TREATMENT OF T.B. A special problem within the field of chemotherapy. A special problem within the field of chemotherapy

TREATMENT OF T.B.TREATMENT OF T.B.

A special problem within the field of A special problem within the field of chemotherapy.chemotherapy.


Treatment is often complex and Treatment is often complex and protracted.protracted.

Host immune defenses are often Host immune defenses are often variable and inadequate.variable and inadequate.


Chemotherapy is probably the Chemotherapy is probably the keystone in the management of T.B.keystone in the management of T.B.

Ancillary treatments are used only in Ancillary treatments are used only in special circumstances. special circumstances.


Divided into chemoprophylaxis and Divided into chemoprophylaxis and treatment of active disease.treatment of active disease.

Careful diagnostic studies must Careful diagnostic studies must always precede therapy.always precede therapy.

CHEMOPROPHYLAXISCHEMOPROPHYLAXIS

To prevent clinically active disease in To prevent clinically active disease in people already infected.people already infected.

Given only to those who will derive Given only to those who will derive the greatest benefit and the least the greatest benefit and the least risk.risk.

CHEMOPROPHYLAXISCHEMOPROPHYLAXIS

300 mg Isoniazid once 300 mg Isoniazid once daily for 6-12 months.daily for 6-12 months.

TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.

First line drugs (used in the initial First line drugs (used in the initial treatment of T.B.) : isoniazid, treatment of T.B.) : isoniazid, rifampin, streptomycin, ethambutol rifampin, streptomycin, ethambutol and pyrazinamide.and pyrazinamide.


Secondary agents: PAS, Secondary agents: PAS, ethionamide, amikacin, ethionamide, amikacin, kanamycin, capreomycin, kanamycin, capreomycin, cycloserine, ciprofloxacin, cycloserine, ciprofloxacin, levofloxacin and clofazimine.levofloxacin and clofazimine.


Therapy requires at least two Therapy requires at least two effective drugs concurrently.effective drugs concurrently.


If the treatment is appropriate If the treatment is appropriate improvement is usually seen within improvement is usually seen within 2 weeks.2 weeks.

Continue treatment for at least 3-6 Continue treatment for at least 3-6 mths after the sputum becomes mths after the sputum becomes negative.negative.


Never use 1 drug and never add Never use 1 drug and never add a single drug to a failing a single drug to a failing regimen. regimen.

TREATMENT OF ACTIVE T.B.TREATMENT OF ACTIVE T.B.

Minimum length of therapy is Minimum length of therapy is 6-9 months.6-9 months.


Initiation phase of 2 months.Initiation phase of 2 months.

Continuation phase of 4-7 months.Continuation phase of 4-7 months.


Initial therapy is a 4 drug regimen of INH, Initial therapy is a 4 drug regimen of INH, rifampin, pyrazinamide and ethambutol.rifampin, pyrazinamide and ethambutol.

For patients with drug-susceptible For patients with drug-susceptible disease the pyrazinamide can be disease the pyrazinamide can be discontinued after 2 months.discontinued after 2 months.

Ethambutol can also be discontinued.Ethambutol can also be discontinued.


Combining daily therapy with Combining daily therapy with intermittent therapy.intermittent therapy.

INTERMITTENT THERAPYINTERMITTENT THERAPY

Daily therapy for 2 weeks (INH, Daily therapy for 2 weeks (INH, rifampin, pyrazinamide and rifampin, pyrazinamide and streptomycin) followed by therapy 2 streptomycin) followed by therapy 2 times a week for six weeks. Then times a week for six weeks. Then INH + Rifampin 2x weekly for 16 INH + Rifampin 2x weekly for 16 weeks.weeks.

DOTDOT

DRUG RESISTANCEDRUG RESISTANCE

Major cause is inadequate therapy. Major cause is inadequate therapy.

Treatment is difficult and requires Treatment is difficult and requires good laboratory support and good laboratory support and experience with the less frequently experience with the less frequently used drugs.used drugs.

MULTIPLE DRUG MULTIPLE DRUG RESISTANT T.B.RESISTANT T.B.

Combined resistance to at least INH Combined resistance to at least INH and rifampin.and rifampin.

Caused by improper treatment, Caused by improper treatment, inadequate drug supplies, or poor inadequate drug supplies, or poor patient supervision.patient supervision.


Patients face chronic disability and Patients face chronic disability and death and represent an infectious death and represent an infectious hazard for the community. hazard for the community.


High cure rates have been obtained High cure rates have been obtained but require prompt recognition, rapid but require prompt recognition, rapid and accurate susceptibility results and accurate susceptibility results and early administration of an and early administration of an individualized retreatment regimen.individualized retreatment regimen.


Regimens are usually based on a Regimens are usually based on a quinolone and an injectable agent quinolone and an injectable agent (e.g.aminoglycoside) supplemented (e.g.aminoglycoside) supplemented with other second line drugs.with other second line drugs.

TREATMENT OF HIV-TREATMENT OF HIV-RELATED TBRELATED TB

Possibility of increased drug toxicity Possibility of increased drug toxicity and possible drug-drug interactions and possible drug-drug interactions (rifamycins plus PI and/or NNRI).(rifamycins plus PI and/or NNRI).

NONTUBERCULOUSNONTUBERCULOUSMYCOBACTERIAMYCOBACTERIA

Atypical mycobacterial infections.Atypical mycobacterial infections.

Resistant to many of the commonly Resistant to many of the commonly used drugs.used drugs.

Examine for sensitivity and treat on Examine for sensitivity and treat on this basis.this basis.

Increased in AIDS (e.g. MAC).Increased in AIDS (e.g. MAC).

MECHANISM OF ACTION OF MECHANISM OF ACTION OF ANTITUBERCULOSIS AGENTSANTITUBERCULOSIS AGENTS

Drugs which interfere with mycolic Drugs which interfere with mycolic acid synthesisacid synthesis

Drugs which inhibit nucleic acid Drugs which inhibit nucleic acid synthesis synthesis

Drugs inhibiting protein synthesisDrugs inhibiting protein synthesis

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ETHETH

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PeptidoglycanPeptidoglycan

PorinPorin

ArabinogalactanArabinogalactan

Mycolic AcidMycolic Acid

Lipid of intermediate lengthLipid of intermediate lengthLipid with C14-C18 acidsLipid with C14-C18 acids

MYCOBACTERIAL CELL WALLMYCOBACTERIAL CELL WALL

ISONIAZID-MECHANISM OF ISONIAZID-MECHANISM OF ACTIONACTION

Interferes with biosynthesis of cell Interferes with biosynthesis of cell wall mycolic acids.wall mycolic acids.

Mycolate depleted cell walls are Mycolate depleted cell walls are structurally weak.structurally weak.

Isoniazid Isoniazid (Prodrug)(Prodrug)

Active Active FormForm

Catalase/PeroxidaseCatalase/Peroxidase

katGkatG

INH MECHANISM OF ACTIONINH MECHANISM OF ACTION

InhA gene encodes an enoyl-ACP InhA gene encodes an enoyl-ACP reductase of fatty acid synthase II reductase of fatty acid synthase II which converts which converts 22 -unsaturated to -unsaturated to saturated fatty acids on the pathway saturated fatty acids on the pathway to mycolic acid biosynthesis.to mycolic acid biosynthesis.

Activated INH inhibits this enzyme.Activated INH inhibits this enzyme.


PorinPorin




Mycobacterial Cell WallMycobacterial Cell Wall

INHINH

RESISTANCERESISTANCE

Mutations in theMutations in the katG katG gene can lead gene can lead to loss of catalase-peroxidase to loss of catalase-peroxidase activity.activity.

Resistance also maps to mutations Resistance also maps to mutations in four other genes including in four other genes including inhAinhA


Overall incidence of resistance is Overall incidence of resistance is higher in certain ethnic groups such higher in certain ethnic groups such as African Americans, Mexican as African Americans, Mexican Americans and Indochinese Americans and Indochinese refugees.refugees.

ETHAMBUTOL-MECHANISM ETHAMBUTOL-MECHANISM OF ACTIONOF ACTION

It is not bactericidal.It is not bactericidal.

Inhibits synthesis of the Inhibits synthesis of the mycobacterial cell wall. mycobacterial cell wall.

MECHANISM OF ACTIONMECHANISM OF ACTION

It is an inhibitor of mycobacterial It is an inhibitor of mycobacterial arabinosyl transferases (encoded by arabinosyl transferases (encoded by the embAB genes).the embAB genes).

Arabinoglycan an essential Arabinoglycan an essential component of the cell wall.component of the cell wall.


PorinPorin




MYCOBACTERIAL CELL WALLMYCOBACTERIAL CELL WALL

EthambutolEthambutol


Mutations in the emb genes.Mutations in the emb genes.

PYRAZINAMIDE-MECHANISM PYRAZINAMIDE-MECHANISM OF ACTIONOF ACTION

PZAPZA POA (pyrazinoic POA (pyrazinoic acid)acid)pyrazinamidasepyrazinamidase

Occurs mostly in the liver.Occurs mostly in the liver.

MECHANISM OF ACTIONMECHANISM OF ACTION

Inhibits fatty acid synthetase I of Inhibits fatty acid synthetase I of Mycobacterium tuberculosis.Mycobacterium tuberculosis.

Short chain fatty acid precursorsShort chain fatty acid precursors

PyrazinamidePyrazinamide


Mutations in the pncA gene which Mutations in the pncA gene which results in impairment in the results in impairment in the conversion of PZA to its active form. conversion of PZA to its active form.

DRUGS INHIBITING NUCLEIC DRUGS INHIBITING NUCLEIC ACID SYNTHESISACID SYNTHESIS

RifampinRifampin

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ETHETH





Results from an alteration in the Results from an alteration in the polymerase enzyme (mutation in the polymerase enzyme (mutation in the rpoB gene).rpoB gene).

STREPTOMYCIN-ANTI TB STREPTOMYCIN-ANTI TB ACTIVITYACTIVITY

Most strains of Most strains of M.TuberculosisM.Tuberculosis are are sensitive.sensitive.

Bactericidal only against the Bactericidal only against the extracellular tuberculosis bacilli.extracellular tuberculosis bacilli.

Overall only suppressive.Overall only suppressive.


Major problem with streptomycin use Major problem with streptomycin use in T.B. in T.B.

Combination therapy will delay or Combination therapy will delay or prevent resistance.prevent resistance.

THERAPEUTIC USES IN T.B.THERAPEUTIC USES IN T.B.

It is used in drug resistant disease.It is used in drug resistant disease.

More serious forms of T.B. More serious forms of T.B. (disseminated T.B. or meningitis).(disseminated T.B. or meningitis).

NN

CCNHNH22

oo

CCNHNH22

ooNN

ISONIAZIDISONIAZID

NICOTINAMIDENICOTINAMIDENN

CCOHOHoo

NICOTINICNICOTINICACIDACID

ooCCNHNHNHNH22

ANTITUBERCULAR ANTITUBERCULAR ACTIVITYACTIVITY

Bactericidal vs actively growing Bactericidal vs actively growing tubercle bacilli .tubercle bacilli .

Also bactericidal vs intracellular Also bactericidal vs intracellular bacteria.bacteria.

Poor activity against atypical Poor activity against atypical organisms.organisms.

ABSORPTION AND ABSORPTION AND DISTRIBUTIONDISTRIBUTION

Readily absorbed when given orally Readily absorbed when given orally or parenterally (food and Alor parenterally (food and Al+++ +++

decrease absorption).decrease absorption).

INH diffuses well into all body fluids INH diffuses well into all body fluids and cells including the CNS.and cells including the CNS.

DISTRIBUTIONDISTRIBUTION

Penetrates cells with ease and is Penetrates cells with ease and is effective against organisms growing effective against organisms growing within cells. within cells.

METABOLISMMETABOLISM

Primary route is by acetylation.Primary route is by acetylation.

Genetic heterogeneity with regard to the Genetic heterogeneity with regard to the rate of acetylation. There are “slow” and rate of acetylation. There are “slow” and “rapid” acetylators.“rapid” acetylators.

Among American and northern European Among American and northern European pops. 50-65% are slow acetylators.pops. 50-65% are slow acetylators.


More rapid clearance of INH by rapid More rapid clearance of INH by rapid acetylators is of no therapeutic acetylators is of no therapeutic consequence when given daily.consequence when given daily.

Subtherapeutic concn’s may occur if Subtherapeutic concn’s may occur if INH is given to rapid acetylators as a INH is given to rapid acetylators as a once-weekly dose.once-weekly dose.


Slow acetylators may be more Slow acetylators may be more susceptible to toxic side effects susceptible to toxic side effects related to higher blood levels of INH related to higher blood levels of INH whereas rapid acetylators have a whereas rapid acetylators have a higher frequency of hepatotoxicity.higher frequency of hepatotoxicity.

IsoniazidIsoniazid Peripheral NeuropathyPeripheral NeuropathyAcute SeizuresAcute Seizures

HydrazineHydrazineAcetyl INHAcetyl INH

Isonicotinic AcidIsonicotinic Acid

Acetyl HydrazineAcetyl Hydrazine

Diacetyl HydrazineDiacetyl Hydrazine (nontoxic)(nontoxic)

Reactive MetaboliteReactive Metabolite

Hepatic NecrosisHepatic Necrosis

AcetylatedAcetylated


HydrolyzedHydrolyzed

Microsomal Microsomal OxidationOxidation


(nontoxic)(nontoxic)

EXCRETIONEXCRETION

75-95% of a dose is excreted in the 75-95% of a dose is excreted in the urine in 24 hrs., mostly as urine in 24 hrs., mostly as metabolites.metabolites.

THERAPEUTIC STATUSTHERAPEUTIC STATUS

Most important drug for all types of Most important drug for all types of T.B.T.B.

Chemoprophylaxis.Chemoprophylaxis.

CONTRAINDICATIONSCONTRAINDICATIONS

Liver diseaseLiver disease

DRUG INTERACTIONSDRUG INTERACTIONS

Aluminum salts.Aluminum salts.

INH inhibits cytochrome P-450 enzymes.INH inhibits cytochrome P-450 enzymes.

INH is a potential inhibitor of MAO and INH is a potential inhibitor of MAO and diamine oxidase (histaminase).diamine oxidase (histaminase).

Induces Cytochrome P4502E1 Induces Cytochrome P4502E1 (acetaminophen).(acetaminophen).

ETHAMBUTOL-ETHAMBUTOL-ANTIMICROBIAL ACTIVITYANTIMICROBIAL ACTIVITY

Nearly all strains of Nearly all strains of Mycobacterium Mycobacterium tuberculosistuberculosis are sensitive are sensitive..

A few atypical organisms are also A few atypical organisms are also sensitive (MAC). sensitive (MAC).

PHARMACOKINETICSPHARMACOKINETICS

Well absorbed from the GI Tract.Well absorbed from the GI Tract.

Mostly excreted unchanged in the Mostly excreted unchanged in the urine.urine.


Initial treatment of TB.Initial treatment of TB.

Used to treat MAC infections in Used to treat MAC infections in certain combinations.certain combinations.

RIFAMPIN (Rifampicin)RIFAMPIN (Rifampicin)

Semi-synthetic derivative of one of Semi-synthetic derivative of one of the rifamycins, a group of complex the rifamycins, a group of complex macrocyclic antibiotics.macrocyclic antibiotics.

RIFAMPIN-ANTI T.B. RIFAMPIN-ANTI T.B. ACTIVITYACTIVITY

Mycobacterium tuberculosisMycobacterium tuberculosis as well as as well as several atypical organisms.several atypical organisms.

Bactericidal against extracellular cavitary Bactericidal against extracellular cavitary bacilli and to organisms in closed lesions.bacilli and to organisms in closed lesions.

Some non-Mycobacterial bacteria and Some non-Mycobacterial bacteria and some viruses.some viruses.


Well absorbed from the GI tract.Well absorbed from the GI tract.

Widely distributed throughout the Widely distributed throughout the body including the CNS.body including the CNS.

RifampinRifampin

RifampinRifampin DeacetylationDeacetylation


Induces its own metabolism.Induces its own metabolism.

About 1/3 of the drug is excreted in About 1/3 of the drug is excreted in urine, and 2/3 in the intestine.urine, and 2/3 in the intestine.

Adjust dose with decreased liver Adjust dose with decreased liver function.function.


Used in combination with INH for the Used in combination with INH for the initial treatment of T.B., in the initial treatment of T.B., in the retreatment of T.B. and in retreatment of T.B. and in intermittent therapy.intermittent therapy.


Possible alternative to INH to prevent Possible alternative to INH to prevent T.B (with pyrazinamide)?T.B (with pyrazinamide)?

Used to treat atypical mycobacterial Used to treat atypical mycobacterial infections.infections.

Protease inhibitorsProtease inhibitorsAzolesAzoles

RIFAPENTINE AND RIFAPENTINE AND RIFABUTINRIFABUTIN

Rifabutin-better activity vs MAC than Rifabutin-better activity vs MAC than rifampin; less an inducer of rifampin; less an inducer of cytochrome P-450 enzymescytochrome P-450 enzymes

Rifapentine-long acting analog.Rifapentine-long acting analog.

NN

CCNHNH22

oo

NN

CC oo

NN

CCNHNH22

ooNN

OHOH

PYRAZINAMIDEPYRAZINAMIDE

NICOTINAMIDENICOTINAMIDEPYRAZINOIC ACIDPYRAZINOIC ACID

NN

ANTIBACTERIAL ACTIVITYANTIBACTERIAL ACTIVITY

Eliminates bacilli that are growing at Eliminates bacilli that are growing at slightly acidic pH.slightly acidic pH.


Well absorbed from the GI tract.Well absorbed from the GI tract.

Excreted primarily through the Excreted primarily through the kidney.kidney.

THERAPEUTIC USESTHERAPEUTIC USES

Important component of short-term Important component of short-term (6 month) multiple-drug therapy of (6 month) multiple-drug therapy of TB .TB .

Preventative therapy in combination Preventative therapy in combination with rifampin when INH resistance is with rifampin when INH resistance is suspected.suspected.

FIXED-DOSE FIXED-DOSE COMBINATIONSCOMBINATIONS

They are strongly encouraged for They are strongly encouraged for adults who are self-administering adults who are self-administering their medications.their medications.

Enhance adherence, may reduce Enhance adherence, may reduce inappropriate monotherapy and may inappropriate monotherapy and may prevent drug resistance.prevent drug resistance.

FIXED-DOSE FIXED-DOSE COMBINATIONSCOMBINATIONS

Fixed-dose combinations are Fixed-dose combinations are available as Rifamate (INH +rifampin) available as Rifamate (INH +rifampin) and Rifater (INH +rifampin and Rifater (INH +rifampin +pyrazinamide).+pyrazinamide).

ADVERSE EFFECTS OF ADVERSE EFFECTS OF ANTITUBERCULOSIS DRUGSANTITUBERCULOSIS DRUGS

GI DISTRESS AND UPSETGI DISTRESS AND UPSET

Most anti TB drugs are irritating to Most anti TB drugs are irritating to the GI tract-INH, rifampin, the GI tract-INH, rifampin, pyrazinamidepyrazinamide

ISONIAZID-HEPATOTOXICITYISONIAZID-HEPATOTOXICITY

Liver Liver enzymesenzymes

HEPATOTOXICITYHEPATOTOXICITY

Hepatitis is the most severe toxicity.Hepatitis is the most severe toxicity.

IsoniazidIsoniazid Peripheral NeuropathyPeripheral NeuropathyAcute SeizuresAcute Seizures

HydrazineHydrazineAcetyl INHAcetyl INH

Isonicotinic AcidIsonicotinic Acid

Acetyl HydrazineAcetyl Hydrazine

Diacetyl HydrazineDiacetyl Hydrazine (nontoxic)(nontoxic)

Reactive MetaboliteReactive Metabolite

Hepatic NecrosisHepatic Necrosis



HydrolyzedHydrolyzed



(nontoxic)(nontoxic)

RIFAMPINRIFAMPIN

JaundiceJaundice

PYRAZINAMIDEPYRAZINAMIDE

Hepatotoxicity is common and can Hepatotoxicity is common and can be seriousbe serious

NEUROTOXICITYNEUROTOXICITY

NEUROTOXICITYNEUROTOXICITY

Peripheral neuritis is common Peripheral neuritis is common (without pyridoxine).(without pyridoxine).

CNS effects of various types can CNS effects of various types can occur (convulsions,ataxia).occur (convulsions,ataxia).

OCULAR TOXICITYOCULAR TOXICITY

ETHAMBUTOLETHAMBUTOL

Optic Neuritis and color blindness.Optic Neuritis and color blindness.

Base-line and monthly vision tests.Base-line and monthly vision tests.

HYPERURICEMIAHYPERURICEMIA

PyrazinamidePyrazinamide

HIGH DOSE INTERMITTENT HIGH DOSE INTERMITTENT THERAPYTHERAPY

Additional toxicities especially with Additional toxicities especially with rifampinrifampin

ADVERSE EFFECTSADVERSE EFFECTS

Orange - pink color is imparted to Orange - pink color is imparted to saliva, tears and other body fluids.saliva, tears and other body fluids.

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TREATMENT OF T.B. A special problem within the field of chemotherapy. A special problem within the field of chemotherapy