1. DOTS PLUS IN DEVELOPING COUNTRIES EXPERIENCES & IMPLICATIONS
Dr. Nirmal Kumar Jain
MD, DNB(RM)
Professor & Head and
Medical Superintendent
Hospital for Chest Disease & Tuberculosis
SMS Medical College, Jaipur

2. To prevent further development and spread of MDR-TB.
DOTS PLUS
A case management strategy under development, designed to manage MDR-TB using second line drugs within the DOTS strategy in low – and middle – income countries.
To prevent further development and spread of MDR-TB.

3. DOTS-PLUS PREREQUISITES
The potential DOTS-Plus pilot project site should :
DOTS strategy is in place and is functioning well.
Government commitment and adequate funding.
Co-ordinated project management plan.
Adequate laboratory services.
Rational treatment strategy.
Adequate information (data) management system.

4. DOTS REFERALS
Name of
Medical
College
2000
2001
2002
2003
2004
Total
Jaipur
3238
4066
4371
4936
5147
21758
Udaipur
513
2719
2554
2227
2536
10549
Bikaner -
424
716
972
1449
3561
Jodhpur
1191
1107
2298
Ajmer
614
604
910
1631
1286
5045
Kota
4365
7813
8551
10957
11525
43211

5. PATIENT PUT ON MDR-TB TREATMENT
MONTH
YEAR-2002
YEAR-2003
YEAR-2004
January
109
214
157
February
125
190
144
March
150
173
154
April
151
178
147
May
159
186
137
June
138
192
213
July
160
119
220
August
175
236
211
September
225
October
181
145
189
November 92
187
December
209
120
Total :
1808
2057
2174

6. Deptt. of Chest Diseases & Tuberculosis, SMS Medical College, Jaipur.
FACTORS RESPONSIBLE FOR TREATMENT FAILURE AMONG PATIENTS ON DOTS REGIMEN BY
Dr. N.K. Jain
Dr. Himanshu Garg
Dr. Shubhranshu
Dr. S.P. Agnihotri
Dr. N. Joshi
Dr. S. Koolwal
Deptt. of Chest Diseases & Tuberculosis,
SMS Medical College, Jaipur.

7. DISTRIBUTION OF PATIENTS ACCORDING TO CATEGORY OF TREATMENT
S.No.
Category
No. % 1.
Cat. I Failure 48
32.88 2.
Cat. II Failure 98
67.12
Total :
146
100

8. MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY I FAILURE PATIENTS
S.No.
Pattern
No. % 1.
Smear Positive Culture Negative 10
20.83 2.
Sensitive to all drugs 16
33.34 3.
HR resistance 12 25 4.
HER resistance 3
6.25 5.
SHR resistance 6.
HRQ 7.
Resistance to all drugs
Atypical Mycobacteria 1
2.08
Total : 48
100
H= Isoniazid, R= Rifampicin, E= Ethambutol, S= Streptomycin, Q= Quinolones

9. After Conventional Chemotherapy
DISTRIBUTION OF CATEGORY II FAILURE PATIENTS ACCORDING TO HISTORY OF CHEMOTHERAPY
S.No.
Group
After Cat. I Treatment
After Conventional Chemotherapy
Total
No. % 1.
Relapses 9 25 12
21.43 21 2.
Defaulters 17
47.22 26
46.43 43
43.88 3.
Failures 10
27.78 18
32.14 28
28.57 4.
Fresh cases
(Wrongly Categorized) -- 6
6.12
Total : 36
100 56 98

10. MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY II FAILURE PATIENTS
S.No.
Pattern
No. % 1.
Smear Positive Culture Negative 8
8.16 2.
Sensitive to all drugs 17
17.35 3.
HR resistance 25
25.51 4.
SHR resistance 24
24.49 5.
SHER resistance 9
9.18 6.
SHR Ed P T resistance 3
3.06 7.
SHER T Q 8. HE 9.
SH resistance 2
2.04
10.
HRQ
11.
Resistance to all drugs Atypical Mycobacteria
Total : 98
100
Ed=Ethionamide, T=Thioaceteazone, P=Para Amino Salicylic Acid

11. DRUGS FOR MDR-TB RESERVE ANTI-TUBERCULOSIS DRUGS.
Aminoglycosides.
Amikacin mg/kg Hearing loss, ataxia,
b.i.d Nystagmus,Azotemia, Protein urea etc.
Kanamycin mg/kg do--
Capreomycin mg/kg --do--
Others.
PAS mg/kg Nausea, Vomiting, Diarrhea, Hepatitis
Ethionamide mg/kg Nausea, Vomiting, Hepatitis
Prothionamide mg/kg --do--
Cycloserine mg/kg Neurotoxicity, Heart failure

12. Newer Anti-tuberculosis Drugs.
Quinolones.
Ciprofloxacin mg/day Nausea, Vomiting,
Ofloxacin mg/day Diarrhoea, Insomnia,
Pefloxacin mg/day Headache, Skin Rash,
Lomefloxacin mg/day Tremulous,
Sparfloxacin mg/day Drug Interactions.
Levofloxacin mg/day -
Gatifloxacin mg/day -
Moxifloxacin mg/day -

13. Newer and Experimental Anti-tuberculosis Drugs.
Macrolides.
Roxithromycin mg/day G.I. Disturbances, Nausea,
Diarrhoea, Dyspepsia & Pain
Clarithromycin mg/day Abdomen, Dysphoria, Enzyme (High Dose).
Azithromycin mg/day
Rifamycin Derivatives.
Rifabutin mg/day Nausea, Vomiting, Hepatitis, Flulike, Syndrome, Renal failure,
Rifabutin mg/day Thrombocytopenia,
Haemolytic anemia.
Rifalazil

14. Newer and Experimental Anti-tuberculosis Drugs.
B-Lactamase Inhibitors.
Amoxycillin (625mg)/ Skin rash, Anaphylaxis,
Clavulanate to 2gm Diarrhea, Candidiasis,
PM, Collitis, Hepatitis
Ticarcillin & Cholstatic Jaundice.
Clavulanate.
Immunophenazine Derivatives.
Clofazemine mg/day. Skin pigmentation,
GI upset.
Oxazolidinones
Nitroimidazopyrans

15. Management of Multi Drug Resistant Tuberculosis.
1. Retreat with at least 3 or 4 new drugs for first 3 to
6 months (Total 5 to 7 drugs).
2. Continue chemotherapy with 2 to 3 new drugs.
3. Previously used drugs may be used in addition.
4. Use combinations with little potential of cross resistance.
5. A single drug should never be added.

16. Management of Multi Drug Resistant Tuberculosis.
6. Start with small dosage, increase to maximum.
7. Treatment should be initiated in hospital/directly
supervised.
8. Careful bacteriological monitoring essential.
9. Surgery/ Immunotherapy should be considered in
patients poorly responding to medical treatment.
All measures – not to stop treatment.
Intermittent therapy usually not effective.
Optimal duration, 18-to-24 months after culture
conversion.

17. MDR TB treatment regimens
Resistance profile Initial phase Continuation phase
drugs months drugs months
Isoniazid Aminoglycoside 3-6 Ethambutol
+rifampicin Ethambutol ± pyrazinamide (ASCC)
± streptomycin Pyrazinamide Quinolone
Quinolone Ethionamide Ethionamide
Comments
Aminoglycoside not previously used as injectable drug for 3 to 6 months
ETB dose may be increased to 25 mg/kg
PZA in the continuation phase may add to response rate
Inclusion of ETB & PZA – associated with favourable outcome
Consider surgery if no conversion after 6 months

18. MDR TB treatment regimens
Resistance profile Initial phase Continuation phase
drugs months drugs months
Isoniazid Aminoglycoside 3-6 ± pyrazinamide
+ rifampicin Pyrazinamide Quinolone (ASCC)
+ ethambutol Quinolone Ethionamide
± streptomycin Ethionamide PAS/Cycloserine
PAS/ Cycloserine
Comments
Aminoglycoside not previously used as injectable drug for 3 to 6 months
PZA in the continuation phase may add to response rate
Consider surgery if no conversion after 6 months

19. MDR TB treatment regimens
Resistance profile Initial phase Continuation phase
drugs months drugs months
Isoniazid Aminoglycoside 3-6 Ethambutol
+ rifampicin Ethambutol Quinolone (ASCC)
+ pyrazinamide Quinolone Ethionamide
± streptomycin Ethionamide PAS/Cycloserine
PAS/ Cycloserine
Comments
Aminoglycoside not previously used as injectable drug for 3 to 6 months
ETB dose may be increased to 25 mg/kg with careful monitoring for retrobulbar neuritis
PZA in the continuation phase may add to response rate
Consider surgery if no conversion after 6 months

20. MDR TB treatment regimens
Resistance profile Initial phase Continuation phase
drugs months drugs months
Isoniazid Aminoglycoside 3-6 Quinolone
+ rifampicin Quinolone Ethionamide (ASCC)
+ ethambutol Ethionamide PAS
+ pyrazinamide PAS Cycloserine
± streptomycin Cycloserine
Comments
Aminoglycoside not previously used as injectable drug for 3 to 6 months

21. Potential Regimen for Patients with Multi Drug Resistant Tuberculosis.
Resistance Suggested Duration.
Regimens.
HR (+ S)* AEZQ 24 months.
HER (+ S)* AZQ months. ASC
HRZ (+ S)* AEQ months. ASC
HRZ (+ S)* AQ months. ASC
A=Aminoglycoside - SM/KM/CM/AM
Q=Quinolones - Cipro/Oflo/Spar/Levo/Gati
+ = 2 or 3 drugs among ETH/PTH/PAS/CYC/Macrolides/-lactam
inhibitor/Others.
* = Surgery may be considered.

22. PRIORITY RESEARCH AGENDA FOR DOTS-PLUS FOR MDR-TB
Primary topics
Identify optimal standardised protocols to treat MDR-TB.
Identify optimal protocols for diagnostic testing.
Identify the minimum requirement for constructing and implementing DOTS-Plus.
Secondary topics
Identify threshold indicators for implementing DOTS-Plus.
Other operational issues.

23. Deptt. of Chest Diseases & Tuberculosis, SMS Medical College, Jaipur.
EFFICACY OF DIFFERENT REGIMENS IN TREATMENT OF DOTS CATEGORY II FAILURE OF PULMONARY TUBERCULOSIS BY
Dr. N.K. Jain
Dr. Shubhranshu
Deptt. of Chest Diseases & Tuberculosis,
SMS Medical College, Jaipur.

24. Radiological Response*
RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 6 MONTHS
Group
Total no. of cases
Sputum Status*
Radiological Response*
Clinical Response*
-Ve
+Ve
Imp.
Stat.
Quo.
Det.
No Imp.
I-KHEZQP 28 23
(82.14%) 5
(17.85%) 22
(78.57%) 6
(21.43%) - 25
(89.28%) 3
(10.71%)
II-KHEZQEd. 27 21
(77.78%)
(22.22%) 19
70.37%) 8
(29.63%)
III-KHEZQPEd.
(81.48%)
(18.51%) 24
(88.89%)
(11.11%)
*Percentages from total no. of cases in each group.
IMP=Improvement, Stat.= Status, Det.= Deterioration.

25. Group & Total No. of Cases
RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 12 MONTHS
Group & Total No. of Cases
Deaths*
Drug Toxicity*
Remaining Cases
Sputum Status*
-Ve
+Ve
I-KHEZQP/HEZQP
(28) - 28 24
(85.47%) 4
14.20%)
II-KHEZQEd./ HEZQEd (27) 1
(3.7%) 26 22
(81.48%)
(14.82%)
III-KHEZQPEd./ HEZQPEd. (27) 21
(77.78%) 5
(18.52%)
*Percentages from total no. of cases in each group. IMP=Improvement,
Stat.= Status, Det.= Deterioration.
Contd…

26. Radiological Response*
RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 12 MONTHS
Group & Total No.
of Cases
Remaining Cases
Radiological Response*
Clinical Response*
Imp.
Stat. Quo
Det.
No Imp.
I-KHEZQP/ HEZQP (28) 28 18
(64.29%) 4
(14.20%) 2
(7.14%) 24
(85.47%)
II-KHEZQEd./ HEZQEd (27) 26 22
(81.48%)
(7.4%)
III-KHEZQPEd./ HEZQPEd. (27) 21
(77.78%) 1
(3.7%)
(14.82%)
*Percentages from total no. of cases in each group. IMP=Improvement,
Stat.= Status, Det.= Deterioration.

27. Group & Total No. of Cases
RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS
Group & Total No. of Cases
Deaths*
Drug Toxicity*
Remaining Cases
Sputum Status*
-Ve
+Ve
I-KHEZQP/
HEZQP (28) 2
(7.14%) 24 17
(60.71%) 7
(25%)
II-KHEZQEd./ HEZQEd (27)
(7.4%) 3
(11.11%) 22 16
(59.26%) 6
(22.22%)
III-KHEZQPEd./ HEZQPEd. (27) 1
(3.7%) 4
(14.82%) 18
(66.67%)
*Percentages from total no. of cases in each group.
IMP=Improvement, Stat.= Status, Det.= Deterioration.
Contd…

28. Radiological Response*
RESPONSE OF DOTS CATEGORY II FAILURE PATIENTS ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS
Group & Total No.
of Cases
Remaining Cases
Radiological Response*
Clinical Response*
Imp.
Stat. Quo
Det.
No Imp.
I-KHEZQP/ HEZQP (28) 24 17
(60.71%) 3
(10.71%) 4
(14.29%) 2
(7.14%) 5
(17.86%)
II-KHEZQEd./ HEZQEd (27) 22 16
(59.26%) - 6
(22.22%)
III-KHEZQPEd./ HEZQPEd. (27) 18
(66.67%)
(14.82%)
(7.4%)
*Percentages from total no. of cases in each group.
IMP=Improvement, Stat.= Status, Det.= Deterioration.

29. Cases Exclude from Response
COMPARISON OF OVERALL RESPONSE OF DOTS CATEGORY II FAILURE ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS
Group & Regimen
No. of Cases
Favorable Response
Unfavorable Response
Cases Exclude from Response
I-KHEZQP/HEZQP 28 17
(60.71%) 8
(28.57%) 3
(10.71%)
II-KHEZQEd./ HEZQEd. 27 16
(59.26%)
(29.63%)
(11.11%)
III-KHEZQPEd./ HEZQPEd. 18
(66.67%) 5
(18.51%) 4
(14.81%)
TOTAL : 82 51
(62.2%) 21
(25.6%) 10
(12.2%)

30. ISSUES DOTS MDR-TB
TB Suspects -H/O cough for 3 weeks Failure of RNTCP Cat.II(Chronic case) or more duration Patients receiving inappropriate, incomplete, irregular teratment, 2 or more time against NTCP policy.
Diagnostic sputum examination Direct microscopy
modalities (Spot-Early Morning-Spot) ,2,3,4,5,6,9,12,15,18,21,24
- Early Morning-Spot Myco C/S test
Cat.I 2,4, ,3,6,9, ---
Cat.II 3,5, X-ray
Cat.III 2, ,3,6,9,12,15,18,24
Outcome -Cure rate in new smear +ve % cases=85% or more Cure rate in re-treatment cases=70% or more

31. ISSUES DOTS MDR-TB
Management -IP: 3/7 (Thrice a week on alternate day) IP: 7/7 (Daily)
-CP: 1/7 (Thrice a week on alternate day, CP: 7/7 (Daily) one dose supervised)
Cost on
Investigation -Rs / ,000/-
Cost Cat. I 2(HRZE)3/ 4(HR)3 Rs.600/ KHEZQEd/HEZQEd Rs.21688
-Catt.II 2(SHRZE)3/ 1(HRZE)3/ KHEZQP/HEZQP Rs.28996
5(HRE)3 Rs / KHEZQPEd/HEZQPEd Rs.37096
-Cat.III 2(HRZ)3/ 4(HR)3 Rs /-

32. DRAFT POLICY SUGGESTIONS
Emphasis should be given to prevent MDR-TB by wider use of DOTS by medical professionals and to achieve cure rate of more than 85% in new sputum positive cases and more then 70% in retreatment cases.
Wider community participation by identifying their strengths.
II line drugs should be used only when resistance to I line drugs exists or patients fails on WHO Category II regimen.
Drugs under EDL should be used on priority basis, as these are effective, less toxic, affordable and well tolerated by patients. Kanamycin and Ethionamide be included in EDL.
Treatment of MDR-TB should be supervised and drugs should be made available for not more than 15 days.
Treatment should be supervised by the nearest DOT provider and empty strip/blister packs be deposited fortnightly.
6. In intensive phase: 1 injectable & 3-4 oral drugs may be administered for 3 to 6 months.
In continuation phase: 3 oral drugs preferably those not used in past may be administered for 18 months.
Contd. …

33. DRAFT POLICY SUGGESTIONS
7. II line drugs should be guaranteed available in specialized units attached with laboratories having culture & sensitivity facility.
8. II line drugs should be available on prescription of highly skilled specialist (Prof./Ass.Prof. of TB & Chest Hospitals).
9. MDR-TB prescription can be scrutinized by EDL committee made for rational use on Anti-TB drugs.
10. EDL committee be asked to submit report on rational use of II line drug in terms of combination, intermittency and length of time, cost incurred, cost effectiveness and prohibitory cost.
11. Since MDR-TB treatment is a last crusade against TB for survival, as per WHO recommendations, II line drugs need to be administered under strict supervision of a personnel who is highly skilled.

38. DOTS PLUS IN DEVELOPING COUNTRIES
Ensure effective DOTS – No further MDR-TB.
Early diagnosis of MDR-TB
High index suspicion - smear +ve at 3rd month
Mycobacterial C/S - continuation of DOTS
Standardized treatment regimens possible
I-KHEZQP/HEZQP
II-KHEZQEd./ HEZQEd.
III-KHEZQPEd./ HEZQPEd.
Reliable supply of high quality II line anti-TB drugs
All measures of strict adherence to therapy
Rigorous quality assurance, monitoring & evaluation
Most cost effective
According to pattern of
local resistance.

39. THANKS