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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

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9 1 st -line oral INH RIF PZA EMB (Rfb) Injectables SM KM AMK CM Fluoroquinolones Cipro Oflox Levo Moxi (Gati) Oral bacteriostatic 2nd line Unclear efficacy ETA/PTA PASA CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid XDR XDR= HR + 1 FQ + 1 Injectable (KM or AMK or CM) Definition

10 1 st -line oral INH RIF PZA EMB (Rfb) Injectables SM KM AMK CM Fluoroquinolones Cipro Oflox Levo Moxi (Gati) Oral bacteriostatic 2nd line Unclear efficacy ETA/PTA PASA CYS Not routinely recommended, efficacy unknown, e.g., amoxacillin/clavulanic acid, clarithromycin, clofazamine, linezolid, inmipenem/cilastatin, high dose isonizid Grouping drugs Group 1 Group 2 Group 3 Group 4 Group 5

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12 Countr y Age/sex Country of birth Radiology at XDR diagnosis N° of previous TX periods > 30 days Drug received during previous TX periods Drug resistance at XDR diagnosis Hospital Admission (days) Smear conversion (days) Culture conversio n (days) Outcome TX duration (months ) 1) It40/MItalyBilateral cavities 3SRHEZ; Rb SRHEZ; FQ,AK,Cyc 220Not achieved Regular TX°, improved 73 2) It61/FPeruMonolateral cavity 1SRHEZ; FQ,Eth,Ak,PAS,Cyc SRHEZ; FQ,AK,Cyc 83Not achieved Died16 3) It27/FMoldovaMonolateral cavity 3SRHEZ; FQ,Eth,AK,PAS,K, Cyc,Clof SRHZ; FQ,Eth,K Regular TX°, improved 10 4) It46/MSenegalBilateral cavities 4SRHEZ; FQ,PAS,Cyc SRHZ; FQ,Eth,AK,PAS Regular TX°, improved 6 5) It43/FItalyBilateral cavities 3SRHEZ; FQ,Eth,AK,PAS,C, K,Cyc,Rb,Clof,Dap, Cl,Th SRHEZ; FQ,Eth,AK,PAS,C, K,Cyc,Rb,Clof 422Not achieved Died94 6) It38/FItalyBilateral cavities 3SRHEZ; FQ,Eth,PAS,C,Cyc SRHEZ; FQ,AK,PAS,Cyc 80Not achieved Died12 7) It49/FItalyBilateral cavities 3SRHEZ; 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 625Not achieved Died60 8) G33/MUzbekistanMonolateral cavity 2SRHEZ; FQ,Eth,AK,C,Rb 120Not achieved Regular TX°, improved 4 9) G29/MUzbekistanBilateral cavities 2SRHEZ; Rb SRHEZ; FQ,C Regular TX°, improved 12 10)G52/MAzerbaijanMonolateral cavity > 1Not availableSRHEZ; FQ,AK,PAS,C,Cyc, Rb Regular TX°, improved 6 11) It36/FRomaniaBilateral cavities 4SRHEZ; FQ,Eth,PAS,Cyc,Rb RHZ; FQ,AK,Rb Not achieved Regular TX° 28

13 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

14 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? Clinical case, March 19th

15 Clinical case: medical history S.A. female, born in Poland 1984 (claiming to be Moldovian) Past medical history Healthy till : 1°episode PTB : unknown therapy for few months in Poland : 2° episode of PTB: unknown therapy for 6 months in Greece with 4 drugs : IDU (cocaine, heroine), smoke (>15 sig/die) - 19 March 07: arrived in Italy: admitted at hospital in XX

16 What is there?

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

18 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 Clinical case management, March 20th

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

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22 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?

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

24 What is there?

25 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 MDR!! In Sondalo, April 27th …

26 2nd line started with 5 drugs –Ethionamide –Terizidon –PAS –Moxifloxacin –Amikacin Clinical case management

27 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 In Sondalo, May 25th

28 25/5/07 CXR

29 Transferred to Intensive Care In Sondalo, May 25th

30 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, paCO 2 141, PaO 2 64, Sat Hb 82%.

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

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34 Clinical case: caveat 1.Treatment history: not well defined 2.Language difficulties 3.Risk factors for low compliance (IDU..) 4.Country of origin  high risk of MDR-TB 5.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!

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 From Z-N to Fluorescence

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38 DL Ling, M Pai, ERJ 08 Diagnosis

39 DL Ling, M Pai, ERJ 08 Diagnosis

40 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/XDR- TB and is useful to develop national MDR/XDR-TB control strategies. It is available at

41 Table of Contents Abbreviations and Acronyms4 Introduction5 General Instructions7 Part 1: National MDR/XDR-TB Situation Analysis11 Part 2: Gap Analysis by Stop TB Strategy Component 22 Appendix 1: MDR/XDR-TB Case Detection and Treatment Outcome Definitions 71 Appendix 2: Sample Outline for Report73

New WHO Guidelines with focus on XDR-TB

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44 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 Cross-resistance

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46 The challenge of XDR

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48 Uninterrupetd drug supply…

49 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

50 Latvia, Side Effects – MDR Cohort % of patients experienced side effects Median of 4 side effect reports per person Most common side effects Nausea73.0% Vomiting38.7% Abdominal pain38.2% Dizziness35.8% Hearing problems 28.4% 61% changed or discontinued drugs during treatment owing to side effects 2 patients stopped treatment due to side effects

51 Results: Final Conversion Over Time N = 129 patients who converted, Latvia

52 MDR-/XDR-TB treatment programme Decentralised case management Consilium

53 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 XDR- vs. 102/126 MDR-TB cases (median: smear: 110 vs. 41 days; culture: 97.5 vs. 58 days) Cost of new infections? Emerging Infectious Diseases 2007

54 XDR-TB MDR-TB, resistant to all 1 st line drugs MDR-TB, susceptible at least one 1 st drug Eur Respir J ,853 C+, 361 MDR, 64 XDR

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57 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

58 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/XDR- TB 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 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 - ACSM

59 Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF % MDR among new Estonia Latvia TB notification rate Tomsk oblast, RF

60 Trend of MDR-TB among new cases, Estonia, Latvia and…Tomsk Oblast, RF % MDR among new Estonia Latvia TB notification rate Tomsk oblast, RF XDR

61 Laboratory room in Eastern Europe

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63 “Nobody wants me around..”

64 Interventions over time: Interventions over time: old weapons might be useful again to manage XDR First sanatorium Germany, 1857 First Dispensary, Scotland, 1897 Koch, Mtb, 1882 Drugs, MMR, Fox:Ambulatory treatment, 1968 Styblo model, 1978 DOTS, 1991 sanatoria Outbreak Management, Risk Group Management screening BCG vaccination drug therapy Socio-economic improvement Pneumotorax, Italy, 1907

65 XDR and TB control: which future ?