1. Successful treatment of tuberculosis requires a combination of drugs that the bacteria are susceptible to, taken regularly and for a sufficient duration of time under direct observation. 2. First line drugs include isoniazid, rifampin, pyrazinamide, and ethambutol. Monitoring for adverse effects is important. Multidrug resistant tuberculosis requires treatment with second line drugs that are more toxic. 3. Treatment of drug resistant tuberculosis involves identifying resistance prior to treatment, using at least four effective drugs including injectable agents, directly observed therapy, and consideration of surgery for localized disease.

1. General Principles in
The Treatment of TB
Dr NahId Ali Sherbini

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%

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

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

15. Monitoring
Adverse effects
Clinical response to therapy

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

18. )Isoniazid (INH
 Adverse effects:
 Hepatic enzyme elevation
 Hepatitis
 Peripheral neuropathy
 CNS effects
 SLE-like symptoms
 Hypersensitivity reaction
 Monoamine (Histamine/tyramine poisoning)
 Diarrhea

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

21. RIF Drug Interactions
 Drug Interactions
 Antiinfectives
 Hormone therapy
 Narcotics
 Anticoagulants
 Immunosuppressive agents
 Anticonvulsants
 Cardiovascular agents
 Bronchodilators
 Sulfonylurea hypoglycemics
 Hypolipidemics
 Psychotropic drugs

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 .