Drug resistance among tuberculosis cases in the European Union and European Economic Area, 2007 to 2012

Transcription

1 Surveillnce nd outbrek reports Drug resistnce mong tuberculosis cses in the Europen Union nd Europen Economic Are, 2007 to 2012 M J vn der Werf (mrieke.vnderwerf@ecdc.europ.eu) 1, C Ködmön 1, V Hollo 1, A Sndgren 1, P Zucs 1 1. Europen Centre for Disese Prevention nd Control (ECDC), Stockholm, Sweden Cittion style for this rticle: vn der Werf MJ, Ködmön C, Hollo V, Sndgren A, Zucs P. Drug resistnce mong tuberculosis cses in the Europen Union nd Europen Economic Are, 2007 to Euro Surveill. 2014;19(10):pii= Avilble online: Article submitted on 04 November 2013 / published on 13 Mrch 2014 The Europen Union nd Europen Economic Are (EU/ EEA) tuberculosis (TB) surveillnce system collects detiled informtion on resistnce to TB drugs. Using this informtion, we provide n overview of the current TB drug resistnce sitution nd trends in the EU/EEA by performing descriptive nlysis, including nlysis of tretment outcomes, of the TB cses reported between Jnury 2007 nd December The percentges of TB cses with different drug resistnce ptterns hve been stble with bout 90% of the new lbortory-confirmed cses pn-susceptible, 6% monodrug-resistnt, 2% polydrug-resistnt, 2% multidrug drug-resistnt (MDR) TB excluding extensively drugresistnt (XDR) TB, nd 0.2% XDR-TB. In previously treted lbortory-confirmed TB cses, the percentge with MDR-TB excluding XDR-TB declined until 2010 to 16% nd remined stble therefter. During the study period, the percentges of cses with monodrug- nd polydrug-resistnt TB remined constnt t bout 8% nd 2% wheres the percentge of XDR-TB cses incresed slightly to 2.6%. Tretment outcome results for ll cses hve been stble with overll 77.9% of the pn-susceptible cses, 69.6% of the monoresistnt cses, 68.2% of the polyresistnt cses, 32.2% of the MDR-TB cses (excluding XDR-TB), nd 19.1% of the XDR-TB cses treted successfully. The tretment success rte trget for new pulmonry culture-positive MDR-TB cses of 70% hs not been reched. In ddition, drug resistnce surveillnce cn be improved by more complete reporting of drug susceptibility results nd tretment outcome. Introduction Anti-tuberculosis (TB) drug resistnce is mjor public helth chllenge. Ptients infected with Mycobcterium tuberculosis bcilli resistnt to TB drugs often require longer, expensive tretment regimens, nd show poorer tretment outcomes. In 2011, the globl incidence of TB ws estimted to be 125 cses per 100,000 popultion, with bout 12 million prevlent TB cses [1]. Of the prevlent cses, 630,000 (5.3%) were estimted to hve multidrug-resistnt (MDR) TB [1]. The 53 countries of the World Helth Orgniztion (WHO) Europen Region notified 380,366 TB cses in For 127,936 (33.6%), drug susceptibility testing (DST) results were vilble, nd 29,473 (19.0%) were dignosed with MDR-TB. In the 29 reporting Europen Union (EU) nd Europen Economic Are (EEA) countries the proportion of MDR-TB ws 4.5%, while in non EU/EEA countries the proportion ws 25.6% [2]. Although informtion on MDR-TB nd extensively drug-resistnt (XDR) TB is systemticlly collected nd reported by the WHO [1], less informtion is vilble on the burden of mono- nd polydrug resistnce, or ny drug resistnce. In the EU/EEA, mny countries hve bsed their system for surveillnce of nti-tuberculosis drug resistnce on recommendtions of WHO nd Interntionl Union Aginst Tuberculosis nd Lung Disese (IUATLD) working group [3]. Strting with the 2007 TB cohort, TB surveillnce dt from the country level re reported nnully to the Europen Surveillnce System (TESSy) dtbse, operted by the Europen Centre for Disese Prevention nd Control (ECDC). The ECDC previously published n nlysis of MDR nd XDR-TB in the EU/ EEA using notifiction dt from 2008 [4]. This nlysis showed tht MDR-TB remined thret nd tht XDR-TB hd been identified within the EU/EEA borders. In the nnul Europen tuberculosis surveillnce nd monitoring reports, notifictions on MDR-TB nd XDR-TB re provided seprtely from dt on resistnce to isonizid or rifmpicin [2]. Although informtion on resistnce to other TB drugs is collected in the TESSy dtbse, this informtion is not routinely reported. Some EU countries or regions in EU countries hve published detiled informtion on drug resistnce to individul TB drugs [5-7]. For exmple, the United Kingdom reported n increse of the proportion of TB cses resistnt to isonizid from 1998 to 2005 [7]. In the sme period, study from Cstill y León, Spin, indicted tht the incidence of primry drug resistnce nd monoresistnce ws low [8] nd this informtion ws used to estblish new stndrd nti-tuberculosis tretment. Systemtic nlysis of drug resistnce dt 1

2 helps to identify strengths nd remining chllenges in TB control s well s to guide ctions. It cn lso be used to ssess whether the trgets set in the EU/ EEA, i.e. to test 100% of the culture-positive TB cses for resistnce to first-line TB drugs, re chieved [9]. Anlysis of chrcteristics of ptients with drug resistnce cn help to identify popultions most t risk. A study in London mong individuls with isonizid monoresistnce showed tht cses were more likely to be young dults, born in the United Kingdom nd of white or blck Cribben ethnicity, imprisoned t the time of dignosis, unemployed, drug delers or sex workers [10]. Another study ssessed risk fctors for resistnce to second-line nti-tuberculosis drugs in eight countries [11]. It showed tht previous tretment with second-line drugs ws the strongest risk fctor, nd resistnce to fluoroquinolones nd XDR-TB were more frequent in women thn in men. In ddition, unemployment, lcohol buse, nd smoking were ssocited with resistnce to second-line injectble drugs. Although some risk fctors for drug resistnce re study-site-specific, others seem to be generl. To ssess whether TB control progrmmes re ble to provide dequte tretment nd support, n nlysis of TB tretment outcomes is useful. In generl, cses infected with TB strin tht is resistnt to TB drugs hve worse tretment outcome [12,13]. Other ptient chrcteristics tht re reported to be relted to unsuccessful tretment outcomes re being mle, older ge, hving pulmonry TB, lcohol dependence, homelessness, unemployment nd dibetes [12,14,15]. In the TESSy dtbse, only few ptient chrcteristics re collected, which llows for limited risk fctor nlysis. An in-depth nlysis of TB drug resistnce in the EU/ EEA hs not been performed. Therefore, we im to provide n overview of the current TB drug resistnce sitution in the EU/EEA nd its trend, chrcteristics of drug-resistnt cses, nd their tretment outcomes. Methods Dt source nd collection Dt were extrcted from the TESSy dtbse on 4 October Dt from 27 EU nd EEA countries reporting DST results to ECDC were nlysed. Frnce, Itly, nd Spin were not included s they re not reporting cse-bsed drug resistnce dt to TESSy but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. DST dt hd been collected for the first line drugs ethmbutol, isonizid, rifmpicin, nd streptomycin, nd for the second line drugs mikcin, cpreomycin, ciprofloxcin, gtifloxcin, knmycin, levofloxcin, moxifloxcin, nd ofloxcin. Dt inclusion nd surveillnce definitions Only confirmed TB cses ccording to the EU cse definition [16] with dt on drug susceptibility for t lest isonizid nd rifmpicin were nlysed. Definitions nd ctegories provided in the ECDC/WHO report on tuberculosis surveillnce nd monitoring in Europe 2013 were used [2]. Pn-susceptible refers to cse susceptible to ll drugs tested. Monodrug resistnce is defined s resistnce to one nti-tb drug, while polydrug resistnce refers to resistnce to two or more drugs, excluding MDR-TB. MDR-TB is defined s resistnce to t lest isonizid nd rifmpicin. XDR-TB is specil form of MDR-TB defined s resistnce to t lest isonizid nd rifmpicin with further resistnce to fluoroquinolone nd second-line injectble gent (mikcin, knmycin or cpreomycin). Any drug resistnce refers to cse with resistnce to t lest one TB drug. The percentge tested for susceptibility to second-line drugs (injectble gents: mikcin, cpreomycin, knmycin; fluoroquinolones: ciprofloxcin, gtifloxcin, levofloxcin, moxifloxcin, nd ofloxcin) ws clculted for cses for whom DST results were reported for t lest one fluoroquinolone nd one injectble drug. Previously treted TB cse mens tht the cse hs received TB tretment before the current TB episode. If dt on previous tretment were not vilble, informtion on previous TB dignosis ws used. Tretment success is defined s tretment outcome reported s cured or completed within 12 months fter dignosis in non-m(x)dr-tb cses, within 24 months in MDR-TB cses nd within 36 months in XDR-TB cses. Anlysis We performed descriptive nlysis of surveillnce dt to ssess the burden nd trends of drug resistnce mong TB cses in EU/EEA countries between Jnury 2007 nd December We described cses with vilble resistnce dt by previous TB tretment history nd resistnce type over the yers covered. We nlysed different resistnce types by sex, ge-group, origin, humn immunodeficiency virus (HIV) sttus, site of disese nd tretment success. Tretment outcome fter 12 months ws nlysed for pn-susceptible, monoresistnt, nd polyresistnt cses notified between 2007 nd 2011, tretment outcome fter 24 months for MDR-TB cses notified between 2007 nd 2010 nd tretment outcome fter 36 months for XDR-TB cses notified between 2007 nd Fisher s exct tests were used to compre ctegoricl dt. Chi-squred test for trends ws used to nlyse chnges over time of ctegoricl dt using the ptrend commnd in STATA. A p vlue of <0.05 ws considered significnt. All dt nlyses were performed using STATA 12.1 (SttCorp LP, Texs, USA). 2

3 Tble 1 Notified lbortory-confirmed tuberculosis cses with reported testing results for the first-line TB drugs isonizid (H) nd rifmpicin (R), nd multidrug-resistnt TB cses with reported testing results for second-line TB drug resistnce, EU/EEA, Yer Number of countries reporting cse-bsed dt for drug susceptibility for the first-line TB drugs H nd R 26,b 25,b 26,b 26,b 26,b 25,b Number of notified lbortory-confirmed TB cses 41,943 39,628 40,220 37,401 37,577 35,279 Notified lbortory-confirmed TB cses with reported testing results for R nd H resistnce 26,622 (63.5) 27,688 (69.9) 28,356 (70.5) 27,831 (74.4) 28,985 (77.1) Number of notified MDR-TB cses 1,511 1,556 1,499 1,382 1,421 1,310 Notified MDR-TB cses with reported testing results for resistnce to second-line TB drugs 310 (20.5) 366 (23.5) 585 (39.0) 869 (62.9) 983 (69.2) Number of notified XDR-TB cses EU/EEA: Europen Union/Europen Economic Are; MDR: multidrug resistnt; TB: tuberculosis; XDR: extensively drug resistnt. 27,694 (78.5) 891 (68.0) 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Greece is not included in 2007, 2008 nd b Liechtenstein is not included fter Results Completeness of drug resistnce testing reporting In 2007, 26 EU/EEA countries reported cse-bsed rifmpicin nd isonizid susceptibility testing results for 63.5% of ll lbortory-confirmed TB cses, while 25 countries reported this dt in Liechtenstein reported cse-bsed dt on DST for rifmpicin nd isonizid only in 2007 nd Greece only from 2009 to 2011 (Tble 1). The percentge of lbortory-confirmed TB cses with testing results reported incresed grdully from 63.5% (26,622/41,943) in 2007 to 78.5% (27,694/35,279) in Five countries reported results for rifmpicin nd isonizid susceptibility testing for 100% of the lbortory-confirmed TB cses in Reporting of DST results for first-line TB drugs for culture-positive non-mdr-tb incresed between 2007 nd 2012 (Tble 2), both for new nd previously treted TB cses. Reporting of testing results of MDR-TB cses for resistnce to second-line TB drugs incresed steeply from 20.5% (320/1,511) of the notified MDR-TB cses in 2007 to 68.0% (891/1,310) in 2012 (Tble 1). In 2012, ten countries reported DST results for more thn 95% of ll MDR-TB cses for second-line TB drugs, while the corresponding number ws six countries in The testing percentge for second-line TB drugs ws lrgely determined by the low percentge of MDR-TB cses for which test result for second-line drugs ws reported in Romni nd the high number of MDR-TB cses reported in this country, i.e. 53.6% (284/530) in Germny (8/60), Irelnd (1/5), nd Polnd (4/31) reported test results for second-line drugs for <50% of the MDR-TB cses. However, these countries reported lower number of cses nd thus ffected the EU/EEA second-line drug susceptibility percentge to lesser extent. DST results to the first-line drugs ethmbutol nd streptomycin were reported in respectively 84.5% (1,107/1,310) nd 82.9% (1,086/1,310) of the MDR-TB cses in This hd incresed from respectively 66.5% (1,005/1,511) nd 64.2% (970/1,511) in For the most frequently tested second-line drugs, knmycin nd ofloxcin, results were reported in 22.0% (332/1,511) nd 20.8% (315/1,511) of the MDR-TB cses in 2007 nd in 64.6% (846/1,310) nd 62.3% (816/1,310) in In 2012, 40.9% (536/1,310) of the MDR-TB cses were reported to be tested for mikcin resistnce nd 37.5% (491/1,310) for cpreomycin resistnce. Reporting on testing results for resistnce to other second-line drugs ws infrequent. DST results for the drugs gtifloxcin, levofloxcin, nd moxifloxcin were only collected from 2013 onwrds with updtes for previous yer dt. None of the EU/EEA countries hve reported susceptibility testing results for gtifloxcin or levofloxcin for the yers 2007 to Drug resistnce notifiction nd trends In new lbortory-confirmed TB cses, the percentge of those with ny resistnce reported remined stble t round 10% (Figure 1A). Also, the percentges of new lbortory-confirmed TB cses with reported monoresistnce, polyresistnce, MDR-TB (excluding XDR-TB), nd XDR-TB remined stble t bout 6%, 2%, 2%, nd 0.2% respectively. 3

4 Tble 2 Resistnce to first-line tuberculosis drugs in new nd previously treted culture-positive non-mdr-tb cses by yer, EU/ EEA, Yer All culture positive non-mdr-tb cses Isonizid Rifmpicin Streptomycin Ethmbutol R New culture-positive non-mdr-tb cses ,904 20,407 (52.5) 1,166 (5.7) 20,407 (52.5) 115 (0.6) 12,933 (33.2) 784 (6.1) 18,378 (47.2) 135 (0.7) ,104 21,034 (56.7) 1,199 (5.7) 21,034 (56.7) 87 (0.4) 12,528 (33.8) 757 (6.0) 18,321 (49.4) 143 (0.8) ,826 21,689 (58.9) 1,128 (5.2) 21,689 (58.9) 91 (0.4) 13,183 (35.8) 681 (5.2) 18,250 (49.6) 84 (0.5) ,468 21,571 (60.8) 1,185 (5.5) 21,571 (60.8) 78 (0.4) 14,801 (41.7) 879 (5.9) 17,989 (50.7) 93 (0.5) ,441 22,955 (64.8) 1,250 (5.4) 22,955 (64.8) 77 (0.3) 16,190 (45.7) 929 (5.7) 19,030 (53.7) 97 (0.5) ,182 22,061 (66.5) 1,125 (5.1) 22,061 (66.5) 89 (0.4) 15,894 (47.9) 874 (5.5) 18,717 (56.4) 77 (0.4) Previously treted culture-positive non-mdr-tb cses ,119 3,129 (44.0) 370 (11.8) 3,129 (44.0) 78 (2.5) 1,570 (22.1) 140 (8.9) 1,926 (27.1) 39 (2.0) ,618 3,616 (54.6) 315 (8.7) 3,616 (54.6) 54 (1.5) 1,509 (22.8) 137 (9.1) 1,950 (29.5) 42 (2.2) ,714 3,872 (57.7) 352 (9.1) 3,872 (57.7) 66 (1.7) 1,642 (24.5) 140 (8.5) 2,083 (31.0) 41 (2.0) ,256 3,671 (58.7) 348 (9.5) 3,671 (58.7) 60 (1.6) 1,706 (27.3) 153 (9.0) 1,925 (30.8) 39 (2.0) ,695 3,469 (60.9) 315 (9.1) 3,469 (60.9) 54 (1.6) 1,657 (29.1) 155 (9.4) 1,811 (31.8) 35 (1.9) ,200 3,263 (62.8) 257 (7.9) 3,263 (62.8) 57 (1.7) 1,667 (32.1) 132 (7.9) 1,871 (36.0) 23 (1.2) EU/EEA: Europen Union/Europen Economic Are; non-mdr-tb: non multidrug-resistnt tuberculosis; R: resistnt; TB: tuberculosis. 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Liechtenstein reported cse-bsed dt on drug susceptibility testing for rifmpicin nd isonizid only in 2007 nd Greece only from 2009 to R Only TB cses with informtion vilble on previous tretment re included. R R In previously treted lbortory-confirmed TB cses, the percentge with ny resistnce nd with MDR- (excluding XDR-TB) declined until 2010 (Figure 1B) nd remined stble therefter with bout 30% of the previously treted cses showing ny resistnce. The percentge of cses with monoresistnce nd polyresistnce did not chnge. The percentge of XDR-TB cses, incresed from 1.4% in 2007 to 2.6% in 2012 (chi-squred (1) for trend=26.8, p<0.0001). In 2012, the percentge of TB cses with ny resistnce vried considerbly cross EU/EEA countries with 3.3% (6/181) showing ny resistnce in Slovki nd 37.7% (90/239) in Estoni (Figure 2). The percentge of TB cses with reported rifmpicin monoresistnce rnged between 0% nd 1.3% in 2012 in the different EU/EEA countries (Tble 3). For isonizid monoresistnce the rnge ws 0% to 6.6% nd for MDR-TB 0% to 25.5%. The totl number of notified MDR-TB (including XDR-TB) cses decresed from 1,511 in 2007 to 1,310 in 2012 (Tble 1). Liechtenstein did not report to TESSy in 2012, but reported 0 MDR TB cses in The number of new cses with MDR-TB (including XDR-TB) remined stble over the yers, 516 in 2007 nd 542 in 2012, wheres the number of MDR-TB (including XDR-TB) cses tht were previously treted decresed from 972 in 2007 to 727 in 2012 (Tble 4). The percentge of new MDR-TB (including XDR-TB) cses of MDR-TB cses for which previous tretment ws known, incresed from 34.7% (516/1,488) in 2007 to (542/1,269) 42.7% in 2012 (chi-squred (1) test for trend=35.4, p<0.001). Of the new MDR-TB (including XDR-TB) cses, 50% were reported to be resistnt to ethmbutol nd >80% to streptomycin (Tble 4). Among previously treted MDR-TB (including XDR-TB) cses, round 70% tested resistnt to ethmbutol, wheres resistnce to streptomycin ws comprble with the percentge in new MDR-TB cses. Resistnce to knmycin ws reported in 40.7% of the new MDR-TB cses in 2007 nd 23.5% in Ofloxcin resistnce ws less frequent in new MDR-TB cses with only 11.7% of the cses showing resistnce in As expected, previously treted cses were more frequently resistnt to both firstline nd second-line TB drugs. Of ll MDR-TB (including XDR-TB) cses tested for resistnce to ny of the second-line TB drugs between 2007 nd 2012, 44.5% (1,782/4,004) were resistnt to ny of the second-line drugs. 4

5 Figure 1 Resistnce pttern mong new () nd previously treted (b) lbortory-confirmed TB cses tested for t lest isonizid nd rifmpicin resistnce by yer, EU/EEA, A. New lbortory-confirmed TB cses Percentge with resistnce Monoresistnce Polyresistnce non-mdr-tb MDR-TB, not XDR-TB XDR-TB Any resistnce B. Previously treted lbortory-confirmed TB cses 40.0 Percentge with resistnce Monoresistnce Polyresistnce non-mdr-tb MDR-TB, not XDR-TB XDR-TB Any resistnce EU/EEA: Europen Union/Europen Economic Are; MDR-TB: multidrug-resistnt tuberculosis; TB: tuberculosis; XDR-TB: extensively drug-resistnt tuberculosis. 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Of the 27 EU/EEA countries included in the study, Liechtenstein reported cse-bsed dt on drug susceptibility testing for rifmpicin nd isonizid only in 2007 nd Greece only from 2009 to For 143 of the 183 (78.1%) MDR-TB cses (including XDR-TB) with ciprofloxcin resistnce, no cross resistnce with other fluoroquinolones ws reported. Of the 815 MDR-TB cses (including XDR-TB) with ofloxcin resistnce, for 727 (89.2%) no resistnce to other fluoroquinolones ws reported, nd of the 55 cses resistnt to moxifloxcin, for three (5.5%) no other resistnce to fluoroquinolones ws reported. Thirty-six MDR-TB cses (including XDR-TB) were reported with resistnce to both ciprofloxcin nd ofloxcin nd 48 showed resistnce to both ofloxcin nd moxifloxcin. Only four MDR-TB (including XDR-TB) cses were reported with resistnce to ll three fluoroquinolones. Chrcteristics of tuberculosis cses with drug resistnce In 2012, 32.6% of ll lbortory-confirmed TB cses tested for t lest isonizid nd rifmpicin resistnce were femle (Tble 5). In the groups with MDR-TB (excluding XDR-TB), nd XDR-TB, femles ccounted for lower proportion compred to the other groups, 25.6% nd 21.9% of ll cses, respectively (p<0.001 nd p=0.008, respectively). 5

6 Figure 2 Percentge of lbortory-confirmed tuberculosis cses tested for t lest isonizid nd rifmpicin resistnce with ny drug resistnce, EU/EEA, 2012 Any resistnce (%) Not reported EU/EEA: Europen Union/Europen Economic Are. The Not reported legend indictes tht cse-bsed drug susceptibility results re not reported to the Europen Surveillnce System (TESSy). Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Liechtenstein nd Greece did not report to TESSy in Most notified TB cses were between 25 nd 64 yersold. The percentges of 25 to 64 yer-olds were higher compred to those ged younger or older for XDR-TB (85.2%) nd MDR-TB (excluding XDR-TB) (82.2%) cses when compred to pn-susceptible (70.1%) or monoresistnt (74.4%) cses (comprison XDR-TB vs pn-susceptible, chi-squred (1)=13.8 p<0.001; comprison MDR-TB (excluding XDR-TB) vs pn-susceptible, chi-squred (1)=79.8 p<0.001; comprison XDR-TB vs monoresistnt, chi-squred (1)=7.4 p=0.007; comprison MDR-TB (excluding XDR-TB) vs monoresistnt, chi-squred (1)=24.4 p<0.001). Cses ged 65 yers were significntly more frequent mong pn-susceptible cses (17.3%, p<0.001) when compred to ll other ge groups ( %). Of the pn-susceptible TB cses, 28.1% were recorded with foreign origin. While monoresistnt cses were more frequently of foreign origin, 34.6% (p<0.001), MDR-TB (excluding XDR-TB), nd XDR-TB cses were 6

7 Tble 3 Rifmpicin monoresistnce, isonizid monoresistnce, nd multidrug-resistnt TB in EU/EEA countries, 2012 Country Number of TB cses with reported susceptibility testing results to t lest isonizid nd rifmpicin Rifmpicin monoresistnt Isonizid monoresistnt MDR-TB Austri (0.0) 14 (3.6) 27 (6.9) Belgium (0.7) 37 (5.0) 20 (2.7) Bulgri (1.1) 27 (3.3) 49 (5.9) Cyprus 49 0 (0.0) 1 (2.0) 0 (0.0) Czech Republic (0.3) 4 (1.0) 4 (1.0) Denmrk (0.0) 8 (2.7) 1 (0.3) Estoni (1.3) 3 (1.3) 61 (25.5) Finlnd (0.0) 8 (3.6) 3 (1.4) Frnce Germny 2,794 5 (0.2) 96 (3.4) 60 (2.1) Greece b Hungry (0.4) 17 (3.8) 11 (2.4) Icelnd 5 0 (0.0) 0 (0.0) 1 (20.0) Irelnd (0.0) 10 (3.8) 5 (1.9) Itly Ltvi (0.0) 28 (3.7) 106 (13.8) Liechtenstein b Lithuni 1, (0.7) 56 (4.1) 271 (19.8) Luxembourg 29 0 (0.0) 0 (0.0) 0 (0.0) Mlt 14 0 (0.0) 0 (0.0) 0 (0.0) Netherlnds (0.2) 23 (3.5) 11 (1.7) Norwy (0.4) 7 (2.5) 6 (2.1) Polnd 4,659 9 (0.2) 104 (2.2) 31 (0.7) Portugl 1,321 1 (0.1) 21 (1.6) 17 (1.3) Romni 5, (1.3) 232 (3.9) 530 (8.9) Slovki (0.0) 4 (2.2) 1 (0.6) Sloveni (0.0) 2 (1.6) 0 (0.0) Spin Sweden (0.2) 33 (6.6) 14 (2.8) United Kingdom 5,151 8 (0.2) 196 (3.8) 81 (1.6) Totl EU/EEA 27, (0.5) 931 (3.4) 1,310 (4.7) EU/EEA: Europen Union/Europen Economic Are; MDR-TB: multidrug-resistnt tuberculosis; TB: tuberculosis. No cse-bsed reporting to the Europen Surveillnce System (TESSy) of drug susceptibility testing results but ggregted results were reported to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. b No reporting to TESSy in less frequently of foreign origin, respectively 18.7% nd 12.5% (p<0.001 for both comprisons). Previous tretment ws reported for 14.4% of ll lbortory-confirmed cses, but it ws much more common in cses with MDR-TB (excluding XDR-TB), nd XDR-TB, ccounting for 53.1% (p<0.001) nd 77.3% (p<0.001), respectively compred to ll other cses (pn-susceptible, monoresistnt nd polyresistnt cses). Surprisingly, only 15.3% of the TB cses with polyresistnt pttern hd previously received TB tretment. This is bit more thn the 11.9% (p=0.022) of the pn-susceptible tht hd previously received TB tretment, nd comprble to the 18.0% (p=0.168) of monoresistnt TB cses. Fifteen countries reported cse-bsed HIV testing results. Overll, only 28.1% of the TB cses hd HIV sttus reported, but this percentge ws much higher for MDR-TB (excluding XDR-TB), nd XDR-TB cses, i.e. respectively 52.7% nd 65.6%. Also, the percentge testing positive for HIV ws higher for MDR-TB (excluding XDR-TB) cses (10.4%, p<0.001), nd XDR-TB cses (13.1%, p<0.001), when compred to ll other cses 7

8 Tble 4 Anti-tuberculosis drug resistnce in new nd previously treted multidrug-resistnt TB cses (including extensively drug resistnt tuberculosis) by yer, EU/EEA, New MDR-TB cses (including XDR-TB) (N MDR-TB=516) Tuberculosis drugs b (N MDR-TB=533) 2009 (N MDR-TB=596) 2010 (N MDR-TB=547) 2011 (N MDR-TB=593) 2012 (N MDR-TB=542) Ethmbutol c (61.0) (58.5) (50.0) (55.0) (63.7) (60.0) Streptomycin c (89.4) (83.6) (86.0) (88.2) (88.3) (85.7) Amikcin d (16.9) (27.8) (21.9) (23.3) (17.9) (19.1) Cpreomycin d (24.3) (29.4) (23.3) (25.1) (19.9) (18.3) Ciprofloxcin d 8 0 (0.0) 40 6 (15.0) 30 5 (16.7) 33 5 (15.2) 58 7 (12.1) 32 2 (6.3) Knmycin d (40.7) (31.1) (30.1) (27.6) (23.9) (23.5) Moxifloxcin d 0 0 ( ) 0 0 ( ) 1 0 (0.0) 47 7 (14.9) (23.2) (7.8) Ofloxcin d (15.2) (15.7) (13.0) (16.1) (18.8) (11.7) Previously treted MDR-TB cses (including XDR-TB) (N MDR-TB=972) Tuberculosis drugs b (N MDR-TB=1,003) 2009 (N MDR-TB=873) 2010 (N MDR-TB=817) 2011 (N MDR-TB=792) 2012 (N MDR-TB=727) Ethmbutol c (73.7) (72.4) (65.3) (62.8) (68.9) (70.9) Streptomycin c (93.2) (77.6) (88.8) (89.1) (87.0) (87.1) Amikcin d (24.0) (34.2) (24.5) (23.9) (22.6) (25.7) Cpreomycin d (25.0) (33.6) (26.7) (23.0) (21.4) (28.6) Ciprofloxcin d 11 8 (72.2) (42.8) (15.5) (17.0) (19.9) (20.8) Knmycin d (66.7) (65.1) (41.7) (36.2) (36.7) (43.3) Moxifloxcin d 0 0 ( ) 0 0 ( ) 1 0 (0.0) 11 3 (27.3) 15 6 (40.0) (26.8) Ofloxcin d (44.4) (20.4) (24.4) (28.3) (30.3) (32.1) EU/EEA: Europen Union/Europen Economic Are; MDR-TB multidrug resistnt tuberculosis; TB: tuberculosis; XDR-TB: extensively drug resistnt tuberculosis. 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Liechtenstein reported cse-bsed dt on drug susceptibility testing for rifmpicin nd isonizid only in 2007 nd Greece only from 2009 to MDR-TB cses (including XDR-TB) with informtion vilble on previous tretment re included. b Drug susceptibility testing results for the drugs levofloxcin, gtifloxcin, nd moxifloxcin were only collected from 2013 onwrds with updtes for previous yer dt. None of the EU/EEA countries hs reported susceptibility testing results for levofloxcin or gtifloxcin. c First line drugs. d Second line drugs. 8

9 Tble 5 Chrcteristics of ll lbortory-confirmed TB cses tested for t lest isonizid nd rifmpicin resistnce by drug resistnce pttern, EU/EEA, 2012 Chrcteristics Pn-susceptible Monoresistnt Polyresistnt non-mdr-tb MDR-TB not XDR-TB XDR-TB Totl 24,199 (100.0) 1,648 (100.0) 537 (100.0) 1,182 (100.0) 128 (100.0) 27,694 (100.0) Sex Femle 7,968 (32.9) 536 (32.5) 180 (33.5) 303 (25.6) 28 (21.9) 9,015 (32.6) Mle 16,227 (67.1) 1,112 (67.5) 356 (66.3) 879 (74.4) 100 (78.1) 18,674 (67.4) Unknown 4 (0.0) 0 (0.0) 1 (0.2) 0 (0.0) 0 (0.0) 5 (0.0) Age groups (yers) (1.5) 34 (2.1) 7 (1.3) 13 (1.1) 0 (0.0) 410 (1.5) ,687 (11.1) 210 (12.7) 64 (11.9) 111 (9.4) 9 (7.0) 3,081 (11.1) ,125 (37.7) 685 (41.6) 246 (45.8) 515 (43.6) 62 (48.4) 10,633 (38.4) ,843 (32.4) 541 (32.8) 174 (32.4) 457 (38.7) 47 (36.7) 9,062 (32.7) 65 4,186 (17.3) 178 (10.8) 46 (8.6) 86 (7.3) 10 (7.8) 4,506 (16.3) Unknown 2 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (0.0) Origin Foreign 6,805 (28.1) 570 (34.6) 174 (32.4) 221 (18.7) 16 (12.5) 7,786 (28.1) Ntive 17,060 (70.5) 1,057 (64.1) 356 (66.3) 959 (81.1) 112 (87.5) 19,544 (70.6) Unknown 334 (1.4) 21 (1.3) 7 (1.3) 2 (0.2) 0 (0.0) 364 (1.3) Previous tretment No 20,343 (84.1) 1,288 (78.2) 430 (80.1) 517 (43.7) 25 (19.5) 22,603 (81.6) Yes 2,885 (11.9) 296 (18.0) 82 (15.3) 628 (53.1) 99 (77.3) 3,990 (14.4) Unknown 971 (4.0) 64 (3.9) 25 (4.7) 37 (3.1) 4 (3.1) 1,101 (4.0) HIV sttus HIV tested 6,431 (26.6) 470 (28.5) 173 (32.2) 623 (52.7) 84 (65.6) 7,781 (28.1) HIV infected 282 (4.4) 41 (8.7) 15 (8.7) 65 (10.4) 11 (13.1) 414 (5.3) Unknown 17,768 (73.4) 1,178 (71.5) 364 (67.8) 559 (47.3) 44 (34.4) 19,913 (71.9) Site of disese Pulmonry 20,450 (84.5) 1,368 (83.0) 461 (85.8) 1,126 (95.3) 127 (99.2) 23,532 (85.0) Extr-pulmonry 3,699 (15.3) 280 (17.0) 75 (14.0) 55 (4.7) 1 (0.8) 4,110 (14.8) Unknown 50 (0.2) 0 (0.0) 1 (0.2) 1 (0.1) 0 (0.0) 52 (0.2) Totl EU/EEA: Europen Union/Europen Economic Are; HIV: humn immunodeficiency virus; MDR-TB: multidrug resistnt tuberculosis; TB: tuberculosis; XDR-TB: extensively drug-resistnt tuberculosis. 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Liechtenstein nd Greece did not report to TESSy in The denomintor for the clcultion of percentge of HIV infected ws the number of HIV-tested cses. (pn-susceptible, monoresistnt nd polyresistnt cses). Over 95% of the MDR-TB (excluding XDR-TB), nd XDR-TB cses hd pulmonry TB. For the other resistnce ptterns, round 85% were reported to hve pulmonry TB. Tretment outcome of tuberculosis cses with drug resistnce In period from 2007 to 2011, 77.9% of the pn-susceptible lbortory-confirmed TB cses with test result for t lest isonizid nd rifmpicin resistnce hd successful tretment outcome. Cses with monoresistnt or polyresistnt non-mdr-tb drug resistnce pttern showed slightly lower (69.6% nd 68.2%, respectively) tretment success rtes. For MDR (excluding XDR-TB) reported in period from 2007 to 2010 nd XDR-TB cses reported in period between 2007 nd 2009, the tretment success rtes were 32.2% nd 19.1%, respectively (Figure 3). Trends in successful tretment outcome were reltively stble over the yers. The tretment success rte of new pulmonry MDR-TB (excluding XDR-TB) cses ws 48.2% nd 21.4% for 9

10 Figure 3 Successful tretment outcome of lbortory-confirmed tuberculosis (TB) cses tested for t lest isonizid nd rifmpicin resistnce, by drug resistnce pttern, EU/EEA, Percentge with successful tretment outcome Pn-susceptible Monoresistnce Polyresistnce non-mdr-tb MDR-TB, not XDR-TB XDR-TB Any resistnce EU/EEA: Europen Union/Europen Economic Are. 27 EU/EEA countries provided cse-bsed dt. Frnce, Itly, nd Spin do not report cse-bsed drug susceptibility results to the Europen Surveillnce System (TESSy) dtbse but report ggregted results to the World Helth Orgniztion s Tuberculosis Monitoring nd Evlution pltform. Of the 27 EU/EEA countries included in the study, Liechtenstein reported cse-bsed dt on drug susceptibility testing for rifmpicin nd isonizid only in 2007 nd Greece only from 2009 to previously treted pulmonry MDR (excluding XDR-TB) cses in the period between 2007 nd For new pulmonry XDR-TB cses the tretment success rte ws 49.2% in the period from 2007 to 2009 nd for previously treted pulmonry XDR-TB cses it ws 13.3%. Of ll MDR-TB cses (including XDR-TB) dignosed between 2007 nd 2009, 32.4% hd successful tretment outcome. Of ll MDR-TB cses (including XDR-TB) tht hd n unsuccessful tretment outcome, 21.4% died, 24.5% filed tretment nd 19.8% defulted from tretment, 0.6% trnsferred out nd for 1.4% outcome ws unknown (Figure 4). Tretment outcomes did not show ny improvement in the yers 2007 to In period between 2007 nd 2009, Romni reported tretment success rte of 20.5% for 2,089 MDR-TB (including XDR-TB) cses. Since this significntly influences the overll picture for the EU/EEA, we provide tretment outcome results without the dt reported by Romni. Without these dt, 49.1% successfully finished tretment, 20.7% died, 7.5% filed tretment, 18.1% defulted, 1.3% were trnsferred out, nd 3.3% were reported s unknown. Discussion The percentge of lbortory-confirmed TB cses with different drug resistnce ptterns, i.e. pn-susceptible, mono-, nd polydrug resistnce, MDR-TB (excluding XDR-TB), nd XDR-TB, hs been stble for new cses during the period of the study, from 2007 to In new TB cses, drug resistnce does not seem to be significnt problem with only 2% being dignosed with MDR-TB. However, in previously treted TB cses, much higher percentge, i.e. 16% is dignosed with MDR-TB. The observed decline in the percentge of previously treted TB cses with MDR-TB from 22.3% in 2007 to 16.5% in 2010 cn prtly be explined by less selective testing. In 2007, 37.2% of ll previously treted TB cses were tested for isonizid nd rifmpicin resistnce nd in 2010 this hd incresed to 46.6%. Our nlysis lso showed tht tretment outcome results hve been stble over the yers with n cceptble tretment success rte in pn-susceptible TB cses, though below the trget of 85% of the monitoring frmework of the Frmework Action Pln to Fight Tuberculosis in the Europen Union [9]. Mesured ginst the set trget of 70% in the monitoring frmework of the Frmework Action Pln to Fight Tuberculosis in the Europen Union [9], the tretment success rte of new pulmonry culture-positive MDR-TB ws uncceptbly low t only 48.2% in the period from 2007 to Not ll notified lbortory-confirmed TB cses hd result reported for rifmpicin nd isonizid sensitivity testing. In 2010, the EU/EEA trget for testing culture-confirmed TB cses for susceptibility to first-line TB drugs ws set t 100% [9]. Even though higher percentge of TB cses ws tested in 2012 (78.5%) 10

11 compred to 2007 (63.5%), the trget ws fr from being reched for the EU/EEA overll. However, five EU/EEA countries hve reched nd nine re close to reching the trget, reporting DST results including for rifmpicin nd isonizid for 95% or more of the lbortory-confirmed TB cses. The low percentge of notified lbortory-confirmed TB cses with result reported for rifmpicin nd isonizid drug sensitivity testing is minly explined by the low percentge of testing results reported by Romni, the country tht reported the highest number of lbortory-confirmed TB cses in the EU/EEA, nd reported rifmpicin nd isonizid DST results for less thn hlf of their cses. In ddition, severl EU countries do not report csebsed DST results to TESSy but report ggregted results to the WHO s Tuberculosis Monitoring nd Evlution pltform. Informtion on the drug susceptibility pttern for second-line TB drugs is likely to be beneficil for the tretment outcome of MDR-TB ptients s drug susceptibility results llow for dequte choice of tretment. The EU/EEA surveillnce dt showed tht in 2012, for 68.0% of MDR-TB cses, testing result for susceptibility to second-line TB drugs ws reported nd between 2008 nd 2010 there ws shrp increse. ECDC strted collection of drug susceptibility results for second line drugs in Few countries provided second line drug susceptibility dt for the yers before After 2008 the number of countries reporting second line drug susceptibility dt incresed nd lso the completeness of reporting improved. TB ptient chrcteristics differed cross resistnce ptterns. Chrcteristics of cses with mono- nd polydrug resistnce were lrgely similr to those of pnsusceptible cses wheres MDR- nd XDR-TB cses seemed to differ from cses with other resistnce ptterns. Of the limited number of risk fctors tht we could evlute, we found tht mle sex, ntive origin, previous TB tretment, nd HIV infection were more frequent in MDR-TB (excluding XDR-TB) nd XDR-TB. Of note is the low percentge of TB cses for which HIV sttus ws reported. Other studies hve shown similr results [17-21]. Especilly history of previous tretment is frequently identified s strong risk fctor for MDR-TB [17, 18, 21]. Other reported risk fctors re history of imprisonment, lcohol buse, smoking, nd hospitlistion for more thn 14 dys [17,18,20]. Tretment outcome results of TB cses with monoor polydrug resistnce (not MDR-TB) were only slightly less fvourble compred to those of pn-susceptible TB cses. The reported tretment success rtes for MDR-TB nd XDR-TB cses were significntly below the EU/EEA trget of 70% [9]. In recently published met-nlysis, using individul MDR-TB ptient dt, the pooled tretment success rte ws 54% nd rnged between 11 nd 89% in the different studies tht were included [22]. Surveillnce dt reported in the Globl Tuberculosis Report 2012 showed tht MDR-TB Figure 4 Tretment outcome of ll MDR-TB cses (including XDR-TB) fter 36 months, EU/EEA countries, Percentge of MDR-TB cses 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% Unknown Trnsferred Still on tretment Defulted from tretment Filed tretment Died Successful tretment EU/EEA: Europen Union/Europen Economic Are; MDR-TB: multidrug resistnt tuberculosis; XDR-TB: extensively drug resistnt tuberculosis. Countries reporting tretment outcome for the different cohorts re provided in [27]. tretment success rtes rnged between 44% nd 58% for the 2009 tretment cohort in the different WHO regions [1]. Since 58.5% of the MDR-TB ptients in the EU/EEA were notified by Romni between 2007 nd 2009, the tretment outcomes chieved in this country hve considerble effect on the overll MDR-TB tretment outcomes in the EU/EEA. In the nlysis we included confirmed TB cses ccording to the EU cse definition with vilble dt on drug susceptibility for t lest isonizid nd rifmpicin. These inclusion criteri my potentilly underestimte the percentge of TB cses with ny resistnce s well s polydrug resistnce. This study is bsed on the TB surveillnce dt submitted to ECDC by the EU/EEA countries. As listed bove, this limits the informtion vilble on risk fctors. Also, not ll reported informtion is complete nd the qulity of the reported informtion is the responsibility of the individul country. However, the substntil mount of dt vilble llows for obtining rther dequte picture of the drug resistnce sitution in the EU/EEA. 11

12 The EU/EEA TB surveillnce system does not contin informtion on drug susceptibility dt for the drug pyrzinmide. This is becuse of the technicl complexity of chieving relible nd reproducible results. Also, there is no externl qulity ssurnce for pyrzinmide vilble [23]. Pyrzinmide is importnt in the tretment of tuberculosis nd is included in mny of the new TB regimens tht re currently evluted [24]. Conclusion nd recommendtions The vilble dt show tht the number of TB cses with drug resistnce is stble in the EU/EEA, but not declining. Ptients hving drug resistnt TB need to sustin longer tretment with more drugs, nd they hve worse tretment outcomes, especilly if dignosed with MDR-TB or XDR-TB. Also, tretment costs of MDR-TB re t lest five times higher compred to tretment costs of drug susceptible TB [25]. Helth systems in EU/EEA countries should be prepred to dequtely dignose nd tret drug-resistnt TB, nd test ll TB cses for drug susceptibility in qulity-ssured lbortory [26]. Monitoring of drug resistnce dt t ntionl nd EU/EEA level should be continued to support identifiction of risk groups nd res where improvement my be needed. Conflict of interest None declred. Authors contributions Mrieke J. vn der Werf designed nd drfted the mnuscript nd coordinted the input from the other uthors. Csb Ködmön performed the dt extrction nd nlysis nd provided input for specific prts of the mnuscript, reviewed the drft mnuscript, nd gve finl pprovl of the version to be published. Vhur Hollo checked the dt provided in the mnuscript, reviewed the drft mnuscript, nd gve finl pprovl of the version to be published. Andres Sndgren checked the dt provided in the mnuscript, performed the sttisticl testing, reviewed the drft mnuscript, nd gve finl pprovl of the version to be published. Phillip Zucs provided input for specific prts of the mnuscript, reviewed the drft mnuscript, nd gve finl pprovl of the version to be published. References 1. World Helth Orgniztion. 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