Transcript Principles of Chemotherapy of Tuberculosis.
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
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.
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.
Name of Medical College Jaipur Udaipur Bikaner Jodhpur Ajmer Kota Total 2000
DOTS REFERALS
2001 2002 2003 2004 Total 3238 513 614 4066 2719 424 604 4371 2554 716 910 4936 2227 972 1191 1631 5147 2536 1449 1107 1286 21758 10549 3561 2298 5045 4365 7813 8551 10957 11525 43211
PATIENT PUT ON MDR-TB TREATMENT
MONTH YEAR-2002 YEAR-2003 YEAR-2004 January February March April May June July August September October November December 109 125 150 151 159 138 160 175 159 181 92 209 214 190 173 178 186 192 119 236 159 145 145 120 157 144 154 147 137 213 220 211 225 189 187 190
Total : 1808 2057 2174
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.
DISTRIBUTION OF PATIENTS ACCORDING TO CATEGORY OF TREATMENT S.No.
1.
Category
Cat. I Failure
No.
48
%
32.88
2.
Cat. II Failure 98 67.12
Total : 146 100
MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY I FAILURE PATIENTS
S.No.
1.
2.
3.
4.
5.
6.
7.
Pattern Smear Positive Culture Negative Sensitive to all drugs HR resistance HER resistance SHR resistance HRQ Resistance to all drugs Atypical Mycobacteria
Total :
No.
10 16 12 3 3 3 1
48
% 20.83
33.34
25 6.25
6.25
6.25
2.08
100
H= Isoniazid, R= Rifampicin, E= Ethambutol, S= Streptomycin, Q= Quinolones
DISTRIBUTION OF CATEGORY II FAILURE PATIENTS ACCORDING TO HISTORY OF CHEMOTHERAPY
S.No.
1.
2.
3.
4.
Group Relapses Defaulters Failures Fresh cases
(Wrongly Categorized) Total :
After Cat. I Treatment No.
9 17 10 - % 25 47.22
27.78
- After Conventional Chemotherapy No.
12 26 18 - % 21.43
46.43
32.14
- No.
21 43 28 6 Total % 21.43
43.88
28.57
6.12
36 100 56 100 98 100
MYCO BACTERIAL CULTURE & SENSITIVITY PATTERN OF CATEGORY II FAILURE PATIENTS S.No.
Pattern No.
%
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
Smear Positive Culture Negative Sensitive to all drugs HR resistance SHR resistance SHER resistance SHR Ed P T resistance SHER T Q HE SH resistance HRQ Resistance to all drugs Atypical Mycobacteria
Total :
8 17 25 24 9 3 3 3 2 2 2
98
8.16
17.35
25.51
24.49
9.18
3.06
3.06
3.06
2.04
2.04
2.04
100
Ed=Ethionamide, T=Thioaceteazone, P=Para Amino Salicylic Acid
DRUGS FOR MDR-TB RESERVE ANTI-TUBERCULOSIS DRUGS.
•
Aminoglycosides.
Amikacin. 7.5mg/kg b.i.d.
Hearing loss, ataxia, Nystagmus,Azotemia, Protein urea etc.
•
Kanamycin 15 mg/kg Capreomycin 15 mg/kg Others.
PAS 200 mg/kg Ethionamide 15 mg/kg Prothionamide 15 mg/kg Cycloserine 15 mg/kg --do- --do- Nausea, Vomiting, Diarrhea, Hepatitis Nausea, Vomiting, Hepatitis --do- Neurotoxicity, Heart failure
Newer Anti-tuberculosis Drugs.
•
Quinolones.
Ciprofloxacin.
Ofloxacin.
Pefloxacin.
Lomefloxacin.
Sparfloxacin.
Levofloxacin.
Gatifloxacin.
Moxifloxacin.
1000-1500 mg/day 200-800 mg/day 400-800 mg/day 400-800 mg/day 200-400 mg/day 500 mg/day 400 mg/day 400 mg/day Nausea, Vomiting, Diarrhoea, Insomnia, Headache, Skin Rash, Tremulous, Drug Interactions.
-
•
Newer and Experimental Anti-tuberculosis Drugs.
Macrolides.
Roxithromycin.
300 mg/day Clarithromycin .
500-2000mg/day G.I. Disturbances, Nausea, Diarrhoea, Dyspepsia & Pain Abdomen, Dysphoria, Enzyme (High Dose).
• Azithromycin. 500 mg/day
Rifamycin Derivatives .
Rifabutin.
300 mg/day Rifabutin.
Rifalazil.
600 mg/day Nausea, Vomiting, Hepatitis, Flulike, Syndrome, Renal failure, Thrombocytopenia, Haemolytic anemia. -
•
Newer and Experimental Anti-tuberculosis Drugs.
B-Lactamase Inhibitors
.
Amoxycillin + Clavulanate.
500+125 (625mg)/ 750 to 2gm Skin rash, Anaphylaxis, Diarrhea, Candidiasis, PM, Collitis, Hepatitis & Cholstatic Jaundice.
•
Ticarcillin + Clavulanate.
Immunophenazine Derivatives.
Clofazemine 100-200 mg/day.
Skin pigmentation, GI upset.
•
Oxazolidinones.
•
Nitroimidazopyrans
.
-
1.
Management of Multi Drug Resistant Tuberculosis.
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.
6.
7.
Management of Multi Drug Resistant Tuberculosis.
Start with small dosage, increase to maximum.
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.
10. All measures – not to stop treatment. 11. Intermittent therapy usually not effective.
12.
Optimal duration, 18-to-24 months after culture conversion.
MDR TB treatment regimens
Resistance profile Initial phase Continuation phase Isoniazid +rifampicin ± streptomycin drugs months drugs months Aminoglycoside Ethambutol Pyrazinamide Quinolone Ethionamide 3-6 Ethambutol 18-24 ± pyrazinamide (ASCC) Quinolone 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
MDR TB treatment regimens
Resistance profile Isoniazid + rifampicin + ethambutol ± streptomycin Initial phase drugs months Aminoglycoside Pyrazinamide Quinolone Ethionamide PAS/ Cycloserine 3-6 Continuation phase drugs months ± pyrazinamide 18-24 Quinolone (ASCC) Ethionamide 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
MDR TB treatment regimens
Resistance profile Isoniazid + rifampicin + pyrazinamide ± streptomycin Initial phase drugs months Aminoglycoside Ethambutol Quinolone Ethionamide PAS/ Cycloserine 3-6 Continuation phase drugs months Ethambutol 18-24 Quinolone (ASCC) Ethionamide 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
MDR TB treatment regimens
Resistance profile Isoniazid + rifampicin + ethambutol + pyrazinamide ± streptomycin Initial phase drugs months Aminoglycoside Quinolone Ethionamide PAS Cycloserine 3-6 Continuation phase drugs months Quinolone 18-24 Ethionamide (ASCC) PAS Cycloserine
•
Comments Aminoglycoside not previously used as injectable drug for 3 to 6 months
Potential Regimen for Patients with Multi Drug Resistant Tuberculosis.
Resistance.
Suggested Regimens. Duration.
HR (+ S)* HER (+ S)* HRZ (+ S)* HRZ (+ S)* AEZQ AZQ+2 AEQ+2 AQ+3 24 months.
24 months. ASC 24 months. ASC 24 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.
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.
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.
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*
I-KHEZQP II-KHEZQEd.
III-KHEZQPEd.
28 27 27
-Ve +Ve
23 (82.14%) 21 (77.78%) 22 (81.48%) 5 (17.85%) 6 (22.22%) 5 (18.51%)
Imp.
22 (78.57%) 19 70.37%) 22 (81.48%)
Stat.
Quo.
6 (21.43%) 8 (29.63%) 5 (18.51%)
Det.
-
Imp.
No Imp.
25 (89.28%) 21 (77.78%) 24 (88.89%) 3 (10.71%) 6 (22.22%) 3 (11.11%)
Det.
-
*Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.
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* I-KHEZQP/HEZQP (28) II-KHEZQEd./ HEZQEd (27) III-KHEZQPEd./ HEZQPEd. (27) 1 (3.7%) 1 (3.7%) 28 26 26 -Ve 24 (85.47%) 22 (81.48%) 21 (77.78%) +Ve 4 14.20%) 4 (14.82%) 5 (18.52%)
*Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.
Contd…
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* I-KHEZQP/ HEZQP (28) II-KHEZQEd./ HEZQEd (27) III-KHEZQPEd./ HEZQPEd. (27) 28 26 26 Imp.
18 (64.29%) 22 (81.48%) 21 (77.78%) Stat. Quo 4 (14.20%) 2 (7.4%) 1 (3.7%) Det.
Imp.
2 (7.14%) 2 (7.4%) 4 (14.82%) 24 (85.47%) 22 (81.48%) 21 (77.78%) No Imp.
2 (7.14%) 2 (7.4%) 1 (3.7%) Det.
2 (7.14%) 2 (7.4%) 4 (14.82%)
*Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.
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* I-KHEZQP/ HEZQP (28) II-KHEZQEd./ HEZQEd (27) III-KHEZQPEd./ HEZQPEd. (27) 2 (7.14%) 2 (7.4%) 1 (3.7%) 2 (7.14%) 3 (11.11%) 4 (14.82%) 24 22 22 -Ve 17 (60.71%) 16 (59.26%) 18 (66.67%) +Ve 7 (25%) 6 (22.22%) 4 (14.82%)
*Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.
Contd…
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* I-KHEZQP/ HEZQP (28) II-KHEZQEd./ HEZQEd (27) III-KHEZQPEd./ HEZQPEd. (27) 24 22 22 Imp.
17 (60.71%) 16 (59.26%) 18 (66.67%) Stat. Quo 3 (10.71%) Det.
Imp.
4 (14.29%) 6 (22.22%) 4 (14.82%) 17 (60.71%) 16 (59.26%) 18 (66.67%) No Imp.
2 (7.14%) 2 (7.4%) Det.
5 (17.86%) 6 (22.22%) 2 (7.4%)
*Percentages from total no. of cases in each group. IMP=Improvement, Stat.= Status, Det.= Deterioration.
COMPARISON OF OVERALL RESPONSE OF DOTS CATEGORY II FAILURE ON DIFFERENT REGIMEN AT THE END OF 18 MONTHS Group & Regimen
I-KHEZQP/HEZQP II-KHEZQEd./ HEZQEd.
III-KHEZQPEd./ HEZQPEd.
No. of Cases Favorable Response Unfavorable Response
28 27 27 17 (60.71%) 16 (59.26%) 18 (66.67%) 8 (28.57%) 8 (29.63%) 5 (18.51%)
Cases Exclude from Response
3 (10.71%) 3 (11.11%) 4 (14.81%)
TOTAL : 82 51 (62.2%) 21 (25.6%) 10 (12.2%)
ISSUES TB Suspects Diagnostic modalities Outcome DOTS -H/O cough for 3 weeks or more duration MDR-TB -Failure of RNTCP Cat.II(Chronic case) -Patients receiving inappropriate, incomplete, irregular teratment, 2 or more time against NTCP policy. -3 sputum examination -Direct microscopy (Spot-Early Morning-Spot) 0,2,3,4,5,6,9,12,15,18,21,24 - Early Morning-Spot - Myco C/S test Cat.I 2,4,6 Cat.II 3,5,8 0,3,6,9, -- -X-ray Cat.III 2,6 0,3,6,9,12,15,18,24 -Cure rate in new smear +ve -40-60% cases=85% or more -Cure rate in re-treatment cases=70% or more
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. 0-100/ -10,000/ Cost -Cat. I 2(HRZE) 3 / 4(HR) 3 Rs.600/ -Catt.II 2(SHRZE) 3 / 1(HRZE) 3 / Rs.37096
5(HRE) 3 Rs.760.78/ -Cat.III 2(HRZ) 3 / 4(HR) 3 Rs.411.90/ - KHEZQEd/HEZQEd Rs.21688
- KHEZQP/HEZQP Rs.28996
- KHEZQPEd/HEZQPEd
2.
3.
4.
1.
5.
6.
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.
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. …
DRAFT POLICY SUGGESTIONS
7.
8.
9.
10.
11.
II line drugs should be guaranteed available in specialized units attached with laboratories having culture & sensitivity facility.
II line drugs should be available on prescription of highly skilled specialist (Prof./Ass.Prof. of TB & Chest Hospitals).
MDR-TB prescription can be scrutinized by EDL committee made for rational use on Anti-TB drugs.
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.
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.
DOTS PLUS IN DEVELOPING COUNTRIES
1.
2.
3.
4.
5.
6.
Ensure effective DOTS – No further MDR-TB.
Early diagnosis of MDR-TB High index suspicion - smear +ve at 3 rd month Mycobacterial C/S - continuation of DOTS Standardized treatment regimens possible
I-KHEZQP/HEZQP II-KHEZQEd./ HEZQEd.
III-KHEZQPEd./ HEZQPEd.
Most cost effective According to pattern of local resistance.
Reliable supply of high quality II line anti-TB drugs All measures of strict adherence to therapy Rigorous quality assurance, monitoring & evaluation