Use LEFT and RIGHT arrow keys to navigate between flashcards;
Use UP and DOWN arrow keys to flip the card;
H to show hint;
A reads text to speech;
21 Cards in this Set
- Front
- Back
Treatment of TB
|
initial therapy be given with four drugs; isoniazid, rifampin (or other rifamycin), pyrazinamide and ethambutol (not recommended for children where visual acuity cannot be monitored) or streptomycin.
|
|
First line TB abx
|
isoniazid (INH; generic)
rifampin (rifadin) pyrazinamide (generic) ethambutol (myambutol) streptomycin (generic) |
|
Second line TB abx
|
Ethionamide, kanamycin, capreomycin, p-aminosalicylic
acid, cycloserine, linezolid, fluoroquinolones The PRIMARY reason for the use of drug combinations in the treatment of TB is to delay the emergency of resistance to INDIVIDUAL drugs |
|
ISONIAZID
|
Acts only upon M, and is the most active drug available for the treatment of TB caused by M susceptible strains; less effective for the treatment of diseases caused by atypical M species.
Small molecule, structurally similar to pyridoxine Prodrug. After activation (by mycobacterial catalase-peroxidase KatG), has lethal effect by forming a covalent complex with an acyl carrier protein (AcpM) and a beta-ketoacyl carrier protein synthetase (KasA), blocking mycolic acid synthesis killing the cell |
|
Resistance to isoniazid
|
1. Over-expression of inhA gene encoding an NADH-dependent
acyl carrier protein reductase 2. Mutation or deletion of the katG gene 3. Promoter mutations resulting in over-expression of ahpC, a putative virulence gene involved in cell protection from oxidative stress. 4. Mutations in kasA A. inhA overproducers express low level resistance to INH and cross resistance to ethionamide. B. KatG mutants express high-level INH resistance and often are not cross-resistant to ethionamide. |
|
Rifampin
|
Semisynthetic analog of the antibiotic rifamycin, present cross- resistance to other rifamycin derived drugs e.g., rifabutin, but
not to other classes of antibiotics. Effective against various bacteria, including bactericidal activity against Mycobacteria. Binds to the beta subunit of bacterial DNA-dependent RNA polymerase, inhibiting RNA synthesis. Resistance results from one of several point mutations in rpoB, the gene for the beta subunit of RNA polymerase, resulting in reduced rifampin binding to RNA polymerase. |
|
SE of rifampin
|
Rifampin give the urine, feces, saliva, sweat, tears, and contact lenses a harmless red orange color, producing patients anxiety. SE include light-chain proteinuria, and occasionally rash, nephritis, jaundice, and hepatitis. Intermittent administration, > 2w, causes a flu-like syndrome e.g., fever, myalgias, thrombocytopenia
Strongly induces most cytochrome P450 isoforms increasing the elimination rate, thus lowering serum levels, of numerous drugs e.g., methadone, oral anticoagulants, some anticonvulsants, etc |
|
ETHAMBUTOL
|
Bacteriostatic agent. Inhibits mycobacterial arabinosyl
tranferases enzymes, encoded by the embCAB operon, which are involved in the polymerization reaction of arabinoglycan, an essential component of the mycobacterial cell. Resistance due to mutations resulting in over expression of emb gene products or within the embB structural gene. Well absorbed from the GI, peak plama levels reached within 2 hrs, excreted in feces and urine. It accumulates in renal failure, reaches CSF only if menigeal inflammation |
|
SE and resistance to ethambutol
|
Rapid resistance emergency occurs if used alone. Given as single daily dose combined with INH or rifampin. Effective against most M TB strains. Sensitivity of other M variable. Most common serious side effect is dose-related retrobulbar
neuritis resulting in loss of visual acuity and red-green color blindness. It disappears after drug discontinuation. Hypersensitivity reaction to this drug is rare. Relatively contraindicated in children too young to permit assessment of visual acuity and red-green color discrimination |
|
PYRAZINAMIDE
|
Synthetic analog of nicotinamide. Converted to pyrazinoic acid, active form of the drug, by mycobacterial pyrazinamidase,
which is encoded by pncA. PZA target and MA of action unknown. Resistance may occur due to mutations in pncA, blocking drug conversion to its active form, or by decreased drug uptake which develops rapidly. Well absorbed from GI, widely distributed including inflamed meninges and macrophages. Peak serum levels reached within 1-2 hrs and t1/2 ~ 10 hrs |
|
SE and resistance to PYRAZINAMIDE
|
Major adverse effects include hepatotoxicity (1-5%
patients), GI disturbances and hyperuricemia, which occurs in most patients; this is not a reason to stop therapy unless patients suffers acute gout attack. Used together with INH and rifampin in short course regimes (i.g., 6 months) as a “sterilizing” agent to prevent relapse. TB bacilli rapidly develops resistance to pyrazinamide, however there is no cross-resistance between this drug and other anti-TB agents |
|
STREPTOMYCIN
|
Unknown MA against M TB. Effective treatment of M
tuberculosis, M avium complex and M kansaii; other M species are resistant to this drug Poor penetration into cells and is effective mainly against extracellular tubercle bacilli. Used when injectable (IV or IM) therapy is recommended e.g., TB meningitis (crosses the BBB achieving therapeutic levels with inflamed meninges) and disseminated infection, or when TB is resistant to other drugs. Inhibits most tubercle bacilli, however all large populations contain some streptomycin-resistant mutants (~ 1 in 100 million bacilli). |
|
SE and adverse rxns of STREPTOMYCIN
|
Resistant due to a point mutation in either the rpsL gene,
encoding the S12 ribosomal protein gene, or the rrs gene, encoding the 16S ribosomal rRNA, thus altering the ribosomal binding site. Dose-related oto- and nephrotoxicity limits its use; most common side effects, vertigo and hearing loss, may become permanent. Risk increasing in the elderly and in patients with impaired renal function. Always given in a multidrug regime to prevent emergency of resistance. Treatment continue for several months and dosage should be adjusted during the course of therapy |
|
Therapy guidelines for 2nd line TB abx
|
These agents are considered only if: Resistance occurs to first-line drugs. Failure o f recommended conventional therapy. Adverse effects limiting conventional therapy
Ability to deal with these drugs toxicity. The dosage, resistance emergency, and long-term toxicity of many of these drugs are not yet well established |
|
2nd line TB abx
|
Ethionamide: Inhibits mycolic acid synthesis. SE: GI
irritation, neurophaties and liver toxicity Capreomycin: Protein synthesis inhibitor, given IM for the treatment of drug-resistant TB. SE: oto- and nephrotoxic Cycloserine: Inhibits cell wall synthesis. SE: peripheral neuropathies and CNS depression and psychotic reactions |
|
Aminosalicylic acid (PAS). Folate synthesis antagonist.
|
Kanamycin, amikacin. Fluoroquinolones: ciprofloxacin,
levofloxacin and others. Linezolid. These drugs have some use, in combination with other agents, in multidrug resistance M tuberculosis |
|
ATYPICAL MYCOBACTERIA. DRUG TREATMENT
|
Approximately 10% of Mycobacterial infections seen in the USA are not due to M tuberculosis or M tuberculosis complex organisms, but to the so-called “atypical” mycobacteria: M
kansaii, marinum, avium complex, etc. These organisms, with specific lab characteristics and present in the environment, are not communicable from person to person. In general, these M species are less responsive than M tuberculosis to anti-TB drugs; however, they may respond to agents not activea gainst M tuberculosis e.g., erythromycin and sulfonamides |
|
TB treatment in late stage AIDS
|
Recommended treatment includes
azithromycin plus ethambutol and ciprofloxacin |
|
Abx Rx for leprosy
|
initial therapy combines dapsone with rifampin and clofazimine
|
|
Clofazimine
|
Clofazimine, an alternative to dapsone, has an erratic absorption
rate, is stored in skin and reticuloendothelial tissues from were is slowly released; t1/2 ~2 months Used in sulfone-resistant leprosy or for sulfone intolerant patients. Prominent SE, skin discoloration from red brown to nearly black |
|
Drugs used to treat atypical Mycobacteria infections:
|
Erythromycin, Azythromycin, Ciprofloxacin
|