Epidemiology, clinical aspects, outcomes and prognostic factors associated with Trichosporon fungaemia: results of an international multicentre study carried out at 23 medical centres.

BACKGROUND: Trichosporon fungaemia (TF) episodes have increased in recent years and mortality rates remain high despite the advances in the management of sepsis. New concepts about its clinical course, treatment and microbiology need to be investigated for the better management of this infection. OBJECTIVES: To describe the aetiology, natural history, clinical management and prognostic factors of TF. METHODS: TF episodes documented between 2005 and 2018 in 23 South American centres were retrospectively investigated by using a standard clinical form. Molecular identification, antifungal susceptibility testing and biofilm production were also performed. RESULTS: Eighty-eight TF episodes were studied. Patients had several underlying conditions, including haematological diseases (47.7%), post-operative status (34%), solid organ transplants (n = 7, 7.9%), among others. Seventy-three (82.9%) patients had a central venous catheter (CVC) at TF diagnosis. The 30 day mortality rate was 51.1%. Voriconazole-based therapy was given to 34 patients (38.6%), with a 30 day mortality rate of 38.2%. Multivariate predictors of 30 day mortality were age (OR 1.036), mechanical ventilation (OR 8.25) and persistent neutropenia (OR 9.299). CVC removal was associated with over 75% decreased risk of 30 day mortality (OR 0.241). Microbiological analyses revealed that 77.7% of the strains were identified as Trichosporon asahii, and voriconazole showed the strongest in vitro activity against Trichosporon spp. Most of the strains (63%) were considered medium or high biofilm producers. CONCLUSIONS: Older age, mechanical ventilation and persistent neutropenia were associated with poor prognosis. CVC may play a role in the pathogenicity of TF and its removal was associated with a better prognosis.

A randomized, double-blind trial investigating the efficacy of caspofungin versus amphotericin B deoxycholate in the treatment of invasive candidiasis in neonates and infants younger than 3 months of age.

OBJECTIVES: Investigate the efficacy of caspofungin in participants <3 months of age with invasive Candida infection (ICI). METHODS: This multicentre, randomized, double-blind, comparator-controlled, Phase 2 study (protocol MK0991-064; NCT01945281) enrolled participants <3 months of age with culture-confirmed ICI within 96 h of study entry. Participants were randomly assigned 2:1 to once-daily intravenous 2 mg/kg caspofungin or intravenous 1 mg/kg amphotericin B deoxycholate (dAMB). The primary endpoint was fungal-free survival (FFS) 2 weeks after treatment in the full-analysis-set (FAS) population, defined as participants with culture-confirmed ICI who received ≥1 dose of therapy. Planned enrolment was 90 participants. RESULTS: Fifty-one participants were enrolled; 49 received treatment (caspofungin, n=33; dAMB, n=16); 2 additional participants did not have confirmed infections at study entry. The study was terminated after ∼ 3.5 years because of low enrolment. Forty-seven participants were included in the FAS population (caspofungin, n=31; dAMB, n=16). FFS rate at 2 weeks after treatment was 71.0% (22/31) in the caspofungin arm and 68.8% (11/16) in the dAMB arm [difference, stratified by weight, - 0.9% (95% CI, - 24.3%-27.7%)]. Adverse events developed in 84.8% (28/33) of participants in the caspofungin arm and 100% (16/16) in the dAMB arm. CONCLUSIONS: Among neonates and infants with confirmed ICI, FFS at 2 weeks was similar in the caspofungin and dAMB treatment arms. A smaller proportion of participants who received caspofungin experienced adverse events.

Fluconazole Doses Used for Prophylaxis of Invasive Fungal Infection in Neonatal Intensive Care Units: A Network Meta-Analysis.

OBJECTIVES: To evaluate the safety and efficacy of different doses of fluconazole used for invasive prophylaxis of fungal infection in neonates. STUDY DESIGN: A systematic search was conducted with PubMed, Scopus, and Web of Science. A manual search was performed as well. Only randomized controlled trials of neonates in a neonatal intensive care unit (NICU) who received fluconazole prophylaxis for invasive fungal infection, regardless of the dose or therapeutic regimen, were included in this review. Data on baseline characteristics, outcomes incidence of proven invasive Candida infection, overall mortality, and invasive Candida infection-related mortality were extracted. RESULTS: Eleven studies were included in the review, with fluconazole doses of 3, 4, or 6?mg/kg. When the incidence of invasive Candida and invasive Candida-related mortality were considered as outcomes, the 3 and 6?mg/kg fluconazole doses were found to be statistically superior to placebo (OR, 5.48 [95% credible interval, 1.81-18.94] and 2.63 [1.18-7.02], respectively, and 15.32 [1.54-54.31] and 9.14 [1.26-142.7], respectively), but data for the 3 doses were not statistically significantly different. CONCLUSIONS: Use of the lowest fluconazole dose (3?mg/kg) should be recommended for Candida prophylaxis in neonates, given that increasing the fluconazole dose is not associated with higher efficacy and has greater potential for toxicity and increased cost.

High-risk clones of carbapenem resistant Klebsiella pneumoniae recovered from pediatric patients in Southern Brazil.

Carbapenem-resistant Klebsiella pneumoniae (CRKP) exhibit high mortality rates in pediatric patients and usually belong to international high-risk clones. This study aimed to investigate the molecular epidemiology and carbapenem resistance mechanisms of K. pneumoniae isolates recovered from pediatric patients, and correlate them with phenotypical data. Twenty-five CRKP isolates were identified, and antimicrobial susceptibility was assessed using broth microdilution. Carbapenemase production and ß-lactamase genes were detected by phenotypic and genotypic tests. Multilocus sequence typing was performed to differentiate the strains and whole-genome sequencing was assessed to characterize a new sequence type. Admission to the intensive care unit and the use of catheters were significantly positive correlates of CRKP infection, and the mortality rate was 36%. Almost all isolates showed multidrug-resistant phenotype, and most frequent resistant gene was blaKPC. We observed the dissemination of ST307 and clones belonging to CG258, which are considered high risk. In pediatric patients, these clones present with high genomic plasticity, favoring adaptation of the KPC and NDM enzymes to healthcare environments.

Effectiveness, Tolerability, and Safety of Different Amphotericin B Formulations in Invasive Fungal Infections: A Multicenter, Retrospective, Observational Study.

PURPOSE: Data on the real-life use of amphotericin B lipid complex (ABLC) compared with other available formulations are limited. This study aimed to evaluate the effectiveness, tolerability, and safety of different amphotericin B (AMB) intravenously administered in the context of hospital practice for the treatment of invasive fungal infections (IFI) and to provide new insights into the profile of ABLC. METHODS: This is a multicenter, retrospective, observational study conducted at 10 tertiary Brazilian hospitals. Patients first exposed to any formulation of AMB for treating endemic and opportunistic IFI who had received at least 2 intravenous doses were screened. Retrospective data (from January 2014 to December 2019) were extracted from the patients' medical records. Clinical parameters were examined pre- and post-treatment to determine effectiveness; acute infusion-related side effects (IRSE) and drug interruption to determine tolerability; and adverse events, toxicity, and treatment interruption were stated to analyze safety. FINDINGS: Overall, 1879 medical records of patients were identified. The median (interquartile rate) duration of treatment was 14 (7-21) days. The overall success rate (95% confidence interval [CI]) was 65% (95% CI 60-65). ABLC proved to be effective among AMB formulations with 59% (95% CI 55.6-62.5) within complete response. This was significantly higher in patients who received the drug for a longer period, ≥4 weeks compared to <1 week treatment (P < 0.001). IRSE was observed in 446 (23.7%) patients. Eight cases (1.4%) of severe IRSE in pediatrics and 14 (1.1%) in adults resulted in treatment discontinuation. Regarding safety, 637 (33.9%) patients presented some alteration in creatinine levels during AMB exposure, and 89 (4.74%) had to interrupt or discontinue the drug within the first 14 days of therapy because of renal dysfunction. Overall mortality was 34%. IMPLICATIONS: ABLC is an effective formulation for the treatment of invasive fungal infections, with few adverse events leading to drug discontinuation or lethal outcomes. Furthermore, this real-life study confirmed the comparative safety of AMB lipid formulations versus AMB deoxycholate.

Amphotericin B in Pediatrics: Analysis by Age Stratification Suggests a Greater Chance of Adverse Events from 13 Months of Age Onwards.

BACKGROUND AND OBJECTIVE: Amphotericin B deoxycholate (AMB-D) remains an antifungal agent with great therapeutic value in pediatric patients. The currrent consensus is that its use in neonates is safer than in older children. However, childhood presents different periods of development that deserve to be evaluated more precisely. Our goal was to assess the usage profile of AMB-D in stratified pediatric age groups, adapted according to the National Institute of Child Health and Human Development classification. METHODS: This retrospective cross-sectional observational study was conducted at a Brazilian tertiary children's hospital between January 2014 and December 2019.  Data of patients who received at least two doses of intravenous AMB-D while hospitalized were extracted from electronic health files. Information on patient demographics, underlying diseases and comorbidities, laboratory examinations, fungal infection diagnosis, and AMB-D use were gathered following specific criteria. Nonparametric tests were applied, such as the chi-square test to compare proportions and Fisher's exact test to assess the association between categorical variables or contingency tables. RESULTS: One hundred and twenty-seven (127) medical records were stratified as preterm neonatal (birth <37 weeks postmenstrual age), term neonatal (birth-27 days), infants (28 days-12 months), toddlers (13 months-2 years), early childhood (3-5 years), middle childhood (6-11 years), and early adolescence (12-18 years). The criteria for the indication of AMB-D followed empirical use as the main indication (n = 74; 58.26%), proven and probable fungal infection (n = 39; 30.71%), and medical suspicion (n = 14; 11.02%). Candida spp. was the main etiologic agent isolated in cultures, with the highest frequency of C. albicans (n = 18; 40%), followed by Candida parapsilosis (n = 14; 31.11%), and Candida tropicalis (n = 6; 13.33%). Very few acute infusion-related adverse effects were observed during the administration of AMB-D in pediatric patients. We found an unfavorable impact of AMB-D use in patients from 13 months of age onwards suggesting this group as a turning point for a greater chance of adverse events, and not soon after the neonatal period. CONCLUSIONS: Clinical or observational studies based on age stratification are essential to accurately elucidate whether potentially toxic drugs can be used safely in the pediatric population. Our search for a turning point was shown to contribute to the accuracy of the study, as it provided data on the impact of D-AMB in specific pediatric age groups.

Risk Adjustment for Congenital Heart Surgery Score as a Risk Factor for Candidemia in Children Undergoing Congenital Heart Defect Surgery.

BACKGROUND: Candida species are the primary cause of invasive fungal infection in hospitalized children. There are few data on risk factors for postoperative candidemia in pediatric patients with congenital heart defects. This study aimed to identify risk factors for candidemia in patients with congenital heart defects who underwent cardiac surgery. METHODS: This was a case-control study conducted in patients admitted to a pediatric cardiology intensive care unit from January 2006 to December 2013. Candidemia cases were matched with control patients without candidemia. Multivariate analyses were conducted to determine predictive probabilities for the incidence of candidemia at a risk higher than 10%. RESULTS: Thirty patients diagnosed with candidemia (incidence: 0.7 cases/1000 patient days) were matched with 75 controls. Risk factors independently associated with candidemia included Risk Adjustment for Congenital Heart Surgery (RACHS-1) category ≥3 [odds ratio (OR) = 3.165, 95% confidence interval: 1.377-8.467], use of acid suppression therapy (OR = 1.9, 95% confidence interval: 0.949-3.979) and thrombocytopenia (OR = 2.2, 95% confidence interval: 1.2-4.2). Predictive probabilities ranged from 11% (only in RACHS-1 category ≥3) to 58% (combined RACHS-1 ≥3, thrombocytopenia and acid suppression therapy use). The case fatality rate within 30 days after candidemia was 50%. CONCLUSION: This is the first report using the RACHS-1 category as a risk factor for invasive candidiasis in patients with congenital heart defects in the pediatric intensive care unit. Further studies must be conducted to validate the risk factors for candidemia in this pediatric population.