TB Drug Guide: First Line Antituberculosis Agents

Dr. NDAYISABA CORNEILLE
CEO of CHG
MBChB,DCM,BCSIT,CCNA
Supported BY
FIRST LINE TB
DRUGS

Antituberculosis
 First line anti-TB
agents
 Isoniazid
 Rifampicin
 Ethambutol
 Pyrazinamide
 Second line agents
 Cycloserine
 Streptomycin
 Rifabutin
 Ethionamide
 Prothionamide
 Capreomycin
Dr Ndayisaba Corneille

Introduction
 Mycobacteria are intrinsically resistant to
most antibiotics & they grow slowly
compared with other bacteria.
 Thus antibiotics that are most active
against growing cells are relatively
ineffective.
 Mycobacterial cells can also be dormant &
thus completely resistant to many drugs or
killed only very slowly.

 The lipid-rich mycobacterial cell wall is
impermeable to many agents.
 Mycobacterial species are intracellular
pathogens & organisms residing within
macrophages are inaccessible to drugs that
penetrate these cells poorly.

 Mycobacteria have ability to develop
resistance.
 Combinations of 2 or more drugs is
required to overcome emergence of
resistance during course of therapy.
 The response to chemotherapy is slow &
Rx must be administered for months to
years, depending on which drugs are used.

FIRST LINE DRUGS USED IN TB RX
1st line agents
 Isoniazid (H)
 Rifampin (R)
 Pyrazinamide(P)
 Ethambutol (E)
 Streptomycin (S)
 Thiacetazone (T)

 Isoniazid & rifampin are the most active
drugs.
 In practice, therapy is initiated with a four-
drug regimen of 2HERZ/6EH OR
2HERZ/4RH after pts are diagnosed of TB.
 Prevalence of isoniazid resistance among
US clinical isolates is approx 10%.
 Prevalence of resistance to both H&R
(multiple drug resistance) is about 3%.

Isoniazid (H) or (INH)
 Most active drug for Rx of TB cozed by susceptible
strains.
 Has structural similarity to pyridoxine
 Its bactericidal for actively growing tubercle bacilli.
 It is less effective against atypical mycobacterial
species.
 It penetrates into macrophages & is active against
both extracellular & intracellular organisms.

Mechanism of Action
 Inhibits synthesis of mycolic acids, which are
essential components of mycobacterial cell walls.
 Blocks mycolic acid synthesis & kills the cell.
Basis of Resistance
 Mutations in certain genes controlling synthesis of
mycolic acids

 Mutants are readily selected out if isoniazid or any
other drug is given as a single agent.
 The use of two or more independently acting
drugs in combination is much more effective.
 Probability that a bacillus is resistant to both drugs
is usually less

 Thus, at least two or more active agents
shld always be used to Rx active TB to
prevent emergence of resistance during
therapy.
Pharmacokinetics
 Typical adult dose is 300 mg o.d. (5
mg/kg/d)
 Up to 10 mg/kg/d may be used for serious
infections or if malabsorption is a problem.

 5 mg/kg/d, or 900 mg, may be used in some
situations
 Given IV or PO & is readily absorbed frm
GIT.
 It diffuses readily into all body fluids &
tissues.
 The [CNS & CSF]s ranges btn 20% & 100%
of simultaneous [serum]s.
 Metabolism is esp by acetylation by liver N-
acetyltransferase & this is genetically
determined.

 Rapid clearance of drug occurs in rapid
acetylators but its usually of no
therapeutic consequence whn appropriate
doses are administered daily.
 [subtherapeutic]s may occur if drug is
administered as a once-weekly dose or if
there is malabsorption.
 Drug metabolites & a small amount of
unchanged drug are excreted mainly in

 The dose need not be adjusted in renal failure.
 Is contraindicated if it is the coz of hepatitis
Clinical Uses
 Rx of active TB in combination with other agents
 Rx of Latent tuberculosis with 300 mg/d

Adverse Reactions
 The incidence & severity of unwanted effects to
isoniazid are related to dosage & duration of
administration.
 Immunologic reactions
 Fever
 skin rashes.
 Drug-induced systemic lupus erythematosus has
been reported. Dr Ndayisaba Corneille

 Direct toxicity
 Isoniazid-induced hepatitis
 Most common major toxic effect.
 Liver aminotransferases increase 3- 4 times
normal.
 This does not require cessation of drug if pt is
asymptomatic
 This is seen in 10–20% of pts.

 Clinical hepatitis with;loss of appetite, nausea,
vomiting, jaundice & right upper quadrant pain
occurs in 1% of (H) recipients & can be fatal,
particularly if drug is not discontinued promptly.
 There is histologic evidence of hepatocellular
damage & necrosis is present

 Pts at high risk of Isoniazid hepatitis;
 Age >50 years
 Alcoholics
 Pregnant women
 Postpartum mothers
 Dev’t of (H) hepatitis contraindicates its further
use.

 Peripheral neuropathy
 Observed in 10–20% of pts given dosages >5
mg/kg/d
 Infrequently seen with standard 300 mg adult
dose.
Patients at risk of neuropathy
 Slow acetylators
 Those with predisposing conditions like AIDS,
malnutrition, alcoholism, DM, & uremia.

 Pyridoxine, 25–50 mg/d, is recommended
for those with conditions predisposing to
neuropathy
 Neuropathy is due to a relative pyridoxine
deficiency as (H) promotes excretion of
pyridoxine

 CNS toxicity;
 less common
 Memory loss,
 Psychosis &
 Seizures.
 These may also respond to pyridoxine.

Miscellaneous adverse effects
 Hematologic abnormalities
 Provocation of pyridoxine deficiency anemia.
 Tinnitus
 GI discomfort
 Reduced metabolism of phenytoin, increasing its
blood level & toxicity

Rifampin
 A semisynthetic derivative of rifamycin, an
antibiotic produced by Streptomyces mediterranei.
Antibacterial activity . Active against;
 Gram-positive & gram-negative cocci,
 Some enteric bacteria,
 Mycobacteria,
 Chlamydia. Dr Ndayisaba Corneille

 Resistant mutants are present in all microbial
popns at approx 1 in 106 & are rapidly
selected out if rifampin is used as a single
drug during active infection.
 No cross-resistance to other classes of
antimicrobial drugs but cross-resistance
occur to other rifamycin derivatives, eg,
rifabutin & rifapentine.

Mechanism of action
 Thus inhibits DNA synthesis
 Bactericidal
 Binds to the subunit of bacterial DNA-dependent
RNA polymerase & thereby inhibits RNA synthesis.

Pharmacokinetics
 Dosage is usually 600 mg/d (10 mg/kg/d)
 Given PO & well absorbed frm GIT with wide
distribution in body fluids & tissues.
 Relatively highly protein-bound & adequate [CSF]s
are achieved only in presence of meningeal
inflammation.

 Readily penetrates most tissues &
phagocytic cells.
 Kills organisms that are inaccessible to
many drugs, such as intracellular organisms
& those sequestered in abscesses + lung
cavities.
 Excreted mainly thru liver into bile. Then
undergoes enterohepatic recirculation, with
the bulk excreted as a deacylated metabolite
in feces & a small amount in urine.

 Dose reduction in liver & renal insufficiency are not
required
Resistance
 Results frm any one of several possible point
mutations in rpoB, the gene for the subunit of RNA
polymerase.
 This result in reduced binding of rifampin to RNA
polymerase.

Clinical uses
1) Mycobacterial infections like
 TB
 Atypical mycobacterial infections
 Leprosy.
 Alternative to (H) prophylaxis for pts with latent
TB only who are unable to take isoniazid.

2) Other indications
 Elimination of meningococcal carriage
 Prophylaxis for haemophilus influenzae type b
disease in contacts of children.
 Eradication of staphylococcal carriage whn
combined with a 2nd agent .
 Rx of serious staphylococcal infections such as
osteomyelitis & prosthetic valve endocarditis whn
used in combination therapy

Adverse Reactions
 Imparts a harmless orange color to urine, sweat,
tears & contact lenses (soft lenses may be
permanently stained).
Occasional adverse effects
 Rashes
 Thrombocytopenia
 Nephritis or ATN

 Cholestatic jaundice
 Hepatitis.
 Light-chain proteinuria.
 If administered less often than twice weekly it
cozes a flu-like syndrome with;
 Fever
 Chills,
 Myalgias,
 Anemia, & thrombocytopenia

Drug interactions
 Strongly induces most P450 enzymes thus
increased elimination of drugs including
methadone, anticoagulants, cyclosporine, some
anticonvulsants, PIs, NNRTIs esp neverapine, oral
contraceptives & a host of others.

ETHAMBUTOL
 Synthetic, water-soluble, heat-stable compound
Mechanism of action
 Inhibit mycobacterial cell wall synthesis
 Inhibits mycobacterial arabinosyl transferases,
which are encoded by embCAB operon.

 Arabinosyl transferases are involved in
polymerization reaction of arabinoglycan, an
essential component of mycobacterial cell wall.
Resistance
 Resistance to ethambutol is due to mutations
resulting in overexpression of emb gene pdts or
within the embB structural gene.

 As with all other anticocks, resistance to emerges
rapidly whn drug is used alone.
Pharmacokinetics
 Given PO & well absorbed frm the gut
 Dosage is 15–25 mg/kg/d ,usually given as a
single daily dose in combination with other drugs.

 It crosses BBB only if meninges are
inflamed with highly variable [CSF]s of drug,
(4% to 64%) of serum levels in the setting of
meningeal inflammation.
 About 20% of drug is excreted in feces &
50% in urine in unchanged form.
 It accumulates in renal failure.
 Dose shld be reduced by half if creatinine
clearance is < 10 mL/min.

Clinical Use
 Rx of active TB
*A higher dose is recommended for Rx of TBM

Adverse Reactions
 Hypersensitivity; Is rare.
 Retrobulbar neuritis, resulting in loss of visual
acuity & red-green color blindness.
 Most common serious adverse event
 This dose-related S/E, more likely to occur at
doses of 25 mg/kg/d continued for several months.

 At 15 mg/kg/d or less, visual disturbances are very
rare.
 Periodic visual acuity testing is desirable if 25
mg/kg/d dosage is used.
Contraindications
 Relatively contraindicated in children too young to
permit assessment of visual acuity & red-green
color discrimination.

PYRAZINAMIDE
 A relative of nicotinamide.
 Stable & slightly soluble in water.
 An important front-line drug used in conjunction
with H&R in short-course (ie, 6-month) regimens
as a "sterilizing" agent active against residual
intracellular organisms that may cause relapse.

Mechanism of action
 The drug target & mechanism of action are
unknown.
 Pyrazinamide is converted to pyrazinoic acid the
active form of the drug—by mycobacterial
pyrazinamidase, which is encoded by pncA.
 The drug is taken up by macrophages & exerts its
activity against mycobacteria residing within acidic
environ’t of lysosomes.

Resistance
 Resistance may be due to impaired uptake of drug
 Mutations in pncA that impair conversion of
pyrazinamide to its active form.
 Tubercle bacilli develop resistance to it fairly
readily.
 No cross-resistance with other anti-cocks.

Pharmacokinetics
 Given PO
 Dose of 25 mg/kg/d.
 Half-life is 8–11 hours.
 Well absorbed frm GIT & widely distributed in body
tissues, including inflamed meninges.
 It is inactive at neutral pH, but at pH 5.5 it inhibits
tubercle bacilli & some other mycobacteria

 Parent compound is metabolized by liver, but
metabolites are renally cleared.
 Thus doses shld be lowered in renal insufficiency.
 In pts with normal renal function, a dose of 40–50
mg/kg is used for thrice-wkly or twice-wkly Rx
regimens.

Adverse Reactions ;
Major adverse effects include
 Hepatotoxicity (1–5% of pts),
 Nausea
 Vomiting
 Drug fever occurs uniformly & is not a reason to
halt therapy.
 Hyperuricemia. May provoke acute gouty
arthritis.

Streptomycin
o Isolated frm a strain of Streptomyces griseus.
o The antimicrobial activity is typical of that of other
aminoglycosides, as are the mechanisms of
resistance.

Spectrum of activity against in mycobacteria
 M.tuberculosis spp
 Mycobacterium avium complex (MAC)
 Mycobacterium kansasii
 Rest of the Spp of mycobacterium are resistant .
Resistance
 All large popns of tubercle bacilli contain some
streptomycin-resistant mutants.

 Resistance is due to a point mutation in either the
rpsL gene encoding the S12 ribosomal protein
gene or the rrs gene encoding 16S ribosomal
rRNA, which alters the ribosomal binding site.
 Ribosomal resistance develops readily, limiting its
role as a single agent.

Pharmacokinetics
 Given IM or IV
 Typical adult dosage is 1g/day (15 mg/kg/d )daily
for adults & 7.5–15 mg/kg/d for children
 It penetrates into cells poorly & is active mainly
against extracellular tubercle bacilli.
 It crosses BBB & achieves [therapeutic]s with
inflamed meninges.

Clinical Uses
1. Mycobacterial infections
 Used when an injectable drug is needed or
desirable
 2nd -line agent for Rx of MDR-TB with other
agents.
 Severe & possibly life-threatening forms of TB eg,
TBM & disseminated disease

Adverse Reactions
 Hypersensitivity
 Fever
 skin rashes & other allergic
manifestations.
 Occurs most frequently with prolonged
contact with drug either in pts who
receive a prolonged course of Rx or in
medical personnel who handle the drug.

 Pain at the injection site
o Common but usually not severe
 Disturbance of vestibular function.
o Most serious toxic effect & manifest by
 Vertigo &
 Loss of balance.
o Toxicity tends to be irreversible.

 Ototoxicity
 Nephrotoxicity
Contraindications
o Pregnancy, can cause deafness in the newborn
o Renal failure
o Vestibular disorders

Thiacetazone
 Is bacteriostatic
 With a low potency
 Dosage is 2.5mg/day
 Is the only essential anti-TB drug that can not be
given intermittently e.g. 2 timely weekly

 Has a narrow therapeutic range thus margin btn
therapeutic & toxic dose is very small
 Some countries still use it in combination with
Isoniazid during continuation phase of Rx
 Known ISS pts shld not be put on this drug bcoz of
its severe skin reactions thus Ethambutol shld
replace this drug in areas where HIV is common

Side effects
Common
 Skin rash often involving mucous membrane &
some times blistering
Others
 Agranulocytosis
 Hepatitis

END
BY
DR NDAYISABA CORNEILLE
MBChB,DCM,BCSIT,CCNA,Cyber Security
contact: amentalhealths@gmail.com ,
ndayicoll@gmail.com
whatsaps :+256772497591 /+250788958241
THANKS FOR LISTENING

TB Drug Guide: First Line Antituberculosis Agents

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TB Drug Guide: First Line Antituberculosis Agents