Chemotherapy Of Chemotherapy Of Mycobacterial Mycobacterial

InfectionsInfections

Dr.Mohamed daoodDr.Mohamed daoodPhD student in PhD student in PharmacologyPharmacology

TUBERCULOSIS: TUBERCULOSIS: caused by caused by mycobacterium aviummycobacterium avium

Problems in ChemotherapyProblems in Chemotherapy.. --grow more slowly than other bacteriagrow more slowly than other bacteria

--develop resistance rapidlydevelop resistance rapidly

--intracellular pathogensintracellular pathogens

Chemotherapy of T.BChemotherapy of T.B..

"First-line" drugs"First-line" drugs isoniazidisoniazid rifamycinsrifamycins ethambutolethambutol pyrazinamidepyrazinamide

second-linesecond-line

AminoglycosidesAminoglycosides ethionamideethionamideaminosalicylic acidaminosalicylic acid cycloserinecycloserine capreomycincapreomycin fluoroquinolonesfluoroquinolones macrolidesmacrolides

IsoniazidIsoniazid

Mechanism of ActionMechanism of Action

PRODRUG

mycobacterial catalase- peroxidase(KatG)

active metabolite

MYCOLIC ACIDS

Antibacterial ActivityAntibacterial Activity::

-bacteriostatic-bacteriostatic& & -bactericidal -bactericidal

Bacterial ResistanceBacterial Resistance::

PharmacokineticsPharmacokinetics

-Absorption-Absorption-Distribution-Distribution-Metabolism: fast slow-Metabolism: fast slow-excretion-excretion

Adverse ReactionsAdverse Reactions::A.A. immunologicalimmunological -Fever -Fever -skin rashes -skin rashes -Drug-induced systemic lupus -Drug-induced systemic lupus

erythematosus erythematosus

B. direct toxicityB. direct toxicity::

--Isoniazid -induced hepatitisIsoniazid -induced hepatitis

--Peripheral neuropathyPeripheral neuropathy

RifamycinsRifamycins: Rifampin, rifabutin : Rifampin, rifabutin and rifapentineand rifapentine

Mechanism of actionMechanism of action

RNA SYNTHESIS

Rifampin

Rifampin RNA polymerase

Antimicrobial spectrumAntimicrobial spectrumRifampin is bactericidal for both intracellular Rifampin is bactericidal for both intracellular

and extracellular mycobacteria, including and extracellular mycobacteria, including M. tuberculosis, and atypical M. tuberculosis, and atypical mycobacteria, such as M. kansasii. It is mycobacteria, such as M. kansasii. It is effective against many gram-positive and effective against many gram-positive and gram-negative organisms .gram-negative organisms .

ResistanceResistance

PharmacokineticsPharmacokinetics-Absorption-Absorption-Distribution-Distribution-Metabolism -Metabolism enterohepatic cyclingenterohepatic cycling

hepatic mixed-function oxidases, hepatic mixed-function oxidases, (autoinduction).(autoinduction).

Adverse effectsAdverse effects::

-nausea, vomiting, and rash. -nausea, vomiting, and rash. -increased incidence of severe hepatic -increased incidence of severe hepatic

dysfunction when rifampin is administered dysfunction when rifampin is administered alone or concomitantly with isoniazid. alone or concomitantly with isoniazid.

-a flu-like syndrome is associated with fever, -a flu-like syndrome is associated with fever, chills, and myalgias chills, and myalgias

-Drug interactions: Because rifampin can -Drug interactions: Because rifampin can induce a number of cytochrome P450 induce a number of cytochrome P450 enzymes, it can decrease the half-lives of enzymes, it can decrease the half-lives of other drugs that are coadministered and other drugs that are coadministered and metabolized by this system. This may lead metabolized by this system. This may lead to higher dosage requirements for these to higher dosage requirements for these agents.agents.

PyrazinamidePyrazinamide

Mechanism of actionMechanism of action::

Pyrazinamidase

Pyrazinamide

pyrazinoic acid ,

Antimicrobial spectrumAntimicrobial spectrum::

bactericidal to only actively dividing bactericidal to only actively dividing organismsorganisms..

ResistanceResistance

PharmacokineticsPharmacokinetics

-Absorption-Absorption-Distribution-Distribution-Metabolism -Metabolism -excretion-excretion

Adverse effectsAdverse effects::

Urate retention can also occur and may Urate retention can also occur and may precipitate a gouty attack .precipitate a gouty attack .

EthambutolEthambutolMechanism of actionMechanism of actionEthambutol inhibits arabinosyl transferaseEthambutol inhibits arabinosyl transferase

Ethambutol

Ethambutol Arabinosyl -T

Arabinogalactan molecules

Antimicrobial spectrumAntimicrobial spectrum

bacteriostatic and specific for most strains of M. bacteriostatic and specific for most strains of M. tuberculosis and M. kansasii.tuberculosis and M. kansasii.

ResistanceResistance

Resistance is not problem if the drug is Resistance is not problem if the drug is employed with other antitubercular agents.employed with other antitubercular agents.

PharmacokineticsPharmacokinetics

Absorbed on oral administration, ethambutol Absorbed on oral administration, ethambutol is well distributed throughout the body. is well distributed throughout the body. Penetration into the central nervous Penetration into the central nervous system (CNS) is therapeutically adequate system (CNS) is therapeutically adequate in tuberculous meningitis. Both parent in tuberculous meningitis. Both parent drug and metabolites are excreted by drug and metabolites are excreted by glomerular filtration and tubular secretion.glomerular filtration and tubular secretion.

Adverse effectsAdverse effects-optic neuritis-optic neuritis

-urate excretion is decreased by the drug; thus, -urate excretion is decreased by the drug; thus, gout may be exacerbatedgout may be exacerbated

Alternate second-line drugsAlternate second-line drugs

-Streptomycin-Streptomycin: : -Capreomycin-Capreomycin: :

CycloserineCycloserine

Mechanism of actionMechanism of actionantagonize the steps in bacterial cell wall antagonize the steps in bacterial cell wall

synthesis involving D-alanine.synthesis involving D-alanine.

Antimicrobial spectrumAntimicrobial spectrum

- tuberculostatic agent- tuberculostatic agent

PharmacokineticsPharmacokinetics

-orally effective,-orally effective,-It distributes well throughout body fluids, -It distributes well throughout body fluids,

including the CSF. Cycloserine is including the CSF. Cycloserine is metabolized, and both parent and metabolized, and both parent and metabolite are excreted in urine. metabolite are excreted in urine. Accumulation occurs with renal Accumulation occurs with renal insufficiency. insufficiency.

Adverse effectsAdverse effects

involve CNS disturbances, and epileptic involve CNS disturbances, and epileptic seizure activity may be exacerbated. seizure activity may be exacerbated. Peripheral neuropathies are also a Peripheral neuropathies are also a problem, but they respond to pyridoxine.problem, but they respond to pyridoxine.

LeprosyLeprosy; caused by ; caused by Mycobacterium lepraeMycobacterium leprae..

ChemotherapyChemotherapyThe triple-drug regimen of dapsone, The triple-drug regimen of dapsone,

clofazimine, and rifampin for 6 to 24 clofazimine, and rifampin for 6 to 24 months. months.

DapsoneDapsone

Mechanism of Action.Mechanism of Action.Dapsone is structurally related to the Dapsone is structurally related to the

sulfonamides and similarly inhibits sulfonamides and similarly inhibits folate synthesis.folate synthesis.

Antibacterial ActivityAntibacterial Activity

is bacteriostatic for Mycobacterium leprae, is bacteriostatic for Mycobacterium leprae, but resistant strains are encountered.but resistant strains are encountered.

PharmacokineticsPharmacokinetics

The drug is well absorbed from the The drug is well absorbed from the gastrointestinal tract and is distributed gastrointestinal tract and is distributed throughout the body, with high levels throughout the body, with high levels concentrated in the skin. The parent drug concentrated in the skin. The parent drug enters the enterohepatic circulation and enters the enterohepatic circulation and undergoes hepatic acetylation. Both undergoes hepatic acetylation. Both parent drug and metabolites are parent drug and metabolites are eliminated through the urine. eliminated through the urine.

Adverse reactionsAdverse reactions

-hemolysis-hemolysis-methemoglobinemia.-methemoglobinemia.- peripheral neuropathy- peripheral neuropathy

ClofazimineClofazimine

Mechanism of ActionMechanism of Action -binds to DNA and prevents it from serving -binds to DNA and prevents it from serving

as a template for future DNA replication. as a template for future DNA replication. -Its redox properties may lead to the -Its redox properties may lead to the

generation of cytotoxic oxygen radicals generation of cytotoxic oxygen radicals that are also toxic to the bacteria. that are also toxic to the bacteria.

Antibacterial ActivityAntibacterial Activity

Clofazimine is bactericidal to M. lepraeClofazimine is bactericidal to M. leprae

PharmacokineticsPharmacokinetics

Following oral absorption, the drug Following oral absorption, the drug accumulates in tissues, allowing accumulates in tissues, allowing intermittent therapy, but it does not enter intermittent therapy, but it does not enter the CNS.the CNS.

Adverse ReactionsAdverse Reactions

-red-brown discoloration of the skin. -red-brown discoloration of the skin. -enteritis -enteritis

RifampinRifampin