DOTS strategy by malj

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         Ó 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
ANNEX 5      Methodology                                        8
Causes of DR




               9
Causes of MDR




Patient mismanagement

                        10
           DOTS                       MDR-TB
FUNDING: Government          > money
Commitment (10$/ case)
                             Up to 20,000 $/ case
DIAGNOSIS: SS microscopy,    +C, DST, SRL, QA,
QA and safety measures       infection control
TREATMENT: SCC,DOT, 6-8      24 months, mandatory DOT
months, no hospitalization   & hospitalization in
                             reference facilities
TB drugs only, no AE         relevant toxicity, need
                             special drugs + expertise
TREATMENT MONITORING:        C, DST, special outcome
SS, standard outcome         definitons
definitions
                                                    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)


                                                    TDR/XXDR TB
          TB with any
          drug        MDR TB              XDR TB

          resistance
XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM)




1st-line
  oral
•INH       Injectables

•RIF       •SM     Fluoroquinolones
                   •Cipro    Oral bacteriostatic 2nd line
•PZA       •KM
                             •ETA/PTA         Unclear efficacy
•EMB       •AMK •Oflox
                                             Not routinely recommended,
•(Rfb)     •CM  •Levo        •PASA           efficacy unknown, e.g.,
                                             amoxacillin/clavulanic acid,
                   •Moxi     •CYS            clarithromycin, clofazamine,
                                             linezolid, inmipenem/cilastatin,
                   •(Gati)                   high dose isonizid          14
                         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
    Estimated absolute numbers of
     reported cases with MDR-TB*




                                        <100
                                        100–999
                                        1000–9999
                                        >10,000
*among reported pulmonary TB patients
Distribution of MDR-TB among new TB
           cases, 1994-2010.




                                      17
    Distribution of MDR-TB among
previously treated TB cases, 1994-2010.




                                      18
13 top settings with highest % of MDR-TB
among new cases, 2001-2010
 Minsk, Belarus (2010)    Preliminary results ERJ 2012   35.3
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
  Notified cases of MDR-TB
                                        estimated numbers not treated
  Global Plan target ~270,000 in 2015   for MDR-TB, among notified TB
                                        patients, 2010
                                                                290,000

                              53,000




   19,000
Proportion of TB patients tested
   for MDR-TB remains low
     New cases            Previously treated



     Global plan target      Global plan target
     for 2015 = 20%          for 2015 = 100%
Trend of MDR-TB among new cases,
Estonia, Latvia and…Tomsk Oblast, RF



                                  Estonia




                                  Latvia




                         Tomsk oblast, RF


                                                              22
           TB notification rate             % MDR among new
Countries that had reported at least one XDR-TB
                case by Oct 2011
                         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
         20/36 HBCs* have insufficient
         capacity to diagnose MDR-TB




                                                                                          ≥1 Culture and DST
                                                                                          <1 laboratories per 5M, 2010

*HBC= high-burden country
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
             Group 2
  oral
•INH       Injectables     Group 3

•RIF       •SM     Fluoroquinolones         Group 4

                   •Cipro     Oral bacteriostatic 2nd line       Group 5
•PZA       •KM
                             •ETA/PTA          Unclear efficacy
•EMB       •AMK •Oflox
                                              Not routinely recommended,
•(Rfb)     •CM  •Levo        •PASA            efficacy unknown, e.g.,
                                              amoxacillin/clavulanic acid,
                   •Moxi     •CYS             clarithromycin, clofazamine,
                                              linezolid, inmipenem/cilastatin,
                   •(Gati)                    high dose isonizid          31
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     Include at least 4 2nd -line anti-TB drugs likely to be effective
almost certain, effectiveness during the intensive phase of     as well as Z during the intensive phase of Tx
Tx
Consider adding more drugs in patients with extensive           No evidence found to support the use of > 4 2nd-line anti-TB
disease or uncertain effectiveness                              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.

The regimen should include Z and/or E one FQ, one               The regimen should include Z a FQ, a parenteral agent,
parenteral agent and 2nd -line oral bacteriostatic anti-TB      ethionamide (or prothionamide), and cycloserine, or else
drugs (no preference of oral bacteriostatic 2nd -line anti-TB   PAS if cycloserine cannot be used.
drug was made).
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         Group 5 drugs may be used but are not included among the
drugs are needed to bring the total to 4                        drugs making up the standard regimen
Intensive phase min 6 months (min 4 months after C              Intensive phase min 8 months for a total duration>=20
conversion) for a total duration of min 18 months after C       months
                                                                                                                       35
conversion
             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
                      N°
                                N°      Treatment Success vs Fail and
Author              Success
                              Treated
                                        Relapse and Death and Default
Avendano               64        72
Burgos                 30        45
Chan                  134       194
Chiang                 72       125
Cox                    54        77
DeRiemer                5        47
Escudero               14        18
Geerligs               40        43
Granich/Banerjee       74       100
Holts                1073      2174
Kim(Shim)             432      1288
Kim(Yim)              118       182
Kwon                   85       129
Leimane/Riekstina     679       945
Lockman               128       218
Masjedi                16        27
Migliori               17        83
Mitnick               417       654
Munsiff/Li            127       671
Narita                 39        66
ORiordan               19        28
Palmero                70       112
                                                      Pooled Success = 0.54 (0.48 to 0.60)
Park                   60       131                   Inconsistency (I-square) = 97.4%
Perez-Guzman           15        33
Quy                    79       157
Schaaf                 20        36
Shin                  353       535
Shiraishi              54        61
Tupasi                 97       159
Uffredi                23        41
Van Deun              440       603
Yew                    84        99




                                                                                  43
     Treatment outcomes by MDR-TB patient group

                     XDR TB        MDR-TB         MDR-TB        MDR-TB,         Total
                      (n=405)       +FQr           +INJr        suscept-
                                    (n = 426)      (n=1130)     to FQ &
                                                                   Inj
                                                                 (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
                                                            N    aOR     (95%CI)
Male sex (vs female)*                                     4653    1.0    (0.9, 1.1)
Older age (per 10 years older)*                           6724    0.8    (0.8, 0.9)
HIV positive (vs HIV neg.)*                                615    0.3    (0.2, 0.4)
Extensive disease (vs not)*                               4792    0.5    (0.4, 0.6)
Prior TB treatment*
   None                                                   1275   1.0    (Reference)
   FLD only                                               4410   0.6     (0.5, 0.8)
   FLD and SLD                                             618   0.2     0.15, 0.3)
MDR sub-groups: †
   Not resistant to a FQN nor a 2nd line injectable       4763   1.0    (Reference)
   Resistant to a second-line injectable, but not a FQN   1130   0.6     (0.5, 0.7)
   Resistant to a fluoroquinolone, but not a 2nd line
   injectable                                             426    0.3     (0.2, 0.40
   Resistant to both a fluoroquinolone and at least one
   2nd line injectable (XDR)                               405   0.2      0.2, 0.3)
Pulmonary resection surgery performed (vs not) †           373   1.5     (0.9, 2.6)
Experienced a serious adverse event (vs not) †            1511   1.0     (0.8, 1.2) 45
                XDR                          MDR–TB+FQr                    MDR–TB+INJr            MDR-TB, susceptible
INTENS
PHASE                                                                                                 to FQ & Inj

N°                                                      (95%C
drugs    N    aOR      (95%CI)      N         aOR       I)    N             aOR      (95%CI)      N     aOR     (95%CI)

                                                                                     (referenc                  (referenc
 0-2     24                             10                            29      1.0        e)       45      1.0       e)
                                                                      27      1.7    (0.5, 5.2)                 (0.5, 2.3)
   3     47    1.0 (reference)          32     1.0 (reference)                                   62       1.1
                                                          (0.7,                      (0.5, 3.1) 165             (1.0, 3.7)
  4      46    1.9     (0.8, 4.3)       49      1.6       3.8)        83      1.3                         1.9
                                                          (0.3,                      (0.4, 3.4) 296             (0.8, 3.8)
   5     36    1.8     (0.5, 6.6)       35      1.4       6.4)    137         1.2                         1.7
                                                          (0.4,                      (0.5, 3.3) 380             (0.5, 1.8)
                         (1.4,                            2.9)
  6+     20    4.9       16.6)          27      1.1               120         1.3                         1.0

CONT            XDR                      MDR–TB+FQr                        MDR–TB+INJr            MDR, susceptible to
PHASE                                                                                                  FQ & Inj
N°                                                      (95%
drugs    N    aOR      (95%CI) N              aOR       CI)       N         aOR      (95%CI)      N     aOR     (95%CI)

 0-2     27     1.0      (ref)      35          1.0      (ref)        46       1.0     (ref)      77      1.0     (ref)
                         (1.3,                           (0.8,        33      12.2   (3.4, 44)                    (3.1,
  3      32     3.3      8.5)       27          2.5      7.4)                                     133     5.9     11.0)
                         (1.4,                           (0.5,    101         3.7    (1.7, 8.2)                   (2.8,
  4      28     6.1      26.3)      27          3.1      21.1)                                    239     6.0     13.1)
                         (0.7,                           (0.7,    100         3.1    (1.7, 6.0)                         46
  5+     17     2.3      7.6)       20          2.3      7.2)                                     233     4.7   (2.7, 8.1)
                   prev
                            Drug received                                Hospit     SS                           TX
Age/    Country    TX >                           Drug resistance at                       C conv     Out
                           during previous                               Admis     conv                          dur
sex     of birth    30                             XDR diagnosis                           (days)    come
                             TX periods                                  (days)   (days)                         (mo
                   days
43/F   IT                 SRHEZ;                  SRHEZ;                  422      No       No      Died
                    3     FQ,Eth,AK,PAS,C,K,C     FQ,Eth,AK,PAS,C,K,
                                                                                                                 94
                          yc,Rb,Clof,Dap,Cl,Th    Cyc,Rb,Clof

49/F   IT                 SRHEZ;                  SRHEZ;                  625      No       No      Died
                    3     FQ,Eth,AK,PAS,C,K,C     FQ,Eth,AK,PAS,C,K,C
                                                                                                                 60
                          yc,Rb,Clof, Dap,Cl,Th   yc,Rb,Clof,Dap,Cl,Th




 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
    Treatment outcome
                           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
   Treatment outcome
                           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)
                                                                                                 49
50
51
52
Building a regimen for XDR-TB




                                53
54
55
                                                               56
AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012
              Meropenem                (De Lorenzo S, Alffenar JW et al- ERJ 2012 in press)

                                                                                                 Controls
Variables                                                                        Cases
                                                                                            Meropenem/cla
                                                                          Meropenem/clavula
                                                                                               vulanate -    p-
                                                            Total          nate -containing
Cases: 37                                                                                   sparing anti-TB value
                                                                           anti-TB regimen
                                                                                                regimen
Controlls: 61                                                               -Italian cohort
                                                                                             -Dutch cohort
Sputum smear conversion at 30 days of treatment, n (%)   16/50 (32.0)          7/32 (21.9)        9/18 (50.0)           0.04
Sputum smear conversion at 60 days of treatment, n
                                                         27/48 (56.3)          20/32 (62.5)       7/16 (43.8)           0.22
(%)
Sputum smear conversion at 90 days of treatment, n
                                                         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
Median (IQR) period from start of anti-TB therapy to
                                                         51 (28.0-75.0)
sputum smear conversion, days
                                                                             42.0 (28.0-65.0)   46.0 (13.0-96.0)        0.96
Median (IQR) period from start of anti-TB therapy to
                                                         42 (16.5-82.0)
culture conversion, days                                                                                           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 27-
     fold 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.   Strengthen basic TB control, to prevent
     M/XDR-TB
2.   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
5.   Expand MDR-TB and XDR-TB surveillance
6.   Introduce infection control, especially in high HIV
     prevalence settings
7.   Mobilize urgently resources domestically and
     internationally
8.   Promote research and development into new
     diagnostics, drugs and vaccines                       60
     Global Policy: MDR-TB and XDR-TB


1.   Strengthen basic TB control, to prevent M/XDR-TB
2.   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
5.   Expand MDR-TB and XDR-TB surveillance
6.   Introduce infection control, especially in high HIV
     prevalence settings
7.   Mobilize urgently resources domestically and
     internationally
8.   Promote research and development into new             61
     diagnostics, drugs and vaccines
     Global Policy: MDR-TB and XDR-TB


1.   Strengthen basic TB control, to prevent M/XDR-TB
2.   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
5.   Expand MDR-TB and XDR-TB surveillance
6.   Introduce infection control, especially in high HIV
     prevalence settings
7.   Mobilize urgently resources domestically and
     internationally
8.   Promote research and development into new
     diagnostics, drugs and vaccines
                                                           62
     Global Policy: MDR-TB and XDR-TB


1.   Strengthen basic TB control, to prevent M/XDR-TB
2.   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
5.   Expand MDR-TB and XDR-TB surveillance
6.   Introduce infection control, especially in
     high HIV prevalence settings
7.   Mobilize urgently resources domestically
     and internationally
8.   Promote research and development into new
     diagnostics, drugs and vaccines
                                                        63
     Global Policy: MDR-TB and XDR-TB


1.   Strengthen basic TB control, to prevent M/XDR-TB
2.   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
5.   Expand MDR-TB and XDR-TB surveillance
6.   Introduce infection control, especially in high HIV
     prevalence settings
7.   Mobilize urgently resources domestically and
     internationally
8. Promote research and development
   into new diagnostics, drugs and                             64
   vaccines
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,                         MMR,1950-1980
             1882                                        Fox:Ambulatory treatment, 1968
                                                               Styblo model, 1978


                                                                              DOTS, 1991

               sanatoria                                                                   Outbreak Management,
                                                                                           Risk Group Management
                                                  screening



                                                drug therapy

             Socio-economic improvement

                                                                                                                   68
69
Pneumothorax




               71
“Nobody wants me
around..”




                   72
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XDR and TB control: which future ?




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