View
0
Download
0
Category
Preview:
Citation preview
BMJ Open is committed to open peer review. As part of this commitment we make the peer review history of every article we publish publicly available. When an article is published we post the peer reviewers’ comments and the authors’ responses online. We also post the versions of the paper that were used during peer review. These are the versions that the peer review comments apply to. The versions of the paper that follow are the versions that were submitted during the peer review process. They are not the versions of record or the final published versions. They should not be cited or distributed as the published version of this manuscript. BMJ Open is an open access journal and the full, final, typeset and author-corrected version of record of the manuscript is available on our site with no access controls, subscription charges or pay-per-view fees (http://bmjopen.bmj.com). If you have any questions on BMJ Open’s open peer review process please email
info.bmjopen@bmj.com
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
Impact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia
(IRONIC study)
Journal: BMJ Open
Manuscript ID bmjopen-2018-025744
Article Type: Protocol
Date Submitted by the Author: 29-Aug-2018
Complete List of Authors: Albasanz-Puig, Adaia; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI) Gudiol, Carlota; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI) Parody, Rocío; Institut Catala d' Oncologia, Haematology Department Tebe, Cristian; Institut d\'Investigacio Biomedica de Bellvitge, Statistics Advisory Service Akova, Murat; Hacettepe Universitesi Araos, Rafael; Universidad del Desarrollo Facultad de Medicina Bote, Anna; Consorcio Corporacion Sanitaria Parc Tauli, Infectious Diseases Brunnel, Anne-Sophie; Centre Hospitalier Universitaire Vaudois, Infectious Diseases Calik, Sebnem; Izmir Bozyaka Egitim ve Arastirma Hastanesi, Infectious Diseases Department Drgona, Lubos; Univerzita Komenskeho v Bratislave, Oncohematology Department García, Estefanía; Hospital Universitario Reina Sofia, Oncohematology Department Hemmati, Philipp; Klinikum Ernst von Bergmann, Haematology Department Herrera, Fabián; Centro de Educación Médica e Investigaciones Clínicas, Infectious Diseases Department Ibrahim, Karim Yaqub; Universidade de Sao Paulo Faculdade de Medicina Isler, Burcu; Istanbul Fizik Tedavi Rehabilitasyon Egitim ve Arastirma Hastanesi, Infectious Diseases Department Kanj, Souha; American University of Beirut Medical Center, Internal Medicine-Division of Infectious Diseases Kern, Winfried; Universite de Fribourg Departement de medecine, Infectious Diseases Department Maestro-de la Calle, Guillermo; Hospital Universitario 12 de Octubre, Infectious Diseases Unit Manzur, Adriana; Hospital Rawson, Infectious Diseases Department Marin, Jorge Iván; Clínica Maraya, Infectious Diseases Department Márquez-Gómez, Ignacio; Hospital Regional Universitario de Malaga, Infectious Diseases Department Martín-Dávila, Pilar; Hospital Universitario Ramon y Cajal, Infectious Diseases Department Mikulska, Malgorzata; Ospedale Policlinico San Martino, Infectious Diseases Department
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on January 13, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2018-025744 on 24 M
ay 2019. Dow
nloaded from
For peer review only
Montejo, José Miguel; Hospital Universitario Cruces, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI) Montero, Milagros; Institut Hospital del Mar d'Investigacions Mediques, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI) Morales, Hugo Manuel Paz; Hospital Erasto Gaertner, Infectious Diseases Department Morales, Isabel; Hospital Universitario Virgen Macarena, Emergency Clinical Unit; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI) Novo, Andrés; Hospital Universitari Son Espases, Haematology Department Oltolini, Chiara; Ospedale San Raffaele, Infectious and Tropical Diseases Department Peghin, Maddalena; Hospital Santa Maria Misericordia, Infectious Diseases Del Pozo, Jose Luis; Clinica Universitaria de Navarra, Infectious Diseases And Microbiology Department Puerta-Alcalde, Pedro; Hospital Clinic de Barcelona, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI) Ruiz-Camps, Isabel; Hospital Vall d'Hebron, Infectious Diseases Department; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI) Sipahi, Oguz Resat; Ege Universitesi Tip Fakultesi Tilley, Robert; University Hospital Plymouth NHS Trust, Mircobiology Department Yáñez, Lucrecia; Hospital Universitario Marques de Valdecilla, Haematology Department Ribeiro Gomes, Marisa Zenaide; Hospital Federal Servidores do Estado, Ministério da Saúde and Instituto Oswaldo Cruz Carratala, Jordi; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)
Keywords: Pseudomonas aeruginosa, Onco-Haematological Patients, Bacteraemia, Bloodstream Infection, Neutropenia, Multidrug-Resistant
Page 1 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
Impact of antibiotic resistance on outcomes of neutropenic cancer patients with 1
Pseudomonas aeruginosa bacteraemia (IRONIC study) 2
3
Authors: Albasanz-Puig ADAIA1,37, Gudiol CARLOTA1,37, Parody ROCÍO2, Tebe CRISTIAN3, 4
Akova MURAT4, Araos RAFAEL5, Boté ANNA6, Brunel ANNE-SOPHIE7, Calik SEBNEM8, 5
Drgona LUBOS9, García ESTEFANÍA10, Hemmatti PHILIPP11, Herrera FABIÁN12, Ibrahim 6
KARIM-YAQUB13, Isler BURCU14, Kanj SHARARAH SOUHA15, Kern WINFRIED16, Maestro-7
de la Calle GUILLERMO17, Manzur ADRIANA18, Marin JORGE IVÁN19, Márquez-Gómez 8
IGNACIO20, Martín-Dávila PILAR21, Mikulska MALGORZATA22, Montejo MIGUEL23,37, 9
Montero MILAGROS24,37, Morales HUGO MANUEL PAZ25, Morales ISABEL26,37 Novo 10
ANDRÉS27, Oltolini CHIARA28, Peghin MADDALENA29, del Pozo JOSE LUIS30, Puerta-11
Alcalde PEDRO31,37, Ruiz-Camps ISABEL32,37, Sipahi OGUZ RESAT33, Tilley ROBERT34, 12
Yáñez LUCRECIA35, Gomes MARISA ZENAIDE RIBEIRO36, and Carratalà JORDI1,37 for the 13
IRONIC study group*. 14
15
Affiliations: 1Infectious Diseases Department, Bellvitge University Hospital, IDIBELL, 16
University of Barcelona, Spain. 2Haematology Department, Institut Català d’Oncologia 17
(ICO) – Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. 3Statistics Advisory Service, 18
Institute of Biomedical Research of Bellvitge, Rovira i Virgili University. 4Department of 19
Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey. 5Instituto 20
de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana 21
Universidad del Desarrollo, Santiago de Chile, Chile. 6Infectious Diseases Department, 22
Parc Taulí University Hospital, Sabadell, Barcelona, Spain. 7Infectious Diseases 23
Department, Department of Medicine, Lausanne University Hospital, (CHUV), 24
Page 2 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
2
Lausanne, Switzerland. 8University of Health Science Izmir Bozyaka Training and 25
Research Hospital, Turkey. 9Oncohematology Department, Comenius University and 26
National Cancer Institute, Bratislava, Slovakia. 10Salvador Tabares Carrasco and 27
Josefina Serrano López, Haematology Department, Reina Sofía University Hospital-28
IMIBIC-UCO, Córdoba. 11Department of Hematology, Oncology and Palliative Care, 29
Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University 30
Medical School, Berlin, Germany. 12Infectious Diseases Section, Department of 31
Medicine, Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos 32
Aires, Argentina. 13Instituto do Câncer do Estado de São Paulo, Faculty of Medicine, 33
Univesity of São Paulo, Brazil 14Department of Infectious Diseases and Clinical 34
Microbiology, Istanbul Education and Research Hospital, Istanbul, Turkey.15Infectious 35
Diseases Division, American University of Beirut Medical Center, Beirut, 36
Lebanon.16Division of Infectious Diseases, Department of Medicine II, University of 37
Freiburg Medical Center and Faculty of Medicine, Freiburg, Germany. 17Infectious 38
Diseases Unit, Instituto de Investigación Hospital “12 de Octubre” (i+12), “12 de 39
Octubre” University Hospital, School of Medicine, Universidad Complutense, Madrid, 40
Spain. 18Infectious Diseases, Hospital Rawson, San Juan, Argentina. 19Infectious 41
Diseases and Clinical Microbiology Department, Clínica Maraya, Pereira Colombia. 42
Critical care and Clinical Microbiology Department, Manizales, Colombia. 20Infectious 43
Diseases Department, Hospital Regional de Málaga, Málaga, Spain. 21Infectious 44
Diseases Department, Ramon y Cajal Hospital, Madrid, Spain. 22Division of Infectious 45
Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, 46
Italy. 23Infectious Diseases Unit, Cruces University Hospital, Bilbao, Spain. 24Infectious 47
Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research 48
Page 3 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
3
Group (IPAR), Institut Hospital del Mar d' Investigacions Mèdiques (IMIM), Universitat 49
Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain. 50
25Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil. 51
26Emergency Clinial Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain. 52
27Haematology Department, Son Espases University Hospital, Palma de Mallorca, 53
Spain. 28Unit of Infectious and Tropical Diseases, IRCCS San Raffaele Scientific Institute, 54
Milan, Italy. 29Infectious Diseases Clinic, Department of Medicine, University of Udine 55
and Azienda Sanitaria Universitaria Integrata, Udine, Italy.30Infectious Diseases and 56
Microbiology Unit, Navarra University Clinic, Pamplona, Spain. 31Infectious Diseases 57
Department, Hospital Clínic i Provincial, Barcelona, Spain. 32Infectious Diseases 58
Department, Vall d’Hebron University Hospital, Barcelona, Spain. 33Ege University 59
Faculty of Medicine, Izmir Turkey. 34Microbiology Department, University Hospitals 60
Plymouth NHS Trust, United Kingdom. 35Haematology Department, Marqués de 61
Valdecilla University Hospital, Santander, Spain. 36Hospital Federal Servidores do 62
Estado, Ministério da Saúde and Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio 63
de Janeiro, Brazil 37REIPI (Spanish Network for Research in Infectious Disease), Instituto 64
de Salud Carlos III, Madrid, Spain. 65
66
Corresponding author: Dr. Carlota Gudiol 67
Infectious Diseases Department 68
Bellvitge University Hospital 69
Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain. 70
Tel. +34 93 260 7625 71
Fax. + 34 93 260 7537 72
Page 4 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
4
Email: cgudiol@iconcologia.net 73
*IRONIC STUDY INVESTIGATORS 74
Guillermo Cuervo and Francesc Escrihuela-Vidal, Infectious Diseases Department, and 75
Fe Tubau, Microbiology Department, Bellvitge University Hospital, IDIBELL, Barcelona, 76
Spain. Marisol Rodríguez Arias, Oncology Department, Institut Català d’Oncologia (ICO) 77
- Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. Caglayan Merve Ayaz, Infectious 78
Diseases Department, Hacettepe University School of Medicine, Ankara, Turkey. Jose 79
Munita, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica 80
Alemana Universidad del Desarrollo, Santiago de Chile, Chile. Oriol Gasch, Infectious 81
Diseases Department, and Sílvia Capilla, Microbiology Department, Parc Taulí 82
University Hospital, Sabadell, Barcelona, Spain. Pierre-Yves Bochud and Oriol Manuel, 83
Infectious Diseases Department, Lausanne University Hospital (CHUV), Lausanne, 84
Switzerland. Diego Torres, Infectious Diseases Section, Department of Medicine, 85
Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, 86
Argentina. Saeed El Zein and Jean-Francois Jabbour, Infectious Diseases Division, 87
American University of Beirut Medical Center, Beirut, Lebanon. Hartmut Bertz, 88
Haematology-Oncology Department, and Gabriele Peyerl-Hoffmann, Division of 89
Infectious Diseases, Department of Medicine II, University of Freiburg Medical Center 90
and Faculty of Medicine, Freiburg, Germany. Manuel Lizasoain and José María Aguado, 91
Infectious Diseases Unit, 12 de Octubre University Hospital, Madrid Spain. Begoña 92
Palop, Microbiology Deparment, Hospital Regional de Málaga, Málaga, Spain. Jesús 93
Fortún, Infectious Diseases Department, Ramón y Cajal Hospital, Madrid, Spain. Philipp 94
Hemmati, Department of Haematology, Oncology and Palliative Care, Klinikum Ernst 95
von Bergmann, Academic Teaching Hospital of Charité University Medical School, 96
Page 5 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
5
Berlin, Germany. Laura Magnasco, Division of Infectious Diseases, University of Genoa 97
(DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy. Roberto Céspedes, 98
Haematology Department, and Leire López-Soria, Microbiology Department, Cruces 99
University Hosptial, Bilbao, Spain. Juan Pablo Horcajada, Infectious Diseases Service, 100
Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), 101
Institut Hospital del Mar d’Investigations Mèdiques (IMIM), Universitat Autònoma de 102
Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain. Mia Hold 103
Montaguti, Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil. 104
Marina de Cueto and Jesús Rodríguez-Baño, Clinical Unit of Infectious Diseases, 105
Microbiology and Preventive Medicine, University Hospitals Virgen Macarena and 106
Virgen del Rocío - IBiS; Departament of Medicine, University of Seville, Seville, Spain. 107
Raffaella Greco, Haematology and Bone Marrow Transplantation Unit, and Paola 108
Cichero, Microbiology and Virology Laboratory, IRCCS San Raffaele Scientific Institute, 109
Milan, Italy. Matteo Bassetti and Nadia Castaldo, Infectious Diseases Clinic, 110
Department of Medicine, University of Udine and Azienda Sanitaria Universitaria 111
Integrata, Udine, Italy. Paloma Sangro del Alcázar, Internal Medicine Department, 112
Navarra University Clinic, Pamplona, Spain. Celia Cardozo and Carolina Garcia-Vidal, 113
Infectious Diseases Department, Hospital Clínic i Provincial, Barcelona, Spain. Juan 114
Aguilar-Company, Oncology Department, and Nieves Larrosa, Microbiology 115
Department, Vall d’Hebron University Hospital, Barcelona, Spain. Ayse Uyan-Onal 116
Department of Infectious Diseases and Clinical Microbiology, Ege University Faculty of 117
Medicine, Izmir Turkey. Arzu Nazli-Zeka Department of Infectious Diseases and Clinical 118
Microbiology, Dokuz Eylul University Faculty of Medicine, Izmir Turkey. Lina Clemencia 119
Correa, Clinica Maraya, Pereira, Colombia. Wania Vasconcelos de Freitas and Amanda 120
Page 6 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
6
Aparecida da Silva Machado, Hospital Federal Servidores do Estado, Ministério da 121
Saúde, Rio de Janeiro, Brazil. 122
123
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
Page 7 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
7
Abstract 145
Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe 146
sepsis and death among neutropenic cancer patients. The emergence and increasing 147
prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and may 148
determine a worse prognosis, especially in immunosuppressed patients. The aim of 149
this study is to establish the impact of antibiotic resistance on the outcome of 150
neutropenic onco-haematological patients with PA bacteraemia, and to identify the 151
risk factors for MDRPA bacteraemia and for mortality. 152
Methods and Analysis 153
This is a retrospective, observational, multicentre, international study. All episodes of 154
PA bacteraemia occurring in neutropenic onco-haematological patients followed up at 155
the participating centres from January 1st 2006 to May 31st 2018 will be retrospectively 156
reviewed. The primary end-point will be overall case-fatality rate within 30 days of 157
onset of PA bacteraemia. The secondary end-points will be to describe the following: 158
the incidence and risk factors for MDR and extremely drug-resistant PA bacteraemia, 159
the efficacy of ceftolozane-tazobactam, the rates of persistent bacteraemia and 160
bacteraemia relapse, and the risk factors for very early (48h), early (7 day), and overall 161
(30-day) case-fatality rates. 162
Sample size 163
The total number of episodes of PA bacteraemia at the participating centres during the 164
study period will determine the sample size. We expect collecting approximately 1000 165
episodes during the study period, allowing the estimation of 95% confidence intervals 166
with a 3% margin of error. 167
168
Page 8 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
8
Ethics and Dissemination 169
The Research Ethics Committee (REC) of Bellvitge University Hospital approved the 170
protocol of the study at the primary site. To protect personal privacy, identifying 171
information of each patient in the electronic database will be encrypted. The 172
processing of the patients’ personal data collected in the study will comply with the 173
Spanish Data Protection Act of 1998 and with the European Directive on the Privacy of 174
Data. All data collected, stored and processed will be anonymised. 175
176
Keywords: Pseudomonas aeruginosa, onco-haematological patients, bacteraemia, 177
bloodstream infection, neutropenia, multidrug-resistant, mortality. 178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
Page 9 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
9
Main strengths and limitations of this study: 193
Strengths 194
• The multicentre design of the study will allow the recording of a large number 195
of episodes. 196
• The international and multicentre design will provide representative results 197
regarding the current epidemiology of Pseudomonas aeruginosa (PA) 198
bacteraemia in onco-haematological patients worldwide. 199
• Information will be provided on risk factors for resistance acquisition and their 200
impact on mortality in the current era of multidrug resistance. 201
• Information will be provided on the use of the new beta-lactam antibiotic 202
ceftolozane-tazobactam. 203
Limitations 204
• Due to the retrospective design some information may be lost. 205
• We may not be able to control for certain measured and unmeasured 206
confounders. 207
• Information regarding the specific mechanisms of resistance among PA isolates 208
may not be provided by all centres. 209
210
211
212
213
214
215
Page 10 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
10
INTRODUCTION 216
The epidemiology of bacteraemia among neutropenic cancer patients has changed 217
over the years. In 1960s, Gram-negative bacilli were the leading cause of bacteraemia 218
in this population. In the mid-1980s, a shift from Gram-negative to Gram-positive 219
organisms was observed albeit to varying extents in different countries. This trend 220
appears to have been reversed in recent years, with a re-emergence of Gram-negative 221
bacilli at some institutions, especially those where prophylaxis with quinolones is no 222
longer used [1-3]. These changes in aetiology are accompanied by an alarming increase 223
in multidrug resistance among Gram-negative bacilli [1-5]. 224
Pseudomonas aeruginosa (PA) has historically been one of the major causes of 225
severe sepsis and death among neutropenic cancer patients [6-10]. The emergence and 226
increasing prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and 227
adds to the overall burden of PA infections in immunocompromised patients [11]. 228
Moreover, new treatment modalities such as aggressive myelosuppressive therapies 229
and hematopoietic stem cell transplantation, and the wide use of invasive procedures 230
may have had an impact on risk factors for PA infections and the outcome of affected 231
patients. 232
Very few studies have examined the epidemiology and the clinical course of PA 233
infections in patients with cancer in this new situation and in this era of widespread 234
antimicrobial resistance [12-14]. Moreover, data regarding bacteraemia in neutropenic 235
patients with solid tumours are particularly scarce [15]. In addition, very little is known 236
about the impact of the introduction of the new broad-spectrum β-lactams (such as 237
ceftolozane/tazobactam) in the therapeutic armamentarium for the treatment of 238
bacteraemia due to MDRPA in neutropenic cancer patients. 239
Page 11 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
11
Identifying the risk factors for infection due to MDRPA in neutropenic cancer 240
patients could help physicians to recognize patients at risk more rapidly. Therefore, the 241
early administration of a broader empirical antibiotic therapy in these high-risk 242
patients might have a positive influence on their outcomes. In the present 243
international study, we aim to determine the impact of antibiotic resistance on 244
outcomes in neutropenic cancer patients with PA bacteraemia in the current era of 245
widespread antimicrobial resistance, and also to identify predisposing factors for 246
multidrug resistance and for mortality. 247
248
249
250
251
252
253
254
255
256
257
258
259
260
261
262
Page 12 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
12
OBJECTIVES OF THE STUDY 263
Primary Objective: 264
• To determine the impact of antibiotic resistance on outcomes in neutropenic 265
cancer patients with PA bacteraemia, measured by all-cause case-fatality rate 266
at 30 days. 267
268
Secondary Objectives: 269
• To assess the prevalence of multidrug and extremely drug resistance among PA 270
isolates causing bacteraemia. 271
• To identify the risk factors for infection due to multidrug-resistant (MDR) and 272
extremely drug resistant (XDR) PA. 273
• To assess the efficacy of the new β-lactam ceftolozane-tazobactam for the 274
treatment of bacteraemia due to PA. 275
• To estimate the cumulative incidence rates of persistent bacteraemia, 276
bacteraemia relapse, and other complications at 30 days. 277
• To identify the risk factors for very early (48 hours), early (7-day), and all-cause 278
(30-day) case-fatality rates. 279
280
METHODS AND ANALYSIS 281
Study design 282
This is an international, multicentre, retrospective, observational cohort study 283
involving neutropenic cancer patients diagnosed with PA bacteraemia followed up at 284
Page 13 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
13
any of the participating centres during the study period. The study will be conducted in 285
accordance with the STROBE recommendations (See Research Checklist)[16]. 286
287
Study population 288
Data will be collected on all adult (≥ 18 years) onco-haematological neutropenic 289
patients diagnosed with at least one episode of PA bacteraemia during the study 290
period. 291
292
Study period 293
Participating centres will retrospectively review all episodes of PA bacteraemia 294
occurring in neutropenic onco-haematological patients from January 1st 2006 to May 295
31st 2018. 296
297
Setting 298
The study will be conducted at 34 centres from 12 different countries: Spain (14), 299
Turkey (4), Brazil (3), Italy (3), Argentina (2), Germany (2), Chile (1), Colombia (1), 300
Lebanon (1), Slovakia (1), Switzerland (1) and United Kingdom (1). 301
302
Selection of cases 303
Patients will be identified from previous retrospective and prospective databases or 304
from the records of the Microbiology laboratory at each hospital. 305
306
Inclusion Criteria 307
1. Adult patients (≥ 18 years) 308
Page 14 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
14
2. Patients diagnosed with a haematological malignancy and/or hematopoietic stem 309
cell transplant (HSCT) recipients, or with solid organ tumour. 310
3. The presence of neutropenia (<500 neutrophils/mm3) at the bacteraemia onset. 311
4. Episodes of monomicrobial PA bacteraemia or polymicrobial bacteraemia in which 312
PA is one of the etiological agents, including community, health-care and 313
nosocomial infections. 314
5. Subsequent episodes of PA bacteraemia diagnosed in a patient may be included if 315
the interval between them is >1 month. 316
317
Exclusion criteria 318
Patients with any of the following will be excluded from the study: 319
1. Unavailability of key data (empirical and targeted therapy and vital status at 30- 320
days). 321
2. Episodes occurring in non-neutropenic cancer patients. 322
3. Episodes occurring outside the study period. 323
4. Age <18 years old. 324
325
Data collection 326
Patients’ data will be collected retrospectively. These data will be obtained from 327
various sources, including patients’ electronic records, patients’ notes, the hospital 328
laboratory systems, and the hospital patient administration system. 329
The following data will be collected for all cases: sex, age, type of underlying 330
disease and comorbidities, underlying malignancy status, severity of the episode of 331
febrile neutropenia according to the MASCC index score [17], place of acquisition of 332
Page 15 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
15
infection [18], source of bacteraemia, bacteraemia source control status, clinical and 333
microbiological data, duration of neutropenia, prior therapies received (including 334
antibiotics and immunosuppressive treatments), empirical and definitive antimicrobial 335
therapy, doses and duration of each antibiotic therapy, need for intensive care unit 336
admission and mechanical ventilation, persistent bacteraemia, relapse of bacteraemia, 337
colonisation and/or superinfection by resistant organisms, development of other 338
complications, 48-hours, 7-day and 30-day case-fatality rates. 339
340
Patient and Public Involvement 341
Patients and public will not be involved in the design or development of the study. 342
Definitions 343
- Empirical antibiotic therapy: Antimicrobial therapy administered before reception of 344
definitive antibiotic susceptibility results. 345
- Definitive antibiotic therapy: antimicrobial therapy administered according to 346
definitive antibiotic susceptibility results. 347
- Adequate antibiotic therapy: therapy based on at least one in vitro active antibiotic 348
against the PA strain causing the infection. Monotherapy with an active 349
aminoglycoside will be considered adequate. 350
351
Microbiological studies 352
Clinical samples are processed at the microbiology laboratories of each participating 353
centre in accordance with standard operating procedures. PA will be identified using 354
standard microbiological techniques at each centre. In vitro susceptibility is 355
determined according to the EUCAST recommendations [19]. The specific mechanisms 356
Page 16 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
16
of resistance will be provided when possible, according to molecular analyses. 357
Phenotype stratification of PA isolates is made in accordance with recent standard 358
definitions [20]. MDR PA: the isolate is non-susceptible to at least one agent in three or 359
more of the following antimicrobial categories: aminoglycosides, antipseudomonal 360
carbapenems, antipseudomonal fluoroquinolones, antipseudomonal cephalosporins, 361
antipseudomonal penicillins + beta-lactamase-inhibitors, monobactams, fosfomycin, 362
polymyxins. XDR PA: the isolate is non-susceptible to at least one agent in all but two 363
or fewer of the antimicrobial categories listed above. 364
365
Participant timeline 366
The follow-up period will last one month after bacteraemia onset. 367
368
Study outcomes and endpoint assessment 369
Primary endpoint 370
• Case-fatality rate at 30 days from onset of bacteraemia. 371
Secondary endpoints 372
• 48-hours and 7-day case-fatality rates from onset of bacteraemia. 373
• Prevalence and risk factors for multidrug and extremely drug resistance 374
acquisition 375
• Efficacy of ceftolozane-tazobactam for the treatment of bacteraemia due to PA, 376
measured by all-cause (30-day) case-fatality rate. 377
• Rate of persistent bacteraemia beyond the first 48 hours of adequate antibiotic 378
therapy. 379
Page 17 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
17
• Rate of bacteraemia relapse within 14 days of treatment discontinuation. 380
• Rate of other complications within 30 days from bacteraemia onset (e.g. ICU 381
admission, etc). 382
Sample size 383
The total number of episodes of PA bacteraemia in the participating centres during the 384
study period will determine the sample size. According to the previous experience of 385
each participating centre, we expect to record around 1000 episodes during the study 386
period, allowing the estimation of 95% confidence intervals with a 3% margin of error. 387
388
Statistical analysis 389
Baseline characteristics of participants will be described using mean and standard 390
deviation for continuous variables and frequencies for categorical variables. 391
Cumulative incidence rate will be calculated as the number of events divided by 392
participants at risk at bacteraemia onset. The 95% confidence interval will be 393
estimated using normal approximation for large incidence values (above 10%) and 394
Poisson approximation for small ones. A set of demographic and clinical factors will be 395
analyzed to quantify their association with the following outcomes: 30-day mortality, 396
MDR and XDR. To do so, a logistic regression model will be used, and odds ratios with 397
confidence intervals will be presented. Patients’ mortality survival functions will be 398
estimated using Kaplan-Meier curves and compared using the log-rank test. Moreover, 399
survival functions will also be analysed at 7, 14 and 30 days. No missing data are 400
expected regarding the main outcomes, since unavailability of related data is an 401
exclusion criterion. With sensitivity purposes, the main analyses will be replicated in 402
patients with high-risk bacteremia, such as those with pneumonia. Model 403
Page 18 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
18
assumptions, conditions and residuals will be assessed. A p-value <0.05 will be 404
considered statistically significant. The analysis will be performed using R software (R 405
v. 3.2.5). 406
407
Ethical Issues 408
The study has been approved by the Comité Ético de Investigación Clínica del Hospital 409
Universitari de Bellvitge (Institutional Review Board of Clinical Research, Bellvitge 410
University Hospital). To protect personal privacy, identifying information of each 411
patient in the electronic database will be encrypted. The processing of the patients’ 412
personal data collected in this study shall comply with the Data Protection Act 1998 413
and with the European Directive on the Privacy of Data. All data collected, stored and 414
processed will be anonymised. The investigator/research lead at each site will 415
guarantee that all team members or other persons involved at the site in question will 416
respect the confidentiality of any information concerning the study patients. The 417
Clinical Research Ethics Committee has waived the need for informed consent due to 418
the retrospective nature of the study. 419
PUBLICATION PLAN 420
Results will be reported at conferences and in peer-reviewed publications. The first 421
publication will be based on data from all sites, and will be analysed as stipulated in 422
the protocol with supervision by statisticians. Any formal presentation or publication 423
of data collected from this study will be considered as a joint publication by the 424
participating investigators and will follow the recommendations of the International 425
Committee of Medical Journal Editors (ICMJE). 426
Page 19 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
19
DISCUSSION 427
In recent years, a shift towards an increase of Gram-negative bacterial infections has 428
been described worldwide. This trend has been especially notable among neutropenic 429
cancer patients, in whom Gram-negative bacilli (GNB) are the leading cause of 430
bacteraemia at some institutions [1]. Neutropenic patients with onco-haematological 431
malignancies are considered a population at high risk for MDR bacterial infections 432
because of their need for long hospitalization and significant antibiotic pressure [21]. In 433
this regard, recent studies have described an alarming increase in the incidence of 434
bacteraemia due to extended-spectrum beta-lactamase-producing (ESBL) and 435
carbapenem-resistant (CP) Enterobacteriaceae among neutropenic cancer patients, 436
which may substantially impair patients’ outcomes [4,5,22]. 437
Classically, PA has been one of the leading causes of bacteraemia in 438
neutropenic patients with haematological malignancies and solid tumours, and is 439
associated with poor prognosis [6,8-10]. In recent years, particular attention has been 440
paid to the emergence of MDR Enterobacteriaceae, and data on the current 441
epidemiology of PA bacteraemia and the impact of antibiotic resistance in this high-442
risk population are lacking. The existing literature is based on heterogeneous studies 443
some of which present methodological shortcomings [12-14,23-25]. 444
Firstly, most of the studies have a retrospective and single-centre design [12,13,23-445
25]. Only three prospective studies have addressed this issue and all have a small 446
sample size; in addition, the fact they were conducted more than seven years ago does 447
not allow the extrapolation of the data to the current era of multidrug resistance 448
[4,12,13,]. In addition, the few studies with a multicentre design have included only 449
centres from the same country, and therefore, the results may not be representative 450
Page 20 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
20
of different geographical areas [14,26]. Secondly, some studies include a diverse variety 451
of infections due to PA, and only a few focus exclusively on patients with PA 452
bacteraemia [12,14,23,24]. Thirdly, only two recent studies describe the current risk factors 453
for MDR-PA acquisition and for mortality in this high-risk population [14, 24] However, 454
one of these studies is a retrospective, single-centre Korean study involving only 455
paediatric patients [24], and the other is a retrospective, 3-centre study limited to the 456
city of Athens [14]. 457
The published data comparing the efficacy of combined empirical antibiotic 458
treatment including two active antipseudomonal agents versus monotherapy in 459
patients with febrile neutropenia are controversial. The aim of empirical combination 460
therapy is to provide extended-spectrum coverage against MDR organisms in high-risk 461
patients, since a delayed initiation of adequate antibiotic treatment has been 462
associated with poorer outcomes, particularly in patients with PA bacteraemia 463
[12,14,24,25]. However, an important meta-analysis published in 2013 was unable to show 464
any advantage of combination antibiotic treatment in cancer patients with 465
neutropenia [27]. Nonetheless, in a recently published report, Tofas et al. found a trend 466
towards improved survival with combination therapy in this setting [14]. Clearly, more 467
studies are needed to analyse whether combination therapy could be beneficial in the 468
current era of multidrug resistance. 469
Clinical experience with the use of new broad-spectrum beta-lactams to treat 470
MDR-PA infections, such as ceftolozane-tazobactam, is gradually accumulating in the 471
general population. However, little is known about its use for the treatment of MDR-472
PA bacteraemia in neutropenic cancer patients. 473
Page 21 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
21
The present study aims to identify the current impact of the antibiotic 474
resistance on outcomes in neutropenic patients with PA bacteraemia, and to 475
determine the risk factors associated with multidrug resistance and mortality. We will 476
also assess the efficacy of new broad-spectrum beta-lactams against MDRPA strains, 477
since alternative treatments are urgently needed in this vulnerable population. This 478
study shall provide useful information for physicians’ daily clinical practice, who need 479
to rapidly identify patients at high risk for MDRPA bacteraemia, to be able to promptly 480
initiate effective antimicrobial therapy and improve patients’ outcomes. 481
482
483
484
485
486
487
488
489
490
491
492
493
494
495
496
497
Page 22 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
22
498
499
REFERENCES 500
1- Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features, 501
antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer 502
patients. Clin Microbiol Infect 2013; 19: 474–9. 503
2- Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: A 504
practical update. Virulence 2016; 7:280-97. 505
3- Mikulska M, Viscoli C, Orasch C, et al. Fourth European Conference on Infections in 506
Leukemia Group a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID. 507
Aetiology and resistance in bacteraemias among adult and paediatric haematology and 508
cancer patients. J Infect 2014; 68:321-31. 509
4- Trecarichi EM, Tumbarello M, Spanu T, et al. Incidence and clinical impact of 510
extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance 511
in bloodstream infections caused by Escherichia coli in patients with hematological 512
malignancies. J Infect 2009; 58:299-307. 513
5- Satlin MJ, Cohen N, Ma KC, et al. Bacteremia due to carbapenem-resistant 514
Enterobacteriaceae in neutropenic patients with hematologic malignancies. J Infec 515
2016; 73:336-45. 516
6- Cherif H, Kronvall G, Bjorkholm M, Kalin M. Bacteraemia in hospitalised patients 517
with malignant blood disorders: a retrospective study of causative agents and their 518
resistance profiles during a 14-year period without antibacterial prophylaxis. Hematol J 519
2003; 4:420-6. 520
Page 23 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
23
7- Gratwohl A, Baldomero H, Gratwohl M, et al. Quantitative and qualitative 521
differences in use and trends of hematopoietic stem cell transplantation: a Global 522
Observational Study. Haematologica 2013; 98:1282-90. 523
8- Kara O, Zarakolu P, Ascioglu S, et al. Epidemiology and emerging resistance in 524
bacterial bloodstream infections in patients with hematologic malignancies. Infect Dis 525
(Lond) 2015; 47:690-7. 526
9- Spanik S, Kukuckova E, Pichna P, et al. Analysis of 553 episodes of monomicrobial 527
bacteraemia in cancer patients: any association between risk factors and outcome to 528
particular pathogen? Support Care Cancer 1997; 5:330-3. 529
10- Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia: 530
epidemiology, microbiology, and risk stratification. Clin Infect Dis 2005; 40 Suppl 531
4:S240-S5. 532
11- Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated 533
with healthcare-associated infections: summary of data reported to the National 534
Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009- 535
2010. Infect Control Hosp Epidemiol 2013; 34:1-14. 536
12- Cattaneo C, Antoniazzi F, Casari S, et al. P. aeruginosa bloodstream infections 537
among hematological patients: an old or new question? Ann Hematol 2012; 91:1299-538
304. 539
13- Trecarichi EM, Tumbarello M, Caira M, et al. Multidrug resistant Pseudomonas 540
aeruginosa bloodstream infection in adult patients with hematologic malignancies. 541
Haematologica 2011; 96:e1-e3. 542
Page 24 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
24
14- Tofas P, Samarkos M, Piperaki ET, et al. Pseudomonas aeruginosa bacteraemia in 543
patients with hematologic malignancies: risk factors, treatment and outcome. Diagn 544
Microbiol Infect Dis 2017; 88:335-41. 545
15- Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients with solid 546
tumors. Virulence 2016; 7:298-308. 547
16- Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; 548
STROBE Initiative. The Strengthening the Reporting of Observational Studies in 549
Epidemiology (STROBE) statement: guidelines for reporting observational studies. 550
Lancet 2007; 370:1453–7. 551
17- Klastersky J, Paesmans M, Ruberstein EB, Boyer M, Elting L, Feld R et al. The 552
Multinational Association for Supportive Care in Cancer Risk Index: a multinational 553
scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 554
2000; 18:3038-51. 555
18- Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al.Health 556
care–associated bloodstream infections in adults: a reason to change the accepted 557
definition of community-acquired infections Ann Intern Med 2002;137:791–7. 558
19- The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables 559
for interpretation of MICs and zone diameters, version 8.0, 2018. 560
20- Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug resistant, extensively drug-561
resistant and pandrug-resistant bacteria: an International expert proposal for interim 562
standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–81. 563
21-Kang Cl, Kim SH, Park WB, et al. Bloodstream infections caused antibiotic-resistant 564
Gram-negative bacilli: risk factors for mortality and impact of innapropiate initial 565
antimicrobial therapy on outcome. Antimicrob Agent Chemother 2005;49:760-6. 566
Page 25 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
25
22-Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias 567
among adult and paediatric haematology and cancer patients. J Infect (2013). 568
23-Vuotto F, Berthon C, Lemaitre N, etc al. Risk factors, clinical features and outcomes 569
of Pseudomonas aeruginosa bacteraemia in patients with haematological 570
malignancies: a case-control study. American Journal of Infection Control 2013;41:527-571
30. 572
24-Kim H, Park B, Kim S, et al. Clinical characteristics and outcomes of Pseudomonas 573
aeruginosa bacteraemia in febrile neutropenic children and adolescents with the 574
impact of antibiotic resistance: a retrospective study. BMC Infectious Diseases 2017 575
17:500-10. 576
25-Samonis G, Vardakas K, Kofteridis D, et al. Characteristics, risk factors and outcomes 577
of adult cancer patients with extensively drug-resistant Pseudomonas aeruginosa 578
infections. Infection 2014. 579
26-Trecarichi E, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial 580
resistance data for bacterial bloodstream infections in patients with haematological 581
malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect 2015; 582
21:337-343. 583
27- Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-lactam-584
aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane 585
Database of Systematic Reviews 2013, Issue 6. Art. No.: CD003038 586
587
588
589
590
Page 26 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
26
591
592
593
Authors’ contributions: 594
All authors were involved in the study concept. AA, CG, CT, and JC were involved in 595
design of the study. RP, EA, MA, RA, AB, ASB, SC, LD, EG, FH, BI, SSK, KW, GMC, AM, 596
JIM, IMG, PMD. GM, MM, MM, MM, MI, AN, CO, HMPM, MP, JLP, PP, ORS, IRC, RT, LY, 597
MZ, GC, MR, FT, CMA, JM, SC, PYB, JFJ, GPH, ML, BP, JF, PH, LM, LLS, MHM, JPH, MdC, 598
PC, MB, NC, PS, CC, NL, AUO, ANZ, LCC, WVdF, FEV, OG, OM, SEZ, HB, JMA, RC, SRB, 599
RG, CGV, JA and AA were responsible for identification of the cases and data collection. 600
DT was the responsible for the elaboration of the online database. CT was the 601
statistician in charge of the statistical analysis. AA, CG and JC drafted and revised the 602
manuscript. All authors reviewed and approved the final version of the manuscript. 603
Acknowledgement: 604
We thank the ESGBIS and the ESGICH study groups for supporting the study. 605
Funding statement: 606
This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud 607
Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, 608
Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in 609
Infectious Diseases (REIPI RD16/0016/0001) - co-financed by European Development 610
Regional Fund “A way to achieve Europe”, Operative Programme Intelligent Growth 611
2014-2020. 612
Competing interests’ statement 613
Page 27 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
27
ASB received grant from Promex Stiftung fur die Forschung (by Carigest SA), and 614
funding by Gilead to assist to the ECCMID congress (2018). Oguz Resat Sipahi received 615
speaker’s honorarium from MSD, Astellas, Novartis and Pfizer. 616
Page 28 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
STROBE Statement—checklist of items that should be included in reports of observational studies
Item
No. Recommendation
Page
No.
Relevant text from
manuscript
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1
(b) Provide in the abstract an informative and balanced summary of what was done and what was
found
7
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 10
Objectives 3 State specific objectives, including any prespecified hypotheses 12
Methods
Study design 4 Present key elements of study design early in the paper 12-13
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure,
follow-up, and data collection
13
Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of
participants. Describe methods of follow-up
Case-control study—Give the eligibility criteria, and the sources and methods of case
ascertainment and control selection. Give the rationale for the choice of cases and controls
Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of
participants
13-15
(b) Cohort study—For matched studies, give matching criteria and number of exposed and
unexposed
Case-control study—For matched studies, give matching criteria and the number of controls per
case
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers.
Give diagnostic criteria, if applicable
14-15
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment
(measurement). Describe comparability of assessment methods if there is more than one group
16-17
Bias 9 Describe any efforts to address potential sources of bias 17
Study size 10 Explain how the study size was arrived at 7
Continued on next page
Page 29 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review only
2
Quantitative
variables
11 Explain how quantitative variables were handled in the analyses. If applicable, describe which
groupings were chosen and why
17
Statistical
methods
12 (a) Describe all statistical methods, including those used to control for confounding 17
(b) Describe any methods used to examine subgroups and interactions 17
(c) Explain how missing data were addressed 17
(d) Cohort study—If applicable, explain how loss to follow-up was addressed
Case-control study—If applicable, explain how matching of cases and controls was addressed
Cross-sectional study—If applicable, describe analytical methods taking account of sampling
strategy
17
(e) Describe any sensitivity analyses 17
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined
for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed
NA
(b) Give reasons for non-participation at each stage NA
(c) Consider use of a flow diagram NA
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on
exposures and potential confounders
NA
(b) Indicate number of participants with missing data for each variable of interest NA
(c) Cohort study—Summarise follow-up time (eg, average and total amount) NA
Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time NA
Case-control study—Report numbers in each exposure category, or summary measures of exposure NA
Cross-sectional study—Report numbers of outcome events or summary measures NA
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision
(eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were
included
NA
(b) Report category boundaries when continuous variables were categorized NA
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time
period
Continued on next page
Page 30 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review only
3
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses NA
Discussion
Key results 18 Summarise key results with reference to study objectives NA
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss
both direction and magnitude of any potential bias
9
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of
analyses, results from similar studies, and other relevant evidence
NA
Generalisability 21 Discuss the generalisability (external validity) of the study results 19-21
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the
original study on which the present article is based
26
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
Page 31 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review onlyImpact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia
(IRONIC study): Study protocol of a retrospective multicentre international study.
Journal: BMJ Open
Manuscript ID bmjopen-2018-025744.R1
Article Type: Protocol
Date Submitted by the Author: 23-Jan-2019
Complete List of Authors: Albasanz-Puig, Adaia; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Gudiol, Carlota; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Parody, Rocío; Institut Catala d' Oncologia, Haematology DepartmentTebe, Cristian; Institut d\'Investigacio Biomedica de Bellvitge, Statistics Advisory ServiceAkova, Murat; Hacettepe UniversitesiAraos, Rafael; Universidad del Desarrollo Facultad de MedicinaBote, Anna; Consorcio Corporacion Sanitaria Parc Tauli, Infectious Diseases Brunnel, Anne-Sophie; Centre Hospitalier Universitaire Vaudois, Infectious DiseasesCalik, Sebnem; Izmir Bozyaka Egitim ve Arastirma Hastanesi, Infectious Diseases DepartmentDrgona, Lubos; Univerzita Komenskeho v Bratislave, Oncohematology DepartmentGarcía, Estefanía; Hospital Universitario Reina Sofia, Oncohematology DepartmentHemmati, Philipp; Klinikum Ernst von Bergmann, Haematology DepartmentHerrera, Fabián; Centro de Educación Médica e Investigaciones Clínicas, Infectious Diseases DepartmentIbrahim, Karim Yaqub; Universidade de Sao Paulo Faculdade de MedicinaIsler, Burcu; Istanbul Fizik Tedavi Rehabilitasyon Egitim ve Arastirma Hastanesi, Infectious Diseases DepartmentKanj, Souha; American University of Beirut Medical Center, Internal Medicine-Division of Infectious DiseasesKern, Winfried; Universite de Fribourg Departement de medecine, Infectious Diseases DepartmentMaestro-de la Calle, Guillermo; Hospital Universitario 12 de Octubre, Infectious Diseases UnitManzur, Adriana; Hospital Rawson, Infectious Diseases DepartmentMarin, Jorge Iván; Clínica Maraya, Infectious Diseases DepartmentMárquez-Gómez, Ignacio; Hospital Regional Universitario de Malaga, Infectious Diseases Department
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on January 13, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2018-025744 on 24 M
ay 2019. Dow
nloaded from
For peer review only
Martín-Dávila, Pilar; Hospital Universitario Ramon y Cajal, Infectious Diseases DepartmentMikulska, Malgorzata; Ospedale Policlinico San Martino, Infectious Diseases DepartmentMontejo, José Miguel; Hospital Universitario Cruces, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Montero, Milagros; Institut Hospital del Mar d'Investigacions Mediques, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Morales, Hugo Manuel Paz; Hospital Erasto Gaertner, Infectious Diseases DepartmentMorales, Isabel; Hospital Universitario Virgen Macarena, Emergency Clinical Unit; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Novo, Andrés; Hospital Universitari Son Espases, Haematology DepartmentOltolini, Chiara; Ospedale San Raffaele, Infectious and Tropical Diseases DepartmentPeghin, Maddalena; Hospital Santa Maria Misericordia, Infectious DiseasesDel Pozo, Jose Luis; Clinica Universitaria de Navarra, Infectious Diseases And Microbiology DepartmentPuerta-Alcalde, Pedro; Hospital Clinic de Barcelona, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Ruiz-Camps, Isabel; Hospital Vall d'Hebron, Infectious Diseases Department; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Sipahi, Oguz Resat; Ege Universitesi Tip FakultesiTilley, Robert; University Hospital Plymouth NHS Trust, Mircobiology DepartmentYáñez, Lucrecia; Hospital Universitario Marques de Valdecilla, Haematology DepartmentRibeiro Gomes, Marisa Zenaide; Hospital Federal Servidores do Estado, Ministério da Saúde and Instituto Oswaldo CruzCarratala, Jordi; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)
<b>Primary Subject Heading</b>: Infectious diseases
Secondary Subject Heading: Oncology, Haematology (incl blood transfusion)
Keywords: Pseudomonas aeruginosa, Onco-Haematological Patients, Bacteraemia, Bloodstream Infection, Neutropenia, Multidrug-Resistant
Page 1 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
1 Impact of antibiotic resistance on outcomes of neutropenic cancer patients with
2 Pseudomonas aeruginosa bacteraemia (IRONIC study): Study protocol of a
3 retrospective multicentre international study.
4
5 Authors: Albasanz-Puig, Adaia1,37, Gudiol, Carlota1,37, Parody, Rocío2, Tebe, Cristian3,
6 Akova, Murat4, Araos, Rafael5, Bote, Anna6, Brunel, Anne-Sophie7, Calik, Sebnem8,
7 Drgona, Lubos9, García, Estefanía10, Hemmati, Philipp11, Herrera, Fabián12, Ibrahim,
8 Karim Yaqub13, Isler, Burcu14, Kanj, Souha15, Kern, Winfried16, Maestro-de la Calle,
9 Guillermo17, Manzur, Adriana18, Marin, Jorge Iván19, Márquez-Gómez, Ignacio20,
10 Martín-Dávila, Pilar21, Mikulska, Malgorzata22, Montejo, Miguel23,37, Montero,
11 Milagros24,37, Morales, Hugo Manuel Paz25, Morales, Isabel26,37, Novo, Andrés27,
12 Oltolini, Chiara28, Peghin, Maddalena29, Del Pozo, Jose Luis30, Puerta-Alcalde,
13 Pedro31,37, Ruiz-Camps, Isabel32,37, Sipahi, Oguz Resat33, Tilley, Robert34, Yáñez
14 Lucrecia35, Ribeiro Gomes, Marisa Zenaide36, and Carratalà, Jordi1,37 for the IRONIC
15 study group*.
16
17 Affiliations: 1Infectious Diseases Department, Bellvitge University Hospital, IDIBELL,
18 University of Barcelona, Spain. 2Haematology Department, Institut Català d’Oncologia
19 (ICO) – Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. 3Statistics Advisory Service,
20 Institute of Biomedical Research of Bellvitge, Rovira i Virgili University. 4Department of
21 Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey. 5Instituto
22 de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana
23 Universidad del Desarrollo, Santiago de Chile, Chile. 6Infectious Diseases Department,
24 Parc Taulí University Hospital, Sabadell, Barcelona, Spain. 7Infectious Diseases
Page 2 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
2
25 Department, Department of Medicine, Lausanne University Hospital, (CHUV),
26 Lausanne, Switzerland. 8University of Health Science Izmir Bozyaka Training and
27 Research Hospital, Turkey. 9Oncohematology Department, Comenius University and
28 National Cancer Institute, Bratislava, Slovakia. 10Salvador Tabares Carrasco and
29 Josefina Serrano López, Haematology Department, Reina Sofía University Hospital-
30 IMIBIC-UCO, Córdoba. 11Department of Hematology, Oncology and Palliative Care,
31 Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University
32 Medical School, Berlin, Germany. 12Infectious Diseases Section, Department of
33 Medicine, Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos
34 Aires, Argentina. 13Instituto do Câncer do Estado de São Paulo, Faculty of Medicine,
35 Univesity of São Paulo, Brazil 14Department of Infectious Diseases and Clinical
36 Microbiology, Istanbul Education and Research Hospital, Istanbul, Turkey.15Infectious
37 Diseases Division, American University of Beirut Medical Center, Beirut,
38 Lebanon.16Division of Infectious Diseases, Department of Medicine II, University of
39 Freiburg Medical Center and Faculty of Medicine, Freiburg, Germany. 17Infectious
40 Diseases Unit, Instituto de Investigación Hospital “12 de Octubre” (i+12), “12 de
41 Octubre” University Hospital, School of Medicine, Universidad Complutense, Madrid,
42 Spain. 18Infectious Diseases, Hospital Rawson, San Juan, Argentina. 19Infectious
43 Diseases and Clinical Microbiology Department, Clínica Maraya, Pereira Colombia.
44 Critical care and Clinical Microbiology Department, Manizales, Colombia. 20Infectious
45 Diseases Department, Hospital Regional de Málaga, Málaga, Spain. 21Infectious
46 Diseases Department, Ramon y Cajal Hospital, Madrid, Spain. 22Division of Infectious
47 Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa,
48 Italy. 23Infectious Diseases Unit, Cruces University Hospital, Bilbao, Spain. 24Infectious
Page 3 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
3
49 Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research
50 Group (IPAR), Institut Hospital del Mar d' Investigacions Mèdiques (IMIM), Universitat
51 Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain.
52 25Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil.
53 26Emergency Clinial Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain.
54 27Haematology Department, Son Espases University Hospital, Palma de Mallorca,
55 Spain. 28Unit of Infectious and Tropical Diseases, IRCCS San Raffaele Scientific Institute,
56 Milan, Italy. 29Infectious Diseases Clinic, Department of Medicine, University of Udine
57 and Azienda Sanitaria Universitaria Integrata, Udine, Italy.30Infectious Diseases and
58 Microbiology Unit, Navarra University Clinic, Pamplona, Spain. 31Infectious Diseases
59 Department, Hospital Clínic i Provincial, Barcelona, Spain. 32Infectious Diseases
60 Department, Vall d’Hebron University Hospital, Barcelona, Spain. 33Ege University
61 Faculty of Medicine, Izmir Turkey. 34Microbiology Department, University Hospitals
62 Plymouth NHS Trust, United Kingdom. 35Haematology Department, Marqués de
63 Valdecilla University Hospital, Santander, Spain. 36Hospital Federal Servidores do
64 Estado, Ministério da Saúde and Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio
65 de Janeiro, Brazil 37REIPI (Spanish Network for Research in Infectious Disease), Instituto
66 de Salud Carlos III, Madrid, Spain.
67
68 Corresponding author: Dr. Carlota Gudiol
69 Infectious Diseases Department
70 Bellvitge University Hospital
71 Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain.
72 Tel. +34 93 260 7625
Page 4 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
4
73 Fax. + 34 93 260 7537
74 Email: cgudiol@iconcologia.net
75 *IRONIC STUDY INVESTIGATORS
76 Guillermo Cuervo and Francesc Escrihuela-Vidal, Infectious Diseases Department, and
77 Fe Tubau, Microbiology Department, Bellvitge University Hospital, IDIBELL, Barcelona,
78 Spain. Marisol Rodríguez Arias, Oncology Department, Institut Català d’Oncologia (ICO)
79 - Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. Caglayan Merve Ayaz, Infectious
80 Diseases Department, Hacettepe University School of Medicine, Ankara, Turkey. Jose
81 Munita, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica
82 Alemana Universidad del Desarrollo, Santiago de Chile, Chile. Oriol Gasch, Infectious
83 Diseases Department, and Sílvia Capilla, Microbiology Department, Parc Taulí
84 University Hospital, Sabadell, Barcelona, Spain. Pierre-Yves Bochud and Oriol Manuel,
85 Infectious Diseases Department, Lausanne University Hospital (CHUV), Lausanne,
86 Switzerland. Diego Torres, Infectious Diseases Section, Department of Medicine,
87 Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires,
88 Argentina. Saeed El Zein and Jean-Francois Jabbour, Infectious Diseases Division,
89 American University of Beirut Medical Center, Beirut, Lebanon. Hartmut Bertz,
90 Haematology-Oncology Department, and Gabriele Peyerl-Hoffmann, Division of
91 Infectious Diseases, Department of Medicine II, University of Freiburg Medical Center
92 and Faculty of Medicine, Freiburg, Germany. Manuel Lizasoain and José María Aguado,
93 Infectious Diseases Unit, 12 de Octubre University Hospital, Madrid Spain. Begoña
94 Palop, Microbiology Deparment, Hospital Regional de Málaga, Málaga, Spain. Jesús
95 Fortún, Infectious Diseases Department, Ramón y Cajal Hospital, Madrid, Spain. Georg
96 Maschmeyer, Department of Haematology, Oncology and Palliative Care, Klinikum
Page 5 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
5
97 Ernst von Bergmann, Academic Teaching Hospital of Charité University Medical School,
98 Berlin, Germany. Laura Magnasco, Division of Infectious Diseases, University of Genoa
99 (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy. Roberto Céspedes,
100 Haematology Department, and Leire López-Soria, Microbiology Department, Cruces
101 University Hosptial, Bilbao, Spain. Juan Pablo Horcajada, Infectious Diseases Service,
102 Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR),
103 Institut Hospital del Mar d’Investigations Mèdiques (IMIM), Universitat Autònoma de
104 Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain. Mia Hold
105 Montaguti, Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil.
106 Marina de Cueto and Jesús Rodríguez-Baño, Clinical Unit of Infectious Diseases,
107 Microbiology and Preventive Medicine, University Hospitals Virgen Macarena and
108 Virgen del Rocío - IBiS; Departament of Medicine, University of Seville, Seville, Spain.
109 Raffaella Greco, Haematology and Bone Marrow Transplantation Unit, and Paola
110 Cichero, Microbiology and Virology Laboratory, IRCCS San Raffaele Scientific Institute,
111 Milan, Italy. Matteo Bassetti and Nadia Castaldo, Infectious Diseases Clinic,
112 Department of Medicine, University of Udine and Azienda Sanitaria Universitaria
113 Integrata, Udine, Italy. Paloma Sangro del Alcázar, Internal Medicine Department,
114 Navarra University Clinic, Pamplona, Spain. Celia Cardozo and Carolina Garcia-Vidal,
115 Infectious Diseases Department, Hospital Clínic i Provincial, Barcelona, Spain. Juan
116 Aguilar-Company, Oncology Department, and Nieves Larrosa, Microbiology
117 Department, Vall d’Hebron University Hospital, Barcelona, Spain. Ayse Uyan-Onal
118 Department of Infectious Diseases and Clinical Microbiology, Ege University Faculty of
119 Medicine, Izmir Turkey. Arzu Nazli-Zeka Department of Infectious Diseases and Clinical
120 Microbiology, Dokuz Eylul University Faculty of Medicine, Izmir Turkey. Lina Clemencia
Page 6 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
6
121 Correa, Clinica Maraya, Pereira, Colombia. Wania Vasconcelos de Freitas and Amanda
122 Aparecida da Silva Machado, Hospital Federal Servidores do Estado, Ministério da
123 Saúde, Rio de Janeiro, Brazil.
124
125
126
127
128
129
130
131
132
133
134
135
136
137
138
139
140
141
142
143
144
Page 7 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
7
145 Abstract
146 Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe
147 sepsis and death among neutropenic cancer patients. The emergence and increasing
148 prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and may
149 determine a worse prognosis, especially in immunosuppressed patients. The aim of
150 this study is to establish the impact of antibiotic resistance on the outcome of
151 neutropenic onco-haematological patients with PA bacteraemia, and to identify the
152 risk factors for MDRPA bacteraemia and for mortality.
153 Methods and Analysis
154 This is a retrospective, observational, multicentre, international study. All episodes of
155 PA bacteraemia occurring in neutropenic onco-haematological patients followed up at
156 the participating centres from January 1st 2006 to May 31st 2018 will be retrospectively
157 reviewed. The primary end-point will be overall case-fatality rate within 30 days of
158 onset of PA bacteraemia. The secondary end-points will be to describe the following:
159 the incidence and risk factors for MDR and extremely drug-resistant PA bacteraemia
160 (by comparing the episodes due to susceptible PA with those produced by MDRPA),
161 the efficacy of ceftolozane-tazobactam, the rates of persistent bacteraemia and
162 bacteraemia relapse, and the risk factors for very early (48h), early (7 day), and overall
163 (30-day) case-fatality rates.
164 Ethics and Dissemination
165 The Research Ethics Committee (REC) of Bellvitge University Hospital approved the
166 protocol of the study at the primary site. To protect personal privacy, identifying
167 information of each patient in the electronic database will be encrypted. The
168 processing of the patients’ personal data collected in the study will comply with the
Page 8 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
8
169 Spanish Data Protection Act of 1998 and with the European Directive on the Privacy of
170 Data. All data collected, stored and processed will be anonymised.
171
172 Keywords: Pseudomonas aeruginosa, onco-haematological patients, bacteraemia,
173 bloodstream infection, neutropenia, multidrug-resistant, mortality.
174
175
176
177
178
179
180
181
182
183
184
185
186
187
188
189
190
191
192
Page 9 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
9
193 Main strengths and limitations of this study:
194 Strengths
195 The multicentre design of the study will allow the recording of a large number
196 of episodes.
197 The international and multicentre design will provide representative results
198 regarding the current epidemiology of Pseudomonas aeruginosa (PA)
199 bacteraemia in onco-haematological patients worldwide.
200 Information will be provided on risk factors for resistance acquisition and their
201 impact on mortality in the current era of multidrug resistance.
202 Limitations
203 Due to the retrospective design some information may be lost.
204 We may not be able to control for certain measured and unmeasured
205 confounders.
206
207
208
209
210
211
212
213
214
215
Page 10 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
10
216 INTRODUCTION
217 The epidemiology of bacteraemia among neutropenic cancer patients has changed
218 over the years. In 1960s, Gram-negative bacilli were the leading cause of bacteraemia
219 in this population. In the mid-1980s, a shift from Gram-negative to Gram-positive
220 organisms was observed albeit to varying extents in different countries. This trend
221 appears to have been reversed in recent years, with a re-emergence of Gram-negative
222 bacilli at some institutions, especially those where prophylaxis with quinolones is no
223 longer used [1-3]. These changes in aetiology are accompanied by an alarming increase
224 in multidrug resistance among Gram-negative bacilli [1-5].
225 Pseudomonas aeruginosa (PA) has historically been one of the major causes of
226 severe sepsis and death among neutropenic cancer patients [6-10]. The emergence and
227 increasing prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and
228 adds to the overall burden of PA infections in immunocompromised patients [11].
229 Moreover, new treatment modalities such as aggressive myelosuppressive therapies
230 and hematopoietic stem cell transplantation, and the wide use of invasive procedures
231 may have had an impact on risk factors for PA infections and the outcome of affected
232 patients.
233 Very few studies have examined the epidemiology and the clinical course of PA
234 infections in patients with cancer in this new situation and in this era of widespread
235 antimicrobial resistance [12-14]. Moreover, data regarding bacteraemia in neutropenic
236 patients with solid tumours are particularly scarce [15]. In addition, very little is known
237 about the impact of the introduction of the new broad-spectrum β-lactams (such as
238 ceftolozane/tazobactam) in the therapeutic armamentarium for the treatment of
239 bacteraemia due to MDRPA in neutropenic cancer patients.
Page 11 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
11
240 Identifying the risk factors for infection due to MDRPA in neutropenic cancer
241 patients could help physicians to recognize patients at risk more rapidly. Therefore, the
242 early administration of a broader empirical antibiotic therapy in these high-risk
243 patients might have a positive influence on their outcomes. In the present
244 international study, we aim to determine the impact of antibiotic resistance on
245 outcomes in neutropenic cancer patients with PA bacteraemia in the current era of
246 widespread antimicrobial resistance, and also to identify predisposing factors for
247 multidrug resistance and for mortality. For this purpose, we will compare episodes due
248 to susceptible PA with those produced by MDRPA, and we will compare patients who
249 died with those who survived.
250
251
252
253
254
255
256
257
258
259
260
261
262
263
Page 12 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
12
264 OBJECTIVES OF THE STUDY
265 Primary Objective:
266 To determine the impact of antibiotic resistance on outcomes in neutropenic
267 cancer patients with PA bacteraemia, measured by all-cause case-fatality rate
268 at 30 days.
269
270 Secondary Objectives:
271 To assess the prevalence of multidrug and extremely drug resistance (XDR)
272 among PA isolates causing bacteraemia.
273 To identify the risk factors for infection due to multidrug-resistant (MDR) and
274 XDR PA.
275 To assess the efficacy of the new β-lactam ceftolozane-tazobactam for the
276 treatment of bacteraemia due to PA.
277 To estimate the cumulative incidence rates of persistent bacteraemia,
278 bacteraemia relapse, and other complications at 30 days.
279 To identify the risk factors for very early (48 hours), early (7-day), and all-cause
280 (30-day) case-fatality rates.
281
282 METHODS AND ANALYSIS
283 Study design
284 This is an international, multicentre, retrospective, observational cohort study
285 involving neutropenic cancer patients diagnosed with PA bacteraemia followed up at
Page 13 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
13
286 any of the participating centres during the study period. The study will be conducted in
287 accordance with the STROBE recommendations (See Research Checklist)[16].
288
289 Study population
290 Data will be collected on all adult (≥ 18 years) onco-haematological neutropenic
291 patients diagnosed with at least one episode of PA bacteraemia during the study
292 period.
293
294 Study period
295 Participating centres will retrospectively review all episodes of PA bacteraemia
296 occurring in neutropenic onco-haematological patients from January 1st 2006 to May
297 31st 2018.
298
299 Setting
300 The study will be conducted at 34 centres from 12 different countries: Spain (14),
301 Turkey (4), Brazil (3), Italy (3), Argentina (2), Germany (2), Chile (1), Colombia (1),
302 Lebanon (1), Slovakia (1), Switzerland (1) and United Kingdom (1).
303
304 Selection of cases
305 Patients will be identified from previous retrospective and prospective databases or
306 from the records of the Microbiology laboratory at each hospital.
307
308 Inclusion Criteria
309 1. Adult patients (≥ 18 years)
Page 14 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
14
310 2. Patients diagnosed with a haematological malignancy and/or hematopoietic stem
311 cell transplant (HSCT) recipients, or with solid organ tumour.
312 3. The presence of neutropenia (<500 neutrophils/mm3) at the bacteraemia onset.
313 4. Episodes of monomicrobial PA bacteraemia or polymicrobial bacteraemia in which
314 PA is one of the etiological agents, including community, health-care and
315 nosocomial infections.
316 5. Subsequent episodes of PA bacteraemia diagnosed in a patient may be included if
317 the interval between them is30 days.
318
319 Exclusion criteria
320 Patients with any of the following will be excluded from the study:
321 1. Unavailability of key data (empirical and targeted therapy and vital status at 30-
322 days).
323 2. Episodes occurring in non-neutropenic cancer patients.
324 3. Episodes occurring outside the study period.
325 4. Age <18 years old.
326
327 Data collection
328 Patients’ data will be collected retrospectively. These data will be obtained from
329 various sources, including patients’ electronic records, patients’ notes, the hospital
330 laboratory systems, and the hospital patient administration system.
331 The following data will be collected for all cases: sex, age, type of underlying
332 disease and comorbidities, underlying malignancy status, severity of the episode of
333 febrile neutropenia according to the MASCC index score [17], place of acquisition of
Page 15 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
15
334 infection [18], source of bacteraemia, bacteraemia source control status, clinical and
335 microbiological data, total duration of neutropenia (including days of neutropenia
336 before and after BSI onset), prior therapies received (including antibiotics and
337 immunosuppressive treatments), empirical and definitive antimicrobial therapy, doses
338 and duration of each antibiotic therapy, need for intensive care unit admission and
339 mechanical ventilation, persistent bacteraemia, relapse of bacteraemia, colonisation
340 and/or superinfection by resistant organisms, development of other complications, 48-
341 hours, 7-day and 30-day case-fatality rates.
342
343 Patient and Public Involvement
344 Patients and public will not be involved in the design or development of the study.
345 Definitions
346 - Empirical antibiotic therapy: Antimicrobial therapy administered before reception of
347 definitive antibiotic susceptibility results.
348 - Definitive antibiotic therapy: antimicrobial therapy administered according to
349 definitive antibiotic susceptibility results.
350 - Adequate antibiotic therapy: therapy based on at least one in vitro active antibiotic
351 against the PA strain causing the infection. Monotherapy with an active
352 aminoglycoside will be considered adequate.
353 - Persistent bacteremia: persistent BSI beyond the first 48 hours of adequate antibiotic
354 therapy.
355 - Bacteremia Relapse: relapse of BSI within 7 days of treatment discontinuation.
356
357
Page 16 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
16
358 Microbiological studies
359 Clinical samples are processed at the microbiology laboratories of each participating
360 centre in accordance with standard operating procedures. PA will be identified using
361 standard microbiological techniques at each centre. In vitro susceptibility is
362 determined according to the EUCAST recommendations [19]. The specific mechanisms
363 of resistance will be provided when possible, according to molecular analyses.
364 Phenotype stratification of PA isolates is made in accordance with recent standard
365 definitions [20]. MDR PA: the isolate is non-susceptible to at least one agent in three or
366 more of the following antimicrobial categories: aminoglycosides, antipseudomonal
367 carbapenems, antipseudomonal fluoroquinolones, antipseudomonal cephalosporins,
368 antipseudomonal penicillins + beta-lactamase-inhibitors, monobactams, fosfomycin,
369 polymyxins. XDR PA: the isolate is non-susceptible to at least one agent in all but two
370 or fewer of the antimicrobial categories listed above. PDR PA: the isolate is non-
371 susceptible to all antimicrobial agents listed above.
372 Participant timeline
373 The follow-up period will last one month after bacteraemia onset.
374
375 Study outcomes and endpoint assessment
376 Primary endpoint
377 Case-fatality rate at 30 days from onset of bacteraemia.
378 Secondary endpoints
379 48-hours and 7-day case-fatality rates from onset of bacteraemia.
Page 17 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
17
380 Prevalence and risk factors for multidrug and extremely drug resistance
381 acquisition
382 Efficacy of ceftolozane-tazobactam for the treatment of bacteraemia due to PA,
383 measured by all-cause (30-day) case-fatality rate.
384 Rate of persistent bacteraemia beyond the first 48 hours of adequate antibiotic
385 therapy.
386 Rate of bacteraemia relapse within 14 days of treatment discontinuation.
387 Rate of other complications within 30 days from bacteraemia onset (e.g. ICU
388 admission, etc).
389 Sample size
390 The total number of episodes of PA bacteraemia in the participating centres during the
391 study period will determine the sample size. According to the previous experience of
392 each participating centre, we expect to record around 1000 episodes during the study
393 period, allowing the estimation of 95% confidence intervals with a 3% margin of error.
394
395 Statistical analysis
396 Baseline characteristics of participants will be described using mean and standard
397 deviation for continuous variables and frequencies for categorical variables.
398 Cumulative incidence rate will be calculated as the number of events divided by
399 participants at risk at bacteraemia onset. The 95% confidence interval will be
400 estimated using normal approximation for large incidence values (above 10%) and
401 Poisson approximation for small ones. A set of demographic and clinical factors will be
402 analyzed to quantify their association with the following outcomes: 30-day mortality,
Page 18 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
18
403 MDR and XDR. To do so, a logistic regression model will be used, and odds ratios with
404 confidence intervals will be presented. Patients’ mortality survival functions will be
405 estimated using Kaplan-Meier curves and compared using the log-rank test. Moreover,
406 survival functions will also be analysed at 7, 14 and 30 days. No missing data are
407 expected regarding the main outcomes, since unavailability of related data is an
408 exclusion criterion. With sensitivity purposes, the main analyses will be replicated in
409 patients with high-risk bacteremia, such as those with pneumonia. Model
410 assumptions, conditions and residuals will be assessed. A p-value <0.05 will be
411 considered statistically significant. The analysis will be performed using R software (R
412 v. 3.2.5).
413
414 Ethical Issues
415 The study has been approved by the Comité Ético de Investigación Clínica del Hospital
416 Universitari de Bellvitge (Institutional Review Board of Clinical Research, Bellvitge
417 University Hospital). To protect personal privacy, identifying information of each
418 patient in the electronic database will be encrypted. The processing of the patients’
419 personal data collected in this study shall comply with the Data Protection Act 1998
420 and with the European Directive on the Privacy of Data. All data collected, stored and
421 processed will be anonymised. The investigator/research lead at each site will
422 guarantee that all team members or other persons involved at the site in question will
423 respect the confidentiality of any information concerning the study patients. The
424 Clinical Research Ethics Committee has waived the need for informed consent due to
425 the retrospective nature of the study.
426
Page 19 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
19
427 PUBLICATION PLAN
428 Results will be reported at conferences and in peer-reviewed publications. The first
429 publication will be based on data from all sites, and will be analysed as stipulated in
430 the protocol with supervision by statisticians. Any formal presentation or publication
431 of data collected from this study will be considered as a joint publication by the
432 participating investigators and will follow the recommendations of the International
433 Committee of Medical Journal Editors (ICMJE).
434 DISCUSSION
435 In recent years, a shift towards an increase of Gram-negative bacterial infections has
436 been described worldwide. This trend has been especially notable among neutropenic
437 cancer patients, in whom Gram-negative bacilli (GNB) are the leading cause of
438 bacteraemia at some institutions [1]. Neutropenic patients with onco-haematological
439 malignancies are considered a population at high risk for MDR bacterial infections
440 because of their need for long hospitalization and significant antibiotic pressure [21]. In
441 this regard, recent studies have described an alarming increase in the incidence of
442 bacteraemia due to extended-spectrum beta-lactamase-producing (ESBL) and
443 carbapenem-resistant (CP) Enterobacteriaceae among neutropenic cancer patients,
444 which may substantially impair patients’ outcomes [4,5,22].
445 Classically, PA has been one of the leading causes of bacteraemia in
446 neutropenic patients with haematological malignancies and solid tumours, and is
447 associated with poor prognosis [6,8-10]. In recent years, particular attention has been
448 paid to the emergence of MDR Enterobacteriaceae, and data on the current
449 epidemiology of PA bacteraemia and the impact of antibiotic resistance in this high-
Page 20 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
20
450 risk population are lacking. The existing literature is based on heterogeneous studies
451 some of which present methodological shortcomings [12-14,23-25].
452 Firstly, most of the studies have a retrospective and single-centre design [12,13,23-
453 25]. Only three prospective studies have addressed this issue and all have a small
454 sample size; in addition, the fact they were conducted more than seven years ago does
455 not allow the extrapolation of the data to the current era of multidrug resistance
456 [4,12,13,]. In addition, the few studies with a multicentre design have included only
457 centres from the same country, and therefore, the results may not be representative
458 of different geographical areas [14,26]. Secondly, some studies include a diverse variety
459 of infections due to PA, and only a few focus exclusively on patients with PA
460 bacteraemia [12,14,23,24]. Thirdly, only two recent studies describe the current risk factors
461 for MDR-PA acquisition and for mortality in this high-risk population [14, 24] However,
462 one of these studies is a retrospective, single-centre Korean study involving only
463 paediatric patients [24], and the other is a retrospective, 3-centre study limited to the
464 city of Athens [14].
465 The published data comparing the efficacy of combined empirical antibiotic
466 treatment including two active antipseudomonal agents versus monotherapy in
467 patients with febrile neutropenia are controversial. The aim of empirical combination
468 therapy is to provide extended-spectrum coverage against MDR organisms in high-risk
469 patients, since a delayed initiation of adequate antibiotic treatment has been
470 associated with poorer outcomes, particularly in patients with PA bacteraemia
471 [12,14,24,25]. However, an important meta-analysis published in 2013 was unable to show
472 any advantage of combination antibiotic treatment in cancer patients with
473 neutropenia [27]. Nonetheless, in a recently published report, Tofas et al. found a trend
Page 21 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
21
474 towards improved survival with combination therapy in this setting [14]. Clearly, more
475 studies are needed to analyse whether combination therapy could be beneficial in the
476 current era of multidrug resistance.
477 Clinical experience with the use of new broad-spectrum beta-lactams to treat
478 MDR-PA infections, such as ceftolozane-tazobactam, is gradually accumulating in the
479 general population. However, little is known about its use for the treatment of MDR-
480 PA bacteraemia in neutropenic cancer patients.
481 The present study aims to identify the current impact of the antibiotic
482 resistance on outcomes in neutropenic patients with PA bacteraemia, and to
483 determine the risk factors associated with multidrug resistance and mortality. We will
484 also assess the efficacy of new broad-spectrum beta-lactams against MDRPA strains,
485 since alternative treatments are urgently needed in this vulnerable population. This
486 study shall provide useful information for physicians’ daily clinical practice, who need
487 to rapidly identify patients at high risk for MDRPA bacteraemia, to be able to promptly
488 initiate effective antimicrobial therapy and improve patients’ outcomes.
489
490
491
492
493
494
495
496
497
Page 22 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
22
498 REFERENCES
499 1- Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features,
500 antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer
501 patients. Clin Microbiol Infect 2013; 19: 474–9.
502 2- Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: A
503 practical update. Virulence 2016; 7:280-97.
504 3- Mikulska M, Viscoli C, Orasch C, et al. Fourth European Conference on Infections in
505 Leukemia Group a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID.
506 Aetiology and resistance in bacteraemias among adult and paediatric haematology and
507 cancer patients. J Infect 2014; 68:321-31.
508 4- Trecarichi EM, Tumbarello M, Spanu T, et al. Incidence and clinical impact of
509 extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance
510 in bloodstream infections caused by Escherichia coli in patients with hematological
511 malignancies. J Infect 2009; 58:299-307.
512 5- Satlin MJ, Cohen N, Ma KC, et al. Bacteremia due to carbapenem-resistant
513 Enterobacteriaceae in neutropenic patients with hematologic malignancies. J Infec
514 2016; 73:336-45.
515 6- Cherif H, Kronvall G, Bjorkholm M, Kalin M. Bacteraemia in hospitalised patients
516 with malignant blood disorders: a retrospective study of causative agents and their
517 resistance profiles during a 14-year period without antibacterial prophylaxis. Hematol J
518 2003; 4:420-6.
519 7- Gratwohl A, Baldomero H, Gratwohl M, et al. Quantitative and qualitative
520 differences in use and trends of hematopoietic stem cell transplantation: a Global
521 Observational Study. Haematologica 2013; 98:1282-90.
Page 23 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
23
522 8- Kara O, Zarakolu P, Ascioglu S, et al. Epidemiology and emerging resistance in
523 bacterial bloodstream infections in patients with hematologic malignancies. Infect Dis
524 (Lond) 2015; 47:690-7.
525 9- Spanik S, Kukuckova E, Pichna P, et al. Analysis of 553 episodes of monomicrobial
526 bacteraemia in cancer patients: any association between risk factors and outcome to
527 particular pathogen? Support Care Cancer 1997; 5:330-3.
528 10- Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia:
529 epidemiology, microbiology, and risk stratification. Clin Infect Dis 2005; 40 Suppl
530 4:S240-S5.
531 11- Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated
532 with healthcare-associated infections: summary of data reported to the National
533 Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-
534 2010. Infect Control Hosp Epidemiol 2013; 34:1-14.
535 12- Cattaneo C, Antoniazzi F, Casari S, et al. P. aeruginosa bloodstream infections
536 among hematological patients: an old or new question? Ann Hematol 2012; 91:1299-
537 304.
538 13- Trecarichi EM, Tumbarello M, Caira M, et al. Multidrug resistant Pseudomonas
539 aeruginosa bloodstream infection in adult patients with hematologic malignancies.
540 Haematologica 2011; 96:e1-e3.
541 14- Tofas P, Samarkos M, Piperaki ET, et al. Pseudomonas aeruginosa bacteraemia in
542 patients with hematologic malignancies: risk factors, treatment and outcome. Diagn
543 Microbiol Infect Dis 2017; 88:335-41.
544 15- Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients with solid
545 tumors. Virulence 2016; 7:298-308.
Page 24 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
24
546 16- Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP;
547 STROBE Initiative. The Strengthening the Reporting of Observational Studies in
548 Epidemiology (STROBE) statement: guidelines for reporting observational studies.
549 Lancet 2007; 370:1453–7.
550 17- Klastersky J, Paesmans M, Ruberstein EB, Boyer M, Elting L, Feld R et al. The
551 Multinational Association for Supportive Care in Cancer Risk Index: a multinational
552 scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol
553 2000; 18:3038-51.
554 18- Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al.Health
555 care–associated bloodstream infections in adults: a reason to change the accepted
556 definition of community-acquired infections Ann Intern Med 2002;137:791–7.
557 19- The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables
558 for interpretation of MICs and zone diameters, version 8.0, 2018.
559 20- Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug resistant, extensively drug-
560 resistant and pandrug-resistant bacteria: an International expert proposal for interim
561 standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–81.
562 21-Kang Cl, Kim SH, Park WB, et al. Bloodstream infections caused antibiotic-resistant
563 Gram-negative bacilli: risk factors for mortality and impact of innapropiate initial
564 antimicrobial therapy on outcome. Antimicrob Agent Chemother 2005;49:760-6.
565 22-Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias
566 among adult and paediatric haematology and cancer patients. J Infect (2013).
567 23-Vuotto F, Berthon C, Lemaitre N, etc al. Risk factors, clinical features and outcomes
568 of Pseudomonas aeruginosa bacteraemia in patients with haematological
Page 25 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
25
569 malignancies: a case-control study. American Journal of Infection Control 2013;41:527-
570 30.
571 24-Kim H, Park B, Kim S, et al. Clinical characteristics and outcomes of Pseudomonas
572 aeruginosa bacteraemia in febrile neutropenic children and adolescents with the
573 impact of antibiotic resistance: a retrospective study. BMC Infectious Diseases 2017
574 17:500-10.
575 25-Samonis G, Vardakas K, Kofteridis D, et al. Characteristics, risk factors and outcomes
576 of adult cancer patients with extensively drug-resistant Pseudomonas aeruginosa
577 infections. Infection 2014.
578 26-Trecarichi E, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial
579 resistance data for bacterial bloodstream infections in patients with haematological
580 malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect 2015;
581 21:337-343.
582 27- Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-lactam-
583 aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane
584 Database of Systematic Reviews 2013, Issue 6. Art. No.: CD003038
585
586
587
588
589
590
591
592
Page 26 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
26
593 Authors’ contributions:
594 All authors were involved in the study concept. APu-Al, CGu, RP, and JCa were involved
595 in the design of the study. CTe was responsible for the elaboration of the statistical
596 analysis plan. DTo will be responsible of the elaboration of the online database. APu-
597 Al, MAk, RAr, ABo, A-SBr, SCa, LDr, EGa, PHe, FHe, K-YIb, BIs, SSKa, WKe, GMa-Ca, AMa,
598 JIMa, IMa-Go, PMa-Da, MMi, MMo, MMo, HMPMo, IMo, ANo, COl, MPe, JLPo, PPu-Al,
599 IRu-Ca, ROSi, RTi, LYa, MZRGo, GCu, FEs-Vi, MRoAr, CMeAy, JMu, OGa, P-YBo, OMa,
600 SEZe, J-FJa, HBe, GPe-Ho, MLi, JMAg, BPa, JFo, GMa, LMa, RCe, LLo-So, JPHo, MHMo,
601 MdCu, JRo-Ba, RGr, PCi, MBa, NCa, PSaAl, CCa, CGa-Vi, Jag-Co, NLa, AUy-On, ANa-Ze,
602 LClCo, WVaFr, and AApSiMa will be responsible for the data collection and
603 introduction in the online database. FTu will be responsible for the microbiological
604 supervision of the study. APu-Al, CGu, CTe, and JCa drafted and revised the
605 manuscript. All authors reviewed and approved the final version of the manuscript.
606 Acknowledgement:
607 We thank the ESGBIS and the ESGICH study groups for supporting the study.
608 Funding statement:
609 This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud
610 Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa,
611 Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in
612 Infectious Diseases (REIPI RD16/0016/0001) - co-financed by European Development
613 Regional Fund “A way to achieve Europe”, Operative Programme Intelligent Growth
614 2014-2020.
615 Competing interests’ statement
Page 27 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
27
616 ASB received grant from Promex Stiftung fur die Forschung (by Carigest SA), and
617 funding by Gilead to assist to the ECCMID congress (2018). Oguz Resat Sipahi received
618 speaker’s honorarium from MSD, Astellas, Novartis and Pfizer.
Page 28 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
STROBE Statement—checklist of items that should be included in reports of observational studies
Item
No. Recommendation
Page
No.
Relevant text from
manuscript
Title and abstract 1 (a) Indicate the study’s design with a commonly used term in the title or the abstract 1
(b) Provide in the abstract an informative and balanced summary of what was done and what was
found
7
Introduction
Background/rationale 2 Explain the scientific background and rationale for the investigation being reported 10
Objectives 3 State specific objectives, including any prespecified hypotheses 12
Methods
Study design 4 Present key elements of study design early in the paper 12-13
Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure,
follow-up, and data collection
13
Participants 6 (a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of
participants. Describe methods of follow-up
Case-control study—Give the eligibility criteria, and the sources and methods of case
ascertainment and control selection. Give the rationale for the choice of cases and controls
Cross-sectional study—Give the eligibility criteria, and the sources and methods of selection of
participants
13-15
(b) Cohort study—For matched studies, give matching criteria and number of exposed and
unexposed
Case-control study—For matched studies, give matching criteria and the number of controls per
case
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers.
Give diagnostic criteria, if applicable
14-15
Data sources/
measurement
8* For each variable of interest, give sources of data and details of methods of assessment
(measurement). Describe comparability of assessment methods if there is more than one group
16-17
Bias 9 Describe any efforts to address potential sources of bias 17
Study size 10 Explain how the study size was arrived at 7
Continued on next page
Page 29 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review only
2
Quantitative
variables
11 Explain how quantitative variables were handled in the analyses. If applicable, describe which
groupings were chosen and why
17
Statistical
methods
12 (a) Describe all statistical methods, including those used to control for confounding 17
(b) Describe any methods used to examine subgroups and interactions 17
(c) Explain how missing data were addressed 17
(d) Cohort study—If applicable, explain how loss to follow-up was addressed
Case-control study—If applicable, explain how matching of cases and controls was addressed
Cross-sectional study—If applicable, describe analytical methods taking account of sampling
strategy
17
(e) Describe any sensitivity analyses 17
Results
Participants 13* (a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined
for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed
NA
(b) Give reasons for non-participation at each stage NA
(c) Consider use of a flow diagram NA
Descriptive data 14* (a) Give characteristics of study participants (eg demographic, clinical, social) and information on
exposures and potential confounders
NA
(b) Indicate number of participants with missing data for each variable of interest NA
(c) Cohort study—Summarise follow-up time (eg, average and total amount) NA
Outcome data 15* Cohort study—Report numbers of outcome events or summary measures over time NA
Case-control study—Report numbers in each exposure category, or summary measures of exposure NA
Cross-sectional study—Report numbers of outcome events or summary measures NA
Main results 16 (a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision
(eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were
included
NA
(b) Report category boundaries when continuous variables were categorized NA
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time
period
Continued on next page
Page 30 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review only
3
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses NA
Discussion
Key results 18 Summarise key results with reference to study objectives NA
Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss
both direction and magnitude of any potential bias
9
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of
analyses, results from similar studies, and other relevant evidence
NA
Generalisability 21 Discuss the generalisability (external validity) of the study results 19-21
Other information
Funding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the
original study on which the present article is based
26
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE
checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at
http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
Page 31 of 30
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright. http://bmjopen.bmj.com/ BMJ Open: first published as 10.1136/bmjopen-2018-025744 on 24 May 2019. Downloaded from
For peer review onlyImpact of antibiotic resistance on outcomes of neutropenic cancer patients with Pseudomonas aeruginosa bacteraemia
(IRONIC study): Study protocol of a retrospective multicentre international study.
Journal: BMJ Open
Manuscript ID bmjopen-2018-025744.R2
Article Type: Protocol
Date Submitted by the Author: 05-Mar-2019
Complete List of Authors: Albasanz-Puig, Adaia; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Gudiol, Carlota; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Parody, Rocío; Institut Catala d' Oncologia, Haematology DepartmentTebe, Cristian; Institut d\'Investigacio Biomedica de Bellvitge, Statistics Advisory ServiceAkova, Murat; Hacettepe UniversitesiAraos, Rafael; Universidad del Desarrollo Facultad de MedicinaBote, Anna; Consorcio Corporacion Sanitaria Parc Tauli, Infectious Diseases Brunnel, Anne-Sophie; Centre Hospitalier Universitaire Vaudois, Infectious DiseasesCalik, Sebnem; Izmir Bozyaka Egitim ve Arastirma Hastanesi, Infectious Diseases DepartmentDrgona, Lubos; Univerzita Komenskeho v Bratislave, Oncohematology DepartmentGarcía, Estefanía; Hospital Universitario Reina Sofia, Oncohematology DepartmentHemmati, Philipp; Klinikum Ernst von Bergmann, Haematology DepartmentHerrera, Fabián; Centro de Educación Médica e Investigaciones Clínicas, Infectious Diseases DepartmentIbrahim, Karim Yaqub; Universidade de Sao Paulo Faculdade de MedicinaIsler, Burcu; Istanbul Fizik Tedavi Rehabilitasyon Egitim ve Arastirma Hastanesi, Infectious Diseases DepartmentKanj, Souha; American University of Beirut Medical Center, Internal Medicine-Division of Infectious DiseasesKern, Winfried; Universite de Fribourg Departement de medecine, Infectious Diseases DepartmentMaestro-de la Calle, Guillermo; Hospital Universitario 12 de Octubre, Infectious Diseases UnitManzur, Adriana; Hospital Rawson, Infectious Diseases DepartmentMarin, Jorge Iván; Clínica Maraya, Infectious Diseases DepartmentMárquez-Gómez, Ignacio; Hospital Regional Universitario de Malaga, Infectious Diseases Department
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open on January 13, 2021 by guest. P
rotected by copyright.http://bm
jopen.bmj.com
/B
MJ O
pen: first published as 10.1136/bmjopen-2018-025744 on 24 M
ay 2019. Dow
nloaded from
For peer review only
Martín-Dávila, Pilar; Hospital Universitario Ramon y Cajal, Infectious Diseases DepartmentMikulska, Malgorzata; Ospedale Policlinico San Martino, Infectious Diseases DepartmentMontejo, José Miguel; Hospital Universitario Cruces, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Montero, Milagros; Institut Hospital del Mar d'Investigacions Mediques, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Morales, Hugo Manuel Paz; Hospital Erasto Gaertner, Infectious Diseases DepartmentMorales, Isabel; Hospital Universitario Virgen Macarena, Emergency Clinical Unit; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Novo, Andrés; Hospital Universitari Son Espases, Haematology DepartmentOltolini, Chiara; Ospedale San Raffaele, Infectious and Tropical Diseases DepartmentPeghin, Maddalena; Hospital Santa Maria Misericordia, Infectious DiseasesDel Pozo, Jose Luis; Clinica Universitaria de Navarra, Infectious Diseases And Microbiology DepartmentPuerta-Alcalde, Pedro; Hospital Clinic de Barcelona, Infectious Diseases Department; Instituto de Salud Carlos III, Spanish Network for Research in Infectious Diseases (REIPI)Ruiz-Camps, Isabel; Hospital Vall d'Hebron, Infectious Diseases Department; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)Sipahi, Oguz Resat; Ege Universitesi Tip FakultesiTilley, Robert; University Hospital Plymouth NHS Trust, Mircobiology DepartmentYáñez, Lucrecia; Hospital Universitario Marques de Valdecilla, Haematology DepartmentRibeiro Gomes, Marisa Zenaide; Hospital Federal Servidores do Estado, Ministério da Saúde and Instituto Oswaldo CruzCarratala, Jordi; Hospital Universitari de Bellvitge, Infectious Diseases; Instituto de Salud Carlos III, Network for Research in Infectious Diseases (REIPI)
<b>Primary Subject Heading</b>: Infectious diseases
Secondary Subject Heading: Oncology, Haematology (incl blood transfusion)
Keywords: Pseudomonas aeruginosa, Onco-Haematological Patients, Bacteraemia, Bloodstream Infection, Neutropenia, Multidrug-Resistant
Page 1 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
1 Impact of antibiotic resistance on outcomes of neutropenic cancer patients with
2 Pseudomonas aeruginosa bacteraemia (IRONIC study): Study protocol of a
3 retrospective multicentre international study.
4
5 Authors: Albasanz-Puig, Adaia1,37, Gudiol, Carlota1,37, Parody, Rocío2, Tebe, Cristian3,
6 Akova, Murat4, Araos, Rafael5, Bote, Anna6, Brunel, Anne-Sophie7, Calik, Sebnem8,
7 Drgona, Lubos9, García, Estefanía10, Hemmati, Philipp11, Herrera, Fabián12, Ibrahim,
8 Karim Yaqub13, Isler, Burcu14, Kanj, Souha15, Kern, Winfried16, Maestro-de la Calle,
9 Guillermo17, Manzur, Adriana18, Marin, Jorge Iván19, Márquez-Gómez, Ignacio20, Martín-
10 Dávila, Pilar21, Mikulska, Malgorzata22, Montejo, Miguel23,37, Montero, Milagros24,37,
11 Morales, Hugo Manuel Paz25, Morales, Isabel26,37, Novo, Andrés27, Oltolini, Chiara28,
12 Peghin, Maddalena29, Del Pozo, Jose Luis30, Puerta-Alcalde, Pedro31,37, Ruiz-Camps,
13 Isabel32,37, Sipahi, Oguz Resat33, Tilley, Robert34, Yáñez Lucrecia35, Ribeiro Gomes, Marisa
14 Zenaide36, and Carratalà, Jordi1,37 for the IRONIC study group*.
15
16 Affiliations: 1Infectious Diseases Department, Bellvitge University Hospital, IDIBELL,
17 University of Barcelona, Spain. 2Haematology Department, Institut Català d’Oncologia
18 (ICO) – Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. 3Statistics Advisory Service,
19 Institute of Biomedical Research of Bellvitge, Rovira i Virgili University. 4Department of
20 Infectious Diseases, Hacettepe University School of Medicine, Ankara, Turkey. 5Instituto
21 de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana
22 Universidad del Desarrollo, Santiago de Chile, Chile. 6Infectious Diseases Department,
23 Parc Taulí University Hospital, Sabadell, Barcelona, Spain. 7Infectious Diseases
24 Department, Department of Medicine, Lausanne University Hospital, (CHUV), Lausanne,
Page 2 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
2
25 Switzerland. 8University of Health Science Izmir Bozyaka Training and Research Hospital,
26 Turkey. 9Oncohematology Department, Comenius University and National Cancer
27 Institute, Bratislava, Slovakia. 10Salvador Tabares Carrasco and Josefina Serrano López,
28 Haematology Department, Reina Sofía University Hospital-IMIBIC-UCO, Córdoba.
29 11Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von
30 Bergmann, Academic Teaching Hospital of Charité University Medical School, Berlin,
31 Germany. 12Infectious Diseases Section, Department of Medicine, Centro de Educación
32 Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina. 13Instituto do
33 Câncer do Estado de São Paulo, Faculty of Medicine, Univesity of São Paulo, Brazil
34 14Department of Infectious Diseases and Clinical Microbiology, Istanbul Education and
35 Research Hospital, Istanbul, Turkey.15Infectious Diseases Division, American University
36 of Beirut Medical Center, Beirut, Lebanon.16Division of Infectious Diseases, Department
37 of Medicine II, University of Freiburg Medical Center and Faculty of Medicine, Freiburg,
38 Germany. 17Infectious Diseases Unit, Instituto de Investigación Hospital “12 de Octubre”
39 (i+12), “12 de Octubre” University Hospital, School of Medicine, Universidad
40 Complutense, Madrid, Spain. 18Infectious Diseases, Hospital Rawson, San Juan,
41 Argentina. 19Infectious Diseases and Clinical Microbiology Department, Clínica Maraya,
42 Pereira Colombia. Critical care and Clinical Microbiology Department, Manizales,
43 Colombia. 20Infectious Diseases Department, Hospital Regional de Málaga, Málaga,
44 Spain. 21Infectious Diseases Department, Ramon y Cajal Hospital, Madrid, Spain.
45 22Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico
46 San Martino, Genoa, Italy. 23Infectious Diseases Unit, Cruces University Hospital, Bilbao,
47 Spain. 24Infectious Diseases Service, Hospital del Mar, Infectious Pathology and
48 Antimicrobials Research Group (IPAR), Institut Hospital del Mar d' Investigacions
Page 3 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
3
49 Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu
50 Fabra, Barcelona, Spain. 25Infectious Diseases Department, Hospital Erasto Gaertner,
51 Curitiba, Brazil. 26Emergency Clinial Unit, Hospital Universitario Virgen Macarena,
52 Sevilla, Spain. 27Haematology Department, Son Espases University Hospital, Palma de
53 Mallorca, Spain. 28Unit of Infectious and Tropical Diseases, IRCCS San Raffaele Scientific
54 Institute, Milan, Italy. 29Infectious Diseases Clinic, Department of Medicine, University
55 of Udine and Azienda Sanitaria Universitaria Integrata, Udine, Italy.30Infectious Diseases
56 and Microbiology Unit, Navarra University Clinic, Pamplona, Spain. 31Infectious Diseases
57 Department, Hospital Clínic i Provincial, Barcelona, Spain. 32Infectious Diseases
58 Department, Vall d’Hebron University Hospital, Barcelona, Spain. 33Ege University
59 Faculty of Medicine, Izmir Turkey. 34Microbiology Department, University Hospitals
60 Plymouth NHS Trust, United Kingdom. 35Haematology Department, Marqués de
61 Valdecilla University Hospital, Santander, Spain. 36Hospital Federal Servidores do Estado,
62 Ministério da Saúde and Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro,
63 Brazil 37REIPI (Spanish Network for Research in Infectious Disease), Instituto de Salud
64 Carlos III, Madrid, Spain.
65
66 Corresponding author: Dr. Carlota Gudiol
67 Infectious Diseases Department
68 Bellvitge University Hospital
69 Feixa Llarga s/n, 08907, L’Hospitalet de Llobregat, Barcelona, Spain.
70 Tel. +34 93 260 7625
71 Fax. + 34 93 260 7537
72 Email: cgudiol@iconcologia.net
Page 4 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
4
73 *IRONIC STUDY INVESTIGATORS
74 Guillermo Cuervo and Francesc Escrihuela-Vidal, Infectious Diseases Department, and
75 Fe Tubau, Microbiology Department, Bellvitge University Hospital, IDIBELL, Barcelona,
76 Spain. Marisol Rodríguez Arias, Oncology Department, Institut Català d’Oncologia (ICO)
77 - Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. Caglayan Merve Ayaz, Infectious
78 Diseases Department, Hacettepe University School of Medicine, Ankara, Turkey. Jose
79 Munita, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica
80 Alemana Universidad del Desarrollo, Santiago de Chile, Chile. Oriol Gasch, Infectious
81 Diseases Department, and Sílvia Capilla, Microbiology Department, Parc Taulí University
82 Hospital, Sabadell, Barcelona, Spain. Pierre-Yves Bochud and Oriol Manuel, Infectious
83 Diseases Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.
84 Diego Torres, Infectious Diseases Section, Department of Medicine, Centro de Educación
85 Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina. Saeed El Zein and
86 Jean-Francois Jabbour, Infectious Diseases Division, American University of Beirut
87 Medical Center, Beirut, Lebanon. Hartmut Bertz, Haematology-Oncology Department,
88 and Gabriele Peyerl-Hoffmann, Division of Infectious Diseases, Department of Medicine
89 II, University of Freiburg Medical Center and Faculty of Medicine, Freiburg, Germany.
90 Manuel Lizasoain and José María Aguado, Infectious Diseases Unit, 12 de Octubre
91 University Hospital, Madrid Spain. Begoña Palop, Microbiology Deparment, Hospital
92 Regional de Málaga, Málaga, Spain. Jesús Fortún, Infectious Diseases Department,
93 Ramón y Cajal Hospital, Madrid, Spain. Georg Maschmeyer, Department of
94 Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic
95 Teaching Hospital of Charité University Medical School, Berlin, Germany. Laura
96 Magnasco, Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale
Page 5 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
5
97 Policlinico San Martino, Genoa, Italy. Roberto Céspedes, Haematology Department, and
98 Leire López-Soria, Microbiology Department, Cruces University Hosptial, Bilbao, Spain.
99 Juan Pablo Horcajada, Infectious Diseases Service, Hospital del Mar, Infectious
100 Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar
101 d’Investigations Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-
102 Universitat Pompeu Fabra, Barcelona, Spain. Mia Hold Montaguti, Infectious Diseases
103 Department, Hospital Erasto Gaertner, Curitiba, Brazil. Marina de Cueto and Jesús
104 Rodríguez-Baño, Clinical Unit of Infectious Diseases, Microbiology and Preventive
105 Medicine, University Hospitals Virgen Macarena and Virgen del Rocío - IBiS;
106 Departament of Medicine, University of Seville, Seville, Spain. Raffaella Greco,
107 Haematology and Bone Marrow Transplantation Unit, and Paola Cichero, Microbiology
108 and Virology Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy. Matteo
109 Bassetti and Nadia Castaldo, Infectious Diseases Clinic, Department of Medicine,
110 University of Udine and Azienda Sanitaria Universitaria Integrata, Udine, Italy. Paloma
111 Sangro del Alcázar, Internal Medicine Department, Navarra University Clinic, Pamplona,
112 Spain. Celia Cardozo and Carolina Garcia-Vidal, Infectious Diseases Department,
113 Hospital Clínic i Provincial, Barcelona, Spain. Juan Aguilar-Company, Oncology
114 Department, and Nieves Larrosa, Microbiology Department, Vall d’Hebron University
115 Hospital, Barcelona, Spain. Ayse Uyan-Onal Department of Infectious Diseases and
116 Clinical Microbiology, Ege University Faculty of Medicine, Izmir Turkey. Arzu Nazli-Zeka
117 Department of Infectious Diseases and Clinical Microbiology, Dokuz Eylul University
118 Faculty of Medicine, Izmir Turkey. Lina Clemencia Correa, Clinica Maraya, Pereira,
119 Colombia. Wania Vasconcelos de Freitas and Amanda Aparecida da Silva Machado,
120 Hospital Federal Servidores do Estado, Ministério da Saúde, Rio de Janeiro, Brazil.
Page 6 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
6
121 Abstract
122 Pseudomonas aeruginosa (PA) has historically been one of the major causes of severe
123 sepsis and death among neutropenic cancer patients. The emergence and increasing
124 prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and may determine
125 a worse prognosis, especially in immunosuppressed patients. The aim of this study is to
126 establish the impact of antibiotic resistance on the outcome of neutropenic onco-
127 haematological patients with PA bacteraemia, and to identify the risk factors for MDRPA
128 bacteraemia and for mortality.
129 Methods and Analysis
130 This is a retrospective, observational, multicentre, international study. All episodes of
131 PA bacteraemia occurring in neutropenic onco-haematological patients followed up at
132 the participating centres from January 1st 2006 to May 31st 2018 will be retrospectively
133 reviewed. The primary end-point will be overall case-fatality rate within 30 days of onset
134 of PA bacteraemia. The secondary end-points will be to describe the following: the
135 incidence and risk factors for MDR and extremely drug-resistant PA bacteraemia (by
136 comparing the episodes due to susceptible PA with those produced by MDRPA), the
137 efficacy of ceftolozane-tazobactam, the rates of persistent bacteraemia and
138 bacteraemia relapse, and the risk factors for very early (48h), early (7 day), and overall
139 (30-day) case-fatality rates.
140 Ethics and Dissemination
141 The Research Ethics Committee (REC) of Bellvitge University Hospital approved the
142 protocol of the study at the primary site. To protect personal privacy, identifying
143 information of each patient in the electronic database will be encrypted. The processing
144 of the patients’ personal data collected in the study will comply with the Spanish Data
Page 7 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
7
145 Protection Act of 1998 and with the European Directive on the Privacy of Data. All data
146 collected, stored and processed will be anonymised.
147
148 Keywords: Pseudomonas aeruginosa, onco-haematological patients, bacteraemia,
149 bloodstream infection, neutropenia, multidrug-resistant, mortality.
150
151
152
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
Page 8 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
8
169 Main strengths and limitations of this study:
170 Strengths
171 The multicentre design of the study will allow the recording of a large number of
172 episodes.
173 The international and multicentre design will provide representative results
174 regarding the current epidemiology of Pseudomonas aeruginosa (PA)
175 bacteraemia in onco-haematological patients worldwide.
176 Information will be provided on risk factors for resistance acquisition and their
177 impact on mortality in the current era of multidrug resistance.
178 Limitations
179 Due to the retrospective design some information may be lost.
180 We may not be able to control for certain measured and unmeasured
181 confounders.
182
183
184
185
186
187
188
189
190
191
Page 9 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
9
192 INTRODUCTION
193 The epidemiology of bacteraemia among neutropenic cancer patients has changed over
194 the years. In 1960s, Gram-negative bacilli were the leading cause of bacteraemia in this
195 population. In the mid-1980s, a shift from Gram-negative to Gram-positive organisms
196 was observed albeit to varying extents in different countries. This trend appears to have
197 been reversed in recent years, with a re-emergence of Gram-negative bacilli at some
198 institutions, especially those where prophylaxis with quinolones is no longer used [1-3].
199 These changes in aetiology are accompanied by an alarming increase in multidrug
200 resistance among Gram-negative bacilli [1-5].
201 Pseudomonas aeruginosa (PA) has historically been one of the major causes of
202 severe sepsis and death among neutropenic cancer patients [6-10]. The emergence and
203 increasing prevalence of multidrug-resistant PA (MDRPA) isolates is worrisome and adds
204 to the overall burden of PA infections in immunocompromised patients [11]. Moreover,
205 new treatment modalities such as aggressive myelosuppressive therapies and
206 hematopoietic stem cell transplantation, and the wide use of invasive procedures may
207 have had an impact on risk factors for PA infections and the outcome of affected
208 patients.
209 Very few studies have examined the epidemiology and the clinical course of PA
210 infections in patients with cancer in this new situation and in this era of widespread
211 antimicrobial resistance [12-14]. Moreover, data regarding bacteraemia in neutropenic
212 patients with solid tumours are particularly scarce [15]. In addition, very little is known
213 about the impact of the introduction of the new broad-spectrum β-lactams (such as
214 ceftolozane/tazobactam) in the therapeutic armamentarium for the treatment of
215 bacteraemia due to MDRPA in neutropenic cancer patients.
Page 10 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
10
216 Identifying the risk factors for infection due to MDRPA in neutropenic cancer
217 patients could help physicians to recognize patients at risk more rapidly. Therefore, the
218 early administration of a broader empirical antibiotic therapy in these high-risk patients
219 might have a positive influence on their outcomes. In the present international study,
220 we aim to determine the impact of antibiotic resistance on outcomes in neutropenic
221 cancer patients with PA bacteraemia in the current era of widespread antimicrobial
222 resistance, and also to identify predisposing factors for multidrug resistance and for
223 mortality. For this purpose, we will compare episodes due to susceptible PA with those
224 produced by MDRPA, and we will compare patients who died with those who survived.
225
226
227
228
229
230
231
232
233
234
235
236
237
238
Page 11 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
11
239 OBJECTIVES OF THE STUDY
240 Primary Objective:
241 To determine the impact of antibiotic resistance on outcomes in neutropenic
242 cancer patients with PA bacteraemia, measured by all-cause case-fatality rate at
243 30 days.
244
245 Secondary Objectives:
246 To assess the prevalence of multidrug and extremely drug resistance (XDR)
247 among PA isolates causing bacteraemia.
248 To identify the risk factors for infection due to multidrug-resistant (MDR) and
249 XDR PA.
250 To assess the efficacy of the new β-lactam ceftolozane-tazobactam for the
251 treatment of bacteraemia due to PA.
252 To estimate the cumulative incidence rates of persistent bacteraemia,
253 bacteraemia relapse, and other complications at 30 days.
254 To identify the risk factors for very early (48 hours), early (7-day), and all-cause
255 (30-day) case-fatality rates.
256
257 METHODS AND ANALYSIS
258 Study design
259 This is an international, multicentre, retrospective, observational cohort study involving
260 neutropenic cancer patients diagnosed with PA bacteraemia followed up at any of the
Page 12 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
12
261 participating centres during the study period. The study will be conducted in accordance
262 with the STROBE recommendations (See Research Checklist)[16].
263
264 Study population
265 Data will be collected on all adult (≥ 18 years) onco-haematological neutropenic patients
266 diagnosed with at least one episode of PA bacteraemia during the study period.
267
268 Study period
269 Participating centres will retrospectively review all episodes of PA bacteraemia
270 occurring in neutropenic onco-haematological patients from January 1st 2006 to May
271 31st 2018.
272
273 Setting
274 The study will be conducted at 34 centres from 12 different countries: Spain (14), Turkey
275 (4), Brazil (3), Italy (3), Argentina (2), Germany (2), Chile (1), Colombia (1), Lebanon (1),
276 Slovakia (1), Switzerland (1) and United Kingdom (1).
277
278 Selection of cases
279 Patients will be identified from previous retrospective and prospective databases or
280 from the records of the Microbiology laboratory at each hospital.
281
282 Inclusion Criteria
283 1. Adult patients (≥ 18 years)
Page 13 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
13
284 2. Patients diagnosed with a haematological malignancy and/or hematopoietic stem
285 cell transplant (HSCT) recipients, or with solid organ tumour.
286 3. The presence of neutropenia (<500 neutrophils/mm3) at the bacteraemia onset.
287 4. Episodes of monomicrobial PA bacteraemia or polymicrobial bacteraemia in which
288 PA is one of the etiological agents, including community, health-care and nosocomial
289 infections.
290 5. Subsequent episodes of PA bacteraemia diagnosed in a patient may be included if
291 the interval between them is30 days.
292
293 Exclusion criteria
294 Patients with any of the following will be excluded from the study:
295 1. Unavailability of key data (empirical and targeted therapy and vital status at 30-
296 days).
297 2. Episodes occurring in non-neutropenic cancer patients.
298 3. Episodes occurring outside the study period.
299 4. Age <18 years old.
300
301 Data collection
302 Patients’ data will be collected retrospectively. These data will be obtained from various
303 sources, including patients’ electronic records, patients’ notes, the hospital laboratory
304 systems, and the hospital patient administration system.
305 The following data will be collected for all cases: sex, age, type of underlying
306 disease and comorbidities, underlying malignancy status, severity of the episode of
307 febrile neutropenia according to the MASCC index score [17], place of acquisition of
Page 14 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
14
308 infection [18], source of bacteraemia, bacteraemia source control status, clinical and
309 microbiological data, total duration of neutropenia (including days of neutropenia
310 before and after BSI onset), prior therapies received (including antibiotics and
311 immunosuppressive treatments), empirical and definitive antimicrobial therapy, doses
312 and duration of each antibiotic therapy, need for intensive care unit admission and
313 mechanical ventilation, persistent bacteraemia, relapse of bacteraemia, colonisation
314 and/or superinfection by resistant organisms, development of other complications, 48-
315 hours, 7-day and 30-day case-fatality rates.
316
317 Patient and Public Involvement
318 Patients and public will not be involved in the design or development of the study.
319 Definitions
320 - Empirical antibiotic therapy: Antimicrobial therapy administered before reception of
321 definitive antibiotic susceptibility results.
322 - Definitive antibiotic therapy: antimicrobial therapy administered according to
323 definitive antibiotic susceptibility results.
324 - Adequate antibiotic therapy: therapy based on at least one in vitro active antibiotic
325 against the PA strain causing the infection. Monotherapy with an active aminoglycoside
326 will be considered adequate.
327 - Persistent bacteremia: persistent BSI beyond the first 48 hours of adequate antibiotic
328 therapy.
329 - Bacteremia Relapse: relapse of BSI within 7 days of treatment discontinuation.
330
331
Page 15 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
15
332 Microbiological studies
333 Clinical samples are processed at the microbiology laboratories of each participating
334 centre in accordance with standard operating procedures. PA will be identified using
335 standard microbiological techniques at each centre. In vitro susceptibility is determined
336 according to the EUCAST recommendations [19]. The specific mechanisms of resistance
337 will be provided when possible, according to molecular analyses. Phenotype
338 stratification of PA isolates is made in accordance with recent standard definitions [20].
339 MDR PA: the isolate is non-susceptible to at least one agent in three or more of the
340 following antimicrobial categories: aminoglycosides, antipseudomonal carbapenems,
341 antipseudomonal fluoroquinolones, antipseudomonal cephalosporins,
342 antipseudomonal penicillins + beta-lactamase-inhibitors, monobactams, fosfomycin,
343 polymyxins. XDR PA: the isolate is non-susceptible to at least one agent in all but two or
344 fewer of the antimicrobial categories listed above. PDR PA: the isolate is non-susceptible
345 to all antimicrobial agents listed above.
346 Participant timeline
347 The follow-up period will last one month after bacteraemia onset.
348
349 Study outcomes and endpoint assessment
350 Primary endpoint
351 Case-fatality rate at 30 days from onset of bacteraemia.
352 Secondary endpoints
353 48-hours and 7-day case-fatality rates from onset of bacteraemia.
Page 16 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
16
354 Prevalence and risk factors for multidrug and extremely drug resistance
355 acquisition
356 Efficacy of ceftolozane-tazobactam for the treatment of bacteraemia due to PA,
357 measured by all-cause (30-day) case-fatality rate.
358 Rate of persistent bacteraemia beyond the first 48 hours of adequate antibiotic
359 therapy.
360 Rate of bacteraemia relapse within 14 days of treatment discontinuation.
361 Rate of other complications within 30 days from bacteraemia onset (e.g. ICU
362 admission, etc).
363 Sample size
364 The total number of episodes of PA bacteraemia in the participating centres during the
365 study period will determine the sample size. According to the previous experience of
366 each participating centre, we expect to record around 1000 episodes during the study
367 period, allowing the estimation of 95% confidence intervals with a 3% margin of error.
368
369 Statistical analysis
370 Baseline characteristics of participants will be described using mean and standard
371 deviation for continuous variables and frequencies for categorical variables. Cumulative
372 incidence rate will be calculated as the number of events divided by participants at risk
373 at bacteraemia onset. The 95% confidence interval will be estimated using normal
374 approximation for large incidence values (above 10%) and Poisson approximation for
375 small ones. A set of demographic and clinical factors will be analyzed to quantify their
376 association with the following outcomes: 30-day mortality, MDR and XDR. To do so, a
Page 17 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
17
377 logistic regression model will be used, and odds ratios with confidence intervals will be
378 presented. Patients’ mortality survival functions will be estimated using Kaplan-Meier
379 curves and compared using the log-rank test. Moreover, survival functions will also be
380 analysed at 7, 14 and 30 days. No missing data are expected regarding the main
381 outcomes, since unavailability of related data is an exclusion criterion. With
382 sensitivity purposes, the main analyses will be replicated in patients with high-risk
383 bacteremia, such as those with pneumonia. Model assumptions, conditions and
384 residuals will be assessed. A p-value <0.05 will be considered statistically significant. The
385 analysis will be performed using R software (R v. 3.2.5).
386
387 Ethical Issues
388 The study has been approved by the Comité Ético de Investigación Clínica del Hospital
389 Universitari de Bellvitge (Institutional Review Board of Clinical Research, Bellvitge
390 University Hospital). A list with the participating centers that obtained the approval by
391 their IRB, and the centers that did not need the approval is provided in the
392 supplementary material (Suppl 1). To protect personal privacy, identifying information
393 of each patient in the electronic database will be encrypted. The processing of the
394 patients’ personal data collected in this study shall comply with the Data Protection Act
395 1998 and with the European Directive on the Privacy of Data. All data collected, stored
396 and processed will be anonymised. The investigator/research lead at each site will
397 guarantee that all team members or other persons involved at the site in question will
398 respect the confidentiality of any information concerning the study patients. The Clinical
399 Research Ethics Committee has waived the need for informed consent due to the
400 retrospective nature of the study.
Page 18 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
18
401 PUBLICATION PLAN
402 Results will be reported at conferences and in peer-reviewed publications. The first
403 publication will be based on data from all sites, and will be analysed as stipulated in the
404 protocol with supervision by statisticians. Any formal presentation or publication of data
405 collected from this study will be considered as a joint publication by the participating
406 investigators and will follow the recommendations of the International Committee of
407 Medical Journal Editors (ICMJE).
408 DISCUSSION
409 In recent years, a shift towards an increase of Gram-negative bacterial infections has
410 been described worldwide. This trend has been especially notable among neutropenic
411 cancer patients, in whom Gram-negative bacilli (GNB) are the leading cause of
412 bacteraemia at some institutions [1]. Neutropenic patients with onco-haematological
413 malignancies are considered a population at high risk for MDR bacterial infections
414 because of their need for long hospitalization and significant antibiotic pressure [21]. In
415 this regard, recent studies have described an alarming increase in the incidence of
416 bacteraemia due to extended-spectrum beta-lactamase-producing (ESBL) and
417 carbapenem-resistant (CP) Enterobacteriaceae among neutropenic cancer patients,
418 which may substantially impair patients’ outcomes [4,5,22].
419 Classically, PA has been one of the leading causes of bacteraemia in neutropenic
420 patients with haematological malignancies and solid tumours, and is associated with
421 poor prognosis [6,8-10]. In recent years, particular attention has been paid to the
422 emergence of MDR Enterobacteriaceae, and data on the current epidemiology of PA
423 bacteraemia and the impact of antibiotic resistance in this high-risk population are
Page 19 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
19
424 lacking. The existing literature is based on heterogeneous studies some of which
425 present methodological shortcomings [12-14,23-25].
426 Firstly, most of the studies have a retrospective and single-centre design [12,13,23-
427 25]. Only three prospective studies have addressed this issue and all have a small sample
428 size; in addition, the fact they were conducted more than seven years ago does not allow
429 the extrapolation of the data to the current era of multidrug resistance [4,12,13,]. In
430 addition, the few studies with a multicentre design have included only centres from the
431 same country, and therefore, the results may not be representative of different
432 geographical areas [14,26]. Secondly, some studies include a diverse variety of infections
433 due to PA, and only a few focus exclusively on patients with PA bacteraemia [12,14,23,24].
434 Thirdly, only two recent studies describe the current risk factors for MDR-PA acquisition
435 and for mortality in this high-risk population [14, 24] However, one of these studies is a
436 retrospective, single-centre Korean study involving only paediatric patients [24], and the
437 other is a retrospective, 3-centre study limited to the city of Athens [14].
438 The published data comparing the efficacy of combined empirical antibiotic
439 treatment including two active antipseudomonal agents versus monotherapy in patients
440 with febrile neutropenia are controversial. The aim of empirical combination therapy is
441 to provide extended-spectrum coverage against MDR organisms in high-risk patients,
442 since a delayed initiation of adequate antibiotic treatment has been associated with
443 poorer outcomes, particularly in patients with PA bacteraemia [12,14,24,25]. However, an
444 important meta-analysis published in 2013 was unable to show any advantage of
445 combination antibiotic treatment in cancer patients with neutropenia [27]. Nonetheless,
446 in a recently published report, Tofas et al. found a trend towards improved survival with
447 combination therapy in this setting [14]. Clearly, more studies are needed to analyse
Page 20 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
20
448 whether combination therapy could be beneficial in the current era of multidrug
449 resistance.
450 Clinical experience with the use of new broad-spectrum beta-lactams to treat
451 MDR-PA infections, such as ceftolozane-tazobactam, is gradually accumulating in the
452 general population. However, little is known about its use for the treatment of MDR-PA
453 bacteraemia in neutropenic cancer patients.
454 The present study aims to identify the current impact of the antibiotic resistance
455 on outcomes in neutropenic patients with PA bacteraemia, and to determine the risk
456 factors associated with multidrug resistance and mortality. We will also assess the
457 efficacy of new broad-spectrum beta-lactams against MDRPA strains, since alternative
458 treatments are urgently needed in this vulnerable population. This study shall provide
459 useful information for physicians’ daily clinical practice, who need to rapidly identify
460 patients at high risk for MDRPA bacteraemia, to be able to promptly initiate effective
461 antimicrobial therapy and improve patients’ outcomes.
462
463
464
465
466
467
468
469
470
471
Page 21 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
21
472 REFERENCES
473 1- Gudiol C, Bodro M, Simonetti A, et al. Changing aetiology, clinical features,
474 antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer
475 patients. Clin Microbiol Infect 2013; 19: 474–9.
476 2- Gustinetti G, Mikulska M. Bloodstream infections in neutropenic cancer patients: A
477 practical update. Virulence 2016; 7:280-97.
478 3- Mikulska M, Viscoli C, Orasch C, et al. Fourth European Conference on Infections in
479 Leukemia Group a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID.
480 Aetiology and resistance in bacteraemias among adult and paediatric haematology and
481 cancer patients. J Infect 2014; 68:321-31.
482 4- Trecarichi EM, Tumbarello M, Spanu T, et al. Incidence and clinical impact of
483 extended-spectrum-beta-lactamase (ESBL) production and fluoroquinolone resistance
484 in bloodstream infections caused by Escherichia coli in patients with hematological
485 malignancies. J Infect 2009; 58:299-307.
486 5- Satlin MJ, Cohen N, Ma KC, et al. Bacteremia due to carbapenem-resistant
487 Enterobacteriaceae in neutropenic patients with hematologic malignancies. J Infec
488 2016; 73:336-45.
489 6- Cherif H, Kronvall G, Bjorkholm M, Kalin M. Bacteraemia in hospitalised patients with
490 malignant blood disorders: a retrospective study of causative agents and their resistance
491 profiles during a 14-year period without antibacterial prophylaxis. Hematol J 2003;
492 4:420-6.
493 7- Gratwohl A, Baldomero H, Gratwohl M, et al. Quantitative and qualitative differences
494 in use and trends of hematopoietic stem cell transplantation: a Global Observational
495 Study. Haematologica 2013; 98:1282-90.
Page 22 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
22
496 8- Kara O, Zarakolu P, Ascioglu S, et al. Epidemiology and emerging resistance in bacterial
497 bloodstream infections in patients with hematologic malignancies. Infect Dis (Lond)
498 2015; 47:690-7.
499 9- Spanik S, Kukuckova E, Pichna P, et al. Analysis of 553 episodes of monomicrobial
500 bacteraemia in cancer patients: any association between risk factors and outcome to
501 particular pathogen? Support Care Cancer 1997; 5:330-3.
502 10- Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia:
503 epidemiology, microbiology, and risk stratification. Clin Infect Dis 2005; 40 Suppl 4:S240-
504 S5.
505 11- Sievert DM, Ricks P, Edwards JR, et al. Antimicrobial-resistant pathogens associated
506 with healthcare-associated infections: summary of data reported to the National
507 Healthcare Safety Network at the Centers for Disease Control and Prevention, 2009-
508 2010. Infect Control Hosp Epidemiol 2013; 34:1-14.
509 12- Cattaneo C, Antoniazzi F, Casari S, et al. P. aeruginosa bloodstream infections among
510 hematological patients: an old or new question? Ann Hematol 2012; 91:1299-304.
511 13- Trecarichi EM, Tumbarello M, Caira M, et al. Multidrug resistant Pseudomonas
512 aeruginosa bloodstream infection in adult patients with hematologic malignancies.
513 Haematologica 2011; 96:e1-e3.
514 14- Tofas P, Samarkos M, Piperaki ET, et al. Pseudomonas aeruginosa bacteraemia in
515 patients with hematologic malignancies: risk factors, treatment and outcome. Diagn
516 Microbiol Infect Dis 2017; 88:335-41.
517 15- Gudiol C, Aguado JM, Carratalà J. Bloodstream infections in patients with solid
518 tumors. Virulence 2016; 7:298-308.
Page 23 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
23
519 16- Von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE
520 Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology
521 (STROBE) statement: guidelines for reporting observational studies. Lancet 2007;
522 370:1453–7.
523 17- Klastersky J, Paesmans M, Ruberstein EB, Boyer M, Elting L, Feld R et al. The
524 Multinational Association for Supportive Care in Cancer Risk Index: a multinational
525 scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol
526 2000; 18:3038-51.
527 18- Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, et al.Health care–
528 associated bloodstream infections in adults: a reason to change the accepted definition
529 of community-acquired infections Ann Intern Med 2002;137:791–7.
530 19- The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables
531 for interpretation of MICs and zone diameters, version 8.0, 2018.
532 20- Magiorakos AP, Srinivasan A, Carey RB, et al. Multidrug resistant, extensively drug-
533 resistant and pandrug-resistant bacteria: an International expert proposal for interim
534 standard definitions for acquired resistance. Clin Microbiol Infect 2012; 18:268–81.
535 21-Kang Cl, Kim SH, Park WB, et al. Bloodstream infections caused antibiotic-resistant
536 Gram-negative bacilli: risk factors for mortality and impact of innapropiate initial
537 antimicrobial therapy on outcome. Antimicrob Agent Chemother 2005;49:760-6.
538 22-Mikulska M, Viscoli C, Orasch C, et al. Aetiology and resistance in bacteraemias
539 among adult and paediatric haematology and cancer patients. J Infect (2013).
540 23-Vuotto F, Berthon C, Lemaitre N, etc al. Risk factors, clinical features and outcomes
541 of Pseudomonas aeruginosa bacteraemia in patients with haematological malignancies:
542 a case-control study. American Journal of Infection Control 2013;41:527-30.
Page 24 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
24
543 24-Kim H, Park B, Kim S, et al. Clinical characteristics and outcomes of Pseudomonas
544 aeruginosa bacteraemia in febrile neutropenic children and adolescents with the impact
545 of antibiotic resistance: a retrospective study. BMC Infectious Diseases 2017 17:500-10.
546 25-Samonis G, Vardakas K, Kofteridis D, et al. Characteristics, risk factors and outcomes
547 of adult cancer patients with extensively drug-resistant Pseudomonas aeruginosa
548 infections. Infection 2014.
549 26-Trecarichi E, Pagano L, Candoni A, et al. Current epidemiology and antimicrobial
550 resistance data for bacterial bloodstream infections in patients with haematological
551 malignancies: an Italian multicentre prospective survey. Clin Microbiol Infect 2015;
552 21:337-343.
553 27- Paul M, Dickstein Y, Schlesinger A, et al. Beta-lactam versus beta-lactam-
554 aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane
555 Database of Systematic Reviews 2013, Issue 6. Art. No.: CD003038
556
557
558
559
560 Authors’ contributions:
561 All authors were involved in the study concept. APu-Al, CGu, RP, and JCa were involved
562 in the design of the study. CTe was responsible for the elaboration of the statistical
563 analysis plan. DTo will be responsible of the elaboration of the online database. APu-Al,
564 MAk, RAr, ABo, A-SBr, SCa, LDr, EGa, PHe, FHe, K-YIb, BIs, SSKa, WKe, GMa-Ca, AMa,
565 JIMa, IMa-Go, PMa-Da, MMi, MMo, MMo, HMPMo, IMo, ANo, COl, MPe, JLPo, PPu-Al,
566 IRu-Ca, ROSi, RTi, LYa, MZRGo, GCu, FEs-Vi, MRoAr, CMeAy, JMu, OGa, P-YBo, OMa,
Page 25 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
25
567 SEZe, J-FJa, HBe, GPe-Ho, MLi, JMAg, BPa, JFo, GMa, LMa, RCe, LLo-So, JPHo, MHMo,
568 MdCu, JRo-Ba, RGr, PCi, MBa, NCa, PSaAl, CCa, CGa-Vi, Jag-Co, NLa, AUy-On, ANa-Ze,
569 LClCo, WVaFr, and AApSiMa will be responsible for the data collection and introduction
570 in the online database. FTu will be responsible for the microbiological supervision of the
571 study. APu-Al, CGu, CTe, and JCa drafted and revised the manuscript. All authors
572 reviewed and approved the final version of the manuscript.
573 Acknowledgement:
574 We thank the ESGBIS and the ESGICH study groups for supporting the study.
575 Funding statement:
576 This study was supported by Plan Nacional de I+D+i 2013-2016 and Instituto de Salud
577 Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa,
578 Ministerio de Economía, Industria y Competitividad, Spanish Network for Research in
579 Infectious Diseases (REIPI RD16/0016/0001) - co-financed by European Development
580 Regional Fund “A way to achieve Europe”, Operative Programme Intelligent Growth
581 2014-2020.
582 Competing interests’ statement
583 ASB received grant from Promex Stiftung fur die Forschung (by Carigest SA), and funding
584 by Gilead to assist to the ECCMID congress (2018). Oguz Resat Sipahi received speaker’s
585 honorarium from MSD, Astellas, Novartis and Pfizer.
Page 26 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
Supplementary material
Institutions that obtained the IRB approval (reference number)
-Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires,
Argentina (nº 1139).
-Hacettepe University School of Medicine, Ankara, Turkey (nº GO 18/219-37).
-American University of Beirut Medical Center, Beirut, Lebanon (nº BIO-2018-0241)
-IRCCS San Raffaele Scientific Institute, Milan, Italy (nº 78/2018).
-Hospital Federal Servidores do Estado, Ministério da Saúde and Instituto Oswaldo
Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil (nº 2.740.186).
-University of Freiburg Medical Center and Faculty of Medicine, Freiburg, Germany (nº
52/17).
-Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR),
Institut Hospital del Mar d' Investigacions Mèdiques (IMIM), Universitat Autònoma de
Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain (nº 2018/7870/I).
-Instituto do Câncer do Estado de São Paulo, Faculty of Medicine, Univesity of São
Paulo, Brazil (nº NP 1304/18).
-Istanbul Education and Research Hospital, Istanbul, Turkey (nº 1195).
-Comenius University and National Cancer Institute, Bratislava, Slovakia (nº 2018-
1100).
-Hospital Regional de Málaga, Málaga, Spain (nº 03/2019-EO1).
Page 27 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
-University of Udine and Azienda Sanitaria Universitaria Integrata, Udine, Italy (nº
445/2018).
In the following centers, the IRB approval was not necessary due to the
retrospective, observational, non-intervention, and anonymised design of the study:
-University Hospitals Plymouth NHS Trust, United Kingdom.
-Instituto de Investigación Hospital “12 de Octubre” (i+12), “12 de Octubre” University
Hospital, School of Medicine, Universidad Complutense, Madrid, Spain.
-Navarra University Clinic, Pamplona, Spain.
-Clínica Maraya, Pereira Colombia.
-Hospital Erasto Gaertner, Curitiba, Brazil.
-Marqués de Valdecilla University Hospital, Santander, Spain.
-Hospital Clínic i Provincial, Barcelona, Spain.
-University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy.
-Ege University Faculty of Medicine, Izmir Turkey.
-Parc Taulí University Hospital, Sabadell, Barcelona, Spain.
-University of Health Science Izmir Bozyaka Training and Research Hospital, Turkey.
-Cruces University Hospital, Bilbao, Spain.
-Ramon y Cajal Hospital, Madrid, Spain.
Page 28 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
-Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University
Medical School, Berlin, Germany.
-Instituto de Ciencias e Innovación en Medicina. Facultad de Medicina Clínica Alemana
Universidad del Desarrollo, Santiago de Chile, Chile.
-Hospital Rawson, San Juan, Argentina.
-Son Espases University Hospital, Palma de Mallorca, Spain.
-Lausanne University Hospital, (CHUV), Lausanne, Switzerland.
In the following Spanish centers the IRB approval was not necessary because they
belong to a Spanish network of multicentre studies in which it is only necessary to
get the approval from one of the participating centres in order to be able to
participate.
- Reina Sofía University Hospital-IMIBIC-UCO, Córdoba.
- Hospital Universitario Virgen Macarena, Sevilla, Spain.
-Vall d’Hebron University Hospital, Barcelona, Spain.
Page 29 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
1
STROBE Statement—checklist of items that should be included in reports of observational studies
Item No. Recommendation
Page No.
Relevant text from manuscript
(a) Indicate the study’s design with a commonly used term in the title or the abstract 1Title and abstract 1(b) Provide in the abstract an informative and balanced summary of what was done and what was found
6
IntroductionBackground/rationale 2 Explain the scientific background and rationale for the investigation being reported 9Objectives 3 State specific objectives, including any prespecified hypotheses 11
MethodsStudy design 4 Present key elements of study design early in the paper 11-12Setting 5 Describe the setting, locations, and relevant dates, including periods of recruitment, exposure,
follow-up, and data collection 12
(a) Cohort study—Give the eligibility criteria, and the sources and methods of selection of participants. Describe methods of follow-upCase-control study—Give the eligibility criteria, and the sources and methods of case ascertainment and control selection. Give the rationale for the choice of cases and controlsCross-sectional study—Give the eligibility criteria, and the sources and methods of selection of participants
12-13Participants 6
(b) Cohort study—For matched studies, give matching criteria and number of exposed and unexposedCase-control study—For matched studies, give matching criteria and the number of controls per case
Variables 7 Clearly define all outcomes, exposures, predictors, potential confounders, and effect modifiers. Give diagnostic criteria, if applicable
14
Data sources/ measurement
8* For each variable of interest, give sources of data and details of methods of assessment (measurement). Describe comparability of assessment methods if there is more than one group
13-14
Bias 9 Describe any efforts to address potential sources of bias 16-17Study size 10 Explain how the study size was arrived at 16
Continued on next page
Page 30 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
2
Quantitative variables
11 Explain how quantitative variables were handled in the analyses. If applicable, describe which groupings were chosen and why
16-17
(a) Describe all statistical methods, including those used to control for confounding 16-17(b) Describe any methods used to examine subgroups and interactions 16-17(c) Explain how missing data were addressed 16-17(d) Cohort study—If applicable, explain how loss to follow-up was addressedCase-control study—If applicable, explain how matching of cases and controls was addressedCross-sectional study—If applicable, describe analytical methods taking account of sampling strategy
16-17
Statistical methods
12
(e) Describe any sensitivity analyses 16-17
Results(a) Report numbers of individuals at each stage of study—eg numbers potentially eligible, examined for eligibility, confirmed eligible, included in the study, completing follow-up, and analysed
NA
(b) Give reasons for non-participation at each stage NA
Participants 13*
(c) Consider use of a flow diagram NA(a) Give characteristics of study participants (eg demographic, clinical, social) and information on exposures and potential confounders
NA
(b) Indicate number of participants with missing data for each variable of interest NA
Descriptive data 14*
(c) Cohort study—Summarise follow-up time (eg, average and total amount) NACohort study—Report numbers of outcome events or summary measures over time NACase-control study—Report numbers in each exposure category, or summary measures of exposure NA
Outcome data 15*
Cross-sectional study—Report numbers of outcome events or summary measures NA(a) Give unadjusted estimates and, if applicable, confounder-adjusted estimates and their precision (eg, 95% confidence interval). Make clear which confounders were adjusted for and why they were included
NA
(b) Report category boundaries when continuous variables were categorized NA
Main results 16
(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period
Continued on next page
Page 31 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
For peer review only
3
Other analyses 17 Report other analyses done—eg analyses of subgroups and interactions, and sensitivity analyses NA
DiscussionKey results 18 Summarise key results with reference to study objectives NA Limitations 19 Discuss limitations of the study, taking into account sources of potential bias or imprecision. Discuss
both direction and magnitude of any potential bias 8
Interpretation 20 Give a cautious overall interpretation of results considering objectives, limitations, multiplicity of analyses, results from similar studies, and other relevant evidence
NA
Generalisability 21 Discuss the generalisability (external validity) of the study results 18-20
Other informationFunding 22 Give the source of funding and the role of the funders for the present study and, if applicable, for the
original study on which the present article is based 25- 26
*Give information separately for cases and controls in case-control studies and, if applicable, for exposed and unexposed groups in cohort and cross-sectional studies.
Note: An Explanation and Elaboration article discusses each checklist item and gives methodological background and published examples of transparent reporting. The STROBE checklist is best used in conjunction with this article (freely available on the Web sites of PLoS Medicine at http://www.plosmedicine.org/, Annals of Internal Medicine at http://www.annals.org/, and Epidemiology at http://www.epidem.com/). Information on the STROBE Initiative is available at www.strobe-statement.org.
Page 32 of 31
For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml
BMJ Open
123456789101112131415161718192021222324252627282930313233343536373839404142434445464748495051525354555657585960
on January 13, 2021 by guest. Protected by copyright.
http://bmjopen.bm
j.com/
BM
J Open: first published as 10.1136/bm
jopen-2018-025744 on 24 May 2019. D
ownloaded from
Recommended