Chemotherapy of Tuberculosis

CHEMOTHERAPY OF TUBERCULOSIS
LEPROSY
PR Nermine Bouchi
Pharmacologie S2 4ème durée :

INTRODUCTION:
 Mycobacteria responsible of 2 “epic” diseases : tuberculosis (TB) leprosy

 Mycobacteria characteristics :
 The cell wall of Mycobacteria is more than 60% lipid , mainly mycolic
acids prevents many agents to arrive to the bacterial cell membane or
inside the cytosol
 Presence of efflux pumps in the cell membrane : native resistance of
mycobacteria to many standard antibiotics
 Bacilly hide inside the patient’s cell (macrophage) extra
physicochemical barrier that antibiotics must cross to be effective
 First line drugs  isoniazid, ethambutol, pyrazinamide, rifampin and
streptomycin
 Second line drugs  rifabutin and rifapentine, FQs drugs (Moxifloxacin),
cycloserine, capreomycin, ethionamide, macrolides (azithromycin), linezolid
and aminosalicylic acid.
 New drugs : bedaquiline , delamanid
Rifamycins
 Rifampin= rifampicin: RIFADIN
 Rifapentine, Rifabutin
 Mechanism of action:
 Bactericidal concentration-dependent, kill intracellular bacteria
 Inhibition of RNA polymerase  prevents the enzyme from binding to DNA 
inhibition of transcription
 Spectrum:
 Mycobacteria: tuberculosis, leprae,
 cocci gram +: S aureus, coagulase negative staph
 Cocci gram -: N. meningitidis, H. influenzae
 Bacilli Gram-: E. coli, pseudomonas, indole , proteus
 Bacilli gram+: clostridium including C. difficile
 Therapeutic uses
 Tuberculosis, leprosy
 Prophylaxis of meningococcal disease and H. influenzae meningitis

Rifamycins
 Resistance:
 Alteration of DNA dependant RNA polymerase
 Occurs rapidly if used alone
 no cross resistance with other antibiotics
 Pharmacokinetics:
 Rifampicin should be taken on an empty stomach
 Rifapentine should be taken with food
 Excellent tissue diffusion: CSF, bones, abscess, bronchial secretions, in CNS

level reaches 5% of those in plasma due to Pglycoprotein
 Intracellular diffusion & concentration
 Rifampin converted by liver to active metabolite = desacetyl-rifampin
 Drugs and metabolites are excreted by bile and eliminated via feces
 Enzyme inducers  induce their own and other drugs metabolism

Rifamycins
 Side effects:
 Well tolerated mostly : rash, fever, nausea, vomiting
 Hepatotoxicity :
 Can impair liver function,  serum bilirubin and transaminase levels
 Hepatitis of rifampin is rare, but occurred when combined to hepatotoxic
drugs as isoniazid
 Liver function tests should be conducted every 2 to 4 weeks during
treatment  D/C if dysfuntion
 Hypersensitivity at high doses :Porphyria, flu like syndrome

 Rifabutuin :pain ,blurred vision  arrest of drug
 All overdoses  reddish -orange to reddish –brown discoloration of
skin, saliva, tears , urine, mucosal surfaces  red man syndrome
Rifamycins
 Therapeutic uses:
 M. tuberculosis
 Rifampin per os alone or in combination with isoniazid
(150mg ISN, 300mg rifampin) or
 (ISN 50mg, 120mg rifampin, 300mg pyrazinamide :
RIFATER
 Dose for tuberculosis is 600mg given once daily
 M. leprae
 Prophylaxis of H. influenza meningitis
PYRAZINAMIDE

 Synthetic
analog of nicotinamide,
 Prodrug, bactericidal kill dormant mycobacteria
 activity only at acidic pH
 Mechanism of action:
 In M. Tuberculosis converted by pyrazinaminidasesto
pyrazinoic acid (POA)  POA transported to extracellular by

efflux pump  in acidic extracellular medium formation of
POAH (a more lipid-soluble form ) POAH enters the
bacillus 
 Inhibition of mycolic acid synthesis
 Reduction of intracellular pH
 Disruption of membrane transport by POAH
PYRAZINAMIDE
 Resistance:
 Mutation  low affinity of Pyrazinaminidases to the prodrug
 Pharmacokinetics:
 oral bioavailability>90%
 Variability : GI fast absorbers (56%) & low absorbers(44%)
 Concentrated 20x in lung epithelial lining fluid
 Excreted in urine
 Side effects:
 Injury liver :most serious
 symptoms of hepatic disease appear in ~15% of patients, with jaundice in 2-3% and death
due to hepatic necrosis : bilan hépatique
 Hyperuricemia: inhibits urate excretion
 Therapeutic uses:
 anti TB: co administration with ISN or rifampin
 Including pyrazinamide in initial treatment regimens made it possible to reduce the treatment
duration from 9-12 months to 6 months
ISONIAZID = ISN
 Nicotinic acid derivatives
 Primary drug, bactericidal to rapidly dividing bacteria
 prodrug
 Short course therapy: ISN + pyrazinamide+ rifampin
 Spectrum: only M. tuberculosis & M. kansasii
 Mechanism of action :
 Enters bacilli by passive diffusion
 Activated to its toxic form within the bacillus by KatG, a multifunctionnal
catalase peroxydase  isonicotynolradical inhibition of mycolic acid

synthesis  bacterial death
 Resistance:
 strains resistant to ISN are selected by monotherapy  never used alone
 alteration of KatG prevents conversion
 KatG mutants : high probability of co-occurrence with ethambutol resistance
 Efflux pumps  cross resistance to INH and ethambutol
Isoniazid = INH
 PK
 Complete oral bioavailability
 Excellent tissue perfusion (including CNS)
 Extensively metabolized  parent & metabolites are excreted in the

urine
 Primary metabolism : acetylation  acetylisoniazid

 variability: "slow" (Middle Eastern populations) and "fast" acetylators
 Other metabolism  CYP2E1  acetylhydrazine (responsible of
hepatic toxicity)
 Inducer of CYP2E1 (rifampicine)  enhances hepatotoxicity
 Potent inhibitor of CYP2C19, CYP3A, and a weak inhibitor of CYP2D6
Isoniazid = INH
14
Isoniazid = INH
 Adverse effects
 Hepatotoxicity
 liver enzymes commonly encountered  normalize with time
 Severe hepatic injury is rare
 Risk linked to several factors: acetylator phenotype (fast acetylators), sex (women), age (>50), daily
alcohol consumption, and concurrent rifampin use
 Most cases of hepatitis occur 4-8 weeks after the start of therapy.
 Peripheral neuritis
 Paresthesiasof feet and hands
 Prevented or treated by administration of pyridoxine (vitB6)
 More frequent in "slow" acetylators and in individuals with diabetes mellitus, poor nutrition,
or anemia
 Miscellaneous : dryness of the mouth, epigastric distress, methemoglobinemia,
tinnitus, and urinary retention
 Rare effects
 Nervous system disorders : dizziness, ataxia, seizures, psychosis, toxic encephalopathy

Ethambutol
 Bacteriostatic against a wide range of mycobacteria
 Inhibits arabinosyl transferase III  disrupts the assembly of
mycobacterial cell wall
 Resistance by mutation of the target & enhanced efflux pump activity
 PK : oral administration, little hepatic biotransformation, and 80%

excreted unchanged in the urine
 Adverse effects
 Visual : dose-dependent optic neuritis   visual acuity & impaired red-
green color discrimination.
 Others: hyperuricemia, gout, rash, fever
Drug resistance
 Multidrug resistance (MDR)
 Resistant to at least isoniazid & rifampicin
 Extensive drug resistance (XDR)

 MDR strains also resistant to any fluoroquinolone & at
least one injectable second-line drugs (amikacin,
capreomycin, kanamycin)
pretomanid
delamanid
sutezolid
bedaquiline
Bedaquiline
 FDA approved 2012
 MAO:
 Inhibits mycobacterial ATP synthetase and depletes cellular
energy stores.
 Indication:
 its mechanism differs from those of other available
antimycobacterial drug →active against some M.

tuberculosis isolates that are resistant to other drugs
 important treatment option for patients with multidrug-
resistant pulmonary tuberculosis (MDR -TB): bacteria
resistant to two of the main TB drugs isoniazid (INH) and
rifampicin (RMP).
 used in combination with at least 3TB drugs
Bedaquiline
 Contra indication :
 Latent infections due to Mycobacterium tuberculosis
 Drug sensitive tuberculosis
 Extrapulmonary tuberculosis
 Infections caused by non tuberculosis mycobacteria.
 Side effects :
 headache, dizziness, feeling sick, being sick,
 joint pain and increases in liver enzymes
 QT prolongation
Delamanid
 EMA approved 2013 for Multidrug-resistant tuberculosis (MDR-TB)
 Pro-drug activated by the enzyme deazaflavin dependent nitroreductase
 Inhibits the synthesis of mycolic acid
 PK:
 Absobtion improved by food
 t½ : 38h after drug discontinuation: post antibiotic effect
 Steady-state concentration is reached after 10-14 days.
 Side effects :
 QT prolongation
 Advantages
 High potent action,
 No drug-drug interactions,
 Better toxicity profile,
 Post antibiotic effect

Chemotherapy of Tuberculosis

Uploaded by

Copyright:

Available Formats

Chemotherapy of Tuberculosis

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Chemotherapy of Tuberculosis

Uploaded by

Copyright:

Available Formats

CHEMOTHERAPY OF TUBERCULOSIS

Pharmacologie S2 4ème durée :

 Mycobacteria responsible of 2 “epic” diseases : tuberculosis (TB) leprosy

 Inhibition of RNA polymerase  prevents the enzyme from binding to DNA 

 cocci gram +: S aureus, coagulase negative staph

 Cocci gram -: N. meningitidis, H. influenzae

 Bacilli Gram-: E. coli, pseudomonas, indole , proteus

 Bacilli gram+: clostridium including C. difficile

 Prophylaxis of meningococcal disease and H. influenzae meningitis

 Occurs rapidly if used alone

 no cross resistance with other antibiotics

 Rifapentine should be taken with food

 Excellent tissue diffusion: CSF, bones, abscess, bronchial secretions, in CNS

 Rifampin converted by liver to active metabolite = desacetyl-rifampin

 Enzyme inducers  induce their own and other drugs metabolism

 Hypersensitivity at high doses :Porphyria, flu like syndrome

pyrazinoic acid (POA)  POA transported to extracellular by

 Activated to its toxic form within the bacillus by KatG, a multifunctionnal

catalase peroxydase  isonicotynolradical inhibition of mycolic acid

 Extensively metabolized  parent & metabolites are excreted in the

 Primary metabolism : acetylation  acetylisoniazid

 Resistance by mutation of the target & enhanced efflux pump activity

 PK : oral administration, little hepatic biotransformation, and 80%

 Extensive drug resistance (XDR)

antimycobacterial drug →active against some M.

 t½ : 38h after drug discontinuation: post antibiotic effect

 Steady-state concentration is reached after 10-14 days.

You might also like

Pfad - The Proxy pFad of © 2024 Garber Painting. All rights reserved.