treatment of t.b. a special problem within the field of chemotherapy. a special problem within the...
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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 OF T.B.TREATMENT OF T.B.
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.
TREATMENT OF T.B.TREATMENT OF T.B.
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.
TREATMENT OF T.B.TREATMENT OF T.B.
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.
TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.
Secondary agents: PAS, Secondary agents: PAS, ethionamide, amikacin, ethionamide, amikacin, kanamycin, capreomycin, kanamycin, capreomycin, cycloserine, ciprofloxacin, cycloserine, ciprofloxacin, levofloxacin and clofazimine.levofloxacin and clofazimine.
TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.
Therapy requires at least two Therapy requires at least two effective drugs concurrently.effective drugs concurrently.
TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.
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.
TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.
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.
TREATMENT OF ACTIVE T.B.TREATMENT OF ACTIVE T.B.
Initiation phase of 2 months.Initiation phase of 2 months.
Continuation phase of 4-7 months.Continuation phase of 4-7 months.
TREATMENT OF ACTIVE T.B.TREATMENT OF ACTIVE T.B.
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.
TREATMENT OF ACTIVE TREATMENT OF ACTIVE T.B.T.B.
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.
MULTIPLE DRUG MULTIPLE DRUG RESISTANT T.B.RESISTANT T.B.
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.
MULTIPLE DRUG MULTIPLE DRUG RESISTANT T.B.RESISTANT T.B.
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.
MULTIPLE DRUG MULTIPLE DRUG RESISTANT T.B.RESISTANT T.B.
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
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.
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
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
RESISTANCERESISTANCE
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.
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
EthambutolEthambutol
RESISTANCERESISTANCE
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
RESISTANCERESISTANCE
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
RESISTANCERESISTANCE
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.
RESISTANCERESISTANCE
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.
METABOLISMMETABOLISM
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.
METABOLISMMETABOLISM
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
AcetylatedAcetylated
HydrolyzedHydrolyzed
Microsomal Microsomal OxidationOxidation
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.
THERAPEUTIC STATUSTHERAPEUTIC STATUS
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.
PHARMACOKINETICSPHARMACOKINETICS
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
PHARMACOKINETICSPHARMACOKINETICS
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.
THERAPEUTIC STATUSTHERAPEUTIC STATUS
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.
THERAPEUTIC STATUSTHERAPEUTIC STATUS
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.
PHARMACOKINETICSPHARMACOKINETICS
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
AcetylatedAcetylated
AcetylatedAcetylated
HydrolyzedHydrolyzed
Microsomal Microsomal OxidationOxidation
Microsomal Microsomal OxidationOxidation
(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.