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).

To test the hypothesis that the addition of an aminoglycoside to a ß-lactam antibiotic could provide better outcomes than ß-lactam monotherapy for the initial empirical treatment of hematological neutropenic patients with subsequently documented Gram-negative bacillus (GNB) bloodstream infection (BSI), a multinational, retrospective, cohort study of GNB BSI episodes in hematological neutropenic patients in six centers (2010 to 2017) was conducted. Combination therapy (ß-lactam plus aminoglycoside) was compared to ß-lactam monotherapy. The primary endpoint was the case fatality rate, assessed at 7 and 30 days from BSI onset. Secondary endpoints were nephrotoxicity and persistent BSI. Propensity score (PS) matching was performed. Among 542 GNB BSI episodes, 304 (56%) were initially treated with combination therapy, with cefepime plus amikacin being most common (158/304 [52%]). Overall, Escherichia coli (273/304 [50.4%]) was the main etiological agent, followed by Pseudomonas aeruginosa, which predominated in the combination group (76/304 [25%] versus 28/238 [11.8%]; P < 0.001). Multidrug resistance rates were similar between groups (83/294 [28.2%] versus 63/233 [27%]; P = 0.95). In the multivariate analysis, combination therapy was associated with a lower 7-day case fatality rate (odds ratio [OR], 0.37; 95% CI, 0.14 to 0.91; P = 0.035) with a tendency toward lower mortality at 30 days (OR, 0.56; 95% CI, 0.29 to 1.08; P = 0.084). After PS matching, these differences remained for the 7-day case fatality rate (OR, 0.33; 95% CI, 0.13 to 0.82; P = 0.017). In addition, aminoglycoside use was not significantly associated with renal function impairment (OR, 1.12; 95% CI, 0.26 to 4.87; P = 0.9). The addition of an aminoglycoside to the initial empirical therapy regimen for febrile neutropenic hematological patients should be considered.

Low frequency of cytomegalovirus (CMV) disease despite high prevalence of CMV viraemia in patients with advanced HIV infection: a clinical and immunological 48-week follow-up study.

OBJECTIVES: The aim of the study was to investigate the dynamics of cytomegalovirus (CMV) replication and CMV-specific immune response recovery after antiretroviral treatment (ART) initiation in patients with advanced HIV infection. METHODS: A prospective observational study of patients with HIV infection and CD4 counts of < 100 cells/µL was carried out (September 2015 to July 2018). HIV viral load (VL), CD4 count and CMV VL were determined by quantitative polymerase chain reaction (PCR) at baseline and at 4, 12, 24 and 48 weeks, and CMV-specific immune response was determined by QuantiFERON-CMV assay at baseline and 48 weeks. All patients were started on ART but only those with CMV end-organ disease (EOD) received anti-CMV treatment. RESULTS: Fifty-three patients with a median age of 43.6 [interquartile range (IQR) 36.7-52.4] years were included in the study. At baseline, the median CD4 count was 30 cells/µL (IQR 20-60 cells/µL) and the median HIV VL was 462 000 HIV-1 RNA copies/mL (IQR 186 000-1 300 000 copies/mL). At baseline, 32% patients had detectable CMV viraemia but none had detectable CMV viraemia at 48 weeks. Only one of 53 (1.9%) patients developed EOD during follow-up. Seven (13.2%) patients were lost to follow-up and six (11.3%) died; none of the deaths was related to CMV. Similar percentages of patients had a CMV-specific immune response at baseline (71.7%) and at 48 weeks (70.0%). The magnitude of this response tended to increase over time [median 1.63 (IQR 0.15-5.77) IU/mL at baseline vs. median 2.5 (IQR 0.1-8.325) IU/mL at 48 weeks; P = 0.11]. We did not find any risk factors associated with 48-week mortality. CONCLUSIONS: Although the prevalence of CMV viraemia in patients with advanced HIV infection remains high, achieving a good immunological recovery through ART is enough to suppress CMV viraemia, without an increased risk of CMV EOD. The prevalence of a CMV-specific immune response was high and endured over time.

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.

Necrotizing fasciitis in haematological patients: a different scenario.

To describe and compare the characteristics of necrotizing fasciitis (NF) in patients with and without haematological malignancy. All adult patients diagnosed with NF and treated at our hospital were included (January 2010-March 2019). Diagnosis was based on intraoperative findings or consistent clinical/radiological characteristics, and patients were classified as group A (with haematological malignancy) or group B (without haematological malignancy). Student's t (quantitative), Fisher's exact (qualitative), and Kaplan-Meyer tests were used for the statistical analysis. The study included 29 patients: 8 in group A and 21 in group B. All haematological patients had severe neutropenia (0.2 [0.02-0.5] ×109 cells/L; p < 0.001) and positive blood cultures (100% vs. 61.9%; p = 0.04) at diagnosis. Gram-negative bacilli NF was more common in group A (87.5% vs. 9.5%; p = 0.001), predominantly due to Escherichia coli (50% vs. 9.5%; p = 0.056). Surgical treatment was less common in haematological patients (5 [62.5%] vs. 21 [100%]; p = 0.015). Overall, 9 (31%) patients died: 4 (50%) in group A and 5 (23.8%) in group B (p = 0.17). The univariate analysis showed that mortality tended to be higher (OR 3.2; 95%CI 0.57-17.7; p = 0.17) and to occur earlier (2.2 ± 2.6 vs. 14.2 ± 19.9 days; p = 0.13) in haematological patients. The LRINEC index > 6 did not predict mortality in either group. In our study, NF in patients with haematological malignancies was mainly due to Gram-negative bacilli, associated to high and early mortality rates. In our experience, the LRINEC scale was not useful for predicting mortality.

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.

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.