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 2012 by the author
Evidence provided by recent
metanalyses on treatment: what is
new?
GB Migliori
WHO Collaborating Centre for TB and Lung Diseases,
Fondazione S. Maugeri, Tradate Italy
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
Epidemiology of MDR-TB in Europe and globally
derived from surveillance and M&E (Monitoring and
Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment deriving
from recent meta-analyses
The principles of MDR-TB control, with prevention and
public health aspects
3
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
Epidemiology of MDR-TB in Europe and globally
derived from surveillance and M&E (Monitoring and
Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment deriving
from recent meta-analyses
The principles of MDR-TB control, with prevention and
public health aspects
4
200
0
5
6
Guidelines for the programmatic management of
drug-resistant tuberculosis (1)
1 Background information on DR-TB
2 Framework for effective control of DR-TB
3 Political commitment and coordination
4 Definitions: case registration, bacteriology and treatment
outcomes
5 Case-finding strategies
6 Laboratory aspects
7 Treatment strategies for MDR-TB and XDR-TB
8 Mono- and poly-resistant strains
9 Treatment of DR-TB in special conditions and situations
10 DR-TB and HIV infection
11 Initial evaluation, monitoring of treatment and management of
adverse effects
7
Guidelines for the programmatic management of
drug-resistant tuberculosis (2)
12 Treatment delivery and community-based DR-TB support
13 Management of patients with MDR-TB treatment failure
14 Management of contacts of MDR-TB patients
15 Drug resistance and infection control
16 Human resources: training and staffing
17 Management of second-line antituberculosis drugs
18 Category IV recording and reporting system
19 Managing DR-TN through patient-centered care
ANNEX 1
Drug information sheets
ANNEX 2
Weight-based dosing of drugs for adults
ANNEX 3
Suggestions for further reading
ANNEX 4
Legislation, human rights, and patient’s right in TB
care prevention and control
ANNEX 5
Use of experimental drugs outside of clinical trials
8
ANNEX 5
Methodology
Causes of DR
9
Causes of MDR
Patient mismanagement
10
DOTS
FUNDING: Government
Commitment (10$/ case)
DIAGNOSIS: SS microscopy,
QA and safety measures
MDR-TB
> money
Up to 20,000 $/ case
+C, DST, SRL, QA,
infection control
TREATMENT: SCC,DOT, 6-8
months, no hospitalization
24 months, mandatory DOT
& hospitalization in
reference facilities
TB drugs only, no AE
relevant toxicity, need
special drugs + expertise
TREATMENT MONITORING:
SS, standard outcome
definitions
C, DST, special outcome
definitons
11
Definitions
•
•
•
•
Mono-R
Poly-R
MDR
XDR
• SS+, C+
• Cure, failure
• Treatment monitoring
12
Definitions
MDR-TB = Strains resistant to at least INH and RIF (most
important 1st-line drugs)
XDR-TB = MDR TB strains with additional resistance to any
fluoroquinolone and any of the 3 injectable second-line drugs
(amikacin, kanamycin, capreomycin)
TDR, XXDR = Resistance to all drugs (not standardised defin)
TB with any
MDR TB
drug
resistance
TDR/XXDR TB
XDR TB
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)
1st-line
oral
•INH
Injectables
•RIF
•SM
Fluoroquinolones
•PZA
•KM
•Cipro
•EMB
•AMK •Oflox
•Levo
•CM
•(Rfb)
•Moxi
•(Gati)
Oral bacteriostatic 2nd line
•ETA/PTA
•PASA
•CYS
Unclear efficacy
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
14
high dose isonizid
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
Epidemiology of MDR-TB in Europe and globally
derived from surveillance and M&E (Monitoring and
Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment deriving
from recent meta-analyses
The principles of MDR-TB control, with prevention and
public health aspects
15
Notified cases of MDR-TB
Estimated absolute numbers of
reported cases with MDR-TB*
Notified cases of MDR-TB
Cases of
MDR-TB
<100
0–99
100–999
100–999
1000–9999
1000–9999
≥10 000
>10,000
NA
*among reported pulmonary TB patients
Distribution of MDR-TB among new TB
cases, 1994-2010.
0-<3
3-<6
6-<12
12-<18
>18
No data available
Subnational data only
17
Distribution of MDR-TB among
previously treated TB cases, 1994-2010.
0-<6
6-<12
12-<30
30-<50
>50
No data available
Subnational data only
18
13 top settings with highest % of MDR-TB
among new cases, 2001-2010
35.3
Preliminary results ERJ 2012
Minsk, Belarus (2010)
28.3
Murmansk Oblast, Russian Federation (2008)
27.3
Pskov Oblast, Russian Federation (2008)
23.8
Arkhangelsk Oblast, Russian Federation (2008)
22.3
Baku city, Azerbaijan (2007)
20.0
Ivanovo Oblast, Russian Federation (2008)
Republic of Moldova (2006)
19.4
Kaliningrad Oblast, Russian Federation (2008)
19.3
Belgorod Oblast, Russian Federation (2008)
19.2
Dushanbe city and Rudaki district, Tajikistan (2009)
16.5
Mary El Republic, Russian Federation (2008)
16.1
Donetsk Oblast, Ukraine (2006)
16.0
Estonia (2008)
15.4
Tashkent, Uzbekistan (2005)
14.8
0
5
10
15
20
25
30
Notifications of MDR-TB increasing
BUT only ~ 1 in 6 (16%) of estimated cases of MDR-TB
among reported TB patients diagnosed and treated in 2010
MDR-TB cases treated and
estimated numbers not treated
for MDR-TB, among notified TB
patients, 2010
Notified cases of MDR-TB
60
290,000
300
50
53,000
Not on treatment
250
Treated
40
200
30
150
20
100
2010
or
ld
2009
W
2008
Am R
er
ic
as
2007
A
2006
W
2005
EM
0
ic
a
0
Af
r
50
si
.P a
ac
ifi
c
Eu
ro
pe
19,000
10
SE
Number of patients (thousands)
Global Plan target ~270,000 in 2015
Proportion of TB patients tested
for MDR-TB remains low
New cases
40%
Previously treated
60%
51%
35%
50%
30%
% of patients
Global plan target
for 2015 = 20%
25%
20%
15%
40%
Global plan target
for 2015 = 100%
30%
20%
19%
10%
10%
2%
0.3%
Af
r
ic
a
0%
Pa
ci
fic
SE
A
si
a
W
O
R
LD
W
O
R
LD
ic
a
Af
r
R
0%
EM
3%
2%
R
0.4% 0.2% 0.1%
EM
1%
Eu
ro
p
Am e
er
ic
as
5%
6%
6%
W
5%
Eu
ro
p
Am e
er
ic
as
SE
A
si
a
W
Pa
ci
fic
% of patients
30%
Trend of MDR-TB among new cases,
Estonia, Latvia and…Tomsk Oblast, RF
70
0.35
60
0.30
50
0.25
40
0.20
30
0.15
20
0.10
Estonia
10
0
1997
1999
2001
2003
2005
0.05
0.00
1997
2007
100
90
80
0.35
70
60
50
40
30
0.25
20
10
0
1997
p=0.6213
1999
2001
2003
2005
0.30
0.20
0.15
0.10
Latvia
1999
2001
2003
2005
2007
0.05
0.00
1997
120
0.35
100
0.30
p=0.3260
1999
2001
2003
2005
0.25
80
0.20
60
0.15
40
Tomsk oblast, RF
20
0
1998
2000
2002
2004
TB notification rate
2006
0.10
p=0.0055
0.05
0.00
1997
1999
2001
2003
% MDR among new
2005
22
Countries that had reported at least one XDR-TB
case by Oct 2011
Argentina
Armenia
Australia
Austria
Azerbaijan
Bangladesh
Belarus
Belgium
Benin
Botswana
Brazil
Burkina Faso
Bhutan
Cambodia
Canada
Chile
China
Colombia
Czech Republic
Dominican Republic
Ecuador
Egypt
Estonia
Japan
France
Kazakhstan
Georgia
Kenya
Germany
Kyrgyzstan
Greece
Latvia
India
Lesotho
Indonesia
Lithuania
Iran (Islamic Rep. of) Mexico
Ireland
Mongolia
Israel
Mozambique
Italy
Myanmar
Namibia
Nepal
Netherlands
Niger
Norway
Pakistan
Peru
Philippines
Poland
Portugal
Qatar
Republic of Korea
Republic of Moldova
Romania
Russian Federation
Slovenia
South Africa
Spain
Swaziland
Sweden
Tajikistan
Thailand
The Former Yugoslav Republic of Macedonia
Togo
Tunisia
Turkey
Ukraine
United Arab Emirates
United Kingdom
United Republic of Tanzania
United States of America
Uzbekistan
Viet Nam
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
Epidemiology of MDR-TB in Europe and globally
derived from surveillance and M&E (Monitoring and
Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment deriving
from recent meta-analyses
The principles of MDR-TB control, with prevention and
public health aspects
24
ulture and DST laboratories to diagnose MDR-TB, 2010
20/36 HBCs* have insufficient
capacity to diagnose MDR-TB
Culture and DST laboratories to diagnose MDR-TB, 2010
Laboratories per
5M population
≥1
≥1
Culture and DST
<1
<1 laboratories per 5M, 2010
*HBC= high-burden country
NA
Countries = Afghanistan, Armenia, Azerbaijan, Bangladesh, Belarus, Brazil, Bulgaria, Cambodia, China, DR Congo, Estonia, Ethiopia, Georgia, India,
Indonesia, Kazakhstan, Kenya, Kyrgyzstan, Latvia, Lithuania, Mozambique, Myanmar, Nigeria, Pakistan, Philippines, Republic of Moldova, Russian
Federation, South Africa, Tajikistan, Tanzania, Thailand, Uganda, Ukraine, Uzbekistan, Viet Nam, Zimbabwe
The “magic” Gene Xpert
The message
Any person at high risk of MDR-TB should
• undergo rapid testing
• to start an appropriate treatment immediately
• while an additional sputum specimen undergoes
conventional culture and DST
27
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
Epidemiology of MDR-TB in Europe and globally
derived from surveillance and M&E (Monitoring and
Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment deriving
from recent meta-analyses
The principles of MDR-TB control, with prevention and
public health aspects
28
The challenge of MDR
29
Expensive and
toxic drugs are
necessary
30
Grouping drugs
Group 1
1st-line
oral
•INH
Injectables
•RIF
•SM
Fluoroquinolones
•PZA
•KM
•Cipro
•EMB
•AMK •Oflox
•Levo
•CM
•(Rfb)
Group 2
Group 3
•Moxi
•(Gati)
Group 4
Oral bacteriostatic 2nd line
•ETA/PTA
•PASA
•CYS
Group 5
Unclear efficacy
Not routinely recommended,
efficacy unknown, e.g.,
amoxacillin/clavulanic acid,
clarithromycin, clofazamine,
linezolid, inmipenem/cilastatin,
31
high dose isonizid
How to design a MDR-TB regimen
32
33
Metanalysis of 9,153 cases from
32 Countries
• Treatment success vs. to failure/relapse, was associated with
use of:
• later generation quinolones, ofloxacin, ethionamide or
prothionamide
• use of 4 or more likely effective drugs in the initial intensive
phase, and 3 or more likely effective drugs in the continuation
phase.
• Maximum odds of success: initial intensive phase of 7.1-8.5
months and total treatment duration of 18.6-21.5 months
Changes to the recommendations on regimen composition between the
2008 and 2011 updates of WHO MDR-TB guidelines
2008 emergency update
2011 update
Include at least four anti-TB drugs with either certain, or
almost certain, effectiveness during the intensive phase of
Tx
Consider adding more drugs in patients with extensive
disease or uncertain effectiveness
Include at least 4 2nd -line anti-TB drugs likely to be effective
as well as Z during the intensive phase of Tx
The regimen should include Z and/or E one FQ, one
parenteral agent and 2nd -line oral bacteriostatic anti-TB
drugs (no preference of oral bacteriostatic 2nd -line anti-TB
drug was made).
The regimen should include Z a FQ, a parenteral agent,
ethionamide (or prothionamide), and cycloserine, or else
PAS if cycloserine cannot be used.
No evidence found to support the use of > 4 2nd-line anti-TB
drugs in patients with extensive disease. Increasing the
number of 2nd -line drugs in a regimen is permissible if the
effectiveness of some of the drugs is uncertain.
E may be considered effective and included in the regimen E may be used but is not included among the drugs making
if DST shows susceptibility
up the standard regimen.
Tx with Group 5 drugs is recommended only if additional
drugs are needed to bring the total to 4
Group 5 drugs may be used but are not included among the
drugs making up the standard regimen
Intensive phase min 6 months (min 4 months after C
conversion) for a total duration of min 18 months after C
conversion
Intensive phase min 8 months for a total duration>=20
months
35
Treatment monitoring
• Treatment failure was detected best with monthly
culture in MDR-TB cases.
• Thus the available evidence does not support
replacing monthly culture (or quarterly culture) with
monthly smear
37
38
39
Consilium for MDR-TB case and
programme management
40
41
4,853 C+, 361 MDR, 64 XDR
MDR-TB, suscep to at least one FLD
MDR-TB, resistant to all FLD
XDR-TB
TDR-TB (MDR+FQ+ Gr IV)
42
Eur Respir J 2007
Author
Avendano
Burgos
Chan
Chiang
Cox
DeRiemer
Escudero
Geerligs
Granich/Banerjee
Holts
Kim(Shim)
Kim(Yim)
Kwon
Leimane/Riekstina
Lockman
Masjedi
Migliori
Mitnick
Munsiff/Li
Narita
ORiordan
Palmero
Park
Perez-Guzman
Quy
Schaaf
Shin
Shiraishi
Tupasi
Uffredi
Van Deun
Yew
N°
Success
64
30
134
72
54
5
14
40
74
1073
432
118
85
679
128
16
17
417
127
39
19
70
60
15
79
20
353
54
97
23
440
84
N°
Treated
72
45
194
125
77
47
18
43
100
2174
1288
182
129
945
218
27
83
654
671
66
28
112
131
33
157
36
535
61
159
41
603
99
Treatment Success vs Fail and
Relapse and Death and Default
Pooled Success = 0.54 (0.48 to 0.60)
Inconsistency (I-square) = 97.4%
43
Treatment outcomes by MDR-TB patient group
XDR TB
(n=405)
MDR-TB
+FQr
MDR-TB
+INJr
(n = 426)
(n=1130)
MDR-TB,
susceptto FQ &
Inj
Total
(n=4763)
Pooled Outcomes
(From study level
meta-analysis)
Success
40% (27, 53)
48% (36, 60)
56% (45, 66) 64% (57, 72)
62% (54,69)
Failed/Relapse
22% (15, 28)
18% (14, 21)
12% (9, 15)
4% (2, 6)
7% (4, 9)
Died
15% (8, 23)
11% (3, 19)
8% (3, 14)
8% (5, 11)
9% (5, 12)
Defaulted
16% (8, 24)
12% (1,23)
16% (7, 24)
18% (12,24)
17% (11, 22)
44
Association between clinical characteristics and treatment
success vs. failure/relapse/death in the different MDR-TB
sub-groups
Odds of success vs
Characteristics
failure/relapse/death
Male sex (vs female)*
Older age (per 10 years older)*
HIV positive (vs HIV neg.)*
Extensive disease (vs not)*
Prior TB treatment*
None
FLD only
FLD and SLD
MDR sub-groups: †
Not resistant to a FQN nor a 2nd line injectable
Resistant to a second-line injectable, but not a FQN
Resistant to a fluoroquinolone, but not a 2nd line
injectable
Resistant to both a fluoroquinolone and at least one
2nd line injectable (XDR)
Pulmonary resection surgery performed (vs not) †
Experienced a serious adverse event (vs not) †
N
4653
6724
615
4792
aOR
1.0
0.8
0.3
0.5
(95%CI)
(0.9, 1.1)
(0.8, 0.9)
(0.2, 0.4)
(0.4, 0.6)
1275
4410
618
1.0
0.6
0.2
(Reference)
(0.5, 0.8)
0.15, 0.3)
4763
1130
1.0
0.6
(Reference)
(0.5, 0.7)
426
0.3
(0.2, 0.40
405
373
1511
0.2
1.5
1.0
0.2, 0.3)
(0.9, 2.6)
(0.8, 1.2) 45
XDR
INTENS
PHASE
N°
drugs
N
0-2
24
3
47
4
5
6+
46
36
20
(95%CI)
1.0 (reference)
1.9
(0.8, 4.3)
1.8
(0.5, 6.6)
4.9
(1.4,
16.6)
N
aOR
32
49
35
27
(95%CI) N
1.0
3
32
3.3
(ref)
(1.3,
8.5)
6.1
(1.4,
26.3)
2.3
(0.7,
7.6)
28
17
(95%C
I)
N
1.0 (reference)
(0.7,
3.8)
1.6
(0.3,
6.4)
1.4
(0.4,
2.9)
1.1
29
27
83
aOR
35
1.0
27
27
20
(95%
CI)
aOR
1.0
1.7
(95%CI)
(referenc
e)
(0.5, 5.2)
MDR-TB, susceptible
to FQ & Inj
N
aOR
45
1.0
62
(0.5, 3.1) 165
1.1
1.3
137
1.2
(0.8, 3.8)
1.7
1.3
aOR
46
33
2.5
(ref)
(0.8,
7.4)
101
3.1
(0.5,
21.1)
100
2.3
(0.7,
7.2)
1.0
12.2
3.7
3.1
(0.5, 1.8)
1.0
MDR–TB+INJr
N
(referenc
e)
(0.5, 2.3)
1.9
(0.5, 3.3) 380
120
(95%CI)
(1.0, 3.7)
(0.4, 3.4) 296
MDR–TB+FQr
27
5+
aOR
MDR–TB+INJr
10
0-2
4
N
XDR
CONT
PHASE
N°
drugs
aOR
MDR–TB+FQr
(95%CI)
(ref)
(3.4, 44)
MDR, susceptible to
FQ & Inj
N
aOR
77
1.0
133
5.9
(1.7, 8.2)
239
6.0
233
4.7
(1.7, 6.0)
(95%CI)
(ref)
(3.1,
11.0)
(2.8,
13.1)
46
(2.7, 8.1)
prev
TX >
30
days
Drug received
during previous
TX periods
Age/
sex
Country
of birth
43/F
IT
3
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
49/F
IT
3
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof, Dap,Cl,Th
Hospit
Admis
(days)
SS
conv
(days)
C conv
(days)
SRHEZ;
FQ,Eth,AK,PAS,C,K,
Cyc,Rb,Clof
422
No
No
Died
94
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
625
No
No
Died
60
Drug resistance at
XDR diagnosis
TX
dur
(mo
Out
come
First tuberculosis cases in Italy resistant to all tested drugs
GB Migliori (gbmigliori@fsm.it), G De Iaco, G Besozzi, R Centis, DM Cirillo
WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri,
Care and Research Institute, Tradate
Eurosurveillance 2007
47
48
XDR alone
XDR+2sli
XDR+sliG4†
XDR+sliG4EZ
n = 301
n = 68
n = 48
n =42
Cured
43 (27, 58)
30 (17, 43)
34 (-, -)
19 (0, 48)*
Failed
20 (15, 25)
29 (8, 50)
33 (-, -)
26 (14, 38)
Died
13 (6, 20)
18 (7, 29)
30 (18, 41)*
35 (21, 50)*
Failed or died
35 (26, 45)
54 (40, 69)*
48 (-, -)
49 (37, 61)
Defaulted
15 (5, 24)
15 (3, 27)
18 (-, -)
19 (6, 32)
XDR-alone
XDR+2sli
XDR+sliG4
XDR+sliG4EZ
n = 301
n = 68
n = 48
n =42
Cured
1.0 (reference)
0.4 (0.2, 0.8)
0.6 (0.2, 1.6)
0.5 (0.2, 1.7)
Failed
1.0 (reference)
2.1 (1.0, 4.5)
1.8 (0.7, 4.7)
1.9 (0.7, 5.3)
Died
1.0 (reference)
1.6 (0.6, 4.4)
1.7 (0.6, 4.9)
1.8 (0.6, 5.3)
Failed or Died
1.0 (reference)
2.6 (1.2, 4.4)
2.6 (1.1, 6.7)
2.8 (1.0, 7.9)
Defaulted
1.0 (reference)
1.0 (0.3, 2.6)
0.5 (0.2, 1.8)
0.5 (0.1, 2.0)
Treatment outcome
Treatment outcome
49
50
51
52
Building a regimen for XDR-TB
53
54
55
Proportion of adverse events (95% CI)
Alffenaar JWC et al. [46]
Anger HA/Condos R et al. [34]
De Lorenzo S et al. [35]
FortunJ et al. [22]
Koh WJ et al. [45]
Migliori GB et al. [8]
Park IN et al. [44]
Schecter GF et al. [30]
Singla R et al. [31]
Udwadia ZF et al. [32]
Villar M et al. [33]
Von der Lippe B et al. [43]
0
0.2
0.4
0.6
Adverse events
0.8
0.00
1.00
0.67
1.00
0.82
1.00
0.71
0.22
0.71
1.00
0.22
0.80
(0.00 - 0.37)
(0.78 - 1.00)
(0.09 - 0.99)
(0.29 - 1.00)
(0.48 - 0.98)
(0.03 - 1.00)
(0.29 - 0.96)
(0.07 - 0.44)
(0.42 - 0.92)
(0.29 - 1.00)
(0.03 - 0.60)
(0.44 - 0.97)
Pooled Proportion = 0.59 (0.49 to 0.68)
Chi-square = 61.94; df = 11 (p = 0.0000)
1 Inconsistency (I 2 ) = 82.2 %
Proportion of linezolid interruption due to adverse events (95% CI)
Alffenaar JWC et al. [46]
Anger HA/Condos R et al. [34]
FortunJ et al. [22]
Koh WJ et al. [45]
Migliori GB et al. [8]
Park IN et al. [44]
Schecter GF et al. [30]
Singla R et al. [31]
Udwadia ZF et al. [32]
Villar M et al. [33]
Von der Lippe B et al. [43]
0
0.2
0.4
0.6
0.8
Linezolid interruption due to adverse events
0.00
0.87
1.00
0.82
1.00
0.40
1.00
1.00
0.54
1.00
0.70
(0.00 - 0.37)
(0.60 - 0.98)
(0.29 - 1.00)
(0.48 - 0.98)
(0.03 - 1.00)
(0.05 - 0.85)
(0.03 - 1.00)
(0.69 - 1.00)
(0.25 - 0.81)
(0.03 - 1.00)
(0.35 - 0.93)
Pooled Proportion = 0.69 (0.58 to 0.79)
Chi-square = 37.19; df = 10 (p = 0.0001)
1 Inconsistency (I2) = 73.1 %
AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012
56
Meropenem
(De Lorenzo S, Alffenar JW et al- ERJ 2012 in press)
Cases
Variables
Total
Cases: 37
Controlls: 61
Controls
Meropenem/cla
Meropenem/clavula
vulanate pnate -containing
sparing anti-TB value
anti-TB regimen
regimen
-Italian cohort
-Dutch cohort
16/50 (32.0)
7/32 (21.9)
9/18 (50.0)
0.04
27/48 (56.3)
20/32 (62.5)
7/16 (43.8)
0.22
37/48 (77.1)
28/32 (87.5)
9/16 (56.3)
0.02
Culture conversion at 30 days of treatment, n (%)
24/66 (36.4)
12/37 (32.4)
12/29 (41.4)
0.45
Culture conversion at 60 days of treatment, n (%)
37/62 (59.7)
24/37 (64.9)
13/25 (52.0)
0.31
Culture conversion at 90 days of treatment, n (%)
46/61 (75.4)
31/37 (83.8)
15/24 (62.5)
0.06
52.5 (38.5-65.0)
46.0 (6.0-157.0)
0.85
42.0 (28.0-65.0)
46.0 (13.0-96.0)
0.96
Sputum smear conversion at 30 days of treatment, n (%)
Sputum smear conversion at 60 days of treatment, n
(%)
Sputum smear conversion at 90 days of treatment, n
(%)
Median (IQR) period from start of anti-TB therapy to
sputum smear conversion, days
Median (IQR) period from start of anti-TB therapy to
culture conversion, days
51 (28.0-75.0)
42 (16.5-82.0)
57
Aims
•
•
•
•
•
To describe and discuss:
Existing guidelines and definitions
The epidemiology of TB and MDR-TB in Europe and
globally derived from surveillance and M&E
(Monitoring and Evaluation)
The new information on MDR-TB diagnosis
The new information on MDR-TB treatment
The principles of MDR-TB control, with prevention and
public health aspects
58
TB patients with inappropriate regimen have a 27fold higher risk of developing MDR-TB
Multidrug resistance after inappropriate tuberculosis treatment: A
meta-analysis
Marieke J. van der Werf, Miranda W. Langenda, Emma Huitric, Davide
Manissero
ERJ 2012 in press
59
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
Strengthen basic TB control, to prevent
M/XDR-TB
Scale-up programmatic management and
care of MDR-TB and XDR-TB
Strengthen laboratory services for adequate and
timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their
rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV
prevalence settings
Mobilize urgently resources domestically and
internationally
Promote research and development into new
diagnostics, drugs and vaccines
60
Global Policy: MDR-TB and XDR-TB
1.
2.
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of
MDR-TB and XDR-TB
3.
Strengthen laboratory services for
adequate and timely diagnosis of MDR-TB
and XDR-TB
4.
Ensure availability of quality drugs and their
rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV
prevalence settings
Mobilize urgently resources domestically and
internationally
Promote research and development into new
diagnostics, drugs and vaccines
5.
6.
7.
8.
61
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of
MDR-TB and XDR-TB
Strengthen laboratory services for adequate and
timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and
their rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV
prevalence settings
Mobilize urgently resources domestically and
internationally
Promote research and development into new
diagnostics, drugs and vaccines
62
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
8.
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of
MDR-TB and XDR-TB
Strengthen laboratory services for adequate and
timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their
rational use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in
high HIV prevalence settings
Mobilize urgently resources domestically
and internationally
Promote research and development into new
diagnostics, drugs and vaccines
63
Global Policy: MDR-TB and XDR-TB
1.
2.
3.
4.
5.
6.
7.
Strengthen basic TB control, to prevent M/XDR-TB
Scale-up programmatic management and care of
MDR-TB and XDR-TB
Strengthen laboratory services for adequate and
timely diagnosis of MDR-TB and XDR-TB
Ensure availability of quality drugs and their rational
use
Expand MDR-TB and XDR-TB surveillance
Introduce infection control, especially in high HIV
prevalence settings
Mobilize urgently resources domestically and
internationally
8. Promote research and development
into new diagnostics, drugs and
vaccines
64
1966, the last anti-TB drug was discovered
65
Bedaquiline
Delamanid
66
Carlo Forlanini,
first notes on Pneumothorax
January 7th, 1907
67
Interventions over time: old weapons might
be useful again to manage XDR
First sanatorium
Germany, 1857 First Dispensary,
Scotland, 1897
BCG vaccination
Pneumotorax, Italy, 1907
Drugs, 1945-1962
Koch, Mtb,
1882
MMR,1950-1980
Fox:Ambulatory treatment, 1968
Styblo model, 1978
DOTS, 1991
Outbreak Management,
sanatoria
Risk Group Management
screening
drug therapy
Socio-economic improvement
68
69
Pneumothorax
71
“Nobody wants me
around..”
72
73
XDR and TB control: which future ?
74

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