Transcript Treatment of TB

TREATMENT OF T.B.
A special problem within the field of
chemotherapy.
TREATMENT OF T.B.
Treatment is often complex and
protracted.
Host immune defenses are often
variable and inadequate.
TREATMENT OF T.B.
Chemotherapy is probably the
keystone in the management of T.B.
Ancillary treatments are used only in
special circumstances.
TREATMENT OF T.B.
Divided into chemoprophylaxis and
treatment of active disease.
Careful diagnostic studies must
always precede therapy.
CHEMOPROPHYLAXIS
To prevent clinically active disease in
people already infected.
Given only to those who will derive
the greatest benefit and the least
risk.
CHEMOPROPHYLAXIS
300 mg Isoniazid once
daily for 6-12 months.
TREATMENT OF ACTIVE T.B.
First line drugs (used in the initial
treatment of T.B.) : isoniazid,
rifampin, streptomycin, ethambutol
and pyrazinamide.
TREATMENT OF ACTIVE T.B.
Secondary agents: PAS,
ethionamide, amikacin,
kanamycin, capreomycin,
cycloserine, ciprofloxacin,
levofloxacin and clofazimine.
TREATMENT OF ACTIVE T.B.
Therapy requires at least two
effective drugs concurrently.
TREATMENT OF ACTIVE T.B.
If the treatment is appropriate
improvement is usually seen within
2 weeks.
Continue treatment for at least 3-6
mths after the sputum becomes
negative.
TREATMENT OF ACTIVE
T.B.
Never use 1 drug and never add
a single drug to a failing
regimen.
TREATMENT OF ACTIVE T.B.
Minimum length of therapy is
6-9 months.
TREATMENT OF ACTIVE T.B.
Initiation phase of 2 months.
Continuation phase of 4-7 months.
TREATMENT OF ACTIVE T.B.
 Initial therapy is a 4 drug regimen of INH,
rifampin, pyrazinamide and ethambutol.
 For patients with drug-susceptible
disease the pyrazinamide can be
discontinued after 2 months.
 Ethambutol can also be discontinued.
TREATMENT OF ACTIVE T.B.
Combining daily therapy with
intermittent therapy.
INTERMITTENT THERAPY
Daily therapy for 2 weeks (INH,
rifampin, pyrazinamide and
streptomycin) followed by therapy 2
times a week for six weeks. Then
INH + Rifampin 2x weekly for 16
weeks.
DOT
DRUG RESISTANCE
Major cause is inadequate therapy.
Treatment is difficult and requires
good laboratory support and
experience with the less frequently
used drugs.
MULTIPLE DRUG
RESISTANT T.B.
Combined resistance to at least INH
and rifampin.
Caused by improper treatment,
inadequate drug supplies, or poor
patient supervision.
MULTIPLE DRUG
RESISTANT T.B.
Patients face chronic disability and
death and represent an infectious
hazard for the community.
MULTIPLE DRUG
RESISTANT T.B.
High cure rates have been obtained
but require prompt recognition, rapid
and accurate susceptibility results
and early administration of an
individualized retreatment regimen.
MULTIPLE DRUG
RESISTANT T.B.
Regimens are usually based on a
quinolone and an injectable agent
(e.g.aminoglycoside) supplemented
with other second line drugs.
TREATMENT OF HIVRELATED TB
Possibility of increased drug toxicity
and possible drug-drug interactions
(rifamycins plus PI and/or NNRI).
NONTUBERCULOUS
MYCOBACTERIA
Atypical mycobacterial infections.
Resistant to many of the commonly
used drugs.
Examine for sensitivity and treat on
this basis.
Increased in AIDS (e.g. MAC).
MECHANISM OF ACTION OF
ANTITUBERCULOSIS AGENTS
Drugs which interfere with mycolic
acid synthesis
Drugs which inhibit nucleic acid
synthesis
Drugs inhibiting protein synthesis
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MYCOBACTERIAL CELL WALL
Lipid of intermediate length
Porin
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
ISONIAZID-MECHANISM OF
ACTION
Interferes with biosynthesis of cell
wall mycolic acids.
Mycolate depleted cell walls are
structurally weak.
katG
Active
Isoniazid
Form
(Prodrug)
Catalase/Peroxidase
INH MECHANISM OF ACTION
InhA gene encodes an enoyl-ACP
reductase of fatty acid synthase II
which converts 2 -unsaturated to
saturated fatty acids on the pathway
to mycolic acid biosynthesis.
Activated INH inhibits this enzyme.
Mycobacterial Cell Wall
Lipid of intermediate length
Porin
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
INH
RESISTANCE
Mutations in the katG gene can lead
to loss of catalase-peroxidase
activity.
Resistance also maps to mutations
in four other genes including inhA
RESISTANCE
Overall incidence of resistance is
higher in certain ethnic groups such
as African Americans, Mexican
Americans and Indochinese
refugees.
ETHAMBUTOL-MECHANISM
OF ACTION
It is not bactericidal.
Inhibits synthesis of the
mycobacterial cell wall.
MECHANISM OF ACTION
It is an inhibitor of mycobacterial
arabinosyl transferases (encoded by
the embAB genes).
Arabinoglycan an essential
component of the cell wall.
MYCOBACTERIAL CELL WALL
Lipid of intermediate length
Porin
Lipid with C14-C18 acids
Mycolic Acid
Arabinogalactan
Peptidoglycan
Ethambutol
RESISTANCE
Mutations in the emb genes.
PYRAZINAMIDE-MECHANISM
OF ACTION
PZA
POA (pyrazinoic
pyrazinamidase acid)
Occurs mostly in the liver.
MECHANISM OF ACTION
Inhibits fatty acid synthetase I of
Mycobacterium tuberculosis.
Pyrazinamide
Short chain fatty acid precursors
RESISTANCE
Mutations in the pncA gene which
results in impairment in the
conversion of PZA to its active form.
DRUGS INHIBITING NUCLEIC
ACID SYNTHESIS
Rifampin
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RESISTANCE
Results from an alteration in the
polymerase enzyme (mutation in the
rpoB gene).
STREPTOMYCIN-ANTI TB
ACTIVITY
Most strains of M.Tuberculosis are
sensitive.
Bactericidal only against the
extracellular tuberculosis bacilli.
Overall only suppressive.
RESISTANCE
Major problem with streptomycin use
in T.B.
Combination therapy will delay or
prevent resistance.
THERAPEUTIC USES IN T.B.
It is used in drug resistant disease.
More serious forms of T.B.
(disseminated T.B. or meningitis).
Co
OH
Co
NH2
N
NICOTINAMIDE
N
N
Co
NH2
CNHNH2 ISONIAZID
o
NICOTINIC
ACID
ANTITUBERCULAR
ACTIVITY
Bactericidal vs actively growing
tubercle bacilli .
Also bactericidal vs intracellular
bacteria.
Poor activity against atypical
organisms.
ABSORPTION AND
DISTRIBUTION
Readily absorbed when given orally
or parenterally (food and Al+++
decrease absorption).
INH diffuses well into all body fluids
and cells including the CNS.
DISTRIBUTION
Penetrates cells with ease and is
effective against organisms growing
within cells.
METABOLISM
 Primary route is by acetylation.
 Genetic heterogeneity with regard to the
rate of acetylation. There are “slow” and
“rapid” acetylators.
 Among American and northern European
pops. 50-65% are slow acetylators.
METABOLISM
More rapid clearance of INH by rapid
acetylators is of no therapeutic
consequence when given daily.
Subtherapeutic concn’s may occur if
INH is given to rapid acetylators as a
once-weekly dose.
METABOLISM
Slow acetylators may be more
susceptible to toxic side effects
related to higher blood levels of INH
whereas rapid acetylators have a
higher frequency of hepatotoxicity.
Peripheral Neuropathy
Acute Seizures
Isoniazid
Acetylated
Microsomal
Oxidation
Acetyl INH
Hydrazine
Acetylated
Reactive Metabolite
Hydrolyzed
Acetyl Hydrazine
Microsomal
Oxidation
Isonicotinic Acid
(nontoxic)
Hepatic Necrosis
Diacetyl Hydrazine
(nontoxic)
EXCRETION
75-95% of a dose is excreted in the
urine in 24 hrs., mostly as
metabolites.
THERAPEUTIC STATUS
Most important drug for all types of
T.B.
Chemoprophylaxis.
CONTRAINDICATIONS
Liver disease
DRUG INTERACTIONS
 Aluminum salts.
 INH inhibits cytochrome P-450 enzymes.
 INH is a potential inhibitor of MAO and
diamine oxidase (histaminase).
 Induces Cytochrome P4502E1
(acetaminophen).
ETHAMBUTOLANTIMICROBIAL ACTIVITY
Nearly all strains of Mycobacterium
tuberculosis are sensitive.
A few atypical organisms are also
sensitive (MAC).
PHARMACOKINETICS
Well absorbed from the GI Tract.
Mostly excreted unchanged in the
urine.
THERAPEUTIC STATUS
Initial treatment of TB.
Used to treat MAC infections in
certain combinations.
RIFAMPIN (Rifampicin)
Semi-synthetic derivative of one of
the rifamycins, a group of complex
macrocyclic antibiotics.
RIFAMPIN-ANTI T.B.
ACTIVITY
 Mycobacterium tuberculosis as well as
several atypical organisms.
 Bactericidal against extracellular cavitary
bacilli and to organisms in closed lesions.
 Some non-Mycobacterial bacteria and
some viruses.
PHARMACOKINETICS
Well absorbed from the GI tract.
Widely distributed throughout the
body including the CNS.
Rifampin
Deacetylation
Rifampin
PHARMACOKINETICS
Induces its own metabolism.
About 1/3 of the drug is excreted in
urine, and 2/3 in the intestine.
Adjust dose with decreased liver
function.
THERAPEUTIC STATUS
Used in combination with INH for the
initial treatment of T.B., in the
retreatment of T.B. and in intermittent
therapy.
THERAPEUTIC STATUS
Possible alternative to INH to prevent
T.B (with pyrazinamide)?
Used to treat atypical mycobacterial
infections.
Azoles
Protease inhibitors
RIFAPENTINE AND
RIFABUTIN
Rifabutin-better activity vs MAC than
rifampin; less an inducer of
cytochrome P-450 enzymes
Rifapentine-long acting analog.
N
Co
NH2
N
NICOTINAMIDE
N
N
N
Co
NH2
PYRAZINAMIDE
Co
OH
PYRAZINOIC ACID
ANTIBACTERIAL ACTIVITY
Eliminates bacilli that are growing at
slightly acidic pH.
PHARMACOKINETICS
Well absorbed from the GI tract.
Excreted primarily through the
kidney.
THERAPEUTIC USES
Important component of short-term
(6 month) multiple-drug therapy of
TB .
Preventative therapy in combination
with rifampin when INH resistance is
suspected.
FIXED-DOSE
COMBINATIONS
They are strongly encouraged for
adults who are self-administering
their medications.
Enhance adherence, may reduce
inappropriate monotherapy and may
prevent drug resistance.
FIXED-DOSE
COMBINATIONS
Fixed-dose combinations are
available as Rifamate (INH +rifampin)
and Rifater (INH +rifampin
+pyrazinamide).
ADVERSE EFFECTS OF
ANTITUBERCULOSIS DRUGS
GI DISTRESS AND UPSET
Most anti TB drugs are irritating to
the GI tract-INH, rifampin,
pyrazinamide
ISONIAZID-HEPATOTOXICITY
Liver
enzymes
HEPATOTOXICITY
Hepatitis is the most severe toxicity.
Peripheral Neuropathy
Acute Seizures
Isoniazid
Acetylated
Microsomal
Oxidation
Acetyl INH
Hydrazine
Acetylated
Reactive Metabolite
Hydrolyzed
Acetyl Hydrazine
Microsomal
Oxidation
Isonicotinic Acid
(nontoxic)
Hepatic Necrosis
Diacetyl Hydrazine
(nontoxic)
RIFAMPIN
Jaundice
PYRAZINAMIDE
Hepatotoxicity is common and can
be serious
NEUROTOXICITY
NEUROTOXICITY
Peripheral neuritis is common
(without pyridoxine).
CNS effects of various types can
occur (convulsions,ataxia).
OCULAR TOXICITY
ETHAMBUTOL
Optic Neuritis and color blindness.
Base-line and monthly vision tests.
HYPERURICEMIA
Pyrazinamide
HIGH DOSE INTERMITTENT
THERAPY
Additional toxicities especially with
rifampin
ADVERSE EFFECTS
Orange - pink color is imparted to
saliva, tears and other body fluids.