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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