Anti-Mycobacterial Therapy Flashcards
What is the general idea in drug therapy of TB?
Multiple drugs are used
Isoniazid HCl MOA
- Isoniazid is a “prodrug” that is activated by catalase peroxidase, which is regulated by the TB katG gene
- Targets the TB inhA gene product – enoyl- reductase – and therefore inhibits synthesis of mycolic acid in the TB cell wall
Isoniazid HCl Resistance Mechanisms
- Mutations in katG gene result in inactivation of catalase-peroxidase
- Mutation in regulatory region of inhA gene, which is involved in mycolic acid synthesis
Isoniazid HCl Metabolism
INH acetylation in liver by N-acetyltransferase - rate is dependent upon genetics
Does INH cross the BBB?
Yes - CSF levels 20% plasma levels but may equal
plasma levels with meningeal inflammation
Isoniazid HCl SE
- Hepatotoxicity
- Neurotoxicity
- Hypersensitivity Reactions
How is a diagnosis of TB made?
- PPD skin test is shown to be positive
- The Hx will then be reviewed for any signs of risk factors
- Presence of risk factors will prompt a CXR
- Abnormal CXR will lead to AFB of the sputum for mycobacteria
- Positive AFB will the lead to the NAAT test for TB
What are the drug interactions of INH?
• INH + rifampin increases occurrence of hepatitis
Rifampin MOA
Inhibits DNA-dependent RNA polymerase encoded by the rpoB gene
Rifampin Resistance Mechanisms
Mutations in the rpoB gene will grant resistance
Does rifampin cross the BBB into the CNS?
Yes it penetrates well
Rifampin SE
- Hepatotoxicity increased with other hepatotoxic drugs like INH
- Red discoloration of body fluids – urine, tears, soft contacts
- Acute renal failure, interstitial nephritis
What are the drug interactions of rifampin?
Induces hepatic microsomal enzymes - interacts with hundreds of drugs
What is the clinical use of ethambutol?
A “helper” drug that inhibits resistance to other drugs
Ethambutol MOA
Inhibits synthesis mycobacterial arabinosyl transferase encoded by embB which affects wall synthesis
Does ethambutol cross the BBB into the CNS?
No - very poorly even with inflammation
Ethambutol SE
- Optic neuritis
- Peripheral neuropathy
What is the clinical use of pyrazinamide?
First line TB drug – for the 1st two months of therapy - increases the cure rate and reduces the likelihood of relapse
Pyrazinamide MOA
A “prodrug” activated by TB pyrazinamidase, encoded by pncA
Does pyrazinamide cross the BBB into the CNS?
Distribution is good, including in the CSF in tuberculous meningitis
Pyrazinamide SE
- Hepatitis, worse in patients with preexisting liver disease
- Skin rash and gastrointestinal intolerance
- Increased serum uric acid levels, but acute gout is uncommon
What is the clinical use of streptomycin in TB?
Second line TB drug
Streptomycin MOA
Inhibits protein synthesis by binding to ribosome
Streptomycin SE
- Ototoxicity
- Nephrotoxicity
What is primary TB resistance?
Infection by a source case with drug-resistant TB - acquired with the infection
What is secondary TB resistance?
From ineffective therapy causing resistance to develop during treatment
Why is multi drug therapy used in cases of TB?
Risk of evolution of resistance to two drugs is the product of the risk of the development of resistance to each drug - FAR lower
What is multi-drug resistant TB?
Resistance to both INH and rifampin - more common in those with HIV
What is extensively drug resistant TB?
- Resistance to INH and Rifampin
- Resistance to a fluoroquinolone antibiotic
- Resistance to one of three injectable antibiotics (amikacin, kanamycin, capreomycin)
What is the problem with therapy in MDR-TB?
Requires therapy for at least 18-24 months because rifampin resistance eliminates the short course therapy
What is the 6 month TB treatment regimen?
- 4-drug regimen (“RIPE” therapy = Rifampin-INH-PZA-Ethambutol)
- Initial phase: RIPE
- Continuation phase: RI (Note: Emb not needed if pan-suceptible)
How is intermittent treatment of TB administered (2-3 times a week)?
Directly Observed Therapy
Why is rifampin resistance so important clinically?
Loss of rifampin from the regimen means loss of the option for short-course (6 month) TB therapy
What are some of the treatments for latent TB infection?
- INH monotherapy for 9 months is highly effective
- Rifampin – 4 month, daily therapy
What are the drugs that are unique to NTM treatment?
- Clarithromycin
- Azithromycin
What drugs are used for both TB and NTM?
- Rifampin
- Ethambutol
- FQs
- AGs
Is the treatment of leprosy different than that of TB?
Yes. Leprosy treatment is different treatment from TB treatment.
Paucibacillary Leprosy Treatment
Rifampin + dapsone daily for 12 months
Multibacillary Leprosy Treatment
Rifampin + dapsone + clofazimine daily for 24 months
