What are the potential side effects of Multi-Drug Therapy (MDT) in adults or children with chronic or infectious diseases, such as tuberculosis or leprosy?

Multi-Drug Therapy (MDT) Side Effects

MDT for tuberculosis and leprosy carries significant organ-specific toxicities that require systematic monitoring, with hepatotoxicity, neurotoxicity, and ototoxicity being the most clinically important adverse effects that can impact morbidity and quality of life.

Tuberculosis MDT Side Effects

First-Line Anti-TB Drugs

Isoniazid (INH)

• Peripheral neuropathy is the most common toxic effect, dose-related and occurs most often in malnourished patients, alcoholics, and diabetics, usually preceded by paresthesias of the feet and hands 1
• Hepatotoxicity occurs in 10-20% of patients with mild transient elevation of serum transaminases in the first 1-3 months, but progressive liver damage increases with age (rare under 20 years, up to 2.3% in those over 50 years) 1
• Discontinue INH if SGOT exceeds 3-5 times the upper limit of normal 1
• Other neurotoxic effects include convulsions, toxic encephalopathy, optic neuritis and atrophy, memory impairment, and toxic psychosis 1
• Hematologic reactions include agranulocytosis, hemolytic/sideroblastic/aplastic anemia, thrombocytopenia, and eosinophilia 1
• Hypersensitivity reactions manifest as fever, skin eruptions (morbilliform, maculopapular, purpuric, or exfoliative), lymphadenopathy, and vasculitis 1

Rifampin (RIF)

• Hepatotoxicity, gastrointestinal symptoms, and hypersensitivity reactions are common 2
• Rarely causes severe immunologic reactions including acute renal failure and thrombocytopenia 2

Pyrazinamide (PZA)

• Maximum daily dose should not exceed 3 grams, with CDC recommendations not exceeding 2 grams per day for daily regimens 3
• Gastrointestinal symptoms and hepatic transaminase elevations are the primary side effects 2
• Not recommended routinely during pregnancy because teratogenicity risk has not been determined 2

Ethambutol (EMB)

• Generally not used for children whose visual acuity cannot be monitored (those less than 6 years of age) 2
• Optic neuritis is the primary concern requiring visual monitoring 2

Second-Line Anti-TB Drugs

Streptomycin (SM)

• Ototoxicity is the most important adverse reaction, including vestibular and hearing disturbances, with risk increasing with age and cumulative doses above 100-120 grams 2
• Nephrotoxicity requiring discontinuation occurs in approximately 2% of patients 2
• Circumoral paresthesias commonly occur immediately after injection 2
• Contraindicated in pregnancy due to risk of fetal hearing loss 2
• Requires dose adjustment in renal insufficiency: reduce frequency to 2-3 times weekly while maintaining 12-15 mg/kg per dose 2

Ethionamide

• Profound gastrointestinal side effects including metallic taste, nausea, vomiting (often severe), loss of appetite, and abdominal pain are common 2
• Hepatotoxicity occurs in approximately 2% of patients 2
• Neurotoxicity (peripheral neuritis, optic neuritis, anxiety, depression, psychosis) reported in 1-2% with short courses, higher rates with prolonged treatment 2
• Endocrine disturbances including gynecomastia, alopecia, hypothyroidism, and impotence 2
• Diabetes may be more difficult to manage 2
• Teratogenic in laboratory animals and should not be used in pregnancy 2

Cycloserine

• CNS effects including anxiety, depression, psychosis, seizures, and suicidal ideation are the primary concerns 2
• Peripheral neuritis can occur, often prevented with pyridoxine 100-200 mg/day 2
• Increased risk of seizures in patients with alcohol-related hepatitis 2
• Requires dose reduction in renal impairment; should not be used if creatinine clearance <50 ml/minute unless on hemodialysis 2

Fluoroquinolones (Levofloxacin/Ofloxacin)

• Gastrointestinal symptoms and hepatic transaminase elevations 2
• Long-term use in children should be avoided due to deleterious effects on growing cartilage observed in animals 2

Leprosy MDT Side Effects

MAC (Mycobacterium Avium Complex) Treatment

Clarithromycin

• Toxicity is dose and serum-level related; most adult patients cannot tolerate more than 1,000 mg/day 2
• Elderly patients with low creatinine clearance or low body weight may require even lower doses (250-500 mg/day) 2
• Most common toxicities are gastrointestinal (metallic taste, nausea, vomiting) 2
• More than doubles rifabutin serum levels by inhibiting hepatic metabolism 2

Azithromycin

• Toxicity is dose and serum-level related; most patients with MAC lung disease do not tolerate doses greater than 300 mg/day 2
• Frequent adverse events include gastrointestinal symptoms (primarily diarrhea) and reversible hearing impairment 2
• Maximum recommended doses are 250 mg/day or 500 mg three times weekly 2

Rifabutin

• Toxicity is dose-related and common, frequently requiring dosage adjustment 2
• Most common toxicity is fever, chills, and flulike illness 2
• Uveitis and polyarthralgia syndrome common in patients receiving 450-600 mg/day with clarithromycin 2
• Reduction in white blood cell count below 5,000 cells/μL is common with doses of 300-600 mg/day 2
• Reduction to 150 mg/day may be necessary in older patients with nodular/bronchiectatic disease when combined with clarithromycin 2

Critical Monitoring Requirements

Baseline and Ongoing Monitoring

For Streptomycin:

• Audiogram, vestibular testing, Romberg testing, and serum creatinine at baseline 2
• Monthly assessment of renal function and questioning regarding auditory or vestibular symptoms 2
• Repeat audiogram and vestibular testing if symptoms of eighth nerve toxicity develop 2

For Ethionamide:

• Liver function tests at baseline and monthly if underlying liver disease 2
• Thyroid-stimulating hormone at baseline and monthly intervals 2

For Cycloserine:

• Neuropsychiatric status assessment at least monthly and more frequently if symptoms develop 2
• Serum drug concentration measurements may be necessary until appropriate dose established 2

Special Population Considerations

Pregnancy

• Streptomycin is the only licensed anti-TB drug documented to have harmful effects on the fetus (congenital deafness) and is contraindicated 2
• Pyrazinamide routine use not recommended during pregnancy due to undetermined teratogenicity risk 2
• Ethionamide is teratogenic in laboratory animals and should not be used 2
• Preferred initial treatment regimen in pregnancy is INH, RIF, and EMB for minimum 9 months 2

Renal Impairment

• Streptomycin requires dosing frequency reduction to 2-3 times weekly while maintaining 12-15 mg/kg per dose in renal insufficiency 2
• Ethionamide dose should be reduced to 250-500 mg/day for creatinine clearance <30 ml/minute or hemodialysis 2
• Cycloserine should not be used if creatinine clearance <50 ml/minute unless patient is receiving hemodialysis 2

HIV-Infected Patients

• Should be treated for total of 9 months and at least 6 months after sputum conversion due to risk of rapid disease progression with inadequate therapy 2
• If drug susceptibility results unavailable, EMB or SM should be continued for entire course of therapy 2

Common Pitfalls to Avoid

• Never discontinue pyridoxine supplementation in patients at risk for peripheral neuropathy (malnourished, alcoholics, diabetics) taking isoniazid 1
• Do not ignore mild transaminase elevations in the first 3 months of INH therapy, but monitor closely as most resolve without discontinuation 1
• Always obtain baseline audiometry and vestibular testing before initiating streptomycin, as ototoxicity is often irreversible 2
• Avoid combining clarithromycin with full-dose rifabutin (450-600 mg/day) due to significantly increased rifabutin toxicity risk 2
• Do not use ethambutol in young children (<6 years) whose visual acuity cannot be monitored 2