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  1. Thank you for viewing this presentation. • We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author. • 2008 by the author

  2. 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

  3. 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

  4. XDR-TB in the News: 5/07-8/07 The flying lawyer

  5. Definition XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM) 1st-line oral Injectables • INH • RIF • PZA • EMB • (Rfb) Fluoroquinolones • SM • KM • AMK • CM Oral bacteriostatic 2nd line • Cipro • Oflox • Levo • Moxi • (Gati) Unclear efficacy • ETA/PTA • PASA • CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid

  6. Grouping drugs Group 1 1st-line oral Group 2 Injectables • INH • RIF • PZA • EMB • (Rfb) Group 3 Fluoroquinolones Group 4 • SM • KM • AMK • CM Oral bacteriostatic 2nd line • Cipro • Oflox • Levo • Moxi • (Gati) Group 5 Unclear efficacy • ETA/PTA • PASA • CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid

  7. 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

  8. 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?

  9. 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

  10. What is there?

  11. CXR : “large infiltrate in the left lower lobe, Inflitrate in the right lobe, upper and lower. Mediastinal stretched towards left” What to do now?

  12. 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

  13. March 28, CT Scan: what is there? Caso clinico Ricovero a Padova

  14. 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 COMMENTS? Transferred to Sondalo, April 20th …..

  15. in Sondalo… - Moxi and Strepto stopped - Treatment with R,H,E,Z continued - Sputum: still smear positive

  16. What is there?

  17. In Sondalo, April 27th … • On 27 april 2007 DST results from XX arrive: Mycobacterium tuberculosisRESISTANT to: • RIFAMPICIN • ISONIAZID • STREPTOMYCIN • PYRAZINAMIDE • ETHAMBUTOL DST FOR SECOND LINE IN PROGRESS…… • TREATMENT modified including SECOND-LINE DRUGS MDR!!

  18. Clinical case management • 2nd line started with 5 drugs • Ethionamide • Terizidon • PAS • Moxifloxacin • Amikacin

  19. 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

  20. 25/5/07 CXR

  21. In Sondalo, May 25th • Transferred to Intensive Care

  22. XDR TB!! ICU, May 28th The second line DST shows resistance to: • Cycloserin • Ciprofloxacin • Ethionamide • Amikacin Added to the regimen : Imipenen Linezolid - Mechanical ventilation started - General conditions further worsened - EGA pH 7,119, paCO2 141, PaO2 64, Sat Hb 82%.

  23. Clinical case death 28 May 07: Death (Respiratory Failure)

  24. Clinical case: caveat • 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..) • Late DST (first line drugs)19/3-27/4!

  25. 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

  26. From Z-N to Fluorescence

  27. Diagnosis DL Ling, M Pai, ERJ 08

  28. Diagnosis DL Ling, M Pai, ERJ 08

  29. Development of a standardized MDR/XDR-TB assessmentand 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/XDRTB 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/XDR-TB and is useful to develop national MDR/XDR-TB control strategies. It is available at http://www.path.org/publications/details.php?i=1678.

  30. Table of Contents

  31. New WHO Guidelines with focus on XDR-TB 2000

  32. 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

  33. The challenge of XDR

  34. Uninterrupetd drug supply…

  35. 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

  36. 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 73.0% • Vomiting 38.7% • Abdominal pain 38.2% • Dizziness 35.8% • Hearing problems 28.4% • 61% changed or discontinued drugs during treatment owing to side effects • 2 patients stopped treatment due to side effects