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Isoniazid (INH) is an antibiotic indicated in the first-line treatment of active Mycobacterium tuberculosis (TB) infection. INH has been a significant drug in TB treatment regimens for decades. INH functions as a prodrug activated by the catalase-peroxidase KatG, generating various radicals and adducts that inhibit the production of mycolic acids, the essential components of the mycobacterium's cell wall. This mechanism of action makes INH a potent bactericidal agent. Moreover, INH exhibits synergistic effects with other species generated by KatG and other medications utilized in TB treatment. Mutations in the katG, inhA, kasA, and ahpC genes can lead to resistance against INH therapy. Resistance of M tuberculosis can occur more rapidly with INH monotherapy. This activity reviews the indications, mechanism of action, and contraindications of INH as a valuable agent in treating both active and latent TB infections. This activity also highlights the drug's adverse event profile, regimens and dosing, and other key factors pertinent to the interprofessional healthcare team when using INH for TB treatment. Objectives: Identify patients with active or latent tuberculosis who can benefit from isoniazid (INH) treatment based on clinical guidelines and risk factors. Screen patients for risk factors predisposing them to adverse reactions or interactions with isoniazid (INH), considering comorbidities and concomitant medications. Apply knowledge of isoniazid's (INH's) mechanism of action and pharmacokinetics to optimize dosing and minimize the risk of resistance. Collaborate with other healthcare professionals to coordinate comprehensive tuberculosis management, including monitoring for adverse effects, drug interactions, and treatment outcomes. Access free multiple choice questions on this topic.

The liver metabolizes INH primarily by acetylation with N-acetyl transferase 2 (NAT2). Three metabolites have implications that correlate with the liver injury associated with the drug: acetyl hydrazine (AcHz), hydrazine (Hz), and a metabolite from the bioactivation of INH itself. Considerable variation is apparent in the acetylation rate and elimination half-life from individual to individual, which is not accounted for by dose and concentration. This appears to contribute to the risk of hepatotoxicity and the other adverse effects associated with the drug.[30] Mild liver injury will occur in up to 20% of patients taking INH. Clinical manifestations of hepatotoxicity include fever, fatigue, nausea, and vomiting. However, most patients experiencing INH-induced liver injury are asymptomatic. Usually, the condition is detected only by measuring increased levels of ALT and AST, which may rise to as high as 5 times the normal limit. In “adaptation,” the hepatic markers will return to normal in most patients with continued drug administration. About 1% of patients will experience severe liver injury; INH therapy should cease immediately. Reintroducing INH in these cases is contraindicated as it can cause rapid symptom onset, and fatal hepatitis during INH treatment is associated with continued use after symptoms of hepatitis are present.[31] INH-induced severe liver injury is generally associated with older patients and can be further exacerbated by concurrent treatment with rifampin, which induces CYP metabolism. Incidence is also higher in slow acetylators, which correlates with higher serum levels of INH and the AcHz metabolite. Additional risk factors include preexisting liver disease, a history of heavy alcohol use, and patients in the postpartum period. More recently identified risk factors include polymorphisms in glutathione S-transferase, CYP2E1, TNF-α, and others.[30] Most patients recover entirely from INH hepatotoxicity following drug discontinuation, although complete regression takes weeks.[32] INH doses above 30 mg/kg typically cause seizures, and doses exceeding 80 mg/kg can cause death. The most commonly reported adverse reactions to INH include seizures, coma, hyperthermia, and oliguria. Additionally, acute INH toxicity is associated with excess lactic acid produced during episodes of intense muscular rigidity.

INH doses above 30 mg/kg typically cause seizures, and doses exceeding 80 mg/kg can cause death. The most commonly reported adverse reactions to INH include seizures, coma, hyperthermia, and oliguria. Additionally, acute INH toxicity is associated with excess lactic acid produced during episodes of intense muscular rigidity. Treating INH overdose requires establishing a secure airway and prompt treatment for hypotension and seizures. Pyridoxine helps to terminate seizures and should be administered in a 1:1 ratio of grams of INH ingested. Pyridoxine should be supplemented with IV benzodiazepines as pyridoxine and benzodiazepines display pharmacological synergism. INH has a low volume of distribution and low plasma protein binding; hemodialysis may be considered in refractory cases.[33]

Clinicians treating TB patients with INH must be aware of the patient's baseline liver function and the hepatotoxic risks associated with INH. Although estimates of fatal hepatitis associated with INH treatment are only 0.023%, these cases correlate with continued administration despite symptoms of hepatitis during treatment.[1] TB has widespread effects and greatly burdens individual patients and communities. Appropriate treatment is crucial for limiting the spread of TB and preventing drug resistance. Therefore, a clinician treating TB prescribes the appropriate treatment regimen and ensures adequate treatment adherence and completion.[1] A growing concern is INH-resistant strains of TB, and it appears that these may serve as precursors to multidrug-resistant strains. Thus, clinicians should monitor patient progress to promptly detect patients not responding to INH treatment and who may harbor a resistant strain. INH-resistant strains require an altered regimen and increased efforts to prevent disease transmission.[34][35] Public health departments typically provide TB treatment. They frequently collaborate as part of an interprofessional healthcare team with other entities such as private providers, community health centers, shelters, and others to ensure the completion of treatment. The interprofessional team should use a patient-centered approach to tailor a treatment plan specific to each patient's needs to provide the best opportunity for treatment completion. This approach often involves social workers, case managers, and medical professionals; optimal communication and coordination of services are essential. One way for the team to maximize adherence is through direct observation of therapy (DOT), in which healthcare professionals provide the medications directly to the patient and watch as they swallow them. This approach has become the preferred method of drug administration for TB treatment. DOT allows for early identification of nonadherence, adverse effects, or worsening of a patient's condition.[1]

Public health departments typically provide TB treatment. They frequently collaborate as part of an interprofessional healthcare team with other entities such as private providers, community health centers, shelters, and others to ensure the completion of treatment. The interprofessional team should use a patient-centered approach to tailor a treatment plan specific to each patient's needs to provide the best opportunity for treatment completion. This approach often involves social workers, case managers, and medical professionals; optimal communication and coordination of services are essential. One way for the team to maximize adherence is through direct observation of therapy (DOT), in which healthcare professionals provide the medications directly to the patient and watch as they swallow them. This approach has become the preferred method of drug administration for TB treatment. DOT allows for early identification of nonadherence, adverse effects, or worsening of a patient's condition.[1] Nurses and pharmacists are also valuable members of this interprofessional approach by verifying doses, providing patient counsel, monitoring therapeutic progress, ensuring medication compliance, and monitoring adverse events. Nurses can use the DOT method to ensure medication compliance. Consultation from obstetricians is necessary for TB in pregnancy. Pediatricians play an essential role in the overall management of TB in children. Infectious disease consultation is crucial for multidrug-resistant TB and nontuberculous mycobacterial pulmonary disease. Interprofessional coordination and collaboration among physicians, advanced practice practitioners, specialists, pharmacists, nurses, and public health professionals can enhance patient outcomes when using INH therapy in treating TB infection.