2. Introduction
ā¢ Tuberculosis is a kind of communicable
chronic disease caused by M.tuberculosis,
which can invade various tissues and organs
of the whole body.
ā¢ The mycobacteria are slow-growing
intracellular bacilli that cause tuberculosis.
ā¢ In the past decade, tuberculosis cases have
significantly increased, chiefly among AIDS.
3. ā¢ The response of mycobaterial infections
(tuberclulosis) to chemotherapy is slow, and
treatment must be administered for months
to years depending on which drugs are used.
ā¢ Usually, a drug-combination regimen is
required for treatment of tuberculosis;
otherwise microbial resistance to any single
drug, develops rapidly.
4. Classification
ā¢ Anti-tuberculosis drugs can be divided into two
major categories: base on their efficacies and
toxicities
ā¢ First-line drugs: good efficacy, less toxicity and
being well tolerated for patients
ā¢ Second-line drugs: usually used as alternatives
to the first-line drug when drug resistance occurs
or when a particular therapy is required.
5. ā¢ There are 10 drugs approved by the U.S. FDA
for the treatment of TB disease.
ā¢ Of the approved drugs, isoniazid (INH),
rifampin (RIF), ethambutol (EMB), and
pyrazinamide (PZA) are considered first-line
anti-TB drugs and form the core of standard
treatment regimens
6. Anti-TB Drugs Currently Used
DRUG
CLASS
ANTI-TB DRUGS COMMENTS
First-
Line
Drugs
Isoniazid (INH)
Rifampin (RIF)
Pyrazinamide (PZA)
Ethambutol (EMB)
INH, RIF, PZA, and EMB form the core
of initial treatment regimen.
Rifabutin* (RBT) May be used as a substitute for RIF in
the treatment of all forms of TB caused
by organisms that are known or presumed
to be susceptible to this agent.
Rifapentine (RPT) May be used once weekly with INH in
the continuation phase treatment for HIV-
negative patients with noncavitary, drug-
susceptible pulmonary TB who have
negative sputum smears at completion
of the initial phase of treatment.
7. Secon
d-
Line
Drugs
Streptomycin (SM) ļ· SM was formerly considered to be a
first-line drug and in some
instances, is still used in initial
treatment.
ļ· Increasing prevalence of resistance
to SM in many parts of the world
has decreased its overall usefulness.
Cycloserine
Capreomycin
Ļ-Aminosalicylic acid
Levofloxacin*
Moxifloxacin*
Gatifloxacin*
Amikacin/Kanamycin*
Ethionamide
These drugs are reserved for
special situations such as drug
intolerance or resistance.
8. ISONIAZID (INH)
ā¢ It is the most active drug for the treatment of
tuberculosis
ā¢ Fast multiplying organism rapidly killed
ā¢ Act intracellular and extracellular located bacilli
---Active in both acidic and alkaline
environment
9. Pharmacokinetic
ā¢ PEAK BLOOD LEVELS W/IN 1 - 2 hrs AFTER ORAL ADMINISTRATION
ā¢ PEAK BLOOD LEVELS DECLINE TO 50% W/IN 6 HOURS; 50-70% OF DOSE
EXCRETED IN URINE IN 24 HOURS
ā¢ DIFFUSES READILY INTO ALL BODY FLUIDS (cerebrospinal, pleural, and
ascitic fluids), TISSUES, ORGANS & EXCRETA (saliva, sputum,
ā¢ and feces)
ā¢ PASSES THROUGH PLACENTA & INTO BREAST MILK IN
CONCENTRATIONS COMPARABLE TO THOSE IN PLASMA
ā¢ Most INH is metabolized in the liver. [N-Acetylation]
ā¢ RATE OF INH ACETYLATION SHOWS GENETIC VARIATION Fast/Slow =
50:50 Western countries (whites and blacks), Fast/Slow = 90/10
Eskimos and Japanese.
ā¢ EFFECT OF ACETYLATION ON EFFECTIVNESS OF INH
10. Isoniazid: Mechanism of action
ā¢ Probably related to the inhibition of synthesis of
mycolic acids, which are important and characteristic
components of mycobacterial cell wall.
ā¢ As a result of the activity, tubercle bacilli lose their
features of acid-resistance, water-resistance and
proliferating ability, leading to death.
ā¢ Main target site of Isonaizid ā inhA and kasA gene
product in mycolic acid synthesis
Reactive INH+ NAD ā inhA & kasA
Reactive INH + NADP ā Inhibit ,mycobacterial
DHFRs ā intrupt in DNA synthesis
11. Mechanism of Resistance
ā¢ Mutation in catalase peroxidase gene
ā¢ Mutation in inhA or kasA gene
ā¢ Efflux of INH
ā¢ Loss of INH concentrating process in TB bacilli
ā¢ In India resistance with INH ā 18% (In alone or
in combination)
ā¢ No cross resistance reported
12. Isoniazid: Pharmacologic activity
ā¢ It is bactericidal for actively growing tubercle
bacilli. But, for resting tubercle bacilli, it is
bacteriostatic.
ā¢ Isoniazid is able to penetrate into phagocytic
cells and thus is active against both
extracellular and intracellular organisms.
ā¢ This drug is not effective against atypical
mycobacteria.
13. ISONIAZIDE - Clinical uses
ā¢ Isoniazid is the most widely used agent in the
treatment and prophylaxis of tuberculosis.
ā¢ Dose : 300 mg/day
14. Isoniazid: Adverse effects
ā¢ Allergic Reaction: fever, skin rash
ā¢ Hepatotoxicity : Up to 20% of patients taking INH
develop elevated serum amino transferase levels.
ĀØSevere hepatic injury occurs more frequently in
patients over the age of 35, especially in those
who drink alcohol daily.
ĀØIsoniazid is discontinued if symptoms of hepatitis
develop or if the aminotransferase activity
increases to more than three times normal.
15. Peripheral and CNS toxicity occur.
ā¢ ĀØThis toxicity probably results from an increased
excretion of pyridoxine induced by isoniazid, which
produces a pyridoxine deficiency.
ā¢ ĀØPeripheral neuritis, neurological manifestation
(paresthesia, numbness, mental disturbances)
urinary retention, insomnia, and psychotic episodes
can occur.
ā¢ ĀØConcurrent pyridoxine administration with INH
prevents most of these complications.
Prophylactic doseā 10 mg of pyridoxine
Treatment dose ā 100 mg/day of Pyridoxine
ā¢ Other : Lethargy, rashes, fever, acnes, arthralgia
16. Drug Interactions
ā¢ Absorption affect by Alluminium hydroxide
ā¢ INH inhibit the metabolism of Phenytoin,
diazepam, theophylline, Warfarin
ā¢ Rifampicin (inducer) counteract the inhibitory
effect of INH
ā¢ PAS inhibit metabolism of INHā Prolong plasma
half life
17. RIFAMPIN
ā¢ Synthetic derivates of rifamycin B produced by
Sterptomyces mediterranei
ā¢ Efficacy comparable with INH against TB and
better than others
ā¢ It act best on the slowly or intermittently dividing
bacilli
ā¢ It is highly sensitive against M. Leprae
ā¢ Both extra and intracellular bacilli affected
ā¢ It has good sterilizing and resistance preventing
action
18. Mechanism of Rifampin
ā¢ RFP binds strongly to the Ī²-subunit of DNA-
dependent RNA polymerase and thereby
inhibits RNA synthesis.
ā¢ Drug-resistance to RFP, due to target
mutations in RNA polymerase, occurs readily.
ā¢ No cross-resistance to other classes of
antimicrobial drugs.
19. RIM-Pharmacokinetic
ā¢ Oral administration, well absorbed, widely distributed
in body, including sputum and tuberculotic caverna.
Absorption decreased 30% if taken w/food
ā¢ Adequate CSF concentrations of Rifampin achieved only
in the presence of meningeal inflammation.
ā¢ Most of the drug is excreted as a deacylated metabolite
in feces and in the urine. half-life is about 4 hours.
ā¢ Crosses placenta & distributes into breast milk
ā¢ Protein binding is 89%.
20. Rifampin: Pharmacologic activity
ā¢ broad-spectrum
ā¢ It is active against G+ cocci (including drug resistant
S.aureus), some bacteria, mycobacteria
ā¢ It is bactericidal for mycobacteria.
ā¢ It can kill organisms that are poorly accessible to
many other drugs, such as intracellular organisms
and those sequestered in abscesses and lung
cavities.
ā¢ Dose = 600mg = (2) 300mg capsules = well absorbed
21. Rifampin: Clinical uses
ā¢ Mycobacterial infections
ā¢ It often uses in combination with other agents in
order to prevent emergence of drug-resistant
mycobacteria.
ā¢ Leprosy
ā¢ Other infections
ļ¼ Rifampin can be used in a variety of gram-positive
coccal infections, especially the serious cases that
cannot be effectively treated with other drugs.
ļ¼It is also used as prophylaxis for meningitis caused
by highly penicillin-resistant strains of pneumococci.
ļ¼Combination with doxycycline used in brucellosis
22. Rifampin: Adverse effects
ā¢ Urine, sweat, tears, and contact lenses may take
on an orange color because of rifampin
administration, this effect is harmless.
ā¢ Light-chain proteinuria and impaired antibody
response may occur.
ā¢ Rifampin induces hepatic microsomal enzymes
and therefore, affects the half-life of a number
of drugs.
ā¢ When taken erratically in large doses, a febrile
āflu-likeā syndrome can occur.
23. ā¢ Hepatitis is major adverse effect and it is dose
related. Jaundice develop require discontinuation
of drug ā Reversible reaction
ā¢ Cutaneous syndrome: flushng, pruritus, rashes,
redness and watering of eyes.
ā¢ Abdominal Syndrome: Nausea, vomiting,
abdominal cramp
24. Drug Interaction-EMP
ā¢ Major problem with RMP is drug-drug interaction
ā¢ Induces hepatic microsomal enzymes: P450 system; accelerates
metabolism of many drugs making them less effective or ineffective
when Rifampin is being given:
ā Methadone
ā Coumadin
ā Estrogen: Oral Contraceptives
ā Glucocorticoids
ā Digitoxin
ā Anti-arrhythmic agents (quinidine, verapamil, mexiletene)
ā Theophylline
ā Anti-convulsants
ā cyclosporin
HIV-PROTEASE INHIBITORS
25. ETHAMBUTOL
ā¢ Inhibits many strains of M. tuberculosis,
bacteriostatic
ā¢ Well absorbed from the gut and widely
distributed in all body tissues and fluids.
ā¢ As with all anti-tuberculotic drugs, resistance
to ethambutol emerges rapidly when the drug
is used alone.
26. ā¢ No effect on bacteria other than
mycobacteria. Suppresses growth (static) of
organisms resistant to streptomycin and
isoniazid, i.e., no cross resistance.
ā¢ Resistance to ethambutol develops.
27. Mechanism of Action
ā¢ Not clear. May be interfering RNA synthesis
or inhibits synthesis of component of
mycobacterial cell wall ā Arabinogalactan- by
inhibiting the enzyme arabinosyl transferase
(enbAB gene).
ā¢ It resulted into interference in incorporation
of mycolic acid in mycobacterial cell wall
28. Adverse Effects
ā¢ The most common serious adverse effect is dose related
optic neuritis, causing loss of visual acuity and red-green
color-blindness, but are reversible.
ETHAMBUTOL TOXICITY= RETROBULBAR NEURITIS
ā¢ Minimally toxic (<2%) at 15 mg/kg per day (usual dose),
decreased visual acuity, rash, drug fever.
ā¢ Optic neuritis (reversible) -- most important adverse
effect and Dose related: Occurs in 15% of patients
receiving 50 mg/kg per day and 5% of those receiving
25 mg/kg per day and <1% 15 mg/day.
29. PYRAZINAMIDE [PZA]
ā¢ Pyrazinamide is a pyrazine analogue of
nicotinamide. Chemically similar to INH
ā¢ Quickly absorbed after orally administered
ā¢ Widely distributed in body tissues, including
inflamed meninges.
ā¢ Excreted mainly by glomerular filtration
ā¢ It is used in combination with INH and RFP in
short-term therapy to exert its activity against
residual intracellular organisms that may cause
relapse.āGood sterilizing activity
30. ā¢ Main role in sensitive disease is to reduce length
of treatment from 9 months to 6 months
ā¢ At neutral pH, it is inactive, but at pH 5.5 it
inhibits tubercle bacilli and some other
mycobacteria.
ā¢ More lethal to intracellular located bacilli and
those site showing inflammatory response (pH is
acidic in these environment). Highly effective
during first 2 months of therapy when
inflammatory changes are present.
31. Mechanism of Action
ā¢ The MOA of PZA is not well established but it is
like to INH.
ā¢ Similar with INH, PZA also get converted into
reactive metabolite (pyrazinoic acid) by enzyme
pyrazinamidase (pncA gene). The metabolite get
accumulate in mycobacterial and inhibit the
synthesis of mycolic acid but interacting with
different fatty acid synthesis
ā¢ It disrupt the mycobacterial cell membrane and
transport function
ā¢ Resistance develop rapidly if use alone
32. PYRAZINAMIDE TOXICITY
HYPERURICEMIA:
ā PZA inhibits renal excretion of urates
ā All patients have increase in uric acid levels: usually entirely
asymptomatic
ā Occasionally causes arthralgias: Offer patient choice of NSAIDS
or D/C PZA and treat longer
ā Rarely causes acute gouty arthritis, most often in elderly: STOP
PZA
Liver damage is the most serious and common adverse
reactions (Increase in transaminases). Therefore, liver function
studies should be performed before and during therapy.
33. The second-line drugs
The second-line drugs used for tuberculosis infections when
first-line drugs have been discontinued owing to resistance or
adverse effects.
The five drug groups
ā¢ Group 1: First-line oral drugs
ā¢ Group 2: Injectables
ā¢ Group 3: Fluoroquinolones
ā¢ Group 4: Other second-line drugs
ā¢ Group 5: Possible reinforcing drugs (drugs with unclear efficacy)
An MDR-TB treatment regimen requires the use of at least four
active medications against TB (but often involves five)
34. AMINOGLYCOSIDE
ā¢ The poor oral absorption of Aminoglycosides- need
parenteral administration,
ā¢ Toxicity profile of the aminoglycosides, have favored
the use of EMB in first-line anti-tuberculosis therapy
Mechanism of action
ā¢ The mode of action of the aminoglycosides against
mycobacterial species is through their binding to the
30S ribosomal subunit, which affects polypeptide
synthesis, ultimately resulting in inhibition of
translation.
35. Mechanism of resistance
ā¢ Resistance to streptomycin and the other
aminoglycosides in M. tuberculosis usually
develops by mutation of the ribosome target
binding sites.
ā¢ Interestingly, although cross resistance is
observed between amikacin and kanamycin
while these drugs are not cross-resistant with
streptomycin.
36. Streptomycin
ā¢ Streptomycin is the 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.
ā¢ Streptomycin penetrates into cells poorly, and drug
resistance is produced easily.
ā¢ At present, streptomycin is employed when an
injectable drug is needed or desirable, principally
in individuals with severe, possibly life-threatening
forms of tuberculosis , and in treatment of
infections resistant to other drugs.
ā¢ It is always given together with other drugs to
prevent emergence of resistance.
ā¢ Dose: 1 g IM/IV (15-20 mg/kg) daily
37. Kanamycin (Km)
Toxicity
- auditory
- vestibular
- Renal (Nephrotoxicity)
- Electrolyte wasting
ā¢ Assess vestibular function and hearing function prior to initiation of
therapy and at regular intervals during treatment
ā¢ Measure blood urea nitrogen and creatinine throughout treatment
ā¢ Adjust dose for renal failure
ā¢ After bacteriologic conversion, dosage may be reduced to 2 -3 times
per week
ā¢ Dose: 1 g IM/IV (15-20 mg/kg)
38. Amikacin (Amk)
ā¢ Highly similar to kanamycin (can be essentially
considered the same drug)
Dose: 1 g IM/IV (15-20 mg/kg) daily
Side effects:
ā¢ Same as kanamycin; renal failure and ototoxicity,
chemical imbalance, Dizziness
High cross-resistance with kanamycin
Adjust dose in renal failure (same as kanamycin)
39. Macrocyclic Polypeptide Antibiotic
Capreomycin
ā¢ Capreomycin is a macrocyclic polypeptide antibiotic
isolated from Streptomyces capreolus.
ā¢ Capreomycin, like streptomycin and kanamycin, inhibits
protein synthesis through modification of ribosomal
structures at the 16S rRNA
ā¢ Structurally and functionally similar to aminoglycosides
Dose: 1 g IM/IV (15-20 mg/kg) daily
Side effects
ā same as Km/Amk
Some cross-resistance with Km/Amk
Adjust dose for renal failure
40. FLUOROQUINOLONES
ā¢ The fluoroquinolones (moxifloxacin, gatifloxacin,
sparfloxacin, levofloxacin, ofloxacin, and
ciprofloxacin), are bactericidal antibiotics with
excellent activity against M. tuberculosis and are
currently used as second-line drugs in TB
treatment.
ā¢ New-generation fluoroquinolones [moxofloxacin,
gatifloxacin] are under clinical evaluation as first-
line antibiotics with the goal of shortening the
duration of TB treatment.
41. Mechanism of action
ā¢ Fluoroquinolones exert their powerful
antibacterial activity by trapping gyrase and
topoisomerase IV on DNA as ternary complexes,
thereby blocking the movement of replication
forks and transcription complexes.
ā¢ Unlike most other bacterial species, M.
tuberculosis lacks topoisomerase IV, but contains
the genes gyrA and gyrB encoding the A and B
subunits, respectively, of DNA gyrase
42. Ofloxacin (Ofx)
Dose: 800 mg daily
Side effects
ā Generally well-tolerated
ā GI upset, rash, CNS disturbance
Avoid antacids around time of ingestion
(reduces absorption)
Near complete cross-resistance with other
fluoroquinolones
43. Levofloxacin (Lfx)
Dose: 750 mg daily for <50 kg (1000 mg daily for
> 75kg)
ā A higher dose for tuberculosis is used than for
other infections
Side effects
ā Generally well-tolerated
ā GI upset, restlessness, rash, CNS disturbance
ā¢ Adjust dose in renal failure
44. Moxifloxacin (Mfx)
May be more active than earlier generation quinolones
Dose: 400 mg daily
Near complete cross-resistance with other
fluoroquinolones
ā Moxifloxacin may have limited efficacy against some
strains resistant to ofloxacin
No dose adjustment in renal failure
ā Hepatically cleared
45. Macrolides Antibiotics
ā¢ The macrolides are broad-spectrum antibiotics,
which exert their antibacterial effect by binding to
the bacterial 50S ribosomal subunit and inhibiting
RNA-dependent protein synthesis.
ā¢ However, these drugs have limited activity against
wild-type M. tuberculosis.
ā¢ The possible role of macrolides in TB treatment is
an area of active investigation, as recent studies
have reported synergy of macrolides in combination
with other antibiotics.
46. ETHIONAMIDE
ā¢ Ethionamide, a synthetic compound structurally related
to INH, is a pro-drug, requiring activation by the
monooxygenase EthA
ā¢ Similar to INH, ethionamide inhibits mycolic acid
synthesis by binding the ACP reductase InhA.
Dose: 500-1000 mg daily in divided doses
Side effects
ā GI upset, hepatotoxicity, hypothyroidism, peripheral
neuropathy, mettalic taste
Partial cross-resistance with isoniazid, complete with
prothionamide
Hepatically excreted, Measure hepatic enzymes
Co-administer vitamin B6
47. Prothionamide (Pto)
Structurally similar to ethionamide
Dose: 500-1000 mg daily in divided doses
Overall side effect profile similar to ethionamide
ā Slightly less GI side effects
Complete cross-resistance with ethionamide
48. Cycloserine (Cs)
ā Alanine analogue
ā Interferes with cell-wall proteoglycan synthesis
Dose: 500-1000 mg daily in divided doses
Side effects:
ā Seizures, psychosis, depression, irritability, headache, rashes
Renally excreted
Effective CNS penetration
Co-administer B6
ā¢ Assess mental status
ā¢ Measure serum drug levels
49. Terizidone (Trd)
ā Structure is composed of two connected molecules
of cycloserine
ā Commonly used in South Africa in place of
cycloserine
Dose: 500-1000 mg daily in divided doses
Possibly less side effects than cycloserine
Not yet recommended by the WHO
ā There is less information on terizidone than
cycloserine and no direct studies comparing the two
50. Para-aminosalicylic acid (PAS)
ā Various formulations; delayed-
release microcapsules (PASER) best
tolerated
ā Paraaminosalicylic acid (PAS) is
thought to inhibit folic acid
biosynthesis and uptake of iron
Dose of PASER is 4 g (1 sachet) twice
daily
Side effects
ā GI upset, hypothyroidism
ā Hepatitis, electrolyte abnormalities
Hepatic metabolism, renal excretion
Administer with acidic food or drink
51. Group 5: Possible reinforcing
agents
Minimal clinical data to support use in MDR-TB
therapy.
Should only be used in cases of extreme drug
resistance (XDR-TB):
ā Amoxicillin/clavulanic acid
ā Clofazamine
ā Linezolid
ā High dose isoniazid
ā Imipenem
52. Amoxicillin-clavulanic acid (AMX-CLV)
GROUP 5
ā Beta-lactam antibiotic with beta-lactamase
inhibitor
Dose
ā 1000/250 mg twice daily or
ā 875/125mg twice daily
Side effects
ā GI upset, rash
Contraindicated: Penicillin allergy
53. Clofazimine (CFZ)
GROUP 5
ā Substituted iminophenazine
Usual adult dose is 100 mg daily
Side effects
ā Bronzing of skin
ā Malabsorption
ā Abdominal pain (can be severe)
54. Oxazolidinones
ā¢ Oxazolidinones are a new chemical class of
synthetic antibiotics related to cycloserine with
broad-spectrum activity against gram-positive
pathogens through inhibition of protein
synthesis.
55. Linezolid (LZD)
GROUP 5
ā Oxazolidinone: inhibits protein
synthesis, interacting with
ribosomal RNA (50s)
Dosing
ā Coated tablets: 400 and 600 mg
ā Intravenous solution: 2 mg/ml; 100, 200, or
300 mg bags
ā Usual dose: 600 mg twice daily.
ā Some case series have successfully used daily
half dosing (600 mg once daily) to decrease
toxicity and maintain efficacy, however
neuropathic reactions seem to be related to
duration of therapy rather than dose.
56. Linezolid (LZD) (Continued)
Side effects
ā Generally well tolerated for treatment courses
ā¤28 days.
ā Common: diarrhea, nausea, headache, insomnia,
and rash.
ā More serious:
ā¢ myelosuppression (generally reversible with
discontinuation of the drug)
ā¢ optic neuropathy (usually resolved over time with
drug discontinuation)
ā¢ peripheral neuropathy (possibly irreversible).
ā Rare: hypertension, lactic acidosis, pancreatitis
57. Linezolid (LZD) (Continued)
Monitoring
ā CBC weekly during the initial period, then monthly, and
then as needed based on symptoms.
ā There is little clinical experience with prolonged use.
ā Visual function should be monitored in all patients taking
linezolid for extended periods (ā„3 months) and in all
patients reporting new visual symptoms regardless of length
of therapy.
Alerting symptoms:
ā Black, tarry stools or severe diarrhea
ā Unusual bleeding or bruising
ā Extreme tiredness or weakness
ā Numbness, tingling, or burning pain in your hands, arms,
legs, or feet
ā Change in visual acuity, vision blurring, or visual field defect
ā Headache, nausea, or vomiting
58. High-dose isoniazid (H)
GROUP 5 (AT HIGH DOSES)
Dosing
ā 16 to 18 mg/kg per day, typically 600 mg to 1200
mg per week
ā Some clinicians give it three times a week
instead of daily at the 16 to 18 mg/kg dosing
59. Imipenem/Cilastin
GROUP 5āBETA-LACTAM/CARBAPENEM
In vitro activityāvery limited clinical experience
Dosing
ā Adults: 1000 mg IV every 12 hours
ā In children, meropenem preferred: 20-40 mg/kg/dose IV
every 8 hours up to 2 grams per day (high rates of seizures
were seen in children treated with imipenem for TB
meningitis
Side effects
ā Diarrhea, nausea, vomiting
ā Seizure noted in CNS infections
62. General Principles of TB Therapy
Understand
ā¢ Growth patterns of M. tuberculosis,
ā¢ Presence of naturally occurring resistant strains,
ā¢ Mechanisms of available drugs against TB
ā¢ M. tuberculosis exist in faster-growing extracellular
population (e.g., as seen in pulmonary cavities), a
slow-growing intracellular group, and a dormant
population.
ā¢ No existing drug treatment exists against the dormant
group, isoniazid (INH) and rifampin (RIF) do have
bactericidal activity against the growing populations.
ā¢ Pyrazinamide (PZA) is particularly effective within
intracellular environments where the pH is more
acidic.
63. Basic Principles of Treatment
ā¢ Combination therapy with INH, RIF, and PZA. PZA
allows treatment length to be shorter than the use of
INH and RIF alone.
ā¢ Two phases of treatment are given:
ļ¼ First eradicates the many viable, rapidly growing
organisms
ļ¼ The second targets persistent, slower-growing
organisms.
ā¢ Successful treatment can only occur if a patient
adheres to an appropriate course of medication.
ā¢ DOT and combination drugs are strategies to
encourage adherence and prevent drug resistance.
ā¢ Never add one drug to a failing regimen. At least
two drugs must be added to prevent the further
development of drug resistance.
64. Agenda for Tuberculosis Treatment
New anti-tuberculosis drugs are needed for three
main reasons:
ā¢ To shorten or otherwise simplify treatment of
tuberculosis caused by drug-susceptible organisms,
ā¢ To improve treatment of drug-resistant
tuberculosis, and
ā¢ To provide more efficient and effective treatment
of latent tuberculosis infection.
65. STANDARD TREATMENT REGIMENS
FOR PULMONARY TB
ā¢ There are four basic treatment regimens
recommended for treating adults with TB disease
caused by organisms that are known or
presumed to be susceptible to INH, RIF, PZA, and
EMB.
ā¢ Each treatment regimen consists of an initial 2-
month treatment phase followed by a
continuation phase of either 4 or 7 months.
ā¢ Four drugsā INH, RIF, PZA, and EMBā should be
included in the initial treatment regimen until
the results of drug-susceptibility tests are
available.
66. Role of drugs in Initial regimen
ā¢ INH and RIF allow for short-course regimens with
high cure rates.
ā¢ PZA has potent sterilizing activity, which allows
further shortening of the regimen from 9 to 6
months.
ā¢ EMB helps to prevent the emergence of RIF
resistance when primary INH resistance is
present. If drug-susceptibility test results are
known and the organisms are fully susceptible,
EMB need not be included.
ā¢ For children whose clarity or sharpness of vision
cannot be monitored, EMB is usually not
recommended
67. Continuation Phase
ā¢ The continuation phase of treatment is given for either 4
or 7 months.
ā¢ The 4-month continuation phase should be used in
patients with uncomplicated, noncavitary, drug-
susceptible TB, if there is documented sputum conversion
within the first 2 months.
The 7-month continuation phase is recommended only for
ā¢ Patients with cavitary or extensive pulmonary TB disease
caused by drug-susceptible organisms and whose sputum
culture obtained at the time of completion of 2 months of
treatment is positive;
ā¢ Patients whose initial phase of treatment did not include
PZA; or
ā¢ Patients being treated with once-weekly INH and RPT and
whose sputum culture at the time of completion of the
initial phase (i.e., after 2 months) is positive.
68. Purpose of different phases in TB
Treatment
Phase Purpose
Initial phase
ļ· Kills most of the tubercle bacilli during the first 8 weeks
of treatment, but some bacilli can survive longer
ļ· Prevents the emergence of drug resistance
ļ· Determines the ultimate outcome of the regimen
Continuation
phase ļ· Kills remaining tubercle bacilli (after initial phase)
ļ· If treatment is not continued long enough, the surviving
bacilli may cause TB disease in the patient at a later
time
69. Treatment completion
ā¢ The duration of therapy depends on the drugs
used, the drug-susceptibility test results of the
isolate, and the patientās response to therapy.
ā¢ Most patients with previously untreated
pulmonary TB disease can be treated with either
a 6-month or a 9-month regimen, although the
6-month regimen is used for the majority of
patients.
ā¢ All 6-month regimens must contain INH, RIF, and
initially, PZA. The goal is to complete all doses
within 1 year
ā¢ Follow-Up after Treatment
71. ALTERNATIVE TB TRETMENT REGIMENS
ā¢ Alternative TB treatment regimens may be
considered if it is not possible to employ the
standard four-drug regimen, either because
of drug intolerance, toxicity, or resistance to
one primary drug.
75. REGIMENS FOR DRUG-RESISTANT TB
INCLUDING MDR-TB
ā¢ Mono-drug resistance is defined as resistance to only
one anti-TB drug.
ā¢ MDR-TB is defined as TB that is resistant to at least
INH and RIF.
ā¢ TB patients infected with multidrug-resistant
organisms are much more difficult to treat because
they often require the use of second-line, more toxic
drugs and they often require a more prolonged
treatment course.
ā¢ Patients with acquired drug resistance can infect
others who will then develop infection and disease
that will have the same resistance pattern (primary
resistance)
76. ā¢ Due to differences in susceptibility patterns, reduced
efficacy or longer duration of treatment, and higher
toxicities of second- line anti-TB drugs, therapy for MDR-
TB must be individualized and must involve consultation
with TBC.
77. Treatment Regimens for MDR-TB
ā¢ Use at least three drugs to which the organism is
sensitive. Preferably, the patient should never
have been treated with those drugs. Initially, one
drug should be a bactericidal injectable agent.
ā¢ Duration of treatment must be 18 to 24 months
post culture conversion to negative.
ā¢ All patients with MDR-TB must be treated with
daily DOT.
ā¢ Women of childbearing age with MDR-TB should
generally not begin treatment until pregnancy is
ruled out, and should be strongly encouraged to
use birth control throughout the treatment
course, as certain second- line drugs have a
potential for teratogenicity during pregnancy.
78. TREATMENT REGIMENS IN HIV-
INFECTED INDIVIDUALS
Clinicians who manage TB and HIV co-infection
should understand the following concepts in
addition to initial TB treatment principles:
ā¢ Side effect profiles of HIV antiretroviral (ARV)
drugs
ā¢ Drug-drug interactions between anti-TB drugs,
particularly the rifamycins, and ARV drugs
ā¢ Rifabutin dosing and toxicity
79. ā¢ In certain situations, it may be recommended that ARV
therapy be started somewhat after initiation of TB
therapy.
ā¢ It is therefore important that the TB clinician and the
HIV specialist work to coordinate their efforts.
Initial Treatment Regimen for Persons not Receiving
Antiretroviral Therapy
ā¢ HIV- infected individuals who are not receiving and are
not considered candidates for ARV therapy should
receive standard four-drug therapy.
ā¢ A six month regimen is considered adequate for
treatment completion in most cases, in some cases a
longer treatment course may be necessary, depending
upon clinical response to therapy.
80. Initial Treatment Regimen for Persons Currently
Receiving Antiretroviral Therapy
ā¢ Drug interactions between ARV regimens
[notably the protease inhibitors (PIs) and
nonnucleoside transcriptase inhibitors (NNRTIs)]
and the rifamycins occur via the cytochrome
P450-3A (CYP3A) pathway.
ā¢ Rifamycins induce the CYP3A pathway, which
may decrease the serum concentrations of
certain anti-HIV drugs.
ā¢ Rifabutin (RFB), however, is a less potent inducer
of CYP3A, and thus may be used as a substitute
for RIF when treating TB in patients on certain
PIs or NNRTIs.
81. ā¢ Six months of a rifabutin regimen is the
standard treatment length, although in some
cases a longer treatment course may be
necessary.
ā¢ Pyridoxine (vitamin B6) may decrease the risk
of peripheral neuropathy in patients on both
NRTIs and INH, and be added to all treatment
regimens containing INH.
ā¢ Alternative regimens for patients who are
unable to tolerate a rifamycin must be
obtained through consultation with TBC.
82. TB treatment regimens for drug-susceptible strains in HIV-
infected persons with a six month rifabutin regimen
*Pyridoxine should be administered for the entire treatment course; all individuals must
be on DOT
ā EMB should be continued throughout the entire induction phase
84. Treatment of TB in Pregnancy
Initiation with four drug regimen (INH, RIF, PZA, EMB) as in non-pregnant
women, with the following considerations:
ā¢ While PZA has not been recommended by the CDC for use in pregnancy due to
lack of data, no adverse effects have been documented to the fetus so the
advantage of a shorter regimen must be taken into consideration as compared
to the unknown risk to the fetus.
ā¢ SM and other Aminoglycosides are contraindicated due to toxic effects on the
fetus.
ā¢ Anti-TB therapy can be administered to the breast-feeding mother; no known
harm to the infant has been documented.
ā¢ Postpartum Antituberculosis medications received by the mother do not
produce adequate levels in the breast milk to protect the infant against TB
infection if such protection is indicated.
ā¢ Pyridoxine (vitamin B6) should be administered during the course of therapy
unless the woman is taking a prenatal vitamin with equivalent amounts of
pyridoxine.
ā¢ Suspected or known MDR-TB cases require immediate consultation with TBC
because second- line drugs for TB may have teratogenic risks.
85. Pregnancy in HIV-Infected Women
ā¢ A number of issues complicate the treatment of the
HIV-infected pregnant woman who has TB disease.
ā¢ Pregnancy alters the distribution and metabolism of a
number of drugs, including antiretroviral drugs (there
is very little information on whether the metabolism
of anti-TB drugs is altered during pregnancy).
ā¢ The serum concentrations of protease inhibitors are
decreased during the latter stages of pregnancy.
There are no published data on drug-drug interactions
between anti-TB and antiretroviral drugs among
pregnant women. However, it is likely that the effects
of RIF on protease inhibitors are exacerbated during
pregnancy.
86. PERSONS WITH ADDITIONAL
TREATMENT CONSIDERATIONS
ā¢ Renal Insufficiency and End-stage Renal
Disease
Renal insufficiency complicates the management of TB disease
because some anti-TB drugs are cleared by the kidneys.
Alteration in dosing of anti-TB drugs is commonly necessary in
patients with renal insufficiency and end-stage renal disease
(ESRD) requiring hemodialysis.
87. ā¢ Visual toxicity from EMB is more common in patients
with renal insufficiency.
ā¢ Monitoring serum concentrations will be very useful to
ensure that adequate, yet safe, doses are given.
ā¢ INH and RMP are safe to give in the usual doses since
these drugs are metabolized mostly by the liver.
ā¢ The use of injectables (streptomycin, amikacin,
kanamycin and capreomycin) should be avoided in
patients with impaired renal function, as these drugs are
excreted by the kidney and may cause worsening renal
function as well as other toxicities
88. Hepatic Disease
The treatment of TB disease in patients with
unstable or advanced liver disease is problematic
for several reasons:
ā¢ The likelihood of drug-induced hepatitis is greater;
ā¢ The implications of drug-induced hepatitis for
patients with marginal hepatic reserve are
potentially serious, even life-threatening; and
ā¢ Fluctuations in the indicators of liver function
related to the pre-existing liver disease can
confound monitoring for drug-induced hepatitis.
ā¢ A suggested regimen is an FQN plus EMB plus an
injectable (amikacin) for the first 2 months
followed by an FQN and EMB for a total of 18
months.