Open access Protocol BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. Impact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia (IRONIC study): study protocol of a retrospective multicentre international study Adaia Albasanz-Puig,1,2 Carlota Gudiol, 1,2 Rocío Parody,3 Cristian Tebe,4 Murat Akova,5 Rafael Araos,6 Anna Bote,7 Anne-Sophie Brunel,8 Sebnem Calik,9 Lubos Drgona,10 Estefanía García,11 Philipp Hemmati,12 Fabián Herrera,13 Karim Yaqub Ibrahim,14 Burcu Isler,15 Souha Kanj,16 Winfried Kern,17 Guillermo Maestro de la Calle,18 Adriana Manzur,19 Jorge Iván Marin,20,21 Ignacio Márquez-Gómez,22 Pilar Martín-Dávila,23 Malgorzata Mikulska,24 José Miguel Montejo,2,25 Milagros Montero,2,26 Hugo Manuel Paz Morales,27 Isabel Morales,2,28 Andrés Novo,29 Chiara Oltolini,30 Maddalena Peghin,31 Jose Luis del Pozo,32 Pedro Puerta-Alcalde,2,33 Isabel Ruiz-Camps,2,34 Oguz Resat Sipahi,35 Robert Tilley,36 Lucrecia Yáñez,37 Marisa Zenaide Ribeiro Gomes,38,39 Jordi Carratalà,1,2 for the IRONIC study group Protected by copyright. To cite: Albasanz-Puig A, Abstract Gudiol C, Parody R, et al. Impact Strengths and limitations of this study Introduction Pseudomonas aeruginosa (PA) has of antibiotic resistance on historically been one of the major causes of severe sepsis outcomes of neutropenic cancer ►► The multicentre design of the study will allow the and death among neutropenic cancer patients. There has recording of a large number of episodes. patients with Pseudomonas aeruginosa bacteraemia been a recent increase of multidrug-resistant PA (MDRPA) ►► The international and multicentre design will provide (IRONIC study): study protocol isolates that may determine a worse prognosis, particularly representative results regarding the current epide- of a retrospective multicentre in immunosuppressed patients. The aim of this study is miology of Pseudomonas aeruginosa bacteraemia in international study. BMJ Open to establish the impact of antibiotic resistance on the onco-haematological patients worldwide. 2019;9:e025744. doi:10.1136/ outcome of neutropenic onco-haematological patients with ►► Information will be provided on risk factors for resis- bmjopen-2018-025744 PA bacteraemia, and to identify the risk factors for MDRPA tance acquisition and their impact on mortality in the ►► Prepublication history and bacteraemia and mortality. current era of multidrug resistance. additional material for this Methods and analysis This is a retrospective, ►► Due to the retrospective design some information paper are available online. To observational, multicentre, international study. All episodes may be lost. view these files, please visit of PA bacteraemia occurring in neutropenic onco- ►► We may not be able to control for certain measured the journal online (http://​dx.​doi.​ org/​10.​1136/​bmjopen-​2018-​ haematological patients followed up at the participating and unmeasured confounders. 025744). centres from 1 January 2006 to 31 May 2018 will be retrospectively reviewed. The primary end point will be overall case-fatality rate within 30 days of onset of PA Received 29 August 2018 bacteraemia. The secondary end points will be to describe comply with the Spanish Data Protection Act of 1998 and Revised 5 March 2019 the following: the incidence and risk factors for multidrug- with the European Directive on the privacy of data. All Accepted 28 March 2019 data collected, stored and processed will be anonymised. resistant and extremely drug-resistant PA bacteraemia (by comparing the episodes due to susceptible PA with Results will be reported at conferences and in peer- reviewed publications. © Author(s) (or their those produced by MDRPA), the efficacy of ceftolozane/ employer(s)) 2019. Re-use tazobactam, the rates of persistent bacteraemia and permitted under CC BY-NC. No bacteraemia relapse and the risk factors for very early commercial re-use. See rights (48 hours), early (7 days) and overall (30 days) case-fatality Introduction and permissions. Published by rates. During the last 10 years the aetiology of blood- BMJ. stream infections (BSI) among neutropenic Ethics and dissemination The Clinical Research Ethics For numbered affiliations see Committee of Bellvitge University Hospital approved cancer patients has significantly changed. end of article. Several studies have shown an increase of BSI the protocol of the study at the primary site. To protect Correspondence to personal privacy, identifying information of each patient in caused by Gram-negative bacilli that may be Dr Carlota Gudiol; the electronic database will be encrypted. The processing explained by the use of reduced-intensive ​cgudiol@​iconcologia.n​ et of the patients’ personal data collected in the study will chemotherapy regimens, associated to less Albasanz-Puig A, et al. BMJ Open 2019;9:e025744. doi:10.1136/bmjopen-2018-025744 1 Open access BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. severe mucositis, and by the discontinuation of quinolone Methods and analysis prophylaxis in some institutions.1 2 Study design Pseudomonas aeruginosa (PA) has historically been one This is an international, multicentre, retrospective, of the major causes of severe sepsis and death among observational cohort study involving neutropenic cancer neutropenic cancer patients. BSIs due to multidrug-re- patients diagnosed with PA bacteraemia followed up at sistant PA (MDRPA) and multidrug-resistant Enterobacte- any of the participating centres during the study period. riaceae are increasing worldwide and are both associated The study will be conducted in accordance with the with poorer outcomes, particularly in immunocompro- STrengthening the Reporting of OBservational studies in mised patients.3–5 Epidemiology (STROBE) recommendations (see research There is limited published data describing the char- checklist).9 acteristics of PA infections in patients with cancer in Study population this era of widespread antimicrobial resistance.5–7 More- Data will be collected on all-adult (≥18 years) onco-hae- over, data regarding BSIs in neutropenic patients with matological neutropenic patients diagnosed with at least solid tumours are particularly scarce.8 In addition, very one episode of PA bacteraemia during the study period. little is known about the impact of the introduction of the new broad-spectrum beta-lactam plus beta-lact- Study period amase inhibitor combinations (such as ceftolozane/ Participating centres will retrospectively review all tazobactam) in the therapeutic armamentarium for the episodes of PA bacteraemia occurring in neutropenic treatment of BSI due to MDRPA in neutropenic cancer onco-haematological patients from 1 January 2006 to patients. 31 May 2018. Identifying the risk factors for infection due to MDRPA Setting in neutropenic cancer patients could help physicians to The study will be conducted at 34 centres from 12 different recognise patients at risk more rapidly. Therefore, the countries: Spain (14), Turkey (4), Brazil (3), Italy (3), early administration of a broader empirical antibiotic Argentina (2), Germany (2), Chile (1), Colombia (1), therapy in these high-risk patients might have a positive Lebanon (1), Slovakia (1), Switzerland (1) and UK (1). influence on their outcomes. In the present international Protected by copyright. study, we aim to determine the impact of antibiotic resis- Selection of cases tance on outcomes in neutropenic cancer patients with PA Patients will be identified from previous retrospective and bacteraemia in the current era of widespread antimicro- prospective databases or from the records of the microbi- bial resistance, and also to identify predisposing factors ology laboratory at each hospital. for multidrug resistance and mortality. For this purpose, Inclusion criteria we will compare episodes due to susceptible PA with those 1. Adult patients (≥18 years). produced by MDRPA, and we will compare patients who 2. Patients diagnosed with a haematological malignancy died with those who survived. and/or haematopoietic stem cell transplant recipients, or with solid organ tumour. 3. The presence of neutropenia (<500 neutrophils/mm3) at the bacteraemia onset. Objectives of the study 4. Episodes of monomicrobial PA bacteraemia or poly- Primary objective microbial bacteraemia in which PA is one of the eti- ►► To determine the impact of antibiotic resistance on ological agents, including community, healthcare and outcomes in neutropenic cancer patients with PA nosocomial infections. bacteraemia, measured by all-cause case-fatality rate 5. Subsequent episodes of PA bacteraemia diagnosed in at 30 days. a patient may be included if the interval between them Secondary objectives is 30 days. ►► To assess the prevalence of multidrug and extremely Exclusion criteria drug resistance (XDR) among PA isolates causing Patients with any of the following will be excluded from bacteraemia. the study: ►► To identify the risk factors for infection due to multi- 1. Unavailability of key data (empirical and targeted ther- drug-resistant (MDR) and XDR PA. apy and vital status at 30 days). ►► To assess the efficacy of the new beta-lactam ceftolo- 2. Episodes occurring in non-neutropenic cancer pa- zane/tazobactam for the treatment of bacteraemia tients. due to PA. 3. Episodes occurring outside the study period. ►► To estimate the cumulative incidence rates of persis- 4. Age<18 years old. tent bacteraemia, bacteraemia relapse and other complications at 30 days. Data collection ►► To identify the risk factors for very early (48 hours), Patients’ data will be collected retrospectively. These data early (7 days) and all-cause (30 days) case-fatality rates. will be obtained from various sources, including patients’ 2 Albasanz-Puig A, et al. BMJ Open 2019;9:e025744. doi:10.1136/bmjopen-2018-025744 Open access BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. electronic records, patients’ notes, the hospital laboratory agent in all but two or fewer of the antimicrobial catego- systems and the hospital patient administration system. ries listed earlier. PDR PA: the isolate is non-susceptible to The following data will be collected for all cases: sex, all antimicrobial agents listed earlier. age, type of underlying disease and comorbidities, under- lying malignancy status, severity of the episode of febrile Participant timeline neutropenia according to the Multinational Association The follow-up period will last 1 month after bacteraemia of Supportive Care in Cancer (MASCC) index score,10 onset. place of acquisition of infection,11 source of bacteraemia, bacteraemia source control status, clinical and microbi- Study outcomes and endpoint assessment ological data, total duration of neutropenia (including Primary endpoint days of neutropenia before and after BSI onset), prior ►► Case-fatality rate at 30 days from onset of bacteraemia. therapies received (including antibiotics and immuno- Secondary endpoints suppressive treatments), empirical and definitive anti- ►► 48 hours and 7-day case-fatality rates from onset of microbial therapy, doses and duration of each antibiotic bacteraemia. therapy, need for intensive care unit admission and ►► Prevalence and risk factors for multidrug and mechanical ventilation, persistent bacteraemia, relapse extremely drug resistance acquisition of bacteraemia, colonisation and/or superinfection by ►► Efficacy of ceftolozane/tazobactam for the treatment resistant organisms, development of other complications, of bacteraemia due to PA, measured by all-cause 48 hours, 7-day and 30-day case-fatality rates. (30 days) case-fatality rate. ►► Rate of persistent bacteraemia beyond the first Patient and public involvement 48 hours of adequate antibiotic therapy. Patients and public will not be involved in the design or ►► Rate of bacteraemia relapse within 14 days of treat- development of the study. ment discontinuation. ►► Rate of other complications within 30 days from bacte- Definitions raemia onset (eg, ICU admission). Empirical antibiotic therapy: Antimicrobial therapy ad- Protected by copyright. ministered before reception of definitive antibiotic Sample size susceptibility results. The total number of episodes of PA bacteraemia in the Definitive antibiotic therapy: antimicrobial therapy ad- participating centres during the study period will deter- ministered according to definitive antibiotic suscepti- mine the sample size. According to the previous experi- bility results. ence of each participating centre, we expect to record Adequate antibiotic therapy: therapy based on at least one around 1000 episodes during the study period, allowing in vitro active antibiotic against the PA strain causing the estimation of 95% CIs with a 3% margin of error. the infection. Monotherapy with an active aminoglyco- side will be considered adequate. Statistical analysis Persistent bacteraemia: persistent BSI beyond the first Baseline characteristics of participants will be described 48 hours of adequate antibiotic therapy. using mean and SD for continuous variables and frequen- Bacteraemia relapse: relapse of BSI within 7 days of treat- cies for categorical variables. Cumulative incidence rate ment discontinuation. will be calculated as the number of events divided by participants at risk at bacteraemia onset. The 95% CI Microbiological studies will be estimated using normal approximation for large Clinical samples are processed at the microbiology labo- incidence values (above 10%) and Poisson approxima- ratories of each participating centre in accordance with tion for small ones. A set of demographic and clinical standard operating procedures. PA will be identified using factors will be analysed to quantify their association with standard microbiological techniques at each centre. In the following outcomes: 30-day mortality, MDR and XDR. vitro susceptibility is determined according to the Euro- To do so, a logistic regression model will be used, and pean Committee on Antimicrobial Susceptibility Testing OR with CIs will be presented. Patients’ mortality survival (EUCAST) recommendations.12 The specific mechanisms functions will be estimated using Kaplan-Meier curves of resistance will be provided when possible, according to and compared using the log-rank test. Moreover, survival molecular analyses. Phenotype stratification of PA isolates functions will also be analysed at 7, 14 and 30 days. No is made in accordance with recent standard definitions.13 missing data are expected regarding the main outcomes, MDRPA: the isolate is non-susceptible to at least one agent since unavailability of related data is an exclusion crite- in three or more of the following antimicrobial catego- rion. With sensitivity purposes, the main analyses will be ries: aminoglycosides, antipseudomonal carbapenems, replicated in patients with high-risk bacteraemia, such antipseudomonal fluoroquinolones, antipseudomonal as those with pneumonia. Model assumptions, condi- cephalosporins, antipseudomonal penicillins+beta lact- tions and residuals will be assessed. A p value<0.05 will amase-inhibitors, monobactams, fosfomycin, polymyxins. be considered statistically significant. The analysis will be XDR PA: the isolate is non-susceptible to at least one performed using R software (R V.3.2.5). Albasanz-Puig A, et al. BMJ Open 2019;9:e025744. doi:10.1136/bmjopen-2018-025744 3 Open access BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. Ethical issues First, most of the studies have a retrospective and single- The study has been approved by the Comité Ético de Inves- centre design.5 6 14 20 21 Only three prospective studies tigación Clínica del Hospital Universitari de Bellvitge (Insti- have addressed this issue and all have a small sample tutional Review Board of Clinical Research, Bellvitge size; in addition, the fact they were conducted more than University Hospital). A list with the participating centres 7 years ago does not allow the extrapolation of the data to that obtained the approval by their institutional review the current era of multidrug resistance.5 6 16 In addition, board, and the centres that did not need the approval the few studies with a multicentre design have included is provided in the online Supplementary file 1. To only centres from the same country, and therefore, the protect personal privacy, identifying information of each results may not be representative of different geograph- patient in the electronic database will be encrypted. The ical areas.3 7 Second, some studies include a diverse processing of the patients’ personal data collected in this variety of infections due to PA, and only a few focus exclu- study shall comply with the Data Protection Act 1998 and sively on patients with PA bacteraemia.5 7 14 20 Third, only with the European Directive on the privacy of data. All two recent studies describe the current risk factors for data collected, stored and processed will be anonymised. MDR-PA acquisition and for mortality in this high-risk The investigator/research lead at each site will guar- population.7 20 However, one of these studies is a retro- antee that all team members or other persons involved spective, single-centre Korean study involving only paedi- at the site in question will respect the confidentiality of atric patients,20 and the other is a retrospective, 3-centre any information concerning the study patients. The Clin- study limited to the city of Athens.7 ical Research Ethics Committee has waived the need for The published data comparing the efficacy of combined informed consent due to the retrospective nature of the empirical antibiotic treatment including two active study. antipseudomonal agents versus monotherapy in patients with febrile neutropenia are controversial. The aim of empirical combination therapy is to provide extend- Publication plan Results will be reported at conferences and in peer-re- ed-spectrum coverage against MDR organisms in high-risk viewed publications. The first publication will be based patients, since a delayed initiation of adequate antibiotic Protected by copyright. on data from all sites, and will be analysed as stipulated in treatment has been associated with poorer outcomes, the protocol with supervision by statisticians. Any formal particularly in patients with PA bacteraemia.5 7 20 21 presentation or publication of data collected from this However, an important meta-analysis published in 2013 study will be considered as a joint publication by the was unable to show any advantage of combination anti- participating investigators and will follow the recom- biotic treatment in cancer patients with neutropenia.22 mendations of the International Committee of Medical Nonetheless, in a recently published report, Tofas et al Journal Editors. found a trend towards improved survival with combina- tion therapy in this setting.7 Clearly, more studies are needed to analyse whether combination therapy could be Discussion beneficial in the current era of multidrug resistance. In recent years, a trend towards an increase of Gram-neg- Clinical experience with the use of new broad-spec- ative BSI among neutropenic cancer patients has been trum beta-lactams to treat MDR-PA infections, such as reported.1 Neutropenic patients with onco-haematolog- ceftolozane/tazobactam, is gradually accumulating in the ical malignancies are considered a population at high general population. However, little is known about its use risk for MDR bacterial infections because of their need for the treatment of MDR-PA bacteraemia in neutropenic for long hospitalisation and significant antibiotic pres- cancer patients. sure.14 In this regard, recent studies have described an The present study aims to identify the current impact alarming increase in the incidence of bacteraemia due of the antibiotic resistance on outcomes in neutropenic to extended-spectrum beta-lactamase-producing and patients with PA bacteraemia, and to determine the risk carbapenem-resistant Enterobacteriaceae among neutro- factors associated with multidrug resistance and mortality. penic cancer patients, which may substantially impair We will also assess the efficacy of new broad-spectrum patients’ outcomes.2 15 16 beta-lactams against MDR-PA strains, since alternative Classically, PA has been one of the leading causes of treatments are urgently needed in this vulnerable popula- bacteraemia in neutropenic patients with haematological tion. This study shall provide useful information for physi- malignancies and solid tumours, and is associated with cians’ daily clinical practice, who need to rapidly identify poor prognosis.8 17–19 In recent years, particular attention patients at high risk for MDR-PA bacteraemia, to be able has been paid to the emergence of MDR Enterobacteriaceae, to promptly initiate effective antimicrobial therapy and and data on the current epidemiology of PA bacteraemia improve patients’ outcomes. and the impact of antibiotic resistance in this high-risk population are lacking. The existing literature is based Author affiliations on heterogeneous studies some of which present meth- 1 Infectious Diseases Department, Bellvitge University Hospital, IDIBELL, University of odological shortcomings.5–7 14 20 21 Barcelona, Spain 4 Albasanz-Puig A, et al. BMJ Open 2019;9:e025744. doi:10.1136/bmjopen-2018-025744 Open access BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. 2 37 Spanish Network for Research in Infectious Diseases (REIPI), Instituto de Salud Haematology Department, Marques de Valdecilla University Hospital, Santander, Carlos III, Madrid, Spain Spain 3 38 Haematology Department, Institut Català d' Oncologia (ICO)-Hospital Duran i Instituto Oswaldo Cruz, Fundaçao Oswaldo Cruz, Rio de Janeiro, Brazil 39 Reynals, IDIBELL, Barcelona, Spain Hospital Federal Servidores do Estado, Ministerio da Saúde, Rio de Janeiro, Brazil 4 Statistics Advisory Service, Institute of Biomedical Research of Bellvitge, Rovira i Virgili University, Barcelona, Spain Acknowledgements We thank the European Study Group for Bloodstream 5 Infectious Diseases Department, Hacettepe University School of Medicine, Ankara, Infections, Endocarditis and Sepsis (ESGBIS) and the European Study Group for Turkey Infections in Compromised Hosts (ESGICH) for supporting the study. We thank 6 Infectious Diseases Department, Instituto de Ciencias e Innovación en Medicina, CERCA (Institució Centres de Recerca de Catalunya) Programme/Generalitat de Facultad de Medicina, Clínica Alemana, Universidad del Desarrollo, Santiago de Catalunya for institutional support. Chile, Chile Collaborators IRONIC STUDY INVESTIGATORS Guillermo Cuervo and Francesc 7 Infectious Diseases Department, Parc Taulí University Hospital, Sabadell, Barcelona, Escrihuela-Vidal, Infectious Diseases Department, and Fe Tubau, Department of Spain Microbiology, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. Marisol 8 Infectious Diseases Department, Department of Medicine, Lausanne University Rodríguez Arias, Department of Oncology, Institut Català d’Oncologia (ICO) - Hospital Hospital (CHUV), Lausanne, Switzerland Duran i Reynals, IDIBELL, Barcelona, Spain. Caglayan Merve Ayaz, Department 9 of Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey. Department of Infectious Diseases and Clinical Microbiology, University of Health Science Izmir Bozyaka Training and Research Hospital, Izmir, Turkey Jose Munita, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, 10 Oncohematology Department, Comenius University and National Cancer Institute, Clínica Alemana Universidad del Desarrollo, Santiago de Chile, Chile. Oriol Gasch, Bratislava, Slovakia Department of Infectious Diseases. Sílvia Capilla, Department of Microbiology, 11 Haematology Department, Reina Sofía University Hospital-IMIBIC-UCO, Córdoba, Parc Taulí University Hospital, Sabadell, Barcelona, Spain. Pierre-Yves Bochud and Oriol Manuel, Department of Infectious Diseases, Lausanne University Hospital Spain 12 (CHUV), Lausanne, Switzerland. Julián Torre-Cisneros, Salvador Tabares and Department of Haematology, Oncology and Palliative Care, Klinikum Ernst von Josefina Serrano López, Infectious Diseases Department, Reina-Sofía University Bergmann, Academic Teaching Hospital of Charité University Medical School, Berlin, Hospital IMIBIC-UCO, Córdoba. Georg Maschmeyer, Department of Haematology, Germany Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic Teaching 13 Infectious Diseases Section, Department of Medicine, Centro de Educación Hospital of Charité University Medical School, Berlin, Germany. Diego Torres, Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina Infectious Diseases Section, Department of Medicine, Centro de Educación Médica 14 Instituto do Câncer do Estado de São Paulo, Faculdade de Medicina da e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina. Edson Abdala and Universidade de São Paulo, Brazil Driele Peixoto Bittencourt, Instituto do Cancer do Estado de Sao Paulo, Faculdade 15 Department of Infectious Diseases and Clinical Microbiology, Istanbul Education de Medicina da Universidade de Sao Paulo, Brazil. Saeed El Zein and Jean-Francois and Research Hospital, Istanbul, Turkey Jabbour, Infectious Diseases Division, Ameritimacan University of Beirut Medical Protected by copyright. 16 Infectious Diseases Division, American University of Beirut Medical Center, Beirut, Center, Beirut, Lebanon. Hartmut Bertz, Department of Haematology-Oncology, Lebanon and Gabriele Peyerl-Hoffmann, Department of Medicine II, Division of Infectious 17 Division of Infectious Diseases, Department of Medicine II, University of Freiburg, Diseases, University of Freiburg Medical Center and Faculty of Medicine, Freiburg, Medical Center and Faculty of Medicine, Freiburg, Germany Germany. Manuel Lizasoain and José María Aguado, Infectious Diseases Unit, 18 Infectious Diseases Unit, Instituto de Investigación Hospital "12 de Octubre" 12 de Octubre University Hospital, Madrid Spain. Lina Clemencia Correa, Clinica (i+12), " 12 de Octubre" University Hospital, School of Medicine, Universidad Maraya, Pereira, Colombia. Begoña Palop, Department of Microbiology, Hospital Regional de Málaga, Málaga, Spain. Jesús Fortún, Department of Infectious Complutense, Madrid, Spain 19 Diseases, Ramón y Cajal Hospital, Madrid, Spain. Laura Magnasco, Division of Infectious Diseases, Hospital Rawson, San Juan, Argentina 20 Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Infectious Diseases and Clinical Microbiology Department, Clínica Maraya, Pereira, Martino, Genova, Italy. Roberto Céspedes, Department of Haematology, and Leire Colombia López-Soria, Department of Microbiology, Cruces University Hospital, Bilbao, Spain. 21 Critical Care and Clinical Microbiology Department, Universidad de Manizales, Juan Pablo Horcajada, Infectious Diseases Service, Hospital del Mar, Infectious Manizales, Colombia Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar 22 Infectious Diseases Department, Hospital Regional Universitario de Málaga, d’Investigations Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), Málaga, Spain CEXS-Universitat Pompeu Fabra, Barcelona, Spain. Mia Hold Montaguti, Department 23 Infectious Diseases Department, Ramon y Cajal Hospital, Madrid, Spain of Infectious Diseases, Hospital Erasto Gaertner, Curitiba, Brazil. Marina de Cueto 24 Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale and Jesús Rodríguez-Baño, Clinical Unit of Infectious Diseases, Microbiology and Policlinico San Martino, Genova, Italy Preventive Medicine, University Hospitals Virgen Macarena - IBiS; Department of 25 Infectious Diseases Unit, Cruces University Hospital, Bilbao, Spain Medicine, University of Seville, Seville, Spain. Raffaella Greco, Haematology and 26 Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Bone Marrow Transplantation Unit, and Paola Cichero, Microbiology and Virology Antimicrobials Research Group (IPAR), Institut Hospital del Mar d'Investigacions Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy. Matteo Bassetti and Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Nadia Castaldo, Infectious Diseases Clinic, Department of Medicine, University of Pompeu Fabra, Barcelona, Spain Udine and Azienda Sanitaria Universitaria Integrata, Udine, Italy. Paloma Sangro 27 del Alcázar, Department of Internal Medicine, Navarra University Clinic, Pamplona, Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil 28 Spain. Celia Cardozo and Carolina Garcia-Vidal, Department of Infectious Diseases, Emergency Clinical Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain 29 Hospital Clínic i Provincial, Barcelona, Spain. Juan Aguilar-Company, Department of Haematology Department, Son Espases University Hospital, Palma de Mallorca, Oncology, and Nieves Larrosa, Department of Microbiology, Vall d’Hebron University Spain Hospital, Barcelona, Spain. Ayse Uyan-Onal, Department of Infectious Diseases 30 Unit of Infectious and Tropical Diseases, IRCCS San Raffaele Scientific Institute, and Clinical Microbiology, Ege University Faculty of Medicine, Izmir Turkey. Arzu Milan, Italy Nazli-Zeka, Department of Infectious Diseases and Clinical Microbiology, Dokuz 31 Infectious Diseases Clinic, Department of Medicine, University of Udine and Eylul University Faculty of Medicine, Izmir Turkey. Wania Vasconcelos de Freitas and Azienda Sanitaria Universitaria Integrata, Udine, Italy Amanda Aparecida da Silva Machado, Hospital Federal dos Servidores do Estado, 32 Infectious Diseases and Microbiology Unit, Navarra University Clinic, Pamplona, Ministério da Saúde, Rio de Janeiro, Brazil. Spain Contributor All authors were involved in the study concept. AA-P, CG, RP and JC 33 Infectious Diseases Department, Hospital Clinic i Provincial de Barcelona, were involved in the design of the study. CT was responsible for the elaboration of Barcelona, Spain the statistical analysis plan. DT was responsible for the elaboration of the online 34 Infectious Diseases Department, Vall d'Hebron University Hospital, Barcelona, database. AA-P, MA, RA, AB, A-SB, SC, LD, EG, PH, FH, K-YI, BI, SK, WK, GMa-Ca, AM, Spain JIM, IM-G, PM-D, MMi, MMo, HMPM, IM, AN, CO, MP, JLDP, PP-A, IR-C, ORS, RT, LY, 35 Faculty of Medicine, Ege University, Izmir, Turkey MZRG, GC, FE-V, MRA, CMA, JM, OG, P-YB, OM, SEZ, J-FJ, HB, GP-H, ML, JMA, BP, 36 Microbiology Department, University Hospitals Plymouth NHS Trust, UK JF, GM, LM, RC, LL-S, JPH, MHM, MC, JR-B, RG, PC, MB, NC, PSA, CC, CG-V, JA-C, Albasanz-Puig A, et al. BMJ Open 2019;9:e025744. doi:10.1136/bmjopen-2018-025744 5 Open access BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from http://bmjopen.bmj.com/ on February 17, 2021 at Univesity Autonomous of Barcelona. NL, AU-O, AN-Z, LCC, WVF and AASM were responsible for the data collection and 8. Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients introduction in the online database. FTu was responsible for the microbiological with solid tumors. Virulence 2016;7:298–308. supervision of the study. AA-P, CG, CT and JC drafted and revised the manuscript. 9. Von Elm E, Altman DG, Egger M, et al. The strengthening the All authors reviewed and approved the final version of the manuscript. reporting of observational studies in epidemiology (strobe) statement: Guidelines for reporting observational studies. Lancet Funding This study was supported by Plan Nacional de I+D+i 2013‐2016 2007;370:1453–7. and Instituto de Salud Carlos III, Subdirección General de Redes y Centros de 10. Klastersky J, Paesmans M, Rubenstein EB, et al. The multinational Investigación Cooperativa, Ministerio de Economía, Industria y Competitividad, association for supportive care in cancer risk index: A multinational Spanish Network for Research in Infectious Diseases (REIPI RD16/0016/0001) and scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 2000;18:3038–51. co-financed by European Development Regional Fund “A way to achieve Europe”, 11. Friedman ND, Kaye KS, Stout JE, et al. Health care–associated Operative Programme Intelligent Growth 2014‐2020. bloodstream infections in adults: a reason to change the accepted Competing interests A-SB received grant from Promex Stiftung fur die Forschung definition of community-acquired infections. Ann Intern Med (by Carigest SA), and funding by Gilead to assist to the ECCMID Congress (2018). 2002;137:791–7. 12. The European Committee on Antimicrobial Susceptibility Testing. ORS received speaker’s honorarium from MSD, Astellas, Novartis and Pfizer. 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