Antituberculars

Rifampicin

Isoniazid

Pyrazinamide

Ethambutol

inhibits bacterial DNA-dependent RNA-polymerase → prevention of transcription (mRNA synthesis) → inhibition of bacterial protein synthesis → cell death (bactericidal effect)

biliary

• Mycobacteria

  • Tuberculosis (together with isoniazid, pyrazinamide, and ethambutol)

  • Leprosy

    • Long-term treatment of tuberculoid form: dapsone and rifampin (rifampin delays resistance to dapsone)

    • Long-term treatment of lepromatous form: combination of dapsone, clofazimine, and rifampin

  • M. avium-intracellulare prophylaxis and treatment (rifabutin)

• Meningococcal prophylaxis

• Chemoprophylaxis for people who had contact with children infected with H. influenzae type b

• Rifaximin: second-line therapy in hepatic encephalopathy.

• Harmless red-orange discoloration of body fluids (e.g., urine, tears)

• Flu-like symptoms (fever, arthralgia; in severe cases hemolytic anemia, thrombocytopenia, and renal failure)

• Minor hepatotoxicity

• Cytochrome P450 induction (CYP3A4, CYP2C9)

  • Causes minor drug interactions

  • Rifabutin is preferred for the treatment of mycobacterial infections in patients with HIV because it has a lower potential for CYP induction than rifampin.

• Intermittent therapy is associated with an increased risk of renal failure, so rifamycins should be administered daily [73]

• False positive urine opiate screening

• Breastfeeding women

• Should be used during pregnancy only if clearly needed

• Cautious use in patients with hepatic dysfunction

• RNA polymerase mutations decrease the affinity of rifamycins to RNA polymerase. [75]

• Resistance develops rapidly if used as monotherapy.

• Isoniazid is a prodrug and needs to be converted into its active metabolite by bacterial catalase-peroxidase (encoded by KatG).

• Prevents cell wall synthesis by inhibiting the synthesis of mycolic acid

variable

• INH is converted into various metabolites (e.g., via acetylation), some of which are hepatotoxic (e.g., hydrazine, acetylhydrazine).

• Main metabolic enzyme: N-acetyltransferase (NAT): involved in metabolite formation and subsequent neutralization

• The rate of NAT acetylation is genetically determined.

  • Individuals with slow acetylation: higher half-life due to lack of hepatic NAT → increased risk of drug-induced toxicity

  • Individuals with fast acetylation: lower half-life of active drug → administration of a higher dose is required for reaching the same blood concentration compared to individuals with slow acetylation [76][77]

• Inhibits cytochrome P450 isoforms (CYP1A2, CYP2A6, CYP2C19, and CYP3A4)

renal elimination after hepatic metabolism

• Treatment of TB (together with rifampin, pyrazinamide, and ethambutol)

• The only drug that can be used as monoprophylaxis against TB

• Hepatotoxicity (drug-induced hepatitis)

• Anion gap metabolic acidosis

• Drug-induced lupus erythematosus

• High doses of INH can precipitate benzodiazepine-refractory seizures

• Vitamin B6 deficiency: INH should be administered with pyridoxine to avoid vitamin B6 deficiency.

  • Peripheral neuropathy due to S-adenosylmethionine accumulation

  • Sideroblastic anemia, aplastic anemia, thrombocytopenia

  • Pellagra

• Should be used during pregnancy only if clearly needed

• Cautious use in patients with renal and/or hepatic dysfunction

mutations causing decreased KatG → decreased expression of catalase-peroxidase → less/no biologically active INH

• Not completely understood

  • Prodrug: converted into active form pyrazinoic acid

  • Most effective at acidic pH (e.g., in acidic phagolysosomes)

• Bactericidal effect

only when meninges are inflamed

renal elimination after hepatic metabolism

• Clinical use: M. tuberculosis

• Adverse effects

  • Hyperuricemia

  • Hepatotoxicity

• Contraindications

  • Consider use in pregnant and breastfeeding women only if benefits outweigh the risks

  • Hepatic failure

  • Acute gout

• Mechanisms of resistance: mutations in RpsA gene coding for ribosomal protein S1

: inhibits arabinosyltransferase → ↓ carbohydrate polymerization → prevention of mycobacterial cell wall synthesis (bacteriostatic effect)

• CNS penetration: only when meninges are inflamed

• Route of elimination: primarily renal

• M. tuberculosis therapy (together with isoniazid, rifampin, and pyrazinamide)

• M. avium-intracellulare treatment

  • Together with azithromycin or clarithromycin

  • Ciprofloxacin or rifabutin can be added

• Adverse effects

  • Optic neuropathy with decreased visual acuity and red-green color blindness which may result in irreversible blindness

  • Resistance develops rapidly if used as monotherapy

  • Hyperuricemia

• Contraindications

  • Contraindicated in patients who are unable to report visual changes

  • Contraindicated in patients with optic neuritis

  • Consider use in the following populations only if benefits outweigh the risks, as safety in these has not been established

    • Children < 13 years of age

    • Pregnant women

    • Breastfeeding women

• Mechanisms of resistance: mutations of EmbCAB gene coding for arabinosyltransferase