Transcript rif 59

MDR & MOTT in Lebanon
George F Araj,
PhD, ABMM, FAAM
Professor & Director of Clinical Microbiology
Dept. Pathology & Laboratory Medicine,
American University of Beirut Medical Center
e-mail: [email protected]
TB Day- First LATA Conference in Lebanon
Crown Plaza Hotel-Beirut, 24 March, 2016
Appraisal of TB in Lebanon
• TB is one of the important ID and PH
persisting problems in Lebanon.
• Scattered Data are available
• Exact/Accurate overall consolidated
info (e.g. epid., clinical, resistance)
remains to be determined.
Outline
-Background
-TB Burden
-MOTT
-TB-R: MDR-XDR-TDR
-Lab R Aspects & Detection
-Conclusion
Lebanon TB- Burden
Lebanon: Evolution of TB cases vs Years (1999-2015)
T
o
t
a
l
800
700
600
500
400
No
Of
c
a
s
e
s
DOTS implementation
2006
war
663
568
519
426
476
380
393
391
375
689
NN………..
523
501
666
630
515
499
424
300
200
100
0
1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015
Years
Epi-Monitor vol 3; Issue 3-March 2016
Trends of TB & MOTT recovery over time at AUBMC
2006 & 2009 to 2015
100
SPCP study
92
Syrian Refugees !!!
90
80
70
65
70
%60
44
50
56
56
56
52
44
42
35
40
44
MOTT
30
30
20
10
8
0
2006
2009-2010
2010-2011
2011-2012
2012-2013
TB
2013-2014
2014 Total of requests for Mycobacterial culture = 1065 requests.
2014-2015
Lebanon MOTT- Burden
MOTT Studies- AUB & HD
-Kattar MM, Abi Rached R, Sabra RA, Itani L, Kanj SS, Balkis M, Araj GF.
A three –year survey of non-tuberculous Mycobacterium spp. at a reference
mycobacterial Mycobacteriology Laboratory in Lebanon. 109th Annual
Meeting of the American Society for Microbiology, Philadelphia, USA, May
17-21, 2009. Abstract U-001.
-Balkis MM, Kattar MM, Araj GF, Kanj SK. Fatal Disseminated M. simiae Infection in
a non-HIV Patient. Intl J Infect dis 2009; 13: e286-e287.
-Abbas O, Marrouch N, Kattar MM, Zeynoun S, Kibbi AG, Abi-Rachid R, Araj GF,
Ghoson S. Cutaneous nontuberculous mycobacterial infections: a clinical
and histopathological study of 17 cases from Lebanon. J Europ Acad Derm
Vener (JEADV) 2011; 25: 33-44.
-Atallah D, el Kassis N, Araj G, Nasr M, Sarkis D, Nasnas R. Mycobacterial
infection on breast prosthesis – a conservative treatment M. canariasense.
BMC Infectious Diseases 2014; 14: 238.
MOTT-AUBMC-Pilot Study speciation of 72 Recovered MOTT/
NTM by gene sequencing
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MOTT
Respiratory
Skin/ biopsy
M. simiae
27 (38%)
2 (3%)
M. fortuitum
8 (11%)
3 (4%)
M. marinum
9 (13%)
M. immunogenum
6 (8%)
M. chelonae/abscessus 4 (6%)
2 (3%)
M. intracellulare
2 (2%)
M. avium
2 (2%)
M. xenopi
1 (1%)
M. szulgai
1 (1%)
M. gordonae
3 (3%)
M. scrofulaceum
1 (1%)
M. asiaticum
1 (1%)_________________
Total (%)
55 (76%)
17( 24%)
-Kattar MM, Abi Rached R, Sabra RA, Itani L, Kanj SS, Balkis M, Araj GF. A three –year survey of nontuberculous Mycobacterium spp. at a reference mycobacterial Mycobacteriology Laboratory in Lebanon.
109th Annual Meeting of the American Society for Microbiology, Philadelphia, USA, May 17-21, 2009.
Abstract U-001.
Most common MOTT species Recovered Among Requested for
Speciation vs. Time (% of isolates)
MOTT species
2005-6
2008-9
2010-11
2014 (n= 18)
2015 (n=22)
M. simiae
41
54
38
65
59
M. fortuitum
16
8.5
10
6
9
M. imunogenum
8
12
M. chelonae
abscessus
7
8.5
MAC
2
7
M.
paratuberculosis
2
M. xenopi
2
1
M. szulgai
2
2.5
M. gordonae
No of Isolate recovered in
4.5
6
6.5
2014: MOTT = 61 & TB = 56
2015 : MOTT = 58 & TB = 51
12
14
6
14
6
9
Global MOTT: Geographic diversity of
NTM isolated from Pulmonary samples
Study encompassed :
• 20182 patients; 62 Labs; 30 Countries; 6 Continents
• 91 Different MOTT spp. recovered , most predominant in
different countries were:
• M. avium Cplx (MAC)
• M. gordonae
• M. xenopi
M. simiae was traditionally thought to be confined to the Southern
USA, Cuba and Israel, but this study demonstrated it has a
global distribution.
Concluded:
• NTM differed by continent & by country within these
continents.
MOTT Global Survey -2008-Network Eur Group [www.ntm-net.org]
Hoefsloot W et al. Eur Respir J 2013; 42: 1604-1613.
M. simiae
- Isr:
Huminer D et al. M. simiae Infection in Israeli Patients with AIDS.
CID1993;17:508.
- San Antonio:
VALERO G et al. Clinical Isolates of M. simiae in San Antonio, Texas: An
11-Yr Review. Am J Resp Crit Care Med 1995;152:1555.
-Cuba
Examples of Susc Results for
M. simae among 4 pts at AUBMC
Anti - TB
PH (8.13)
MT (8.13)
YK (10.13)
MF (10.13)
Cipro
R
R
R
R
Moxi
R
S
S
R
Clarithro.
S
S
S
S
Amikacin
S
S
S
S
SXT
R
S
R
R
Linezolid
R
R
R
R
Rif
R
R
R
R
Ethambutol
R
R
R
R
Rifabutin
R
S
R
R
TB R Global: MDR-XDR-TDR
MDR TB & XDR TB
MDR TB = R to at least INH & RIF.
XDR TB = R to MDR plus any FQ & at least 1 of 3
injectable 2nd- line drugs (i.e., Amk, Kana, or capreo).
LoBue P. Extensively drug-resistant tuberculosis. Current Opinion in Infectious Diseases 2009, 22:167–173
MDR-TB Global Estimates 2000-2015
Cases x 1000
600
500
500
480
480
460
425
400
300
300
275
200
100
0
2000
2004
2005
2012
2013
2014
2015
Year
WHO Global tuberculosis report 2015.
Globally, 9.8 mil TB cases were reported by WHO in 2015
Country reports of MDR TB among all new cases in
some Arabian countries-2012-2014 (How accurate???)
%
14
12.4
2012
12
10.1
2014
10
8
6.3
5.6
6
4
2
3
2.8
2.6 2.2
1.4 0.8
1
0.7
6.76.2
3.4
3.3
2.2
1.8
3.4
1.7
1
1.7
WHO Global tuberculosis report 2012 and 2015.
en
Ye
m
an
Su
d
Sy
ria
Eg
yp
t
no
n
Le
ba
ait
Ku
w
di
Sa
u
da
n
Jo
r
oc
co
M
or
Om
an
Al
ge
ri a
0
Beyond XDR-TB: Totally Drug- R TB
-Several reports have been published documenting patients with
TB who have failed treatment with all 1st & 2nd line drugs or are
infected with strains that are resistant in vitro to all available
drugs; tested by MGIT DST and genotypic DST
-Review of each case revealed mismanaged treatment of MDR-TB
in the private sector.
-Udwadia ZF. MDR, XDR, TDR tuberculosis: ominous progression. Thorax 2012; 67:286–8.
(India)
-Migliori GB, et al. First tuberculosis cases in Italy resistant to all tested drugs.
Euro Surveill 2007;12:E070517.1.
- Velayati AA, et al. Emergence of new forms of totally drug-resistant tuberculosis bacilli: super
extensively drug-resistant tuberculosis or totally drug-resistant strains in Iran. Chest
2009;136:420–5.
-Shah NS, et al. Increasing drug resistance in extensively drug-resistant tuberculosis,
South Africa. Emerg Infect Dis 2011;17:510–3.
TB R -Lebanon
Studies on Mycobacterial Resistance-AUBMC
1995 Primary & Secondary - AUB & IH
-Hamze M & Araj GF. Int J Tuber Lung Dis 1997; 1: 314-8
(Total patients=96; Primary = 78 ; Secondary = 18)
1998- Not differentiated - AUB
-Araj GF et al. LMJ 2000; 48: 18-22 (Total = 76)
2006 - AFB Smear-Positive Nationwide, WHO- sponsored, (Total = 206)
-Araj GF, Saade M, Itani LY. Int J Tuberc Lung Dis 2006; 10: 63-7.
2000- 2008 : Genetic Mutations: in RIF, INH & EMB. Finger printing
-Ahmad S, Araj GF, Akbar PK, et al. DMID 2000; 38: 227-32
-Ahmad S, Mokaddas E, Abal AT, Araj GF, Fares E, Mustafa AS. Medical
Principles and Practice 2001; 10: 129-134
-Ahmad S, Fares E, Araj GF, Mustafa AS. Int’l J Tuberc Lung Dis 2002; 6: 920-6
-Ahmad S, Itani LY, Araj GF. Lebanese Medical journal 2003; 5: 4-8.
-Ahmad S, Itani LY, Fares E, Araj GF. J of Chemotherapy 2008; 20: 285-287
2005: BACTEC vs LJ
-Itani LY, Cherry MA, Araj GF. Efficacy of BACTEC TB in the rapid diagnosis of
mycobacterial infections A Lebanese tertiary care center experience.
Leb Med J 2005; 53: 208-212.
2016: TB burden in Lebanon
-Araj GF, Saade M, Itani LY, Avedessian A Z. Leb Med J 2016; 64: 1-7.
Codons Predictive of MDR-TB
Anti-TB drugs
RIF
SM
EMB
6 codons to screen
rpoB 531, rpoB 526
rrs513, rpsL43
embB 306
% prediction of R_
90%
INH
katG 315
70%
____________________________________________________
• 90% of RIF, SM, EMB, & 70% of INH R can be predicted by
screening for 6 codons
• Useful with directly observed therapy short course (DOT-S)
Van Rie A et al. J Clin Microbiol 2001; 39:636-41.
CHEST 2001: 67th Ann Sci Assembly of the Amer Coll of Chest Physicians
Prevalence of Mutations for RIF, INH & EMB in MTB
Country/ City
1. RIF rpoB 531 mutation
Beirut
Greece
St. Petersburg
NY
South Korea
Prevalence of mutation %
61
55
55
31
24
2. INH Kat gene S315 S315T mutation
Beirut
Dubai
Egypt
35
66
35
3. EMB-embB codons
Beirut
Dubai
71
18
1.
2.
3.
Ahmad S, Araj GF, Akbar PK, et al. Diag Microbial & Infect Dis 2000; 38: 227-32
Ahmad S, Fares E, Araj GF, Mustafa AS. Int’l J Tuberc Lung Dis 2002; 6: 920-6 .
Ahmad S, Itani LY, Fares E, Araj GF. J of Chemotherapy 2008; 20: 285-7.
Lebanon: MDR-TB burden reported to WHO in:
2012 vs 2014
Aspect
New
% of TB cases with MDR-TB
1.1 vs 1
MDR-TB cases among notified pul
TB cases
Reported cases of MDR-TB
Cases tested for MDR-TB
Re treatment
67 vs 29
4 vs 5
6 vs 5
New
Re treatment
10 (4%) vs 299(98%)
Lab-confirmed MDR-TB cases
Total 10
2 vs ???
Patients started on MDR-TB treatment
6 vs 5
WHO. Global tuberculosis report 2012 and 20155
6 (67%) vs 40 (211%)
???
4
???
???
vs ???
Patterns of Drug R among MTB recovered at AUBMC*
2006-7 vs 2012-13 vs 2014-2015
TB isolates response to
Drug
No (%)
2006-7
N=44
2012-13
N=61
2014-15
N=64
34 (77)
32 (52)
49 (76)
(7)
(16)
(9)
INH
1
3
1
RIF
SM
EMB
R to 2 drugs only
INH & RIF
INH & SIM
SM & RIF
R to 3 drugs only
INH + RIF + SM
INH + RIF + EMB
R to all
MDR
2
3
3
1
(10)
3
3
4
4
1
(5)
2
S to all drugs
R to 1 drug only
(7)
2
1
(4)
2
2 (4)
4 (9)
(21)
6
1
6 (10)
15 (25)
1
(3)
2
4 (6)
8 (13)
*Encompassed both AUBMC & MOH.
The % of total TB requested for Susc testing in 2014 was 55% and in 2015 was 54%.
Globally; % of MDR TB among treated cases: 3.3% of New and 20% of previously treated. [ TB WHO Report 2015]
Lebanon: TB R Among Tested Isolates in
2006-7 vs 2012-13
2006 - 7
%
R
E
S
I
S
T
A
N
T
2012 - 13
70
70
60
59
60
60
50
47
50
50
40
40
30
MOH-N 40
MOH-O 30
AUB
20
30
20
35 35
MOH-N
35
30
20
MOH-O
22
20
22
10
6
10
10
0
0
S
I
R
E
S
Anti- TB Primary Drugs
2006-7 No. tested: MOH-N =4 ; MOH-O =10 ; AUB =18;
2012-13 No. tested: MOH-N =20 ; MOH-O =17 ; AUB =23;
MDR = 9
MDR = 18
I
R
E
N= new cases; O= Old cases
-AUBMC data reflects recovery only per patient: 2006-7 (n= 1040) & 2012-13 ( n= 1395)
-Total no. of specimens : 2006-7 (n= 1355) & 2012-13 ( n= 1856)
AUB
Prevalence (%) of MDR-TB at AUBMC vs. Yrs (1995-2015)
%
Years
TB– Lab Detection
Technologies for Detection-Identification-Susceptibility
Testing and strain characterization of Mycobacteria
-Conventional & other novel methods
Culture, BACTEC, MGIT, MALDI-TOF
-Molecular Methods
• Probing
• Amplification
• Sequencing
• Strain “typing”
• Other
AFB Smear
Culture & differentiation TB & MOTT
Susc Primary drugs- MTB
Susc for 2nd drugs (Ref-specialized lab)
MOTT Speciation & Susc (Ref-specialized lab)
Gene X-pert-available
TB Xpert MTB/RIF
•
•
•
•
•
•
Sensitivity (%)
Smear-pos specimens 98 [97–99]
Smear-neg specimens 68 [59–75]
Specificity (%)
Smear-pos specimens 98 [92–100]
Smear-neg specimens 98 [97–99]
-Steingart KR, Sohn H, Schiller I, Kloda LA, Boehme CC, et al (2013) Xpert (R) MTB/RIF assay for pulmonary
tuberculosis and rifampicin resistance in adults.Cochrane Database Syst Rev 1: CD009593‫ز‬
-Steingart KR, et al. Fluorescence versus conventional sputum smear microscopy for tuberculosis: A
systematic review. Lancet Infect Dis 2006; 6: 570–581.
Comparative Aspects: MGIT vs X-pert
Aspect
MGIT
X-pert
Detection
TB+MOTT
TB only
Pulmonary - SP
+++
+++
Pulmonary- SN
+++
+
Extra Pulmonary
+++
+
Susceptibility TB
+++
+ (RIF)
TAT
ID : 3 – 10 D
Suscp.: 7D post Pos.
1D
Culture recovery & for
Drug susc plus other
characterization
+++
-
Cost Culture/ ID TB vs MOTT $ 82
$ 250
Cost Drug Susceptibility
Test
$ 262 (4 primary drugs)
1 drug (RIF)
MOTT ID + Susc.
$ 120 (Ref Lab)
-
MALDI-TOF
organism
Pulsed Laser Beam
Ionized proteins
Flight tube-ion detector
Mass analyzer
Dekker JP, MALDI-TOF Mass
Spectrometry in the Clinical
Microbiology Laboratory. CMN
2011; 33: No. 12.
The CombiChip Mycobacteria Drug-Resistance
Detection DNA Chip (Kim SY et al.2006)
-Developed by GeneIn (Pusan, South Korea)
An oligonucleotide microchip coupled with PCR for
the detection of mutations associated with
resistance to INH & RIF
– Highly specific: 95% -100%.
Take Home Message
-Lebanon is a country with low TB incidence. However, shows fluctuating trends, and
currently on the rise due to influx of refugees and NN.
-Mistreatment, poor drugs and incompliance lead to the development of drug R
-MDR - & XDR-TB pose greater challenge for effective TB management.
-MOTT have been showing increasing prevalence & clinical problems, thus
necessitates close attention
-Collaboration between Public and Private sectors are the key for success in
control/elimination; In hospitals prevention proper IC is the key.
Recommendations to accelerate control/elimination:
-Elaborate a national strategic plan for five years
-Revise the country treatment guidelines
-Strengthen DOTS activities and quality of TB diagnostic services.
-Yearly evaluation of the TB program by internal and/or external consultant or
expert, together with impact assessment every 3 years (External )
-Enhance TB case finding in high risk groups and vulnerable populations.
-More action is needed to minimize the burden of NN TB patients,
-Continue support to MDR management (Drugs, IC & Laboratory)
-Scale up TB/HIV collaboration and developing a comprehensive action plan.
Thanks for your Attention