What are the major adverse reactions associated with the medications used to treat latent and active tuberculosis?

Major Adverse Reactions to Tuberculosis Medications

The most serious adverse reactions to TB medications are hepatotoxicity (particularly with isoniazid, rifampin, and pyrazinamide), peripheral neuropathy, hypersensitivity reactions, and organ-specific toxicities including nephrotoxicity and ototoxicity with injectable agents. 1

First-Line Drugs for Active and Latent TB

Isoniazid (INH)

Hepatotoxicity:

• Hepatotoxicity occurs at an incidence of 9.2 per 1000 compliant patients, with a case fatality rate of 4.7% 2
• Risk increases significantly with age over 35 years, regular alcohol use, chronic liver disease, HIV infection, and pregnancy or immediate postpartum period 1
• Drug-induced liver injury is suspected when ALT is ≥3 times upper limit of normal with hepatitis symptoms, or ≥5 times upper limit without symptoms 1
• Stop all hepatotoxic drugs immediately when these thresholds are met 1

Peripheral Neuropathy:

• HIV-infected patients have higher predisposition to isoniazid-related peripheral neuropathy 1
• Effectively prevented with pyridoxine 100-200 mg/day 1

Monitoring Requirements:

• Monthly clinical visits for all patients receiving LTBI treatment 1
• Baseline liver function tests (AST, ALT, bilirubin) required for patients with: history of liver disease, regular alcohol use, chronic liver disease, HIV infection, age >35 years, pregnancy or within 3 months postpartum 1
• Patients should immediately report anorexia, nausea, vomiting, abdominal discomfort, persistent fatigue, dark urine, pale stools, or jaundice 1

Rifampin/Rifapentine

Hepatotoxicity:

• Hepatotoxicity occurs at an incidence of 0.43 per 100 person-months of exposure 3
• Risk increases with age over 60 years (adjusted hazard ratio 3.9) and HIV-positive status (adjusted hazard ratio 8.0) 3

Hypersensitivity Reactions:

• Cutaneous reactions, hypersensitivity or flu-like reactions, and gastrointestinal intolerance are common 1
• Discontinue rifapentine at first appearance of skin rash, mucosal lesions, or any sign of hypersensitivity 4
• Rifabutin toxicity (when used with protease inhibitors) includes arthralgias, uveitis, and leukopenia 1

Drug Interactions:

• Rifamycins induce hepatic cytochrome P450 metabolism, reducing effectiveness of hormonal contraceptives, methadone, corticosteroids, theophylline, and anticoagulants 1
• Use effective non-hormonal contraception or add barrier method during rifapentine treatment 4

Other Effects:

• Permanently stains contact lenses and dentures red-orange 4
• Colors urine, tears, sweat, and body fluids orange 1

Pyrazinamide (PZA)

Hepatotoxicity:

• Pyrazinamide has the highest incidence of major adverse effects at 1.48 per 100 person-months of exposure 3
• Risk increases with age over 60 years (adjusted hazard ratio 2.6) and birthplace in Asia (adjusted hazard ratio 3.4) 3
• Fulminant hepatitis has poorer prognosis in regimens containing pyrazinamide 5
• Avoid combination of pyrazinamide with ethionamide due to frequent hepatotoxicity 5

Other Effects:

• Gastrointestinal upset is most common side effect 1
• Hyperuricemia occurs commonly, but acute gout is uncommon 1

Ethambutol (EMB)

Retrobulbar Neuritis:

• Manifested as decreased visual acuity or decreased red-green color discrimination affecting one or both eyes 1
• Risk is dose-related with minimal risk at 15 mg/kg daily (18% at doses >30 mg/kg daily) 1
• Discontinue immediately and permanently if any signs of visual toxicity occur 1

Monitoring Requirements:

• Baseline visual acuity testing (Snellen chart) and color discrimination (Ishihara tests) 1
• Monthly questioning about visual disturbances including blurred vision or scotomata 1
• Monthly visual acuity and color discrimination testing for patients taking doses >15-25 mg/kg, receiving drug >2 months, or with renal insufficiency 1

Renal Considerations:

• Dose adjustment required when creatinine clearance <70 ml/minute 1
• Administer 15-20 mg/kg three times weekly after dialysis in end-stage renal disease 1

Streptomycin

Ototoxicity:

• Most important adverse reaction, including vestibular and hearing disturbances 1
• Risk increases with age, concomitant loop diuretics (furosemide, ethacrynic acid), and cumulative doses above 100-120 g 1

Nephrotoxicity:

• Occurs less commonly than with amikacin, kanamycin, or capreomycin 1
• Renal insufficiency requiring discontinuation occurs in approximately 2% of patients 1

Pregnancy:

• Contraindicated in pregnancy due to risk of fetal hearing loss 1

Monitoring Requirements:

• Baseline audiogram, vestibular testing, Romberg testing, and serum creatinine 1
• Monthly assessment of renal function and questioning about auditory or vestibular symptoms 1
• Repeat audiogram and vestibular testing if symptoms of eighth nerve toxicity develop 1

Renal Dosing:

• Reduce dosing frequency to 2-3 times weekly in renal insufficiency, maintaining 12-15 mg/kg per dose 1
• Administer after dialysis 1

Second-Line Drugs for Drug-Resistant TB

Fluoroquinolones (Levofloxacin, Moxifloxacin)

Cardiac Effects:

• QT interval prolongation, particularly when combined with bedaquiline, delamanid, or clofazimine 1
• Use with caution in patients with underlying cardiac dysrhythmia 1

Other Effects:

• Side effects are rare (3-7%) and usually mild: abdominal pain, nausea, vomiting, dizziness, headache, increased liver enzymes 1

Cycloserine

Central Nervous System Effects:

• Range from headache and restlessness to psychosis and seizures 1
• Seizures occur in up to 16% of patients receiving 500 mg twice daily but only 3% at 500 mg once daily 1
• Toxicity more common at doses >500 mg/day 1
• Pyridoxine 100-200 mg/day helps prevent neurotoxic effects 1

Monitoring:

• Serum concentration measurements targeting peak of 20-35 mg/ml 1
• Neuropsychiatric status assessment at least monthly 1

Renal Considerations:

• Should not be used in patients with creatinine clearance <50 ml/minute unless receiving hemodialysis 1
• For hemodialysis patients: 500 mg three times weekly or 250 mg daily 1

Ethionamide/Prothionamide

Gastrointestinal Effects:

• Most frequent side effect is gastrointestinal intolerance (abdominal pain, nausea, vomiting) 1
• Daily doses of 0.5-1 g given in 2-3 divided doses usually limit gastrointestinal upset 1

Hepatotoxicity:

• Hepatotoxic and may cause hyperglycemia in diabetics 1

Endocrine Effects:

• Gynecomastia, alopecia, hypothyroidism, and impotence have been described 1

Monitoring:

• Baseline liver function tests and monthly intervals if underlying liver disease 1
• Thyroid-stimulating hormone at baseline and monthly 1

Pregnancy:

• Contraindicated in pregnancy due to teratogenicity in laboratory animals 1

Aminoglycosides (Amikacin, Kanamycin) and Capreomycin

Major Toxicities:

• Nephrotoxicity, ototoxicity, and neuromuscular blockade 1
• Dosage reduction required in renal impairment 1

Linezolid

Hematologic Effects:

• Myelosuppression/cytopenias, particularly when combined with zidovudine 1

Metabolic Effects:

• Lactic acidosis, especially with concurrent stavudine or zidovudine 1

Neurologic Effects:

• Peripheral neuropathy 1

Bedaquiline and Delamanid

Cardiac Effects:

• QT interval prolongation 1
• Avoid concurrent use with other QT-prolonging agents including fluoroquinolones, clofazimine, and certain antiretrovirals (lopinavir/ritonavir, efavirenz) 1

Drug Interactions:

• Metabolized by hepatic cytochrome P450 system 1
• Protease inhibitors impede CYP P450 metabolism, potentially increasing drug levels 1

Special Population Considerations

HIV-Infected Patients

Increased Risks:

• Up to fourfold higher mortality risk with MDR-TB compared to HIV-negative patients 1
• Low CD4 counts (<50 cells/ml or <350 cells/mm³) correlate with higher mortality and increased adverse reaction risk (adjusted hazard ratio 2.6-5.5) 1, 6

Overlapping Toxicities:

• Hepatotoxicity risk increased with nevirapine (especially elevated CD4 counts) and protease inhibitors 1
• Peripheral neuropathy with stavudine, zidovudine combined with TB drugs 1
• Nephrotoxicity with tenofovir combined with aminoglycosides or capreomycin 1

Paradoxical Reactions:

• Temporary exacerbation of TB symptoms (fever, enlarged lymph nodes, new cavitation) among patients with restored immune function from antiretroviral therapy 1
• Rule out TB treatment failure before attributing symptoms to paradoxical reaction 1
• Some experts recommend delaying antiretroviral therapy initiation 4-8 weeks from TB therapy start to avoid paradoxical reactions 1

Pregnancy and Postpartum

Increased Hepatotoxicity Risk:

• Pregnancy and immediate postpartum period (within 3 months of delivery) require baseline laboratory testing 1

Contraindicated Drugs:

• Streptomycin: contraindicated due to fetal hearing loss risk 1
• Ethionamide: contraindicated due to teratogenicity 1

Elderly Patients (>60 Years)

Increased Risks:

• Age >60 years associated with overall adverse reaction risk (adjusted hazard ratio 2.9) 3
• Pyrazinamide-associated events (adjusted hazard ratio 2.6) 3
• Rifampin-associated events (adjusted hazard ratio 3.9) 3
• Streptomycin dose should be reduced to 10 mg/kg daily (750 mg maximum) for persons >59 years 1
• Elderly persons highly intolerant to rifampin 5

Other Risk Factors

Female Sex:

• Associated with increased risk of any major side effect (adjusted hazard ratio 2.5) 3

Asian Birthplace:

• Associated with increased overall adverse reaction risk (adjusted hazard ratio 2.5) and pyrazinamide-associated events (adjusted hazard ratio 3.4) 3

Diabetes Mellitus:

• Statistically significant relationship with adverse drug reactions (p=0.042) 7
• Dysglycemia risk with ethionamide, p-aminosalicylic acid, fluoroquinolones, linezolid, and certain antiretrovirals 1

Alcoholism:

• Associated with adverse reactions (relative risk 3.0) 6
• Increased risk of seizures with cycloserine in alcohol-related hepatitis 1

Common Pitfalls and Management Strategies

Gastrointestinal Intolerance:

• Patients receiving self-administered therapy may take medications at bedtime to minimize symptoms 1
• Antacids have less impact on drug absorption than food administration 1
• Any combination of unexplained nausea, vomiting, and abdominal pain requires physical examination and liver function tests to assess for hepatotoxicity 1

Hepatotoxicity Management:

• Stop treatment immediately if patients develop symptoms and cannot consult healthcare provider 1
• Exclude other causes: viral hepatitis (A, B, C, EBV, CMV, HSV in immunosuppressed), biliary tract disease, alcohol, other hepatotoxic drugs, herbal supplements 1

Drug Discontinuation Impact:

• Adverse reactions resulted in drug discontinuation in 79% of cases in one study 6
• Average treatment time changed by 1.0±2.6 months (range -3.4 to 10.6 months) due to adverse reactions 7
• Prolonged hospital stay averaged 58.4 days for patients with adverse reactions versus 26 days without 6

Mortality:

• Among patients who died with adverse reactions, the reaction was directly implicated in 4.4% of deaths 6