The slideset offers an overview of MDR-TB: the epidemiology, the efficacy of the available treatments, and the new perspectives in the management of the pathology. The slideset underlines, moreover, the existence of a free cost online instrument developed by ERS together with WHO to help clinician from all Europe to manage difficult-to-treat TB cases: TB Consilium.

1. New perspectives in the treatment of MDR-
TB
G. B. Migliori, ERS Secretary General
WHO Collaborating Centre for TB and Lung Disease,
Fondazione S. Maugeri, Care and Research Institute
Tradate, Italy

2. Introduction
AIMS: to discuss
 The global MDR/XDR-TB threat
 The (poor) outcomes of M/XDR-TB treatment
 New drugs & new regimens with new insights
 The ERS/WHO TB Consilium

4. WHO Global Report 2015
sont réduitssont réduitssont réduitssont réduitssont réduits
Proportion of MDR-TB among new cases

5. Number of MDR-TB cases estimated to occur among
notified P TB cases, 2014

6. 10 areas with top % of MDR-TB among new and previously
treated cases

7. 7
Age/
sex
Country
of birth
prev
TX >
30
days
Drug received
during previous
TX periods
Drug resistance at
XDR diagnosis
Hospit
Admis
(days)
SS
conv
(days)
C conv
(days)
Out
come
TX
dur
(mo
43/F IT 3 SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,K,
Cyc,Rb,Clof
422 No No Died
94
49/F IT 3 SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof, Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,K,C
yc,Rb,Clof,Dap,Cl,Th
625 No No Died
60
First tuberculosis cases in Italy resistant to all tested drugs
Eurosurveillance 2007

8. WHO Global Report 2015
1/3 MDR-TB cases
diagnosed and
1/4 treated

9. Esposito S. et al, ERJ 2015
The face of TB in
low incidence
countries: micro-
epidemics

10. Treatment
OCT
NOV
DEC
JAN
FEB
MAR
APR
MAY
JUNE
JULY
AUG
SEPT
OCT
NOV
DEC
JAN
FEB
MAR
APR
MAY
JUNE
JULY
AUG
SEPT
OCT
NOV
DELAMANID
ETHIONAMIDE
CLOFAZIMINE
AMIKACIN
MEROPENEM
PAS
LINEZOLID
CLARITHROMYCIN
TERIZIDON
AMOXI/CLAV
MOXIFLOXACIN
ISONIAZIDE
PYRAZINAMID
ETHAMBUTOL
2013 2014 2015

11. History of the large cohort

12. Resistance to fluoroquinolones and second-line injectable drugs: impact on MDR-TB outcomes. Eur Respir J. 2012 Oct 25; doi:
10.1183/09031936.00134712
Treatment success among different MDR-TB patient groups

13. 13
Treatment outcome
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
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)
Increased severity

14. 14
1966, the last anti-TB drug was discovered
After 40 yrs, 2 new drugs approved by
the American Food and Drug
Administration (FDA) and/or the
European Medicine Agency (EMA)

15. After > 40 yrs…
Bedaquiline and Delamanid
Approved in 2012 by FDA Approved in 2013 by EMA

16. Drug group Drug name Acronym
A. Fluoroquinolones Levofloxacin
Moxifloxacin
Gatifloxacin
Lfx
Mfx
Gfx
B. Second-line injectable agents Amikacin
Capreomycin
Kanamycin
(Streptomycin)¶
Am
Cm
Km
(S)
C. Other core second-line agents Ethionamide / Prothionamide
Cycloserine / Terizidone
Linezolid
Clofazimine
Eto / Pto
Cs / Trd
Lzd
Cfz
D. Add-on agents
(not part of the core MDR-TB
regimen)
D1 Pyrazinamide
Ethambutol
High-dose isoniazid
Z
E
Hh
D2 Bedaquiline
Delamanid
Bdq
Dlm
D3 p-aminosalicylic acid
Imipenem-cilastatin#
Meropenem#
Amoxicillin-clavulanate#
PAS
Ipm
Mpm
Amx-Clv

17. Delamanid
• Favourable outcomes in 143/192 pts (74.5%)
receiving delamanid ≥6 months, compared to
126/229 patients (55.0%) receiving delamanid ≤2
months.
• Mortality reduced to 1.0% among those
receiving long-term delamanid, VS short-
term/no delamanid (8.3%), p<0.001.
• Treatment benefit also among XDR-TB pts
Skripconoka V, ERJ 201317
Delamanid added to a
background MDR-TB regimen
improves significantly SS-C
conversion at month 2 (45.4 vs
29.6%)

18. Bedaquiline (Bq) and Pretomanid (PA-824)
• New phase IIb trial comparing
bactericidal activity of 8-week
regimens: moxifloxacin + pretomanid
(100 mg or 200 mg, according to the
arm), + Z vs standard anti-TB regimen
to treat sputum SS + pts with DS and
DR-TB.
• Bactericidal activity higher vs current
WHO-recommended regimen in both
DS and DR-TB after 2 months of TX.
• Experimental treatment well tolerated
(no episode of QT interval exceeding
500 msec identified )
Lancet 2014
18
IIb trial, BQ + background regimen VS placebo:
reduced median time to C conversion,(125 to 83
days) and increased C conversion at 24 weeks
(79% VS. 58%) and at 120 weeks (62% vs. 44%).
Cure rates at 120 weeks were 58% VS 32%
Similar incidence AE (10 deaths BQ gr)
• EBA at 2 w: PA-824+moxi+Z better
than: bq, bq+Z, bq+PA-824 Comparable
to WHO Cat 1

19. WHO recommendations on Bq and Delamanid
• 100 mg BD added
to OBR in adults
• Pharmacovigilance
• Informed consent
• Not added to BQ
19
• 400 mg daily 2/12 200
mg 3/w 22 w added to
OBR in adults
• Pharmacovigilance
• Informed consent
• QT monitoring
1. Country prepardness & planning
2. National plan new tools
3. M&E (DRS & pharmacovigilance)
4. Private sector engaged
5. Uniterrupded supply
6. Operational research

20. 20
Adverse events
0 0.2 0.4 0.6 0.8 1
Alffenaar JWC et al. [46] 0.00 (0.00 - 0.37)
AngerHA/CondosR et al. [34] 1.00 (0.78 - 1.00)
De Lorenzo S et al. [35] 0.67 (0.09 - 0.99)
FortunJ et al. [22] 1.00 (0.29 - 1.00)
Koh WJ et al. [45] 0.82 (0.48 - 0.98)
Migliori GB et al. [8] 1.00 (0.03 - 1.00)
Park IN et al. [44] 0.71 (0.29 - 0.96)
SchecterGF et al. [30] 0.22 (0.07 - 0.44)
Singla R et al. [31] 0.71 (0.42 - 0.92)
Udwadia ZF et al. [32] 1.00 (0.29 - 1.00)
VillarM et al. [33] 0.22 (0.03 - 0.60)
Von der Lippe B et al. [43] 0.80 (0.44 - 0.97)
Proportionof adverse events (95% CI)
Pooled Proportion = 0.59 (0.49 to 0.68)
Chi-square = 61.94; df = 11 (p = 0.0000)
Inconsistency (I2)= 82.2 %
Linezolid interruption due to adverse events
0 0.2 0.4 0.6 0.8 1
Alffenaar JWC et al. [46] 0.00 (0.00 - 0.37)
Anger HA/Condos R et al. [34] 0.87 (0.60 - 0.98)
FortunJ et al. [22] 1.00 (0.29 - 1.00)
Koh WJ et al. [45] 0.82 (0.48 - 0.98)
Migliori GB et al. [8] 1.00 (0.03 - 1.00)
ParkIN et al. [44] 0.40 (0.05 - 0.85)
Schecter GF et al. [30] 1.00 (0.03 - 1.00)
Singla R et al. [31] 1.00 (0.69 - 1.00)
Udwadia ZF et al. [32] 0.54 (0.25 - 0.81)
Villar M et al. [33] 1.00 (0.03 - 1.00)
Von der Lippe B et al. [43] 0.70 (0.35 - 0.93)
Proportion of linezolid interruption due to adverse events (95% CI)
Pooled Proportion = 0.69 (0.58 to 0.79)
Chi-square = 37.19; df = 10 (p = 0.0001)
Inconsistency (I2) = 73.1 %
AE in Linezolid- containing regimens. Sotgiu et al, ERJ 2012

21. TDM: is it the future of
MDR-TB treatment?

22. Meropenem
22
Variables Total 37 Cases 61 Controls p-value
SS conv at 90 d, n (%)
37/48
(77.1)
28/32 (87.5) 9/16 (56.3) 0.02
C conv at 30 d, n (%)
24/66
(36.4)
12/37 (32.4) 12/29 (41.4) 0.45
C conv at 60 d, n (%)
37/62
(59.7)
24/37 (64.9) 13/25 (52.0) 0.31
C conv at 90 d, n (%)
46/61
(75.4)
31/37 (83.8) 15/24 (62.5) 0.06

23. New evidence on Carbapenems

24. International Carbapenems Study Group (ICSG)
Meropenem 96 cases (49.0% XDR) Imipenem 84 cases (67.9% XDR)
Setting 5 centres /15 countries, 4
continents
10 centros /15 countriess, 4
continents
Age/sex M 34±10.3 yr/56.3% (76.0% migr) 36±11.2 yr/60.7% (32.1% migr)
HIV+/ART 8 HIV+ (9%)/ 6 ART 2 HIV+ (2.4%) on ART
Previous Diagnosis Failure 79.0%; success 11.3% Failure 87.2%; success 1.3%
P<0.05
Previous Tx Median 2 (IQR 1-4) Median 2 (IQR 1-3)
Resistant to Median 8 drugs (IQR 6-9) Median 8 drugs (IQR 7-8) P<0.05
Duration 85 d (IQR 49-156) 187 d (IQR 60-428)
SS neg 45 d (IQR 28-68) 30 d (IQR 30-60)
C neg 44 d (IQR 28-75) 60 d (IQR 30-90) P<0.05
Outcomes Success 57.3%; continue Tx 25.0%;
died 11.4%; default 5.2%
Success 40.5%; continue Tx 27.3%;
died 23.9%; adefault 7.1%
P <0.0001
Interruptions AE Linezolid 17.1%; Meropenem 8.5% Linezolid 22.5%;Imipenem 7.3%
New drugs 1 Delamanid, 9 BQ 0 Delamanid, 7 BQ

26. Ertapenem to treat M/XDR-TB
Tiberi S, et al. ERJ 2016 in press

27. Alsaad N et al, ERJ 2014

28. Co-trimoxazole to treat MDR-TB
Alsaad N et al, ERJ 2013
Median dose: 6.5 mg/kg BW OD for 381 days (IQR 129-465)
8/10 cured, 2 still on treatment
100% bacteriological conversion
2 G/I adverse events

30. 30

31. Bangladesh regimen
Gati+clofa+EMB+Z for all 9 months
+
prothio+kana+HDH for the initial 4 months
IF DRUG RESISTANCE PREVALENCE IS LOW,
MAJORITY OF DRUGS LIKELY TO BE ACTIVE
IF DRUG RESISTANCE PREVALENCE IS HIGH,
MAJORITY OF DRUGS LIKELY TO BE INACTIVE

32. Bangladesh regimen
Gati+clofa+EMB+Z for all 9 months
+ prothio+kana+HDH for initial 4 months
Probability of DR in Former Soviet Union:
Fq: 30%; Clofa: ??; EMB: 65%; Z: 70%
Prothio: 45%; Kana: 45%; HDH: ??
Günter G et al, EID 2015 and IJTLD 2015
HDH works when we have inhA withut katG: 12,3% global average
Seifert M y Catanzaro A, PLoS One 2015

34. Prevalence of resistance to the drugs
composing the Bangladesh regimen (ERJ 2016)
Cohort
FQ
(95% CI)
Clofa
(95% CI)
E
(95% CI)
Z
(95% CI)
Prothio
(95% CI)
Kana
(95% CI)
International
Carbapenems
Study Group
(ICSG)
137/336,
40.8%
(35.6-46.1)
-
232/339,
68.4%
(63.5-73.4)
195/300,
65.0%
(59.6-70.4)
174/314,
55.4%
(49.9-60.9)
100/225,
44.4%
(37.9-50.9)
ICSG Europe
91/283,
32.2%
(26.8-37.6)
-
195/284,
68.7%
(63.3-74.1)
165/255,
64.7%
(58.8-70.6)
150/279,
53.8%
(48.0-59.7)
64/172,
37.2%
(30.0-44.4)
ICSG S.
America
46/53,
86.8%
(77.7-95.9)
-
37/55,
67.3%
(54.9-79.7)
30/45, 66.7%
(52.9-80.5)
24/35,
68.6%
(53.2-84.0)
36/53,
67.9%
(55.3-80.5)

36. The cost (€) to treat TB and M/XDR is enormous:
prevention is cost-effective
Cost per case Susceptible MDR-TB XDR-TB
Estonia* 2,615 15,344 15,344
France 5,691
Germany 7,7,51 55,003 188.466
UK 6,234 62,343
Netherlands 8,340 46,990 148,136
Italy 9,294
Finland 8,243
Spain 9,384
AVERAGE 7,848 54,779 168,310

37. Treating M/XDR-TB is difficult
www.tbconsilium.org

38. ERS/WHO Consilium for M/XDR-TB
Objectives:
 To allow a European clinician, free cost, to
load patient’s data (20’) and receive in
suggestions (36 hrs) by 2 experts on how to
manage a difficult-to treat TB case
 To support follow-up of TB patients
travelling within Europe
 Web-based platform managed by ERS in
collaboration with WHO (MoU) and ECDC
 Specialized team able to cover several
perspectives: clinical (adults and children,
surgical, radiological), public health,
psychological, etc.
 > 200 cases manged in 4 languages (ENG,
SPA, PORT, RU)

39. www.tbconsilium.org

41. 2014; Cited 29 times

42. [
First case of extensively drug-resistant
tuberculosis treated with both delamanid and
bedaquiline
Researchers have described the first case of
severe extensively drug-resistant tuberculosis
(XDR-TB) treated with both delamanid and
bedaquiline. The findings, published as a letter in
the European Respiratory Journal, reports the
rationale for prescribing both delamanid and
bedaquiline in an XDR-TB case and describes the
difficulties encountered in the early phase of
treatment.
Read the full study
Access the ERS/WHO TB Consilum

43. First case treated with DLM+BQ
Variable Details
Details India, 39 years, Female, 65 kg (at diagnosis: 31/08/2015)
Case category Retreatment case; 4 previous treatment rounds
Drugs administered in
previous anti-TB
treatments
Kanamycin 750 mg im (12 months)
Levofloxacin 1g, PAS 10 g, Cycloserine 750 mg, Ethionamide 750 mg,
Capreomycin 1g im (14months) High dose Isoniazid 900mg; Rifabutin 300mg;
Clofazimine 200mg; Clarythromycin 1g; Amoxicillin-clavulanate 625mg;
Terizidone 1g TDS; Imipenem 500mg iv TDS (12 months); Linezolid 600 mg
then 300mg
Previous outcome Cured (twice)
Bacteriology at baseline Sputum smear +; Culture +; Xpert + At Day 18: SS -; C: ongoing
Radiology Bilateral upper zones fibrocavitary lesions
Drug resistances Resistant to 12 drugs: H,R, Km,Amk,Cm,Mfx,Ofx,Eto, PAS,Lzd, HdH, High
dose Mfx
Susceptible to: Cfz
Last treatment regimen delamanid, bedaquiline, clofazimine (200 mg) and terizidone (1 g), all started on
25/2/2016; and meropenem 1g TDS plus amoxi/clav 1g/200mg TDS iv (started
28/2/2016) BQ stopped on 07/03/2016 restarted 12/03/2016
[

44. UPDATE ON THE CASE
Tadolini M et al. ERJ 2016, in press

46. New and Repurposed Drugs and Novel Regimens for Children and Adolescents
with Multidrug-Resistant Tuberculosis: Practice-Based Recommendations
Authors
Elizabeth P. Harausz1
, Anthony Garcia-Prats2
, James A. Seddon3
, H. Simon Schaaf2
, Anneke
Hesseling2
, Jay Achar4
, Jonathan Bernheimer5
, Andrea Cruz6
, Lia D’Ambrosio7,8
, Anne
Detjen9
, Stephen Graham10
, Jennifer Hughes5
, Sylvie Jonckheree11
, Ben Marais12
, Giovanni
Battista Migliori7
, Lindsay McKenna13
, Alena Skrahina14
, Marina Tadolini15
Peyton
Wilson16
, and Jennifer Furin17
on behalf of the Sentinel Project on Pediatric Drug-Resistant
Tuberculosis
Delamanid
Recommended dose:
>35kg: 100mg twice daily
20-34kg: 50 mg twice daily
<20kg: consult with exper
Duration: 24 weeks; longer duration could be considered on a case-by-case basis (no alternative drug option).
Indications for use: children > 6 years old and > 20kg
• Confirmed MDR-TB when a four drug-regimen plus pyrazinamide cannot be constructed due to resistance or significant
intolerance;
• Probable MDR-TB with a source case with known or suspected additional resistance to second-line agents;
• Confirmed or probable MDR-TB with a high risk of treatment failure.
Indications for use: children < 6 years old and < 20kg
It is recommended that consultation with expert clinicians be sought prior to administering delamanid to children in this age range via
consultation with the European Respiratory Society0hosted TB Consilium (https://www.tbconsilium.org) or the Sentinel Project on Pediatric

47. MINIMUM REQUIREMENTS COMBINED
USED DLM+BQ – LANCET ID 2015
Requisite Comment
1 Clinical centre
qualified
The clinical centre is highly qualified in terms of clinical expertise,
number of cases managed and laboratory services. The eligibility
criteria for these centres should comply with national regulation, and,
ideally, to international ones to be developed
2 Informed consent The patient should sign it, as recommended by the World Health
Organization separately for delamanid5 and bedaquiline
3 Pharmaco-
vigilance
Pharmacivigilance to be seen as both a guarantee for the patient and
an additional source of information complementing existing trials
4 Expert opinion on
rational use of
drugs
The use of the drugs is considered rationale by an independent and
qualified body such as the ERS TB Consilium (available at:
www.tbconsilium.org in different languages and free of charge ). This
step is also an essential component of the Otsuka’s delamanid
compassionate use programme

48. Conclusions
• Although MDR cases are decreasing in Russia, Indian and
China the burden is still important (FSU)
• Case-detection and treatment proportions still below targets
• Outcomes still unsatisfactory
• Two core new drugs and several repurposed ones
• ERS and WHO have developed a platform (the ERS/WHO
Consilium) to support clinicians (in different languages)
• New evidence supporting Delamanid in children
• We have the possibility to further strengthen what done to
achieve together TB Elimination but much resources and
commitment are necessary.

49. THANK
YOU !