microorganisms Article Effect of Combination Antibiotic Empirical Therapy on Mortality in Neutropenic Cancer Patients with Pseudomonas aeruginosa Pneumonia Adaia Albasanz-Puig 1,2,† , Xavier Durà-Miralles 1,† , Júlia Laporte-Amargós 1 , Alberto Mussetti 3 , Isabel Ruiz-Camps 2,4 , Pedro Puerta-Alcalde 5 , Edson Abdala 6 , Chiara Oltolini 7 , Murat Akova 8 , José Miguel Montejo 9 , Malgorzata Mikulska 10 , Pilar Martín-Dávila 2,11 , Fabián Herrera 12 , Oriol Gasch 13 , Lubos Drgona 14 , Hugo Manuel Paz Morales 15 , Anne-Sophie Brunel 16 , Estefanía García 17 , Burcu Isler 18 , Winfried V. Kern 19 , Pilar Retamar-Gentil 2,20 , José María Aguado 2,21 , Milagros Montero 22 , Souha S. Kanj 23 , Oguz R. Sipahi 24 , Sebnem Calik 25 , Ignacio Márquez-Gómez 26 , Jorge I. Marin 27 , Marisa Z. R. Gomes 28 , Philipp Hemmati 29 , Rafael Araos 30 , Maddalena Peghin 31 , José Luis del Pozo 32 , Lucrecia Yáñez 33 , Robert Tilley 34 , Adriana Manzur 35 , Andres Novo 36 , Natàlia Pallarès 37 , Alba Bergas 1 , Jordi Carratalà 1,2, *, Carlota Gudiol 1,2,38 and on behalf of the IRONIC Study Group ‡ 1 Infectious Diseases Department, Bellvitge University Hospital, IDIBELL, University of Barcelona, 08907 Barcelona, Spain; adaia.albasanz@gmail.com (A.A.-P.); xavierduramiralles@gmail.com (X.D.-M.); jlaporte@iconcologia.net (J.L.-A.); albabergas@gmail.com (A.B.); cgudiol@iconcologia.net (C.G.) 2  Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC),  Instituto de Salud Carlos III, 28029 Madrid, Spain; iruiz@vhebron.net (I.R.-C.); Citation: Albasanz-Puig, A.; pmartindav@gmail.com (P.M.-D.); pilaretamar@hotmail.com (P.R.-G.); jaguadog1@gmail.com (J.M.A.) 3 Hematology Department, Catalan Institute of Oncology (ICO)-Duran i Reynals Hospital, IDIBELL, Durà-Miralles, X.; Laporte-Amargós, J.; Mussetti, A.; Ruiz-Camps, I.; 08907 Barcelona, Spain; amussetti@iconcologia.net 4 Infectious Diseases Department, Vall d’Hebron University Hospital, 08035 Barcelona, Spain Puerta-Alcalde, P.; Abdala, E.; 5 Infectious Diseases Department, Hospital Clínic i Provincial, 08035 Barcelona, Spain; puerta@clinic.cat Oltolini, C.; Akova, M.; Montejo, J.M.; 6 Instituto do Câncer do Estado de São Paulo, Faculty of Medicine, University of São Paulo, et al. Effect of Combination Sao Paulo 01246, Brazil; eabdala@uol.com.br Antibiotic Empirical Therapy on 7 Unit of Infectious and Tropical Diseases, IRCCS San Raffaele Scientific Institute, 20132 Milan, Italy; Mortality in Neutropenic Cancer oltolini.chiara@hsr.it Patients with Pseudomonas aeruginosa 8 Department of Infectious Diseases, Hacettepe University School of Medicine, 06230 Ankara, Turkey; Pneumonia. Microorganisms 2022, 10, akova.murat@gmail.com 9 Infectious Diseases Department, Cruces University Hospital, 48903 Bilbao, Spain; 733. https://doi.org/10.3390/ microorganisms10040733 josemiguel.montejobaranda@osakidetza.eus 10 Division of Infectious Diseases, Department of Health Sciences, University of Genoa (DISSAL) and Ospedale Academic Editor: Célia F. Rodrigues Policlinico San Martino, 16132 Genoa, Italy; m.mikulska@unige.it 11 Infectious Diseases Department, Ramon y Cajal Hospital, 28034 Madrid, Spain 12 Infectious Diseases Section, Department of Medicine, Centro de Educación Médica e Investigaciones Received: 24 February 2022 Clínicas (CEMIC), Buenos Aires C1430EFA, Argentina; fabian1961@gmail.com Accepted: 21 March 2022 13 Infectious Diseases Department, Parc Taulí University Hospital, Sabadell, 08208 Barcelona, Spain; Published: 29 March 2022 ogasch@tauli.cat 14 Oncohematology Department, Comenius University and National Cancer Institute, Publisher’s Note: MDPI stays neutral 81499 Bratislava, Slovakia; lubos.drgona@gmail.com with regard to jurisdictional claims in 15 Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba 81520-060, Brazil; published maps and institutional affil- moraleshmp@gmail.com iations. 16 Infectious Diseases Department, Department of Medicine, Lausanne University Hospital, Centre Hospitalier Universitaire Vaudois (CHUV), 1011 Lausanne, Switzerland; anne-sophie.brunel@chuv.ch 17 Haematology Department, Reina Sofía University Hospital-IMIBIC-UCO, 14004 Córdoba, Spain; estefania.garcia.sspa@juntadeandalucia.es 18 Department of Infectious Diseases and Clinical Microbiology, Istanbul Education and Research Hospital, Copyright: © 2022 by the authors. Istanbul 34668, Turkey; burcubayrak85@gmail.com Licensee MDPI, Basel, Switzerland. 19 Division of Infectious Diseases, Department of Medicine II, University of Freiburg Medical Center and This article is an open access article Faculty of Medicine, 79110 Freiburg, Germany; winfried.kern@uniklinik-freiburg.de distributed under the terms and 20 Unit of Infectious Diseases and Microbiology, University Hospital Virgen Macarena, Department of Medicine, conditions of the Creative Commons Universidad de Sevilla, Institute of Biomedicine of Seville, Virgen del Rocío and Virgen Macarena University Attribution (CC BY) license (https:// Hospitals/CSIC/University of Seville, 41013 Seville, Spain 21 Infectious Diseases Unit, Instituto de Investigación Hospital “12 de Octubre” (i + 12), “12 de Octubre” creativecommons.org/licenses/by/ 4.0/). University Hospital, School of Medicine, Universidad Complutense, 28041 Madrid, Spain Microorganisms 2022, 10, 733. https://doi.org/10.3390/microorganisms10040733 https://www.mdpi.com/journal/microorganisms Microorganisms 2022, 10, 733 2 of 14 22 Infectious Diseases Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigations Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, 08003 Barcelona, Spain; mmontero@parcdesalutmar.cat 23 Infectious Diseases Division, American University of Beirut Medical Center, Beirut 110236, Lebanon; sk11@aub.edu.lb 24 Faculty of Medicine, Ege University, Izmir 35040, Turkey; oguz.resat.sipahi@gmail.com 25 Department of Infectious Diseases and Clinical Microbiology, University of Health Science Izmir Bozyaka Training and Research Hospital, Izmir 35170, Turkey; sebnemozkoren@yahoo.com 26 Infectious Diseases Department, Hospital Regional de Málaga, 29010 Málaga, Spain; nachomarquezgomez@gmail.com 27 Infectious Diseases and Clinical Microbiology Department, Clínica Maraya, Pereira, Colombia, Critical Care and Clinical Microbiology Department, Manizales 170001-17, Colombia; jimarin.uribe@gmail.com 28 Hospital Federal dos Servidores do Estado, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Ministério da Saúde, Rio de Janeiro 20221-161, Brazil; marisargomes@ioc.fiocruz.br 29 Department of Hematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University Medical School, 10117 Berlin, Germany; philipp@hemmati.de 30 Facultad de Medicina Clínica, Instituto de Ciencias e Innovación en Medicina, Alemana Universidad del Desarrollo, Santiago de Chile, and Millennium Initiative for Collaborative Research on Bacterial Resistance (MICROB-R), Santiago de Chile 12461, Chile; rafaaraos@gmail.com 31 Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata, 33100 Udine, Italy; maddalena.peghin@gmail.com 32 Infectious Diseases and Microbiology Unit, Faculty of Medicine, Navarra University Clinic, 31008 Pamplona, Spain; jdelpozo@unav.es 33 Haematology Department, Marqués de Valdecilla University Hospital, 39008 Santander, Spain; lucrecia.yanez@scsalud.es 34 Microbiology Department, University Hospitals Plymouth NHS Trust, Plymouth 8DH, UK; robert.tilley@nhs.net 35 Infectious Diseases, Hospital Rawson, San Juan J5400, Argentina; admanzur74@yahoo.com.ar 36 Haematology Department, Son Espases University Hospital, 07120 Palma de Mallorca, Spain; andres.novo@ssib.es 37 Statistics Advisory Service, Institute of Biomedical Research of Bellvitge, Rovira i Virgili University, 08908 Tarragona, Spain; npallares@idibell.cat 38 Infectious Diseases Unit, Catalan Institute of Oncology (ICO), Duran i Reynals Hospital, IDIBELL, 08908 Barcelona, Spain * Correspondence: jcarratala@bellvitgehospital.cat; Tel.: +34-93-260-7625; Fax: + 34-93-260-7537 † These authors contributed equally to this work. ‡ Ironic Study Investigators: Enric Sastre, Infectious Diseases Department, and Fe Tubau, Microbiology Department, Bellvitge University Hospital, IDIBELL, Barcelona, Spain. Cristian Tebé, Statistics Advisory Service, Institute of Biomedical Research of Bellvitge, Rovira i Virgili University. Marisol Rodríguez Arias, Oncology Department, Institut Català d’Oncologia (ICO)—Hospital Duran i Reynals, IDIBELL, Barcelona, Spain. Juan Aguilar-Company, Oncology Department, and Nieves Larrosa, Microbiology Department, Vall d’Hebron University Hospital, Barcelona, Spain. Celia Cardozo and Carolina Garcia-Vidal, Infectious Diseases Department, Hospital Clínic i Provincial, Barcelona, Spain. Ibrahim Karim-Yaqub, Instituto do Câncer do Estado de São Paulo da Faculdade de Medicina da Universidade de São Paulo, Brazil. Raffaella Greco, Haematology and Bone Marrow Transplantation Unit, and Paola Cichero, Microbiology and Virology Laboratory, IRCCS San Raffaele Scientific Institute, Milan, Italy. Roberto Céspedes, Haematology Department, and Leire López-Soria, Microbiology Department, Cruces University Hospital, Bilbao, Spain. Laura Magnasco, Division of Infectious Diseases, University of Genoa (DISSAL) and Ospedale Policlinico San Martino, Genoa, Italy. Jesús Fortún, Infectious Diseases Department, Ramón y Cajal Hospital, Madrid, Spain. Diego Torres, Infectious Diseases Section, Department of Medicine, Centro de Educación Médica e Investigaciones Clínicas (CEMIC), Buenos Aires, Argentina. Anna Boté, Infectious Diseases Department, and Mateu Espasa, Microbiology Department, Parc Taulí University Hospital, Sabadell, Barcelona, Spain. Mia Hold Montaguti, Infectious Diseases Department, Hospital Erasto Gaertner, Curitiba, Brazil. Oriol Manuel and Pierre-Yves Bochud, Infectious Diseases Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland. Salvador Tabares Carrasco and Josefina Serrano López, Haematology Department, Reina Sofía University Hospital-IMIBIC-UCO, Córdoba. Hartmut Bertz, Haematology-Oncology Department, and Siegbert Rieg, Division of Infectious Diseases, Department of Medicine II, University of Freiburg Medical Center and Faculty of Medicine, Freiburg, Germany. Jesús Rodriguez Baño and Marina de Cueto, Institute of Biomedicine of Seville, Virgen del Rocío and Virgen Macarena University Hospitals/CSIC/University of Seville, Seville, Spain; Unit of Infectious Diseases and Microbiology, University Hospital Virgen Macarena, Seville, Spain; Department of Medicine, Universidad de Sevilla, Seville, Spain. Manuel Lizasoain, Infectious Diseases Unit, 12 de Octubre University Hospital, Madrid, Spain. Juan Pablo Horcajada, Infectious Diseases Microorganisms 2022, 10, 733 3 of 14 Service, Hospital del Mar, Infectious Pathology and Antimicrobials Research Group (IPAR), Institut Hospital del Mar d’Investigations Mèdiques (IMIM), Universitat Autònoma de Barcelona (UAB), CEXS-Universitat Pompeu Fabra, Barcelona, Spain. Saeed El Zein and Jean-Francois Jabbour, Infectious Diseases Division, American University of Beirut Medical Center, Beirut, Lebanon. Ayse Uyan-Onal, Department of Infectious Diseases and Clinical Microbiology, Ege University Faculty of Medicine, Izmir, Turkey. Arzu Nazli-Zeka, Department of Infectious Diseases and Clinical Microbiology, Dokuz Eylul University Faculty of Medicine, Izmir, Turkey. Begoña Palop, Microbiology Deparment, Hospital Regional de Málaga, Málaga, Spain. Lina Clemencia Correa, Clinica Maraya, Pereira, Colombia. João Pedro Silva Tonhá and Luciana Sênos de Mello, Instituto Oswaldo Cruz, Fundação Oswaldo Cruz, Rio de Janeiro, Brazil. Georg Maschmeyer, Department of Haematology, Oncology and Palliative Care, Klinikum Ernst von Bergmann, Academic Teaching Hospital of Charité University Medical School, Berlin, Germany. Jose Munita, Instituto de Ciencias e Innovación en Medicina, Facultad de Medicina, Clínica Alemana Universidad del Desarrollo, Santiago de Chile, Chile, and Millennium Initiative for Collaborative Research on Bacterial Resistance (MICROB-R). Nadia Castaldo, Infectious Diseases Clinic, Department of Medicine, University of Udine and Azienda Sanitaria Universitaria Integrata, Udine, Italy. Paloma Sangro del Alcázar, Internal Medicine Department, Navarra University Clinic, Pamplona, Spain. Abstract: To assess the effect of combination antibiotic empirical therapy on 30-day case-fatality rate in neutropenic cancer patients with Pseudomonas aeruginosa (PA) bacteremic pneumonia. This was a multinational, retrospective cohort study of neutropenic onco-hematological patients with PA blood- stream infection (BSI) (2006–2018). The effect of appropriate empirical combination therapy, appropri- ate monotherapy and inappropriate empirical antibiotic therapy [IEAT] on 30-day case-fatality was assessed only in patients with PA bacteremic pneumonia. Among 1017 PA BSI episodes, pneumonia was the source of BSI in 294 (28.9%). Among those, 52 (17.7%) were caused by a multidrug-resistant (MDR) strain and 68 (23.1%) received IEAT, mainly when the infection was caused by an MDR strain [38/52 (73.1%) vs. 30/242 (12.4%); p < 0.001]. The 30-day case-fatality rate was higher in patients with PA bacteremic pneumonia than in those with PA BSI from other sources (55.1% vs. 31.4%; p < 0.001). IEAT was associated with increased 30-day case-fatality (aHR 1.44 [95%CI 1.01–2.03]; p = 0.042), whereas the use of appropriate combination empirical treatment was independently associated with improved survival (aHR 0.46 [95%CI 0.27–0.78]; p = 0.004). Appropriate empiri- cal monotherapy was not associated with improved overall survival (aHR 1.25 [95%CI 0.76–2.05]; p = 0.39). Combination antibiotic empirical therapy should be administered promptly in febrile neutropenic patients with suspected pneumonia as the source of infection. Keywords: Pseudomonas aeruginosa; bloodstream infection; pneumonia; septic shock; neutropenia 1. Introduction Pseudomonas aeruginosa (PA) bloodstream infection (BSI) remains one of the leading causes of death among neutropenic cancer patients [1,2]. The administration of inadequate initial empirical antibiotic treatment for PA BSI in this population has been associated with impaired outcomes [3–5]. Importantly, due to the worrisome increase in multidrug resistance among PA isolates, the rates of inadequate empirical antibiotic treatment are increasing with a detrimental impact on mortality [1,6]. Data from a few retrospective studies suggest that an initial combination empirical ther- apy with two active antipseudomonal antibiotics raises levels of appropriate treatment in patients with PA BSI, and consequently improves outcomes [4,7]. Nevertheless, the possible benefit of combined treatment over monotherapy is still a matter of vivid debate [8–11]. The issue is controversial because the mortality attributed to PA BSI might not be determined only by the appropriateness of the empirical antibiotic treatment, but also by the source of infection, the baseline characteristics of the infected host and the severity of the clinical presentation [12–14]. In this regard, bacterial pneumonia is common in febrile neutropenic patients, with a prevalence that ranges from 16% to 40% of cases [15]. More specifically, 31.5% of patients with acute leukemia [16] and 64% of allogeneic hematopoietic stem cell Microorganisms 2022, 10, 733 4 of 14 transplant recipients will develop an episode of pneumonia [17], with unacceptably high case-fatality rates, particularly when compared with infections from other sources [18–20]. PA is one of the main causative agents of pneumonia in neutropenic cancer pa- tients [21,22]. It frequently presents with BSI, septic shock and/or requires intensive care unit admission [20,23,24]. Even though the most recent Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) guidelines recommend an initial empiri- cal therapy with two active antipseudomonal antibiotics for hospital-acquired pneumonia in patients at high risk for mortality and/or antimicrobial resistance [25], the true impact of this strategy in febrile neutropenic patients with PA pneumonia is still unknown. In fact, the currently available guidelines for the management of febrile neutropenia lack specific recommendations regarding the empirical treatment of pneumonia in neutropenic patients [26]. In this study, we assess the effect of combination antibiotic empirical therapy versus monotherapy on 30-day mortality in neutropenic cancer patients with PA bacteremic pneumonia. 2. Materials and Methods 2.1. Study Design and Setting This study is part of the IRONIC project: a multicenter, international, retrospective cohort study conducted from 1 January 2006 to 31 May 2018 at 34 centers in 12 countries. The number of participating centers is provided in the Supplementary material. The number of patients recruited at each participating center has been reported elsewhere [27]. 2.2. Ethics The study was approved by the Institutional Review Board at Bellvitge University Hospital (local reference number PR408/17) and by the local Research Ethics Committees at the participating centers. It was conducted in accordance with the Declaration of Helsinki guidelines. The need for informed consent was waived by the Clinical Research Ethics Committee due to the retrospective design. The study results are reported following the STROBE recommendations [28] (Supplementary Material). 2.3. Participants All adult (≥18 years) onco-hematological neutropenic patients, including hematopoi- etic stem cell transplant (HSCT) recipients, were eligible for the study if they were diagnosed with at least one episode of PA BSI during the study period. Subsequent episodes caused by PA occurring in the same patient were included in the study if they occurred at intervals of >1 month. Only monomicrobial PA BSI episodes were selected for this study. The exclusion criteria were unavailability of key data (related to death) and polymicrobial BSI. The follow-up period was 30 days from BSI onset. 2.4. Variables Data regarding baseline characteristics, clinical and microbiological features and end- points were collected. Empirical antibiotic therapy was considered when the antibiotic was administered before reception of definitive susceptibility results. Appropriate empirical antibiotic therapy was defined when patients received at least one in vitro active antibiotic against the PA strain. Empirical combination therapy was considered appropriate when both antibiotics that were empirically administered were active against the PA strain. If a patient received two empirical antibiotics but only one was active, this was considered appropriate monotherapy. Inappropriate empirical antibiotic treatment (IEAT) was con- sidered when the patient did not receive any empirical antibiotic with in vitro activity or an empirical antibiotic therapy was lacking. In addition, in the cohort of patients with PA pneumonia, empirical monotherapy with an aminoglycoside was considered inappropri- ate. Thus, three treatment categories were observed: appropriate empirical combination therapy, appropriate empirical monotherapy and IEAT. The antipseudomonal β-lactams Microorganisms 2022, 10, 733 5 of 14 were uniformly administered at the current standard doses for the treatment of febrile neutropenia [26,29]. In case of renal impairment, the dosing was adjusted accordingly. 2.5. Outcomes The 30-day case-fatality rate of patients with bacteremic PA pneumonia was compared with those with BSI from other sources. The rate of persistent BSI, need for intensive care unit (ICU) admission and mechanical ventilation were also analyzed. Risk factors for overall 30-day case-fatality and the effect of the use of appropriate combination antibiotic empirical therapy, monotherapy or IEAT on mortality were analyzed only in patients with PA pneumonia. 2.6. Microbiological Studies Clinical samples were processed at the microbiology laboratories of each participating center in accordance with standard operating procedures. PA was identified using standard microbiological techniques at each center. In vitro susceptibility was determined according to the EUCAST recommendations [30], except at the Lebanese center and at one center from Argentina where the CLSI breakpoints were used, and in the center in the UK where the BSAC recommendations were used before 2016 [31]. PA isolate phenotypes were stratified in accordance with recent standard definitions [32]. 2.7. Definitions Neutropenia and severe neutropenia were defined as an absolute neutrophil count below 0.5 × 109 cells/mm and 0.1 × 109 cells/mm, respectively. Previous corticosteroid treatment was defined as the administration of ≥20 mg of prednisone, or equivalent dosing, for at least four weeks within 30 days of BSI onset. Patients with refractory/relapsed disease and those receiving palliative chemotherapy were classified as having refractory disease. Bacteremic PA pneumonia was defined as the presence of an acute respiratory illness and a new pulmonary infiltrate on a chest radiograph and/or CT in association with concurrent PA BSI. Other BSI sources were established using standard US Centers for Disease Control and Prevention criteria for secondary BSI [33]. In addition, the source of BSI was defined as unknown or endogenous in patients in whom no other sources were identified. Septic shock was defined as a systolic blood pressure <90 mmHg that was unresponsive to fluid treatment or required vasoactive drug therapy [34]. Mucositis was considered in patients with ulcerative lesions involving only the oral cavity. Comorbidities were defined as the presence of one or more of the following diseases: chronic obstructive pulmonary disease, heart disease, hepatic disease, diabetes mellitus, renal failure and cerebrovascular disease. Persistent BSI was considered if blood cultures were positive after 48 h of adequate antibiotic therapy. The 30-day case-fatality rate was defined as death from any cause within 30 days of BSI onset. 2.8. Statistical Analysis To define cohort characteristics, categorical variables were presented as the number of cases and percentages, while continuous variables were presented as the mean and standard deviation (SD) or median and interquartile range (IQR). Continuous variables were compared using the Student’s t-test or the Mann–Whitney U test where appropriate. Fisher’s exact test or Pearson’s χ2 test were applied to assess the relationship between categorical variables. Microorganisms 2022, 10, 733 6 of 14 Time until death, or last follow-up, was assessed using the Kaplan–Meier estimator. The log-rank test was used to compare the survival curves between treatment strategies. The Cox proportional hazards model was used to perform an adjusted analysis of the treatment strategies with age, sex, septic shock and the presence of multidrug resistance as clinically relevant factors. The proportionality of risks in the Cox model was checked using the Schoenfeld residuals. The presence of septic shock at admission violated the proportional hazard assumption of the Cox model. To address this problem, we performed a time-dependent covariates analysis on septic shock. Data were split into three groups (from day 0 to day 2, from day 2 to day 10, and from day 10 to day 30), defined after the exploration of the Schoenfeld residuals plot, to estimate different coefficients over different time intervals [35]. The effects of the treatment strategies were reported with hazard ratio (HR) and 95% confidence interval adjusted for age, sex, and multi-drug resistant pneumonia. Statistical analyses were performed with R software 4.1.0. 3. Results 3.1. Clinical Characteristics Among the 1217 eligible PA BSI episodes, pneumonia was the second most frequent source, with 311 episodes (25.5%), after an endogenous source (37.4%). Two hundred episodes met at least one of the exclusion criteria and were excluded from the analysis, leaving 1017 included episodes, in which pneumonia was the source of BSI in 294 (28.9%). Baseline characteristics of patients included in the study are detailed in the supplementary material (Table S1). Patients with bacteremic PA pneumonia had more comorbidities and presented more frequently with septic shock than those with PA BSI from other sources. In total, 17.7% (52/294) of PA pneumonia episodes were caused by multidrug-resistant (MDR) strains, and 30.6% (90/294) were due to carbapenem-resistant isolates, without significant differences between groups. 3.2. Treatment Characteristics Table 1 shows the different treatment regimens administered in patients with PA pneumonia. Overall, an antipseudomonal β-lactam in monotherapy was the most frequent empirical antibiotic used (173/294, 58.9%). When a combination empirical therapy was preferred, a combination of a β-lactam plus an aminoglycoside was predominant (87/118, 73.7%). Of note, 68 episodes (23.1%) received IEAT, particularly when the PA BSI was caused by an MDR strain [38/52 (73.1%) vs. 30/242 (12.4%); p < 0.001]. Almost 49% of these 68 episodes were initially treated with an antipseudomonal β-lactam in monotherapy with no in vitro activity against the PA isolate (mainly carbapenems or piperacilin/tazobactam). Compared with PA BSI from other sources, no differences were found between the rate of inappropriate empirical antibiotic treatment [68/294 (23.1%) vs. 142/723 (19.6%); p = 0.29]. Among those episodes caused by a MDR PA strain, only 14 received an appropriate empirical antibiotic treatment that was mainly based on a monotherapy (10 of 14 cases). Microorganisms 2022, 10, 733 7 of 14 Table 1. Treatment characteristics of the 294 patients with Pseudomonas aeruginosa bacteremic pneu- monia. No Antibiotic Treatment (Death < 48 h) 3/294 (1) Initial empirical monotherapy 173/294 (58.9) Piperacillin/tazobactam 84 (48.6) Antipseudomonal carbapenems (imipenem, meropenem) 54 (31.2) Antipseudomonal cephalosporins 24 (13.9) Polymyxins (Colistin/Polymyxin B) 2 (1.1) Fluoroquinolones 1 (0.6) Aminoglycoside 1 (0.6) Others a 7 (4) Initial empirical combination therapy 118/294 (40.1) β-lactam + AG 87 (73.7) β-lactam + non-AG 27 (22.9) Non-β-lactam combination 4 (3.4) Appropriate empirical treatment 226/294 (76.9) Monotherapy b 147/226 (65) Piperacillin/tazobactam 73 (49.7) Anti-pseudomonal carbapenems (imipenem, meropenem) 37 (25.2) Anti-pseudomonal cephalosporins 23 (15.7) Polymyxins (Colistin, Polymyxin B) 12 (8.2) Fluoroquinolone (levofloxacin/ciprofloxacin) 2 (1.4) Combined therapy 79/226 (35) β-lactam + AG 59 (74.7) β-lactam + non-AG 20 (25.3) Inappropriate empirical treatment 68/294 (23.1) No antibiotic treatment (Death < 48 h) 3/68 (4.4) Monotherapy 41/68 (60.3) Anti-pseudomonal carbapenems (imipenem, meropenem) 16 (39) Piperacillin/tazobactam 15 (36.6) Anti-pseudomonal cephalosporins 2 (4.9) Aminoglycosides 1 (2.4) Others c 7 (17) Combination therapy 24/68 (35.3) β-lactam + AG d 21 (87.5) β-lactam + non-AG 1 (4.2) Non-β-lactam combination 2 (8.3) Qualitative data are expressed as numbers (%), unless otherwise indicated. Abbreviations: AG: Aminoglycoside. a Clindamycin (n = 1), Azithromycin (n = 1), Ceftriaxone (n = 2), Amoxicillin/clavulanate (n = 2), Metronidazole (n = 1). b 12 patients received an initial empirical combination treatment but were classified as receiving an appropriate empirical monotherapy because only one of the antibiotics showed in vitro activity against the PA strain: Colistin (n = 9), fluoroquinolone (n = 1), antipseudomonal cephalosporin (n = 1), piperacillin/tazobactam (n = 1). c Amoxicillin/clavulanate (n = 2), Ceftriaxone (n = 2), Metronidazole (n = 1), Clindamycin (n = 1), Azithromycin (n = 1). d 19 episodes received inappropriate empirical combination antibiotic treatment where only the aminoglycoside showed in vitro activity against the PA isolate. 3.3. Outcomes The 30-day case-fatality rate was significantly higher in patients with PA bacteremic pneumonia than in those with PA BSI from other sources (Table 2). Moreover, the rates of persistent BSI and the need for ICU admission and mechanical ventilation were also higher in patients with pneumonia. Microorganisms 2022, 10, 733 8 of 14 Table 2. Outcomes. PA Pneumonia n = 294 (%) PA BSI n = 723 (%) p-Value 30-day case-fatality rate 162 (55.1) 227 (31.4) <0.001 Persistent BSI (48h from BSI onset) 41 (14.5) 71 (9.9) 0.048 ICU admission 126 (42.9) 186 (25.7) <0.001 Need for mechanical ventilation 83 (28.2) 115 (15.9) <0.001 Abbreviations: PA: Pseudomonas aeruginosa, BSI: Bloodstream infection, ICU: Intensive care unit. 3.4. Risk Factors for Mortality in Patients with Bacteremic PA Pneumonia In the univariate Cox analysis, septic shock at presentation (HR 3.56 [95%CI 2.56–4.94]; p < 0.001), infection due to a MDR strain (HR 2.05 [95%CI 1.43–2.93]; p < 0.001) and IEAT (HR 1.57 [95%CI 1.21–2.21]; p = 0.009) were associated with higher 30-day case-fatality rate, whereas the use of an appropriate empirical combination treatment was associated with improved survival (HR 0.46 [95%CI 0.29–0.72]; p = 0.001). In the multivariate Cox analysis, receiving IEAT was an independent risk factor for increased 30-day case-fatality (aHR 1.44 [95%CI 1.01–2.03]; p = 0.042). In addition, when focusing on the impact of the three treatment strategies, we ob- served that the benefit on survival of the administration of an appropriate empirical combination treatment was maintained after adjusting for potential confounders (aHR 0.46 [95%CI 0.27–0.78]; p = 0.004). The univariate and multivariate Cox models are detailed in Tables 3 and 4). Figures 1 and 2 show the Kaplan–Meier curves stratified by the appro- priateness of empirical treatment. Table 3. Univariate Cox model for the 30-day case-fatality rate in patients with PA bacteremic pneumonia. Variables Alive n = 132 Dead n = 162 HR CI 95% p-Value Age (y), mean (SD) 61.6 (14.8) 61.1 (13.6) 1.00 0.99–1.01 0.781 Gender (female) 41 (31.1) 51 (31.5) 1.13 0.81–1.58 0.534 Acute leukemia 39 (29.5) 56 (34.6) 1.12 0.81–1.55 0.448 Refractory disease 48 (36.4) 71 (43.8) 1.29 0.95–1.76 0.122 HSCT 20 (15.2) 35 (21.6) 1.17 0.81–1.71 0.344 GVHD 7 (43.8) 14 (48.3) 1.09 0.53–2.27 0.806 Comorbidities a 77 (62.1) 95 (60.1) 0.97 0.71–1.34 0.810 BSI acquisition (hospital-acquired) 58 (43.9) 88 (54.3) 1.18 0.87–1.61 0.223 Prior corticosteroid treatment (1 month) 71 (53.8) 94 (58.8) 1.13 0.83–1.55 0.417 Severe neutropenia 68 (54) 96 (59.6) 1.26 0.92–1.73 0.165 Septic shock 34 (26) 107 (66) 3.56 2.56–4.94 <0.001 Multidrug-resistant strain 11 (8.3) 41 (25.3) 2.05 1.43–2.93 <0.001 Inappropriate empirical antibiotic treatment 21 (15.9) 47 (29.0) 1.57 1.21–2.21 0.009 Empirical treatment adequacy 0.016 Inappropriate empirical antibiotic treatment 21 (15.9) 47 (29) Ref Ref Ref Appropriate empirical treatment (monotherapy) 65 (49.2) 82 (50.6) 0.75 0.52–1.07 0.115 Appropriate empirical treatment (combination treatment) 46 (34.8) 33 (20.4) 0.46 0.29–0.72 0.001 Abbreviations: PA: Pseudomonas aeruginosa; BSI: bloodstream infection; HSCT: Hematopoietic stem cell trans- plant; GVHD: Graft versus host disease; HR: Hazard Ratio; CI: Confidence Interval. a Comorbidities are defined as the presence of one or more of the following diseases: COPD, heart or hepatic disease, diabetes mellitus, renal failure, and cerebrovascular disease. Table 4. Multivariate Cox model for the 30-day case-fatality rate in patients with PA bacteremic pneumonia. Predictors Microorganisms 2022, 10, 733 30-Day Case-Fatality Rate 9 of 14 aHR Std. Error CI 95% p-Value Age 1.00 0.01 0.99–1.01 0.616 Table 4. Multivariate Cox model for the 30-day case-fatality rate in patients with PA bacteremic Gender pneumonia. 1.17 0.20 0.83–1.64 0.376 Inappropriate empirical antibiotic treatment Predictors 1.44 0.26 Rate 1.01–2.03 30-Day Case-Fatality 0.042 Septic shock aHR Std. Error CI 95% p-Value Age Group 1 (0–48 h from BSI onset) 1.00 6.530.01 1.870.99–1.013.73–11.43 0.616 <0.001 Gender 1.17 0.20 0.83–1.64 0.376 Groupempirical Inappropriate 2 (48 h–10 days antibiotic from BSI onset) treatment 1.44 2.890.26 0.221.01–2.03 1.66–5.05 0.042 <0.001 Septic shock Group Group 1 (0–483h (10 days–30 from BSI onset) days from BSI onset)6.53 1.411.87 0.583.73–11.430.63–3.14 <0.001 0.400 Group 2 (48 h–10 days Abbreviations: PA:from BSI onset) Pseudomonas 2.89 BSI: bloodstream aeruginosa; 0.22 1.66–5.05 infection; <0.001 Hazard aHR: adjusted Group 3 (10 days–30 days from BSI onset) 1.41 0.58 0.63–3.14 0.400 Ratio, CI: Confidence Abbreviations: Interval. PA: Pseudomonas aeruginosa; BSI: bloodstream infection; aHR: adjusted Hazard Ratio, CI: Confidence Interval. 1. Kaplan–Meier Figuresurvival Figure 1. Kaplan–Meier survivalof analysis analysis of patients patients with Pseudomonas aeruginosa with Pseudomonas bacteremic bacteremic aeruginosa pneu- monia, stratified by the appropriateness of empirical treatment. pneumonia, stratified by the appropriateness of empirical treatment. x FOR PEER REVIEW 10 of 14 Microorganisms 2022, 10, 733 10 of 14 Figure 2. Kaplan–Meier Figuresurvival analysis 2. Kaplan–Meier ofanalysis survival patients withwith of patients Pseudomonas aeruginosa Pseudomonas aeruginosa bacteremic bacteremic pneu- pneumonia, stratifiedmonia, stratified bygroup. by treatment treatment group. 4. Discussion 4. Discussion In this large multicenter, international cohort study of high-risk neutropenic cancer patients, we found that pneumonia was a frequent cause of PA BSI and was associated with In this large multicenter, a strikingly high international cohort 30-day case-fatality study patients rate. Among of high-risk neutropenic with bacteremic cancer PA pneumonia, patients, we foundthe that pneumonia presence of septic was shock aandfrequent the use of cause an IEAT of had PA aBSI and impact negative was associated on overall survival. Conversely, the administration of appropriate with a strikingly high 30-day case-fatality rate. Among patients with bacteremic PA initial combined empirical antibiotic pneu- treatment, mainly based on an active antipseudomonal β-lactam and an aminoglycoside, monia, the presence wasof septic shock independently and the associated with use of an improved IEAT had a negative impact on outcomes. overall survival. Conversely, We found thethat administration 23% of patients of appropriate with bacteremic PA initial combined pneumonia receivedempirical IEAT, a antibiotic treatment,percentage mainly that basedroseonsignificantly an active in antipseudomonal the case of MDR strains. IEAT was and β-lactam also found to be an amino- an independent risk factor for mortality; indeed, it has previously been shown to have a glycoside, was independently detrimental effect associated on mortalitywith improved in neutropenic outcomes. cancer patients with PA BSI [3,4,6,36] and We found thatbacteremic 23% of patients PA pneumonia with[7,14]. bacteremic However,PA the pneumonia received presence of multidrug IEAT, resistance was a not per- independently associated with a poor prognosis in our centage that rose significantly in the case of MDR strains. IEAT was also found to be an study. In this regard, even though the association between IEAT and multidrug resistance has been previously reported [3,37], independent risk factor for mortality; indeed, it has previously been shown to have a det- its real impact on mortality is still controversial [6,7,12,13,38]. rimental effect on mortalityIn the in neutropenic current cancer era of emerging patients antibiotic with PA resistance, BSI reasonable it seems [3,4,6,36]toand opt bac- for teremic PA pneumonia initial empirical combination the [7,14]. However, treatment in order presence oftomultidrug increase the probability resistance of adequateness was not in- and also to take advantage of the potential antibiotics’ synergism [39]. Nevertheless, dependently associated with a poor prognosis in our study. In this regard, even though the benefit for survival of using a combined empirical antibiotic therapy rather than the association between monotherapyIEAT andPAmultidrug to treat resistance severe infections in the generalhas been previously population reported remains a long-standing controversy [8,37,40]. Specifically, when focusing [3,37], its real impact on mortality is still controversial [6,7,12,13,38]. on PA bacteremic pneumonia, Park et al. In the current era of emerging antibiotic resistance, it seems reasonable to opt for initial empirical combination treatment in order to increase the probability of adequate- ness and also to take advantage of the potential antibiotics’ synergism [39]. Nevertheless, the benefit for survival of using a combined empirical antibiotic therapy rather than mon- Microorganisms 2022, 10, 733 11 of 14 found that the use of adequate combined empirical antibiotic treatment was associated with improved 28-day survival and higher 2 and 4-week bacterial eradication rates [7]. Conversely, Recio et al. did not confirm this beneficial effect on mortality [5]; however, these authors found neutropenia to be a risk factor for early 5-day mortality. Importantly, this knowledge gap is even greater in the setting of febrile neutrope- nia [41]. Indeed, a meta-analysis by Paul et al. focusing on neutropenic cancer patients found no benefit of combination therapy, although the rate of PA infections was only 1.7% and the number of pneumonia episodes was not specified [11]. Of note, we found that the use of a combined empirical antibiotic treatment for PA bacteremic pneumonia in neutropenic patients, mainly based on a β-lactam and an aminoglycoside, was associated with improved 30-day mortality. Our results may be explained by the synergistic effect of combining an adequate β-lactam antibiotic and aminoglycoside, as suggested by early studies [42]. In this line, in a previous study, we observed an improved early (7-day) mortality rate in those neutropenic cancer patients with GNB BSI who received initial appropriate combination therapy [39]. In addition, the beneficial effect of adding an aminoglycoside to an active β-lactam has recently been shown to be particularly relevant in febrile neutropenic patients presenting with septic shock [43]. Similarly, in our study, the beneficial effect of a combined therapy over monotherapy was mainly observed within the first 7 days of BSI onset, probably when the empirical use of an aminoglycoside is more important to increase the rate of bacterial clearance and consequently improve outcomes. In this regard, choosing the optimal empirical β-lactam for the treatment of PA pneu- monia according to the individual risk of resistance is crucial. Here, the newly available β-lactam + β-lactamase inhibitors may play a very important role [44,45]. The use of colistin instead of an aminoglycoside is an appealing proposal, but no firm conclusions regarding its appropriateness can be drawn from the present study; however, it is an empirical treatment strategy that urgently deserves further investigation. The main strength of this study is that it is based on one of the largest cohorts of neutropenic cancer patients with PA pneumonia, with a multicenter international design, that allows the generalization of the results. To account for a possible bias, multivariate Cox analyses were performed with septic shock as a time-dependent variable. Nevertheless, this study also has some limitations that should be acknowledged. First, this was not a randomized clinical trial (RCT); thus, the choice of therapy may have been influenced by patient-related variables and by the clinical presentation. Second, we included various em- pirical combination antibiotic regimens, which may have had different effects on mortality. Finally, some information may have been lost due to the retrospective design, and we may not have adequately controlled for certain confounders. 5. Conclusions In conclusion, we found that appropriate initial combination antibiotic empirical treatment improved 30-day mortality compared with monotherapy in neutropenic patients with PA bacteremic pneumonia. Therefore, combination empirical therapy should be promptly administered in febrile neutropenic patients with suspected pneumonia as the source of infection. However, further RCTs are warranted to confirm our results. Supplementary Materials: The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/microorganisms10040733/s1, detailed list of the number of par- ticipating centers in each country and Table S1. Clinical and microbiological characteristics of patients with Pseudomonas aeruginosa bacteremic pneumonia. Microorganisms 2022, 10, 733 12 of 14 Author Contributions: Conceptualization, A.A.-P., C.G. and J.C.; methodology, A.A.-P., A.B., C.G. and J.C.; validation, A.A.-P., C.G. and J.C.; formal analysis, N.P.; investigation, A.A.-P., A.B., C.G. and J.C.; resources, C.G. and J.C.; data curation, A.A.-P., X.D.-M., J.L.-A., A.M. (Alberto Mussetti), I.R.-C., P.P.-A., E.A., C.O., M.A., J.M.M., M.M. (Malgorzata Mikulska), P.M.-D., F.H., O.G., L.D., H.M.P.M., A.-S.B., E.G., B.I., W.V.K., P.R.-G., J.M.A., M.M. (Milagros Montero), S.S.K., O.R.S., S.C., I.M.-G., J.I.M., M.Z.R.G., P.H., R.A., M.P., J.L.d.P., L.Y., R.T., A.M. (Adriana Manzur), A.N., A.B., C.G. and J.C.; writing—original draft preparation, A.A.-P., C.G. and J.C.; writing—review and editing, A.A.-P., C.G. and J.C.; funding acquisition, A.A.-P., C.G. and J.C. All authors have read and agreed to the published version of the manuscript. Funding: This work was supported by the Instituto de Salud Carlos III, Subdirección General de Redes y Centros de Investigación Cooperativa, Ministerio de Economía, Industria y Compet- itividad, Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC) [CB21/13/00009, CB21/13/00079, CB21/13/00054, CB21/13/00086, CB21/13/00012], Madrid, Spain. Institutional Review Board Statement: The study was approved by the Institutional Review Board at Bellvitge University Hospital (local reference number PR408/17) and by the local Research Ethics Committees at the participating centers. It was conducted in accordance with the Declaration of Helsinki guidelines. Informed Consent Statement: The need for informed consent was waived by the Clinical Research Ethics Committee due to the retrospective design. The study results are reported following the STROBE recommendations [28] (Supplementary Material). Data Availability Statement: Not applicable. Acknowledgments: We thank the ESCMID Study Group for Bloodstream Infections, Endocarditis and Sepsis (ESGBIES) and the ESCMID Study Group for Immunocompromised Hosts (ESGICH) for supporting the study. We thank Centres de Recerca de Catalunya (CERCA) Program and Generalitat de Catalunya for institutional support. We thank the Spanish Network for Research in Infectious Diseases and the Río Hortega program of the Instituto de Salud Carlos III for the financial support of pre-doctoral students X. Durà, J. Laporte-Amargós and A. Albasanz-Puig. Conflicts of Interest: F.H. received speaker’s fees from MSD and Pfizer and Research and Educational grants from Pfizer. P.R.-G. received speaker’s fees from MSD, Menarini and Shionogui. References 1. Cattaneo, C.; Antoniazzi, F.; Casari, S.; Ravizzola, G.; Gelmi, M.; Pagani, C.; D’Adda, M.; Morello, E.; Re, A.; Borlenghi, E.; et al. P. aeruginosa bloodstream infections among hematological patients: An old or new question? Ann. Hematol. 2012, 91, 1299–1304. [CrossRef] [PubMed] 2. Tofas, P.; Samarkos, M.; Piperaki, E.T.; Kosmidis, C.; Triantafyllopoulou, I.D.; Kotsopoulou, M.; Pantazatou, A.; Perlorentzou, S.; Poulli, A.; Vagia, M.; et al. Pseudomonas aeruginosa bacteraemia in patients with hematologic malignancies: Risk factors, treatment and outcome. Diagn. Microbiol. Infect. Dis. 2017, 88, 335–341. [CrossRef] [PubMed] 3. Martinez-Nadal, G.; Puerta-Alcalde, P.; Gudiol, C.; Cardozo, C.; Albasanz-Puig, A.; Marco, F.; Laporte-Amargós, J.; Moreno- García, E.; Domingo-Doménech, E.; Chumbita, M.; et al. Inappropriate Empirical Antibiotic Treatment in High-risk Neutropenic Patients with Bacteremia in the Era of Multidrug Resistance. Clin. Infect. Dis. 2020, 70, 1068–1074. [CrossRef] [PubMed] 4. Kim, Y.J.; Jun, Y.H.; Kim, Y.R.; Park, K.G.; Park, Y.J.; Kang, J.Y.; Kim, S.I. Risk factors for mortality in patients with Pseudomonas aeruginosa bacteremia; retrospective study of impact of combination antimicrobial therapy. BMC Infect. Dis. 2014, 14, 1–7. [CrossRef] 5. Recio, R.; Viedma, E.; González-Bodí, S.; Villa, J.; Orellana, M.Á.; Mancheño-Losa, M.; Lora-Tamayo, J.; Chaves, F. Clinical and bacterial characteristics of Pseudomonas aeruginosa affecting the outcome of patients with bacteraemic pneumonia. Int. J. Antimicrob. Agents 2021, 58, 106450. [CrossRef] 6. Trecarichi, E.M.; Tumbarello, M.; Caira, M.; Candoni, A.; Cattaneo, C.; Pastore, D.; Fanci, R.; Nosari, A.; Vianelli, N.; Busca, A.; et al. Multidrug resistant Pseudomonas aeruginosa bloodstream infection in adult patients with hematologic malignancies. Haematologica 2011, 96, 32–34. [CrossRef] 7. Park, S.Y.; Park, H.J.; Moon, S.M.; Park, K.H.; Chong, Y.P.; Kim, M.N.; Kim, S.H.; Lee, S.O.; Kim, Y.S.; Woo, J.H.; et al. Impact of adequate empirical combination therapy on mortality from bacteremic Pseudomonas aeruginosa pneumonia. BMC Infect. Dis. 2012, 12, 1. [CrossRef] 8. Peña, C.; Suarez, C.; Ocampo-Sosa, A.; Murillas, J.; Almirante, B.; Pomar, V.; Aguilar, M.; Granados, A.; Calbo, E.; Rodríguez- Baño, J.; et al. Effect of adequate single-drug vs combination antimicrobial therapy on mortality in pseudomonas aeruginosa bloodstream infections: A post hoc analysis of a prospective cohort. Clin. Infect. Dis. 2013, 57, 208–216. [CrossRef] Microorganisms 2022, 10, 733 13 of 14 9. Bowers, D.R.; Liew, Y.X.; Lye, D.C.; Kwa, A.L.; Hsu, L.Y.; Tam, V.H. Outcomes of appropriate empiric combination versus monotherapy for pseudomonas aeruginosa bacteremia. Antimicrob. Agents Chemother. 2013, 57, 1270–1274. [CrossRef] 10. Paul, M.; Leibovici, L. Combination therapy for pseudomonas aeruginosa bacteremia: Where do we stand? Clin. Infect. Dis. 2013, 57, 217–220. [CrossRef] 11. Paul, M.; Dickstein, Y.; Schlesinger, A.; Grozinsky-Glasberg, S.; Soares-Weiser, K.; Leibovici, L. Beta-lactam versus beta-lactam- aminoglycoside combination therapy in cancer patients with neutropenia. Cochrane Database Syst. Rev. 2013, 2013, CD003038. [CrossRef] 12. Babich, T.; Naucler, P.; Valik, J.K.; Giske, C.G.; Benito, N.; Cardona, R.; Rivera, A.; Pulcini, C.; Fattah, M.A.; Haquin, J.; et al. Risk factors for mortality among patients with Pseudomonas aeruginosa bacteraemia: A retrospective multicentre study. Int. J. Antimicrob. Agents 2020, 55, 105847. [CrossRef] 13. Recio, R.; Mancheño, M.; Viedma, E.; Villa, J.; Orellana, M.Á.; Lora-Tamayo, J.; Chaves, F. Predictors of Mortality in Bloodstream Infections Caused by Pseudomonas aeruginosa and Impact of Antimicrobial Resistance and Bacterial Virulence. Antimicrob. Agents Chemother. 2020, 64, 1–13. [CrossRef] 14. Joo, E.J.; Kang, C.I.; Ha, Y.E.; Park, S.Y.; Kang, S.J.; Wi, Y.M.; Lee, N.Y.; Chung, D.R.; Peck, K.R.; Song, J.H. Impact of inappropriate empiric antimicrobial therapy on outcome in Pseudomonas aeruginosa bacteraemia: A stratified analysis according to sites of infection. Infection 2011, 39, 309–318. [CrossRef] 15. Lanoix, J.P.; Schmit, J.L.; Douadi, Y. Bacterial lung sepsis in patients with febrile neutropenia. Curr. Opin. Pulm. Med. 2012, 18, 175–180. [CrossRef] 16. Specchia, G.; Pastore, D.; Carluccio, P.; Mele, G.; Montagna, M.T.; Liso, A.; Rizzi, R.; Stabile Ianora, A.; Liso, V. Pneumonia in acute leukemia patients during induction therapy: Experience in a single institution. Leuk. Lymphoma 2003, 44, 97–101. [CrossRef] 17. Aguilar-Guisado, M.; Jiménez-Jambrina, M.; Espigado, I.; Rovira, M.; Martino, R.; Oriol, A.; Borrell, N.; Ruiz, I.; Martín-Dávila, P.; de la Cámara, R.; et al. Pneumonia in allogeneic stem cell transplantation recipients: A multicenter prospective study. Clin. Transplant. 2011, 25, 629–638. [CrossRef] 18. Hakki, M.; Limaye, A.P.; Kim, H.W.; Kirby, K.A.; Corey, L.; Boeckh, M. Invasive Pseudomonas aeruginosa infections: High rate of recurrence and mortality after hematopoietic cell transplantation. Bone Marrow Transplant. 2007, 39, 687–693. [CrossRef] 19. Rabello, L.S.C.F.; Silva, J.R.L.; Azevedo, L.C.P.; Souza, I.; Torres, V.B.L.; Rosolem, M.M.; Lisboa, T.; Soares, M.; Salluh, J.I.F. Clinical outcomes and microbiological characteristics of severe pneumonia in cancer patients: A prospective cohort study. PLoS ONE 2015, 10, e0120544. [CrossRef] 20. Guarana, M.; Nucci, M.; Nouér, S.A. Shock and early death in hematologic patients with febrile neutropenia. Antimicrob. Agents Chemother. 2019, 63, 1–25. [CrossRef] 21. Gudiol, C.; Royo-Cebrecos, C.; Laporte, J.; Ardanuy, C.; Garcia-Vidal, C.; Antonio, M.; Arnan, M.; Carratalà, J. Clinical features, aetiology and outcome of bacteraemic pneumonia in neutropenic cancer patients. Respirology 2016, 21, 1411–1418. [CrossRef] 22. Carratalà, J.; Rosón, B.; Fernández-Sevilla, A.; Alcaide, F.; Gudiol, F. Bacteremic Pneumonia in Neutropenic Patients with Cancer. Arch. Intern. Med. 1998, 158, 868. [CrossRef] 23. Gruson, D.; Vargas, F.; Hilbert, G.; Bui, N.; Maillot, T.; Mayet, T.; Pillet, O.; Chene, G.; Gbikpi-Benissan, G. Predictive factors of intensive care unit admission in patients with haematological malignancies and pneumonia. Intensive Care Med. 2004, 30, 965–971. [CrossRef] 24. Vuotto, F.; Berthon, C.; Lemaitre, N.; Duhamel, A.; Balkaran, S.; Le Ray, E.; Micol, J.B.; Faure, K.; Alfandari, S. Risk factors, clinical features, and outcome of Pseudomonas aeruginosa bacteremia in patients with hematologic malignancies: A case-control study. Am. J. Infect. Control 2013, 41, 527–530. [CrossRef] 25. Kalil, A.C.; Metersky, M.L.; Klompas, M.; Muscedere, J.; Sweeney, D.A.; Palmer, L.B.; Napolitano, L.M.; O’Grady, N.P.; Bartlett, J.G.; Carratalà, J.; et al. Executive Summary: Management of Adults with Hospital-acquired and Ventilator-associated Pneumonia: 2016 Clinical Practice Guidelines by the Infectious Diseases Society of America and the American Thoracic Society. Clin. Infect. Dis. 2016, 63, 575–582. [CrossRef] 26. Averbuch, D.; Orasch, C.; Cordonnier, C.; Livermore, D.M.; Viscoli, C.; Gyssens, I.C.; Kern, W.V.; Klyasova, G.; Marchetti, O.; Engelhard, D. European guidelines for emperical antibacterial therapy for febrile neutropenic patients in the era of growing resistance. Haematologica 2013, 98, 1826. [CrossRef] 27. Gudiol, C.; Albasanz-Puig, A.; Laporte-Amargós, J.; Pallarès, N.; Mussetti, A.; Ruiz-Camps, I.; Puerta-Alcalde, P.; Abdala, E.; Oltolini, C.; Akova, M.; et al. Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa. Antimicrob. Agents Chemother. 2020, 64, 1–12. [CrossRef] 28. von Elm, E.; Altman, D.G.; Egger, M.; Pocock, S.J.; Gøtzsche, P.C.; Vandenbroucke, J.P. Strengthening the reporting of observational studies in epidemiology (STROBE) statement: Guidelines for reporting observational studies. BMJ 2007, 335, 806–808. [CrossRef] 29. Freifeld, A.G.; Bow, E.J.; Sepkowitz, K.A.; Boeckh, M.J.; Ito, J.I.; Mullen, C.A.; Raad, I.I.; Rolston, K.V.; Young, J.A.H.; Wingard, J.R. Clinical practice guideline for the use of antimicrobial agents in neutropenic patients with cancer: 2010 Update by the Infectious Diseases Society of America. Clin. Infect. Dis. 2011, 52, e56–e93. [CrossRef] 30. The European Committee on Antimicrobial Susceptibility Testing. Breakpoint tables for Interpretation of MICs and Zone Diameters. Version 12.0. 2022. Available online: http://www.eucast.org (accessed on 23 February 2022). 31. Wootton, M. Laboratory Methods for Antimicrobial Susceptibility Testing. In Antimicrobial/Anti-Infective Materials; CRC Press: Boca Raton, FL, USA, 1999; Volume 44, pp. 308–332. Microorganisms 2022, 10, 733 14 of 14 32. Magiorakos, A.P.; Srinivasan, A.; Carey, R.B.; Carmeli, Y.; Falagas, M.E.; Giske, C.G.; Harbarth, S.; Hindler, J.F.; Kahlmeter, G.; Olsson-Liljequist, B.; et al. Multidrug-resistant, extensively drug-resistant and pandrug-resistant bacteria: An international expert proposal for interim standard definitions for acquired resistance. Clin. Microbiol. Infect. 2012, 18, 268–281. [CrossRef] 33. Garner, J.S.; Jarvis, W.R.; Emori, T.G.; Horan, T.C.; Hughes, J.M. CDC definitions for nosocomial infections, 1988. Am. J. Infect. Control 1988, 16, 128–140. [CrossRef] 34. Evans, L.; Rhodes, A.; Alhazzani, W.; Antonelli, M.; Coopersmith, C.M.; French, C.; Machado, F.R.; Mcintyre, L.; Ostermann, M.; Prescott, H.C.; et al. Surviving sepsis campaign: International guidelines for management of sepsis and septic shock 2021. Intensive Care Med. 2021, 47, 1181–1247. [CrossRef] [PubMed] 35. Therneau, T.M.; Grambsch, P.M. Modeling Survival Data: Extending the Cox Model, Statistics for Biology and Health, 1st ed.; Springer: New York, NY, USA, 2000; ISBN 978-1-4419-3161-0. 36. Righi, E.; Peri, A.M.; Harris, P.N.A.; Wailan, A.M.; Liborio, M.; Lane, S.W.; Paterson, D.L. Global prevalence of carbapenem resistance in neutropenic patients and association with mortality and carbapenem use: Systematic review and meta-analysis. J. Antimicrob. Chemother. 2017, 72, 668–677. [CrossRef] [PubMed] 37. Deconinck, L.; Meybeck, A.; Patoz, P.; Van Grunderbeeck, N.; Boussekey, N.; Chiche, A.; Delannoy, P.Y.; Georges, H.; Leroy, O. Impact of combination therapy and early de-escalation on outcome of ventilator-associated pneumonia caused by Pseudomonas aeruginosa. Infect. Dis. 2017, 49, 396–404. [CrossRef] 38. Suárez, C.; Peña, C.; Gavaldà, L.; Tubau, F.; Manzur, A.; Dominguez, M.A.; Pujol, M.; Gudiol, F.; Ariza, J. Influence of carbapenem resistance on mortality and the dynamics of mortality in Pseudomonas aeruginosa bloodstream infection. Int. J. Infect. Dis. 2010, 14 (Suppl. 3), e73–e78. [CrossRef] 39. Albasanz-Puig, A.; Gudiol, C.; Puerta-Alcalde, P.; Ayaz, C.M.; Machado, M.; Herrera, F.; Martín-Dávila, P.; Laporte-Amargós, J.; Cardozo, C.; Akova, M.; et al. Impact of the Inclusion of an Aminoglycoside to the Initial Empirical Antibiotic Therapy for Gram- Negative Bloodstream Infections in Hematological Neutropenic Patients: A Propensity-Matched Cohort Study (AMINOLACTAM Study). Antimicrob. Agents Chemother. 2021, 65, e00045-21. [CrossRef] 40. Vardakas, K.Z.; Tansarli, G.S.; Bliziotis, I.A.; Falagas, M.E. β-Lactam plus aminoglycoside or fluoroquinolone combination versus β-lactam monotherapy for Pseudomonas aeruginosa infections: A meta-analysis. Int. J. Antimicrob. Agents 2013, 41, 301–310. [CrossRef] 41. McCarthy, K.L.; Cherian, J.D.; Avent, M.L.; Paterson, D.L. Combination antibiotic therapy for Pseudomonas aeruginosa bacteremia in febrile neutropenic patients? The question still remains. Infect. Dis. 2018, 50, 403–406. [CrossRef] 42. Giamarellou, H. Aminoglycosides plus beta-lactams against gram-negative organisms: Evaluation of in vitro synergy and chemical interactions. Am. J. Med. 1986, 80, 126–137. [CrossRef] 43. Chumbita, M.; Puerta-Alcalde, P.; Gudiol, C.; Garcia-Pouton, N.; Laporte-Amargós, J.; Ladino, A.; Albasanz-Puig, A.; Helguera, C.; Bergas, A.; Grafia, I.; et al. Impact of empirical antibiotic regimens on mortality in neutropenic patients with bloodstream infection presenting with septic shock. Antimicrob. Agents Chemother. 2021, 66, AAC-01744. [CrossRef] 44. Criscuolo, M.; Trecarichi, E.M. Ceftazidime/avibactam and ceftolozane/tazobactam for multidrug-resistant gram negatives in patients with hematological malignancies: Current experiences. Antibiotics 2020, 9, 58. [CrossRef] 45. Fernández-Cruz, A.; Alba, N.; Semiglia-Chong, M.A.; Padilla, B.; Rodríguez-Macías, G.; Kwon, M.; Cercenado, E.; Chamorro- de-Vega, E.; Machado, M.; Pérez-Lago, L.; et al. A case-control study of real-life experience with ceftolozane-tazobactam in patients with hematologic malignancy and pseudomonas aeruginosa infection. Antimicrob. Agents Chemother. 2019, 63, e02340-18. [CrossRef]