Post on 07-Apr-2018
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ANTIMYCOBACTERIAL DRUGS
Frederick C. Loyola, M.D.
Department of Pharmacology
Therapeutics & Toxicology
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ANTI-MYCOBACTERIALS
(ANTI-TB)First line agents:
- Isoniazid (H)
- Rifampin (R)- Pyrazinamide (Z)
- Ethambutol (E)
- Streptomycin (S)
Second line agents: Amikacin; Aminosalicylic acid;Capreomycin; Ciprofloxacin; Moxifloxacin; Cycloserine;
Ethionamide; Kanamycin; Levofloxacin
H & R: 2 most active drugs
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CHARACTERISTICS OF
MYCOBACTERIUM TUBERCULOSIS
Naturally occurring drug resistant mutants arepresent within large bacterial populations evenbefore chemotherapy is started
Replicates slowly, can remain dormant forprolonged periods & can be eradicated onlyduring replication
Bacilli live in several sites within the host & each
site contains organisms with a differentpopulation size, metabolic activity & replicationrate
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PRINCIPLES ON TREATMENT
Treatment of disease must contain
multiple drugs to which the organisms are
susceptible
Drugs must be taken regularly
Drug therapy must continue for a sufficient
length of time
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Isoniazid (INH)
Inhibits mycolic acid synthesis. (bactericidal)
Acts on extra- & intra-cellular bacillary
populations A prodrug activated by KatG ( mycobacterialcatalase-peroxidase)
High level resistance- deletion of Cat K gene
(codes for catalase); low level (changed inhAgene).
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ISONIAZID Readily absorbed from GIT w/ peak concentration
w/in 1-2 hours; absorption decreased by aluminumhydroxide
Diffuses into all body fluids and tissues
Metabolism genetically determined : fast acetylators
(t1/2= 1 hr); slow acetylators (t1/2= 3 hrs) Excreted in urine but dose not adjusted in renal
failure but in hepatic insufficiency
Increases plasma conc.of phenytoin &
carbamazepine Adverse effects: hepatitis (age-dependent),peripheral neuritis (use B6), hemolysis in G6PDdeficiency, SLE in slow acetylators (rare)
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Rifampin
Inhibits DNA dependent RNA polymerase;
resistance (changed enzyme) emerges
rapidly if used alone Acts on extra- & intra-cellular bacillary
populations
Adverse effects: proteinuria, hepatitis, flu-
like syndrome, induction of P450,
thrombocytopenia, red-orange metabolites
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USES OF RIFAMPIN
Tuberculosis: in combination w/ INH etc.
Atypical mycobacterial infections
Leprosy: with sulfone
Meningococcal carriage
H. influenzae type b prophylaxis
Staphylococcal carriage: in combination
Penicillin-resistant pneumococcal meningitis:
combine with Ceftriaxone or Vancomycin
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Pyrazinamide
Mechanism unknown, but metabolicallyactivated-bacterial strains lacking bioactivatingenzymes are resistant
Relative of nicotinamide
Exerts activity against intracellular organisms inacidic environment; weakly bactericidal,sterilizing agent
No cross resistance
Adverse effects:polyarthralgia-myalgia, hepatitis, rash,hyperuricemia, phototoxicity, increase porphyrinsynthesis.
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Ethambutol
Blocks formation of Arabinoglycan, an essentialcomponent of mycobacterial cell wall by inhibitingArabinosyl transferases
Bacteriostatic but with some bactericidal action athigher doses
Acts on extra- & intra- cellular bacillary population Resistance due to mutations of emb gene;
resistance rapid when given alone
Accumulates in renal failure: dose reduced to half
Dose-dependent retrobulbar neuritis decreasevisual acuity. Not to be given in children below 6years because of unreliable monitoring of visualacuity
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STREPTOMYCIN
MOA: irreversible inhibitor of protein synthesis;
Resistance & features of aminoglycoside
Poor penetration into cells; active against extra-
cellular tubercle bacilli
Serum con. achieved 30-60 min. after IM
Do not give together with other nephrotoxic or
ototoxic drugs Monitor renal function & reduce dose to 50% if
with decrease urine output
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DIRECT OBSERVED THERAPY
SHORT-COURSE (D
OTS) Political commitment
Case detection by sputum smear
microscopy Standardized short course therapy with
direct observation of drug intake
Regular uninterrupted supply of allessential anti-TB drugs
Standardized recording and reporting
system
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TREATMENT REGIMEN FOR TB
Regimen Patient Dose adj. (kg)
Regimen I
2HRZE/ 4HR
New smear (+)
New smear (-) w/
extensive parenchymal
involvementNew extra-pulmonary
Add 1 tab INH (100
mg), PZA (500 mg),
Etham (400 mg) for
> 50 kg body wtbefore treatment
Regimen II
2 HRZES/
1HREZ/ 5HRE
Previously treated
smear (+) PTB w/
relapse, treatment
failure, treatment afterinterruption
Regimen III
2HRZ/ 4HR
New Smear (-) PTB
other than Cat 1
Extra-pulmonary TB
less severely ill
Add one tab of INH
(100 mg), PZA (500
mg) each for >50 kg
before treatment
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MAJOR SIDE-EFFECTS OF DRUGS
SIDE EFFECTS DRUG (S) WHAT TO DO?Severe skin rash from
hypersensitivity
Any drug esp Strep. Discontinue drug & refer to
MHO/CHO
Jaundice 2ry to hepatitis Any drug esp. INH,
Rifam. & PZA
Discontinue drugs & refer to
MHO/CHO
If Sx subside, resume Rx &
monitor clinicallyImpairment of visual acuity
& color vision due to optic
neuritis
Ethambutol Discontinue drug
Refer to ophthalmologist
Hearing impairment, ringing
of the ear & dizziness due
to damage of CN VIII
Streptomycin Discontinue & refer to
MHO/CHO
Oliguria or albuminuria due
to renal disorder
Streptomycin
Rifampicin
Psychosis & convulsion Isoniazid
Thrombocytopenia, anemia,
shock
Rifampicin
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MINOR SIDE-EFFECTS OF DRUGS
SIDE EFFECTS DRUG (S) WHAT TODO?
Gastrointestinal intolerance Rifampicin Give meds at bedtime
Mild skin reactions Any drug Give anti-histamines
Orange-red colored urine Rifampicin Reassure patient
Pain at injection site Streptomycin Apply warm compress
Rotate sites of
injection
Burning sensation in the feetfrom peripheral neuropathy
Isoniazid Give Pyridoxine 100-200 mg daily for Rx; 10
mg daily for prevention
Arthralgia due to
hyperuricemia
Pyrazinamide Give aspirin or NSAID
Flu-like symptoms Rifampicin Give antipyretics
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ANTI-TB DRUGS ON
PREGNANCY AN
DLACTATION
INH, rifampin & ethambutol cross placenta; standarddrugs given to pregnant women
PAS can be safely used but could be poorly tolerated
Streptomycin & other aminoglycosides should beavoided; effect on ear development & function
Capreomycin, ethiomide, quinolones & cycloserine notrecommended
PZA avoided; inadequate data on teratogenicity
Breastfeeding not discouraged; feed infants first beforetaking meds
Drugs in breast milk not considered effective treatmentof tuberculosis in infants
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M. avium-intracellulare (MAC)
Prophylaxis: Azithromycin or Clarithromycin
Treatment: Clarithromycin or Azithromycin +
Ethambutol +/- Rifabutin or Ciprofloxacin
M. kansasii
Rifamicin, Ethambutol, Isoniazid( )
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ANTI-MYCOBACTERIALS(ANTI-LEPROSY)
Dapsone & other sulfones (anti-folate);bacteriostatic
Resistance if very low doses are given;
combination recommended for initial therapy t1/2= 1-2 days; tends to be retained in skin,
muscle, liver, kidney
Dose adjusted in renal failure
ADR: hemolysis if w/ G6PD deficiency;methemoglobinemia;GI intolerance; fever;pruritus; erythema nodosum leprosum
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ANTI-LEPROSY
Rifampin : effective in lepromatous leprosy
Clofazimine: unknown MOA (DNA binding)
- stored in reticuloendothelial tissue &
skin; slow release; t1/2= 2 months- for sulfone-resistant leprosy
- ADR: skin discoloration (red-brown to black)
Prednisone
Thalidomide- inhibits angiogenesis; anti-inflammatory; immunomodulatory; for multiplemyeloma
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MARAMING SALAMAT PO!
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ISONIAZID
MOA: Inhibits mycolic acid synthesis (essentialcomponent of mycobacterial cell wall); bactericidal
A prodrug activated by KatG ( mycobacterial catalase-peroxidase)
Acts on extra- & intra-cellular bacillary populations Resistance due to:
- overexpression of inhA: low-level res; cross
resistance to ethionamide
- mutation or deletion of katG: high-level res
no cross resistance to ethionamide- overexpression of ahpC
- mutation in kasA
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RIFAMPICIN
Active against gram (+) and gram (-) cocci, some enteric bacteria,mycobacteria and chlamydia; bactericidal
MOA: inhibits RNA synthesis
Acts on extra- & intra-cellular bacillary populations
Resistance: mutations prevent binding of rifampin to RNA
polymerase Well-absorbed orally in the fasting state; distributed widely; highly
protein-bound; t1/2=1.5-5 hrs.
CSF conc. achieved in inflammation
Induces hepatic enzymes
Excreted through liver into bile; re-circulated and excreted in feces
and urine No dose adjustment for renal insufficiency
Protect drug from light
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ETHAMBUTOL
MOA: inhibitor of mycobacterial arabinosyl transferases
Bacteriostatic but with some bactericidal action at higherdoses
Acts on extra- & intra- cellular bacillary population
Resistance due to mutations of emb gene; resistancerapid when given alone
Well-absorbed in GIT; conc. reached in 2-4 hours
t1/2= 3-4 hours
Excretion: feces & urine
Accumulates in renal failure: dose reduced to half Not to be given in children below 6 years because of
unreliable monitoring of visual acuity
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RECOMMENDED TREATMENT
FOR LEPROSY
Indeterminate- smear (-), flat hyposthetic lesionusually in face, arms, legs
- single dose Rif + Oflo + Minocycline
Paucibacillary- smear (-), flat hyposthetic,hyperpigmented lesions no more than 5
- Rif once a month + Dapsone OD x 6 mos.
Multibacillary- smear (+) which are multiple,erythematous, copper-colored plaques, nodulesw/ or w/o anesthesia
- Rifam + Dapsone + Clofazimine once a
month x 12 months