What are the major adverse effects of the medications used to treat active and latent tuberculosis?

Major Side Effects of Tuberculosis Medications

The most clinically significant adverse effects of TB medications are hepatotoxicity (particularly with isoniazid, rifampin, and pyrazinamide), peripheral neuropathy (isoniazid), ocular toxicity (ethambutol), and systemic hypersensitivity reactions (rifapentine-containing regimens).

First-Line Agents: Active and Latent TB

Isoniazid (INH)

Hepatotoxicity is the most important adverse effect:

• Age-related hepatitis risk increases significantly with age (0.5–1% incidence, higher in females) 1
• Risk factors include alcohol consumption, acute or chronic hepatitis, HIV infection, pregnancy/postpartum status (≤3 months), and chronic liver disease 1
• Transient asymptomatic transaminase elevations may occur early in therapy but do not necessarily progress to clinical hepatitis 1
• When combined with rifampin, hepatocellular damage occurs in 3–4% of patients, typically within the first 2 weeks 1

Peripheral neuropathy:

• Preventable with pyridoxine 10 mg daily 1
• High-risk groups requiring prophylaxis include diabetics, alcoholics, HIV-positive patients, those with chronic renal failure, and malnourished individuals 1

Other neuropsychiatric effects:

• Drowsiness, mood changes, and lupus erythematosus syndrome can occur 1

Rifampin (RIF)

Hepatotoxicity:

• Liver transaminases can rise transiently, more commonly with intermittent than daily regimens 1
• When combined with isoniazid, hepatitis occurs in 3–4% of patients 1

Severe hypersensitivity reactions:

• Shock, acute renal failure, and thrombocytopenic purpura may occur rarely, usually with intermittent treatment 1
• If these reactions occur, rifampin must be withdrawn permanently and never reintroduced 1

Drug interactions:

• Rifampin is a potent inducer of hepatic cytochrome P450 enzymes, significantly reducing levels of protease inhibitors, NNRTIs, methadone, warfarin, glucocorticoids, hormonal contraceptives, oral hypoglycemics, digitalis, anticonvulsants, and cyclosporine 1
• Methadone dose may need temporary increase due to increased clearance 1
• Corticosteroid dose should be doubled in patients on maintenance therapy when starting rifampin 1

Other effects:

• May permanently stain soft contact lenses red-orange 2
• Gastrointestinal distress, thrombocytopenia, and diarrhea can occur 1

Pyrazinamide (PZA)

Hepatotoxicity:

• The most concerning adverse effect, particularly when combined with rifampin 1
• In HIV-negative adults, rifampin-pyrazinamide regimens showed unacceptably high rates of severe hepatotoxicity with 17 of 402 patients experiencing AST elevations >100 IU, compared to only 1 in rifampin-alone and 5 in isoniazid-alone groups 1
• Fifteen patients discontinued due to adverse reactions in the rifampin-pyrazinamide group versus none in rifampin-alone and two in isoniazid-alone groups 1

Musculoskeletal effects:

• Arthralgia or arthritis is common 1
• Hyperuricemia occurs but is usually asymptomatic 1

Gastrointestinal effects:

• Abdominal distress, nausea, and rash may occur 1

Ethambutol (EMB)

Retrobulbar (optic) neuritis:

• Manifests as decreased visual acuity or impaired red-green color discrimination affecting one or both eyes 1
• Dose-related toxicity with minimal risk at 15 mg/kg daily (18% risk at doses >30 mg/kg daily) 1
• Risk is higher in patients with renal insufficiency due to drug accumulation 1
• Monthly visual acuity (Snellen chart) and color discrimination (Ishihara) testing is required for patients taking >15–25 mg/kg, receiving therapy >2 months, or with renal insufficiency 1
• Ethambutol must be discontinued immediately and permanently if any visual toxicity signs appear 1

Renal toxicity:

• Pre-existing renal insufficiency significantly increases nephrotoxicity risk 3
• Higher doses (>30 mg/kg/day) increase all toxicity risks including renal effects 3
• Dosage adjustment is mandatory when creatinine clearance <70 mL/minute 1

Other effects:

• Peripheral neuritis (rare) and cutaneous reactions requiring discontinuation occur in 0.2–0.7% of patients 1

Rifapentine (RPT)

Systemic hypersensitivity reactions:

• The most significant adverse effect with the 3-month once-weekly isoniazid-rifapentine (3HP) regimen 1
• Can include influenza-like syndrome, syncope, and hypotension 1
• Severe events requiring hospitalization occurred in 20.1% of patients 1
• The reaction is typically self-limited and mild; no deaths have been reported 1
• Rifapentine is contraindicated in patients with known hypersensitivity to any rifamycin 2

Hepatotoxicity:

• Despite more discontinuations due to adverse effects, 3HP was associated with less hepatotoxicity than 9 months of isoniazid in HIV-negative persons 1

Drug interactions:

• Similar to rifampin, rifapentine induces cytochrome P450 metabolism 2
• Decreases effectiveness of hormonal contraceptives; non-hormonal or barrier methods must be used during treatment 2

Practical considerations:

• Requires taking numerous pills simultaneously (10 pills once weekly for most adults versus 2–3 pills daily for other regimens) 1
• Higher medication cost than most alternatives 1

Second-Line Agents: Drug-Resistant TB

Fluoroquinolones (Levofloxacin, Ofloxacin, Moxifloxacin)

Cardiac effects:

• QT interval prolongation and arrhythmias, particularly when combined with bedaquiline, delamanid, or clofazimine 1

Other effects:

• Gastrointestinal symptoms, dysglycemia, and abdominal distress 1
• Long-term use in children should be avoided due to potential cartilage damage observed in animal studies 1

Cycloserine

Neuropsychiatric toxicity:

• Mood and cognitive deterioration, psychosis, seizures, anxiety, depression, and peripheral neuritis occur in 1–2% with short courses but higher rates with prolonged treatment 1
• Increased seizure risk in patients with alcohol-related hepatitis 1
• Neuropsychiatric status must be assessed at least monthly and more frequently if symptoms develop 1

Contraindications:

• Should not be used in patients with creatinine clearance <50 mL/minute unless receiving hemodialysis 1

Ethionamide

Gastrointestinal effects:

• Profound side effects including metallic taste, severe nausea and vomiting, loss of appetite, and abdominal pain are common 1
• Symptoms may improve if taken with food or at bedtime 1

Hepatotoxicity:

• Structurally similar to isoniazid; causes hepatotoxicity in approximately 2% of patients 1

Endocrine disturbances:

• Gynecomastia, alopecia, hypothyroidism, and impotence have been reported 1
• Diabetes may be more difficult to manage 1
• Thyroid-stimulating hormone should be measured at baseline and monthly 1

Neurotoxicity:

• Peripheral neuritis, optic neuritis, anxiety, depression, and psychosis occur in 1–2% with short courses 1

Teratogenicity:

• Crosses the placenta and is teratogenic in animals; should not be used in pregnancy 1

Aminoglycosides (Streptomycin, Amikacin, Kanamycin) and Capreomycin

Ototoxicity:

• Hearing loss, ataxia, and nystagmus are characteristic 1

Nephrotoxicity:

• Azotemia, proteinuria, and serum electrolyte abnormalities occur 1
• Particularly concerning when combined with tenofovir in HIV-infected patients 1

Hematologic effects:

• Eosinophilia and cytopenias may develop 1

Linezolid

Hematologic toxicity:

• Myelosuppression and cytopenias, particularly when combined with zidovudine 1

Metabolic effects:

• Lactic acidosis can occur, especially problematic in patients on stavudine or zidovudine 1

Neurologic effects:

• Peripheral neuropathy 1

Para-aminosalicylic Acid (PAS)

Gastrointestinal effects:

• Abdominal distress, nausea, bloating, and diarrhea are common 1

Hepatotoxicity:

• Hepatitis may occur 1

Metabolic effects:

• Dysglycemia has been reported 1

Critical Monitoring Recommendations

Baseline Assessment

Liver function testing is mandatory only for high-risk groups:

• HIV-infected patients 1
• Pregnant women and those ≤3 months postpartum 1
• Chronic liver disease or regular alcohol use 1
• Clinical suspicion of liver disorder 1
• Routine baseline testing is NOT indicated for all patients or based solely on age 1

During Treatment Monitoring

For isoniazid-only or rifampin-only regimens:

• Monthly clinical evaluations for fever, malaise, vomiting, jaundice, or unexplained deterioration 1

For rifampin-pyrazinamide regimens:

• Clinical assessments at weeks 2,4, and 8 1

Hepatotoxicity thresholds:

• Withhold isoniazid if AST/ALT >3× upper limit of normal with symptoms or >5× upper limit of normal without symptoms 1
• Patients must stop medication immediately and seek urgent care if hepatotoxicity symptoms develop 1

Key Clinical Pitfalls

• Never use rifampin-pyrazinamide regimens in HIV-negative adults due to unacceptably high hepatotoxicity rates 1
• Never reintroduce rifampin after severe hypersensitivity reactions (shock, renal failure, thrombocytopenia) 1
• Never continue ethambutol if visual changes occur; discontinuation must be immediate and permanent 1
• Never assume baseline liver testing is needed for all patients; reserve for high-risk groups only 1
• Never overlook drug interactions with rifamycins, particularly in HIV-infected patients on antiretrovirals or women using hormonal contraceptives 1, 2