2. Introduction
Tuberculosis (TB) is the most common
cause of infection-related death
worldwide.
In 1993, the World Health Organization
(WHO) declared TB to be a global public
health emergency.
Mycobacterium tuberculosis is the most
common cause of TB.
3. Current therapy of TB follows
several basic principles
1. successful treatment requires more
than one drug to which the organisms
are susceptible .
2. drugs must be taken in appropriate
dose .
3. drugs must be taken regularly.
4. drugs must continue for a sufficient
period of time.
4. Basic Principles of Combination
Drug Regimens
Ithas to be chosen based on
knowledge of the likely drug
susceptibility .
Most include at least two effective
drugs.
Fixed drug combinations contains
INH,RIF or INH,RIF,PZA.
5. DOT
Itis the best way to reassure completion
of appropriate therapy.
One report from Texas compare
407 episodes of TB between 1980-1986
treated with standard therapy.
&581 episodes of TB between 1986-1992
treated with DOT.
Results: despite higher rate of TB among
IV drug abuse &homelessness.
6. Results
Lower rate of 1ry drug resistance
6.7 Vs 13%
Lower rate of acquired drug resistance
2.1 Vs 14%
Lower relapse rate
5.5 Vs 20.9%
7.
8.
9. Recommended Regimens by
ATS/CDC/IDSA
Initial phase Continuation phase
Reg drugs duration Reg drugs duration
1 INH 7d/w 1a INH 7d/w for18w
RIF or 5d/w /RIF or 5d/w 18w
PZA 1b INH 2x/w for 18w
EMB /RIF
PUPLISHED IN 2004
10. Initial phase Continuation phase
Reg drugs duration Reg drugs duration
2 INH 7d/w 2a INH 2x/w
RIF for 2w /RIF for 18w
PZA 2x/w 2b INH once/w
EMB for 6w /RPF for 18w
11.
12. Major Anti-TB drugs
1st line therapy
INH daily dose of 5mg/kg
RIF daily dose of 10 mg /kg
RIFABUTIN daily dose of 5mg/kg
RIFAPANTINE weekly dose of 10mg/kg
PZA daily dose of 15- 30 mg/kg
EMB daily dose of 15-20 mg/kg
13. 2nd line therapy
Reserved for:
Drug intolerance
(include hypersensitivity)
Resistance to 1st line drugs
FDA approved :
Cycloserine , Ethionamide ,Streptomycin &
Capreomycin
Not approved but used to treat MDR-TB:
Levofloxacin , Moxifloxacin, Gatifloxacin,
P-aminosalicylic acid & Amikacin
/Kanamycin.
14. Classified as 2nd for many reasons
1. Lack of clinical experience with the drug
relative to 1st line .
2. More toxicity.
3. Unfavourable pharmacokinitic
4. Increase incidence & severity of adverse
events
16. Monitoring of adverse effects
Baseline :
AST ,BIL, ALP
PLT
CREATININE
VISUAL ACUITY
RED- GREEN COLOR DISCRIMINATION
17. Repeated Measurement should be
:obtained in the following conditions
1. The baseline results are abnormal
2. A drug reaction is suspected
3. HIV infection
4. Liver disease
5. Pregnancy or 1st 3 months of post partum
period
6. Patients on combination therapy with
PZA
19. INH Drug Interactions & Monitoring
Drug Interaction
Phenytoin
Monitoring
Routine monitoring is not necessary
For patients with pre-existing liver disease or who
develop abnormal liver function test should be
measured monthly and when symptoms occur
Prevention
VitaminB6 may prevent peripheral neuropathy and
CNS effects
20. )Rifampin (RIF
Adverse effects:
Cutaneous reactions
Gastrointestinal reactions
Flu-like syndrome
Hepatotoxicity
Severe immunologic reactions
Orange discoloration of bodily fluids
Patientsshould be informed in advance of urine
and contact lens discoloration
22. RIF Monitoring
Monitoring
No routine monitoring required
Whengiven with drugs that interact, may
necessitate regular measurements of the
serum concentrations of the drugs in question
23. )Rifabutin (RFB
Adverse effects:
Hematologic toxicity
Uveitis
GI symptoms
Polyarthralgia
Hepatitis
Rash
Orange discoloration of bodily fluids
Drug interactions and monitoring – see
RIF
24. )Rifapentine (RPT
Adverse effects:
Similarto those associated with RIF
May increase metabolism of co-administered
drugs that are metabolized by hepatic
enzymes
Drug Interactions:
Are likely to be similar to those of RIF
Monitoring:
Similar to that for RIF
25. (Ethambutol (EMB
Adverse effect:
Opticneuritis (impaired perception of the red
and green colors(
Cutaneous reactions
Monitoring
Baseline and monthly tests of visual acuity
and color vision
Educate patient about self monitoring their
vision and reporting any visual changes to
their physician immediately
26. (Pyrazinamide (PZA
Adverse effects:
Hepatotoxicity
GIsymptoms
Non-gouty polyarthralgia
Hyperuricemia
Acute gouty arthritis
Rash
Monitoring
Serum uric acid measurements are not routinely
recommended
Liver function tests should be performed when the
drug is used in patients with underlying liver disease
27. Second-Line Anti-TB Medications
Cycloserine
Psychosis, seizures
Ethionamide and PAS
GI upset
Fluoroquinolones
Tendon rupture
Aminoglycosides
Deafness
Renal failure
28. Importance of Monitoring
Closemonitoring of patients throughout
treatment can:
Prevent serious complications
Promote continuity of care
Improve patient-health care provider
relationship
Encourage adherence
Ensure successful completion of treatment
29. Response to Therapy
Patients
of pulmonary TB should have
monthly sputum smear until two
consecutive negative smears.
For extrapulmonary depends on site.
30. Drug-Resistant Tuberculosis
DEFINITIONS
D rug-resistant tuberculosis" refers to cases of
tuberculosis caused by an isolate of Mycobacterium
tuberculosis, which is resistant to one of the first-line
antituberculosis drugs: isoniazid, rifampin, pyrazinamide,
or ethambutol.
Multidrug-resistant tuberculosis (MDR-TB( is
caused by an isolate of M. tuberculosis, which is
resistant to at least isoniazid and rifampin.
Primary drug-resistance : occur in a patient who has
never received antituberculosis therapy.
Secondary resistance refers to the development of
resistance during or following chemotherapy, for what
had previously been drug-susceptible TB.
31. DIAGNOSIS
The diagnosis of drug-resistant
tuberculosis depends upon the collection
and processing of adequate specimens for
culture and sensitivity testing prior to the
institution of therapy .
Sputum cultures are positive in 85 to 90
percent of cases of pulmonary
tuberculosis, and every attempt should be
made to collect adequate material before
treatment is initiated.
32. The following are important risk
. factors for drug resistance
Previous treatment for tuberculosis
especially if prolonged.
Contact with another patient known to
have drug resistant disease.
Immigration from an area with a high
incidence of drug resistance.
HIV seropositivity.
Substance abuse.
Homelessness.
33. Management of treatment failure
Retreatment of patients with MDR-TB
should be made after careful review of
previous medications.
This includes patients whose :
-disease is progressing despite
compliance with the drug regimen,
-patients presenting for treatment who
have been noncompliant with previous
regimens.
34. The following general principles
apply in these settings
• Any agent taken previously for more than
30 days is likely to have decreased
efficacy.
• An empiric retreatment regimen should
include at least four drugs likely to be
effective, one of them a parenteral agent.
This will usually entail the use of second-
line drugs that have increased toxicity
compared with first line drugs.
35. Patients considered to be at high risk for
relapse who have localized disease may
benefit from surgical resection.
Patients should receive either hospital-
based or domiciliary DOT.
The implications of treatment failure and
further acquired resistance are such that
these cases should receive highest priority
for DOT.
36. Glucocorticoid
Controversial
Predinsone 1mg /kg po od initialy has
been used in combination with anti-TB
drugs for life threatening complication
such as meningitis &pericarditis.
37. Surgical Care
Pulmonary resection in patients with TB
may be required in drug-resistant cases
because of the high likelihood of failure of
the medication regimen.
Surgical resection also may be required in
patients with advanced disease with
extensive caseation necrosis.
Tubercular abscesses and
bronchopleural fistulae also should be
removed surgically.
38. Immunotherapy for Tuberculosis
Protectiveimmunity against
Mycobacterium tuberculosis is believed to
be mediated by T-lymphocytes that
produce the type 1 (Th1) helper T cell
cytokines IFN- and interleukin (IL)-2
39. Administration of low-dose recombinant
human interleukin 2 (rhuIL-2) in
combination with multidrug chemotherapy
to patients with multidrug-resistant
tuberculosis (MDR TB) induces
measurable changes in in vitro immune
response parameters which are
associated with changes in the clinical and
bacteriologic status of the patients
40. interleukin-2 (IL-2) has received increasing
attention as an immunomodulatory drug in
human infectious diseases.
This cytokine is a pivotal regulator of cell-
mediated immunity and has been shown
to induce the proliferation and
differentiation of lymphoid cells .
41. reported that patients with MDR TB
treated with low-dose recombinant human
IL-2 (rhuIL-2), in combination with
optimized antituberculosis chemotherapy,
show evidence of an enhanced
antimicrobial response.
42. Changes included decreased sputum
bacterial load and viability, improved chest
X-ray results, and decreased symptoms in
approximately 60% of patients .
43. IL-2stimulates expansion and enhanced
functional capacity of natural killer cells,
which can eliminate intracellular M.
tuberculosis .
Small studies also suggested that IL-2
has favorable clinical effects on patients
with multidrug-resistant tuberculosis.
44. Potential Effects of IL-2
1st:in
patients with multidrug-resistant
tuberculosis, current therapy is
suboptimal, and adjunctive
immunomodulation may facilitate initial
bacillary clearance and increase cure
rates.
45. 2nd: potential use for immunotherapy is to
shorten the duration of treatment for drug-
susceptible tuberculosis, reducing cost
and increasing treatment completion rate
3rd: down regulate the host inflammatory
responses.
All are still in vitro experiments .