synthesis, pyrazinamide acts on membrane transport and protein synthesis, and ethambutol prevents cell wall synthesis. Monotherapy is not recommended because of the increased risk of drug resistance. Multidrug treatment takes several months and requires sputum monitoring. As for leprosy, an infection due to Mycobacterium leprae, rifampin is also used, with dapsone. The lepromatous form requires a 3rd agent (clofazimine). Pulmonary infections with MAC are managed with macrolides (azithromycin), rifampin, and ethambutol.

Last update:

Table of Contents

Share this concept:

Share on facebook
Share on twitter
Share on linkedin
Share on reddit
Share on email
Share on whatsapp

Overview

Definition

Antimycobacterial agents represent a diverse group of compounds used against mycobacterial infections (e.g., TB, leprosy, Mycobacterium avium complex).

Antimycobacterial agents

Table: Treatment regimens for mycobacterial infections
BacteriaTreatment regimen*Prophylaxis
Mycobacterium tuberculosis
  • RIPE: Rifampin (RIF), Isoniazid (isoniazid (isonicotinic acid hydrazine (INH)), Pyrazinamide (PZA), Ethambutol (EMB)
  • 3- to 4-drug regimen (to reduce resistance)
Isoniazid
M. leprae
  • Dapsone + rifampin (for tuberculoid form)
  • Add clofazimine in lepromatous form
None
M. avium complex (MAC) predominant species within the complex include:
  • M. avium
  • M. intracellulare
  • M. chimaera
  • MAC pulmonary disease: macrolides (azithromycin or clarithromycin) + rifamycin (e.g., rifampin) + EMB
  • If not tolerated: 2-drug regimen
  • If cavitary disease: add parenteral aminoglycoside
Azithromycin or rifabutin
*1st-line agents

Rifampin

Description and pharmacodynamics

  • Most commonly used rifamycin (rifamycins also include rifabutin and rifapentine)
  • Macrocyclic antibiotic
  • Resistance if used alone
  • Ramps up cytochrome P450 (leads to ↓ bioavailability of coadministered drugs) 
  • Red-orange to orange body fluids (e.g., urine, sweat, tears, saliva)
  • Mechanism of action: inhibit DNA-dependent RNA polymerase enzyme, blocking the synthesis of mRNA
Chemical structure Rifampin

Skeletal formula of rifampin

Image: “Skeletal formula of rifampin” by Vaccinationist. License: Public Domain

Pharmacokinetics

  • Absorption: reduced by food (take on an empty stomach)
  • Distribution: lipophilic, widely distributed in all tissues and fluids (including CSF)
  • Metabolism: hepatic (caution needed in hepatic disease)
  • Elimination: mainly excreted in bile/feces, some urine (≤ 30%)

Drug–drug interactions

  • Increases cytochrome P450 (↓ levels of other drugs)
  • Interactions include: 
    • Warfarin
    • Oral or other hormonal contraceptives
    • Glucocorticoids
    • Cyclosporine
    • HMG-CoA reductase inhibitors (statins)
    • Macrolides, azole antifungals
    • Phenytoin
    • Levothyroxine
    • Sulfonylurea 
    • Antiretrovirals

Adverse effects and contraindications

  • Adverse effects:
    • Hepatic: ↑ liver function tests (hepatotoxicity) especially those at risk (e.g., alcoholic individuals, individuals taking other hepatotoxic drugs)
    • Rash
    • Orange/red discoloration of bodily secretions
    • Hemolytic anemia, neutropenia, thrombocytopenia
    • Nephritis
    • Flu-like syndrome
  • Contraindications: 
    • Hypersensitivity or previous severe reaction to rifampin
    • Precaution in liver disease
    • Concurrent use with protease inhibitors (↑ hepatotoxicity)

Mechanism of resistance

  • Mutations in the rpoB gene (encodes the beta chain of mycobacterial RNA polymerase)
  • Effect of mutation: reduced drug binding

Isoniazid

Description and pharmacodynamics

  • Also known as isonicotinic acid hydrazide
  • Bactericidal
  • A prodrug activated by M. tuberculosis catalase-peroxidase (encoded by KatG) → N-acetyl INH (major metabolite)
  • Prophylaxis against TB
  • Monotherapy for latent TB
  • Mechanism of action: inhibits mycolic acid synthesis (affects mycobacterial cell wall)
Chemical structure of isoniazid

Skeletal formula of isoniazid (isonicotinic acid hydrazine (INH))

Image: “Skeletal formula of isoniazid” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Absorption: well absorbed orally, but may be reduced or delayed by food
  • Distribution: widely distributed throughout the body
  • Metabolism: hepatic metabolism via acetylation (genetically determined)
    • 50% of Caucasians and Blacks → rapid acetylators (exhibit lower peak serum concentrations)
    • 80%–90% of Asians and those of the Alaska and Arctic regions → rapid acetylators
  • Elimination: renal (up to 96% excreted unchanged)

Drug–drug interactions

  • Inhibition of the cytochrome P (CYP) hepatic enzyme system by INH leads to drug interactions (↑ concentration of other drugs). 
  • Include (but not limited to):
    • Carbamazepine
    • Phenytoin
    • Theophylline

Adverse effects and contraindications

  • Adverse effects (“INH Injures Nerves and Hepatocytes”):
    • Hepatic: ↑ liver function tests (hepatotoxicity)
    • Neurologic: 
      • Peripheral neuropathy, ataxia, paresthesia (depletes vitamin B6, so supplementation is needed)
      • Headache
      • Depression and dysphoria
      • Seizures and psychosis
    • Hematologic: hemolytic anemia (triggered by INH in glucose-6-phosphate dehydrogenase deficiency)
    • Immunologic: flu-like syndrome, drug-induced systemic lupus erythematosus
    • Rash
  • Contraindications: 
    • Hypersensitivity or previous severe reaction to INH
    • Precaution in liver disease

Mechanism of resistance

  • Mutation of inhA (protein involved in mycobacterial cell wall synthesis)
  • Mutation of KatG (down-regulated enzyme activity)

Pyrazinamide

Description and pharmacodynamics

  • Synthetic pyrazine analogue of nicotinamide
  • Metabolized to pyrazinoic acid (POA), the active form of pyrazinamide through the action of M. tuberculosis pyrazinamidase 
  • ↑ Activity in acidic pH
  • Mechanism of action: 
    • Exact mechanism is uncertain.
    • Likely to involve POA (initially excreted from the cell), which is then protonated
    • Protonated POA diffuses back into the cell, acidifying the intracellular environment and inhibiting membrane transport and protein synthesis.
Chemical structure of Pyrazinamide antimycobacterial agents

Structure of pyrazinamide

Image: “Structure of pyrazinamide” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Absorption: rapid absorption, with oral bioavailability of approximately 90%
  • Distribution: widely distributed in tissues and fluids, including CSF
  • Metabolism: hepatic metabolism to active and inactive metabolites
  • Elimination: renally excreted; metabolites accumulate in kidney dysfunction (requires dose adjustment)

Drug–drug interactions

  • Rifampin: ↑ risk of hepatotoxicity (can be fatal)
  • Cyclosporine: ↓ serum concentrations of cyclosporine

Adverse effects and contraindications

  • Adverse effects:
    • Hepatic: ↑ liver function tests (hepatotoxicity)
    • Hyperuricemia (metabolite of pyrazinamide inhibits uric acid elimination)
    • Nongouty polyarthralgia
    • GI upset
    • Thrombocytopenia, sideroblastic anemia
    • Rash, photosensitivity
  • Contraindications:
    • Hypersensitivity to pyrazinamide
    • Acute gout
    • Severe hepatic damage
    • Not safe in pregnancy

Mechanism of resistance

  • Mutation of pncA (encodes pyrazinamidase) → M. tuberculosis produces pyrazinamidase with reduced affinity to pyrazinamide.
  • Effect: ↓ conversion to POA → no effect on cell wall synthesis

Ethambutol

Description and pharmacodynamics

  • Bacteriostatic
  • Activity against different species of Mycobacteria, but no effect on other genuses
  • Mechanism of action:
    • Inhibits arabinosyltransferase, an enzyme encoded by embB genes
    • Arabinosyltransferase polymerizes arabinose (required in arabinogalactan synthesis in the cell wall)
    • Effect: disruption of mycobacterial cell wall synthesis
Chemical structure of ethambutanol

Structure of ethambutol

Image: “Structure of ethambutol” by Fvasconcellos. License: Public Domain

Pharmacokinetics

  • Absorption: approximately 80% absorbed by oral administration 
  • Distribution: widely in most tissues and fluids, but not CSF
  • Metabolism: partial hepatic metabolism 
  • Elimination: most (up to 80%) excreted renally

Drug–drug interactions

Aluminum hydroxide ↓ drug absorption

Adverse effects and contraindications

  • Adverse effects:
    • Optic neuropathy (“Eye-thambutol”) often noted as:
      • A change in visual acuity
      • Red-green color blindness
    • Hepatotoxicity
    • GI (nausea, vomiting, abdominal pain)
    • Hematologic (neutropenia, thrombocytopenia)
    • Headache, dizziness, confusion
    • Peripheral neuritis
  • Contraindications: 
    • Hypersensitivity to ethambutol 
    • Optic neuritis

Mechanism of resistance

  • Mutations involving the embB genes 
  • Effect: ↑ production of arabinosyltransferase causes varying degrees of resistance.

Other Anti-TB Agents

Other agents are used depending on the underlying conditions and presence of multidrug-resistant Mycobacterium.

  • Aminoglycosides:
    • Streptomycin and amikacin
    • Bactericidal 
    • Mechanism: inhibits translation by binding the 30S ribosomal subunit
    • Adverse effects:
      • Nephrotoxicity → accumulation of aminoglycosides in the renal cortex
      • Ototoxicity (can be irreversible; in pregnant women, can cause permanent deafness in the child)
      • Neuromuscular blockade (rare)
  • Bedaquiline:
    • Part of the BPaL (bedaquiline + pretomanid + linezolid) regimen (pulmonary extensively drug-resistant TB [XDR-TB] or multidrug-resistant TB [MDR-TB]): bedaquiline + pretomanid + linezolid
    • Classified as a diarylquinoline  
    • Bactericidal 
    • Mechanism: inhibits mycobacterial ATP synthase 
    • Adverse effect: QT prolongation
  • Bicyclic nitroimidazoles:
    • Pretomanid: 
      • Part of the BPaL regimen (pulmonary XDR-TB or MDR-TB)
      • Mechanism: inhibition of cell wall synthesis (blocks the oxidation of hydroxymycolate to ketomycolate)
    • Delamanid: inhibits mycolic acid synthesis (for MDR-TB approved in Europe, not yet in the Uninted States)
  • Clofazimine:
    • For drug-resistant TB
    • Requires approval from FDA for anti-TB use 
    • Available in areas where clofazimine is used for leprosy
    • Adverse effects: GI problems
  • Cycloserine: 
    • For drug-resistant TB
    • Mechanism: blocks peptidoglycan production, thus disrupting mycobacterial cell wall synthesis
    • Adverse effects: neuropsychiatric symptoms
  • Ethionamide:
    • For drug-resistant TB
    • Structural analog of INH
    • A prodrug
    • Mechanism: inhibits mycolic acid synthesis (similar to INH)
    • Adverse effects: GI irritation, peptic ulcer
  • Fluoroquinolones:
    • Levofloxacin and moxifloxacin (greater in vitro activity than ciprofloxacin)
    • Bactericidal 
    • Mechanism: inhibit bacterial DNA gyrase and disrupt DNA replication
  • Oxazolidinones: 
    • Part of the BPaL regimen (pulmonary XDR-TB or MDR-TB)
    • Mechanism:
      • Bind to the bacterial 23S rRNA of the 50S subunit 
      • Blocks the formation of the 70S initiation complex → prevents translation
    • Adverse effects: bone marrow suppression, neuropathy, GI symptoms, and/or retinitis
  • Para-aminosalicylic acid (PAS):
    • Bacteriostatic
    • Efficacy against TB limited
    • Mechanism: interrupts folate synthesis
    • Adverse effects:
      • GI side effects
      • With ethionamide → hypothyroidism
  • Rifabutin:
    • A rifamycin, like rifampin
    • Less drug–drug interactions than rifampin, as it is a less potent inducer of the cytochrome P450 enzyme system
    • Preferred in HIV
  • Additional information: kanamycin (an aminoglycoside) and capreomycin (a cyclic peptide):
    • No longer recommended for anti-TB treatment 
    • Both drugs were associated with worse outcomes.
Anti-TB agents and mechanisms

Anti-TB agents and mechanisms
Left:
Thioamides (ethionamide) inhibit cell wall synthesis (affect mycolic acid); mechanism similar to isoniazid.
Bicyclic nitroimidazoles inhibit mycolic acid synthesis.
Ethambutol inhibits cell wall synthesis (affects arabinogalactan).
Cycloserine inhibits cell wall synthesis.
Pyrazinamide affects the plasma membrane transport.
Diarylquinoline (bedaquiline) inhibits ATP synthase.
Right:
Para-aminosalicylic acid (PAS) interrupts DNA precursors by disrupting folate synthesis.
Fluoroquinolones inhibit DNA gyrase.
Cyclic peptides (capreomycin) inhibit protein synthesis (no longer recommended).
Aminoglycosides inhibit protein synthesis by blocking translation.

Image: “Mechanisms of action of current TB drugs” by NIAID. License: CC BY 2.0

Agents against Mycobacterium leprae and Mycobacterium avium Complex

Agents against Mycobacterium leprae

  • 1st-line regimen:
    • Dapsone + rifampin for 12 months for tuberculoid leprosy
    • Dapsone + rifampin + clofazimine for 24 months for lepromatous leprosy
  • Medications:
    • Dapsone: 
      • Agent with antibacterial, antifungal and antiprotozoal activity
      • Mechanism of action: inhibits bacterial dihydropteroate synthase in the folate pathway → ↓ synthesis of nucleic acid
      • Adverse effects: hemolysis (especially at doses > 200 mg/day), methemoglobinemia
    • Rifampin (see anti-TB drugs)
    • Clofazimine (see anti-TB drugs)

Agents against Mycobacterium avium complex

  • For MAC pulmonary disease, use a 3-drug combination regimen:
    • Azithromycin: 
      • Macrolide (inhibits bacterial protein synthesis by binding reversibly to the 50S ribosomal subunit)
      • Adverse effects: hepatotoxicity, QT prolongation
    • Rifampin
    • Ethambutol
  • For cavitary disease, add parenteral streptomycin or amikacin (aminoglycosides) as a 4th agent (for the first 8–12 weeks).

References

  1. Drew, R., Sterling, T. (2021). Antituberculous drugs: an overview. UpToDate. Retrieved August 21, 2021, from https://www.uptodate.com/contents/antituberculous-drugs-an-overview
  2. Drew, R. (2021). Rifamycins (rifampin, rifabutin, rifapentine). UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/rifamycins-rifampin-rifabutin-rifapentine
  3. Drew, R. (2021). Isoniazid: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/isoniazid-an-overview
  4. Drew, R. (2021). Ethambutol: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/ethambutol-an-overview
  5. Drew, R. (2021). Pyrazinamide: an overview. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/pyrazinamide-an-overview
  6. Gumbo, T. (2017). Chemotherapy of tuberculosis, mycobacterium avium complex disease, and leprosy. Chapter 60 of Brunton, L.L., Hilal-Dandan, R., Knollmann, B.C. (Eds.), Goodman & Gilman’s: The Pharmacological Basis of Therapeutics, 13th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2189&sectionid=172485532
  7. National Institute of Diabetes and Digestive and Kidney Diseases. (2018). Rifampin LiverTox: clinical and Research Information on drug-induced liver injury. https://www.ncbi.nlm.nih.gov/books/NBK548314/
  8. Schluger, N. (2021). Epidemiology and molecular mechanisms of drug-resistant tuberculosis. UpToDate. Retrieved August 22, 2021, from https://www.uptodate.com/contents/epidemiology-and-molecular-mechanisms-of-drug-resistant-tuberculosis
  9. Soeroto, A.,  Darmawan, G., Supriyadi, R., Bhaskara, P., Santoso, P., Alisjahbana, B., Parwati, I. (2019). Comparison of serum potassium, magnesium, and calcium levels between kanamycin and capreomycin-based regimen-treated multidrug-resistant tuberculosis patients in Bandung (CEASE MDR-TB): a retrospective cohort study. International Journal of Microbiology 2019, Article ID 5065847. https://doi.org/10.1155/2019/5065847

Study on the Go

Lecturio Medical complements your studies with evidence-based learning strategies, video lectures, quiz questions, and more – all combined in one easy-to-use resource.

Learn even more with Lecturio:

Complement your med school studies with Lecturio’s all-in-one study companion, delivered with evidence-based learning strategies.

🍪 Lecturio is using cookies to improve your user experience. By continuing use of our service you agree upon our Data Privacy Statement.

Details