1. Multidrug resistant tuberculosis,
Extended - Drug resistant
tuberculosis, DOTS

2.  A Global Emergency
 Kills 5,000 people per day
 2.3 million people die each year
 Highly prevalent in Pakistan-the estimated incidence is
around 2,50,000 per year
 Ranks 6th among the 22 high burden countries of TB in
the world.

3.  The 22 countries most affected by tuberculosis
are Afghanistan, Bangladesh, Brazil, Cambodia,
China, the Democratic Republic of Congo,
Ethiopia, India, Indonesia, Kenya, Myanmar,
Nigeria, Pakistan, Peru, the Philippines, Russia,
South Africa, Thailand, Tanzania, Uganda,
Vietnam and Zimbabwe

4.  Emergence of multi-drug resistant (MDR-TB),
extremely drug resistant tuberculosis (XDR-
TB) and latent TB have been the major
constraints in the eradication of TB.

5.  Data from the latest 12 month period
 the highest ever number of infectious
patients – 2.3 million people – were cured
with the launch of DOTS
 87% of treated patients being cured
 85% global target was exceeded

6.  estimated half a million MDR-TB cases occur per
year
 almost 30 000 were officially reported
 6000 known to be treated
 but almost 29 ,000 people are expected to be
treated in 2010.

7.  Eradicating M. tuberculosis infection
 Preventing development of drug resistance
 Preventing relapse of infection

8.  Occur in a patient who has never received
antituberculosis therapy

9.  The development of resistance during or
following chemotherapy in patients who
previously had drug-susceptible tuberculosis.
 Main cause of primary drug resistance due to
transmission of resistant strains.

10.  Cases of tuberculosis caused by an isolate of
Mycobacterium tuberculosis that is resistant
to one of the first-line antituberculosis drugs:
INH, RMP, PZA, EMB, or streptomycin

11. A.Genetic mutations occur spontaneously-
confer resistance to Anti-Tuberculous drugs
 are present in Wild type M tuberculosis isolates
 occur by chance alone
 do not depend upon prior drug exposure
 not linked
 occur in frequency specific for each drug
1 in 107 for INH 1 in 108 for STM and INH
1 in 1010 for RMP 1 in 1014 for INH & RMP

12. Wild TB Strain
Spontaneous mutation
Strains with genetic
drug resistance
Selection: Inadequate
treatment
Acquired drug
resistance
Primary Drug
Resistance

13. B. Treatment with a Single TB drug-
Due to natrural occurrence of spontaneous
mutations, treatment with one drug (or one
efective drug) leads to development of
resistance .
- drug susceptible bacteria will be killed
- drug resistant bacteria will survive

14. ))
 1950s-1970s:
Mycobacterium tuberculosis resistant to INH,
streptomycin and / or PAS
 1980s-curreny:
TB that is resistant at least to INH and
RMP
Isolates that are multiply-resistant to any
other combination of anti-TB drugs but not to
INH and RMP are not classed as MDR-TB

15.  While community based information is
lacking, laboratory data suggests an
increasing frequency of MDR from 14% in
1999 to 28% in 2004[6] and 47% in 2006[8].
 (referemces: 6. utt T, Ahmad RN, Kazmi SY, Rafi N. Multi-drug resistant
tuberculosis in Northern Pakistan. J Pak Med Assoc. 2004;54:469–472(PUBMED)
8. rfan S, Hassan Q, Hasan R. Assessment of resistance in multi drug resistant
tuberculosis patients. J Pak Med Assoc. 2006;56:397–400. [PubMed]

16.  MDR Bacilli-resistant to at least INH and RM.
 Are the consequence of human error in any of
the following:
prescription of chemotherapy
management of drug supply
case management
process of drug delivery to the patient

17.  MDR-TB plus
- resistance to one of the fluroquinolones
 Ofloxacin
 Levofloxacin
 Moxifloxacin
AND
-resistance to one of the second line injectables
 Amikacin
 Kanamycin
 Capreomycin

18.  XDR plus cycloserine, PAS, all injectables
 15 TDR isolates identified in IRAN

19.  Resistance to all major
anti-TB drugs
 Treatable but requires
extensive chemotherapy
upto 2 yrs of treatment.
 Expensive
 Drugs are toxic to the
patient

20.  Previous treatment especially if prolonged
 Contact with drug resistant patient
 Country of origin East Europe Former USSR
Middle East South and SE Asia
Latin America Africa
 Age (In MDR area, commoner in children)
 HIV (Where MDR common)
 Substance abuse and homelessness

21. Drug Gene
Rifampicin rpoB
Streptomycin rps
Isoniazid No: base pairs
katG
inhA

22. Programmatic Drugs: Patients:
Inadequate Inadequate drug
Supply/Quantity intake
Absence of guidance Non-availability of Poor adherence (or
or certain drugs (stock outs poor DOT) – lack of
Inappropriate or delivery disruptions) Information
guidelines Poor quality non-availability of
Non-compliance with Poor storage conditions free drugs
 guidelines Wrong dosages or Adverse drug
Inadequate training of combination reactions
health staff Social and
No monitoring of economic barriers
 treatment Malabsorption
Poorly organized or Substance abuse
funded TB control disorders
programmes

23.  Treat with adequate number of drugs to prevent
emergence of further resistance
- use more drugs if susceptibility tests pending (often
start with 5-6 drugs)
 DRUG SELECTION
- at least 3 new drugs not previously not used
- those with proven or suspected susceptibility
- as many bactericidal drugs as possible
-Any first line drugs with proven susceptibility
 Limit toxicity a much as possible

24. Step 1 Use any One of
available plus plus One of
these
these
 Begin Injectable agents
with a 1st line 1st line drugs Fluroquinolones Amikacin
agents to PZA & EBM Levofloxacin Capreomycin
which the isolate
Is susceptible
Moxifloxacin Streptomycin
Add a fluroquinolones a
nd an injectable drug
Kanamycin
Based on susceptibllity
 Add
2 line drugs
nd
Strep 2 Oral 2nd line drugs
Until u have
4-6 drugs to which Cycloserine
isolate is susceptible Ethionamide
PAS
 if there are not 4-6 drugs 3rd line drugs
Available, consider 3rd line
Imepenem
in consult with MDRTB Step 3
experts Macrolides
Linezolid
Amoxicillin/Clavulante

25.  Treat at least 18-24 months after conversion of
the culture to the negative
 Continue injectables to at least 6-12 months
after conversion of the culture to the negative
 Shorter therapy for limited, primary or early
disease

26.  Primarily available for INH & rifampin
 gene probe for rpoB ( for Rifampicin)is
available in some countries & this serves as a
useful marker for MDR-TB
 If a gene probe (rpoB) test - positive, then it is
reasonable to omit RMP and to use
SHEZ+MXF+cycloserine

27.  Careful history taking for previous treatment regimens.
 Compliance of the drugs in the previous regime
 Determine the status of sputum smears at all junctures (in terms of
positivity ,conversions and sensitivities – if available).
 Confirmed/ Strongly suspect MDR TB
 Counsel the Patient and family members
 Send Tissue / sputum for culture and sensitivity testing (if available)
 Start MDR Regimen

28.  Depends on a number of factors:
 How many drugs the organism is resistant to (the
fewer the better),
 How many drugs the patient is given (Patients
treated with five or more drugs do better),
 Whether an injectable drug is given or not (it should
be given for the first three months at least),

29.  The expertise & experience of the physician
responsible
 How co-operative the patient is with treatment
(treatment is long, requires persistence &
determination on the part of the patient),
 HIV positive or not (HIV co-infection is associated
with an increased mortality

30.  Hurdles in the success of the treatment
 Lack of awareness/misconceptions about the disease
 Late / improper diagnosis
 Limited accessibility to diagnostic facilities
 Incorrect treatment by doctors
 Patients’ non-compliance to treatment
 Socio-economic factors

31. Dates and chemotherapy Smear Culture Susceptibility Radiolog Clinical
results results results ical results
results
a)Date of diagnosis: ..................
b ) Date of starting first course of chemotherapy:
Drugs taken
(dose, frequency, duration)
i..e.: H300, 7/7, 6 Months
R450, 7/7, 6 Months
S1g, 7/7, 2 Months
c) Date of completing or stopping first course of
chemotherapy
d) Date of starting second course of chemotherapy:
…………….......................
Drugs taken
(dose, frequency, duration)
......., .........., ........
......., .........., ........
e) Date of completing second course of
chemotherapy: ..........................
f) Date of starting third course of
chemotherapy: ........................
(to be continued ...)

32. Resistance Suggested Length Comments
- regimen
Isoniazid Amik, 9 months to Anticipate
and PZI RIF,E,Mox a year good
response
Isoniazid Amik,RIF, 9-12/12
and E PZI,Mox.
Isoniazid Amik,PZI, At least Consider
and RIF E,Mox. 18/12 surgery

33. Resistance Suggested Length Comments
regimen
INH,RIF, Amik,E, 18-24/12 Consider
PZI Mox,Eth,Cy After cul-ve surgery
INH,RIF, Amik,Mox. As above As above
PZI,E Eth,Cy,Clar

34. The top priority is not the
management but the
prevention of MDR
Tuberculosis

35.  In new cases
 Best prevention - give each new case of
sputum positive pulmonary tuberculosis an
effective regimen of short course
chemotherapy with four drugs at least for 4
months, given under direct observation

36.  In the group of TB patients previously treated
with one or several courses of chemotherapy &
who remain sputum positive (by smear and/or
culture), 3 subpopulations can be observed:
• patients excreting bacilli still susceptible to
all antituberculosis drugs
• patients excreting bacilli resistant to at
least isoniazid, but still susceptible to
rifampicin;
• patients excreting bacilli resistant to at
least isoniazid and rifampicin

37.  In patients who have failure after the 1st course of
chemotherapy ( WHO recommended or any other)–
WHO Tx regimen of 8 months ( using 5 drugs for the 1st 2
months, 4 drugs in the 3rd month and 3 drugs for the
remaining 5 months ( 2 SHRZE/1HRZE/5HRE), given under
direct observation

38. Rank Drugs Average daily Type of antimycobacterial
dosage activity
1 Aminoglycosides 15 mg/kg Bactericidal against actively
a. Streptomycin multiplying organisms
b. Kanamycin/Amikacin
c. Capreomycin
2 Thioamides 10-20 mg/kg Bactericidal
(Ethionamide / rothionamide)
3 Pyrazinamide 20-30 mg/kg Bactericidal at acid pH 7.5-10
4 Ofloxacin 7.5-15 mg/kg Bactericidal
5 Ethambutol 15-20 mg/kg Bacteriostatic
6 Cycloserine 10-20 mg/kg Bacteriostatic
7 PAS acid 10-12 g Bacteriostatic

39. Aminoglycosides
Kanamycin,
Amikacin,
Capreomycin ( useful in cases with tubercle
bacilli resistant to streptomycin, amikacin
and kanamycin)
Thiamides-
Ethionamides
Prothionamides

40. Fluroquinolones
Ofloxacin
Ciprofloxacin
(Complete cross resistance within the group)
Sparfloxacin – should be avoided due to severe
cutaneous side effects ( photo sensitisation)
Norfloxacin should not be used as it does not
give adequate serum level

41. Cycloserine ( or terizidone)-
bactriostatic agent
no cross reaction with other ATT
limited use due to the high toxicity
Para-aminosalicyclic acid-valuable for
preventing resistance to INH-& Streptomycin

42.  Treat for 6 months or observe without
treatmnet
* use drugs source case is sensitive to
* Choose 2: EMB, FQN, PZA
 Follow for 2 years regardless of treatment
* Chest X-ray and clinical evaluation

43.  1970’s Tanzania Dr Karel Styblo strategy
 1991 WHO TB a global problem
 In 1992 The WHO Global Tuberculosis Program
developed a new strategy-DOTS ( brand name of the
WHO Recommended TB Control Strtegy)
 1993 WHO promoted Styblo’s strategy (DOTS)
 Implemented in 200+ countries

44.  That the highest ever number of infectious
patients – 2.3 million people – were cured.
 With 87% of treated patients being cured, the
85% global target was exceeded for the first
time since it was established in 1991
 A total of 53 countries surpassed this treatment
milestone

45.  Directly
 Observed
 Treatment
 Short-course

46.  To achieve universal access to high-quality
 diagnosis and patient-centered treatment
 To reduce suffering and socio-economic burden
associated with TB
 To protect the poor and vulnerable populations from
TB, TB/HIV and MDR-TB
 To support development of new tools and
enable their timely and effective use

47.  National TB Control Program adopted DOTS
strategy first in 1995

48.  Political commitment with increased and sustained
financing
 Case detection through quality assured bacteriology
 Standardized treatment with supervision and
patient support
 An effective drug supply and management system
 Monitoring and evaluation system, and impact
m
measurement

49. DIRECTLY OBSERVED DIRECTLY OBSERVED
TB SHORT COURSE TREATMENT
 Comprehensive TB  A part of the DOTS
management strategy strategy
 Consists of 5 elements  Direct supervision of
 Now expanded Stop individual patients to
TB Strategy ensure treatment
adherence

50.  Health inspectors  Wife of medical officers
 Pharmacists  Mid-wife
 Malaria field workers  Self help group volunteers
 Workplace supervisors  Senior dressers
 Railwayschool teachers  Multi purpose health
 Cured patients workers

51.  Prompt sputum conversion,
cessation of transmission
 Halts generation of resistant (MDR-
TB) strains
 Lessening of relapse rates
 Early recognition of drug toxicity

52.  Treatment with properly implemented DOTS has a
success rate exceeding 95%
 prevents the emergence of further multi-drug
resistant strains of tuberculosis
 The WHO extended the DOTS programme in 1998
to include the treatment of MDR-TB (called "DOTS-
Plus").

53. Country population 163,902,000
Established no. of new TB cases 297,108
Established TB incidence(all cases per one lakh 181
population)
DOTS population coverage (%) 99
Rate of new SS+c ases(per 100.000 population) 81
DOTS caes detection rate 67
(new SS+ cases) (%)
DOTS treatment success rate,2006 88
(new SS+ cases) (%)
New Multidrug resistant TB cases(%) 3.2

54.  New MDR-TB cases rose from 2.0 percent in 2003
to 3.2 percent in 2007.
 Pakistan accounts for 57 percent of the MDR-TB
burden within WHO’s Eastern Mediterranean
Region.
 Extensively drug-resistant TB has not been
reported in the country.

55. New developments in
eradicating tuberculosis

56.  May 2009- a new antibiotic Moxifloxacin
has completed phase II trial and is expected
to reduce the drug regimen by several
months

57.  Standard TB drugs are dissolved into/adsorbed to
fine, particulate carriers (simple and economical)
 Can be given orally (as well as IV), in distinction to
liposomes
 Taken up by RES, mononuclear cells and solid
organs
 Extremely long half-lives (give every 2 weeks?)
 More effective sterilizing than std. drug forms

58.  A new compound exhibiting a completely new
mode of action (inhibition of ATP synthase)
against mycobacteria
 The compound is being developed in phase IIa
trials for the treatment of active tuberculosis as
TMC207

59.  Cytokines
IL-2
Gamma-interferon
 Immunomodulators
Mycobacterium vaccae

60. Development of affordable new
drugs, diagnostics and vaccines

61.  BCG vaccine (for TB) currently administered
against infection only reduces the risk of TB in
infants but offers no protection against
pulmonary TB and infection in adolescence or
adulthood.
 A new TB vaccine, developed at the Oxford
University called MVA85A/AERAS-485 holds
promise. It has entered Phase II b trial in
April 2009 and is being carried out in South
Africa.

62.  New challenges addressed by new Stop TB
Strategy
 Strengthen TB control
 Prevent drug resistance
 Treat 50 million TB cases
 Saves 14 million lives