What is the role of Ethionamide in the treatment of tuberculosis?

Ethionamide in Tuberculosis Treatment

Role and Indications

Ethionamide is a second-line antituberculosis drug reserved exclusively for drug-resistant tuberculosis when organisms demonstrate or are presumed to have susceptibility to the agent. 1

• Ethionamide should never be used as a first-line agent for drug-susceptible tuberculosis 1
• The drug is most commonly employed in multidrug-resistant (MDR-TB) and rifampicin-resistant tuberculosis treatment regimens 1, 2
• WHO now classifies ethionamide in Group C of recommended drugs for MDR-TB treatment 3

Dosing Strategy

Adults

• Administer 15-20 mg/kg/day (maximum 1.0 g/day), typically 500-750 mg/day 1
• Give as a single daily dose at bedtime or with the main meal, or divide into two doses 1
• No data support intermittent (non-daily) dosing schedules 1
• Recent pharmacokinetic data suggest higher doses (20 mg/kg/day) may be necessary to achieve therapeutic targets, particularly when MIC is ≥2.5 mg/L 4, 2

Children

• Dose at 15-20 mg/kg/day (maximum 1.0 g/day) 1, 5
• This weight-based dosing achieves adult-equivalent serum concentrations 5

Special Populations

• Renal impairment (CrCl <30 mL/min or hemodialysis): Reduce dose to 250-500 mg/day 1
• Hepatic disease: Use with extreme caution and increase monitoring frequency 1

Critical Drug Interactions

Isoniazid co-administration reduces ethionamide clearance by 31%, increasing AUC by 44% 4

• This interaction is clinically significant and may improve ethionamide efficacy when both drugs are used together 4
• Consider this pharmacokinetic enhancement when designing MDR-TB regimens 4

Adverse Effects Profile

Gastrointestinal (Most Common)

• Profound GI side effects occur commonly: metallic taste, severe nausea/vomiting, anorexia, and abdominal pain 1
• Mitigate by administering with food or at bedtime 1
• These effects rarely necessitate drug discontinuation but significantly impact quality of life 5

Hepatotoxicity

• Occurs in approximately 2% of patients 1
• Ethionamide is structurally similar to isoniazid and causes similar hepatic injury patterns 1

Neurotoxicity

• Peripheral neuritis, optic neuritis, anxiety, depression, and psychosis occur in 1-2% with short courses; rates increase substantially with prolonged treatment 1, 6
• This is particularly concerning when combined with other neurotoxic TB drugs like cycloserine 6
• Consider pyridoxine supplementation (100-200 mg/day) to reduce neurotoxic effects 6

Endocrine Disturbances

• Hypothyroidism, gynecomastia, alopecia, and impotence have been documented 1
• Diabetes management becomes more difficult in patients taking ethionamide 1, 6

Mandatory Monitoring Requirements

Baseline Assessment

• Liver function tests 1
• Thyroid-stimulating hormone (TSH) 1

Ongoing Monitoring

• Monthly liver function tests if underlying liver disease exists 1
• Monthly TSH measurements throughout treatment 1
• Repeat liver function tests immediately if symptoms develop 1
• Increase neuropsychiatric monitoring to biweekly intervals when combined with cycloserine or in patients with psychiatric comorbidities 6

Contraindications

Ethionamide is absolutely contraindicated in pregnancy due to teratogenicity in animal studies and placental transfer 1

Pharmacokinetic Considerations

• CSF concentrations equal serum concentrations, making ethionamide effective for tuberculous meningitis 1, 7
• Approximately 30% protein-bound 7
• Half-life of 1.92 hours 7
• Extensively hepatically metabolized; less than 1% excreted unchanged in urine 7
• The sulfoxide metabolite retains antimicrobial activity against M. tuberculosis 7

Resistance Patterns and MIC Considerations

Ethionamide should only be used when Sensititre MIC is <2.5 mg/L; above this threshold, clinical failure rates are unacceptably high 2

• Cross-resistance with isoniazid occurs through inhA promoter mutations, but most isoniazid-resistant isolates remain ethionamide-susceptible 7, 2, 3
• ethA gene mutations confer ethionamide monoresistance 5, 3
• No cross-resistance exists with PAS, streptomycin, or cycloserine 7
• Limited cross-resistance may occur with thiosemicarbazones (thiacetazone) 7
• Among XDR, pre-XDR, and MDR strains, 25%, 36%, and 50% respectively have MICs below the breakpoint and remain susceptible 3

Clinical Efficacy Targets

Target AUC₀₋₂₄/MIC ratio >56.2 for maximal bacterial kill and resistance suppression 2

• WHO-recommended doses often fail to achieve this target even at the lowest measurable MIC of 0.3 mg/L 4
• Doses of 20 mg/kg/day achieve target exposures in >95% of patients when MIC <2.5 mg/L 2

Common Pitfalls to Avoid

• Never use ethionamide as monotherapy—resistance develops rapidly through efflux pump induction 2
• Do not use in first-line regimens for drug-susceptible TB 1
• Avoid in pregnancy under all circumstances 1
• Do not overlook the significant drug interaction with isoniazid that increases ethionamide exposure 4
• Recognize that suboptimal exposures lead to efflux pump-mediated resistance to multiple drugs simultaneously (isoniazid, ethambutol) 2
• When combining with cycloserine in patients with psychiatric conditions or diabetes, intensify monitoring and consider alternative antipsychotics with lower metabolic impact 6