Impact of Specific Antimicrobials and MIC Values on the Outcome of Bloodstream Infections Due to ESBL- or Carbapenemase-producing Enterobacterales in Solid Organ Transplantation: an Observational Multinational Study.
Conditions: Clinically Significant Bacteremia, Organ Transplantation, Infection, Bacteremia, Bacterial Infections, Sepsis, Systemic Inflammatory Response Syndrome, Pathologic Processes, Inflammation
Sponsor: Spanish Network for Research in Infectious Diseases

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PROJECT TITLE 
 
Impact of specific antimicrobials and MIC values on the outcome of bloodstream 
infections due to ESBL- or carbapenemase-producing Enterobacteriaceae in Solid 
Organ Transplantation: an observational multinational study. 
 
 
 
 
 
 
 

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PERSONNEL AND CO-INVESTIGATORS 
A total of 58 centres belonging to 18 countries across the world have accepted to participate in this 
project. Herein the list of participating centres: 
Promoter Institutions 
 
Country 
Number 
Institution 
Town 
Investigator 
Spain 
1 
 Reina Sofía Univ. Hospitall /IMIBIC/UCO, 
Cordoba 
Córdoba 
Dr. Julián Torre-Cisneros 
  
  
  
  
Dr. Elena Perez-Nadales 
  
2 
Virgen Macarena University Hospital, Seville 
Seville 
Dr. Jesús Rodríguez-Baño 
  
  
  
  
Dr. Álvaro Pascual 
  
  
  
  
Dr. Belén Gutiérrez Gutiérrez 
  
3 
12 Octubre University Hospital, Madrid 
Madrid 
Dr. José María Aguado 
  
  
  
  
Dr. Jaime Lora-Tamayo 
 
Scientific Committee 
 
Country 
  
Institution 
Town 
Investigator 
Republic of Singapore 
4 
Singapore General Hospital 
Singapore 
Dr. Tan Ban Hock 
Australia 
5 
St Vincent's Hospital 
Sydney 
Dr. Debbie Marriott 
Brazil 
6 
Faculdade de Medicina da Universidade de 
São Paulo  
São Paulo  
Dr. Edson Abdala 
Chile 
7 
Pontifical Catholic University of Chile 
Santiago 
Dr. Ricardo Rabagliati 
Germany 
8 
Albert-Ludwigs-University 
Freiburg 
Dr. Winfried Kern 
Italy 
9 
University of Insubria. Clinica Malattie 
Infettive. Ospedale Di Circolo 
Varese  
Dr. Paolo Grossi 
Spain 
10 
Bellvitge University Hospital 
Barcelona 
Dr. Jordi Carratala 
  
11 
Marqués de Valdecilla University Hospital 
Cantabria 
Dr. Luis Martinez Martinez and Dr. M. 
Carmen fariñas  
  
12 
Virgen del Rocío University Hospital 
Seville 
Dr. Elisa Cordero 
Switzerland 
13 
University Hospital and University of 
Lausanne 
Lausanne 
Dr. Oriol Manuel 
Turkey 
14 
Dept. of Infectious Diseases Hacettepe 
University School of Medicine Sihhiye  
Ankara 
Dr. Murat Akova 
USA 
15 
Northwestern University Feinberg School of 
Medicine 
Chicago 
Dr. Michael Ison 
  
16 
Hospital of the University of Pennsylvania 
Philadelphia 
Dr. Emily Blumberg 
 
Participating Institutions 
 
Country 
Number 
Institution 
Town 
Investigator 
Australia 
17 The Westmead Hospital, Sydney 
Sydney 
Dr. Sharon Chen 
Belgium 
18 Erasme University Hospital, Brussels 
 Brussels 
Dr. Julien Coussement and Dr. Magali 
Dodémont 
Brazil 
19 Instituto Dante Pazzanese de Cardiologia 
Vila Mariana, 
São Paulo 
Dr. Cely Saad Abboud 
  
20 
Faculdade de Medicina da Universidade 
Federal de Minas Gerais 
Santa Efigenia, 
Belo Horizonte 
Dr. Wanessa Trindade Clemente 
  
21 
 Faculdade de Medicina da Universidade 
Federal do Ceará 
Rodolfo Teófilo, 
Fortaleza 
Dr. Evelyne Santana Girão 

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22 
 Instituto do Coração do Hospital das Clíncas 
da Faculdade de Medicina da Universidade de 
São Paulo 
São Paulo 
Dr. Tânia Mara Varejão Strabelli 
  
23 
Hospital Universitário Clementino Fraga Filho, 
Universidade Federal do Rio de Janeiro 
 Rio de Janeiro 
Dr. Guilherme Santoro Lopes 
  
24 Hospital de Clínicas de Porto Alegre 
 Porto Alegre 
Dr. Alexandre Prehn Zavascki 
Canada 
25 University of Alberta 
Edmonton 
Dr. Carlos Cervera 
Germany 
26 
Institute for Medical Microbiology, 
Immunology and Hygiene, University of 
Cologne 
Cologne 
Dr. Axel Hamprecht 
Israel  
27 Rambam Health Care Campus 
 Haifa, 3109601 Dr. Mical Paul 
Italy 
28 Università di Bologna 
Bologna 
Dr. Pierluigi Viale 
  
29 
Azienda Ospedaliera Universitaria Integrata di 
Verona  
Verona  
Dr. Ercole Concia and Dr. Fabio Soldani 
  
30 AO Ospedale Papa Giovanni XXIII 
Bergamo 
Dr. Marco Rizzi 
  
31 Università Cattolica Sacro Cuore 
Milan 
Dr. Mario Tumbarello 
  
32 ISMETT-UPMC 
Palermo 
Dr. Alessandra Mularoni  
  
33 Fondazione IRCCS Policlinico San Matteo 
Pavia 
Dr. Elena Maria Seminari 
Malta 
34 Mater Dei Hospital 
Msida 
Dr. Nina Nina Nestorova 
South Africa 
35 
Wits Donald Gordon Medical Centre; Wits 
School of Pathology, Faculty of Health 
Sciences, University of the Witwatersrand 
Johannesburg 
Dr. Warren Lowman 
Spain 
36 Hospital Ramón y Cajal 
Madrid 
Dr. Jesús Fortún and Dr. Pilar Martín 
  
37 Hospital Clínico Lozano Blesa 
Zaragoza 
Dr. Jose Ramón Paño  and Dr. Pilar Luque 
Gómez 
  
38 Hospital La Paz 
Madrid 
Dr. María Belén Loeches 
  
39 Hospital clínic de Barcelona 
Barcelona 
Dr. Marta Bodro 
  
40 Hospital Universitario A Coruña 
Coruña 
Dr. Germán Bou 
Sweden 
41 Akademiska Hospital 
Uppsala 
Dr. Britt Marie Eriksson 
Switzerland 
42-47 
Swiss Transplant Cohort Study (STCS). 
University Hospitals of Basel, Bern, Geneva, 
Lausanne, Zurich and St Gallen, Switzerland 
Basel, Bern, 
Geneva, 
Lausanne, 
Zurich and St 
Gallen 
Dr. Christian van Delden  
Turkey 
48 
Yildirim Beyazit University, Ankara Ataturk 
T&R Hospital 
Ankara 
Dr. Zeliha Koçak Tufan 
  
49 Akdemiz University, Antalya 
Antalya 
Dr. Filiz Gunseren 
  
50 Başkent University School Of Medicine 
Ankara 
Dr. Hande Arslan   
  
51 Uludag University 
Bursa 
Dr. Esra Kazak 
Ukraine 
52 
National Medical Academy of Postgraduate 
Study 
Kyiv 
Prof.Dmytro Kyryk 
UK 
53 University Hospital Birmingham NHS Trust 
Birmingham, UK Dr. Miruna David 
USA 
54 University of Alabama at Birmingham 
Birmingham, 
USA 
Dr. John Baddley 
  
55 Icahn School of Medicine at Mount Sinai 
New York 
Dr. Shirish Huprikar and Dr. Gopi Patel 
  
56 Ohio State University  
Columbus, Ohio Dr. Nicole Theodoropoulos 
  
57 University of Washington 
Seattle 
Dr. Erika Lease 
  
58 Johns Hopkins University 
Baltimore 
Dr. Seema Metha 
 

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INTRODUCTION 
 
Bloodstream infections (BSI) are a major cause of mortality in solid-organ (SOT) transplant 
recipients. Mortality can reach 50% when bacteremia is accompanied with septic shock. 
 
In recent years, infections due to extended-spectrum beta-lactamases (ESBL) and 
carbapenemase-producing Enterobacteriaceae have emerged as a global threat in SOT. Renal transplant 
recipients seem to be at higher risk of infections with ESBL-producing E. coli, especially in cases of 
simultaneous pancreas transplantation, previous use of antibiotics, post-transplant dialysis and post-
transplant urinary tract infections. Most BSIs in renal transplant patients are due to urinary tract 
infections. Infections due to carbapenemase-producing K. pneumoniae are frequent in liver and 
intestinal transplantation. The main sources of the infections are intra-abdominal collections and the 
biliary tract.  
 
The incidence of EBSL- and carbapenemase-producing Enterobacteriaceae BSI after SOT 
increases proportionally with the prevalence of bowel colonization. Treatment of invasive infections 
caused by these organisms is difficult because agents showing in vitro activity are limited and there are 
scarce clinical studies reporting on their efficacy, particularly in the SOT population. 
 
Regarding ESBL-producers, carbapenems are considered the drugs of choice for invasive/severe 
infections. As a consequence, carbapenems are being increasingly used, which may facilitate the spread 
of carbapenemase-producing organisms. Thus, seeking for alternatives to carbapenems for infections 
caused by ESBL-producers is a priority. Preliminary results from the previous INCREMENT study in non-
transplant patients and a meta-analysis suggested that β-lactams/β-lactamase inhibitors are a good 
alternative, mainly for susceptible E. coli causing urinary or biliary tract BSI. However, it would be 
important to confirm these results in SOT patients and evaluate whether such observation expand to 
other Enterobacteriaceae and sites of infection and if these recommendations can be extended to 
patients with underlying immunosuppression. Also, breakpoints for susceptibility to cephalosporins 
have been changed according to PK/PD data and some case series showing that some ESBL producers 
are susceptible to these drugs, thus clinical data supporting the efficient use of cephalosporins for 
susceptible isolates according to new breakpoints in SOT would be needed. Similarly, more clinical data 
on the efficacy of fluoroquinolones for infections caused by ESBL-producers (which are frequently 
resistant or present decreased susceptibility to these drugs) are awaited. Finally, published experience 
with other drugs is also scarce. 
 
Regarding carbapenemase-producing organisms, similar questions arise. Depending on the 
specific carbapenemase that is expressed, isolates may show low MICs to carbapenems (even in the 
range of susceptibility) and the efficacy of carbapenems for invasive infections caused by such isolates, 

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alone or in combinations, is controversial. Other antibiotics are being used for the treatment of these 
infections. Recent data suggest that combination therapy including one carbapenem plus one or two 
other active drugs may be superior to monotherapy. Whether these data would apply for different 
carbapenemases, MICs of carbapenems, etc., in the particular setting of SOT is not known. Available 
clinical data from non-transplant patients is limited by sample size, lack of control groups, appropriate 
control for confounders and the unicenter nature of the studies conducted so far.  
 
Another aspect of interest is the safety of antibiotics used for treatment of these infections in 
SOT patients. Because these patients frequently receive other drugs and may have impairment of liver 
or renal function, evaluation of the safety of antibiotics is particularly relevant in this population. 
 
In order to compile further clinical evidence, larger, multinational studies are needed. A 
reasonable starting point would be the organization of an international consortium. This project aims to 
both address some of the clinical and scientific questions outlined above and to build an international 
network of contacts among experts in the field of transplant infections and bacterial resistances. We 
expect that creation of such a consortium will stimulate international cooperation for development of 
further projects and ideas in the transplant setting, including randomised control trials. 
 
 
OBJECTIVES 
Main objective: to observationally assess the efficacy and safety of different antimicrobials in BSI due to 
ESBL or carbapenemase-producing Enterobacteriaceae in SOT. 
 
Secondary objectives: 
1. To evaluate the efficacy and safety of different antibiotics used for the treatment of infections 
caused by ESBL- and carbapenemase-producing Enterobacteriaceae in the SOT population. 
2. To compare the efficacy of different antimicrobials between SOT and non-SOT patients (using 
matched controls from the “non-transplant” INCREMENT cohort).  
3. To 
create 
a 
microbiological 
collection 
of 
ESBL- 
and 
carbapenemase-producing 
Enterobacteriaceae isolated from the SOT population. (PENDING ON RESULTS FROM 
FEASIBILITY TEST) 
4. To provide data on specific MICs for each antimicrobial evaluated (PENDING ON RESULTS FROM 
THE FEASABILITY TEST). 
5. To provide data on the prevalence of specific mechanisms of resistance and their clinical impact 
in the particular setting of SOT (PENDING ON RESULTS FROM THE FEASABILITY TEST) 
6. To organise an international consortium capable of developing high quality prospective cohort 
studies and randomised clinical trials in the area of MDR and XDR Enterobacteriaceae in SOT.   
 

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Specific hypothesis and objectives 
 
Bacteremic infections due to ESBL-producing Enterobacteriaceae in SOT:  
 
- 
(A1) β-lactam/β-lactam inhibitors are as effective as the carbapenems in the empiric and 
definitive therapy, irrespective of the empirical therapy, severity of infection, source and 
species.  
o 
Objective: to demonstrate that β-lactam/β-lactam inhibitors are not associated with 
worse cure rate and mortality than carbapenems after controlling for potential 
confounders, including transplantation, both for empirical and definitive therapies.  
- 
(A2) Definitive therapy with fluoroquinolones is as effective as definitive therapy with 
carbapenems, provided that the organism is susceptible to both types of antibiotics according 
to current endpoint criteria (EUCAST/CLSI), irrespective of empirical therapy, severity of 
infection, transplantation status, source and species. 
o 
Objective: to demonstrate that definitive therapy with fluoroquinolones is not 
associated with worse cure rate and mortality than definitive therapy with 
carbapenems, after controlling for potential confounders, including transplantation 
and considering both the dose and type of infusion (continuous/intermittent) and the 
use of single vs combined carbapenems.  
- 
(A3) Empirical therapy with active cephalosporins in monotherapy according to current EUCAST 
and CLSI breakpoints is associated with worse outcome than empirical therapy with 
carbapenems, except for urinary tract infections. 
o 
Objective: to demonstrate that empirical therapy with cephalosporins in monotherapy 
is associated with worse cure rate and mortality in infections, other than the urinary 
tract ones, than carbapenems, after controlling for potential confounders, including 
transplantation,   
- 
(A4) Empirical therapy with active aminoglycosides plus cephalosporins or fluoroquinolones is 
as effective as carbapenem monotherapy in urinary tract infections. 
o 
Objective: to demonstrate that the association of active aminoglycosides with 
cephalosporins or fluoroquinolones is not associated with worse cure rate and 
mortality than carbapenems after controlling for potential confounders, including 
transplantation.  
 
- 
(A5) Combination therapy is not superior to monotherapy and is associated with increased 
renal and/or liver toxicity 
o 
Objective: to demonstrate that combination of empirical and definitive therapy is not 
associated with better cure rate than monotherapy after controlling for potential 
confounders, including transplantation, and is associated with increased toxicity. 

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- 
(A6) For tigecycline, colistin and fosfomycin, no hypothesis. The objective is to provide adjusted 
estimations of their association with outcome variables in comparison with carbapenem 
monotherapy according to the clinical situation and infection.  
 
Bacteremic infections due to carbapenemase-producing Enterobacteriaceae:  
 
- 
(B1) Combined empirical and definitive therapies are associated with better outcome than 
monotherapy with carbapenem, colistin or tigecycline even though they may be associated 
with increased adverse events. 
o 
Objective: to demonstrate that combination therapy is associated with worse cure 
rate and mortality than monotherapy after controlling for potential confounders, 
including transplantation. 
o 
Objective: to comparatively evaluate the extent of renal and liver toxicity for 
combination therapy vs monotherapy. 
- 
(B2) Carbapenems are more effective for infections caused by isolates with low MICs than for 
infections, other than the urinary tract ones, caused by isolates with higher MICs. 
o 
Objective: to show that carbapenems are associated with worse cure rate and 
mortality when used in infections, other than the urinary tract ones, caused by isolates 
showing MIC >2 µg/mL for imipenem or meropenem as compared to infections caused 
by isolates with lower MICs, after controlling for potential confounders and 
considering both the dose and type of infusion (continuous/intermittent) and the use 
of single vs combined carbapenems.  
- 
(B3) Tigecycline is more effective that carbapenems for infections , other than the urinary tract 
ones, caused by isolates with a high level of resistance to carbapenems. 
o 
Objective: to show that carbapenems are associated with worse cure rate and 
mortality than tigecycline when used in infections, other than the urinary tract ones, 
caused by isolates with MICs >32 µg/mL for imipenem or meropenem, after 
controlling for potential confounders as transplantation. 
- 
(B4) β lactam/avibactam is more effective that carbapenems or tigecycline for infections others 
than the urinary tract ones caused by isolates with high level of resistance to carbapenems. 
o 
Objective: to show that carbapenems and tigecycline are associated with worse cure 
rate and mortality than β lactam/avibactam when used in infections other than the 
urinary tract ones, after controlling for potential confounders, including 
transplantation. 
- 
(B5) Colistin is more effective when used in optimized dose. 
o 
Objective: to show that colistin used at a dose >6 million IU per day is associated with 
improved outcomes in comparison with a lower dose, after controlling for potential 
confounders, including transplantation.  

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METHODS 
 
Study design: multicentre, international retrospective cohort study. 
 
Sites: multiple expert investigators from different countries will be invited. Criteria for participation will 
include accessibility to a database with the required data or ability to retrospectively collect the data in 
a timely manner. 
 
Inclusion criteria:  
- 
Solid Organ Transplant patients, including multivisceral transplantation and transplant in HIV-
infected recipients. 
- 
Episodes of clinically significant monomicrobial BSI due to cephalosporin-resistant 
Enterobacteriaceae (CRE), specifically ESBL or carbapenemase-producing Enterobacteriaceae, 
including community and nosocomial ones. 
o 
For cephalosporin resistance, a susceptibility phenotype based in a microdilution 
antibiogram is sufficient. 
o 
For ESBL-producers:  
THREE POSSIBILITIES, PENDING ON RESULTS FROM THE FEASABILITY TEST AND 
APPLICATION FOR FUNDING: 
1. 
Antimicrobial susceptibility profile  
2. 
At least one phenotypic confirmation test according to current endpoints 
(i.e. CLSI, EUCAST).  
3. 
PCR-based characterization 
o 
For carbapenemase-producers:  
TWO POSSIBILITIES, PENDING ON RESULTS FROM THE FEASABILITY TEST AND 
APPLICATION FOR FUNDING: 
1. Characterization of carbapenemase production by these isolates must be 
based on PCR analysis. Determination of carbapenemase production based on 
antimicrobial susceptibility profile and phenotypic tests alone will not be 
acceptable (see below).  
2. Participating Centers may provide bacterial isolates and microbiological 
tests may be centralized in a Microbiology Reference Laboratory. 
- 
Subsequent episodes in a patient caused by the same microorganism may be included if the 
interval between them is >3 months. 
- 
No age limits. 
 
Exclusion criteria: 

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- 
Polymicrobial or non-clinically significant episodes. Episodes in which a potential contaminant 
(e.g., coagulase-negative staphylococci) is isolated only in one set of blood cultures and there is 
not a typical source of infection for that kind of organism (e.g. catheter-related) that can be 
included. 
- 
Unavailability of key data (such cases should be counted to analyse a potential selection bias). 
- 
Episodes occurring before January 2004. 
 
 
Procedure 
The participant centres will be requested to include: 
- 
Previously published cases: all these cases should be included if possible. The fact that the case 
was previously published should be specified in the database. 
- 
Additionally, participants will be requested to include consecutive episodes detected by 
reviewing their databases (clinical, infection control or microbiological records) from January 
2004 to December 2014, according to the following criteria: 
o 
For ESBL producers: Consecutive cases for which the enzyme was characterised at 
least to group level by PCR (it is, CTX-M, SHV, TEM) should be prioritised despite the 
date of diagnosis. If PCR-characterisation was not performed, cases in which ESBL-
production was identified using a standard phenotypic method may be included. 
PENDING ON RESULTS FROM THE FEASABILITY TEST. 
o 
For carbapenemase-producers: only cases in which the carbapenemase was 
characterised by PCR should be included.  
PENDING ON RESULTS FROM THE FEASABILITY TEST. 
Overall, to avoid selection biases, consecutive cases according to previous criteria should be included.  
 
Variables 
 
A common, online database has been designed. Access to this database will be restricted to authorized 
researchers by use of an individual user name and password. 
 
Main outcome variables: Cure rate at day 14 and all-cause mortality until day 30. For safety issues, 
frequency and types of renal and liver toxicity. 
 
Secondary outcome variables: Mortality at 72 hours, 7, 14 and 90 days, clinical improvement at 72 
hours, clinical cure at day 28. Renal and liver toxicity and other serious adverse events. 
 
Explanatory variables: 
- 
Demographics 

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- 
Use of antibiotics within 30 days before the BSI. 
- 
Severity of chronic underlying conditions: McCabe and Charlson index  
- 
Acute severity of underlying disease: Pitt score during the day before BSI. 
- 
Type of acquisition 
- 
Source of BSI 
- 
Severity of SIRS at presentation 
- 
Microorganism, MICs, clinical category  (Susceptible, Intermediate, Resistant), guideline  (CLSI 
or EUCAST), mechanisms of resistance if studied. 
- 
Empirical therapy 
- 
Definitive therapy 
- 
Bacteremia Source Control: drainage within the first four days, removal of prosthetic material, 
removal of infected catheter, etc. 
- 
Renal function when bacteremia occurred (Creatinine clearance). 
- 
Selective Intestinal Decontamination (SID) during the previous 12 months and type of SID 
(drugs used). 
- 
Variables related with transplantation: 
o 
Type of SOT 
o 
Day after transplantation 
o 
Acute rejection within 30 days before the BSI 
o 
Leukopenia  (number of lymphocytes, lymphocyte subpopulations, immunoglobulins 
and complement). 
o 
Basal immunosuppression  
o 
Induction of immunosuppression 
o 
Prophylaxis with TMP/SMX within 30 days before the BSI 
o 
Surgical reoperation. 
o 
Urinary catheter. 
o 
Urinary stenosis (renal) 
o 
Biliary stenosis (liver) 
o 
Traqueal stenosis (lung) 
o 
Post-transplant dialysis within 30 days before the BSI 
o 
CMV replication within 30 days before the BSI 
o 
CMV disease within 30 days before the BSI 
o 
Mechanical ventilation 
o 
Other underlining condition 
 
 
 
 

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Definitions 
- 
Clinically significant bacteremia: bacteremia that occurs in a patient who fulfils criteria for 
systemic inflammatory response (see below, sepsis criteria). 
- 
Charlson index: punctuation is automatically calculated by filling the data in the database. 
Alternatively, if Pitt score was previously calculated, it may be added directly to the database. 
For all diseases, a medical diagnosis in chart is enough. Additionally, the following criteria 
should be used: 1,Diabetes mellitus: antidiabetic therapy (oral or insulin); 2, Chronic pulmonary 
disease: any disease leading to chronic respiratory insufficiency; 3,Myocardial infarction: EKG 
evidence; 4,  Congestive heart failure: NYHA grade II or higher; 5, Peripheral arterial disease: 
when causing skin ulcer or the need for revascularization or amputation;  6. Dementia: if 
significantly limiting independence for basic activities; 7,Connective tissue disease: if requiring 
immunosuppressive therapy, 8.Liver disease: chronic hepatitis, significant liver fibrosis or 
cirrhosis; 9,Kidney disease: creatinine clearance <30 ml/min or the need for chromic dialysis; 10 
Any tumour: any malignancy requiring chemotherapy and/or radiotherapy or palliative care. 
- 
McCabe classification (modified). This is a classification for the chronic underlying condition 
(not the acute condition): non-fatal underlying disease (no underlying disease or related death 
is expected to occur in the next 5 years), ultimately fatal underlying disease (related death is 
expected to occur in the next 5 years), or rapidly fatal disease (related death is expected to 
occur in the next year). 
- 
Pitt score: punctuation is automatically calculated by filling the data in the database, which 
should be retrospectively collected in the 24 hours prior to diagnosis of bacteremia. 
Alternatively, if Pitt score had been calculated previously, it can be directly added.    
- 
SIRS severity 
o 
Sepsis: at least 2 of the following: temperature >38ºC or <36ºC, respiratory rate >20 or 
PaCO2 <32 mmHg, heart rate >90, altered mental status, systolic blood pressure <90 
mmHg, leukocyte count >12.000/mm3 or <4,000/mm3 or immature forms >10%. 
o 
Severe sepsis: sepsis plus one of the following: hypotension (systolic BP <90 mmHg, 
median BP <70 mmHg, decrease in median BO >40 mmGh), organ dysfunction 
(respiratory, renal, liver, neurologic, hematologic), or hyperlactatemia (> 3 mmol/L) 
o 
Septic shock: sustained hypotension not responding to fluid support therapy and 
requiring inotropic support. 
- 
Acquisition. Nosocomial if infection signs/symptoms started >48 hours after hospital admission 
or in less than 48 hours after hospital discharge. Otherwise, the case should be considered 
community-onset. 
o 
If community-onset, the episode is considered healthcare-associated if fulfilling any of 
the following criteria in the previous 3 months: hospitalization in acute care center, 
any kind of dialysis, surgery, specialized home care, attention at day-hospital, any kind 

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of invasive procedure (endoscopy, urinary or vascular catheterization, etc.) or long-
term care facility resident. 
- 
Source: CDC definitions for nosocomial infections will be used as a reference; however, clinical 
and microbiological criteria as evaluated by the investigators may be used for interpretation. A 
source does not need to be microbiologically confirmed if enough clinical criteria are present.  
- 
Empirical therapy: administered before susceptibility report is available. 
- 
Definitive therapy: administered once the susceptibility report is available. If empirical therapy 
was continued, it is not necessary to fill in the definitive therapy data. 
- 
Outcome definitions: 
o 
Improvement: partial control or resolution of signs and symptoms related to the 
infection, or resolution but antibiotic therapy is still necessary.  
o 
Non-improvement or deterioration: clinical situation qualified as similar or worse in 
comparison to that at the point of diagnosis of bacteremia.  
o 
Cure: resolution of all signs and symptoms related to the infection, and antibiotic 
therapy is no longer necessary. 
o 
Dead: death of the patient for whatever the reason. 
o 
Renal toxicity: development of acute kidney injury according to RIFLE criteria (Bellomo 
R, Ronco C, Kellum JA, Mehta RL, Palevsky P, Acute Dialysis Quality Initiative 
workgroup: Acute renal failure - definition, outcome measures, animal models, fluid 
therapy and information technology needs: The second international consensus 
conference of the acute dialysis quality initiative (ADQI) group. Crit Care 2004, 8:R204 - 
R212. 
o 
Liver toxicity: Patients will be considered to have hepatotoxicity when they presented 
alanine transaminase, aspartate aminotransferase or bilirubin elevations of more than 
two times the upper limit of the normal range. Toxicity is considered severe when 
symptomatic elevations are more than three times or asymptomatic elevations are 
more than five times the normal levels. 
o 
Severe adverse event (SAD): Any event that becomes fatal or life-threatening, 
produces a significant or persistent alteration (according to the Principal Investigator), 
requires patient hospitalization or prolongation of an existing hospitalization, 
produces a congenital anomaly or results in overdose of the drugs included in this 
stud. Any toxicity of grade 4 will be considered a SAD (National Cancer Institute 
Common Toxicity Criteria Version 3.0). 
 
Quality of data  
 
Data will be approved and signed by the responsible investigator in each center. All data will be 
centrally reviewed; queries will be sent for missing data as well as data showing inconsistencies or 

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discrepancies. Data will be analysed per center; those centers showing significant differences with the 
average will be requested to review their data. 
 
Statistical Analysis Plan 
- 
Cases that occurred in transplant patients (Transplant-INCREMENT cohort) will be controlled 
with cases in non-transplant patients selected from the INCREMENT cohort. Two control groups 
will be defined according to the following criteria:  
o 
Clinical variables: age, source of BSI, severity of SIRS (septic shock), acquisition 
o 
Propensity score to receive a particular treatment. 
 
- 
Subcohorts with patients treated with the treatments to be compared will be selected.  
- 
Empirical and definitive therapy will be analysed separately; active/inactive empirical therapy 
will be a potential confounder when analysing definitive therapy and vice versa.  
- 
To be assigned to specific treatment arms, patients must have received drugs according to the 
following specific criteria: Empirical therapy: patients received the drug in monotherapy 
(except if combination is considered) within 24 hours of the blood culture being drawn and 
prior to availability of antibiogram results.  The antibiotic must have been administered for at 
least 48 hours, with the single exception of patients who died before 48 hours, who will be 
included if death occurred after 1 complete day of therapy with the assigned regimen (and will 
be otherwise excluded). Definitive therapy: the drug was administered in monotherapy (except 
if combination is considered) once susceptibility data was available When more than one drug 
was used, only drugs that were administered for at least half the duration of the definitive 
therapy will be included in this study. 
- 
A propensity score to receive the two treatment types under comparison will be calculated by 
obtaining a non-parsimonious multivariate model by logistic regression in which the outcome 
variable will be the treatment type. The explanatory variables will include age, gender, center, 
type of ward, acquisition, Charlson index, Pitt score, severity of SIRS and source. 
- 
After univariate analysis, multivariate analysis to investigate the adjusted association of 
treatment type and transplantation with the main and secondary outcome variables will be 
performed by using logistic regression (for clinical response at day 14) and by Cox regression for 
mortality. If time until death is unavailable, logistic regression will be used for 30-day mortality. 
Logistic regression will also be used for 72-hour and 30-day clinical response. The propensity 
score will be added in all cases; also, Charlson score, Pitt score, severity of SIRS, source and 
transplant-related variables will be added. Finally, interaction between treatment type and 
source classified as urinary tract and others will be included. 
 
 
 

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ETHICAL ISSUES 
 
 
This is a retrospective, non-intervention study. The main ethical issue to consider regards 
protection of patients’ data. In the database, patient personal data will be unlinked from any personal 
data that may identify the patient, ensuring confidentiality is preserved. Additionally, access to the 
database will only be allowed by use of an individual access password.  
The project will be submitted for qualification by the Spanish Medicines Agency (AEMPS) as 
post-authorization study (EPA-OD) and will be evaluated by the Reina Sofía University Hospital 
Institutional Review Board together with a specific request to waive the need to obtain written informed 
consent for the retrospective cohort. Local policies should be followed at each centre. 
The study will be registered in ClinicalTrials.gov. 
 
 
FUNDING 
 
The study is supported by Plan Nacional de I+D+i 2008-2011 and Instituto de Salud Carlos III, 
Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía y 
Competitividad, Spanish Network for Research in Infectious Diseases (REIPI RD06/0008 and RD12/0015 ) 
- co-financed by European Development Regional Fund "A way to achieve Europe" ERDF. REIPI provides 
funding for development of the online database and server. Staff hired with REIPI funding dedicated to 
different research projects included in the REIPI Research Program will be dedicated part-time to the 
project. There is no other funding. 
 
PUBLICATION, AUTHORSHIP, AND DATABASE RIGHTS/SECURITY POLICY 
 
- 
Consortium. Each centre or research group may include up to 3 investigators in the Consortium 
(plus one member of the Assistant Scientific Committee in the case of the three Promoter 
Centers). One of them will be designated as principal investigator from their centre. 
- 
The Scientific Committee will advise Promoter Investigators on the scientific content and 
objectives of this project.  It will also be asked to provide a list of potential participating centers 
from their geographical area. 
- 
Publication policy. The promoter group will decide the publication and authorship policy with 
the advice of the Scientific Committee.  Any participating center may propose additional 
analysis and publications beyond those included in the objectives of this project, which will be 
submitted to approval by the Promoter group, with the advice of the Scientific Committee. 
- 
Authorship. To be author, authorship criteria established by medical journals must be fulfilled. 
In general terms, manuscripts will be authored by writer, promoters and assistant scientific 
committee and one author per centre according to the number of cases included in the article 
provided they fulfil authorship criteria; if a limited number of authors is allowed, all other 

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authors will be included in a list in the Acknowledgement section as “Other authors”. All other 
participants in the study will be listed in the Acknowledgement section as “Other participants”.  
Alternatively, group authorship may be considered. 
- 
The database is propriety of REIPI and will be hosted by REIPI in a server accomplishing all 
guarantees for data protection according to Spanish legislation. Investigators from the 
consortium will have access to all data from their institution by use of an individual password. 
The Steering Committee must approve any initiative to report partial results from specific 
institutions, to avoid duplicity in publications. Access to the whole database will be provided 
after specific requests for defined analysis and publications, always after approval by the 
Steering Committee. 
 
 
End of document.