Transcript XDR TB!!

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Case Presentation
PG 12, ERS Conference, Vienna, Sept 12th, 2009
G.B. Migliori
WHO Collaborating Centre for Control of TB and Lung Diseases, Fondazione S.
Maugeri, IRCCS, Tradate, Italy
2
Objectives
•
•
•
To describe:
A drug resistant case who is gradually
transformed into an XDR-TB case
To discuss:
the clinical options to diagnose and treat
drug resistant cases
The public health consequences of the
wrong clinical management of an initially
pan-susceptible case
3
XDR-TB in the News: 5/07-8/07
The flying lawyer
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5
6
7
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Definition
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,
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high dose isonizid
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,
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high dose isonizid
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N° of
previous
TX
periods
> 30
days
TX
duration
(months
)
Hospital
Admission
(days)
Smear
conversion
(days)
Culture
conversio
n (days)
SRHEZ;
FQ,AK,Cyc
220
Not
achieved
Not
achieved
Regular
TX°,
improved
73
SRHEZ;
FQ,Eth,Ak,PAS,Cyc
SRHEZ;
FQ,AK,Cyc
83
Not
achieved
Not
achieved
Died
16
3
SRHEZ;
FQ,Eth,AK,PAS,K,
Cyc,Clof
SRHZ;
FQ,Eth,K
406
300
300
Regular
TX°,
improved
10
Bilateral
cavities
4
SRHEZ;
FQ,PAS,Cyc
SRHZ;
FQ,Eth,AK,PAS
69
49
35
Regular
TX°,
improved
6
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,Dap,
Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof
422
Not
achieved
Not
achieved
Died
94
38/F
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,PAS,C,Cyc
SRHEZ;
FQ,AK,PAS,Cyc
80
Not
achieved
Not
achieved
Died
12
7) It
49/F
Italy
Bilateral
cavities
3
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,
Dap,Cl,Th
SRHEZ;
FQ,Eth,AK,PAS,C,
K,Cyc,Rb,Clof,
Dap,Cl,Th
625
Not
achieved
Not
achieved
Died
60
8) G
33/M
Uzbekistan
Monolateral
cavity
2
SRHEZ;
SRHEZ;
FQ,Eth,AK,C,Rb
120
Not
achieved
Not
achieved
Regular
TX°,
improved
4
9) G
29/M
Uzbekistan
Bilateral
cavities
2
SRHEZ;
Rb
SRHEZ;
FQ,C
240
180
160
Regular
TX°,
improved
12
10)G
52/M
Azerbaijan
Monolateral
cavity
Not available
SRHEZ;
FQ,AK,PAS,C,Cyc,
Rb
140
7
35
Regular
TX°,
improved
6
11) It
36/F
Romania
Bilateral
cavities
SRHEZ;
FQ,Eth,PAS,Cyc,Rb
RHZ;
FQ,AK,Rb
248
110
Not
achieved
Regular
TX°
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Countr
y
Country of
birth
Radiology at
XDR diagnosis
Age/sex
1) It
40/M
Italy
Bilateral
cavities
3
SRHEZ;
Rb
2) It
61/F
Peru
Monolateral
cavity
1
3) It
27/F
Moldova
Monolateral
cavity
4) It
46/M
Senegal
5) It
43/F
6) It
>1
4
Drug received during
previous TX periods
Drug resistance at XDR
diagnosis
Outcome
12
Objectives
•
•
•
To describe:
A drug resistant case who is gradually
transformed into an XDR-TB case
To discuss:
the clinical options to diagnose and treat
drug resistant cases
The public health consequences of the
wrong clinical management of an initially
pan-susceptible case
13
Clinical case, March 19th
Hospitalized in XX
Signs and symptoms: no fever, eupnoic, weight loss 7-9 Kg in the last two yrs,
abdominal pain, productive cough
Med exam: weight 57Kg, height 186 cm. Thorax (auscultation): physiological
sounds reduced, dry sounds on upper right lobe
Lab data: Hb 9,6 g/dL; WBC 14,439 (N%: 81%), PCR 98, albumine 22 g/L;
gamma globuline increased.
VDRL +; HCV Ab +; HBcAb pos, Ab HbsAg +; HBsAg neg; HIV neg
What do we need to have a Clinical suspicion of PTB?
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Clinical case: medical history
• S.A. female, born in Poland 1984 (claiming to be Moldovian)
Past medical history
Healthy till 2002
- 2002: 1°episode PTB : unknown therapy for few months in
Poland
- 2006: 2° episode of PTB: unknown therapy for 6 months in
Greece with 4 drugs
- 2000-2006: IDU (cocaine, heroine), smoke (>15 sig/die)
- 19 March 07: arrived in Italy: admitted at hospital in XX
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What is there?
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What to do now?
CXR : “large infiltrate in the left lower lobe, Inflitrate in the right
lobe, upper and lower. Mediastinal stretched towards left”
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Clinical case management,
March 20th
• Sputum smear positive for AAFB, culture
in progress
Cat 1 regimen started:
• R 600 mg/die
• E 500 mg x 3/die
• Z 500 mg x3/die
• H 300 mg/die
Metadone 30 mg x 5/die
Benzodiazepines
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March 28, CT Scan: what
is there?
Caso clinico
Ricovero a Padova
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20
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Clinical case management
After CT scan (28/3/07)
2 drugs added:
• Strepto 1000 mg/die
• Moxi 400 mg/die
Unchanged clinical picture
Sputum smears: persistently positive for AAFB until
18/4/07
….still DST was pending
Transferred to Sondalo, April 20th …..
COMMENTS?
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in Sondalo…
- Moxi and Strepto stopped
- Treatment with R,H,E,Z continued
- Sputum: still smear positive
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What is there?
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In Sondalo, April 27th …
• On 27 april 2007 DST results from XX arrive:
Mycobacterium tuberculosis RESISTANT to:
– RIFAMPICIN
– ISONIAZID
– STREPTOMYCIN
– PYRAZINAMIDE
– ETHAMBUTOL
DST FOR SECOND LINE IN PROGRESS……
– TREATMENT modified including SECOND-LINE
DRUGS
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MDR!!
Clinical case management
• 2nd line started with 5 drugs
– Ethionamide
– Terizidon
– PAS
– Moxifloxacin
– Amikacin
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In Sondalo, May 25th
Significant worsening of general clinical
conditions
- urgent CXR …
- Blood examination: (30,860 WBC, N 92%,
800 TLC); PCR 123
HeGA: pH 7.29; paCO2 70, PaO2 113
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25/5/07 CXR
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In Sondalo, May 25th
• Transferred to Intensive Care
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ICU, May 28th
The second line DST shows resistance to:
• Cycloserin
• Ciprofloxacin
• Ethionamide
• Amikacin
XDR TB!!
Added to the regimen :
Imipenen
Linezolid
- Mechanical ventilation started
- General conditions further worsened
- EGA pH 7,119, paCO2 141, PaO2 64, Sat Hb 82%.
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Clinical case death
28 May 07: Death (Respiratory Failure)
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Clinical case: caveat
1.
2.
3.
4.
5.
Treatment history: not well defined
Language difficulties
Risk factors for low compliance (IDU..)
Country of origin  high risk of MDR-TB
Mis-management: moxi only added to a failing
regimen (quinolones-Resistance developed after
40 d of monotherapy..)
6. Late DST (first line drugs)19/3-27/4!
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Objectives
•
•
•
To describe:
A drug resistant case who is gradually
transformed into an XDR-TB case
To discuss:
the clinical options to diagnose and treat
drug resistant cases
The public health consequences of the
wrong clinical management of an initially
pan-susceptible case
35
From Z-N to Fluorescence
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37
Diagnosis
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DL Ling, M Pai, ERJ 08
Diagnosis
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DL Ling, M Pai, ERJ 08
Development of a standardized MDR/XDR-TB assessment and monitoring tool
Giovanni Battista Migliori*, Giovanni Sotgiu^, Ernesto Jaramillo#, Fuad Mirzayev# , Rosella Centis*, Charlotte
Colvin†, M. D’Arcy Richardson†
* WHO Collaborating Centre for TB and Lung Diseases, Fondazione S. Maugeri, Care and Research Institute,
Tradate, Italy; ^ Hygiene and Preventive Medicine Institute, University of Sassari, Sassari, Italy; # Stop TB
Department, WHO, Geneva, Switzerland, †PATH, Seattle, Washington, USA
The MDR/XDR TB Assessment and Monitoring Tool was
developed to standardize evaluations of country capacity, to
prevent, diagnose, and treat MDR/XDR-TB and identify program
gaps. It provides data to guide national plans; generates baseline
data to measure progress; provides information for GLC and
GFATM applications; guides technical assistance; and informs
donor investment. In field testing,the tool scoring system
performed equally well in high- and low-prevalence settings. This
GLC endorsed tool supports global efforts to contain MDR/XDRTB and is useful to develop national
MDR/XDR-TB control strategies. It is available at
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http://www.path.org/publications/details.php?i=1678.
Table of Contents
Abbreviations and Acronyms
4
Introduction
5
General Instructions
7
Part 1: National MDR/XDR-TB Situation Analysis
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Part 2: Gap Analysis by Stop TB Strategy
Component
22
Appendix 1: MDR/XDR-TB Case Detection and
Treatment Outcome Definitions
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Appendix 2: Sample Outline for Report
73
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New WHO Guidelines with focus on XDR-TB
200
0
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Cross-resistance
• Rifamycin, high cross-resistance
• FQ, variable cross resistance (but new generation may
be susceptible when earlier generation is already lost;
clinical significance??)
• Amika & Kana, high cross resistance
• Capreo & Vio, high cross-resistance
• Other aminoglycosides and polypeptides, low cross
resistance
• Eth, cross resistance to H if inhA mutation present)
• TH, low cross-resistance to H, Eth, PAS
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The challenge of XDR
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Uninterrupetd drug
supply…
48
Objectives
•
•
•
To describe:
A drug resistant case who is gradually
transformed into an XDR-TB case
To discuss:
the clinical options to diagnose and treat
drug resistant cases
The public health consequences of the
wrong clinical management of an initially
pan-susceptible case
49
Latvia, Side Effects – MDR Cohort 2000
 86% of patients experienced side effects
 Median of 4 side effect reports per person
 Most common side effects
•
•
•
•
•
Nausea
Vomiting
Abdominal pain
Dizziness
Hearing problems
73.0%
38.7%
38.2%
35.8%
28.4%
 61% changed or discontinued drugs during
treatment owing to side effects
2 patients stopped treatment due to side
effects
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Results: Final Conversion Over Time
N = 129 patients who converted, Latvia
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MDR-/XDR-TB treatment programme
Decentralised case management
Consilium
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XDR compared with MDR, Italy-Germany
• Death rate: 36.4 % vs 6.3% (RR 5.45)
• Longer hospitalization (241.2±177.0 vs.
99.1±85.9 days)
Cost?
• Longer treatment duration (30.3±29.4 vs.
15.0±23.8 months)
Cost?
• Bacteriological conversion in 4/11 XDRvs. 102/126 MDR-TB cases (median:
smear: 110 vs. 41 days; culture: 97.5 vs.
58 days)
Cost of new infections?
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Emerging Infectious Diseases 2007
4,853 C+, 361 MDR, 64 XDR
MDR-TB, susceptible at least one 1st drug
MDR-TB, resistant to all 1st line drugs
XDR-TB
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Eur Respir J 2007
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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
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THE BEIJING "CALL FOR ACTION" ON TUBERCULOSIS
CONTROL AND PATIENT CARE:
TOGETHER ADDRESSING THE GLOBAL M/XDR-TB EPIDEMIC
We recognize the key barriers to effective management of M/XDR-TB lie
throughout the health system and beyond…
We therefore commit ourselves to accelerate efforts to prevent M/XDRTB through effective TB care and control, and to scale-up the
diagnosis and treatment of M/XDR-TB:
-
universal access to diagnosis and treatment of M/XDR-TB by
2015
equitable access
comprehensive framework for management and care
HR, laboratories
coordination among public and private sectors
infection control
drug supply
improved surveillance, M&E
addressing social determinants
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Trend of MDR-TB among new cases,
Estonia, Latvia and…Tomsk Oblast, RF
Estonia
Latvia
Tomsk oblast, RF
TB notification rate
% MDR among new
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Trend of MDR-TB among new cases,
Estonia, Latvia and…Tomsk Oblast, RF
Estonia
XDR
Latvia
Tomsk oblast, RF
TB notification rate
% MDR among new
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Laboratory room in Eastern Europe
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“Nobody wants me
around..”
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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
64
XDR and TB control: which future ?
65