Role of TRC in DRS for India Role of TRC in DRS for India & SEAR & SEAR SNRL and ref. Lab of the WHO NRL for India Renders assistance for the following: Preparation of generic protocol Developing laboratories for culture & DST Preparation of manuals and SOPs Training of laboratory personnel Instituting uniform methods for DST Ensuring quality thro’ QAP Supply of standard strains, drugs & reagents Periodic site visits
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Surveillance on drug resistance in tuberculosis C N Paramasivan Tuberculosis Research centre (ICMR)
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Role of TRC in DRS for India & SEARRole of TRC in DRS for India & SEAR SNRL and ref. Lab of the WHO NRL for India
Renders assistance for the following: Preparation of generic protocol Developing laboratories for culture & DST Preparation of manuals and SOPs Training of laboratory personnel Instituting uniform methods for DST Ensuring quality thro’ QAP Supply of standard strains, drugs & reagents Periodic site visits
Earlier reports on combined resistance Earlier reports on combined resistance from India and their limitationsfrom India and their limitations
Case selection
Sample size
Methodology
Source of drugs
Definition of resistance
MDR TB in SEARMDR TB in SEAR
4
1.3
0.9
15.5
20.5
20.2
0 5 10 15 20 25
Treated
New
Thailand (2000 – 02)
172
1505
Nepal (2000 – 02)
177
755
Myanmar (2003 – 04)
166
733
Percentage
Prevalence of primary DRPrevalence of primary DR TRC Studies 1956 - 2001TRC Studies 1956 - 2001
Prevalence of primary DRPrevalence of primary DR TRC Studies 1956 - 2001TRC Studies 1956 - 2001
0
2
4
6
8
10
12
14
16
18
YEARS
H
S
SH
R/H
Prevalence of Primary Drug Resistance Prevalence of Primary Drug Resistance TRC Studies – (1974 -2001)TRC Studies – (1974 -2001)
0
5
10
15
20
XII 74-77
XIII 77-80
XIV80-85
XV 85-86
XVI 86-90
XVII90-95
XVIII95-98
XIX 98-00
XXI2001
per
cen
tag
e
MDR
RIF
STREP
INH
After the introduction of rifampicin in Controlled Clinical Trail at TRC
*
DRS sites of India DRS sites of India (1985-2003)(1985-2003)
North Arcot – 1985-89 (2%), 1989-90 (1.7%), 1999 (3%)
Pondicherry - 1985 (0.9%)
Tamil Nadu - 1995 (3.3%)
AFMS – 1995 -1999 (2.7%)
Bangalore - 2002 (2.2%)
Mysore - 2001 (1.2%)
Raichur - 1989 (3.2%), 1999 (2.5%)
Wardha - 2001 (0.5%)
Jabalpur - 2002 (1%)
Mayurbhanj - 2002 (0.7%)
Hoogli - 2003 (3%)
Population covered = 8.1%
Level of MDR in ‘New’ in different Level of MDR in ‘New’ in different sites in Indiasites in India
Year 2005 DRS sites of India Year 2005 DRS sites of India
Maharashtra, 102.8 millions (9.4%), I Qrt 2005
Gujarat, 53.8 millions (4.9%), I Qrt 2005
Orissa, 38.2 millions (3.5%), II Qrt 2005
Andhra Pradesh, 78.7 millions (7.2%), II Qrt 2005
Population being covered in 2005 = 25%
Resurvey – Tamilnadu DRS-Sikkim,2005-06
TRC Studies on Newer drugs and TRC Studies on Newer drugs and defining resistancedefining resistance
Studies carried out at TRCStudies carried out at TRC
DEFINITION OF RESISITANCE TO RIFAMPICINDEFINITION OF RESISITANCE TO RIFAMPICIN
MIC MIC : 128 : 128µg/ml. µg/ml.
PST (1% or more) : 40 µg/ml PST (1% or more) : 40 µg/ml
BACTEC BACTEC : 2 µg/ml : 2 µg/ml
Indian J. Med. Res. 2001, 114, 187-191.Indian J. Med. Res. 2001, 114, 187-191.
Studies carried out at TRC Studies carried out at TRC
In vitro activity of capreomycin and ciprofloxacin against S.Indian isolates of M.tb Indian J Tuberculosis 1993; 40: 21-25
In vitro activity of ciprofloxacin and ofloxacin against S.Indian isolates of M.tb Indian J Tuberculosis 1994; 41: 87-90
MIC of Lomefloxacin and Minocycline Against Drug-
Sensitive & resistant Isolates of M.tuberculosis Compared on L-J and 7H11 Media Int J Leprosy 1997; 65: 375-378
Studies carried out at TRCStudies carried out at TRC
Evaluation of various methods of susceptibility to ofloxacin in strains of M.tb Indian J Med Res 1999; 110: 186-189 Evaluation of bactericidal action of ofloxacin and sulbactam/ampicillin alone & in combination with R & H on M.tb invitro Antimicrob Agents Chemother 1996; 40: 2296-2299
A multi centre study of the early bactericidal activity of anti- tuberculosis drugs
J Antimicrobial Chemother 2000; 45: 859-870
Recent TRC studies on newer QuinolonesRecent TRC studies on newer Quinolones
1. Bactericidal action of Gatifloxacin, Rifamicin and isoniazid on Logarithmic –
and Stationary – Phase Cultures of Mycobacterium tuberculosis. Antimicrob.
Agents Chemother.2005, 49:627 – 631
2. Moxifloxacin and Gatifloxacin in a new acid model of persistent
M.tuberculosis. Antimicrob. Agents Chemother.2005
3. In vitro activity of fluoroquinlones against M.tuberculosis. J.
Chemotherapy.April,2005 (Accepted)
4. In vitro definitions of MIC of gati and moxifloxacin by different test methods.
FEMS Microbiology.2005
5. Bactericidal action of Moxifloxacin, Rifampicin and Isoniazid on Logarithmic –
and Stationary phase cultures of M.tuberculosis. J Antimicro.Agents and
Chemother. (2005 Communicated)
6. Analysis of Fluoroquinolone resistance in clinical isolates of M.tuberculosis
from India. J. Clinical Microbiology,2005 ( Communicated)
In vitro definition of resistance to gatifloxacin & Moxifloxacin
Type Geometric mean LJ 7H11 Sensitive(46) 63.97 26.73(SHR)
Resistant (46) 65.92 23.82(SHR/HR) Total (92) 65.01 25.23
MIC of S/A against sensitive and MIC of S/A against sensitive and resistant isolates of M.tuberculosisresistant isolates of M.tuberculosis
Microbios 89 135-141 1997 TRC study
SuggestionsSuggestions
Role of IQC and EQAP
Res. Pattern of strain Results obtained
Drug Pattern No. of tests
Agreement
No. %
S
R
S232369
217367
93.599.5
HRS
381299
376286
98.795.7
RRS
384307
382305
99.599.3
E RS
282384
272383
96.599.7
K R S
46169
44168
95.799.4
OflRS
38219
36219
94.7100.0
TOTAL
TRC:IQC IN DST (June’98–Dec 2001)
Res. Pattern of strain Results obtained
Drug Pattern No. of tests
Agreement
No. %
S
R
S334329
334323
10098.2
HRS
567138
567137
10099.3
RRS
417294
416292
99.899.3
E RS
268458
258457
96.399.8
K R S
28266
27261
96.498.1
OflRS
67296
63292
94.099.8
TOTAL
TRC:IQC IN DST (Jan’2003 – Dec 2004)
The role of DST in DECThe role of DST in DEC
Failures of category II cases under DOTFailures of category II cases under DOT
Tests should be very simple & rapid for
Primary culture
Identification &
DST
DST in DECDST in DEC Drug resistance surveillance
The tests should be as per global DRS guidelines
Identification Growth rate. Growth in 500 micrograms of PNB medium Niacin test / NO3 reduction test
DST Indirect economic variant of PST Other methods
Review of simple & rapid tests DST Review of simple & rapid tests DST for DECfor DEC
DirectDirect Primary culture
Sputum swab method Sputum deposit after processing by Petroff’s
Identification Growth in 500 micrograms of PNB medium
DST Standardization of direct PST only for H & R Absolute concentration method Resistance ratio method
? RIF. Resistance as an indicator of MDR TB
Direct methods
MABA
Nitrate reductase assay
MTT Assay
MODS
PhaB & Others
Role of speedier pheneotypic methods
DEFINITION OF RESISTANCE ON LJDEFINITION OF RESISTANCE ON LJSIMPLIFIED VARIANT – PST*SIMPLIFIED VARIANT – PST*
-----------------------------------------------------------DRUGS CONC.(µg/ml) PR (%)------------------------------------------------------------------------ INH 0.2 1 Strep. 4 10 Thioacetazone 2 10 ETH 20 10 Kana 20
10 Cyclo 30 10 Vio 30 10 Capreo 20 10 PZA 100 10 Emb 2 10 Rif 40 1-----------------------------------------------------------------------Only one conc. of drug Canetti et al. Bull. WHO. 1969
DRS – Salient ObservationsDRS – Salient ObservationsDRS – Salient ObservationsDRS – Salient Observations Among new cases : No evidence of an increase in the
prevalence of resistance
Reports on higher prevalence of ADR ( TRC findings, Gujarat, N.Arcot, N.Delhi, Tamilnadu ,Bombay, UP.)
TRC studies :Low level prevalence of MDR TB
TRC studies : Paediatric & Extra-pulmonary cases• low level resistance to H (5-10%)
• low level resistance to S (2-14%)
• absence of MDR TB
Compared to global situation
• a lesser prevalence of primary resistance
• a much higher level of acquired resistance is
observed
Issues to be consideredIssues to be considered Steps and Time Tables