M. Kresken, K. Becker, H. Seifert, E. Leitner, B. Körber-Irrgang, C. Eiff, P.-A. Löschmann

Transcription

1 Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gram-ngativ organisms, including multidrug-rsista pathogns, in Grmany M. Krskn, K. Bckr, H. Sifrt, E. Litnr, B. Körbr-Irrgang, C. Eiff, P.-A. Löschmann To cit this vrsion: M. Krskn, K. Bckr, H. Sifrt, E. Litnr, B. Körbr-Irrgang, t al.. Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gram-ngativ organisms, including multidrug-rsista pathogns, in Grmany. Europan Journal of Clinical Microbiology and Infctious Disass, Springr Vrlag, 2011, 30 (9), pp < /s y>. <hal > HAL Id: hal Submittd on 24 Fb 2012 HAL is a multi-disciplinary opn accss archiv for th dposit and dissmination of sciific rsarch docums, whthr thy ar publishd or not. Th docums may com from taching and rsarch institutions in Franc or abroad, or from public or privat rsarch crs. L archiv ouvrt pluridisciplinair HAL, st dstiné au dépôt t à la diffusion d docums sciifiqus d nivau rchrch, publiés ou non, émana ds établissms d nsignm t d rchrch français ou étrangrs, ds laboratoirs publics ou privés.

2 Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gram-ngativ organisms including multidrug-rsista pathogns in Grmany Michal Krskn, Karstn Bckr, Harald Sifrt, Eva Litnr, Barbara Körbr- Irrgang, Christof von Eiff, Ptr-Andras Löschmann and Study Group Michal Krskn B. Körbr-Irrgang Aiinfctivs Illignc GmbH, Campus Hochschul Bonn-Rhin-Sig, Von-Libig-Straß 20, Rhinbach, Grmany Karstn Bckr ( ) Christof von Eiff Institut of Mdical Microbiology, Univrsity Hospital Münstr, Domagkstr. 10, Münstr, Grmany kbckr@uni-munstr.d Tl.: Fax: Harald Sifrt Institut for Mdical Microbiology, Immunology and Hygin, Univrsity Hospital of Cologn, Goldnflsstraß 19-21, Cologn, Grmany Eva Litnr Christof von Eiff Ptr-Andras Löschmann Pfizr Pharma GmbH, Linkstraß 10, Brlin, Grmany

3 Othr mmbrs of th study group: T. Adam (Institut of Microbiology and Hygin, Univrsity Hospital Charité, Brlin), S. Zimmrmann (Institut for Hygin, Hidlbrg Univrsity Hospital), T. Hopp (Institut of Mdical Microbiology and Immunology, Bonn Univrsity Hospital), F.-J. Schmitz (Institut of Laboratory Mdicin, Microbiology, Hygin, Environmal Mdicin and Transfusion Mdicin, Mühlnkris Hospitals, Mindn), W. Pfistr and E. Straub (Institut of Mdical Microbiology, Jna Univrsity Hospital), M. van dr Lindn (Institut of Mdical Microbiology, Aachn Univrsity Hospital), B. Grabin (Max von Pttnkofr Institut for Hygin and Mdical Microbiology, Großhadrn branch, Ludwig-Maximilian Univrsity, Munich), R. Muttrs (Institut of Mdical Microbiology and Hospital Hygin, Marburg Univrsity Hospital), S. Schubrt (Institut of Mdical Microbiology and Virology, Univrsity Hospital, Schlswig-Holstin, Kil Campus), M. Kaas and S. Gatrmann (Institut of Mdical Microbiology, Bochum Univrsity Hospital), B. Lindnr (Cr for Clinical Chmistry and Microbiology, St. Gorg City Hospital, Lipzig), H. Rüssmann (Hlios Klinikum, Brlin), M. Hrrmann (Institut of Mdical Microbiology and Hygin, Homburg/Saar). Running titl: Activity of tigcyclin against MDR pathogns Ky words: Rsistanc survillanc; tigcyclin; Gram-positiv organisms; Gramngativ organisms; multidrug-rsista pathogns; mthicillin-rsista Staphylococcus aurus Elctronic supplmary matrial Th onlin vrsion of this articl coains supplmary matrial, which is availabl to authorizd usrs. Rsults wr shown in part at th 50 th ICAAC 2010 in Boston (postr E-1599). 2

4 Abstract To docum th dvlopm of rsistanc to tigcyclin in comparison with 17 othr aimicrobials, suscptibilitis of 2,741 isolats comprising 16 bactrial spcis rcovrd from hospitalisd patis in 15 Grman crs in 2009 wr assssd. Th rsults wr compard with thos of prvious trials (G-TEST I/II, 2005 and 2007) conductd prior to and shortly aftr th iroduction of tigcyclin in Grmany. Morovr, th in vitro-activitis of tigcyclin against th subst of multidrug-rsista (MDR) pathogns rcovrd within all thr sampling priods (n=4,988) wr valuatd in comparison to th corrsponding non-mdr isolats. All suscptibility tsts wr prformd by broth microdilution. Btwn 2005 and 2009, tigcyclin rtaind its high activity against Gram-positiv and Gram-ngativ organisms including MDR pathogns. By corast, an in part markd incras in rsistanc to broad-spctrum bta-lactams and fluoroquinolons was obsrvd for many Erobactriaca and for non-frming Gram-ngativ bactria. Against a background of a stadily incrasing numbr of multirsista pathogns, th activity of tigcyclin rmaind still unaltrd. With th xcption of Aciobactr isolats with dcrasd suscptibility to carbapnms, tigcyclin s activity profil was not notably affctd by organisms rsista to othr drug classs and, thus, holds promis as an importa thraputic ag, particularly for situations in which MDR organisms ar suspctd. 3

5 Iroduction Infctious disass rprs on of th most frqu causs of dath and th lading caus of disability-adjustd lif yars worldwid [1], ( Although th past dcads hav bn markd by dclining infctious disas-associatd mortality particularly in middl and high-incom couris, substaial yar-to-yar variation as wll as th adv of (r)mrging infctions undrlins th dynamic natur of infctious disass and th nd for prpardnss to addrss thm [2, 3]. Th Grman Fdral Ministry of Halth rportd that ovr 40,000 patis did from infctions in 2006 and th numbr of daths du to infction ros by 14 pr c in th priod btwn 2002 and 2006 [4]. Dspit th many causs for this incras in mortality, th incrasing numbr of bactrial infctions causd by rsista pathogns during th last two dcads prss on of th gratst challngs to mdicin [5, 6]. Th iroduction of nw classs of aibiotics rprss an importa coribution to limiting th sprad of rsista bactria [7, 8]. Tigcyclin, iroducd in Grmany in May 2006, is th first smisyhtic glycylcyclin aibiotic with in-vitro activity against many arobic and anarobic Gram-positiv and Gram-ngativ organisms [9, 10]. Th broad spctrum of activity includs multidrug-rsista (MDR) pathogns such as mthicillin (oxacillin)-rsista Staphylococcus aurus (MRSA), vancomycinrsista rococci (VRE), xtndd-spctrum bta-lactamas (ESBL) producing Erobactriaca mmbrs and so-calld atypical bactria [11, 12]. Although structurally rlatd to ttracyclins, th bactriostatic ffct of tigcyclin is not impaird by th two main mchanisms lading to ttracyclin rsistanc, i.. ribosomal protction and ttracyclin-spcific fflux pumps [13]. Som taxa, such as Protus, Providncia, Morganlla, Burkholdria cpacia and Psudomonas 4

6 aruginosa, howvr, show irinsic rducd suscptibility to tigcyclin [14, 15]. Rarly, rsistanc to tigcyclin has also bn obsrvd in spcis that ar usually suscptibl such as Klbsilla pnumonia and Eschrichia coli [16-18]. In two prvious rsistanc survillanc survys conductd throughout Grmany (Grman Tigcyclin Evaluation Survillanc Trial, G-TEST I and II, prformd in 2005 and 2007, rspctivly), th suscptibility of ovr 2,500 bactrial isolats, ach collctd on yar prior and on yar aftr th iroduction of th nw compound, was tstd against tigcyclin and comparators [19, 20]. Aim of th prs study was to valuat th in vitro activitis of ths ags against wll-charactrizd clinical isolats rcovrd in 2009 and to compar ths data with thos collctd sinc Morovr, w valuatd th in vitro activity of tigcyclin and comparators against th subst of MDR pathogns rcovrd btwn 2005 and Matrials and mthods Crs and bactrial strains Ovrall, fiftn sits, slctd to mt gographic divrsity within Grmany, wr nrolld in th thr collction priods. Thirtn laboratoris participatd in all thr priods, whil two crs that participatd in 2005 and 2007 wr rplacd by two othrs in Each laboratory was askd to collct a maximum of 200 conscutiv isolats obtaind from hospitalizd patis with community-acquird or nosocomial infctions in th tim priod from April to Sptmbr Data from gram-positiv (Erococcus facalis, Erococcus facium, S. aurus (MRSA and mthicillin (oxacillin)-suscptibl S. aurus, MSSA), Staphylococcus pidrmidis, Staphylococcus hamolyticus, Strptococcus agalactia, 5

7 Strptococcus pnumonia and Strptococcus pyogns) and gram-ngativ (Aciobactr baumannii group, Erobactr cloaca, E. coli, Hamophilus influnza, Klbsilla oxytoca, K. pnumonia, Srratia marcscns and Stnotrophomonas maltophilia) microorganisms wr valuatd. Only first isolats from th following sourcs wr accptd for inclusion: pritonal cavity, rspiratory tract, blood, wounds and urin (<10% of th isolats). Coagulasngativ staphylococci (CoNS) wr only includd if thy wr rcovrd from at last two blood sampls. Idification of th pathogns was prformd using standard laboratory mthods. Th bactrial strains wr thn kpt at 70 C and s to a cral laboratory (Aiinfctivs Illignc, Rhinbach, Grmany) for suscptibility tsting at th nd of th collction priod. Suscptibility tsting Minimal inhibitory concrations (MICs) wr dtrmind using th microdilution broth mthod according to th standard ISO :2006 [21]. Th tst mdium was Mullr-Hion II broth (Bcton Dickinson GmbH, Hidlbrg, Grmany). Tsting of th strptococci was prformd using 3% lysd hors blood (Oxoid GmbH, Wsl, Grmany). BBL Hamophilus tst mdium (Bcton Dickinson GmbH, Hidlbrg, Grmany) was usd to dtrmin th suscptibility of H. influnza. During th tst priod, rfrnc strains wr includd in th suscptibility tsts in th rfrnc laboratory at last four tims. For Gram-positiv bactria, suscptibility to th following aibactrial ags was tstd: amoxicillin/clavulanic acid, cfuroxim, doxycyclin, gamicin, imipnm, linzolid, moxifloxacin, oxacillin, pnicillin G, pipracillin/tazobactam, tigcyclin and vancomycin. For Gram-ngativ bactria, amoxicillin/clavulanic acid, cfpim, 6

8 cfotaxim, cftazidim, ciprofloxacin, doxycyclin, rtapnm, gamicin, imipnm, moxifloxacin, pipracillin/tazobactam and tigcyclin wr includd. Isolats wr dfind as suscptibl or rsista to aimicrobial ags in accordanc with th spcis-rlatd clinical brakpois approvd by th Europan Committ on Aimicrobial Suscptibility Tsting (EUCAST, vrsion 1.1) if availabl [22]. Minimum inhibitory concrations (MICs) of gamicin for rococci (highlvl rsistanc) wr irprtd by th cut-off valus givn by Clinical Laboratory Standards Institut (CLSI) [23]. Isolats of E. coli and Klbsilla spp. wr tstd for ESBL production according to th broth dilution procdur dscribd by CLSI [24]. Comparison of multidrug-rsista (MDR) vrsus non-mdr organisms To compar th activity of tigcyclin against th subst of MDR (i.. in this study: imipnm-nonsuscptibl mmbrs of th A. baumannii group, cfotaximnonsuscptibl E. cloaca and S. marcscns, ESBL-positiv E. coli, K. oxytoca and K. pnumonia, MRSA and vancomycin-rsista E. facalis and E. facium) vrsus corrsponding non-mdr organisms of th includd spcis, a total of 4,988 conscutivly collctd isolats from all thr collction priods (April to August 2005; n=1,673; May to Sptmbr 2007, n=1,649; April to Sptmbr 2009, n=1,666) wr analysd. Th numbrs of isolats of th various spcis wr as follows: A. baumannii group (n=391), E. cloaca (n=681), E. coli (n=889), K. oxytoca (n=305), K. pnumonia (n=558), S. marcscns (n=370), S. aurus (n=910), as wll as rococcal isolats (n=884). Rsults Bactrial isolats, typ of spcimns and patis 7

9 A total of 2,741 clinical isolats wr collctd by th 15 participating crs in 2009, with th numbr of strains pr cr varying btwn 131 and 199. Sixtysvn prc and 33% of th isolats wr obtaind from patis on gnral wards and insiv car units, rspctivly. Mor than 60% of ths patis wr mal. Th ag of th patis rangd from <1 to 98 yars (mdian: 56 yars). Th majority of isolats drivd from rspiratory tract spcimns (n=880, 32.1%), followd by wound spcimns (n=841, 30.7%), blood culturs (n=607, 22.1%) and spcimns of th pritonal cavity (n=228, 8.3%). Fifty-on prc and 30% of th infctions wr hospital-acquird and communityacquird, rspctivly. Th acquisition of th infction was unknown for 19% of th patis. Niy-on of 153 (59.5%) MRSA strains wr associatd with hospitalacquird and 32/153 (20.9%) with community-acquird infctions. 30/153 (19.6%) isolats could not b assignd to hospital-acquird or community-acquird infctions. As for MRSA, ESBL-producing E. coli and Klbsilla isolats wr prdominaly associatd with hospital-acquird infctions (E. coli 59%, K. oxytoca 81.3%, K. pnumonia 70.8%). Suscptibility of th clinical isolats in comparison to prvious G-TEST trials Th suscptibility data ar shown in Tabl 1 (ovrviw) and Onlin Rsourcs 1 and 2 coaining th MIC 50 and MIC 90 valus as wll as th suscptibility and rsistanc rats. In addition, to dmonstrat th trnd of rsistanc, th rsults of th two prvious trials (G-TEST I and II) ar providd for comparison. Th MIC valus obtaind for th rfrnc strains corrspondd wll to th suggstd concration rangs givn in th ISO docum, as far as availabl. 8

10 Gram-positiv bactria. As alrady obsrvd in prvious G-TEST studis, tigcyclin dmonstratd vry good activity against S. aurus, with narly idical activity against MSSA and MRSA isolats. In corast, suscptibility rats of moxifloxacin wr 91.8 % and only 2.0% for MSSA and MRSA, rspctivly. With rgard to CoNS, only on strain (0.7%) of S. pidrmidis was tigcyclin-rsista (MIC 1 mg/l, which is on dilution abov th uppr brakpoi). As in prvious studis, all staphylococcal strains tstd wr suscptibl to vancomycin and linzolid. Against both E. facalis and E. facium, tigcyclin rmaind th most activ compound. Of th 298 rococci tstd, 279 and 17 isolats wr inhibitd by mg/l and 0.25 mg/l of tigcyclin, rspctivly. On strain of E. facium had a tigcyclin MIC of 0.5 mg/l (classifid as irmdiat) and on strain of E. facalis had an MIC of 2 mg/l (classifid as rsista). Th MIC 90 of linzolid was 2 mg/l for both spcis, whil th MIC 90 of vancomycin was 2 mg/l for E. facalis and 32 mg/l for E. facium. Th prcag of vancomycin-rsista strains among E. facium isolats (11.9%) was comparabl to that found in G-TEST I (11.0%), but was lowr than th rat found in G-TEST II (18.3%). In corast, high-lvl rsistanc to gamicin in both spcis ros from approx. 40% in G-TEST I and G-TEST II to about 50% in th prs study. As in th prvious studis, tigcyclin dmonstratd vry good activity against th thr strptococcal spcis tstd with all isolats inhibitd by mg/l of tigcyclin, including thos with rducd suscptibility to doxycyclin and/or pnicillin. Gram-ngativ bactria. As in th G-TEST I and II trials, tigcyclin dmonstratd vry good in vitro activity against E. coli. Whil 296 of th 297 isolats tstd wr tigcyclin-suscptibl, th rmaining isolat was rsista (MIC 4 mg/l). Of irst, 25.3% of th tstd E. coli isolats wr rsista to ciprofloxacin and moxifloxacin. 9

11 Th prcag of isolats producing an ESBL phnotyp was 13.1% (39/297) in this trial compard to 5.7% (17/300) in G-TEST I and 12% (35/292) in G-TEST II. Rsistanc rats of K. oxytoca and K. pnumonia for tigcyclin wr comparabl to thos found in th prvious studis, whil thos of E. cloaca and S. marcscns incrasd, from 6.9% in G-TEST I and 6.3% in G-TEST II to 10.2% in G-TEST III and from 3.4% in G-TEST I and 2.4% in G-TEST II to 7.0% in G-TEST III, rspctivly. Howvr, xcpt for th MIC 90 for E. cloaca (4 mg/l), all MIC 50/90 valus of tigcyclin did not diffr from prvious studis for ths Erobactriaca spcis. Similar to E. coli, th prcag of ESBL-positiv strains among isolats of K. oxytoca and K. pnumonia rmaind almost unchangd btwn 2007 (17.4% and 14.6%, rspctivly) and 2009 (16.7% and 12.8%, rspctivly). This trnd was also obsrvd for ciprofloxacin and moxifloxacin in both Klbsilla spcis and for pipracillin-tazobactam in K. oxytoca. In corast, rsistanc to pipracilliazobactam in K. pnumonia dcrasd from 10.3% (G-TEST II) to 4.8% in G-TEST III. Finally, incrasing rats of rsistanc to pipracillin-tazobactam, cftazidim, and rtapnm wr obsrvd in S. marcscns. With rgard to non-frmrs, tigcyclin xhibitd again vry good activity against isolats of th A. baumannii group, with MIC 50/90 valus of 0.25/0.5 mg/l. Th prcag of imipnm-rsista isolats was 8.2% in this trial, compard to <1% in G-TEST I and 11.1% in G- TEST II. Whil rats of rsistanc in P. aruginosa to pipracillin-tazobactam, cftazidim, cfpim and imipnm for P. aruginosa markdly incrasd compard to thos found in prvious G-TEST-trials, th rat of rsistanc to ciprofloxacin slightly dcrasd. Tigcyclin MIC valus for P. aruginosa wr unchangd (8/ 32 mg/l). MDR vs non-mdr pathogns in G-TEST trials. 10

12 Distributions of tigcyclin MIC valus for MDR isolats (n = 4,988 isolats) and corrsponding non-mdr isolats of th includd spcis rcovrd during all thr study priods (2005, 2007 and 2009), ar displayd in Figurs 1 and 2 (all othr data ar givn in Onlin Rsourcs 3 and 4). With rgard to MDR Gram-positiv pathogns collctd in ths trials, all VRE rcovrd wr E. facium. Suscptibility rats of tigcyclin for VRE and MRSA wr >98% and 100%, rspctivly. With rgard to Gram-ngativ pathogns, tigcyclin had MIC 50 /MIC 90 s (mg/l) for ESBL-producing E. coli (0.25/0.5), K. oxytoca (0.5/1), and K. pnumonia (1/2) and cfotaxim-non-suscptibl S. marcscns isolats (1/2) that wr idical or within on doubling dilution compard to th suscptibl and ESBL-ngativ subpopulations. MIC 50 /MIC 90 s of tigcyclin for cfotaxim-suscptibl and cfotaxim-non-suscptibl E. cloaca isolats wr 0.5/1 and 0.5/4, rspctivly. For bactria of th A. baumannii group, th activity of tigcyclin against imipnmnon-suscptibl isolats (1/2) was 4-fold highr than for imipnm-suscptibl isolats (0.25/0.5). Discussion Th prs study, conductd thr yars following th iroduction of tigcyclin for clinical us in Grmany, valuatd th suscptibility of Grman hospital bactrial isolats to tigcyclin in comparison to othr drugs. Ovrall, suscptibility to tigcyclin did not chang compard to pr-markting baslin valus or thos valuatd on yar aftr th iroduction of tigcyclin [19, 20]. Excpt for P. aruginosa, th glycylcyclin dmonstratd vry good in vitro activity against all spcis tstd, including MDR pathogns such as MRSA and VRE. Similar trnds wr rcly obsrvd in two othr larg survillanc studis, which includd rgions with incrasing rats of MDR pathogns [25, 26]. Of particular irst, 11

13 tigcyclin xhibitd vry good in vitro activity against ESBL- and/or AmpC-producing Erobactriaca. On th whol, th activity profil of tigcyclin was not notably affctd by organisms rsista to othr drug classs xcpt by A. baumannii group isolats with dcrasd suscptibility to carbapnms. Howvr, tigcyclin had th lowst MIC 90 of all study drugs for imipnm non-suscptibl A. baumannii group isolats. In a global survillanc study of Aciobactr from blood sampls collctd btwn 2004 and 2008, an incras in th MIC 90 of tigcyclin was obsrvd [27]. Excpt of two E. facium isolats on ach rcovrd in G-TEST I and G-TEST III, no furthr linzolid-rsista Gram-positiv pathogns wr obsrvd in th thr G- TEST studis. Although 99.55% of th tstd 2,006 isolats in th U.S. LEADER program rmaind suscptibl to linzolid [28], th rportd linzolid-rsista S. aurus (n=1), CoNS (n=13), E. facalis (n=3), and E. facium (n=10) isolats should not b undrstimatd. Bsids th most common mchanism of linzolid rsistanc in S. aurus rportd to dat, mutation G2576T in th domain V of 23S rrna, in particular th cfr mutation giv caus for concrn. This novl multidrug rsistanc phnotyp mdiatd by th Cfr rrna mthyltransfras caus rsistanc not only to oxazolidinons, but also to phnicols, lincosamids, pluromutilins and strptogramin A and is plasmid-ncodd, thus, confrring transfrabl oxazolidinon rsistanc [29]. Thus, not unxpctd, first clinical outbraks of linzolid-rsista MRSA and S. pidrmidis clons hav rcly to b notd in Spain and Ohio, U.S.A. [30, 31]. In corast, suscptibility to β-lactams or fluoroquinolons dcrasd in mmbrs of th family Erobactriaca and in non-frming Gram-ngativ bactria btwn 2005 and Sinc fluoroquinolons hav bcom som of th most frquly prscribd aimicrobial ags worldwid, dcrasing suscptibilitis of Gram-ngativ rods towards this aibiotic class hav bn obsrvd also in othr parts of th world in th past yars [32-34]. Also, a substaial ris in th rat of 12

14 rococci with high-lvl rsistanc to gamicin (HLGR), which rachd about 50% in 2009, was obsrvd. HLGR in rococci has also incrasd in Grc within th past dcad [35]. In corast, in four north Europan couris (Dnmark, Finland, Norway, and Swdn), HLGR occurrd in 11-25% of E. facium and 6-20% of E. facalis isolats, with a significaly highr HLGR rat among E. facalis from hospitalizd patis [36]. Th numbr of vancomycin-rsista E. facium strains varid btwn 11% and 18%, whil vancomycin-rsista E. facalis strains wr not dtctd in th thr G-TEST collction priods. Howvr, dcrasd suscptibility to vancomycin was found among 2.0% and 0.6% of th E. facium and E. facalis isolats, rspctivly, in th multicr study prformd in th four Nordic couris miond abov, [36]. In summary, in this third nationwid survillanc study on tigcyclin suscptibility in Grmany, tigcyclin rtaind its vry good in vitro activity against arobic Grampositiv and Gram-ngativ bactria. Thrfor, tigcyclin still holds promis as a suitabl option most notably for calculatd aibiotic tratm in thos clinical situations in that multi-rsista organisms ar suspctd. Acknowldgms Th study was supportd by Pfizr Pharma GmbH, Brlin. Conflict of irst MK, KB, HS hav rcivd travl, rsarch gra support and/or lctur fs from Pfizr. EL, CvE and PAL ar mploys of Pfizr Pharma GmbH. 13

15 Rfrncs 1. Fauci AS (2001) Infctious disass: considrations for th 21st cury. Clin Infct Dis 32: Armstrong GL, Conn LA, Pinnr RW (1999) Trnds in infctious disas mortality in th Unitd Stats during th 20th cury. JAMA 281: Cohn ML (2000) Changing pattrns of infctious disas. Natur 406: Bundsministrium für Gsundhit, Bundsministrium für Ernährung Landwirtschaft und Vrbrauchrschutz, and Bundsministrium für Bildung und Forschung (2008) DART - Dutsch Aibiotika-Rsistnzstratgi. 5. Ric LB (2007) Emrging issus in th managm of infctions causd by multidrug-rsista gram-ngativ bactria. Clv Clin J Md 74 Suppl 4:S12- S20 6. Gootz TD (2010) Th global problm of aibiotic rsistanc. Crit Rv Immunol 30: Frais AP (2006) Tigcyclin: th answr to bta-lactam and fluoroquinolon rsistanc? J Infct 53: Rodriguz d Castro F, Naranjo OR, Marco JA, Violán JS (2009) Nw aimicrobial molculs and nw aibiotic stratgis. Smin Rspir Crit Car Md 30: Ptrson LR (2008) Currly availabl aimicrobial ags and thir potial for us as monothrapy. Clin Microbiol Infct 14 Suppl 6: Klsidis T, Karagorgopoulos DE, Klsidis I, Falagas ME (2008) Tigcyclin for th tratm of multidrug-rsista Erobactriaca: a systmatic rviw 14

16 of th vidnc from microbiological and clinical studis. J Aimicrob Chmothr 62: Europan Aimicrobial Rsistanc Survillanc Systm (EARSS) (2009) EARSS Annual Rport Fritsch TR, Kirby JT, Jons RN (2004) In vitro activity of tigcyclin (GAR-936) tstd against 11,859 rc clinical isolats associatd with communityacquird rspiratory tract and gram-positiv cutanous infctions. Diagn Microbiol Infct Dis 49: Fluit AC, Florijn A, Vrhof J, Milatovic D (2005) Prsnc of ttracyclin rsistanc dtrminas and suscptibility to tigcyclin and minocyclin. Aimicrob Ags Chmothr 49: Dan CR, Visalli MA, Projan SJ, Sum PE, Bradford PA (2003) Efflux-mdiatd rsistanc to tigcyclin (GAR-936) in Psudomonas aruginosa PAO1. Aimicrob Ags Chmothr 47: Visalli MA, Murphy E, Projan SJ, Bradford PA (2003) AcrAB multidrug fflux pump is associatd with rducd lvls of suscptibility to tigcyclin (GAR- 936) in Protus mirabilis. Aimicrob Ags Chmothr 47: Kny D, Ruzin A, McAls F, Murphy E, Bradford PA (2008) MarA-mdiatd ovrxprssion of th AcrAB fflux pump rsults in dcrasd suscptibility to tigcyclin in Eschrichia coli. J Aimicrob Chmothr 61: McAls F, Ptrsn P, Ruzin A, Dunman PM, Murphy E, Projan SJ, Bradford PA (2005) A novl MATE family fflux pump coributs to th rducd suscptibility of laboratory-drivd Staphylococcus aurus mutas to tigcyclin. Aimicrob Ags Chmothr 49: Ruzin A, Visalli MA, Kny D, Bradford PA (2005) Influnc of transcriptional activator RamA on xprssion of multidrug fflux pump AcrAB and tigcyclin 15

17 suscptibility in Klbsilla pnumonia. Aimicrob Ags Chmothr 49: Krskn M, Litnr E, Braurs J, Giss HK, Hall E, von Eiff C, Ptrs G, Sifrt H (2009) Suscptibility of common arobic pathogns to tigcyclin: rsults of a survillanc study in Grmany. Eur J Clin Microbiol Infct Dis 28: Krskn M, Litnr E, Sifrt H, Ptrs G, von Eiff C (2009) Suscptibility of clinical isolats of frquly ncourd bactrial spcis to tigcyclin on yar aftr th iroduction of this nw class of aibiotics: rsults of th scond multicr survillanc trial in Grmany (G-TEST II, 2007). Eur J Clin Microbiol Infct Dis 28: Dutschs Institut für Normung (DIN) (2006) Labormdizinisch Ursuchungn und In-vitro-Diagnostika-Systm - Empfindlichkitsprüfung von Infktionsrrgrn und Evaluation von Grätn zur aimikrobilln Empfindlichkitsprüfung - Til 1: Rfrnzmthod zur Tstung dr In-vitro- Aktivität von aimikrobilln Substanzn ggn schnll wachsnd arob Baktrin, di Infktionskrankhitn vrursachn (ISO :2006). Buth- Vrlag, Brlin 22. Europan Committ on Aimicrobial Suscptibility Tsting (2010) Brakpoi tabls for irprtation of MICs and zon diamtrs. Vrsion 1.1 April Clinical and Laboratory Standards Institut (2009) Prformanc Standards for Aimicrobial Suscptibility Tsting; Nih Informational Supplm CLSI docum M100-S19. Clinical and Laboratory Standards Institut, Wayn, PA 24. Clinical and Laboratory Standards Institut (CLSI) (2008) Prformanc Standards for Aimicrobial Suscptibility Tsting; Eighth Informational Supplm (M100-S18). CLSI, Wayn 16

18 25. Papaparaskvas J, Tzouvlkis LS, Tsakris A, Pittaras TE, Lgakis NJ (2010) In vitro activity of tigcyclin against 2423 clinical isolats and comparison of th availabl irprtation brakpois. Diagn Microbiol Infct Dis 66: Baar C, Curcio D, Frnandz Canigia L, García P, Guzmán Blanco M, Lal AL (2009) Comparativ in vitro activity of tigcyclin against bactria rcovrd from clinical spcimns in Latin Amrica. J Chmothr 21: Wang YF, Dowzicky MJ (2010) In vitro activity of tigcyclin and comparators on Aciobactr spp. isolats collctd from patis with bactrmia and MIC chang during th Tigcyclin Evaluation and Survillanc Trial, 2004 to Diagn Microbiol Infct Dis 68: Jons RN, Fritsch TR, Sadr HS, Ross JE (2007) LEADER survillanc program rsults for 2006: an activity and spctrum analysis of linzolid using clinical isolats from th Unitd Stats (50 mdical crs). Diagn Microbiol Infct Dis 59: Long KS, Pohlsgaard J, Khrnbrg C, Schwarz S, Vstr B (2006) Th Cfr rrna mthyltransfras confrs rsistanc to Phnicols, Lincosamids, Oxazolidinons, Pluromutilins, and Strptogramin A aibiotics. Aimicrob Ags Chmothr 50: Morals G, Picazo JJ, Baos E, Candl FJ, Arribi A, Pláz B, Andrad R, d la Torr MA, Frrs J, Sánchz-García M (2010) Rsistanc to linzolid is mdiatd by th cfr gn in th first rport of an outbrak of linzolid-rsista Staphylococcus aurus. Clin Infct Dis 50: Bonilla H, Huband MD, Sidl J, Schmidt H, Lsco M, McCurdy SP, Lmmon MM, Brnnan LA, Tait-Kamradt A, Puzniak L, Quinn JP (2010) Multicity outbrak of linzolid-rsista Staphylococcus pidrmidis associatd with clonal sprad of a cfr-coaining strain. Clin Infct Dis 51:

19 32. Lautnbach E, Fishman NO, Mtlay JP, Mao X, Bilkr WB, Tolomo P, Nachamkin I (2006) Phnotypic and gnotypic charactrization of fcal Eschrichia coli isolats with dcrasd suscptibility to fluoroquinolons: rsults from a larg hospital-basd survillanc initiativ. J Infct Dis 194: Zrvos MJ, Hrshbrgr E, Nicolau DP, Ritchi DJ, Blacknr LK, Coyl EA, Donnlly AJ, Eckl SF, Eng RH, Hiltz A, Kuyumjian AG, Krbs W, McDanil A, Hogan P, Lubowski TJ (2003) Rlationship btwn fluoroquinolon us and changs in suscptibility to fluoroquinolons of slctd pathogns in 10 Unitd Stats taching hospitals, Clin Infct Dis 37: Boyd LB, Atmar RL, Randall GL, Hamill RJ, Stffn D, Zchidrich L (2008) Incrasd fluoroquinolon rsistanc with tim in Eschrichia coli from >17,000 patis at a larg couy hospital as a function of cultur sit, ag, sx, and location. BMC Infct Dis 8:4 35. Protonotariou E, Dimitroulia E, Pournaras S, Pitiriga V, Sofianou D, Tsakris A (2010) Trnds in aimicrobial rsistanc of clinical isolats of Erococcus facalis and Erococcus facium in Grc btwn 2002 and J Hosp Infct 75: Classon C, Hällgrn A, Nilsson M, Svnsson E, Hanbrgr H, Nilsson LE (2007) Suscptibility of staphylococci and rococci to aimicrobial ags at diffr ward lvls in four north Europan couris. Scand J Infct Dis 39:

20 Figur lgnds Figur 1. Distributions of tigcyclin MICs for Gram-ngativ non-mdr- and MDR isolats Figur 2. Distributions of tigcyclin MICs for Gram-positiv non-mdr- and MDR isolats 19

21 Tabl 1: Ovrviw about in vitro activity of tigcyclin and comparativ ags against arobic Gram-positiv and Gram-ngativ bactria: rsults of G-TEST 1 (G1), G-TEST 2 (G2) and G-TEST 3 (G3) (for MICs, s Onlin Rsourcs 1 and 2) Collction Microorganism priod (No. of isolats) Aibactrial ag a, b (% Rsista) TGC DOX PEN OXA AMC TZP CTX CXM CAZ FEP IPM EPM CIP MXF GEN LZD VAN Aciobactr baumannii group Erobactr arogns Erobactr cloaca G1 (140) nd nd nd nd nd nd nd 0.7 nd 30.0 nd 13.6 G2 (117) nd nd nd nd nd nd nd 11.1 nd 27.4 nd 22.2 G3 (134) nd nd nd nd nd nd nd 8.2 nd 21.6 nd 15.7 G1 (47) n nd nd n n n n n n n n n G2 (39) n nd nd n n n n n n n n n G3 (52) 5.8 nd G1 (232) 6.9 nd G2 (223) 6.3 nd G3 (226) 10.2 nd G1 (300) 0.0 nd Eschrichia coli G2 (292) 0.0 nd G3 (297) 0.3 nd

22 Hamophilus influnza G1 (185) nd nd nd c nd nd G2 (225) nd nd nd c nd nd G3 (239) nd nd 0.4 nd nd G1 (100) 2.0 nd Klbsilla oxytoca G2 (109) 1.8 nd G3 (96) 1.0 nd Klbsilla pnumonia Psudomonas aruginosa Srratia marcscns Stnotrophomonas maltophilia Erococcus facalis G1 (186) 12.4 nd G2 (185) 7.0 nd G3 (187) 9.6 nd G1 (150) nd nd nd 16.7 nd nd 25.3 nd 16.7 G2 (147) nd nd nd 12.9 nd nd 21.8 nd 7.5 G3 (147) nd nd nd 27.2 nd nd 19.0 nd 15.0 G1 (118) 3.4 nd G2 (124) 2.4 nd G3 (128) 7.0 nd G1 (157) nd nd nd nd nd nd nd nd nd nd nd nd G2 (129) nd nd nd nd nd nd nd nd nd nd nd nd G3 (142) nd nd nd nd nd nd nd nd nd nd nd nd G1 (150) 0.0 nd nd nd 0.0 nd nd 0.0 nd 38.0 d G2 (149) 0.0 nd nd nd 0.7 nd nd 0.7 nd 38.9 d G3 (147) 0.7 nd nd nd 0.0 nd nd 0.0 nd 49.0 d

23 Erococcus facium G1 (145) 0.0 nd nd nd 91.7 nd nd 95.2 nd 43.4 d G2 (142) 0.0 nd nd nd 93.0 nd nd 93.0 nd 37.3 d G3 (151) 0.0 nd nd nd 91.4 nd nd 94.7 nd 51.7 d Staphylococcus G1 (148) aurus (oxacillin- G2 (153) suscptibl, MSSA) G3 (147) Staphylococcus G1 (154) aurus (oxacillin- G2 (155) rsista, MRSA) G3 (153) Staphylococcus pidrmidis G1 (168) G2 (142) G3 (148) Staphylococcus hamolyticus G1 (73) G2 (66) G3 (102) Strptococcus agalactia Strptococcus pnumonia G1 (92) nd nd nd nd nd 0.0 nd G2 (76) nd nd nd nd nd 0.0 nd G3 (74) nd nd nd nd nd 0.0 nd G1 (58) nd nd nd nd nd G2 (70) nd nd nd nd nd G3 (64) nd nd nd nd nd

24 Strptococcus pyogns G1 (54) nd nd nd nd nd 0.0 nd G2 (63) nd nd nd nd nd 0.0 nd G3 (74) nd nd nd nd nd 0.0 nd a AMC, Amoxicillin-clavulanic acid; CAZ, cftazidim; CIP, ciprofloxacin; CTX, cfotaxim; CXM, cfuroxim; DOX, Doxycyclin; EPM, rtapnm; FEP, cfpim; GEN, gamicin; IPM, imipnm; LZD, linzolid; MXF, moxifloxacin; OXA, Oxacillin; PEN, Pnicillin G; TGC, Tigcyclin; TZP, pipracillin-tazobactam; and VAN, vancomycin; b nd, not dtrmind as no spcis-rlatd brakpoi has bn approvd by EUCAST; n, not valuatd bcaus only thos bactrial groups or spcis, of which mor than 50 strains wr collctd, wr analyzd;, not includd for tsting. c d Th prcag could not b dtrmind as th brakpoi is blow th lowst concration tstd. Rsults of Gamicin high-lvl tsting S rsults of oxacillin tsting 23

25 24

26 25

27 Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gramngativ organisms including multidrug-rsista pathogns in Grmany Europan Journal of Clinical Microbiology and Infctious Disass Michal Krskn, Karstn Bckr*, Harald Sifrt, Eva Litnr, Barbara Körbr-Irrgang, Christof von Eiff, Ptr-Andras Löschmann and Study Group *Corrsponding author: Karstn Bckr; Institut of Mdical Microbiology, Univrsity Hospital Münstr, Münstr, Grmany, Onlin Rsourc 1: In vitro activity of tigcyclin and comparativ ags against arobic Gram-ngativ bactria: rsults of G- TEST 1 (G1), G-TEST 2 (G2) and G-TEST 3 (G3) No. of MIC ( g/ml) Organism isolats Aibactrial ag 50% 90% % Suscptibl % Rsista G1 G2 G3 G1 G2 G3 G1 G2 G3 G1 G2 G3 G1 G2 G3 Aciobactr Tigcyclin baumannii group Doxycyclin <0.25 <0.25 < Amoxicillin-clavulanic acid >64 > Pipracillin-tazobactam 2 2 < >128 > Cfotaxim >64 >64 > Cftazidim >64 > Cfpim >64 > Imipnm < < Ertapnm >64 > Ciprofloxacin >16 >16 > Moxifloxacin <0.063 <0.063 < > Gamicin >32 > Erobactr Tigcyclin n.. n n.. n.. 2 n.. n n.. n.. 5.8

28 arogns Doxycyclin n.. n.. 2 n.. n Amoxicillin-clavulanic acid n.. n.. >64 n.. n.. > Pipracillin-tazobactam n.. n.. 2 n.. n.. 16 n.. n n.. n Cfotaxim n.. n.. <0.125 n.. n.. >32 n.. n n.. n Cftazidim n.. n n.. n.. 32 n.. n n.. n Cfpim n.. n.. <0.25 n.. n.. 1 n.. n n.. n Imipnm n.. n.. 1 n.. n.. 2 n.. n n.. n Ertapnm n.. n.. <0.25 n.. n n.. n n.. n Ciprofloxacin n.. n.. <0.063 n.. n.. 8 n.. n n.. n Moxifloxacin n.. n n.. n.. >16 n.. n n.. n Gamicin n.. n.. 1 n.. n.. 2 n.. n n.. n Erobactr Tigcyclin cloaca Doxycyclin Amoxicillin-clavulanic acid >64 >64 >64 >64 >64 > Pipracillin-tazobactam Cfotaxim >64 >64 > Cftazidim >64 >64 > Cfpim <0.25 <0.25 < Imipnm Ertapnm <0.25 <0.25 < Ciprofloxacin <0.063 <0.063 < Moxifloxacin <0.063 <0.063 < Gamicin Eschrichia coli Tigcyclin <0.125 < Doxycyclin > Amoxicillin-clavulanic acid Pipracillin-tazobactam Cfotaxim <0.25 <0.25 <0.125 <0.25 >64 >

29 Cftazidim <0.25 <0.25 < Cfpim <0.25 <0.25 < Imipnm < < < Ertapnm <0.25 <0.25 <0.25 <0.25 <0.25 < Ciprofloxacin <0.063 <0.063 <0.063 >16 >16 > Moxifloxacin <0.063 <0.063 <0.063 >16 >16 > Gamicin Hamophilus Tigcyclin 0.25 <0.125 < influnza Doxycyclin <0.25 <0.25 < Amoxicillin-clavulanic acid <0.25 <0.25 < Pipracillin-tazobactam <0.5 <0.5 <0.5 <0.5 <0.5 < Cfotaxim <0.25 <0.25 <0.125 <0.25 <0.25 < a - a a - a 0.4 Cftazidim <0.25 <0.25 <0.25 <0.25 <0.25 < Cfpim <0.25 <0.25 <0.25 <0.25 <0.25 < Imipnm Ertapnm <0.25 <0.25 <0.25 <0.25 <0.25 < Ciprofloxacin <0.063 <0.063 <0.063 <0.063 <0.063 < Moxifloxacin <0.063 <0.063 <0.063 <0.063 <0.063 < Gamicin Klbsilla oxytoca Tigcyclin Doxycyclin Amoxicillin-clavulanic acid Pipracillin-tazobactam >128 >128 > Cfotaxim <0.25 <0.25 < Cftazidim <0.25 <0.25 <0.25 0, Cfpim <0.25 <0.25 < Imipnm < < Ertapnm <0.25 <0.25 <0.25 <0.25 <0.25 <

30 Ciprofloxacin <0.063 <0.063 < Moxifloxacin < Gamicin Klbsilla Tigcyclin pnumonia Doxycyclin Amoxicillin-clavulanic acid Pipracillin-tazobactam Cfotaxim <0.25 <0.25 < > Cftazidim <0.25 <0.25 < Cfpim <0.25 <0.25 < Imipnm < < Ertapnm <0.25 <0.25 <0.25 <0.25 <0.25 < Ciprofloxacin <0.063 <0.063 < >16 > Moxifloxacin Gamicin Psudomonas Tigcyclin >32 >32 > aruginosa Doxycyclin >64 >64 > Amoxicillin-clavulanic acid >64 >64 >64 >64 >64 > Pipracillin-tazobactam > Cfotaxim >32 >64 >64 > Cftazidim Cfpim > Imipnm Ertapnm >64 >64 > Ciprofloxacin >16 4 > Moxifloxacin >16 >16 > Gamicin >32 4 > Srratia Tigcyclin

31 marcscns Doxycyclin Amoxicillin-clavulanic acid >64 >64 >64 >64 >64 > Pipracillin-tazobactam Cfotaxim < Cftazidim <0.25 < Cfpim <0.25 <0.25 < Imipnm Ertapnm <0.25 <0.25 < Ciprofloxacin <0.063 <0.063 < Moxifloxacin Gamicin Stnotrophomonas Tigcyclin maltophilia Doxycyclin Amoxicillin-clavulanic acid >64 >64 >64 >64 >64 > Pipracillin-tazobactam >128 >128 >128 >128 >128 > Cfotaxim >64 >64 >32 >64 >64 > Cftazidim >64 >64 >64 >64 >64 > Cfpim >64 >64 >64 >64 >64 > Imipnm >64 >64 >64 >64 >64 > Ertapnm >64 >64 >64 >64 >64 > Ciprofloxacin >16 8 > Moxifloxacin Gamicin >32 >32 >32 >32 >32 > , not dtrmind as no spcis-rlatd brakpoi has bn approvd by EUCAST; n.., not valuatd bcaus only thos bactrial groups or spcis, of which mor than 50 strains wr collctd, wr analyzd. a Th prcag could not b dtrmind as th brakpoi is blow th lowst concration tstd. 5

32 Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gramngativ organisms including multidrug-rsista pathogns in Grmany Europan Journal of Clinical Microbiology and Infctious Disass Michal Krskn, Karstn Bckr*, Harald Sifrt, Eva Litnr, Barbara Körbr-Irrgang, Christof von Eiff, Ptr-Andras Löschmann and Study Group *Corrsponding author: Karstn Bckr; Institut of Mdical Microbiology, Univrsity Hospital Münstr, Münstr, Grmany, Onlin Rsourc 2: In vitro activity of tigcyclin and comparativ ags against arobic Gram- positiv bactria: rsults of G- TEST 1 (G1), G-TEST 2 (G2) and G-TEST 3 (G3) Organism No. of isolats Aibactrial ag MIC (mg/l) % Suscptibl % Rsista 50% 90% G1 G2 G3 G1 G2 G3 G1 G2 G3 G1 G2 G3 G1 G2 G3 Erococcus Oxacillin >16 >16 >16 >16 >16 > facalis Tigcyclin <0.125 <0.125 <0.125 <0.125 <0.125 < Doxycyclin Pnicillin G >8 >8 > Amoxicillin-clavulanic acid Pipracillin-tazobactam Cfuroxim >64 >64 >64 >64 >64 > Imipnm Moxifloxacin >16 >16 > Linzolid Vancomycin Gamicin (high lvl) a Erococcus Oxacillin >16 >16 >16 >16 >16 > facium Tigcyclin <0.125 <0.125 <0.125 <0.125 <0.125 <

33 Staphylococcus aurus (oxacillinsuscptibl, MSSA) Staphylococcus aurus (oxacillinrsista, MRSA) Doxycyclin <0.25 <0.25 < Pnicillin G >8 >8 >8 >8 >8 > Amoxicillin-clavulanic acid >32 >32 >32 >32 >32 > Pipracillin-tazobactam >128 >128 >128 >128 >128 > Cfuroxim >64 >64 >64 >64 >64 > Imipnm >64 >64 >64 >64 >64 > Moxifloxacin >16 >16 >16 >16 >16 > Linzolid Vancomycin >32 > Gamicin (high lvl) a Oxacillin Tigcyclin <0.125 <0.125 <0.125 <0.125 < Doxycyclin <0.25 <0.25 <0.25 < < Pnicillin G >8 >8 > Amoxicillin-clavulanic acid s oxacillin Pipracillin-tazobactam <0.5 <0.5 < s oxacillin Cfuroxim s oxacillin Imipnm <0.25 <0.25 <0.25 < <0.25 s oxacillin Moxifloxacin <0.063 <0.063 < Linzolid Vancomycin Gamicin Oxacillin >16 >16 >16 >16 >16 > Tigcyclin < Doxycyclin <0.25 <0.25 < < Pnicillin G >8 >8 >8 >8 >8 >8 s oxacillin Amoxicillin-clavulanic acid 16 >32 16 >32 >32 >32 s oxacillin Pipracillin-tazobactam >128 >128 >128 s oxacillin 2

34 Staphylococcus pidrmidis Staphylococcus hamolyticus Cfuroxim >64 >64 >64 >64 >64 >64 s oxacillin Imipnm >64 32 >64 s oxacillin Moxifloxacin Linzolid Vancomycin Gamicin > Oxacillin >16 >16 >16 >16 >16 > Tigcyclin Doxycyclin Pnicillin G >8 4 >8 >8 >8 > Amoxicillin-clavulanic acid s oxacillin Pipracillin-tazobactam s oxacillin Cfuroxim >64 >64 >64 s oxacillin Imipnm s oxacillin Moxifloxacin Linzolid Vancomycin Gamicin >32 >32 > Oxacillin >16 >16 >16 >16 >16 > Tigcyclin Doxycyclin Pnicillin G >8 >8 >8 >8 >8 > Amoxicillin-clavulanic acid >32 >32 >32 s oxacillin Pipracillin-tazobactam >128 >128 >128 s oxacillin Cfuroxim >64 >64 >64 >64 >64 >64 s oxacillin Imipnm >64 >64 >64 s oxacillin Moxifloxacin Linzolid

35 Strptococcus agalactia Strptococcus pnumonia Strptococcus pyogns Vancomycin Gamicin > >32 >32 > Oxacillin < Tigcyclin <0.125 <0.125 <0.125 <0.125 <0.125 < Doxycyclin Pnicillin G Amoxicillin-clavulanic acid <0.125 <0.125 <0.125 <0.125 <0.125 < Pipracillin-tazobactam <0.5 <0.5 <0.5 <0.5 <0.5 < Cfuroxim <0.25 <0.25 <0.25 <0.25 <0.25 < Imipnm <0.25 <0.25 <0.25 <0.25 <0.25 < Moxifloxacin Linzolid Vancomycin Gamicin Oxacillin <0.125 <0.125 < < Tigcyclin <0.125 <0.125 <0.125 <0.125 <0.125 < Doxycyclin <0.25 <0.25 < Pnicillin G <0.031 <0.031 < Amoxicillin-clavulanic acid <0.125 <0.125 <0.125 < < Pipracillin-tazobactam <0.5 <0.5 <0.5 <0.5 <0.5 < Cfuroxim <0.25 <0.25 <0.25 < Imipnm <0.25 <0.25 <0.25 < < Moxifloxacin Linzolid Vancomycin < Gamicin Oxacillin <0.125 <0.125 <0.125 <0.125 <0.125 < Tigcyclin <0.125 <0.125 <0.125 <0.125 <0.125 <

36 Doxycyclin <0.25 <0.25 < Pnicillin G <0.031 <0.031 <0.031 < < Amoxicillin-clavulanic acid <0.125 <0.125 <0.125 <0.125 <0.125 < Pipracillin-tazobactam <0.5 <0.5 <0.5 <0.5 <0.5 < Cfuroxim <0.25 <0.25 <0.25 <0.25 <0.25 < Imipnm <0.25 <0.25 <0.25 <0.25 <0.25 < Moxifloxacin Linzolid Vancomycin Gamicin , not dtrmind as no spcis-rlatd brakpoi has bn approvd by EUCAST a MIC >500 µg/ml 5

37 Rsistanc trnds and in vitro activity of tigcyclin and 17 othr aimicrobial ags against Gram-positiv and Gramngativ organisms including multidrug-rsista pathogns in Grmany Europan Journal of Clinical Microbiology and Infctious Disass Michal Krskn, Karstn Bckr*, Harald Sifrt, Eva Litnr, Barbara Körbr-Irrgang, Christof von Eiff, Ptr-Andras Löschmann and Study Group *Corrsponding author: Karstn Bckr; Institut of Mdical Microbiology, Univrsity Hospital Münstr, Münstr, Grmany, Onlin Rsourc 3: In vitro activitis of tigcyclin and comparators against Gram-ngativ non-mdr- and MDR strains Organism No. of isolats tstd Aibactrial ag MIC (mg/l) % suscptibl % rsista non-mdr MDR 50% 90% non- MDR non- MDR non- MDR non- MDR MDR MDR MDR MDR A. baumannii Imipnmsuscptiblnonsuscptibl Imipnm- Tigcyclin n.d. n.d. n.d. n.d. group Doxycyclin n.d. n.d. n.d. n.d. (356) (35) Amoxicillin-clavulanic acid n.d. n.d. n.d. n.d. Pipracillin-tazobactam n.d. n.d. n.d. n.d. Cfotaxim n.d. n.d. n.d. n.d. Cftazidim n.d. n.d. n.d. n.d. Cfpim n.d. n.d. n.d. n.d. Imipnm Ertapnm n.d. n.d. n.d. n.d. Ciprofloxacin Moxifloxacin n.d. n.d. n.d. n.d. Gamicin E. cloaca Cfotaximsuscptiblnonsuscptibl Cfotaxim- Tigcyclin Doxycyclin n.d. n.d. n.d. n.d.