Isoniazid: First-line anti-tuberculosis agent against Mycobacterium tuberculosis

Isoniazid (abbreviated INH) has been in use since 1952 and remains one of the four essential first-line anti-tuberculosis agents alongside rifampicin, ethambutol, and pyrazinamide. Despite significant advances in multidrug-resistant tuberculosis treatment, INH remains a cornerstone of global tuberculosis control due to its excellent efficacy, oral bioavailability, and comparatively low treatment costs. According to World Health Organization data, approximately ten million people are infected with Mycobacterium tuberculosis annually, with around four to five thousand cases reported in Germany each year.

The substance is marketed under the trade names Isozid, INH, and in fixed combinations such as Rifater (RHZ) and Rifinah (RH). INH acts bactericidally on dividing mycobacteria and bacteriostatically on dormant pathogens. This dual activity makes it ideal for both active tuberculosis therapy and treatment of latent tuberculosis infection (LTBI).

Mechanism of Action

Isoniazid is a prodrug that is activated by the mycobacterial enzyme KatG (a catalase peroxidase) into a reactive form. This inhibits the enzymes InhA and KasA, both essential for the synthesis of mycolic acids. Mycolic acids are characteristic long-chain fatty acids of the mycobacterial cell wall, and an intact cell wall cannot exist without them.

This explains two clinically important properties. First, INH acts selectively on mycobacteria because other bacteria and human cells possess neither KatG nor the mycolic acid system. Second, resistance primarily develops through mutations in katG (high-level INH resistance) or in the inhA promoter (lower resistance levels with cross-resistance to ethionamide). Tuberculosis is therefore always treated with multiple agents to prevent the development of resistance.

Pharmacokinetically, INH is rapidly and almost completely absorbed following oral administration. Metabolism occurs hepatically via N-acetyltransferase 2 (NAT2). Due to genetic polymorphism, a distinction is made between rapid and slow acetylators, which has clinical implications for efficacy and toxicity.

Indications

• Active pulmonary tuberculosis: Standard therapy of 2 months four-drug regimen (RHZE) plus 4 months RH
• Active extrapulmonary tuberculosis: Lymph nodes, pleura, bones, genital sites; tuberculous meningitis 9 to 12 months
• Latent tuberculosis infection (LTBI): 6 or 9 months INH monotherapy, alternatively 3 months INH plus rifapentin (3HP)
• Post-exposure prophylaxis: Following close contact with active TB cases, particularly in children under 5 years and immunocompromised patients
• HIV/TB coinfection: INH is a central component, drug interactions with antiretroviral therapy must be considered

Dosage and Administration

Adults: 5 mg/kg body weight (maximum 300 mg) once daily orally, ideally one hour before or two hours after a meal, as food delays absorption. Children: 10 mg/kg (range 7 to 15 mg/kg, maximum 300 mg).

Latent infection: Adults 5 mg/kg daily (maximum 300 mg) for six to nine months. Renal insufficiency: No dose adjustment necessary as INH is not significantly eliminated renally. Severe hepatic insufficiency: Contraindicated or to be used with great caution and close monitoring.

Pyridoxine (Vitamin B6) supplementation: 25 to 50 mg daily orally alongside INH, particularly in risk groups such as pregnant women, nursing mothers, diabetics, patients with chronic renal insufficiency, HIV, or malnourished individuals. Pyridoxine prevents peripheral neuropathy resulting from INH-induced vitamin B6 depletion.

Adverse Effects

Common: Elevated liver transaminases (10 to 20 percent), usually mild and reversible; peripheral neuropathy (tingling legs, burning sensation, particularly in slow acetylators and malnourished patients); rash, nausea, fatigue.

Occasional to rare: Hepatitis (clinically relevant in 0.5 to 2 percent), in exceptional cases fulminant liver failure particularly in elderly patients over 35 years, postpartum women, alcohol consumers, or those with hepatitis B/C coinfection. Optic neuritis, seizures, systemic lupus erythematosus-like syndrome with positive ANA, hematological effects (anemia, thrombocytopenia).

Important: Patients receiving INH must watch for warning symptoms: nausea persisting for several days, dark urine, jaundice, persistent fatigue. If suspected, the physician must be contacted immediately and therapy may be discontinued.

Drug Interactions

• Phenytoin and carbamazepine: INH inhibits CYP2C9 and CYP2C19, increasing levels and toxicity of these antiepileptic agents
• Paracetamol: Increased hepatotoxicity, particularly with chronic alcohol consumption
• Antacids: Reduce INH absorption, administer at two-hour intervals
• Tyramine-rich foods (aged cheese, red wine): Rarely hypertensive crisis, as INH possesses weak MAO inhibition
• Disulfiram: Psychotic reactions possible
• Theophylline: Elevated levels
• Alcohol: Significantly increases hepatotoxicity risk

Special Considerations

Pregnancy: In active tuberculosis, treatment is indicated because untreated TB poses greater risk to mother and child than the medications. INH is one of the best-studied anti-tuberculosis agents in pregnancy, and pyridoxine supplementation is mandatory. Lactation: Treatment is possible, and the infant should receive pyridoxine.

Acetylator status: Rapid acetylators have lower INH levels and may require higher doses, while slow acetylators have higher levels and are more susceptible to neuropathy and hepatotoxicity. Genotyping is not routinely performed in Germany but may be useful in cases of repeated adverse effects.

Compliance: Tuberculosis therapy often fails due to incomplete medication adherence. Directly observed therapy (DOT) is recommended by the RKI for patients with unfavorable social circumstances or compliance risk.

You Might Also Be Interested In

• Rifampicin, second cornerstone of TB therapy
• Ethambutol, third agent in the RHZE regimen
• Pyrazinamide, fourth agent in the RHZE regimen
• Pyridoxine, Vitamin B6 for neuropathy prophylaxis
• Levofloxacin, reserve agent for MDR TB

Frequently Asked Questions

Sources

• Robert Koch Institute, Tuberculosis Reporting Germany
• WHO Consolidated Guidelines on Tuberculosis
• AWMF S2k Guideline Tuberculosis in Adults
• Gelbe Liste, Isoniazid Active Ingredient Profile