10 - Antimycobacterials Flashcards
What are some examples of mycobacterial diseases?
TB - M. tuberculosis
Leprosy - M. lebprae
Pulmonary, intestinal, lymph nodes - M. avium intracellulare (MAI or MAC)
What are the challenges of mycobacterial therapy?
Difficult to kill - only vulnerable to cidal drugs when active
Slow growth - hampers identification/susceptibility testing
Lengthy therapy
Intracellular forms
Chronic disease established before symptomatic
Why might multiply drugs be needed to treat mycobacterial infections?
Spontaneous drug resistance can occur and requires multi-drug therapy with cidal drugs to cure.
Describe the cell envelope of mycobacterium?
They have a cytoplasmic membrane, a cell wall, and an outer membrane.
The outer membrane contains mycolic acid and arabinogalactan.
What are the first line drugs for TB therapy in the US?
Rifampin Isoniazid Pyrazinamide Ethambutol Streptomycin
What drug is cidal for actively growing cells and inhibitors synthesis of mycolic acid? How does it work?
Isoniazid (INH)
Activated by the catalase-peroxidase (KatG protein) and targets the enoyl-acyl carrier protein reductase (InhA protein)
What is resistance to isoniazid caused by?
Mutations in KatG
Mutations in InhA
When should isoniazid be used?
All patients infected with INH-sensitive strains should receive INH if possible.
For treatment of active TB, always given in combination.
What polymorphisms are associated with isoniazid metabolism?
Slow and fast acetylators exist.
What are adverse effects of isoniazid?
Neurotoxicity, esp/ peripheral neuritis (but can be improved with pyridoxine (VitB6))
Hepatotoxicity (10-20%)
What drug works by binding RNA polymerase B and thereby inhibiting bacterial RNA synthesis?
Rifampin
What are adverse effects of Rifampin?
Hepatotoxicity
Potent inducer of multiple CYPs, causing increased metabolism of other drugs.
Orange-red color or urine, feces, saliva, and tears
What drug works by interfering with arabinosyl transferase and thereby blocking cell wall synthesis? What is another characteristic of this drug?
Ethambutol
It’s tuberculostatic, but doens’t interfere with the cidal effects of other drugs.
What are side effects of Ethambutol? Describe its distribution.
Gets to adequate levels in the CSF.
Can cause optic neuritis (5-15%)
NOT hepatotoxic
What drug blocks mycolic acid synthesis by inhibiting fatty acid synthase I? What are important characteristics of this drug?
Pyrazinamide (PZA)
Cidal
Important component of short-term therapy, well absorbed-particularly useful for CNS involvement.
What are adverse effects of pyrazinamide?
Hepatic damage, especially when combined with rifampin
What drug binds to several ribosomal sites to stop initiation and cause mRNA misreading? What is this drug used for?
Streptomycin
Usually reserved for the most serious forms of TB
What are adverse effects of streptomycin?
Ototoxicity - affects both balance and hearing
Nephrotoxicity
What are the reasons for simultaneous use of 4 or more drugs to treat TB?
Known exposure to drug-resistant strains.
What bactericidal drugs are used to treat conventional intracellular and extracellular TB?
Isoniazid
Rifampin
Pyranizamide
These are commonly used together because these are -cidal AND intracellular.
Describe an atypical mycobacterial infection and how it differs from TB infections?
MAC: M. avium-intracellulare complex
MAS is less fatal than TB, so if you find an acid-fast bacilli (AFB) institute an anti-TB regimen until the agent is identified
What drug is is used for single-agent prophylaxis of M. avium-intracellulare (MAC) in AIDs patients? What else can this be used for?
Rifambutin
Can also be used as an alternate for rifampin in multi-drug treatment of MAC
What are the adverse effects of Rifambutin?
Similar to rifampin but less frequent.
Drug interactions similar to rifampin, but to a lesser extent (less potent CYP inducer)
What cidal drug is part of a multi-drug regimen for treatment of M. avium-intracellulare (MAC) in AIDs patients and can also be used for MAC prophylaxis?
Clarithromycin
Cidal
