Knowledge gaps in candidaemia/invasive candidiasis in haematological cancer patients.

As neutropenic patients with haematological cancer are not typically included in randomized controlled trials (RCTs) of candidaemia, there is low quality of evidence regarding the management of this common opportunistic mycosis in this patient population, which is at high risk for poor outcomes. Herein we identify the gaps in knowledge that are not addressed by the modern RCTs and candidaemia guidelines, and outline some considerations for the future clinical research agenda in candidaemia/invasive candidiasis in haematological patients.

Clinical Relevance and Prognostic Value of Persistently Negative (1,3)-ß-D-Glucan in Adults With Candidemia: A 5-year Experience in a Tertiary Hospital.

BACKGROUND: The clinical relevance and the potential prognostic role of persistently negative (1,3)-ß-D-glucan (BDG) in adults with proven candidemia is unknown. METHODS: This retrospective study included all adults diagnosed with candidemia our tertiary university hospital from 2012-2017 who had at least 2 serum BDG determinations throughout the episode of fungemia (Fungitell Assay; positive cut-off ≥80pg/mL). Epidemiology and clinical outcomes were compared between patients with all negative versus any positive BDG tests. Poor clinical outcomes included complications due to candidemia or 30-day all-cause mortality. RESULTS: Overall, 26/148 (17.6%) candidemic adults had persistently negative BDG tests. These patients were less likely to present Candida growth in all 3 sets of blood cultures (15.4% vs 45.1%; P = .005) and had less severe clinical presentations (median Pitt score, 0 [interquartile range {IQR} 0-1] vs 1 [IQR 0-2] in patients with any positive BDG test; P = .039). Although adequate treatment was equally provided to both groups (96.2% in persistently negative group vs 93.4 in positive group; P = .599), the persistently negative group had a higher rate of microbiological clearance in the first follow-up blood cultures (92.3% vs 69.7% in positive group; P = .005), fewer complications due to candidemia (7.7% vs 33.6% in positive group; P = .008), a lower 30-day mortality rate (3.8% vs 23.8% in positive group; P = .004), and a shorter in-hospital stay (34 days [IQR 18-55] vs 51 days [IQR 35-91] in positive group; P = .003). In the multivariate analysis, persistently negative BDG tests were independently associated with better prognoses (odds ratio 0.12, 95% confidence interval 0.03-0.49; P = .003). CONCLUSIONS: Candidemic patients with persistently negative BDG tests present a better prognosis than the comparative group, probably due to a lower systemic fungal burden. In this context, the appropriate use of persistently negative BDG results could be an aid to individualize therapeutic management in the near future.

MSH2 Gene Point Mutations Are Not Antifungal Resistance Markers in Candida glabrata.

The high rates of antifungal resistance in Candida glabrata may be facilitated by the presence of alterations in the MSH2 gene. We aimed to study the sequence of the MSH2 gene in 124 invasive C. glabrata isolates causing incident episodes of candidemia (n = 81), subsequent candidemia episodes (n = 9), endocarditis (n = 2), and in vitro-generated echinocandin-resistant isolates (n = 32) and assessed its relationship with genotypes, acquisition of antifungal resistance in vivo and in vitro, and patient prognosis. The MSH2 gene was sequenced, and isolates were genotyped using six microsatellite markers and multilocus sequence typing (MLST) based on six housekeeping genes. According to EUCAST, isolates causing candidemia (n = 90) were echinocandin susceptible, and four of them were fluconazole resistant (MIC ≥64 mg/liter). One isolate obtained from a heart valve was resistant to micafungin and anidulafungin (MICs, 2 mg/liter and 1 mg/liter, respectively). MSH2 gene mutations were present in 44.4% of the incident isolates, the most common being V239L. The presence of MSH2 mutations was not correlated with in vitro or in vivo antifungal resistance. Microsatellite and MLST revealed 27 genotypes and 17 sequence types, respectively. Fluconazole-resistant isolates were unrelated. Most MSH2 mutations were found in cluster isolates; conversely, some mutations were found in more than one genotype. No clinical differences, including previous antifungal use, were found between patients infected by wild-type MSH2 gene isolates and isolates with any point mutation. The presence of MSH2 gene mutations in C. glabrata isolates causing candidemia is not correlated with specific genotypes, the promotion of antifungal resistance, or the clinical outcome.

Persistent Candidemia in adults: underlying causes and clinical significance in the antifungal stewardship era.

To investigate the causes and the clinical significance of persistent candidemia (PC) in adults diagnosed in a tertiary hospital with an active antifungal stewardship program. Retrospective cohort including all adults with candidemia from 2010 to 2018. PC was defined as any positive follow-up blood culture (BC) obtained ≥ 5 days from the first BCs yielding the same Candida species. PC was detected in 35/255 (13.7%) patients. There were no differences regarding antifungal adequacy in PC vs. non-PC (94.3% vs. 82.3%, p = 0.084) and primary source control (63.3% vs. 76.4%, p = 0.172) at the time of the follow-up BCs. The average time until source control (2 [0-37] vs. 2 days [0-44], p = 0.311) or adequate antifungal treatment (2 [0-26] vs. 2 days [- 2-10], p = 0.748) was similar. Patients with PC had more non-ocular complications (31.4% vs. 10.5%, p = 0.002). No impact on 30-day mortality was observed (31.4% vs. 22.3%, p = 0.238). The only independent factor associated with PC was to have a previously undetected site of infection [OR 4.28, 95%CI (1.77-10.34), p = 0.001]. Persistent candidemia was not associated with inadequate or delayed therapeutic management, nor higher 30-day mortality rates. Timely screening and control of unexpected infection sources are encouraged to shorten hospitalization and improve patient care.

Fatal disseminated infection by Gymnascella hyalinospora in a heart transplant recipient.

We report the first case of disseminated infection by Gymnascella hyalinospora in a solid organ transplant recipient. This case highlights the role of low-virulence environmental molds as an emerging cause of breakthrough invasive fungal infection in immunocompromised hosts. Nosocomial strategies of infection control including antimicrobial stewardship and advances on fast diagnostic methods are strongly encouraged to improve patient prognosis.

Prognostic Trends and Current Challenges in Candidemia: A Comparative Analysis of Two Multicenter Cohorts within the Past Decade.

Candidemia remains a major public health challenge due to its high mortality rates, especially in developing countries. Monitoring epidemiological trends may provide insights for better clinical outcomes. This study aimed to describe trends in the epidemiology, therapeutic practices, and mortality in candidemia through a retrospective comparative analysis between two surveillance cohorts of all candidemic adults at eleven tertiary hospitals in Brazil, from 2010-2011 (Period I) versus 2017-2018 (Period II). A total of 616 cases were diagnosed, with 247 being from Period II. These patients were more likely to have three or more coexisting comorbidities [72 (29.1%) vs. 60 (16.3%), p < 0.001], had a prior history of in-hospital admissions more often [102 (40.3%) vs. 79 (21.4%), p = 0.001], and presented with candidemia earlier after admission, within 15 days (0-328) vs. 19 (0-188), p = 0.01. Echinocandins were more frequently prescribed [102 (41.3%) vs. 50 (13.6%), p = 0.001], but time to antifungal initiation [2 days (0-14) vs. 2 (0-13), p = 0.369] and CVC removal within 48 h [90/185 (48.6%) vs. 148/319 (46.4%), p = 0.644] remained unchanged. Additionally, many patients went untreated in both periods I and II [87 (23.6%) vs. 43 (17.4%), p = 0.07], respectively. Unfortunately, no improvements in mortality rates at 14 days [123 (33.6%) vs. 93 (37.7%), p = 0.343] or at 30 days [188 (51.4%) vs. 120 (48.6%), p = 0.511] were observed. In conclusion, mortality rates remain exceedingly high despite therapeutic advances, probably associated with an increase in patients' complexity and suboptimal therapeutic interventions. Management strategies should be tailored to suit epidemiological changes, expedite diagnosis to reduce the number of untreated eligible patients and guarantee early antifungal initiation and source control.

Prognostic factors of Candida spp. bloodstream infection in adults: A nine-year retrospective cohort study across tertiary hospitals in Brazil and Spain.

Background: Mortality rates among adults with candidemia vary widely in different geographical settings. Studies directly comparing epidemiology and clinical practices between countries are scarce and could bring insights into improving clinical outcomes. Methods: Retrospective cohort including adults with candidemia diagnosed in five tertiary hospitals from Brazil and Spain between 2010-2018. Adequate therapeutic management included appropriate antifungal therapy and central-venous-catheter (CVC) removal within 48 h of fungemia. Primary endpoints were mortality rates at 14 and 30 days. Secondary endpoints were prognostic factors associated with 30-day mortality. Findings: Overall, 720 patients were included, being 323 from Spain. Spanish patients received echinocandins more often (52·5% vs. 39·3%, p = 0.001), initiated antifungals earlier [2 (0-7) vs. 2 days (0-16), p<0.001], and had faster CVC-removal [1 (0-42) vs. 2 days (0-38), p = 0.012]. Mortality was higher among Brazilians at 14 days (35·8% vs. 20·1%, p<0.001), and at 30 days (51·9% vs. 31·6%, p < 0.001). Factors associated with mortality included: age [OR 1·02, 95%CI (1·008-1·032), p = 0·001], neutropenia [OR 3·24, 95%CI (1·594-6·585), p = 0·001], chronic pulmonary disease [OR 2·26, 95%CI (1·495-3·436), p < 0·001], corticosteroids [OR 1·45, 95%CI (1·018-2·079), p = 0·039], Pitt-Score>1 [OR 2·56, 95%CI (1·776-3·690), p < 0·001], and inadequate therapeutic management [OR 2·84, 95%CI (1·685-4·800), p < 0·001]. Being from Spain [OR 0·51, 95%CI (0·359-0·726), p < 0·001] and C. parapsilosis [OR 0·36, 95%CI (0·233-0·568), p < 0·001] were protective. Interpretation: Higher mortality rates were observed in Brazil. Factors associated with 30-day mortality included mainly epidemiological characteristics and inadequate therapeutic management. Thus, effective and prompt antifungals combined with CVC-removal still need to be emphasized in order to improve the prognosis of adults with candidemia. Funding: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2017/02203-7); CAPES Foundation (PDSE 88881.187981/2018-01).

Utility of 1,3 ß-d-Glucan Assay for Guidance in Antifungal Stewardship Programs for Oncologic Patients and Solid Organ Transplant Recipients.

The implementation of 1,3 ß-d-glucan (BDG) has been proposed as a diagnostic tool in antifungal stewardship programs (ASPs). We aimed to analyze the influence of serum BDG in an ASP for oncologic patients and solid organ transplant (SOT) recipients. We conducted a pre-post study. In the initial period (PRE), the ASP was based on bedside advice, and this was complemented with BDG in the post-period (POST). Performance parameters of the BDG assay were determined. Antifungal (AF) use adequacy was evaluated using a point score. Clinical outcomes and AF costs were also compared before and after the intervention. Overall, 85 patients were included in the PRE-period and 112 in the POST-period. Probable or proven fungal infections were similar in both groups (54.1% vs. 57.1%; p = 0.67). The determination of BDG contributed to improved management in 75 of 112 patients (66.9%). The AF adequacy score improved in the POST-period (mean 7.75 vs. 9.29; p < 0.001). Median days of empiric AF treatment was reduced in the POST-period (9 vs. 5 days, p = 0.04). All-cause mortality (44.7% vs. 34.8%; p = 0.16) was similar in both periods. The cost of AF treatments was reduced in the POST-period with a difference of 779.6 €/patient. Our data suggest that the use of BDG was a cost-effective strategy that contributed to safely improving the results of an ASP for SOT and oncologic patients.

Infectious endocarditis caused by Candida glabrata: evidence of in vivo development of echinocandin resistance / Endocarditis infecciosa por Candida glabrata: evidencia del desarrollo in vivo de resistencia a equinocandinas

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