1. Para-aminosalicylic acid, PAS

• PAS resembles PABA, a substance bacteria use to make folate.
• It disrupts folate synthesis in Mycobacterium tuberculosis, slowing bacterial growth. It is mainly bacteriostatic, meaning it inhibits multiplication rather than rapidly killing bacteria.

• PAS can increase circulating isoniazid levels by reducing its hepatic acetylation, meaning less isoniazid is inactivated by the liver.
• This can be useful pharmacologically, but also means toxicity monitoring is needed.

• Marked gastrointestinal intolerance: nausea, vomiting, abdominal discomfort, diarrhea.
• Hypersensitivity reactions, including fever and rash.
• Hepatotoxicity.
• Long-term use may cause hypothyroidism, especially with ethionamide.

• It is a reserve option when more effective drugs cannot form an adequate regimen. WHO describes PAS as a last-resource agent in selected longer MDR/RR-TB regimens because it has modest activity and poor GI tolerance. WHO DR-TB guidance

2. Ethionamide

• Ethionamide is structurally related to isoniazid.
• It is a prodrug activated inside the mycobacterium and inhibits mycolic-acid synthesis.
• Mycolic acids are waxy lipids that make the TB cell wall tough and acid-fast. Blocking them weakens cell-wall formation.

• Because ethionamide and isoniazid act on closely related pathways, there can be cross-resistance in some strains.

• Oral drug, metabolized in the liver.
• The dose shown in the slide is historical teaching information. In real care, drug selection and dose must be individualized by a TB specialist, body weight, drug-susceptibility testing, liver function, and the local protocol.

• Severe nausea, vomiting, anorexia, metallic taste.
• Hepatotoxicity.
• Peripheral neuropathy and neuropsychiatric symptoms.
• Hypothyroidism, particularly when combined with PAS.
• May cause gynecomastia.

• It has lower priority because of poor tolerability and limited bactericidal effect. WHO generally reserves ethionamide/prothionamide for when better options such as bedaquiline, linezolid, clofazimine, or delamanid cannot be used. WHO explanation

3. Capreomycin

• Capreomycin is an injectable peptide antibiotic that inhibits mycobacterial protein synthesis.
• It was used for drug-resistant TB, often when resistance limited other choices.

• It must be given by injection, not orally.

• Nephrotoxicity: kidney injury.
• Ototoxicity: hearing loss, tinnitus, vertigo, and vestibular dysfunction. These may be permanent.
• Electrolyte abnormalities, especially low potassium and magnesium.
• Injection-site pain or sterile abscesses.

• Capreomycin is now not recommended in current longer MDR-TB regimens because of toxicity and poorer outcomes compared with newer all-oral approaches. WHO guidance This is a major change from older pharmacology notes.

4. Cycloserine

• Cycloserine inhibits TB cell-wall synthesis.
• More specifically, it blocks enzymes involved in making D-alanine, an essential building block of bacterial peptidoglycan.

• Taken orally.
• Cleared by the kidneys, so the dose must be reduced in significant renal impairment.

• The important toxicity is central nervous system toxicity:
  • irritability, anxiety, depression
  • poor concentration or behavioral changes
  • psychosis
  • seizures
• Peripheral neuropathy can also occur.

• Pyridoxine (vitamin B6) helps reduce neurotoxicity and peripheral neuropathy. The slide’s statement is correct in principle.

• Unlike the other drugs shown, cycloserine or terizidone remains a relatively higher-priority companion drug in longer MDR-TB regimens, provided psychiatric and neurologic toxicity can be monitored. WHO DR-TB guidance

High-yield comparison

Memory aid

• PAS: “PABA analogue” -> folate antagonist
• Ethionamide: “like INH” -> inhibits mycolic acid
• Capreomycin: “ears and kidneys” -> ototoxic + nephrotoxic
• Cycloserine: “CNS” -> psychiatric effects and seizures, give B6

• RR-TB = rifampicin-resistant TB
  The TB strain is resistant to rifampicin, one of the most important first-line TB drugs.
• MDR-TB = multidrug-resistant TB
  The strain is resistant to at least both rifampicin and isoniazid, the two key first-line TB medicines.

All MDR-TB is RR-TB, but not all RR-TB is confirmed MDR-TB.

What it means

• fever and fatigue
• joint pains or joint swelling
• muscle aches
• rash, sometimes photosensitivity
• occasionally inflammation around the heart or lungs, causing chest pain

What happens if it occurs?

The slide sentence in simpler words

“PAS use is discouraged because TB may already be resistant to it, it causes unpleasant GI side effects that make patients less likely to continue treatment, and it can rarely cause a lupus-like immune reaction.”

“Its use is discouraged due to primary resistance, poor adherence caused by GI intolerance, and lupus-like reactions.”

Typical interpretation

Diagnosis depends on the whole pattern

1. Exposure to a known culprit medicine, such as procainamide, hydralazine, isoniazid, or rarely PAS
2. New symptoms such as joint pains, muscle pains, fever, fatigue, or pleuritic chest pain
3. Positive ANA, often with anti-histone antibodies
4. No strong evidence of classic SLE, particularly kidney or central nervous system involvement
5. Improvement after stopping the suspected medicine, under medical supervision