TUBERCULOSIS TREATMENT

 Active tuberculosis will kill about two out of every three people affected if left

untreated. Treated tuberculosis has a mortality rate of less than 5%.

 The standard "short" course treatment for tuberculosis (TB) is isoniazid,

rifampicin, pyrazinamide, and ethambutol for two months, then isoniazid and
rifampicin alone for a further four months.
 The patient is considered cured at six months (although there is still a relapse

rate of 2 to 3%).
 For latent tuberculosis, the standard treatment is six to nine months of isoniazid

alone.
First line tuberculosis drugs;

These include;

oEthambutol (EMB / E)

oIsoniazid (INH / H)

oPyrazinamide (PZA / Z)

oRifampicin (RMP / R)

oStreptomycin (STM / S)
Second line tuberculosis drugs;
There are six classes of second-line drugs (SLDs) used for the treatment of
tuberculosis.
A drug may be classed as second-line instead of first-line for one of two
Possible reasons:
oIt may be less effective than the first-line drugs
(e.g., p-aminosalicylic acid);
oIt may have toxic side-effects (e.g., Cycloserine);
oIt may be unavailable in many developing countries
(e.g., fluoroquinolones):
 Second line drugs include;
oAminoglycosides: e.g., amikacin (AMK), kanamycin (KM);
oPolypeptides: e.g., capreomycin, viomycin, enviomycin;
oFluoroquinolones: e.g., ciprofloxacin (CIP), levofloxacin,
moxifloxacin (MXF);
oThioamides: e.g. ethionamide, prothionamide
oCycloserine (the only antibiotic in its class);
op-aminosalicylic acid (PAS or P).
Third line tuberculosis drugs;
These include other drugs that may be useful, but are not on the WHO list
of SLDs:
 They include;
oRifabutin
oMacrolides: e.g., clarithromycin (CLR);
oLinezolid (LZD);
oThioacetazone (T);
oThioridazine;
oArginine;
oVitamin D;
These drugs may be considered "third-line drugs" and are listed here either
because they are not very effective (e.g., clarithromycin) or because their
efficacy has not been proven e.g. linezolid.
 Rifampicin;
Therapeutic considerations;
Rifampicin is a semisynthetic compound derived from Amycolatopsis
rifamycinica.
It is a bactericidal antibiotic drug of the rifamycin group.
Rifampicin resistance develops quickly during treatment and rifampicin
monotherapy should not be used to treat infections — it should be used in
combination with other antibiotics.
Rifampicin is typically used to treat Mycobacterium infections, including
tuberculosis and leprosy.
With multi-drug therapy in the standard treatment of leprosy, rifampicin is always
used in combination with dapsone and clofazimine to avoid eliciting drug
resistance.
 Other bacteria indication;
oMethicillin-resistant Staphylococcus aureus (MRSA) in combination with

fusidic acid.
oProphylactic therapy against Neisseria meningitidis (meningococcal)

infection.
oNeisseria gonorrhoeae
oListeria species
oHaemophilus influenzae
oLegionella pneumophila.

For these non-standard indications, sensitivity testing should be done (if possible)
before starting rifampicin therapy.
Pharmacokinetics;

Rifampicin acts directly on messenger RNA synthesis.

It inhibits DNA-dependent RNA polymerase, especially those that are

Gram-stain-positive and Mycobacterium tuberculosis.

Much of this acid-fast positive bacteria's membrane is mycolic acid complexed

with peptidoglycan, which allows easy movement of the drug into the cell.

Its lipophilic nature makes it a good candidate to treat the meningitis form of

tuberculosis, which requires distribution to the central nervous system and

penetration through the blood-brain barrier.

It is given orally or intravenously.

Food consumption inhibits absorption from the GI tract

Bioavailability is 90 to 95%

It is de-acetylated in the liver and eliminated mainly by biliary excretion

Excretion is 15 to 30% renal and 60% faecal

Half life is 6 to 7 hours.

Rifampicin is an effective liver enzyme-inducer, promoting the up regulation of

hepatic cytochrome P450 enzymes (such as CYP2C9 and CYP3A4),

 Adverse effects;
Flu-like symptoms - with chills, fever, headache, arthralgia, and malaise
The most serious adverse effect is related to rifampicin's hepatotoxicity, and
patients receiving rifampicin often undergo baseline and frequent liver function
tests to detect liver damage.
Rifampicin is an effective liver enzyme-inducer thereby increasing the rate of
metabolism of many other drugs that are cleared by the liver through these
enzymes including;
oPatients undergoing long term anticoagulation therapy with warfarin have
to
be especially cautious and increase their dosage of warfarin accordingly
otherwise serious consequences of thromboembolism may occur.
oReduction in the efficacy of hormonal contraception.
The more common unwanted effects include fever, gastrointestinal disturbances
(vomiting & abdominal cramps), rashes, and immunological reactions.
Body fluids, such as urine and tears become orange-red in color, a benign but
sometimes frightening side-effect. This may permanently stain soft contact
lenses. It also may be excreted in breast milk; therefore breast feeding should be
avoided.
 Interactions;

Rifampicin has significant interactions with warfarin, oral contraceptives,

cyclosporine, itraconazole, digoxin, verapamil, nifedipine, simvastatin, midazolam

and HIV protease inhibitors.

Other possible interactions include antiretroviral agents, atorvastatin,

rosiglitazone /

pioglitazone, celecoxib, clarithromycin, and lorazepam

Dose;

Rifampicin is given at a dose of 10 mg/kg daily before breakfast.

 Isoniazid;
Therapeutic considerations
Isoniazid also known as isonicotinylhydrazine (INH) is an organic compound that
is the first-line antituberculosis medication in prevention and treatment.
It was first discovered in 1912, and later in 1951 it was found to be effective
against tuberculosis.
Isoniazid is never used on its own to treat active tuberculosis because resistance
quickly develops.

Mechanism of action;
Isoniazid is a prodrug and must be activated by a bacterial catalase-peroxidase
enzyme called KatG.
It acts by inhibiting the synthesis of mycolic acid, required for the mycobacterial
cell wall synthesis.
Isoniazid is bactericidal to rapidly-dividing mycobacteria but is bacteriostatic if
the
mycobacterium is slow-growing.
 Pharmacokinetics;
 Isoniazid is available in tablet, syrup, and injectable forms (given intramuscularly
or intravenously). It is available worldwide, is inexpensive and is generally well
tolerated.
Isoniazid reaches therapeutic concentrations in serum, cerebrospinal fluid (CSF),
and within caseous granulomas.
Isoniazid is metabolized in the liver via acetylation.
There are two forms of the enzyme responsible for acetylation, so that some
patients metabolize the drug more quickly than others. The half-life is hence
bimodal, that is 0.5-1.6 hr in fast acetylators and 2-5 hr in slow acetylators.
Isoniazid inhibits the cytochrome P450 system.
Isoniazid and its metabolites are excreted in the urine with 75 to 95% of the dose
excreted in 24 hours. Small amounts are also excreted in saliva, sputum and
feces.
Isoniazid is removed by haemodialysis and peritoneal dialysis.
 Dosing;

The standard dose of isoniazid in adults is 5 mg/kg/day (max 300mg daily).

When prescribed intermittently (twice or thrice weekly) the dose is

15mg/kg (max 900mg daily).

Patients with slow clearance of the drug (via acetylation as described above)

may require reduced dosages to avoid toxicity.

The recommended dose for children is 8 to 12 mg/kg/day.

 Adverse effects;
Adverse reactions include rash, abnormal liver function tests, hepatitis,
sideroblastic anemia, high anion gap metabolic acidosis, peripheral neuropathy,
mild central nervous system (CNS) effects.
Peripheral neuropathy and CNS effects are associated with the use of isoniazid
and are due to pyridoxine (vitamin B6) depletion.
Persons with conditions in which neuropathy is common (e.g., diabetes, uremia,
alcoholism, malnutrition, HIV-infection), as well as pregnant women and persons
with a seizure disorder, may be given pyridoxine (vitamin B6) (10-50 mg/day) with
isoniazid.
Hepatotoxicity can be avoided with close clinical monitoring of the patient,
specifically nausea, vomiting, abdominal pain and appetite.
INH therapy will decrease the efficacy of hormonal birth control when combined
with Rifampicin.
 Ethambutol;
Therapeutic considerations;
Ethambutol (commonly abbreviated EMB or simply E) is a bacteriostatic
antimycobacterial drug prescribed to treat tuberculosis.
It is usually given in combination with other tuberculosis drugs, such as isoniazid,
rifampicin and pyrazinamide.

Mechanism of action;
Ethambutol is bacteriostatic against actively growing TB bacilli; it works by
obstructing the formation of cell wall.
It disrupts arabinogalactan synthesis by inhibiting the enzyme arabinosyl
transferase. Disruption of the arabinogalactan synthesis inhibits the formation of
the cell wall.
 Pharmacokinetics;

It is well absorbed from the gastrointestinal tract and well distributed in body

tissues

and fluids.

Protein binding 20 to 30%

It is metabolized in the liver.

Half life is 3-4 hr but may be increased in impaired renal function.

Excretion is by the renal route with 50% being excreted unchanged in urine.
Adverse effects;
oOptic neuritis; hence contraindicated in children below 6 yrs of age.

Presents

with red-green color blindness.

oPeripheral neuropathy

oArthralgia

oVertical nystagmus
 Pyrazinamide (PZA);
Therapeutic considerations
Pregnancy risk category C
Pyrazinamide is a drug used to treat tuberculosis.
The drug is largely bacteriostatic, but can be bactericidal on actively replicating
tuberculosis bacteria.
Dosing and presentation;
The usual dose is 20–25 mg/kg daily, or 50–70 mg/kg three times a week.
The British Thoracic Society guidelines are for 1.5 g daily for patients weighing
less
than 50 kg, and 2 g daily for patients weighing 50 kg or more.
Pyrazinamide tablets are usually 500 mg and form the bulkiest part of the
standard
tuberculosis treatment regimen. Pyrazinamide tablets are so large that
pyrazinamide syrup is available as an option for these patients.
Pyrazinamide is also available as part of fixed dose combinations with other TB
drugs such as isoniazid and rifampicin (Rifater/ RIHAZE are examples).
 Pharmacokinetics;
Pyrazinamide is well absorbed orally.
Bioavailability >90%
Half life 9 to 10 hours
It crosses inflamed meninges and is an essential part of the treatment of
tuberculous meningitis.
It is metabolised by the liver and the metabolic products are excreted by the
kidneys.
Pyrazinamide is routinely used in pregnancy. WHO recommend its use in
pregnancy; and there is extensive clinical experience to show that it is safe.
Pyrazinamide is removed by haemodialysis and therefore doses should always
be given at the end of a dialysis session.
 Indications;

Pyrazinamide is only used in combination with other drugs such as isoniazid

and

rifampicin in the treatment of Mycobacterium tuberculosis.

It is never used on its own. It has no other indicated medical uses. In particular,

it

is not used to treat other mycobacteria; Regimens not containing pyrazinamide

must be taken for nine months or more.

Pyrazinamide is a potent antiuricosuric drug.

 Mechanism of action;
Pyrazinamide is a prodrug that stops the growth of Mycobacterium tuberculosis.

M. tuberculosis has the enzyme pyrazinamidase which is only active in acidic

conditions.
Pyrazinamidase converts pyrazinamide to the active form, pyrazinoic acid which

accumulates in the bacilli.

Pyrazinoic acid is thought to inhibit the enzyme fatty acid synthetase I which is

required by the bacterium to synthesize fatty acids.

Pyrazinoic acid is also thought to disrupt membrane potential and interferes with

energy production, necessary for survival of M. tuberculosis.

Mutations of the pyrazinamidase gene are responsible for pyrazinamide

resistance in M. tuberculosis
Side effects;

The most common side effect of pyrazinamide is joint pains

(arthralgia), but this is usually not so severe but can be distressing to patients. It is

never harmful.

The most dangerous side effect of pyrazinamide is hepatotoxicity, which is dose

related.

In the standard four-drug regimen (isoniazid, rifampicin, pyrazinamide, and

ethambutol), pyrazinamide is the most common cause of drug-induced hepatitis. It

is not possible to clinically distinguish pyrazinamide-induced hepatitis from

hepatitis caused by isoniazid or rifampicin; test dosing is required.

Other side effects include nausea and vomiting, anorexia, sideroblastic anemia,

skin rash, urticaria, pruritus, hyperuricemia, dysuria, interstitial nephritis, malaise;

rarely porphyria, and fever.

 Streptomycin;
Therapeutic considerations;

Streptomycin was first isolated in October 19, 1943 by Albert Schatz, a graduate

student, in the laboratory of Selman Abraham Waksman at Rutgers University.

It is derived from the actinobacterium Streptomyces griseus.

Streptomycin is an antibiotic drug, the first of the aminoglycosides to be

discovered, and was the first antibiotic remedy for tuberculosis.

Streptomycin is a bactericidal antibiotic.

 Mechanism of action;

Streptomycin is a protein synthesis inhibitor. It binds to the 30S subunit of the

bacterial ribosome.

This prevents initiation of protein synthesis and leads to death of microbial cells.

Humans have structurally different ribosomes from bacteria, thereby allowing the

selectivity of this antibiotic for bacteria.

 Pharmacokinetics;
Streptomycin is traditionally given intramuscularly.

Aminoglycosides are water soluble and do not readily cross any lipoprotein

barriers. Thus absorption from the intestine is poor.

Plasma protein binding is low approximately 30% or less.

Half life 5 to 6 hours

Aminoglycosides are eliminated as unchanged drug by glomerular filtration and

because of their toxicity, dosage adjustment is necessary to compensate for the

varying degrees of renal impairment, including that of normal aging.

Excretion is by the renal route
 Test dosing for drug-induced hepatitis
Drugs should be re-introduced individually.

This cannot be done in an outpatient setting, and must be done under close
observation.

Patient's pulse and blood pressure should be taken at 15 minute intervals for a minimum

of four hours after each test dose is given for most problems will occur within six hours of

test dosing, (if they are going to occur).

Patients can become very suddenly unwell and access to intensive care facilities must
be

available..
  The drugs should be given in this order:
Day 1: INH at 1/3 or 1/4 dose
Day 2: INH at 1/2 dose
Day 3: INH at full dose
Day 4: RMP at 1/3 or 1/4 dose
Day 5: RMP at 1/2 dose
Day 6: RMP at full dose
Day 7: EMB at 1/3 or 1/4 dose
Day 8: EMB at 1/2 dose
Day 9: EMB at full dose
No more than one test dose per day should be given, and all other drugs should be
stopped
while test dosing is being done.
On day 4, for example, the patient only receives RMP and no other drugs are given. If the
patient completes the nine days of test dosing, then it is reasonable to assume that PZA
has caused the hepatitis and no PZA test dosing need be done