Pharmacotherapy of Tuberculosis

Overview of existing treatment schemes

Antituberculosis treatment has two main objectives.
1. a need to rapidly kill those bacilli living extracellularly in
lung cavities, which are metabolically active and are
dividing continuously;
 in order to attain the negativization of sputum and
 to prevent further transmission of the disease.
2. The necessity to achieve complete sterilization and
elimination of those bacilli replicating less actively in
acidic and anoxic closed lesions, and to kill semi-
dormant bacilli living intracellularly in other host tissues
 responsible for subsequent TB relapses.
• INH
– is the drug with the highest activity against rapidly dividing
bacilli, whereas

• RIF and PZA

– have the greatest sterilizing activity against bacteria that are
not dividing.

• These reasons, along with the prevention of drug

resistance, support the use of a combination therapy
for the treatment of TB.
Drugs for treating TB are usually classified as first- and
second-line drugs.
Traditionally, there are five first-line drugs:
INH, RIF, PZA, EMB, and SM.

Second-line drugs include

the aminoglycosides kanamycin and amikacin, the polypeptide
capreomycin, PAS, cycloserine, the thioamides ethionamide
and prothionamide and several fluoroquinolones such as
moxifloxacin, levofloxacin and gatifloxacin.
Some reports, however, include SM among the second-line
drugs,
since its use has declined in recent years, due to
 the high rates of resistance, and also,

because other more effective drugs have been incorporated

Similarly, new drugs such as the rifamycin derivatives

rifapentine and rifabutin can be considered among the first-line
drugs, and in the near future, it is quite likely that some
fluoroquinolones could be incorporated into the standard
antituberculosis treatment, thus being considered as first-line
drugs.
The current short-course treatment for the complete
elimination of active and dormant bacilli involves two
phases:
initial phase: three or more drugs (usually isoniazid,
rifampicin, pyrazinamide and ethambutol or streptomycin)
are used for two months, and allow a rapid killing of actively
dividing bacteria, resulting in the negativization of sputum
continuation phase: fewer drugs (usually isoniazid and
rifampicin) are used for 4 to 7 months, aimed at killing any
remaining or dormant bacilli and preventing recurrence
• When resistance to any of these first-line drugs is
found or highly suspected, or when adverse effects
to first-line drugs develop during therapy,
– the treatment should include other drugs known
as second-line drugs
INH Inhibit mycolic acid synthesis.
Is prodrug needs catalase for conversion TO active form.

Resistance-high leve deletion of katG gene(encodes catalases synthesis

to increasese).
Low level resistance deletion inhA genes=encodes acyl carrier proteins,
targets.).
*SE=age dependent hepatitis and sidroblastic anemia, SLE.

rifampine Inhibit DNA dependent RNA polymerases(NA-synthesis).

Resistance due to change in enzymes

PYZ Activated by bacterial metabolites=enzymes
Resistance=lack of enzymes
ETAM Inhibit arabinagalactan synthesis(cell wall components)

Dose dependent retrobulbaroptic neuritis, not given<6 years

STM Inhibit protein synthesis, CI=pregnancy
 Treatment regimens
(World Health Organization )

Category I : comprises those patients with

a high priority for treatment who are new smear-
positive patients,
new smear-negative pulmonary TB patients with
extensive parenchymal involvement,
patients with concomitant HIV/acquired
immunodeficiency syndrome (AIDS) disease or
severe forms of extrapulmonary TB.
 Patients
with a lower priority for treatment
Are classified as follows:-
Category II : (relapse, treatment failure or default),
Category III: (new smear-negative pulmonary TB
other than in Category I and less severe forms of
extrapulmonary TB) and
Category IV: (chronic sputum-positive TB after re-
treatment and proven or suspected MDR-TB).
 WHO-recommended treatment regimens
Based on category=smear results and past Tb history
1.Intensive phase=to make patients non-infectious.
4 drugs used, daily used= RHZE
2.Continuation phase.
 further consolidation of elimination of bacilli and prevents
relapses. Monthly collected
RH|HE.
3. Duration of treatment
 menengitis, bone =9-12 months
When drug resistance develops,
patients should be treated with a new combination containing at
least three drugs that they had never received before (or that do
not show cross-resistance with those to which resistance is
suspected).

In these conditions,

the treatment is longer,
more toxic,
more expensive and
less effective than regimens containing first-line drugs, and
should be directly observed.
 Special considerations for drug therapy in
pregnant women include the following:
• pyrazinamide should be reserved for women with
suspected MDR-TB
• Streptomycin should not be used
• Preventive treatment is recommended during pregnancy
• Pregnant women are at increased risk for isoniazid-
induced hepatotoxicity
• Breastfeeding can be continued during preventive therapy
 Special considerations for drug therapy in
children include the following:

• Most children with TB can be treated with isoniazid

and rifampin for 6 months, along with pyrazinamide
for the first 2 months if the culture from the source
case is fully susceptible.
• For postnatal TB, the treatment duration may be
increased to 9 or 12 months
• Ethambutol is often avoided in young children
 Multidrug-resistant TB
• When MDR-TB is suspected,
– start treatment empirically before culture results become available,
then modify the regimen as necessary.
– Never add a single new drug to a failing regimen.
– Administer at least 3 (preferably 4-5) of the following medications,
according to drug susceptibilities:
• An aminoglycoside:
– Streptomycin, • ciprofloxacin,
– amikacin, • ofloxacin
– capreomycin, • A thioamide:
– kanamycin
• Ethionamide, prothionamide
• A fluoroquinolone: • Pyrazinamide
– Levofloxacin • Ethambutol
» best suited over the long term
• Cycloserine
• Terizidone
• Para-aminosalicylic acid
• Rifabutin as a substitute for
rifampin
 isoniazid (INH)
for treatment of active and latent tuberculosis infections.
It is rapidly absorbed and readily diffuses across all body
fluids and tissues.
It penetrates into CSF and is effective for treatment of
central nervous system disease.
is metabolized by the liver and excreted in the urine,
mostly as inactive metabolites.
Although the rate of metabolism is determined by genetic
acetylation phenotype, the acetylation status of an individual
has not been shown to influence the outcome with daily
therapy.
INH is safe during pregnancy.
Hepatitis=0.6%, When it occurs,it usually develops during
the first 4 to 8 weeks of therapy.
Fatal hepathitis=0.02%.
increase the elimination of pyridoxine (vitamin B6), resulting
in peripheral neuropathy=0.2%.
PNP= Increaeses=malnutrition, alcoholism, diabetes,
pregnancy,and uremia increase the risk of peripheral
neuropathy. It usually develops in a “stocking-glove”
fashion and can be prevented by pyridoxine 5 to 50 mg/day.
Hypersensitivity reactions, positive
antinuclear antibody titers=25%, and lupus-like
reactions also can occur with INH therapy=10%.
TIPS ON INH
Hepatotoxicity is the most serious adverse effect
of INH.
Peripheral neuropathy can be prevented with
the coadministration of pyridoxine.
 Rifampin is a potent bactericidal
antimycobacterial agent for active infection.
It is rapidly absorbed and widely distributed
throughout the body and achieves moderate CSF
penetration.
It is predominantly hepatically metabolized with
enterohepatic circulation; lesser amounts are
excreted in the urine.
It is safe in pregnancy.
 Hepatitis = cholestatic =0.6% alone, = 2.7% rifamp
witbilirubinh INH.Cp= an increase in transaminase value
can occur with rifampin; however, increased and
alkaline phosphatase levels are more characteristic.
 Anemia, thrombocytopenia, orange discoloration
of body fluids (including permanent staining of soft
contact lenses), light-chain proteinuria, and
hypersensitivity reactions can occur with rifampin.
 The maximal effect of these drug interactions may be
delayed 1 to 2 weeks.
TIPS ON RIFAMPICINE & ITS GROUP
*• Increased bilirubin and alkaline phosphatase
values may occur with rifampin.
*• Rifampin and (to a lesser extent) rifabutin induce
the hepatic CYP-450 system, decreasing the
serum concentration of many coadministered drugs.
* • Rifabutin may cause uveitis, arthritis or
arthralgias, and bronze skin pigmentation.
Pyrazinamide (PZA)
*is more active in an acidic environment and exerts potent
bactericidal activity within cavitary or suppurative disease.
*the benefit of PZA is less clear beyond the first 2 months of
therapy.
•PZA is readily absorbed and diffuses throughout all body fluids
and tissues and CSF.
•*CDC= recommends it should generally be avoided during
pregnancy.
•PZA
• hepatitis =2% is dose dependent.
• None gouty arthralgia=40%
• * Hyperuricemia is common, although clinical gout is
rare.
•TIPS ON PZA
• PZA is most active during the first 2 months of
therapy and within an acidic medium.
• Hepatitis and hyperuricemia may occur with PZA,
but clinical gout is rare.
Ethambutol
*is readily absorbed, with variable cerebrospinal fluid
penetration.
*It is predominantly excreted in the urine and is safe in
pregnancy.
*Retrobulbar or optic neuritis is the most note worthy toxic
effect of ethambutol.
*It usually manifests as a decrease in red-green color
discrimination, visual acuity, and visual field.
*Caution must be used in young children because visual
testing may be unreliable.
Streptomycin
*is one of the oldest antituberculosis .
*However, because of increased global resistance,
streptomycin is no longer considered a first-line
agent.
* It requires IV or IM injection and is renally excreted.
*Notable toxic effects are vestibular, auditory, and
renal.
* Vestibular, auditory, and renal function should be
closely monitored.
Liver diseases
1. The WHO does not recommend the use of
pyrazinamide in patients who have known chronic liver
disease.
2. If a patient with liver failure requires treatment for TB,
ethambutol, streptomycin and a fluoroquinolone may
be used.
3. The most important risk factor for isoniazid induced
hepatotoxicity is alcohol consumption. Patients receiving
isoniazid should be counseled to stop alcohol.
Renal Disease
1. Isoniazid, rifampicin and pyrazinamide are all
metabolized by the liver and thus safe to use in patients
with renal disease.
2. Avoid etambutol and STM.
2. Ethambutol is excreted through urine and consideration
should be given to replacing it with a second line drug.
3. Patients should receive their medication via DOT after
hemodialysis as dialysis eliminates most of these drugs.
4. Patients with renal disease are at risk for neuropathy and
should receive pyridoxine.
5. Rifampin and INH=<8 mg|kg &<4mg|kg.
Pyridoxine

All patients who are at risk for neuropathy (HIV,

diabetes, renal failure and malnutrition),

pregnant women, and persons with seizures

should receive pyridoxine 50 mg/day while

receiving isoniazid.

**PNP, Sidroblasic anemia (SE-INH)

 TIPS ON SECOND LINE
DRUGS
• • Amikacin, streptomycin, kanamycin, capreomycin,
levofloxacin, gatifloxacin, moxifloxacin, ethionamide,
cycloserine, and PAS are second-line antituberculosis
agents.
• • They usually have reduced activity and increased
toxicity.
• * Increased cost, given daily for 18-24 months.
RESISTANC RESISTANCE RX

INH Rif+PZA+ETHAB+-QUINOLONES|6 MONTHS

RIF INH+PZA+ETHAB+-QUINOLONES|9-12MONTHS

INH+RIF PZA_ETHAM+QUINO+Alternatives|18-24 Months

INH|RIF| PZA+QUINOLONE+2alternatives|18-24 months

ETAMB.
 MDR-MX
• *Treatment with at least4 effective drugs should be
continued for 18 to 24 months .
• *Management of these difficult cases should be
performed by medical personnel with expertise and
experience in administering these complicated
regimens;
• *in addition, appropriate laboratory facilities to
document drug susceptibility and monitor response
should be available .
• *These regimens should be administered by direct
observation.