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.
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
-
-
-
-
-
-
Total
4365
7813
8551
10957 11525 43211
PATIENT PUT ON MDR-TB TREATMENT
MONTH
YEAR-2002 YEAR-2003 YEAR-2004
January
February
109
125
214
190
157
144
March
April
May
June
150
151
159
138
173
178
186
192
154
147
137
213
July
August
September
160
175
159
119
236
159
220
211
225
October
November
December
181
92
209
145
145
120
189
187
190
1808
2057
2174
Total :
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.
Category
No.
%
1.
Cat. I Failure
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
No.
%
Smear Positive Culture Negative
Sensitive to all drugs
HR resistance
HER resistance
SHR resistance
HRQ
Resistance to all drugs
Atypical Mycobacteria
10
16
12
3
3
3
1
20.83
33.34
25
6.25
6.25
6.25
2.08
Total :
48
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
After Cat. I
Treatment
After
Conventional
Chemotherapy
Total
No.
9
17
10
--
%
25
47.22
27.78
--
No.
12
26
18
--
%
21.43
46.43
32.14
--
No.
21
43
28
6
%
21.43
43.88
28.57
6.12
36
100
56
100
98
100
(Wrongly Categorized)
Total :
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
8
17
25
24
9
3
3
3
2
2
2
8.16
17.35
25.51
24.49
9.18
3.06
3.06
3.06
2.04
2.04
2.04
Total :
98
100
Ed=Ethionamide, T=Thioaceteazone, P=Para Amino Salicylic Acid
DRUGS FOR MDR-TB
RESERVE ANTI-TUBERCULOSIS DRUGS.
•
Aminoglycosides.
Amikacin.
Kanamycin
Capreomycin
•
7.5mg/kg
Hearing loss, ataxia,
b.i.d.
Nystagmus,Azotemia, Protein urea
etc.
15 mg/kg
15 mg/kg
--do---do--
Others.
PAS
200 mg/kg
Nausea, Vomiting,
Diarrhea, Hepatitis
Ethionamide
15 mg/kg
Nausea, Vomiting, Hepatitis
Prothionamide
15 mg/kg
Cycloserine
15 mg/kg
--do-Neurotoxicity, Heart failure
Newer Anti-tuberculosis Drugs.
•
Quinolones.
Ciprofloxacin.
1000-1500 mg/day
Nausea, Vomiting,
Ofloxacin.
200-800 mg/day
Diarrhoea, Insomnia,
Pefloxacin.
400-800 mg/day
Headache, Skin Rash,
Lomefloxacin.
400-800 mg/day
Tremulous,
Sparfloxacin.
200-400 mg/day
Drug Interactions.
Levofloxacin.
500 mg/day
-
Gatifloxacin.
400 mg/day
-
Moxifloxacin.
400 mg/day
-
Newer and Experimental
Anti-tuberculosis Drugs.
• Macrolides.
Roxithromycin.
300 mg/day
G.I. Disturbances, Nausea,
Diarrhoea, Dyspepsia &
Pain
Clarithromycin .
Azithromycin.
500-2000mg/day
Abdomen, Dysphoria,
Enzyme (High Dose).
500 mg/day
• Rifamycin Derivatives.
Rifabutin.
300 mg/day
Nausea, Vomiting,
Hepatitis, Flulike,
Syndrome, Renal failure,
Rifabutin.
600 mg/day
Thrombocytopenia,
Haemolytic anemia.
Rifalazil.
-
-
Newer and Experimental
Anti-tuberculosis Drugs.
• B-Lactamase Inhibitors.
Amoxycillin +
500+125 (625mg)/
Skin rash, Anaphylaxis,
Clavulanate.
750 to 2gm
Diarrhea, Candidiasis,
PM, Collitis, Hepatitis
Ticarcillin +
-
& Cholstatic Jaundice.
Clavulanate.
• Immunophenazine Derivatives.
Clofazemine
100-200 mg/day.
Skin pigmentation,
GI upset.
• Oxazolidinones.
-
-
• Nitroimidazopyrans.
-
-
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.
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.
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
drugs
Isoniazid
+rifampicin
± streptomycin
Aminoglycoside
Ethambutol
Pyrazinamide
Quinolone
Ethionamide
Continuation phase
months
3-6
drugs
months
Ethambutol
± pyrazinamide
Quinolone
Ethionamide
18-24
(ASCC)
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
Initial phase
drugs
Isoniazid
+ rifampicin
+ ethambutol
± streptomycin
Aminoglycoside
Pyrazinamide
Quinolone
Ethionamide
PAS/ Cycloserine
Continuation phase
months
3-6
drugs
± pyrazinamide
Quinolone
Ethionamide
PAS/Cycloserine
months
18-24
(ASCC)
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
Initial phase
drugs
Isoniazid
+ rifampicin
+ pyrazinamide
± streptomycin
Aminoglycoside
Ethambutol
Quinolone
Ethionamide
PAS/ Cycloserine
Continuation phase
months
3-6
drugs
months
Ethambutol
Quinolone
Ethionamide
PAS/Cycloserine
18-24
(ASCC)
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
Initial phase
drugs
Isoniazid
+ rifampicin
+ ethambutol
+ pyrazinamide
± streptomycin
Aminoglycoside
Quinolone
Ethionamide
PAS
Cycloserine
Continuation phase
months
3-6
drugs
months
Quinolone
Ethionamide
PAS
Cycloserine
18-24
(ASCC)
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*
-Ve
+Ve
Imp.
Stat.
Quo.
Det.
Imp.
No
Imp.
Det.
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%)
6
(22.22%)
19
70.37%)
8
(29.63%)
-
21
(77.78%)
6
(22.22%)
-
III-KHEZQPEd.
27
22
(81.48%)
5
(18.51%)
22
(81.48%)
5
(18.51%)
-
24
(88.89%)
3
(11.11%)
-
*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
I-KHEZQP/HEZQP
(28)
II-KHEZQEd./
HEZQEd (27)
III-KHEZQPEd./
HEZQPEd. (27)
Deaths*
Drug
Remaining
Toxicity*
Cases
-
-
28
1
(3.7%)
-
-
26
1
(3.7%)
26
Sputum Status*
-Ve
+Ve
24
(85.47%)
22
(81.48%)
21
(77.78%)
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*
Imp.
Stat.
Quo
Det.
Imp.
No
Imp.
Det.
I-KHEZQP/
HEZQP (28)
28
18
(64.29%)
4
(14.20%)
2
(7.14%)
24
(85.47%)
2
(7.14%)
2
(7.14%)
II-KHEZQEd./
HEZQEd (27)
26
III-KHEZQPEd./
HEZQPEd. (27)
26
22
(81.48%)
21
(77.78%)
2
(7.4%)
1
(3.7%)
2
(7.4%)
4
(14.82%)
22
(81.48%)
21
(77.78%)
2
(7.4%)
1
(3.7%)
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
Remaining
Toxicity*
Cases
I-KHEZQP/
HEZQP (28)
II-KHEZQEd./
HEZQEd (27)
2
(7.14%)
2
(7.4%)
2
(7.14%)
3
(11.11%)
24
III-KHEZQPEd./
HEZQPEd. (27)
1
(3.7%)
4
(14.82%)
22
22
Sputum Status*
-Ve
+Ve
17
(60.71%)
16
(59.26%)
7
(25%)
6
(22.22%)
18
(66.67%)
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*
Imp.
Stat.
Quo
Det.
Imp.
No
Imp.
Det.
I-KHEZQP/
HEZQP (28)
24
17
(60.71%)
3
(10.71%)
4
(14.29%)
17
(60.71%)
2
(7.14%)
5
(17.86%)
II-KHEZQEd./
HEZQEd (27)
22
-
22
6
(22.22%)
4
(14.82%)
16
(59.26%)
18
(66.67%)
-
III-KHEZQPEd./
HEZQPEd. (27)
16
(59.26%)
18
(66.67%)
6
(22.22%)
2
(7.4%)
-
*Percentages from total no. of cases in each group.
IMP=Improvement, Stat.= Status, Det.= Deterioration.
2
(7.4%)
COMPARISON OF OVERALL RESPONSE OF DOTS
CATEGORY II FAILURE ON DIFFERENT REGIMEN AT
THE END OF 18 MONTHS
Group &
Regimen
No. of Favorable Unfavorable
Cases Response 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%)
8
(29.63%)
3
(11.11%)
III-KHEZQPEd./
HEZQPEd.
27
18
(66.67%)
5
(18.51%)
4
(14.81%)
TOTAL :
82
51
(62.2%)
21
(25.6%)
10
(12.2%)
ISSUES
DOTS
MDR-TB
TB Suspects
-H/O cough for 3 weeks
or more duration
-Failure of RNTCP Cat.II(Chronic case)
-Patients receiving inappropriate,
incomplete, irregular teratment, 2 or
more time against NTCP policy.
Diagnostic
modalities
-3 sputum examination
(Spot-Early Morning-Spot)
- Early Morning-Spot
Cat.I 2,4,6
Cat.II 3,5,8
Cat.III 2,6
-Direct microscopy
0,2,3,4,5,6,9,12,15,18,21,24
- Myco C/S test
0,3,6,9, ---X-ray
0,3,6,9,12,15,18,24
Outcome
-Cure rate in new smear +ve
cases=85% or more
-Cure rate in re-treatment
cases=70% or more
-40-60%
ISSUES
Management
DOTS
-IP: 3/7 (Thrice a week on alternate day)
-CP: 1/7 (Thrice a week on alternate day,
one dose supervised)
Cost on
Investigation -Rs. 0-100/-
Cost
-Cat. I 2(HRZE)3/ 4(HR)3 Rs.600/-Catt.II 2(SHRZE)3/ 1(HRZE)3/
5(HRE)3 Rs.760.78/Rs.37096
-Cat.III 2(HRZ)3/ 4(HR)3 Rs.411.90/-
MDR-TB
-IP: 7/7 (Daily)
-CP: 7/7 (Daily)
-10,000/-
- KHEZQEd/HEZQEd Rs.21688
- KHEZQP/HEZQP Rs.28996
- KHEZQPEd/HEZQPEd
DRAFT POLICY SUGGESTIONS
1.
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.
2.
Wider community participation by identifying their strengths.
3.
II line drugs should be used only when resistance to I line drugs exists or
patients fails on WHO Category II regimen.
4.
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.
5.
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. …
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.
DOTS PLUS IN DEVELOPING COUNTRIES
1.
Ensure effective DOTS – No further MDR-TB.
2.
Early diagnosis of MDR-TB
High index suspicion - smear +ve at 3rd month
Mycobacterial C/S - continuation of DOTS
3.
Standardized treatment regimens possible
I-KHEZQP/HEZQP
II-KHEZQEd./ HEZQEd.
III-KHEZQPEd./ HEZQPEd.
Most cost effective
According to pattern of
local resistance.
4.
Reliable supply of high quality II line anti-TB drugs
5.
All measures of strict adherence to therapy
6.
Rigorous quality assurance, monitoring & evaluation