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.

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.

Identifying the most important data for research in the field of infectious diseases: thinking on the basis of artificial intelligence.

OBJECTIVE: Clinical data on which artificial intelligence (AI) algorithms are trained and tested provide the basis to improve diagnosis or treatment of infectious diseases (ID). We aimed to identify important data for ID research to prioritise efforts being undertaken in AI programmes. METHODS: We searched for 1,000 articlesfrom high-impact ID journals on PubMed, selecting 288 of the latest articles from 10 top journals. We classified them into structured or unstructured data. Variables were homogenised and grouped into the following categories: epidemiology, admission, demographics, comorbidities, clinical manifestations, laboratory, microbiology, other diagnoses, treatment, outcomes and other non-categorizable variables. RESULTS: 4,488 individual variables were collected, from the 288 articles. 3,670 (81.8%) variables were classified as structured data whilst 818 (18.2%) as unstructured data. From the structured data, 2,319 (63.2%) variables were classified as direct-retrievable from electronic health records-whilst 1,351 (36.8%) were indirect. The most frequent unstructured data were related to clinical manifestations and were repeated across articles. Data on demographics, comorbidities and microbiology constituted the most frequent group of variables. CONCLUSIONS: This article identified that structured variables have comprised the most important data in research to generate knowledge in the field of ID. Extracting these data should be a priority when a medical centre intends to start an AI programme for ID. We also documented that the most important unstructured data in this field are those related to clinical manifestations. Such data could easily undergo some structuring with the use of semi-structured medical records focusing on a few symptoms.

New treatments for multidrug-resistant non-fermenting Gram-negative bacilli Infections.

Ceftolozane/tazobactam, ceftazidime/avibactam and cefiderocol belong to a novel generation of antibiotics that correspond with the ß-lactam family. It is necessary to having new options in treating infections caused by Gram-negative, non-fermenting multidrug-resistant bacilli due to the significant increase in multidrug resistance in the last decades. Knowing the main characteristics of each drug is key for correct use.

Correction to: Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies.

[This corrects the article DOI: 10.1093/ofid/ofab250.].

COVID-19 and fungal infections: Etiopathogenesis and therapeutic implications.

Invasive fungal infection often complicates patients with severe viral infection, especially those admitted to critical care units. Severe SARS-CoV-2 infection has been no exception and a significant association with Aspergillus spp. has been documented, resulting in high patient mortality. In this summary we describe the clinical presentation, the underlying diseases most commonly linked with this association, radiological manifestations and therapeutic management of CAPA.

Early Stepdown From Echinocandin to Fluconazole Treatment in Candidemia: A Post Hoc Analysis of Three Cohort Studies.

BACKGROUND: There are no clear criteria for antifungal de-escalation after initial empirical treatments. We hypothesized that early de-escalation (ED) (within 5 days) to fluconazole is safe in fluconazole-susceptible candidemia with controlled source of infection. METHODS: This is a multicenter post hoc study that included consecutive patients from 3 prospective candidemia cohorts (2007-2016). The impact of ED and factors associated with mortality were assessed. RESULTS: Of 1023 candidemia episodes, 235 met inclusion criteria. Of these, 54 (23%) were classified as the ED group and 181 (77%) were classified as the non-ED group. ED was more common in catheter-related candidemia (51.9% vs 31.5%; P = .006) and episodes caused by Candida parapsilosis, yet it was less frequent in patients in the intensive care unit (24.1% vs 39.2%; P = .043), infections caused by Nakaseomyces glabrata (0% vs 9.9%; P = .016), and candidemia from an unknown source (24.1% vs 47%; P = .003). In the ED and non-ED groups, 30-day mortality was 11.1% and 29.8% (P = .006), respectively. Chronic obstructive pulmonary disease (odds ratio [OR], 3.97; 95% confidence interval [CI], 1.48-10.61), Pitt score > 2 (OR, 4.39; 95% CI, 1.94-9.20), unknown source of candidemia (OR, 2.59; 95% CI, 1.14-5.86), candidemia caused by Candida albicans (OR, 3.92; 95% CI, 1.48-10.61), and prior surgery (OR, 0.29; 95% CI, 0.08-0.97) were independent predictors of mortality. Similar results were found when a propensity score for receiving ED was incorporated into the model. ED had no significant impact on mortality (OR, 0.50; 95% CI, 0.16-1.53). CONCLUSIONS: Early de-escalation is a safe strategy in patients with candidemia caused by fluconazole-susceptible strains with controlled source of bloodstream infection and hemodynamic stability. These results are important to apply antifungal stewardship strategies.

Real-life use of remdesivir in hospitalized patients with COVID-19.

OBJECTIVE: Controversial results on remdesivir efficacy have been reported. We aimed to report our real-life experience with the use of remdesivir from its availability in Spain. METHODS: We performed a descriptive study of all patients admitted for ≥48 hours with confirmed COVID-19 who received remdesivir between the 1st of July and the 30th of September 2020. RESULTS: A total of 123 patients out of 242 admitted with COVID-19 at our hospital (50.8%) received remdesivir. Median age was 58 years, 61% were males and 56.9 % received at least one anti-inflammatory treatment. No adverse events requiring remdesivir discontinuation were reported. The need of intensive care unit admission, mechanical ventilation and 30-days mortality were 19.5%, 7.3% and 4.1%, respectively. CONCLUSIONS: In our real-life experience, the use of remdesivir in hospitalized patients with COVID-19 was associated with a low mortality rate and good safety profile.

Experience with the use of siltuximab in patients with SARS-CoV-2 infection.

OBJECTIVE: The study aims to describe characteristics and clinical outcome of patients with SARS-CoV-2 infection that received siltuximab according to a protocol that aimed to early block the activity of IL-6 to avoid the progression of the inflammatory flare. METHODS: Retrospective review of the first 31 patients with SARS-CoV-2 treated with siltuximab, in Hospital Clinic of Barcelona or Hospital Universitario Salamanca, from March to April 2020 with positive polymerase-chain reaction (PCR) from a nasopharyngeal swab. RESULTS: The cohort included 31 cases that received siltuximab with a median (IQR) age of 62 (56-71) and 71% were males. The most frequent comorbidity was hypertension (48%). The median dose of siltuximab was 800 mg ranging between 785 and 900 mg. 7 patients received siltuximab as a salvage therapy after one dose of tocilizumab. At the end of the study, a total of 26 (83.9) patients had been discharged alive and the mortality rate was 16.1% but only 1 out of 24 that received siltuximab as a first line option (4%). CONCLUSIONS: Siltuximab is a well-tolerated alternative to tocilizumab when administered as a first line option in patients with COVID-19 pneumonia within the first 10 days from symptoms onset and high C-reactive protein.

Tocilizumab reduces the risk of ICU admission and mortality in patients with SARS-CoV-2 infection.

OBJECTIVE: In some patients the immune response triggered by SARS-CoV-2 is unbalanced, presenting an acute respiratory distress syndrome which in many cases requires intensive care unit (ICU) admission. The limitation of ICU beds has been one of the major burdens in the management around the world; therefore, clinical strategies to avoid ICU admission are needed. We aimed to describe the influence of tocilizumab on the need of transfer to ICU or death in non-critically ill patients. METHODS: A retrospective study of 171 patients with SARS-CoV-2 infection that did not qualify as requiring transfer to ICU during the first 24h after admission to a conventional ward, were included. The criteria to receive tocilizumab was radiological impairment, oxygen demand or an increasing of inflammatory parameters, however, the ultimate decision was left to the attending physician judgement. The primary outcome was the need of ICU admission or death whichever came first. RESULTS: A total of 77 patients received tocilizumab and 94 did not. The tocilizumab group had less ICU admissions (10.3% vs. 27.6%, P=0.005) and need of invasive ventilation (0 vs 13.8%, P=0.001). In the multivariable analysis, tocilizumab remained as a protective variable (OR: 0.03, CI 95%: 0.007-0.1, P=0.0001) of ICU admission or death. CONCLUSIONS: Tocilizumab in early stages of the inflammatory flare could reduce an important number of ICU admissions and mechanical ventilation. The mortality rate of 10.3% among patients receiving tocilizumab appears to be lower than other reports. This is a non-randomized study and the results should be interpreted with caution.

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.

Predictors of multidrug-resistant Pseudomonas aeruginosa in neutropenic patients with bloodstream infection.

OBJECTIVES: To assess risk factors for multidrug-resistant Pseudomonas aeruginosa (MDR-PA) infection in neutropenic patients. METHODS: Single-centre retrospective analysis of consecutive bloodstream infection (BSI) episodes (2004-2017, Barcelona). Two multivariate regression models were used at BSI diagnosis and P. aeruginosa detection. Significant predictors were used to establish rules for stratifying patients according to MDR-PA BSI risk. RESULTS: Of 661 Gram-negative BSI episodes, 190 (28.7%) were caused by P. aeruginosa (70 MDR-PA). Independent factors associated with MDR-PA among Gram-negative organisms were haematological malignancy (OR 3.30; 95% CI 1.15-9.50), pulmonary source of infection (OR 7.85; 95% CI 3.32-18.56), nosocomial-acquired BSI (OR 3.52; 95% CI 1.74-7.09), previous antipseudomonal cephalosporin (OR 13.66; 95% CI 6.64-28.10) and piperacillin/tazobactam (OR 2.42; 95% CI 1.04-5.63), and BSI occurring during ceftriaxone (OR 4.27; 95% CI 1.15-15.83). Once P. aeruginosa was identified as the BSI aetiological pathogen, nosocomial acquisition (OR 7.13; 95% CI 2.87-17.67), haematological malignancy (OR 3.44; 95% CI 1.07-10.98), previous antipseudomonal cephalosporin (OR 3.82; 95% CI 1.42-10.22) and quinolones (OR 3.97; 95% CI 1.37-11.48), corticosteroids (OR 2.92; 95% CI 1.15-7.40), and BSI occurring during quinolone (OR 4.88; 95% CI 1.58-15.05) and ß-lactam other than ertapenem (OR 4.51; 95% CI 1.45-14.04) were independently associated with MDR-PA. Per regression coefficients, 1 point was assigned to each parameter, except for nosocomial-acquired BSI (3 points). In the second analysis, a score >3 points identified 60 (86.3%) out of 70 individuals with MDR-PA BSI and discarded 100 (84.2%) out of 120 with non-MDR-PA BSI. CONCLUSIONS: A simple score based on demographic and clinical factors allows stratification of individuals with bacteraemia according to their risk of MDR-PA BSI, and may help facilitate the use of rapid MDR-detection tools and improve early antibiotic appropriateness.

Performance of differential time to positivity as a routine diagnostic test for catheter-related bloodstream infections: a single-centre experience.

OBJECTIVE: To assess the performance of differential time to positivity (DTP) for the diagnosis of catheter-related bloodstream infections (CRBSI). METHODS: From all episodes of bloodstream infections (BSI) diagnosed during a 15-year period (2003-17) those in which a paired set of blood cultures drawn from a catheter and a peripheral vein were positive for the same microorganism and had a clinically and/or microbiologically defined source were selected. To assess diagnostic discrimination ability and accuracy of DTP for CRBSI, area under the receiver operating characteristic curves (AUC) and performance characteristics of a DTP ≥2 h were computed. RESULTS: A total of 512 BSI were included, of which 302 (59%) were CRBSI. Discrimination ability of DTP was low for Staphylococcus aureus (AUC 0.656 ± 0.06), coagulase-negative staphylococci (AUC 0.618 ± 0.081), enterococci (AUC 0.554 ± 0.117) and non-AmpC-producing Enterobacteriaceae (AUC 0.653 ± 0.053); moderate for Pseudomonas aeruginosa (AUC 0.841 ± 0.073), and high for AmpC-producing Enterobacteriaceae (AUC 0.944 ± 0.039). For the entire sample, DTP had a low-to-moderate discrimination ability (AUC 0.698 ± 0.024). A DTP ≥2 h has a low sensitivity for coagulase-negative staphylococci (60%) and very low for S. aureus (34%), enterococci (40%) and non-AmpC-producing Enterobacteriaceae (42%). A DTP cut-off of 1 h improved sensitivity (90%) for AmpC-producing Enterobacteriaceae. CONCLUSIONS: Differential time to positivity performs well for diagnosing CRBSI only when AmpC-producing Enterobacteriaceae and P. aeruginosa are involved. Performance is low for common Gram-positive organisms and non-AmpC-producing enteric bacilli; a negative test should not be used to rule out CRBSI due to these microorganisms. A DTP ≥1 h may improve accuracy for AmpC-producing Enterobacteriaceae, particularly Enterobacter spp.

Prophylaxis of mould infections.

Invasive fungal infection continues to be an important cause of morbidity and mortality in haematological patients. Antifungal prophylaxis in these patients has remarkably increased survival since its introduction. In recent years, new antifungals have been on the rise, being more effective and having less toxicity than previous ones. Nonetheless, the number of patients at risk of fungal infection has also been increasing due to the continuous appearance of new immunosuppressive treatments. As a result of such, we face a changing situation that requires constant updating.

Current time-to-positivity of blood cultures in febrile neutropenia: a tool to be used in stewardship de-escalation strategies.

OBJECTIVES: We aimed to describe the current time-to-positivity (TTP) of blood cultures in individuals with onco-haematological diseases with febrile neutropenia. We assessed the probability of having a multidrug-resistant Gram-negative bacilli (MDR-GNB) bloodstream infection (BSI) 24 h after cultures were taken, to use this information for antibiotic de-escalation strategies. METHODS: BSI episodes were prospectively collected (2003-2017). When a patient experienced more than one BSI, only one episode was randomly chosen. Time elapsed from the beginning of incubation to a positive reading was observed; TTP was recorded when the first bottle had a positive result. RESULTS: Of the 850 patient-unique episodes, 323 (38%) occurred in acute leukaemia, 185 (21.8%) in non-Hodgkin's lymphoma and 144 (16.9%) in solid neoplasms. Coagulase-negative staphylococci (225; 26.5%), Escherichia coli (207; 26.1%), Pseudomonas aeruginosa (136; 16%), Enterococcus spp. (81; 9.5%) and Klebsiella pneumoniae (67; 7.9%), were the most frequent microorganisms isolated. MDR-GNB were documented in 126 (14.8%) episodes. Median TTP was 12 h (interquartile range 9-16.5 h). Within the first 24 h, 92.1% of blood cultures were positive (783/850). No MDR-GNB was positive over 24 h. Of the 67 (7.9%) episodes with a TTP ≥24 h, 25 (37.3%) occurred in patients who were already receiving active antibiotics against the isolated pathogen. Most common isolations with TTP ≥24 h were coagulase-negative staphylococci, candidaemia and a group of anaerobic GNB. CONCLUSIONS: Currently, the vast majority of BSI in individuals with onco-haematological diseases with febrile neutropenia have a TTP <24 h, including all episodes caused by MDR-GNB. Our results support reassessing empiric antibiotic treatment in neutropenic patients at 24 h, to apply antibiotic stewardship de-escalation strategies.

Top-ten papers in fungal infection (2015-2017).

We have clustered the published articles in fungal infection between 2016 and 2017 in four categories. First, the emergence of Candida auris as a nosocomial pathogen associated to high antifungal resistance and high mortality. Second, the growing importance of fungal infections associated to the use of biologic therapies. Third, the approval of isavuconazole for the treatment of filamentous fungi and dymorphic mycoses with positive results and less side effects. And finally, a mix of other important news regarding empiric therapy, fluconazole toxicity and difficult-to-treat fungal infections..

Comments on practice guidelines for the diagnosis and management of aspergillosis made by the IDSA in 2016.

We sought to review the most important updates in the treatment of aspergillosis after the publication of the clinical practice guidelines for the diagnosis and management of invasive aspergillosis (IA) by the Infectious Diseases Society of America. Our aim is to discuss some of the key aspects concerning the following topics: early initiation of antifungal therapy, antifungal agent of choice, follow-up of patients with IA, and breakthrough aspergillosis.

Empirical treatment of adults with hospital-acquired pneumonia: lights and shadows of the 2016 Clinical Practice ATS/IDSA Guidelines.

Hospital-acquired pneumonia (HAP) is a common cause of nosocomial infection associated with significant morbidity and mortality. New clinical practice guidelines for the management of adults with hospital-acquired pneumonia have been published in 2016 by the Infectious Diseases Society of America (IDSA) and the American Thoracic Society (ATS). This review focuses on the recent recommendations and their limitations. We also focus on new therapeutic options that might improve the treatment and outcomes of these patients.