Systematic literature review of the burden and outcomes of infections due to multidrug-resistant organisms in Europe: the ABOUT-MDRO project protocol

1 Anaya- BazB, e al. BMJ Open 2020;10:e030608. doi:10.1136/bmjopen-2019-030608 Open access Sys ema ic li e a u e e iew o he bu den and ou comes o in ec ions due o mul id ug- esis an o ganisms in Eu ope: he ABOUT- MDRO p ojec p o ocol Blanca Anaya- Baz,1 Na alia Maldonado,1 Zai a R Palacios- Baena ,1 Vi ginia Palomo,1 Ma ia Dile a Pezzani,2 Sheila Chiesi ,2 Elisa Razzaboni,2 Monica Comp i,2 E elina Tacconelli,2 Jesús Rod iguez- Baño1 To ci e: Anaya- BazB, MaldonadoN, Palacios- BaenaZR, e al. Sys ema ic li e a u e e iew o he bu den and ou comes o in ec ions due o mul id ug- esis an o ganisms in Eu ope: he ABOUT- MDRO p ojec p o ocol. BMJ Open 2020;10:e030608. doi:10.1136/ bmjopen-2019-030608 ►P epublica ion his o y and addi ional ma e ial o his pape a e a ailable online. To iew hese iles, please isi he jou nal online (h p:// dx. doi. o g/ 10. 1136/ bmjopen- 2019- 030608). Recei ed 25 Ma ch 2019 Re ised 25 Sep embe 2019 Accep ed 03 Ma ch 2020 Fo numbe ed a ilia ions see end o a icle. Co espondence o D Jesús Rod iguez- Baño; jesus b@ us. es P o ocol © Au ho (s) (o hei employe (s)) 2020. Re- use pe mi ed unde CC BY- NC. No comme cial e- use. See igh s and pe missions. Published by BMJ. S eng hs and limi a ions o his s udy. ►Da a syn hesis will in ol e collec ion and summa y o a ailable da a on a es and ou come es ima ions o di e en ypes o in ec ions caused by p io i ised an ibio ic- esis an pa hogens, o e all and o spe- ci ic pa ien popula ions and geog aphical a eas in Eu ope. ►P e ious da abases o in ec ions and pa hogens su eillance iden i ied by sys ema ic e iews om EPI- ne (h ps://epi-ne .eu/) such as Su eillance Sys ems om Public Heal h Ins i u ions and Scien i ic Socie ies o An imic obial Resis ance and Heal hca e- Associa ed In ec ions in Eu ope (doi: 10.1016/j.cmi.2017.07.014) will be a ailable. ►Da a om sou ces o in o ma ion no publicly a ail- able will be missed. Also, a ailable da a a e ex- pec ed o be sca ce o some in ec ions. Howe e , he s udy will also be use ul o iden i y he gaps in in o ma ion. ►De ini ions o ou comes and me hodology o ollow- up o pa ien s may be he e ogeneous ac oss s udies. AbS AC In oduc ion Despi e he inc easing impo ance o in ec ions due o mul id ug- esis an o ganisms (MDROs), he e is a lack o comp ehensi e in o ma ion abou he bu den o disease and ou comes o key in ec ions caused by hese pa hogens. The aim o he ABOUT- MDRO (A sys ema ic e iew on he bu den and ou comes o in ec ions due o mul id ug esi an o ganisms) p ojec is o p o ide es ima ions o he bu den o some key in ec ions and hei ou comes caused by he a ge MDROs. Me hods and analysis A sys ema ic li e a u e sea ch will be pe o med using MEDLINE/PubMed, Else ie ’s SCOPUS, Coch ane lib a y, Clinical ials and Web o Science, as well as he Su eillance Sys ems om Public Heal h Ins i u ions and Scien i ic Socie ies o An imic obial Resis ance and Heal hca e- Associa ed In ec ions in Eu ope da abase o Eu opean su eillance sys ems, o da a on p e alence/ incidence, mo ali y and leng h o s ay o a ge in ec ions in hospi alised pa ien s (including en ila o - associa ed pneumonia, hospi al- acqui ed pneumonia, complica ed in a- abdominal in ec ions, complica ed u ina y ac in ec ions, skin and so issue in ec ions and bloods eam in ec ions) and in speci ic popula ions (child en, hospi al wa ds, neu openic pa ien s) caused by cephalospo in- esis an o ca bapenem- esis an En e obac e iaceae, ca bapenem- esis an Pseudomonas ae uginosa and Acine obac e spp., me hicillin- esis an S aphylococcus au eus, and ancomycin- esis an En e ococcus spp. The in o ma ion e ie ed will be abula ed and pooled es ima es and 95% CIs calcula ed o a es and ou comes, using andom e ec s models. Rela ionships be ween a es and ou comes in andomised con ol ials and epidemiological s udies, and da a o p opo ions and incidence/p e alence a es will also be analysed. The in o ma ion collec ed in his s udy will be use ul o iden i ying gaps in ou knowledge in e ms o incidence/ p e alence and clinical ou comes o in ec ions caused by MDROs, and o in o ming p io i ies in in ec ion con ol and he esea ch and design o app op ia e s udies. E hics and dissemina ion This s udy will be based on published da a so we did no equi e e hical app o al. Fo mal consen is no equi ed. The esul s o his e iew will be epo ed acco ding o he P e e ed Repo ing I ems o Sys ema ic Re iewand Me a- Analyses s a emen . Da a will be p esen ed a in e na ional con e ences and published in pee - e iewed jou nals. egis a ion de ails PROSPERO (h ps://www. c d. yo k. ac. uk/ p ospe o/) (CRD42019124185). In oduC Ion The wo ldwide sp ead o o ganisms ha a e esis an o mul iple an ibio ics, gene ally e e ed o as mul id ug- esis an o gan- isms (MDRO), has become a public heal h conce n.1 2 The WHO ecen ly es ablished a p io i y lis o mic oo ganisms o in o m esea ch p io i ies o he de elopmen o new an ibio ics, wi h ca bapenem- esis an copy igh . on May 19, 2023 a USE/Fac Medicina Biblio eca FME. P o ec ed byh p://bmjopen.bmj.com/BMJ Open: i s published as 10.1136/bmjopen-2019-030608 on 5 May 2020. Downloaded om 2Anaya- BazB, e al. BMJ Open 2020;10:e030608. doi:10.1136/bmjopen-2019-030608 Open access Acine obac e baumannii (CRAB) and Pseudomonas ae ugi- nosa, hi d- gene a ion o ca bapenem- esis an En e o- bac e iaceae, ancomycin- esis an En e ococcus spp. and me hicillin- esis an S aphylococcus au eus conside ed c i - ical and o high p io i y.3 The e is also an u gen need o imp o emen s in su eillance o help op imise empi ical he apy, d i e an imic obial s ewa dship and in ec ion con ol measu es, and help in he a ional use o old and new d ugs agains esis an o ganisms.4 The main sou ces o in o ma ion on a es o in ec ion caused by MDROs come om egional, na ional o in e - na ional su eillance sys ems, published epidemiological s udies and ou b eak epo s. Two da abases de eloped in he con ex o EPI- NET (epidemiologic Eu opean ne wo k)/Comba ing Bac e ial Resis ance in Eu ope - Molecules agains G am- nega i e In ec ions conso ium iden i ied ele an sou ces o in o ma ion: he SUSPIRE S udy (Su eillance Sys ems om Public Heal h Ins i u- ions and Scien i ic Socie ies o An imic obial Resis ance and Heal hca e- Associa ed In ec ions in Eu ope) ecen ly mapped all su eillance sys ems wi h publicly a ailable da a in Eu ope and showed ha , despi e ecen imp o e- men s and s udies which con ol and s udy his issue, he a ailable da a s ill emain o be excessi ely he e ogeneous and sca ce o gene a e an exhaus i e co ela ion and compa ison wi h publicly a ailable su eillance sys ems in o ma ion ac oss Eu ope.5 Addi ionally, published ou b eak epo s we e mapped by he EMBARGO (EpideMiology and con ol measu es o ou B eaks due o An ibio ic- Resis an o Ganisms in Eu Ope) S udy.6 While equen use is made o da a om su eillance sys ems and s udies p o iding p opo ions o isola es wi h esis- ance o speci ic an imic obials, comp ehensi e da a on pa hogen incidence a es and in ec ions a e e y limi ed. This is impo an because da a based on p opo ion o esis an isola es can be misleading i no adequa ely in e p e ed; o gi e an example, i hospi al A ound wo ca bapenem- esis an A. baumannii ou o 4 isola es o his pa hogen in 1 yea , while hospi al B, despi e ha ing a simila numbe o admissions, ound 20/40, in bo h cases, he p opo ion is 50%, bu he bu den o in ec- ion caused by ca bapenem- esis an A. baumannii is e y di e en . Fu he mo e, he clinical bu den a ies acco ding o he p edominan in ec ion ype o popula- ion a ec ed. To ha e such da a a ailable would be o c i - ical impo ance o in o ming he public, as well as policy make s, hospi al manage s, esea ch unding bodies and companies wo king on he de elopmen o diagnos ic and he apeu ic ools o p io i y esea ch and in ec ion con ol ac i i ies. The clinical impac o MDRO in ec ions is usually measu ed using c ude mo ali y and leng h o o e all hospi al s ay. The s udies a emp ing o es ima e he a ibu able in luence o an imic obial esis ance on he ou come o pa ien s a e he e ogeneous in he popu- la ions included and in he me hodology.7–11 O e all, in iew o he da a p o ided, he main esea ch ques ion is: Wha is he bu den o in ec ions and esis- ance caused by MDROs o e all and o speci ic ypes o in ec ions, mic oo ganisms and pa ien s in he di e en coun ies/geog aphical a eas/hospi als in Eu ope, and which is he clinical bu den due o ca bapenem- esis an Klebsiella pneumoniae, CRAB and ancomycin- esis an En e ococci (VRE)? The majo aim o he ABOUT- MDRO p ojec (a sys em- a ic e iew on he bu den and ou comes o in ec ions due o MDRO) is o es ima e he bu den o key in ec ions and hei ou comes caused by a ge MDROs. ME hodS/dESIgn design A sys ema ic e iew o he scien i ic and g ey li e a u e will be pe o med. The a ge MDROs o his s udy a e ca bapenem- esis an Acine obac e spp and P. ae ugi- nosa; cephalospo in- esis an o ca bapenem- esis an En e obac e iaceae; ancomycin- esis an En e ococcus spp., and me hicillin- esis an S. au eus. The a ge in ec ions include en ila o - associa ed pneumonia and hospi al- acqui ed pneumonia, complica ed in a- abdominal in ec ions, complica ed u ina y ac in ec ions, compli- ca ed skin and skin s uc u e in ec ions, and bloods eam in ec ions. Eligibili y c i e ia S udies will be conside ed o inclusion i p o iding any o he ollowing, o he a ge in ec ions caused by he a ge MDROs occu ing in hospi alised pa ien s: incidence a e, incidence densi y, p e alence, all- cause mo ali y o leng h o s ay. S udies no p o iding he es i- ma ions bu o which he nume a o s and denomina o s o hei calcula ion is a ailable will also be included. All o he eligibili y c i e ia a e shown in box 1. S udies om sys ema ic e iews will only be included i he da a om he indi idual s udies included in hem a e no a ailable. In o ma ion sou ces This sys ema ic e iew ollowed he P e e ed Repo ing I ems o Sys ema ic Re iewand Me a- Analysis P o ocols guidelines scheme (online supplemen a y igu e S1) and checklis (online supplemen a y able S1) o me hod- ology de elopmen and s uc u e esea ch. The ollowing elec onic da abases will be sea ched: MEDLINE- PubMed, Coch ane lib a y, SCOPUS and Web o Science. The upda ed su eillance sys ems da abases o an imic obial- esis an pa hogens and hospi al- acqui ed in ec ions om he SUSPIRE p ojec 5 and EPI- NET (h ps:// epi- ne . eu/) will also be sea ched. Sea ch s a egy A comp ehensi e sea ch s a egy will be pe o med o pee - e iewed li e a u e, wi h no language es ic ions. The sea ch s a egy will be pe o med using MeSH (Medical Subjec Headings) e ms and No- MeSH e ms, selec ed a e pilo ing di e en sea ch s a egies. Finally, and acco ding o he pilo ing, No- MeSH sea ch e ms copy igh . on May 19, 2023 a USE/Fac Medicina Biblio eca FME. P o ec ed byh p://bmjopen.bmj.com/BMJ Open: i s published as 10.1136/bmjopen-2019-030608 on 5 May 2020. Downloaded om 3 Anaya- BazB, e al. BMJ Open 2020;10:e030608. doi:10.1136/bmjopen-2019-030608 Open access box 1 Inclusion c i e ia ►S udy designs: sys ema ic e iews, andomised con olled ials, non- con olled ials, quasi- expe imen al s udies, coho s udies, case- con ol s udies, ou b eak epo s, c oss- sec ional s udies and su eillance epo s. ►S udies p o iding da a on any o he a ge ed pa ho- gens: cephalospo in- esis an o ca bapenem- esis an En e obac e iaceae, ca bapenem- esis an Pseudomonas ae ugino- sa, ca bapenem- esis an Acine obac e spp., ancomycin- esis an En e ococcus spp., me hicillin- esis an S aphylococcus au eus. ►S udies p o iding in o ma ion on any o he a ge ed in ec ions: hospi al- acqui ed pneumonia, en ila o - associa ed pneumonia, complica ed in a- abdominal in ec ions, complica ed u ina y ac in ec ions o bloods eam in ec ions. ►Fo da a on he bu den o in ec ions: s udies p o iding es ima es o da a on he equency o a ge ed in ec ions caused by MDROs, including a leas one o he ollowing: p e alence, incidence a e o cumula i e incidence, incidence densi y, pe cen age o esis an isola es. ►Fo da a on ou comes o in ec ions: s udies p o iding da a on ou - comes o a ge ed in ec ions caused by MDROs, including a leas one o he ollowing: mo ali y a es, leng h o s ay. ►Time pe iod and geog aphical scope: Janua y 2005 h ough Decembe 2018, Eu opean coun ies acco ding o he ESCMID (Eu opean Socie y o Clinical Mic obiology and In ec ious Diseases) de ini ion o geog aphical egions (h ps://www.escmid.o g/ ile- admin/s c/media/PDFs/5P o ession_Ca ee /Pa i y_Commission/ ESCMID_De ini ion_o _Geog aphic_Regions_140703.pd ). ►No age o language es ic ions. box 2 Keywo d combina ions o sea ch s a egy. Pa hogens and esis ance e ms ►Ta ge G am nega i es: ‘mul id ug- esis an ’ o ‘MDR’ o ‘ex ensi ely- d ug esis an ’ o ‘XDR’ o ‘cephalospo in- esis ance’ o ‘ex ended- spec um be a- lac amase’ o ‘ESBL’ o ‘CTX- M’ o ‘SHV’ o ‘TEM’ o ‘AmpC’ o ‘imipenem- esis an ’ o ‘me openem- esis an ’ o e apenem- esis an ’ o ‘ca bapenemase’ o ‘KPC’ o ‘me allo- be a- lac amase’ o ‘NDM’ o ‘VIM’ o ‘IMP’ o ‘oxacil- linase’ o ‘OXA-48’ o ‘OXA-48- like’ o ‘CRE’ o ‘CPE’ o ‘po in loss’ AND ‘En e obac e ia’ o ‘En e obac e iaceae’ o ‘Klebsiella’ o ‘coli’ o ‘P o eus’ o ‘Mo ganella’ o ‘Ci obac e ’ o ‘Se a ia’ o ‘En e obac e ’ o ‘Pseudomonas’ o ‘Acine obac e ’ ►Ta ge G am posi i es: ‘mul id ug- esis an ’ o ‘MDR’ o ‘ex ensi e- ly d ug- esis an ’ o ‘XDR’ o ‘me hicillin- esis an ’ o ‘me icillin- esis an ’ o ‘oxacillin- esis an ’ o ‘ ancomycin- esis an ’ o ‘MRSA’ o ‘VRE’ AND ‘S aphylococcus au eus’ o ‘En e ococcus’ o ‘en e ococci’ And in ec ion ype e ms ►‘bac e emia’ o ‘bloods eam in ec ion’ ►‘heal hca e- associa ed pneumonia’ o ‘ en ila o - associa ed pneu- monia’ o ‘hospi al- acqui ed pneumonia’ o ‘pneumonia’ o ‘ espi a- o y in ec ions’ o ‘cys ic ib osis’ o ‘b onchiec asis’ ►‘u ina y ac in ec ions’ o ‘UTI’ o ‘cys i is’ o ‘pyeloneph i is’ o ‘ca he e - associa ed u ina y ac in ec ions’ ►‘in a- abdominal in ec ion’ o ‘pe i oni is’ o ‘cholangi is’ o ‘chole- cys i is’ o ‘appendici is’ o ‘in a- abdominal abscess’ o ‘IAI’ ►‘SSSI’ o ‘skin and skin s uc u es in ec ions’ o ‘su gical si e in ec- ions’ o ‘celluli is’ o ‘skin and so issue in ec ions’ And bu den o ou come ►Fo bu den o in ec ions: ‘p e alence’ o ‘incidence’ o ‘ a e’ o ‘pe - cen age o esis ance’ o ‘p opo ion o esis ance’ ►Fo ou comes o in ec ions: ‘leng h o s ay’ o ‘mo ali y’ o ‘dea h a e’ o ‘ a ali y’ o ‘su i al a e’ o ‘dea h’ o ‘dead’ o ‘died’ ha e been de eloped o his s udy using a combina ion o keywo ds (lis ed in box 2). da a managemen , selec ion p ocess and da a collec ion p ocess A wo- s ep selec ion p ocedu e will be ollowed o he selec ion o s udies. A single e iewe will sc een he i les and abs ac s o s udies e ie ed du ing he sea ch s a egy o disca d ineligible s udies (eg, case epo s, case se ies, basic science s udies). The ull- ex esul s o po en ially eligible documen s will be uploaded o Zo e o so wa e; duplica es will be emo ed. Two e iewe s will assess hese o ele ance agains he p ede ined selec- ion c i e ia. The e e ence lis o iden i ied a icles will be sea ched o po en ial addi ional s udies. The da a will be ex ac ed independen ly by wo e iewe s using a s anda dised elec onic da a ex ac ion o m, o be p e iously pilo es ed on a ep esen a i e sample. Disag eemen s will be esol ed by a hi d e iewe . Da a ex ac ion om a 10% andom sample o included a icles will be checked by a hi d e iewe . da a i ems: p ima y end poin s and o he a iables The main end poin s o collec will be: (1) Fo bu den o in ec ions, incidence a e o densi y o in ec ions (de ined as he numbe o new cases o in ec ion pe 100 hospi alised pa ien s and/o 1000 pa ien - days occu ing in a speci ic ime pe iod, espec i ely) and p e alence (de ined as he p opo ion o exis ing cases o in ec ion pe 100 pa ien s admi ed a a pa icula ime poin ). (2) Fo clinical ou comes, c ude and in ec ion- a ibu able mo ali y, and leng h o hospi al s ay (o e all and in in en- si e ca e uni s). Mo ali y will be collec ed as de ined in each s udy, bu he p ima y in en ion is o analyse in- hos- pi al, 14- day, 30- day and 90- day mo ali ies. Also, leng h o s ay will be collec ed as de ined in he s udies. Da a on he p opo ion o esis an pa hogens causing he in ec- ions will also be collec ed i a ailable. We will calcula e he end poin s e en i no di ec ly p o ided in he a icles, p o ided he nume a o s and denomina o s a e a ailable. O he da a o be collec ed a e shown in able 1; o hese, we will ely on he de ini ions used in he s udies bu will p o ide desc ip i e in o ma ion abou he de ini ions. Quali y assessmen The quali y o he da a e ie ed will be e alua ed by wo e iewe s using he ollowing c i e ia: (1) The isk o selec ion bias (low, medium, high) o measu ing bu den o disease, in e ms o abili y o de ec cases and ep esen- a i eness o speci ic popula ions. (2) The isk o in o - ma ion bias (low, medium, high) based on de ini ion o case, in ec ion ype and mic obiological assessmen . (3) The quali y o andomised con ol ials will be measu ed copy igh . on May 19, 2023 a USE/Fac Medicina Biblio eca FME. P o ec ed byh p://bmjopen.bmj.com/BMJ Open: i s published as 10.1136/bmjopen-2019-030608 on 5 May 2020. Downloaded om 4Anaya- BazB, e al. BMJ Open 2020;10:e030608. doi:10.1136/bmjopen-2019-030608 Open access Table 1 Va iables o be collec ed om included s udies Co e elemen Va iable S udy, si e, ime Fi s au ho , i le, coun y, yea (s) Scope* One hospi al, mul icen e, egion, coun y Design* Su eillance; andomised ial; coho ; case- con ol Popula ion* Age: all/child en/adul s Wa d: all hospi al wa d, speci ic wa ds (ICU, e c) Speci ic unde lying condi ions: neu openia, dialysis, and so on In ec ions* HAP/VAP, cUTI, cIAI, cSSSI, BSI (including sou ce) Mic oo ganism(s)* Gen e and species, pheno ypical esis ance, mechanism(s) o esis ance (i a ailable) Epidemiological si ua ion* Ou b eak, endemic si ua ion End poin a iables† Bu den: P e alence, cumula i e incidence, incidence densi y, p opo ion o esis an isola es Clinical ou comes: all- cause mo ali y, in ec ion- ela ed mo ali y, leng h o hospi al s ay Mo ali y de ini ions* In- hospi al, ix- day *As de ined in he a icles. †De ini ions in he ex . . BSI, bloods eam in ec ion; cIAI, complica ed in a- abdominal in ec ion; cSSSI, complica ed skin and skin s uc u e in ec ion; cUTI, complica ed u ina y ac in ec ion; HAP, hospi al- acqui ed pneumonia; ICU, in ensi e ca e uni ; VAP, en ila o - associa ed pneumonia. using he E ec i e P ac ice and O ganisa ion o Ca e Scale, and he quali y o non- andomised con olled ials wi h he Newcas le- O awa Scale. da a syn hesis and analysis The collec ed da a will be summa ised in abula o m, indica ing he co e cha ac e is ics o su eillance sys ems and s udies. Fo each pa hogen and ype o in ec ion, es ima es o a es and ou comes will be p o ided; s a - i ica ion by geog aphical a ea, ime pe iod, popula ion, epidemiological si ua ion will be pe o med i possible. Pooled es ima es o a es and ou comes wi h 95% CIs will be p o ided; me a- analyses will be pe o med i possible wi h R s a is ical so wa e (V.3.0.2; R Founda ion o S a is ical Compu ing, Vienna, Aus ia). The I2 s a is ic will be used o measu e he he e ogenei y o es ima es be ween s udies, bu because he e ogenei y is expec ed, andom- e ec s models will be used. Co ela ions be ween a es and ou comes in andomised con olled ials and epidemiological s udies, and da a on p opo ions and incidence a es will also be analysed. In addi ion, a desc ip ion o de ini ions o he key a iables used in he di e en s udies will be p o ided. Pa ien and public in ol emen isk o bias Pa ien s o public we e no in ol ed in he sys ema ic e iew design. dISCuSSIon Despi e he epidemiological and clinical impo ance o in ec ions caused by MDROs, comp ehensi e da a abou hei bu dens and ou comes a e la gely missing. Mos in o ma ion seems o come om single- cen e s udies in he con ex o ou b eaks, o om su eillance da a lacking pa ien - de i ed denomina o s. Assessing he bu den o he speci ic ypes o in ec- ion caused by hese o ganisms is c i ically impo an in o de o iden i y p io i ies o in ec ion con ol ac i i- ies and esea ch. Unde s anding he geog aphical and popula ion- ype a iabili y o he a es is also key o he design o clinical s udies o e alua e he e icacy and sa e y o new o old an imic obial d ugs. Se e al ecen s udies ha e es ima ed he bu den o in ec ion and mo ali y caused by mul id ug- esis an pa hogens.7 12 Ne e heless, he es ima es a e based on limi ed and no necessa ily eliable da a, as has been unde lined.13 14 The he e oge- nei y o popula ions and he in luence o mul iple highly in e connec ed a iables (in ec ion ypes, como bidi- ies, se e i y o illness, app op ia eness o he apy, e c), as well as s udy design and analysis me hods mean ha he e alua ion o mo ali y a ibu able o esis ance is highly a iable.8–11 Sou ce o da a o a es o in ec ions due o MDRO may be di icul o ind. Da a in he scien- i ic li e a u e may be limi ed because o publica ion bias, a ou ing epo ing o ou b eaks o da a om uni e si y hospi als; he e o e, we will also sea ch he publicly a ail- able da a om su eillance sys ems p e iously iden i ied by he SUSPIRE p ojec . Finally, as a as we know, he e a e no sys ema ic e iews linking incidence a es wi h ou come o in ec ion. We expec some di icul ies in ou s udy and acknowl- edge some limi a ions. The da a o some pa hogens and in ec ions may be sca ce and some imes based on special epidemiological si ua ions; we would y o s a i y he da a acco ding o he epidemiological si ua ions bu his may be di icul . The s udies and su eillance sys ems may also be he e ogeneous in he popula ion s udies, designs and quali y. Howe e , iden i ying gaps in knowledge will also be impo an o u u e s udies. De ini ions o ou comes, and me hods o assessing hem may be he e ogeneous. copy igh . on May 19, 2023 a USE/Fac Medicina Biblio eca FME. P o ec ed byh p://bmjopen.bmj.com/BMJ Open: i s published as 10.1136/bmjopen-2019-030608 on 5 May 2020. Downloaded om 5 Anaya- BazB, e al. BMJ Open 2020;10:e030608. doi:10.1136/bmjopen-2019-030608 Open access We will also p o ide desc ip i e da a abou his which may be use ul o u u e s udies. In summa y, he aim o he ABOUT- MDRO p ojec is o p o ide pooled es ima es o a ge MDRO bu dens and ou comes ha a e as speci ic as possible o di e en se ings and popula ions as a ool o help policy make s and esea che s es ablish p io i ies and design be e s udies o use in he igh agains an imic obial esis- ance. The s udy will also summa ise g ey li e a u e da a in o de o assess he clinical bu den o MDRO in ec ions a he Eu opean le el. These esul s will also be in o ma- i e o he e icien design o andomised clinical ials. Au ho a ilia ions 1Unidad Clínica de En e medades In ecciosas, Mic obiología y Medicina P e en i a, Hospi al Uni e si a io Vi gen Maca ena / Depa amen o de Medicina, Uni e sidad de Se illa / Ins i u o de Biomedicina de Se illa (IBiS), Se illa, Spain 2Di isione di Mala ie In e i e, Dipa imen o di Diagnos ica e Sani à Pubblica, Ospedale Policlinico Bo go Roma, Ve ona, I aly Con ibu o s JR- B and ET concei ed he s udy. JR- B led he de elopmen o he p o ocol, p o ided supe ision and men o ship o BA- B who w o e he i s d a , and de eloped pa o he sea ch s a egy, and coo dina ed and in eg a ed ideas and commen s om ZRP- B, NM and VP. The o he coau ho s MDP, SC, ER, MC de eloped he clinical ou comes pa o he s udy p o ocol. All he au ho s con ibu ed o he selec ion o a iables and he es o he p o ocol sec ions. Funding The ABOUT- MDRO S udy is pa o he COMBACTE- MAGNET p ojec (Comba ing Bac e ial Resis ance in Eu ope - Molecules agains G am- nega i e In ec ions), Inno a i e Medicines Ini ia i e (IMI), Eu opean Union's Se en h F amewo k P og amme (FP7/2007-2013) and EFPIA companies’ in- kind con ibu ion, G an ag eemen 115737. ZRP- B and JR- B ecei ed unding o esea ch om Plan Nacional de I+D+i 2013‐2016 and he Ins i u o de Salud Ca los III, Subdi ección Gene al de Redes y Cen os de In es igación Coope a i a, Minis e io de Economía, Indus ia y Compe i i idad, Spanish Ne wo k o Resea ch in In ec ious Diseases (REIPI RD16/0016/0001), co- inanced by he Eu opean De elopmen Regional Fund 'A way o achie e Eu ope', Ope a i e P og amme In elligen G ow h 2014‐2020. Compe ing in e es s ZRP- B ecei ed hono a ia o educa ional alks by Gilead. JR- B ecei ed hono a ia o acc edi ed educa ional ac i i ies unded by Me ck h ough un es ic ed g an s. All o he au ho s decla e ha hey ha e no con lic s o in e es . Pa ien and public in ol emen Pa ien s and/o he public we e no in ol ed in he design, o conduc , o epo ing, o dissemina ion plans o his esea ch. Pa ien consen o publica ion No equi ed. P o enance and pee e iew No commissioned; ex e nally pee e iewed. da a a ailabili y s a emen The e a e no da a in his wo k. open access This is an open access a icle dis ibu ed in acco dance wi h he C ea i e Commons A ibu ion Non Comme cial (CC BY- NC 4.0) license, which pe mi s o he s o dis ibu e, emix, adap , build upon his wo k non- comme cially, and license hei de i a i e wo ks on di e en e ms, p o ided he o iginal wo k is p ope ly ci ed, app op ia e c edi is gi en, any changes made indica ed, and he use is non- comme cial. See:h p:// c ea i ecommons. o g/ licenses/ by- nc/ 4. 0/. o CId ids Zai a RPalacios- Baena h p:// o cid. o g/ 0000- 0002- 1713- 6807 SheilaChiesi h p:// o cid. o g/ 0000- 0002- 0108- 0722 EFE EnCES 1 Eu opean Commission. Ac ion plan agains he ising h ea s om an imic obial esis ance. In: Communica ion om he Commission o he Eu opean Pa liamen and he Council. 15. B ussels, 2011. 2 The bac e ial challenge: ime o eac . ECDC/EMEA join echnical epo . EMEA Doc. Re . EMEA/576176/2009. S ockholm, Sep embe 2009.ISBN 978-92-9193-193-4. A ailable: h ps:// ecdc. eu opa. eu/ si es/ po al/ iles/ media/ en/ publica ions/ Publica ions/ 0909_ TER_ The_ Bac e ial_ Challenge_ Time_ o_ Reac . pd [Accessed Ma ch 2019]. 3 Tacconelli E, Ca a a E, Sa oldi A, e al. Disco e y, esea ch, and de elopmen o new an ibio ics: he who p io i y lis o an ibio ic- esis an bac e ia and ube culosis. Lance In ec Dis 2018;18:318–27. 4 Tacconelli E, Si akis F, Ha ba h S, e al. Su eillance o con ol o an imic obial esis ance. Lance In ec Dis 2018;18:e99–106. 5 Núñez- Núñez M, Na a o MD, Palomo V, e al. 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Will 10 million people die a yea due o an imic obial esis ance by 2050? PLoS Med 2016;13:e1002184. 14 Tacconelli E, Pezzani MD. Public heal h bu den o an imic obial esis ance in Eu ope. Lance In ec Dis 2019;19:4–6. copy igh . on May 19, 2023 a USE/Fac Medicina Biblio eca FME. P o ec ed byh p://bmjopen.bmj.com/BMJ Open: i s published as 10.1136/bmjopen-2019-030608 on 5 May 2020. Downloaded om