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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

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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

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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

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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

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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

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Email: [email protected] 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

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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

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Aparecida da Silva Machado, Hospital Federal Servidores do Estado, Ministério da 121

Saúde, Rio de Janeiro, Brazil. 122

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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

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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

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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

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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

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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

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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

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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

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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

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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

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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

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• 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

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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

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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

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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

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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

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498

499

REFERENCES 500

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antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer 502

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Leukemia Group a joint venture of EBMT, EORTC, ICHS, ELN and ESGICH/ESCMID. 507

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among hematological patients: an old or new question? Ann Hematol 2012; 91:1299-538

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13- Trecarichi EM, Tumbarello M, Caira M, et al. Multidrug resistant Pseudomonas 540

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14- Tofas P, Samarkos M, Piperaki ET, et al. Pseudomonas aeruginosa bacteraemia in 543

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Microbiol Infect Dis 2017; 88:335-41. 545

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tumors. Virulence 2016; 7:298-308. 547

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Lancet 2007; 370:1453–7. 551

17- Klastersky J, Paesmans M, Ruberstein EB, Boyer M, Elting L, Feld R et al. The 552

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scoring system for identifying low-risk febrile neutropenic cancer patients. J Clin Oncol 554

2000; 18:3038-51. 555

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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

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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

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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

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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

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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

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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


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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.

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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


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




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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)


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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

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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

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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

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73 Fax. + 34 93 260 7537

74 Email: [email protected]

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

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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

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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.

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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

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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.

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172 Keywords: Pseudomonas aeruginosa, onco-haematological patients, bacteraemia,

173 bloodstream infection, neutropenia, multidrug-resistant, mortality.

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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.

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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.

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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.

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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


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

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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)

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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

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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


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

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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.

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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,

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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

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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-

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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

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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

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498 REFERENCES

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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

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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.

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522 8- Kara O, Zarakolu P, Ascioglu S, et al. Epidemiology and emerging resistance in

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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

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528 10- Viscoli C, Varnier O, Machetti M. Infections in patients with febrile neutropenia:

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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

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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

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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

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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

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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.

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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


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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


(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


(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


(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time

period


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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


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


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.

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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


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




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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)


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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,

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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

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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: [email protected]

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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

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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.

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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


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

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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

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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

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191

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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.

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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

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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


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

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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)

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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

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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


322 - Definitive antibiotic therapy: antimicrobial therapy administered according to


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

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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.

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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

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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.

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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

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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

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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

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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.

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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.

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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.

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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,

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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.

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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).

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-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.

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-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.

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1


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


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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


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


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


Main results 16

(c) If relevant, consider translating estimates of relative risk into absolute risk for a meaningful time period


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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


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


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.

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bmjopen.bmj.com€¦ · for peer review only 19 424 lacking. the existing literature is based on...

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