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5 Antimicobacteria

5 Antimicobacteria

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Published by: Rachel Leslie de Leon on Jun 08, 2011
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05/20/2012

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Lec 5: Antimycobacerial Drugs
by Dr. Frederick Loyola
 July 7, 2010 July 7, 2010
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 and R: 2 most active drugs
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 and can be eradicated only duringreplication
Bacilli live in several sites within the host andeach site contains organisms with a differentpopulation size, metabolic activity and replicationratePrinciples on Treatment
 Treatment of disease must contain multipledrugs to which the organisms are susceptible
Drugs must be taken regularly
Drug therapy must continue for a sufficientlength of time (6 months) to fully eradicate thetubercle bacilli to achieve lasting cureMain Properties of Anti-TB Drugs
Bactericidal Activiy
Streilizing Activity
Ability to prevent or delay emergence of resistance
A.Isoniazid (INH)
Inhibits mycolic acid synthesis (essentialcomponent of mycobacterial cell wall )
bactericidal
Acts on extra- & intra-cellular bacillarypopulations
A prodrug activated by KatG ( mycobacterialcatalase-peroxidase)
Resistance due to:- overexpression of inhA/changed inhAgene: low-level res; cross resistance to ethionamide- mutation or deletion of Cat K gene (codesfor catalase): high-level res; no cross resistance toethionamide- overexpression of ahpC- mutation in kasA
readily absorbed from GIT w/ peak concentrationw/in 1-2 hours; absorption decreased by aluminumhydroxide
oral absorption complete in fasting state; less withfood and antacids
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
Dose not adjusted in renal failure but in hepaticinsufficiency
Increases plasma concentration of Phenytoin &Carbamazepine
Protect drug from light
Adverse effects: allergy, hepatitis (age-dependent),peripheral neuritis (use B6), CNS, tinnitus, GIdiscomfort, hemolysis in G6PD deficiency, SLE in slowacetylators (rare)
B.
Rifampicin (R)
MOA: inhibits RNA synthesis
Inhibits DNA-dependent RNA polymerase; resistance(changed enzyme) emerges rapidly if used alone
Most potent sterilizing drug available
Bactericidal against rapidly dividing and alowlygrowing bacilli
Active against Gram (+) and gram (-) cocci, someenteric bacteria, mycobacteria and chlamydia;bactericidal
Acts on extra- & intra-cellular bacillary populations
Resistance: mutations prevent binding of Rifampin toRNA polymerase
Well-absorbed orally in the fasting state; distributedwidely; highly protein-bound; t1/2=1.5-5 hrs
CSF concentration. achieved in inflammation
Induces hepatic enzymes
Excreted through liver into bile; re-circulated andexcreted in feces and urine
No dose adjustment for renal insufficiency
Protect drug from light
Adverse effects: proteinuria, hepatitis, flu-likesyndrome, induction of P450, thrombocytopenia, red-orange metabolites Therapeutic Uses:
 Tuberculosis: in combination w/ INH etc.
Atypical mycobacterial infections
Leprosy: with sulfone
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  “   G  ”
  R  a  c  h  e  l
   M  a  r  k
  I  v  z
 J  o  b  e
  J  o  c  e  l  l  e
  E   d  o
   G  i  e  n  a  h
 J  h  o
   K  a  t  h
  A  y  n  z
  J  e
   G l  a   d
   N  i  c   k  i  e
  R i  c  o
   T  e  a  c  h  e  r
   D  a   d  a  n  g
   N  i  ň  a
  A  r l  e  n  e
   V  i  v  s
  P  a  u l  F .
  R  i  c  o
  R  e  n
   M  a  i
  R  e  v  s
   M  a  v  i  s
 J  e  p  a  y
   Y  a  n  a
   M  a  y i
  S  e  r  g  e
   H  u  n  g
I. Antimycobacterial AgentsA. IsoniazidB. RifampicinC. PyrazinamideD. EthambutolE. StreptomycinII. Treament Regimen for TB:DOTsIII. Major Side Effects of DrugsIV. Minor Side Effects of DrugsV. Anti-TB Drugs on Pregnancyand LactationVI. Drugs for Non-Tuberculous
 
Meningococcal carriage
H. influenzae type b prophylaxis
Staphylococcal carriage: in combination
Penicillin-resistant pneumococcal meningitis:combine with Ceftriaxone or Vancomycin
C.
Pyrazinamide (Z)
MOA: unknown, but metabolically activated-bacterialstrains lacking bioactivating enzymes are resistant
Relative of nicotinamide
Exerts activity against intracellular organisms inacidic environment; weakly bactericidal, ”sterilizingagent”
Resistance due to mutations in pncA that impairconversion of pyrazinamide to its active form
No cross resistance w/ INH or otherantimycobacterials
Readily absorbed from GIT; distributed to all fluidsand tissues
Inactive at neutral pH
Serum conc. at 1-2 hrs. after oral intake
t1/2= 8-11 hrs
Protect drug from light
Adverse effects
: polyarthralgia-myalgia, hepatitis,rash, hyperuricemia, phototoxicity, increase porphyrinsynthesis
D.
Ethambutol (E)
MOA: inhibitor of mycobacterial arabinosyltransferases
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
Well-absorbed in GIT; conc. reached in 2-4 hours
Not affected by food but delayed by aluminumhydroxide and alcohol
t1/2=3-4 hrs
Resistance due to mutations of emb gene; resistancerapid when given alone
Accumulates in renal failure: dose reduced to half 
Excretion: feces, urine
Dose-dependent retrobulbar neuritis decreasevisual acuity
Not to be given in children below 6 years because of unreliable monitoring of visual acuity
E.Streptomycin (S)
MOA: irreversible inhibitor of protein synthesis bybinding to 30s subunit;
Resistance & features of aminoglycoside
Bactericidal to actively multiplying extracellularbacilli in alkaline medium and in caseous ;ining of thewalls of pulmonary cavitations
Poor penetration into cells; active against extra-cellular tubercle bacilli
Serum conc. achieved 30-60 min. after IM
Not absorbed in the GIT
Do not give together with other nephrotoxic orototoxic drugs
Monitor renal function & reduce dose to 50% if withdecrease urine output
Direct Observed Therapy Short-Course (DOTS)
Political commitment
Case detection by sputum smear microscopy
Standardized short course therapy with directobservation of drug intake
Regular uninterrupted supply of all essentialanti-TB drugs
Standardized recording and reporting system TREATMENT REGIMEN FOR TBREGIMENPATIENTDOSE ADJ.(kg)
RegimenI
2HRZE/4HRNew smear (+)New smear (-)w/ extensiveparenchymalinvolvementNew extra-pulmonary1 tab INH(100 mg)+ PZA(500 mg)+ Etham(400 mg)for > 50 kgbody wtbeforetreatment
RegimenII
2 HRZES/1HREZ/5HREPreviouslytreated smear(+) PTB w/relapse,treatmentfailure,treatment afterinterruption
RegimenIII
2HRZ/4HRNew Smear (-)PTB other thanCat 1Extra-pulmonary TBless severely ill1 tab of INH(100 mg)+ PZA(500 mg)each for>50 kgbody wtbeforetreatmentMAJOR SIDE-EFFECTS OF DRUGS
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    N  i  n  a
 I  a  n
 
MINOR SIDE-EFFECTS OF DRUGSAnti-TB Drugs on Pregnancy and Lactation
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 & cycloserinenot recommended
PZA avoided; inadequate data on teratogenicity
Breastfeeding not discouraged; feed infants firstbefore taking meds
Drugs in breast milk not considered effectivetreatment of tuberculosis in infantsDrugs for Non-Tuberculous Mycobacteria
M. avium-intracellulare
(MAC)
Pulmonary diseases in patients with chroniclung disease, disseminated infections in AIDS
Prophylaxis: Azithromycin or Clarithromycin
 Treatment: Clarithromycin or Azithromycin +Ethambutol +/- Rifabutin or Ciprofloxacin
M. kansasii
Resembles tuberculosis
Rifamicin, Ethambutol, Isoniazid(±)
Anti-Mycobacterials (Anti-Leprosy)
Dapsone & other sulfones (anti-folate)
bacteriostatic
Resistance if very low doses are given; combinationrecommended 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 leprosumRifampin :
effective in lepromatous leprosy
bactericidal for M. lepraeClofazimine: 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 multiple myelomaRecommended Treatment for Leprosy
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