XDR TB IN A HIGH INCOME COUNTRY: A REPORT OF FOUR UNRELATED CASES.

2. XDR TB IN A HIGH INCOME COUNTRY: A REPORT OF FOUR UNRELATED CASES. S. Blaas1, R. Mütterlein2, J. Weig3, A. Neher4, B. Salzberger1, N. Lehn5, L. Naumann6 1 Department of Internal Medicine I, Regensburg University, Germany; 2 District Hospital (Bezirksklinikum), Parsberg, Germany; 3 Public Health Department, Neustadt/Waldnaab, Germany; 4 Center for Respiratory Medicine and Thoracic Surgery, Asklepios Fachkliniken München-Gauting, Germany; 5 Institute of Medical Microbiology and Hygiene, Regensburg University, Germany; 6 Bavarian Health and Food Safety Authority, Oberschleissheim, Germany;

3. XDR TB Definition XDR TB = Extensively Drug Resistant Tuberculosis • Initially defined as MDR + resistance against three of the six main second line drug classes • Reviewed WHO Case Definition 10/06: MDR (= resistance against Isoniazid and Rifampin) + resistance against any fluoroquinolone + resistance to at least 1 of the 3 following injectable drugs used in anti-TB treatment: capreomycin, kanamycin and amikacin

4. Introduction Initial reports about XDR TB showed: Data about development and clinical course of XDR TB in high income countries are limited. - worldwide emergence - rapid and almost uniformly fatal course in mainly HIV infected patients from South Africa Ghandi NR, Lancet 2006 Shah NS, Emerg Inf Dis 2007

5. Methods • All mycobacterial isolates belonging to the Mycobacterium tuberculosis complex, in which drug susceptibility testing was performed at our institution from 1997 to 2006, were evaluated • for MDR resistance • for resistance to second line drugs in MDR TB isolates • Analysis of clinical course of patients with XDR TB • Evaluation of treatment outcome based on international standards (Laserson et al., 2005)

6. MDR / XDR TB isolates at Regensburg University • From 1997 to 2006 2174 isolates were tested for MDR • 112 MDR TB isolates from 84 patients were identified.

7. Epidemiology Country of Origin Patient 2 Patient 4 Patient 1 Patient 3

8. Epidemiology

9. Course of disease, Outcome drugs susceptibility at time of XDR TB diagnosis: SM, PAS, Clr drugs used during XDR TB treatment: RFB, PZA, SM, Am, Cm, Ofx, Pto, Trd, PAS, Cfz, Amx/Clv, Clr, Doxycyclin Treatment Failure drugs susceptibility at time of XDR TB diagnosis: EMB, Mxf, Pto, Cs, PAS, Lzd drugs used during XDR TB treatment: initial empirical therapy EMB, PZA, Am, Mxf, Pto, Trd, Lzd outpatient therapy Cfx, Trd, Lzd drugs susceptibility at time of XDR TB diagnosis: Mxf, Cfz, (PZA: intermediate) drugs used during XDR TB treatment: PZA, Mxf, Pto, Cfz Cure drugs susceptibility at time of XDR TB diagnosis: PZA, Am, Mxf, Cs, Cfz, Lzd drugs used during XDR TB treatment: initial therapy PZA, Am, Mxf, Lzd outpatient therapy PZA, Mxf, Lzd Death Cure Duration between TB diagnosis and immigration Duration between immigration and MDR TB diagnosis Duration between MDR TB and XDR TB diagnosis Duration of XDR TB treatment in Germany Time of immigration Inhospital Treatment in Germany Operative therapy

10. Characteristics of the presented XDR – TB patients • all patients immigrated to Germany • none was HIV-infected • all were pretreated for several years • 2 patients had MDR TB at time of immigration • there was no primary infection with XDR TB • all patients were non adherent Transmission of XDR – TB • Systematic contact investigation did not show transmission of an • XDR strain to close contacts or health care professionals

11. Discussion • WHO guidelines recommend the use of at least four active drugs for treatment of MDR-TB, • for XDR-TB this is often not possible • With only two patients cured observed outcomes are far from optimal • Cure was only achieved in patients • who where operated and • who still had a fluoroquinolone as a therapeutic option. • Directly observed therapy (DOT) was important for successful treatment • Discontinuation of DOT after discharge was an important factor for further resistance development in patients 2 and 3.

12. Discussion • Tremendous impact of XDR TB on quality of life and on health care resources. • Treatment cost estimation for patient 4: • at least € 170.000 (inpatient treatment € 90.000, outpatient drug therapy € 79.000) • Factors contributing to the very high cost of treatment of XDR TB • very long duration of inhospital treatment • closed ward treatment • prolonged administration of expensive and toxic second line agents • operations • non-pharmacological treatment • the use of administrative and legal resources

13. Conclusion • Cases of XDR TB have been treated in our region since 1998 • XDR TB has a tremendous impact on quality of life, outcome and the expense of medical resources in a high income country. • This case series demonstrates that XDR TB does develop not only in countries with suboptimal health care resources. • Therefore, maintenance of structures for TB control and improvement of deficits in outpatient treatment of non-compliant patients is mandatory, even when the incidence of TB in industrialised countries remains low or is even declining.