Materials and methods
EuroTB collects yearly standardised data on TB cases notified in the 51 countries of the World Heath Organisation (WHO) European Region based on a common case definition. Data are reported as aggregate tables and, when possible, as individual anonymous case records. Since 1998, data collected include the results of drug susceptibility testing (DST) at the start of treatment for ioniazide (INH), rifampicin (RMP), ethambutol and streptomycin for culture positive TB cases notified or included in specific studies. Data are collected and analysed by previous anti-TB treatment status (resistance among cases never treated indicates primary resistance, i.e. infection with a resistant strain; resistance among cases previously treated indicates acquired resistance, i.e. due to previous inadequate treatment) and by geographic origin of the cases (born in the country / born abroad (recommended) or citizen / non citizen of the country). In countries providing individual data, cases with a previous tuberculosis diagnosis but no information on previous anti-TB treatments are classified as previously treated. Information on laboratory practices, and on the organisation of drug resistance surveillance is also collected through a questionnaire.

Proportions of resistant cases were calculated using cases with available drug susceptibility testing results for at least INH and RMP as denominator. For analysis, the 51 countries of the WHO European Region were grouped into three geographic areas: West (the 15 countries of the European Union plus Andorra, Iceland, Israel, Malta, Monaco, Norway, San Marino and Switzerland), East (the 15 Newly Independent States of the former Soviet Union, including the Baltic States, Estonia, Latvia and Lithuania), and Centre (the remaining 13 countries of the WHO European Region).

Results
Data provided
Drug susceptibility testing results at the start of treatment for TB cases notified in 1999 were provided from a total of 34 countries, of which 16 provided individual data (table 1). In 22 countries (presented as group A in tables 1 and 2), culture and drug susceptibility testing were routinely performed for the diagnosis of TB, and DST results were available for most notified culture positive cases or from nationwide samples including more than 50% of notified cases (Germany and Croatia) (table 1). Proportions of culture positive cases with available drug susceptibility testing results are shown in table 1.

In the 12 other countries (presented as group B in tables 1
and 2), data did not fulfil the conditions above, and were not considered comparable to those in group A. Among these countries, some provided drug susceptibility testing results linked to TB notifications with low proportions of cases with available testing results (Hungary and Romania), others had incomplete geographic coverage (Yugoslavia), or culture performed on selected cases (Albania).
In France data were provided from a network of university hospital laboratories covering several regions. In Spain, data were provided for selected strains of cases never treated available at the national reference laboratory. In the Russian Federation, data were provided on respiratory cases never treated notified to the Ministry of Health (accounting for 70% of notified cases and not including those from the penitentiary system and other separate administrations). In the remaining countries, culture or drug susceptibility testing were not routinely performed at diagnosis of tuberculosis or drug susceptibility testing results were provided on cases diagnosed in selected laboratories.

Laboratory practices
Thirty three of the 34 countries providing drug susceptibility testing results also provided information on laboratory practices (table 2). The number of laboratories performing susceptibility testing was one in nine countries, 2-10 in 12 countries, 11-20 in six countries and higher than 20 in six countries. In 21 countries, national reference laboratories had exchanged strains with a supranational reference laboratory in 1999 or in a previous year and concordance of results was 100% for isoniazid in 14/19 countries and 100% for rifampicin in 16/19 countries. Among the 24 countries with more than one laboratory performing drug susceptibily testing, 14 had a national proficiency testing scheme for DST and concordance of results for isoniazid and rifampicin was 90% or higher for the vast majority of participating laboratories (data from 11 countries, not shown).

Drug susceptibility testing results, group A
In the 22 countries in group A, a total of 31 365 TB cases were notified in 1999 (table 1), of which 19 171 were culture positive (median 65%, range: 49-84%) and 16 953 had DST results at the start of treatment (median: 99%, range 63-100%). In the 19 countries in the West and in the Centre, 0-13.3% of all cases were resistant to INH alone or in any combination (median: 3.8%), 0-7.9% to RMP (median: 1%) (not shown) and, among them, 0-7.9% (median: 0.6%) were resistant to both INH and RMP (multidrug resistant (MDR) cases) (table 2). Global proportions of resistant and MDR cases were much higher in Israel compared to other countries of the West and Centre. In the three Baltic States, proportions of resistant cases were much higher compared to the West and Centre (cases resistant to INH: 27-32%; RMP: 16-23%; MDR 14-23%).

Excluding Israel, where history of anti-TB treatment was not provided, of 16 622 cases with drug susceptibility testing results,
13 160 (79%) were never treated, 1707 (10%) had a history of previous anti-TB treatment and 1755 (11%) had no information on treatment history (table 2). Among cases never treated, the proportion of cases resistant to isoniazid alone or in any combination ranged from 0 to 9.3% of cases (median 2.1%) in the West and Centre, and from 21.7% to 27.8% in the Baltic States. The proportion of resistance to rifampicin ranged from 0 to 2.1% in the West and Centre (median: 0.7%) and from 10.1% to 17.8% in the Baltic States. Concomitant resistance to isoniazide and rifampicin was observed in 0-2.1% of the cases in the West and Centre (median 0.3%) and in 7.9-17.5% of cases in the Baltic States. Proportions of resistant cases were higher among cases previously treated compared to cases never treated: among cases previously treated, 0-12.9% were MDR in the West and Centre (median 2.6%) and 31.6-53.9% in the Baltic States.

Drug susceptibility testing results by geographic
origin were provided according to country of birth from
most countries. In the West, 49% of all cases with drug susceptibility testing results were of foreign origin (table 3).
Among them, proportions of resistant cases were higher than among cases who were born in/citizens of the country.
Resistance to isoniazid was observed in 0-14.1% cases of foreign origin (median 8.1%) and among 0-5.1% of nationals (median 3.2%) and multidrug resistance was observed in 0-8.6% of the cases of foreign origin (median: 1.9%) compared to 0-1.6% among nationals (median: 0). Cases of foreign origin accounted for 106 / 116 MDR cases notified in the West (91%). In the 10 countries in the West providing individual data, proportions of resistance were analysed by geographic origin according to anti-TB treatment status. The proportion of MDR cases was much higher among the foreign-born than among national cases in both groups of cases never treated (0.92% vs 0.04%) and previously treated (9.7% vs 0.3%). In the Centre and in the East, (data not provided from Lithuania and the Czech Republic), foreign-born cases represented overall 8% of the cases tested. In Estonia and Latvia, proportions of resistant cases did not differ by geographic origin and, in the Centre, small numbers of cases among foreigners did not allow meaningful comparisons (data not shown).

Drug susceptibility testing results, group B
Among countries in group B (table 2), data from France and Spain showed low levels of resistance and data from Greece, not available by anti-TB treatment history, showed higher global proportions of resistance compared to other countries in the West. In the Centre, the level of resistance was low in the region of Belgrade in Yugoslavia and global proportion of MDR cases, not representative of country situations, ranged between 2.7% and 4.9% in the other countries. In the East, data from the Russian Federation, showed proportions on MDR cases of 6.7% among cases never treated. Nationwide laboratory data from Kazakhstan and data from selected laboratories in three other countries showed proportions of MDR cases never treated between 2.9% and 7.8%.

Discussion
Data on anti-TB drug resistance surveillance (DRS) for 1999 were provided from 34 European countries. In the majority of these countries, DST is performed in laboratories which participate in proficiency testing schemes, showing reproducible results. DRS is frequently implemented through the systematic collection of DST results at the start of treatment for all culture positive TB cases notified. In the countries where culture and DST are routinely performed at TB diagnosis and where DST results were available for the majority of culture positive cases notified, data were considered as representative, presented together (in group A in the tables) and used for international comparisons. With the exception of Israel, representative data from western and central Europe indicate consistently low levels of resistance to isoniazid or rifampicin and of multidrug resistance among new cases. Resistance is more frequent among previously treated cases, but comparisons of data for this group should be done more cautiously, as criteria for inclusion in TB notifications may vary across countries (4).

In Western Europe, drug resistance is more frequent among cases of foreign origin, a group with high TB incidence (5). In 1999, cases of foreign origin accounted for over 90% of the MDR cases in the countries in the West and for all MDR cases notified in Israel, where global levels of resistance were very high and where the vast majority of cases are notified among the foreign born. The majority of foreign born cases notified in western Europe in 1999 originated from Africa or Asia (5), where prevalence of drug resistance is likely to be higher compared to western Europe. Information indicating possible transmission or acquisition of resistance in the country of diagnosis (e.g. year of arrival in the country, country of previous treatment) should be collected in specific studies.

In the countries where DST results linked to TB notification are incomplete or where DST results are collected on TB cases diagnosed in selected laboratories (group B in this article), the representativeness of routine DST data is variable and depends largely on diagnostic practices. If DST is routinely performed at start of treatment and data collection is complete, as in France, these data may be useful for assessing drug resistance trends (6). If DST at the start of treatment is only performed for selected cases, DST results are unlikely to be representative of incident TB cases and DRS should be carried out through specific, repeated surveys.

In the East, representative data from the Baltic States show that, overall, 15% of TB cases notified in 1999 were MDR. These levels are among the highest documented worldwide (1) and indicate inadequacies in past treatment programmes. In the other countries of the former Soviet Union, non-representative data show high levels of resistance which, along with data from the Baltic states, and results of surveys (1) are very alarming. Improvement and supervision of laboratory facilities and implementation of specific drug resistance surveys should be part of the urgent measures needed to prevent a further spread of drug resistant TB in this area.

Funding
EuroTB est financé par la DG-SANCO de la Commission européenne (contrat S12.326.478 (2001GV64-022) /
EuroTB is funded by DG-SANCO of the European Commission contract S12.326.478 (2001GV64-022).

Acknowledgements
Nous tenons à remercier les correspondants nationaux d'EuroTB pour leur participation et leur soutien sans lesquels ce travail n'aurait pas été possible (la liste des correspondants officiels actuels est disponible sur www.eurotb.org /
We would like to thank the national correspondents of EuroTB for their participation and support, without which this work would not have been possible (list of current official correspondents available on www.eurotb.org).