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 โIntensive phaseโ, consisting of
four to five drugs to rapidly destroy the majority of the
organisms
๏ a โcontinuation phaseโ 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 25โ50 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 ฮฒ-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
โflu-likeโ 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, 15โ25 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 1โ5% of patients)
๏ nausea, vomiting, drug fever, and
hyperuricemia.
๏ Hyperuricemia may provoke acute gouty
arthritis.
DOSE: 40โ50 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 2โ4 hours
after dosing. The recommended range of peak
concentrations is 20โ40 mcg/mL
32. ๏ Contraindications- Epilepsy; depression; severe
anxiety or psychosis; severe renal insufficiency;
excessive concurrent use of alcohol.
๏ Route/Dosage
ADULTS: PO 250โ500 mg q 12 hr; start with 250
mg q 12 hr for first 2 wk (maximum 1 g/day).
CHILDREN: PO 10โ20 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 3โ8 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 30โ50 mcg/mL are achieved
30โ60 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 500โ750 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
๏ 3โ5 % 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