Anti-Mycobacterial Therapies (Fan) - 5/3/16 Flashcards
Describe mycobacterial-specific cell wall features pertinent to chemotherapy.
Thick cell wall!
Outer membrane:
- Long acyl lipids
- Mycolate (C54-C78) (target of INH, ETA, PAS)
- Arabinogalactan (target of EMB)
State proper TB treatment durations for culture-positive and culture-negative patients free of HIV infection
Culture positive: RIF + INH + PZA + EMB (26 weeks of treatment - 6 mo.)
Culture positive: RIF + INH + EMB (39 weeks of treatment - 9 mo.)
Active TB = ALWAYS multiple drug therapy; NO CROSS-RESISTANCE AMONG FOUR MAJOR DRUGS USED IN TREATMENT
Culture negative:
Initial phase - RIF + INH + PZA + EMB (2 mo)
Continuation phase - RIF + INH (2 mo)
Name first-line and second-line anti-TBs (and abbreviations, when applicable) under CDC guidelines
First-line (6):
- Isoniazid (INH)
- Rifampin (RIF)
- Rifabutin
- Rifapentine
- Pyrazinamide (PZA) - inhibits protein synthesis in dormant bacteria
- Ethambutol (EMB)
Second-line (10):
- Ethionamide (ETA)
- p-Aminosalicylic acid (PAS)
- Cycloserine
- Streptomycin* (WHO lists streptomycin as first line drug)
- Amikacin/kanamycin (aminoglycoside)
- Capreomycin
- Levofloxacin
- Moxifloxacin
- Gatifloxacin
- Bedaquiline
Challenges in treating TB?
- Dormant or slow-growing intracellular infection
- Bacteria live and hide within macrophages
- Slow growth –> less sensitive to drugs that target actively growing cells
- 4-9 mo. treatment is needed - MT readily accumulate mutations that cause drug resistance (chromosomal mutation)
- Which is why multiple drug approach is important! - Doctor/patient compliance (exacerbates resistance!)
- Strong lipid-rich cell wall
- TB (drug-resistant TB) and HIV/AIDS often co-exist (double trouble!)
Name geographical areas with particularly high resistance rates to anti-TBs
Eastern Europe! (15.7-45.3%)
Name first-line anti-TBs that target both extracellular and intracellular dormant Mtb
Isoniazid
Name the drug(s) that specifically target dormant Mtb
PZA
Define de facto mono therapy and describe its possible causes
De Facto Monotherapy - responsible for development of resistance in patients treated w/ multiple drugs
Possible causes:
- Pre-existing resistance
- Poor distribution of certain drugs to fibrotic tissues
- Differential targeting of bacterial forms (active growing vs. dormant bacteria in LTBI)
State the significance of direct observed treatment.
Helps with patient compliance since treatments are lengthy! (6-9 mo)
List the indications for second-line anti-TBs
- Multi-resistant TB (MDR-TB, resistance to both isoniazid and rifampin)
- Extensively drug-resistant TB (XDR-TB: MDR + resistance to a fluoroquinolone + injectable amino glycoside)
- Cases in which first line drugs are effective but can’t be used due to toxicities
List general properties of second-line anti-TBs
- Less effective than first-line drugs
- Significant toxic side-effects
- Expensive
Name the active forms of INH and PZA, and the enzymes that catalyze the activation reaction
Active form: INH-NAD
Catalyst: Bacterial KatG (catalase peroxidase)
Active form: Pyrazinoic acid
Describe the reason and management of major neurological side effects of INH
Peripheral neuropathy due to pyridoxine deficiency
Mild form:
- Sensory abnormalities: temporary numbness, tingling, prickling sensations (paresthesia), sensitivity to touch
- Muscle weakness
Severe form:
- Burning pain (especially at night)
- Muscle asting, paralysis
Organ or gland dysfunction: maldigestion, low BP, abnormal sweating, sexual dysfunction, breathing difficulties
Describe INH metabolic mechanism, and implication of its variation within population for therapeutic regimen
High probability of resistance - almost always used with other drugs
Pro-drug activated by bacterial KatG (catalase peroxidase)
- INH + NAD = active drug
Mycolic Acid Biosynthesis:
Fatty acids are synthesized in two stages in mtb:
- FAS-I = synthesizers chains up to C16-C26 using CoA as carrier
- FAS-II = multi-enzyme system that lengthens fatty acid chains to > C52.
INH-NAD inhibits Fab1 (InhA) of FAS-II:
- Fab1 carries out last step in FAS-II cycle
- Fab1 = NADH-dependent-enoyl-ACP reductase
- Fab1 binds inhibitor INH-NAD tightly within a NADH-binding pocket
Resistance mechanisms:
- Mutations of KatG so INH-NAD can’t be formed
- Mutations in NADH binding pocket of Fab1 that reduce binding affinity for INH-NAD
- Mutations that increase expression of Fab1
Name the enzyme that RIF inhibits.
Blocks departure of bacterial RNAP from gene promoters –> prevents RNA exit from polymerase by interacting with large (beta) subunit of bacterial RNAP –> directly blocks path of growing RNA
Human RNAPs do not bind rifampin and are not inhibited.
Describe the potential advantages of rifabutin and rifapentin over RIF
Higher potencies
Longer 1/2 lives
Better membrane permeability (getting inside macrophages more efficiently)
Less active in CYP3A induction (particularly rifabutin) –> better compatibility with other medications (e.g., for HIV and arrhythmia)
Describe effects of rifampin on excreted body fluids
Induces expression of cytochrome P450 members including CYP3a –> increases elimination of other drugs (anticoagulants, HIV protease inhibitors, contraceptives)
So how do you address this? dosage adjustment or a RIF substitute may be needed
Describe the impact of PZA on TB treatment duration (related to Objective 2)
Reduce chemotherapy from 9 mo. to 6 mo.
Mechanism: inhibits trans-translation
But needs to be used in combo with at least two more other drugs to avoid de facto mono therapy!
Describe the rationale for not prescribing EMB to young children.
Blocks EmbA and EmbB arabinosyl transferases that incorporate arabinose into arinogalactan layer –> weakening cell wall and making M. tuberculosis susceptible to damage
Adverse effets: optic neuritis and red-green color blindness
List two principles governing TB treatment in HIV-infected patients.
6-10% TB patients in US = HIV-positive
Use more aggressive regimen (-12 mo. treatment… even for LTBI)
No once weekly treatment for active TB disease
Note: Adverse interaction of RIF with antiretrovirals - so give patients rifabutin as substitute
