Recommendations on the use of azole antifungals in hematology-oncology patients.

The administration of antifungals for therapeutic and, especially, prophylactic purposes is virtually a constant in patients requiring hematology-oncology treatment. Any attempt to prevent or treat Aspergillus or Mucor infections requires the administration of some drugs in the azole group, which include voriconazole, posaconazole and isavuconazole, noted for their activity against these pathogens. One very relevant aspect is the potential risk of interaction when associated with one of the antineoplastic drugs used to treat hematologic tumors, with serious complications. In this regard, acalabrutinib, bortezomib, bosutinib, carfilzomib, cyclophosphamide, cyclosporine A, dasatinib, duvelisib, gilteritinib, glasdegib, ibrutinib, imatinib, nilotinib, ponatinib, prednisone, ruxolitinib, tacrolimus, all-transretinoic acid, arsenic trioxide, venetoclax, or any of the vinca alkaloids, are very clear examples of risk, in some cases because their clearance is reduced and in others because of increased risk of QTc prolongation, which is particularly evident when the drug of choice is voriconazole or posaconazole.

Co-infections and superinfections complicating COVID-19 in cancer patients: A multicentre, international study.

BACKGROUND: We aimed to describe the epidemiology, risk factors, and clinical outcomes of co-infections and superinfections in onco-hematological patients with COVID-19. METHODS: International, multicentre cohort study of cancer patients with COVID-19. All patients were included in the analysis of co-infections at diagnosis, while only patients admitted at least 48 h were included in the analysis of superinfections. RESULTS: 684 patients were included (384 with solid tumors and 300 with hematological malignancies). Co-infections and superinfections were documented in 7.8% (54/684) and 19.1% (113/590) of patients, respectively. Lower respiratory tract infections were the most frequent infectious complications, most often caused by Streptococcus pneumoniae and Pseudomonas aeruginosa. Only seven patients developed opportunistic infections. Compared to patients without infectious complications, those with infections had worse outcomes, with high rates of acute respiratory distress syndrome, intensive care unit (ICU) admission, and case-fatality rates. Neutropenia, ICU admission and high levels of C-reactive protein (CRP) were independent risk factors for infections. CONCLUSIONS: Infectious complications in cancer patients with COVID-19 were lower than expected, affecting mainly neutropenic patients with high levels of CRP and/or ICU admission. The rate of opportunistic infections was unexpectedly low. The use of empiric antimicrobials in cancer patients with COVID-19 needs to be optimized.

A Phase I/II Clinical Trial to evaluate the efficacy of baricitinib to prevent respiratory insufficiency progression in onco-hematological patients affected with COVID19: A structured summary of a study protocol for a randomised controlled trial.

OBJECTIVES: Baricitinib is supposed to have a double effect on SARS-CoV2 infection. Firstly, it reduces the inflammatory response through the inhibition of the Januse-Kinase signalling transducer and activator of transcription (JAK-STAT) pathway. Moreover, it reduces the receptor mediated viral endocytosis by AP2-associated protein kinase 1 (AAK1) inhibition. We propose the use of baricinitib to prevent the progression of the respiratory insufficiency in SARS-CoV2 pneumonia in onco-haematological patients. In this phase Ib/II study, the primary objective in the safety cohort is to describe the incidence of severe adverse events associated with baricitinib administration. The primary objective of the randomized phase (baricitinib cohort versus standard of care cohort) is to evaluate the number of patients who did not require mechanical oxygen support since start of therapy until day +14 or discharge (whichever it comes first). The secondary objectives of the study (only randomized phase of the study) are represented by the comparison between the two arms of the study in terms of mortality and toxicity at day+30. Moreover, a description of the immunological related changes between the two arms of the study will be reported. TRIAL DESIGN: The trial is a phase I/II study with a safety run-in cohort (phase 1) followed by an open label phase II randomized controlled trial with an experimental arm compared to a standard of care arm. PARTICIPANTS: The study will be performed at the Institut Català d'Oncologia, a tertiary level oncological referral center in the Catalonia region (Spain). The eligibility criteria are: patients > 18 years affected by oncological diseases; ECOG performance status < 2 (Karnofsky score > 60%); a laboratory confirmed infection with SARS-CoV-2 by means of real -time PCR; radiological signs of low respiratory tract disease; absence of organ dysfunction (a total bilirubin within normal institutional limits, AST/ALT≤2.5 X institutional upper limit of normal, alkaline phosphatase ≤2.5 X institutional upper limit of normal, coagulation within normal institutional limits, creatinine clearance >30 mL/min/1.73 m2 for patients with creatinine levels above institutional normal); absence of HIV infection; no active or latent HBV or HCV infection. The exclusion criteria are: patients with oncological diseases who are not candidates to receive any active oncological treatment; hemodynamic instability at time of study enrollment; impossibility to receive oral medication; medical history of recent or active pulmonary embolism or deep venous thrombosis or patients at high-risk of suffering them (surgical intervention, immobilization); multi organ failure, rapid worsening of respiratory function with requirement of fraction of inspired oxygen (FiO2) > 50% or high-flow nasal cannula before initiation of study treatment; uncontrolled intercurrent illness (ongoing or severe active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements); allergy to one or more of study treatments; pregnant or breastfeeding women; positive pregnancy test in a pre-dose examination. Patients should have the ability to understand, and the willingness to sign, a written informed consent document; the willingness to accept randomization to any assigned treatment arm; and must agree not to enroll in another study of an investigational agent prior to completion of Day +28 of study. An electronic Case Report Form in the Research Electronic Data Capture (REDCap) platform will be used to collect the data of the trial. Removal from the study will apply in case of unacceptable adverse event(s), development of an intercurrent illness, condition or procedural complication, which could interfere with the patient's continued participation and voluntary patient withdrawal from study treatment (all patients are free to withdraw from participation in this study at any time, for any reasons, specified or unspecified, and without prejudice). INTERVENTION AND COMPARATOR: Treatment will be administered on an inpatient basis. We will compare the experimental treatment with baricitinib plus the institutional standard of care compared with the standard of care alone. During the phase I, we will define the dose-limiting toxicity of baricitinib and the dose to be used in the phase 2 part of the study. The starting baricitinib dose will be an oral tablet 4 mg-once daily which can be reduced to 2 mg depending on the observed toxicity. The minimum duration of therapy will be 5 days and it can be extended to 7 days. The standard of care will include the following therapies. Antibiotics will be individualized based on clinical suspicion, including the management of febrile neutropenia. Prophylaxis of thromboembolic disease will be administered to all participants. Remdesivir administration will be considered only in patients with severe pneumonia (SatO2 <94%) with less than 7 days of onset of symptoms and with supplemental oxygen requirements but not using high-flow nasal cannula, non-invasive or invasive mechanical ventilation or extracorporeal membrane oxygenation (ECMO). In the randomized phase, tocilizumab or interferon will not be allowed in the experimental arm. Tocilizumab can be used in patients in the standard of care arm at the discretion of the investigator. If it is prescribed it will be used according to the following criteria: patients who, according to his baseline clinical condition, would be an ICU tributary, interstitial pneumonia with severe respiratory failure, patients who are not on mechanical ventilation or ECMO and who are still progressing with corticoid treatment or if they are not candidates for corticosteroids. Mild ARDS (PAFI <300 mmHg) with radiological or blood gases deterioration that meets at least one of the following criteria: CRP >100mg/L D-Dimer >1,000µg/L LDH >400U/L Ferritin >700ng/ml Interleukin 6 ≥40ng/L. The use of tocilizumab is not recommended if there are AST/ALT values greater than 10 times the upper limit of normal, neutrophils <500 cells/mm3, sepsis due to other pathogens other than SARS-CoV-2, presence of comorbidity that can lead to a poor prognosis, complicated diverticulitis or intestinal perforation, ongoing skin infection. The dose will be that recommended by the Spanish Medicine Agency in patients ≥75Kg: 600mg dose whereas in patients <75kg: 400mg dose. Exceptionally, a second infusion can be assessed 12 hours after the first in those patients who experience a worsening of laboratory parameters after a first favourable response. The use of corticosteroids will be recommended in patients who have had symptoms for more than 7 days and who meet all the following criteria: need for oxygen support, non-invasive or invasive mechanical ventilation, acute respiratory failure or rapid deterioration of gas exchange, appearance or worsening of bilateral alveolar-interstitial infiltrates at the radiological level. In case of indication, it is recommended: dexamethasone 6mg/d p.o. or iv for 10 days or methylprednisolone 32mg/d orally or 30mg iv for 10 days or prednisone 40mg day p.o. for 10 days. MAIN OUTCOMES: Phase 1 part: to describe the toxicity profile of baricitinib in COVID19 oncological patients during the 5-7 day treatment period and until day +14 or discharge (whichever it comes first). Phase 2 part: to describe the number of patients in the experimental arm that will not require mechanical oxygen support compared to the standard of care arm until day +14 or discharge (whichever it comes first). RANDOMISATION: For the phase 2 of the study, the allocation ratio will be 1:1. Randomization process will be carried out electronically through the REDcap platform ( https://www.project-redcap.org/ ) BLINDING (MASKING): This is an open label study. No blinding will be performed. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): The first part of the study (safety run-in cohort) will consist in the enrollment of 6 to 12 patients. In this population, we will test the toxicity of the experimental treatment. An incidence of severe adverse events grade 3-4 (graded by Common Terminology Criteria for Adverse Events v.5.0) inferior than 33% will be considered sufficient to follow with the next part of the study. The second part of the study we will perform an interim analysis of efficacy at first 64 assessed patients and a definitive one will analyze 128 assessed patients. Interim and definitive tests will be performed considering in both cases an alpha error of 0.05. We consider for the control arm this rate is expected to be 0.60 and for the experimental arm of 0.80. Considering this data, a superiority test to prove a difference of 0.20 with an overall alpha error of 0.10 and a beta error of 0.2 will be performed. Considering a 5% of dropout rate, it is expected that a total of 136 patients, 68 for each study arm, will be required to complete study accrual. TRIAL STATUS: Version 5.0. 14th October 2020 Recruitment started on the 16th of December 2020. Expected end of recruitment is June 2021. TRIAL REGISTRATION: AEMPs: 20-0356 EudraCT: 2020-001789-12, https://www.clinicaltrialsregister.eu/ctr-search/search (Not publically available as Phase I trial) Clinical trials: BARCOVID19, https://www.clinicaltrials.gov/ (In progress) FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol."

Efficacy of extended infusion of ß-lactam antibiotics for the treatment of febrile neutropenia in haematologic patients: protocol for a randomised, multicentre, open-label, superiority clinical trial (BEATLE).

BACKGROUND: Febrile neutropaenia (FN) is a very common complication in patients with haematological malignancies and is associated with considerable morbidity and mortality. Broad-spectrum antipseudomonal ß-lactam antibiotics (BLA) are routinely used for the treatment of cancer patients with FN. However, the clinical efficacy of BLA may be diminished in these patients because they present with pathophysiological variations that compromise the pharmacokinetic (PK) parameters of these antibiotics. Optimised administration of BLA in prolonged infusions has demonstrated better clinical outcomes in critically ill patients. However, there is a paucity of data on the usefulness of this strategy in patients with FN. The aim of this study is to test the hypothesis that the administration of BLA would be clinically more effective by extended infusion (EI) than by intermittent infusion (II) in haematological patients with FN. METHODS: A randomised, multicentre, open-label, superiority clinical trial will be performed. Patients with haematological malignancies undergoing chemotherapy or haematopoietic stem-cell transplant and who have FN and receive empirical antibiotic therapy with cefepime, piperacillin-tazobactam or meropenem will be randomised (1:1) to receive the antibiotic by EI (during half the time of the dosing interval) in the study group, or by II (30 min) in the control group. The primary endpoint will be clinical efficacy, defined as defervescence without modifying the antibiotic treatment administered within the first 5 days of therapy. The primary endpoint will be analysed in the intention-to-treat population. The secondary endpoints will be pharmacokinetic/pharmacodynamic (PK/PD) target achievement, bacteraemia clearance, decrease in C-reactive protein, overall (30-day) case-fatality rate, adverse events and development of a population PK model of the BLA studied. DISCUSSION: Data on the usefulness of BLA administration in patients with FN are scant. Only three clinical studies addressing this issue have been published thus far, with contradictory results. Moreover, these studies had some methodological flaws that limit the interpretation of their findings. If this randomised, multicentre, phase IV, open-label, superiority clinical trial validates the hypothesis that the administration of BLA is clinically more effective by EI than by II in haematological patients with FN, then the daily routine management of these high-risk patients could be changed to improve their outcomes. TRIAL REGISTRATION: European Clinical Trials Database: EudraCT 2018-001476-37. ClinicalTrials.gov, ID: NCT04233996.

Clinical Predictive Model of Multidrug Resistance in Neutropenic Cancer Patients with Bloodstream Infection Due to Pseudomonas aeruginosa.

We aimed to assess the rate and predictive factors of bloodstream infection (BSI) due to multidrug-resistant (MDR) Pseudomonas aeruginosa in neutropenic cancer patients. We performed a multicenter, retrospective cohort study including oncohematological neutropenic patients with BSI due to P. aeruginosa conducted across 34 centers in 12 countries from January 2006 to May 2018. A mixed logistic regression model was used to estimate a model to predict the multidrug resistance of the causative pathogens. Of a total of 1,217 episodes of BSI due to P. aeruginosa, 309 episodes (25.4%) were caused by MDR strains. The rate of multidrug resistance increased significantly over the study period (P = 0.033). Predictors of MDR P. aeruginosa BSI were prior therapy with piperacillin-tazobactam (odds ratio [OR], 3.48; 95% confidence interval [CI], 2.29 to 5.30), prior antipseudomonal carbapenem use (OR, 2.53; 95% CI, 1.65 to 3.87), fluoroquinolone prophylaxis (OR, 2.99; 95% CI, 1.92 to 4.64), underlying hematological disease (OR, 2.09; 95% CI, 1.26 to 3.44), and the presence of a urinary catheter (OR, 2.54; 95% CI, 1.65 to 3.91), whereas older age (OR, 0.98; 95% CI, 0.97 to 0.99) was found to be protective. Our prediction model achieves good discrimination and calibration, thereby identifying neutropenic patients at higher risk of BSI due to MDR P. aeruginosa The application of this model using a web-based calculator may be a simple strategy to identify high-risk patients who may benefit from the early administration of broad-spectrum antibiotic coverage against MDR strains according to the local susceptibility patterns, thus avoiding the use of broad-spectrum antibiotics in patients at a low risk of resistance development.

Update on the management of febrile neutropenia in hematologic patients.

Febrile neutropenia is a common complication in patients with hematologic malignancies receiving chemotherapy, and is associated with high morbidity and mortality. Infections caused by multidrug-resistant bacteria represent a therapeutic challenge in this high-risk patient population, since inadequate initial empirical antibiotic treatment can seriously compromise prognosis. Besides, reducing antimicrobial exposure is a cornerstone in the fight against resistance.

Is hospital-acquired pneumonia different in transplant recipients?

Hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP) are serious complications in transplant patients. The aim of this review is to summarize the evidence regarding nosocomial pneumonia in transplant recipients, including HAP in non-ventilated patients and VAP, and to identify future directions for improvement.A comprehensive literature search in the PubMed/MEDLINE database was performed. Articles written in English and published between 1990 and November 2018 were included. HAP/VAP in transplant patients usually occurs early post-transplant, particularly during neutropenia in haematopoietic stem cell transplant recipients. Bacteria are the leading cause of nosocomial pneumonia for both immunocompetent and transplant recipients, being Gram negative organisms, and especially Pseudomonas aeruginosa, highly prevalent. Multidrug-resistant bacteria are of special concern. Pneumonia in the transplant setting may be caused by opportunistic pathogens, and the differential diagnosis needs to be extended to other non-infectious complications. The most relevant opportunistic pathogens are Aspergillus fumigatus, Pneumocystis jirovecii and cytomegalovirus. Nevertheless, they are an exceptional cause of nosocomial pneumonia, and usually occur in severely immunosuppressed patients not receiving antimicrobial prophylaxis. Performing bronchoalveolar lavage may improve the rate of aetiological diagnosis, leading to a change in therapeutic management and improved outcomes. The optimal length of antibiotic therapy for bacterial HAP/VAP has not been well defined, but it should perhaps be longer than in the general population. Mortality associated with HAP/VAP is high. HAP/VAP in transplant patients is frequent and is associated with increased mortality. There is room for improvement in gaining knowledge about the management of HAP/VAP in this population.

Bloodstream infection in patients with head and neck cancer: a major challenge in the cetuximab era.

PURPOSE: To assess the impact of bloodstream infection (BSI) in patients with head and neck cancer (HNC) in the cetuximab era. METHODS: We prospectively analysed the epidemiology, microbiology and outcomes of 51 BSI episodes occurring in 48 patients with HNC (2006-2017). We performed a retrospective matched-cohort study (1:2) to determine the risk factors for BSI. Finally, we compared patients who died with those who survived to identify risk factors for mortality. RESULTS: The most frequent HNC localization was the oropharynx (43%), and pneumonia was the most frequent source (25%). Gram-positive BSI occurred in 55% cases, mainly due to Streptococcus pneumoniae (21%), and among Gram-negatives, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae were the most frequent. Hypoalbuminemia (OR 8.4; 95% CI, 3.5-19.9), previous chemotherapy (OR, 3.2; 95% CI, 1.3-7.4) and cetuximab therapy (OR, 2.8; 95% CI, 1.6-6.7) were significant risk factors for BSI. Patients with BSI had a higher overall case-fatality rate than patients without BSI (OR, 4.4; 95% CI, 1.7-11.8). Hypoalbuminemia was an independent risk factor for the early (7 day) and overall (30 day) case-fatalities, with ORs of 0.8 (95% CI, 0.6-0.9) and 0.8 (95% CI, 0.7-0.97), respectively. The presence of comorbidities (OR, 7; 95% CI, 1.4-34) was also an independent risk factor for overall case-fatality. CONCLUSIONS: BSI causes high mortality in patients with HNC and is most often secondary to pneumonia. It occurs mainly among patients with hypoalbuminemia who receive treatment with cetuximab or chemotherapy. The development of BSI in patients with HNC impairs their outcome, especially in the presence of hypoalbuminemia and comorbidities.

Administration of taurolidine-citrate lock solution for prevention of central venous catheter infection in adult neutropenic haematological patients: a randomised, double-blinded, placebo-controlled trial (TAURCAT).

BACKGROUND: Catheter-related bloodstream infection (CRBSI) is one of the most frequent complications in patients with cancer who have central venous catheters (CVCs) implanted and is associated with substantial morbidity and mortality. Taurolidine is a non-antibiotic agent with broad-spectrum antimicrobial activity, which has been used as a lock solution to prevent CRBSI in some settings. However, little is known about its usefulness in high-risk adult neutropenic patients with cancer. This prospective randomised clinical trial aims to test the hypothesis that taurolidine-citrate lock solution is more effective than placebo for preventing catheter infection in neutropenic haematological patients. METHODS: This study is a prospective, multicentre, randomised, double-blinded, parallel, superiority, placebo-controlled trial. Patients with haematological cancer who are expected to develop prolonged neutropenia (> 7 days) and who have a non-tunnelled CVC implanted will be randomised to receive prophylactic taurolidine-citrate-heparin solution using a lock technique (study group) or heparin alone (placebo group). The primary endpoint will be bacterial colonisation of the CVC hubs. The secondary endpoints will be the incidence of CRBSI, CVC removal, adverse events, and 30-day case-fatality rate. DISCUSSION: The lock technique is a preventive strategy that inhibits bacterial colonisation in the catheter hubs, which is the initial step of endoluminal catheter colonisation and the development of infection. Taurolidine is a nontoxic agent that does not develop antibiotic resistance because it acts as an antiseptic rather than an antibiotic. Taurolidine has shown controversial results in the few trials conducted in cancer patients. These studies have important limitations due to the lack of data on adult and/or high-risk neutropenic patients, the type of catheters studied (tunnelled or ports), and the lack of information regarding the intervention (e.g. dwelling of the solution, time, and periodicity of the lock technique). If our hypothesis is proven, the study could provide important solid evidence on the potential usefulness of this preventive procedure in a population at high risk of CRBSI, in whom this complication may significantly impair patient outcome. TRIAL REGISTRATION: ISRCTN, ISRCTN47102251 . Registered on 9 September 2015.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid or myeloid cells surface antigens [II]: CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD22, CD30, CD33, CD38, CD40, SLAMF-7 and CCR4 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: The risk and spectrum of infections in patients receiving CD22-targeted agents (i.e. inotuzumab ozogamicin) are similar to those observed with anti-CD20 antibodies. Anti-Pneumocystis prophylaxis and monitoring for cytomegalovirus (CMV) infection is recommended for patients receiving CD30-targeted agents (brentuximab vedotin). Due to the scarcity of data, the risk posed by CD33-targeted agents (gemtuzumab ozogamicin) cannot be assessed. Patients receiving CD38-targeted agents (i.e. daratumumab) face an increased risk of varicella-zoster virus (VZV) infection. Therapy with CD40-targeted agents (lucatumumab or dacetuzumab) is associated with opportunistic infections similar to those observed in hyper-IgM syndrome, and prevention strategies (including anti-Pneumocystis prophylaxis and pre-emptive therapy for CMV infection) are warranted. SLAMF-7 (CD319)-targeted agents (elotuzumab) induce lymphopenia and increase the risk of infection (particularly due to VZV). The impact of CCR4-targeted agents (mogamulizumab) on infection susceptibility is difficult to distinguish from the effect of underlying diseases and concomitant therapies. However, anti-Pneumocystis and anti-herpesvirus prophylaxis and screening for chronic hepatitis B virus (HBV) infection are recommended. IMPLICATIONS: Specific management strategies should be put in place to reduce the risk and/or the severity of infectious complications associated to the reviewed agents.

ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies: an infectious diseases perspective (Agents targeting lymphoid cells surface antigens [I]: CD19, CD20 and CD52).

BACKGROUND: The present review is part of the ESCMID Study Group for Infections in Compromised Hosts (ESGICH) Consensus Document on the safety of targeted and biological therapies. AIMS: To review, from an Infectious Diseases perspective, the safety profile of agents targeting CD19, CD20 and CD52 and to suggest preventive recommendations. SOURCES: Computer-based MEDLINE searches with MeSH terms pertaining to each agent or therapeutic family. CONTENT: Although CD19-targeted agents (blinatumomab or inebilizumab) are not associated with an increased risk of infection, they may cause IgG hypogammaglobulinaemia and neutropenia. The requirement for prolonged intravenous infusion of blinatumomab may increase the risk of catheter-associated bloodstream infections. Infection remains the most common non-haematological adverse effect of anti-CD20 monoclonal antibodies, including severe respiratory tract infection, hepatitis B virus (HBV) reactivation and varicella-zoster virus infection. Screening for chronic or resolved HBV infection is recommended for patients receiving anti-CD20 monoclonal antibodies. Antiviral prophylaxis should be offered for 12-18 months to hepatitis B surface antigen (HBsAg)-positive and HBsAg-negative/anti-hepatitis B core antibody (HBc)-positive patients. Anti-Pneumocystis prophylaxis should be considered in patients receiving concomitant chemotherapy, particularly steroids. Alemtuzumab (anti-CD52) increases the risk of infections, in particular among leukaemia and solid organ transplant patients. These populations benefit from anti-Pneumocystis prophylaxis, prevention strategies for cytomegalovirus infection, and screening for HBV, hepatitis C virus and tuberculosis. Antiviral prophylaxis for at least 6-12 months should be provided for HBsAg-positive patients. IMPLICATIONS: As there are limited clinical data for many of the reviewed agents, special attention must be given to promptly detect and report emerging infectious complications.

Clinical efficacy of ß-lactam/ß-lactamase inhibitor combinations for the treatment of bloodstream infection due to extended-spectrum ß-lactamase-producing Enterobacteriaceae in haematological patients with neutropaenia: a study protocol for a retrospective observational study (BICAR).

INTRODUCTION: Bloodstream infection (BSI) due to extended-spectrum ß-lactamase-producing Gram-negative bacilli (ESBL-GNB) is increasing at an alarming pace worldwide. Although ß-lactam/ß-lactamase inhibitor (BLBLI) combinations have been suggested as an alternative to carbapenems for the treatment of BSI due to these resistant organisms in the general population, their usefulness for the treatment of BSI due to ESBL-GNB in haematological patients with neutropaenia is yet to be elucidated. The aim of the BICAR study is to compare the efficacy of BLBLI combinations with that of carbapenems for the treatment of BSI due to an ESBL-GNB in this population. METHODS AND ANALYSIS: A multinational, multicentre, observational retrospective study. Episodes of BSI due to ESBL-GNB occurring in haematological patients and haematopoietic stem cell transplant recipients with neutropaenia from 1 January 2006 to 31 March 2015 will be analysed. The primary end point will be case-fatality rate within 30 days of onset of BSI. The secondary end points will be 7-day and 14-day case-fatality rates, microbiological failure, colonisation/infection by resistant bacteria, superinfection, intensive care unit admission and development of adverse events. SAMPLE SIZE: The number of expected episodes of BSI due to ESBL-GNB in the participant centres will be 260 with a ratio of control to experimental participants of 2. ETHICS AND DISSEMINATION: The protocol of the study was approved at the first site by the Research Ethics Committee (REC) of Hospital Universitari de Bellvitge. Approval will be also sought from all relevant RECs. Any formal presentation or publication of data from this study will be considered as a joint publication by the participating investigators and will follow the recommendations of the International Committee of Medical Journal Editors (ICMJE). The study has been endorsed by the European Study Group for Bloodstream Infection and Sepsis (ESGBIS) and the European Study Group for Infections in Compromised Hosts (ESGICH).

Characteristics, aetiology, antimicrobial resistance and outcomes of bacteraemic cholangitis in patients with solid tumours: A prospective cohort study.

OBJECTIVES: To asses the clinical features, aetiology, antimicrobial resistance and outcomes of bacteraemic cholangitis in patients with solid tumours (ST). METHODS: All consecutive episodes of bacteraemia in hospitalized patients were prospectively analysed (2006-2015). RESULTS: Of 1852 episodes of bacteraemia, 750 involved patients with ST. Among them, 173 episodes (23%) were due to cholangitis. The most frequent neoplasms were hepato-biliary-pancreatic tumours (68.2%) and gastrointestinal cancer (18.5%); 57.2% of patients had a biliary stent in place. The most frequent causative agents were Escherichia coli (39.3%) followed by Klebsiella pneumoniae (15.1%) and Enterococcus faecium (7.8%). Forty-one episodes (18.7%) were caused by multidrug-resistant (MDR) microorganisms. Patients with a second episode of cholangitis were more likely to have an MDR isolate and to had received inadequate empirical antibiotic therapy. 7-day and 30-day case-fatality rates were 7.6% and 26%, respectively. The only risk factors independently associated with 30-day case-fatality rate were corticosteroids and malignancy-related complications. CONCLUSIONS: Bacteraemic cholangitis is frequent in patients with ST, and is mainly caused by Enterobacteriaceae and E. faecium. The emergence of MDR is of special concern, particularly in patients with a second episode of bacteraemia. Case-fatality rates are high, especially among patients receiving corticosteroids and presenting malignancy-related complications.

Management of infection and febrile neutropenia in patients with solid cancer.

An expert group from the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC, for its acronym in Spanish) and the Spanish Society of Medical Oncology (SEOM, for its acronym in Spanish) have reviewed the main aspects to be considered when evaluating patients with solid cancer and infectious complications contained in this article. Recommendations have, therefore, been put forth regarding the prophylaxis of the most prevalent infections in these patients, the use of vaccines, measures to control infection through vascular catheters, and preventing infection in light of certain surgical maneuvers. The following is a revision of the criteria for febrile neutropenia management and the use of colony-stimulating factors and closes with several guidelines for treating the cancer patient with serious infection. The document concludes with a series of measures to control hospital infection.

Factors influencing mortality in neutropenic patients with haematologic malignancies or solid tumours with bloodstream infection.

The purpose of this study was to identify factors influencing mortality in neutropenic patients with haematologic malignancies or solid tumours with bloodstream infection (BSI). All episodes of BSI occurring in adult neutropenic patients with haematologic malignancies or solid tumours were prospectively recorded from January 2006 to December 2013. We analysed the factors influencing mortality in both groups of patients. We documented 602 consecutive episodes of BSI; 510 occurred in patients with haematologic malignancies and 92 in patients with solid tumours. The overall case-fatality rates were 12% and 36%, respectively. Independent risk factors associated with a higher case-fatality rate in patients with haematologic malignancies were: intensive care unit admission (odds ratio (OR), 15.2; 95% confidence interval (CI), 5.4-42.7), advanced neoplasm (OR, 8.7; 95% CI, 2.9-25.7), corticosteroid therapy (OR, 7.0; 95% CI, 3-16.4), multidrug-resistant Gram-negative BSI (OR, 3.8; 95% CI, 1.2-11.8) and a Multinational Association for Supportive Care in Cancer risk score of <21 (OR, 3.1; 95% CI, 1.3-7.4). By contrast, coagulase-negative staphylococci BSI (OR, 0.04; 95% CI, 0.004-0.5) and empirical antibiotic combination therapy (OR, 0.1; 95% CI, 0.05-0.3) were found to be protective. Independent risk factors for overall case-fatality rate in patients with solid tumours were: shock at presentation (OR, 14.3; 95% CI, 3.2-63.8), corticosteroid therapy (OR, 10; 95% CI, 2.3-44) and advanced neoplasm (OR, 7.8; 95% CI, 1.4-41.4). Prognostic factors identified in this study may help to detect those patients at higher risk of death in each group. Medical intervention addressing some of these factors might improve the outcome of BSI in neutropenic patients with haematologic malignancies or solid tumours.

Unusual forms of subacute invasive pulmonary aspergillosis in patients with solid tumors.

OBJECTIVES: Aspergillus spp. can cause acute invasive disease in severely immunocompromised patients. Nonetheless, there are few reports of solid tumors complicated with subacute invasive pulmonary aspergillosis (subacute IPA). METHODS: Retrospective observational cohort study, performed in patients with primary lung cancer or secondary lung metastasis complicated with subacute IPA in three referral hospitals. RESULTS: From 2008 to 2011, 14 episodes of subacute IPA were diagnosed, including 11 (78.6%) probable and 3 proven (21.4%). Nine patients (64.3%) had primary lung cancer. Thirteen patients (92.9%) had more than one local or systemic predisposing factor for subacute IPA. No patient had previous fungal colonization. Aspergillus spp. was isolated in 6 specimens of bronchoalveolar lavage, 6 sputum, 2 biopsies, and 1 percutaneous lung puncture. At the time Aspergillus spp. was isolated, the most common radiologic findings on chest computed tomography (CT) were cavitary masses, and development or expansion of cavitation in existing masses or nodules (10/14, 71.4%). On CT follow-up, most patients (8/12, 66.7%) had new cavity formation or expansion of one or more existing cavities. All patients were treated with azoles and two underwent surgery. Ten (71.4%) patients died after Aspergillus spp. was detected (median time 73 days, IQR 33-243): 2 (20%) deaths were subacute IPA-attributable and 6 (60%) were related. CONCLUSIONS: Primary lung cancer and secondary lung metastasis seem to be triggering factors for Aspergillus spp. implantation, and predispose to subacute IPA. Once localized in the damaged lung, the mold can grow and cause or expand cavities. In lung cancer patients, Aspergillus spp. detection is associated with a very poor prognosis.

Environmental variables associated with an increased risk of invasive aspergillosis.

Information on the environmental variables that may affect the incidence of invasive aspergillosis (IA) is scarce. We sought to determine the relationship between airborne spore counts, climatic conditions and IA. We also examined whether circulating respiratory viruses predispose patients to IA in a multicentre cohort study of hospitalized adults with IA. Data on environmental mould spores, climatic conditions and circulating respiratory viruses were obtained from the Environmental Department of the Autonomous University of Barcelona, the Meteorological Service of Catalonia and the Acute Respiratory Infection Surveillance Project in Catalonia, respectively. Between 2008 and 2011, 165 patients with IA were identified. Diagnosis was based on one or more of the following: culture (125 cases), galactomannan antigen (98) and histology (34). One hundred and twenty-seven cases (77%) had criteria for probable IA and the remainder for proven IA. Environmental mould spore counts from the period 28-42 days preceding infection presented significant associations with admissions due to IA. None of the climatic conditions were associated with an increased risk of IA, but the presence of circulating respiratory viruses was associated with a higher risk of infection: the most strongly associated viruses were respiratory syncytial virus, influenza A(H1N1)pdm09 and adenovirus. In conclusion, the presence of high numbers of spores in the air increases the risk of admission due to IA. Circulating respiratory viruses appear to be associated with a higher risk of developing IA. Physicians should be aware of this association in order to optimize prevention and diagnosis strategies for IA during viral epidemic periods.

Etiology, clinical features and outcomes of pre-engraftment and post-engraftment bloodstream infection in hematopoietic SCT recipients.

We conducted an observational study to assess the etiology, clinical features and outcomes of bloodstream infection (BSI) in 172 hematopoietic SCT (HCST) recipients. One hundred episodes of BSI in the pre-engraftment period (early onset) were compared with 89 episodes in the post-engraftment phase (late onset). More patients with late-onset BSI received an allogeneic HSCT, had GVHD and had received corticosteroids, whereas patients with early-onset BSI were more likely to have neutropenia, severe mucositis and a central venous catheter (CVC) in place. CVC was the most frequent site of infection, followed by an endogenous source. Pneumonia and gastrointestinal infection were particularly frequent in late-onset BSI, whereas mucositis was more frequent in the early-onset group. Gram-positive organisms predominated over Gram negatives. Streptococcus pneumoniae was more frequent in patients with late-onset BSI. Patients with late-onset BSI presented worse outcomes regarding septic shock, intensive care unit admission and early and overall case-fatality rates. Early-onset BSI was mainly related to the presence of neutropenia, mucositis and CVC, whereas late-onset BSI mainly affected severely immunosuppressed allogeneic HSCT recipients with GVHD and corticosteroids. Late-onset BSI caused high case-fatality rates. BSI due to S. pneumoniae was especially frequent late after transplantation. The development of better vaccination strategies is needed.

Changing aetiology, clinical features, antimicrobial resistance, and outcomes of bloodstream infection in neutropenic cancer patients.

Recent changes in the management of patients with haematological malignancies might have influenced the aetiology, characteristics, antimicrobial resistance and outcomes of bloodstream infection (BSI) during neutropenia. We compared 272 episodes of BSI in adult neutropenic patients with cancer prospectively collected from January 1991 to December 1996 (first period), when quinolone prophylaxis was used, with 283 episodes recorded from January 2006 to March 2010 (second period), when antibacterial prophylaxis was stopped. Patients in the second period were significantly older and were more likely to have graft-versus-host disease and a urinary catheter in place, whereas the presence of a central venous catheter, parenteral nutrition, corticosteroids and antifungal and quinolone prophylaxis, were more frequent in the first period. More patients in the first period had mucositis and soft-tissue infection as the origin of BSI, but an endogenous source was more common during the second. Gram-positive BSI was more frequent in the first period (64% versus 41%; p <0.001), mainly due to coagulase-negative staphylococci and viridans group streptococci. In the second period gram-negative BSI increased (28% versus 49%; p <0.001), quinolone susceptibilities were recovered, but multidrug-resistant gram-negative BSI also increased (1% versus 6%; p <0.001). Although patients in the second period were more likely to need admission to the intensive-care unit, overall case-fatality rate was similar in the two periods (19% versus 15%). The aetiology of BSI in neutropenic patients with cancer has shifted from gram-positive to gram-negative organisms. Multidrug resistance among gram-negative bacilli is emerging as a therapeutic challenge. Overall case-fatality rate remains high.

Bacteraemia due to multidrug-resistant Gram-negative bacilli in cancer patients: risk factors, antibiotic therapy and outcomes.

OBJECTIVES: To assess the risk factors, antibiotic therapy and outcomes of multidrug-resistant Gram-negative bacilli (MDRGNB) bacteraemia in hospitalized patients with cancer. METHODS: Episodes of MDRGNB bacteraemia were compared with a susceptible control group in a 4 year prospective study. RESULTS: Of 747 bacteraemias, 372 (49.7%) were caused by a Gram-negative bacilli (GNB). Fifty-one of these (13.7%) were caused by a multidrug-resistant (MDR) strain. Previous antibiotics [odds ratio (OR) 3.57; 95% confidence interval (CI) 1.63-7.80] and urinary catheter (OR 2.41; 95% CI 1.01-5.74) were identified as independent risk factors for MDRGNB acquisition. The most frequent mechanism of resistance was extended-spectrum ß-lactamase (ESBL) production (45%), mainly by Escherichia coli, followed by Amp-C cephalosporinase hyperproduction (24%). Patients with MDRGNB bacteraemia more frequently received inadequate initial antibiotic therapy (69% versus 9%; P < 0.001) and time to adequate therapy was longer in this group (41% versus 4%; P < 0.001). Patients in the resistant group more frequently required intensive care unit (ICU) admission (14% versus 5%; P = 0.023), had greater need for mechanical ventilation (14% versus 3%; P = 0.005) and had a higher overall case-fatality rate (41% versus 21%; P = 0.003). Risk factors for mortality were solid tumour (OR 5.04; 95% CI 2.49-10.19), current corticosteroid use (OR 4.38; 95% CI 2.39-8.05), ICU admission (OR 11.40; 95% CI 3.19-40.74) and MDRGNB bacteraemia (OR 3.52; 95% CI 1.36-9.09). CONCLUSIONS: MDRGNB bacteraemia was common among cancer patients, especially in those exposed to antibiotics and urinary catheter. The most frequent mechanism of resistance was ESBL production. Patients with MDRGNB more frequently received inadequate empirical antibiotic therapy and presented poorer outcomes with a higher overall case-fatality rate (within 30 days).