3. Categories of tuberculosis and their treatment regimens
have been recommended by WHO.
bone tuberculosis is classified to be a severe form of
extrapulmonary tuberculosis and hence should be given
Category I treatment (2HRZE & 4HR i.e. 2 months of
H,R,Z and E followed by 4 months of H and R).
two phases: an initial ‘Intensive phase’, consisting of
four to five drugs to rapidly destroy the majority of the
organisms
a ‘continuation phase’ which consists of two to three
drugs.
4. Historically, the recommended duration was - 18 to 24-no scientific
basis
Even today there is lack of consensus regarding the ideal duration of
treatment for bone TB.
Uncertainty about the penetration of osteoarticular lesions by the
available drugs and the fear of early or late recurrence forced the
surgeons to continue chemotherapy for prolonged periods.
Modern anti-tuberculous drugs have been shown to penetrate
osseous tissue in amounts much higher than the minimal inhibitory
concentrations.
Wallace Fox for the first time proved that addition of R or Z to
regimens containing H made it possible to shorten the duration of
treatment
6. ISONIAZID (INH)
Isoniazid is the most active drug for the
treatment of tuberculosis caused by
susceptible strains
structural similarity to pyridoxine.
MOA: Isoniazid inhibits synthesis of mycolic
acids, which are essential components of
mycobacterial cell walls.
.
7. orally administered, well absorbed, widely
distributed in body, including cerebrospinal
fluid.
INH can also penetrate into macrophages.
Most INH is metabolized in the liver.
8. PHARMACOLOGIC ACTIVITY
bactericidal - actively growing tubercle bacilli.
bacteriostatic -resting tubercle bacilli.
Isoniazid is able to penetrate into phagocytic
cells and thus is active again both extracellular
and intracellular organisms.
DOSE: ADULTS: PO/IM 5 mg/kg/day as single
daily dose (max 300 mg/day). INFANTS &
CHILDREN: PO/IM 10 to 20 mg/kg/day in
single daily dose (max 300 mg/day).
9. ADVERSE EFFECTS
Allergic Reaction: fever,skin rash
Hepatotoxicity : Up to 20% of patients taking INH
develop elevated serum amino transferase levels.
Severe hepatic injury occurs more frequently in
patients over the age of 35, especially in those
who are alcoholic.
Isoniazid is discontinued if symptoms of hepatitis
develop or if the aminotransferase activity
increases to more than three times normal.
10. Peripheral and CNS toxicity - toxicity results
from an increased excretion of pyridoxine
induced by isoniazid, which produces a
pyridoxine deficiency.
Peripheral neuritis, urinary retention, insomnia,
and psychotic episodes can occur.
Concurrent pyridoxine 25–50 mg/d
administration with INH prevents most of these
complications.
11. Isoniazid as a single agent is also indicated for
treatment of latent tuberculosis. The dosage is
300 mg/d (5 mg/kg/d) or 900 mg twice weekly
for 9 months.
12. RIFAMPIN
Synthetic derivates of rifamycin B produced by
Sterptomyces mediterranei
oral administration, well absorbed, widely
distributed in body.
most of the drug is excreted as a deacylated
metabolite in feces and in the urine.
half-life is about 4 hours.
13. PHARMACOLOGY
It is bactericidal for mycobacteria.
It can kill organisms that are poorly accessible to
many other drugs, such as intracellular organisms
and those sequestered in abscesses.
MOA: It binds strongly to the β-subunit of DNA-
dependent RNA polymerase and thereby inhibits
RNA synthesis.
Drug-resistance is due to target mutations in RNA
polymerase, occurs readily.
No cross-resistance to other classes of
antimicrobial drugs.
14. ADVERSE EFFECTS
Urine, sweat, tears, and contact lenses may take
on an orange color because of rifampin
administration, this effect is harmless.
Light-chain proteinuria and impaired antibody
response may occur.
Rifampin induces hepatic microsomal enzymes
and therefore, affects the half-life of a number of
drugs.
When taken erratically in large doses, a febrile
“flu-like” syndrome can occur.
15. DOSE
Rifampin, usually 600 mg/d (10 mg/kg/d)
orally, must be administered with isoniazid or
other antituberculous drugs to patients with
active tuberculosis to prevent emergence of
drug-resistant mycobacteria.
16. ETHAMBUTOL
bacteriostatic
Well absorbed from the gut and widely
distributed in all body tissues and fluids.
resistance to ethambutol emerges rapidly
when the drug is used alone.
The most common serious adverse effect is
dose-related optic neuritis, causing loss of
visual acuity and red-green color-blindness, but
are reversible.
17. Ethambutol hydrochloride, 15–25 mg/kg, is
usually given as a single daily dose
50 mg/kg when a twice-weekly dosing
schedule
18. PYRAZINAMIDE
Pyrazinamide is a pyrazine analogue of
nicotinamide.
pH 5.5 it inhibits tubercle bacilli and some
other mycobacteria.
Quickly absorbed after oral administration
Widely distributed in body tissues,including
inflamed meninges.
Excreted mainly by glomerular filtration
19. ADVERSE EFFECTS
Major adverse effects of pyrazinamide include
hepatotoxicity (in 1–5% of patients)
nausea, vomiting, drug fever, and
hyperuricemia.
Hyperuricemia may provoke acute gouty
arthritis.
DOSE: 40–50 mg/kg is used for thrice-weekly or
twice-weekly treatment regimens
20. STREPTOMYCIN
Streptomycin - first antimicrobial drug used to
treat tuberculosis.
It is effective against most tubercle bacilli, but
its activity is weaker than that of INH and RFP.
Streptomycin penetrates cells poorly-produce
drug resistance.
It is always given together with other drugs to
prevent emergence of resistance.
21. The typical adult dose is 1 g/d (15 mg/kg/d). If
the creatinine clearance is less than 30
mL/min or the patient is on hemodialysis, the
dose is 15 mg/kg two or three times a week
22. MDR TB
Multi-drug-resistant tuberculosis (MDR-TB) is
defined as tuberculosis that is resistant to at
least isoniazid (INH) and rifampicin.
multidrug-resistant tuberculosis can be cured
with long treatments of second-line drugs, but
these are more expensive than first-line drugs
and have more adverse effects.
25. WHEN CAN IT BE USED
(1) in case of resistance to first-line agents;
(2) in case of failure of clinical response to
conventional therapy;
(3) in case of serious treatment-limiting
adverse drug reactions;
(4) when expert guidance is available to deal
with the toxic effects
26. ETHIONAMIDE
Ethionamide is chemically related to isoniazid
blocks the synthesis of mycolic acids.
It is poorly water-soluble and available only in
oral form.
It is metabolized by the liver
Ethionamide is administered at an initial dose
of 250 mg once daily, which is increased in
250-mg increments to the recommended
dosage of 1 g/d (or 15 mg/kg/d), if possible.
27. ADVERSE EFFECTS
intense gastric irritation , neurologic symptoms
Ethionamide is also hepatotoxic.
Neurologic symptoms may be alleviated by
pyridoxine.
Resistance to ethionamide as a single agent
develops rapidly in vitro and in vivo.
low-level cross-resistance between isoniazid
and ethionamide.
28. CAPREOMYCIN
peptide protein synthesis inhibitor, antibiotic
obtained from Streptomyces capreolus.
Daily injection of 1 g intramuscularly
Capreomycin (15 mg/kg/d) is an important
injectable agent for treatment of drug-resistant
tuberculosis.
Strains of M tuberculosis resistant to
streptomycin or amikacin (eg, the multidrug-
resistant W strain) are susceptible to
capreomycin.
Resistance to capreomycin, may be due to an rrs
mutation.
29. nephrotoxic and ototoxic.
Tinnitus, deafness, and vestibular disturbances
occur.
The injection causes significant local pain, and
sterile abscesses may occur.
Toxicity is reduced if 1 g is given two or three
times weekly after an initial response has been
achieved with a daily dosing schedule
30. CYCLOSERINE
Cycloserine is an inhibitor of cell wall synthesis.
Cycloserine is cleared renally, and the dose
should be reduced by half if creatinine
clearance is less than 50 mL/min.
ADVERSE:peripheral neuropathy and central
nervous system dysfunction, depression and
psychotic reactions
31. Pyridoxine 150 mg/d should be given with
cycloserine to ameliorates neurologic toxicity.
Adverse effects - most common during the first 2
weeks of therapy, occur at higher doses.
Side effects can be minimized by monitoring peak
serum concentrations.
The peak concentration is reached 2–4 hours
after dosing. The recommended range of peak
concentrations is 20–40 mcg/mL
32. Contraindications- Epilepsy; depression; severe
anxiety or psychosis; severe renal insufficiency;
excessive concurrent use of alcohol.
Route/Dosage
ADULTS: PO 250–500 mg q 12 hr; start with 250
mg q 12 hr for first 2 wk (maximum 1 g/day).
CHILDREN: PO 10–20 mg/kg/day administered
in 2 equally divided doses (maximum 1 g/day).
33. AMINOSALICYLIC ACID (PAS)
Competitively antagonizes metabolism of para-
aminobenzoic acid, resulting in bacteriostatic
activity against Mycobacterium tuberculosis.
Adverse:Peptic ulceration and hemorrhage may
occur. Hypersensitivity reactions may occur
after 3–8 weeks of aminosalicylic acid therapy.
34. Infrequently used now since better tolerated
drugs are available
ADULTS: PO 12 to 16 g/day in 2 to 3 divided
doses. CHILDREN: PO 275 to 420 mg/kg/day
in 3 to 4 divided doses.
Contraindications; Severe hypersensitivity to
aminosalicylate sodium and its congeners
35. KANAMYCIN & AMIKACIN
Aminoglycoside antibiotics
Kanamycin has been used for treatment of TB
caused by streptomycin-resistant strains, but
the availability of less toxic alternatives (eg,
capreomycin and amikacin) has rendered it
obsolete
Most MDR strains are amikacin sensitive
Amikacin is also active against atypical
mycobacteria
36. no cross-resistance between streptomycin and
amikacin, but kanamycin resistance often indicates
resistance to amikacin as well.
Serum concentrations of 30–50 mcg/mL are achieved
30–60 minutes after a 15 mg/kg intravenous infusion.
indication- treatment of tuberculosis suspected or
known to be caused by streptomycin-resistant or
multidrug-resistant strains.
Amikacin must be used in combination .
The recommended dosages are the same as that for
streptomycin.
37. FLUOROQUINOLONES
ciprofloxacin, levofloxacin, gatifloxacin, and
moxifloxacin inhibit strains of M tuberculosis
Moxifloxacin is the most active against M
tuberculosis by weight
the drug must be used in combination with two or
more other active agents-to prevent resistance
standard dosage of ciprofloxacin is 750 mg orally
twice a day, levofloxacin is 500–750 mg once a
day, moxifloxacin is 400 mg once a day.
38. LINEZOLID
Prevents the formation of a functional 70S
initiation complex, which is essential to the
bacterial translation process.
It achieves good intracellular concentrations.
Linezolid has been used in combination with
other second- and third-line drugs to treat
patients with tuberculosis caused by multidrug-
resistant strains
39. adverse effects; bone marrow suppression and
irreversible peripheral and optic neuropathy,
have been reported with the prolonged courses
600-mg (adult) dose administered once a day
it should be considered a drug of last resort for
infection caused by multidrug-resistant strains.
40. RIFABUTIN
Inhibits DNA-dependent RNA polymerase in
susceptible strains of bacteria.
Its activity is similar to that of rifampin, and
cross-resistance with rifampin is virtually
complete.
Rifabutin is both substrate and inducer of
cytochrome P450 enzymes.
41. it is a less potent inducer, rifabutin is indicated
in place of rifampin for treatment of
tuberculosis in HIV-infected patients who are
receiving concurrent antiretroviral therapy with
a protease inhibitor or NNRTI (eg, efavirenz)
DOSE;
ADULTS: PO 300 mg once daily. INFANTS AND
CHILDREN: PO Up to 5 mg/kg/day.
42. RIFAPENTINE
Rifapentine is an analog of rifampin
it is a bacterial RNA polymerase inhibitor.
potent inducer of CYT P450
600 mg (10 mg/kg) once weekly is indicated for
treatment of tuberculosis caused by rifampin-
susceptible strains during the continuation phase
only .
Rifapentine should not be used to treat HIV-
infected patients because of an unacceptably high
relapse rate with rifampin-resistant organism.
43. XDR TB
XDR-TB is defined as TB that has developed
resistance to at least rifampicin and isoniazid ,
as well as to any member of
the quinolone family and at least one of the
following second-line anti-TB injectable
drugs: kanamycin, capreomycin, or amikacin
44. TB AND HIV CO-INFECTION
3–5 % of patients with pulmonary TB develops
musculoskeletal lesions but the incidence of
musculoskeletal lesions increases to 60 % in
patients who are HIV positive.
Direct observational therapy is even more
important for HIV-positive tuberculosis patients
and is known to significantly decrease mortality
in these patients
45. addition of rifampicin to the drug regimens in
HIV patients significantly reduces mortality ,
protease inhibitors and NNRTI interact with
rifampicin and therefore should not be
prescribed along with rifampicin.
PARADOXICAL WORSENING- when antiretroviral
therapy is started in a patient being treated
with tb, there is rapid worsening of symptoms-
improvement in inflamatory response
46. anti-retroviral is known to activate latent
tuberculosis in HIV-positive patients which is
supposed to be due to the immune
reconstitution syndrome
