Breakthrough Candidemia Research Articles

Antifungal Resistance and Breakthrough Candidemia Among Pediatric Cancer Patients: An Emerging Threat

Abstract Background Cancer patients are at risk for candidemia. Resistance and breakthrough Candida represent an emerging threat. The study aims to analyze the clinical features, resistance patterns and breakthrough candidemia among pediatric cancer patients. Methods The retrospective study was conducted from 2014 - 2020 in children admitted to Children Cancer Hospital, Egypt. Clinical, microbiological, and outcomes were analyzed. Mortality was estimated within 30 days from Candida spp. Isolation from blood. Results Three hundred fifty (350) pediatric cancer patients were diagnosed with candidemia. The median age was four years (4 months- 18 years). Most of the patients had hematological malignancies (54%) while solid tumors represent (46%). Clinical features of the patients included neutropenia (80%), the presence of central venous line (57%), ICU admission (44%), and steroid use (43%). Non-Albicans candida was predominant (71%) compared to Candida Albicans (29%). The isolated species were: C. Albicans (29%), C.Tropicalis (29%), C. parapsilosis (21%), C. krusei (7%), C.glabrata(3%), C. guilliermondii (1.5%)and C. famata (2%). Chronic disseminated candidiasis was reported in 30 (9%) patients, with the liver being the most affected organ. Breakthrough candidemia on top of echinocandin prophylaxis was reported among 62(18%) patients with C. parapsilosis is the most common 31(50%) isolated pathogen. From 96 patients with breakthrough candidemia, all-cause mortality was reported in 32 patient (33%) while candida attributable cause of death in elven (11%) patients. Antifungal resistance was reported in 74(21%) patients: fluconazole (15%), liposomal ampho-B (6%), echinocandin (5%) and voriconazole (3%). Among 74 patients with resistant candidemia, death was reported in 24%. Echinocandin Resistant candida was a direct cause of mortality in 3(17%) patients. The overall day- 30 mortality rate was 24% (85/350 patients), while candida attributable of mortality was (10%). Patients with septic shock, ICU admission, and resistant candida had a higher mortality risk. Conclusion Echinocandin-resistant and breakthrough Candida are significant threat with a high mortality rate among pediatric cancer patients. Antifungal stewardship may be helpful. Figure 1. Resistance Pattern of Candidemia among Pediatric Cancer Patients

Breakthrough candidemia with hematological disease: Results from a single-center retrospective study in Japan, 2009-2020.

Breakthrough candidemia (BrC) is a significant problem in immunocompromised patients, particularly those with hematological disorders. To assess the characteristics of BrC in patients with hematologic disease treated with novel antifungal agents, we collected clinical and microbiological information on said patients from 2009 to 2020 in our institution. Forty cases were identified, of which 29 (72.5%) received hematopoietic stem cell transplant (HSCT)-related therapy. At BrC onset, the most administered class of antifungal agents were echinocandins, administered to 70% of patients. Candida guilliermondii complex was the most frequently isolated species (32.5%), followed by C. parapsilosis (30%). These two isolates were echinocandin-susceptible in vitro but had naturally occurring FKS gene polymorphisms that reduced echinocandin susceptibility. Frequent isolation of these echinocandin-reduced-susceptible strains in BrC may be associated with the widespread use of echinocandins. In this study, the 30-day crude mortality rate in the group receiving HSCT-related therapy was significantly higher than in the group not receiving it (55.2% versus 18.2%, P=.0297). Most patients affected by C. guilliermondii complex BrC (92.3%) received HSCT-related therapy and had a 30-day mortality rate of 53.8%; despite treatment administration, 3 of 13 patients had persistent candidemia. Based on our results, C. guilliermondii complex BrC is a potentially fatal condition in patients receiving HSCT-related therapy with echinocandin administration.

Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia

IntroductionBiofilm formation causes virulence and resistance in Candida albicans. However, little is known about breakthrough candidemia isolates. We evaluated the antifungal activity of fluconazole, anidulafungin, deoxycholate amphotericin B (dAMB), and amphotericin B lipid complex (ABLC) against biofilms of C. albicans isolated from patients with breakthrough candidemia. MethodsThe present study used strains of C. albicans isolated from breakthrough and non-breakthrough candidemia patients (control group). The susceptibility of planktonic cells to amphotericin B, anidulafungin, and fluconazole was determined by broth microdilution. Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration (MBEC), metabolic activity was estimated by reducing MTT, and biomass was estimated using crystal violet retention. ResultsThe planktonic strains were susceptible to amphotericin B, anidulafungin, and fluconazole, with minimum inhibitory concentrations of 1, ≤0.03, and 2mg/L, respectively. However, fluconazole and anidulafungin did not exert an antifungal effect on biofilms. Additionally, dAMB and ABCL reduced the metabolic activity and biomass. However, eradication was only achieved using 16mg/L dAMB. C. albicans isolates of breakthrough candidemia exhibited strong biofilm production, and the in vitro activity of available therapeutic options was poor. ConclusionIn the present study, only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates.

Prognosis of Amphotericin B in the Treatment of Breakthrough Candidemia in Patients with Hematologic Malignancies

Background Candidemia is greatly affects patient mortality, especially in patients with malignant hematologic diseases, despite improvements in diagnosis, prophylaxis, and management, but also with a crude mortality rate of 25-50% . The choice of the antifungal therapy for candidemia must take into account several factors such as type of patient, presence of devices, severity of illness, recent exposure to antifungals, local epidemiology, organs involvement, and Candida species. Echinocandin is a broad-spectrum antifungal agent that is effective against most Candida species,and also choice for neutropenic patients, but their resistance limits their clinical application, especially for immunodeficient patients we often need stronger antifungal drugs, Amphotericin B and liposomal amphotericin B are still widely used, and the effectiveness and safety of both are subject to further clinical analysis. Objective Analyze the clinical characteristics of patients with hematologic malignancies complicated by candidemia. compared the prognosis of patients with candidemia treated with amphotericin B and amphotericin B liposomes, and compared the differences in overall survival rate of breakthrough candidemia between patients who received or did not receive allogeneic hematopoietic stem cell transplantation. Method We collected clinical and microbiological data from a single centre of patients with hematological malignancies and breakthrough candidemia, recording results at 7, 30 and 100 days of follow-up, comparing the prognosis of patients with hematological malignancies complicated by breakthrough candidemia with amphotericin B. Kaplan-Meier survival estimates were used to generate survival curves. Result Of 30 enrolled patients, 10 were diagnosed with acute lymphoblastic leukaemia, 10 with acute myeloid leukaemia, 2 with chronic myeloid leukaemia, 4 with lymphoma, 3 with myelodysplastic syndrome and 1 with aplastic anemia. All patients had agranulocytosis during the course of the disease, with a median duration of 19.5 days of agranulocytosis, and 28 of these patients had sepsis at the time of agranulocytosis. Of the 30 pathogenic breakthrough Candida strains, one was Candida albicans, one was Candida guilliermondi, three were Candida subsmoothis and 25 were Candida tropicalis. 14 of these patients received hematopoietic stem cell transplants. Attributable mortality was 5/14 (35.71%) and 4/12 (33.33%) in the transplant and non-transplant groups respectively (P=0.694).At day 7, 30 and 100, overall survival rates were 100%, 82.6% and 39.1% for patients in the amphotericin B group and 85.6%, 28.6% and 28.6% for patients in the non-amphotericin B group respectively, with significant differences in 30-day survival rates between the two groups(P=0.00051). We found that among patients in the transplant group, the overall survival rates at 30 and 100 days were 91.0% and 36.3% for patients using amphotericin B, respectively, and 0% and 0% for patients without amphotericin B at 30 and 100 days, and that there was a significant difference between them (P=0.0025, P=0.0023). In the transplant group, the overall survival rates at 30 and 100 days were higher in patients with post-transplant candidemia than in those with peri-transplant candidemia, but none of the differences were statistically significant (P=0.40, P=0.38). Conclusion Early candidemia in transplant patients severely affects patient prognosis, increasing non-recurrent post-transplant mortality and reducing overall survival. Amphotericin B has shown good efficacy in the treatment of breakthrough candidemia in both transplant and non-transplant patients, and although the guideline recommendation for candidemia is caspofungin or micafungin, amphotericin and amphotericin liposomes as an alternative, the choice of antifungal agent for breakthrough candidemia in immunodeficient patients may need to be patient-specific.

Comparison of amphotericin B lipid complex, deoxycholate amphotericin B, fluconazole, and anidulafungin activity against Candida albicans biofilm isolated from breakthrough candidemia

IntroductionBiofilm formation causes virulence and resistance in Candida albicans. However, little is known about breakthrough candidemia isolates. We evaluated the antifungal activity of fluconazole, anidulafungin, deoxycholate amphotericin B (dAMB), and amphotericin B lipid complex (ABLC) against biofilms of C. albicans isolated from patients with breakthrough candidemia. MethodsThe present study used strains of C. albicans isolated from breakthrough and non-breakthrough candidemia patients (control group). The susceptibility of planktonic cells to amphotericin B, anidulafungin, and fluconazole was determined by broth microdilution. Antifungal activity in sessile cells was evaluated using the minimum biofilm eradication concentration (MBEC), metabolic activity was estimated by reducing MTT, and biomass was estimated using crystal violet retention. ResultsThe planktonic strains were susceptible to amphotericin B, anidulafungin, and fluconazole, with minimum inhibitory concentrations of 1, ≤0.03, and 2mg/L, respectively. However, fluconazole and anidulafungin did not exert an antifungal effect on biofilms. Additionally, dAMB and ABCL reduced the metabolic activity and biomass. However, eradication was only achieved using 16mg/L dAMB. C. albicans isolates of breakthrough candidemia exhibited strong biofilm production, and the in vitro activity of available therapeutic options was poor. ConclusionIn the present study, only dAMB and ABCL exhibited antibiofilm effects against sessile breakthrough candidemia isolates.

Fatal Breakthrough Candidemia in an Immunocompromised Patient in Kuwait Due to Candida auris Exhibiting Reduced Susceptibility to Echinocandins and Carrying a Novel Mutation in Hotspot-1 of FKS1

Candida auris is an emerging yeast pathogen that has recently caused major outbreaks in healthcare facilities worldwide. Clinical C. auris isolates are usually resistant to fluconazole and readily develop resistance to echinocandins and amphotericin B (AMB) during treatment. We describe here an interesting case of C. auris infection in an immunocompromised patient who had previously received AMB and caspofungin treatment. Subsequently, C. auris was isolated from tracheal (tracheostomy) secretions and twice from urine and all three isolates were susceptible to AMB and micafungin. The patient received a combination therapy with AMB and caspofungin. Although the C. auris was cleared from the urine, the patient subsequently developed breakthrough candidemia and the bloodstream isolate exhibited a reduced susceptibility to micafungin and also showed the presence of a novel (S639T) mutation in hotspot-1 of FKS1. Interestingly, C. auris from the tracheal (tracheostomy) secretions recovered one and four days later exhibited a reduced susceptibility to micafungin and S639Y and S639T mutations in hotspot-1 of FKS1, respectively. Although the treatment was changed to voriconazole, the patient expired. Our case highlights a novel FKS1 mutation and the problems clinicians are facing to treat invasive C. auris infections due to inherent or developing resistance to multiple antifungal drugs and limited antifungal armamentarium.

Breakthrough Candidemia in Pediatric Patients With Cancer From a Brazilian Center.

We analyzed 19 cases of breakthrough candidemia from a referral pediatric cancer center in Brazil. All patients had neutropenia and were under antifungal prophylactic regimens, mostly micafungin (68%). Most of the patients were treated with amphotericin B formulations and 30-day mortality was 21%. Candida parapsilosis was the main etiologic agent (63%), and horizontal transmission was not evidenced by microsatellite analysis.

Clinical Characteristics and Outcomes of Breakthrough Candidemia in 71 Hematologic Malignancy Patients and/or Allogeneic Hematopoietic Stem Cell Transplant Recipients: A Single-center Retrospective Study From China, 2011-2018.

Antifungal prophylaxis may result in breakthrough infections in hematology patients with severe agranulocytosis, with few studies assessing risk factors and clinical outcomes of breakthrough candidemia. We described the distribution of Candida species, assessed risk factors for mortality in such patients, and determined differences in the incidence and mortality of breakthrough candidemia between patients who did or did not receive an allogeneic hematopoietic stem cell transplant. We collected clinical and microbiological data of patients with hematologic malignancies and breakthrough candidemia from a single center. Seven-day and 30-day follow-up outcomes were recorded; the incidence and mortality of breakthrough candidemia between patients who did or did not undergo an allogeneic transplant were compared. Kaplan-Meier survival estimates were used to generate survival curves, and predictors were identified using Cox regression analyses. Of 71 enrolled patients, 17 received allogeneic transplants. Incidences of breakthrough candidemia were 17 of 2924 (0.58%) and 54 of 12 015 (0.45%) in the transplant and nontransplant groups, respectively (P = .35). The most common isolate was Candida tropicalis, and antifungal agent combinations were the most common first-line treatment. Cumulative mortality rates of patients were 21.1% and 31.0% at days 7 and 30, respectively, and they significantly differed between both groups. Septic shock, central venous catheter removal, and granulocyte recovery were significantly associated with 7-day mortality; the latter 2 remained independent predictors of 30-day mortality. Breakthrough candidemia-related mortality was higher in the allogeneic transplant group, although the incidence was not significantly different between the groups. Prompt and adequate antifungal treatment with catheter removal may reduce mortality.

Candidaemia in haematological malignancy patients from a SEIFEM study: Epidemiological patterns according to antifungal prophylaxis.

Candidaemia is an important infectious complication for haematological malignancy patients. Antifungal prophylaxis reduces the incidence of candidaemia but may be associated with breakthrough candidaemia. To analyse the Candida species' distribution and relative antifungal susceptibility profiles of candidaemia episodes in relation to the use of antifungal prophylaxis among Italian SEIFEM haematology centres. This multicentre retrospective observational SEIFEM study included 133 single-species candidaemia episodes of haematological malignancy patients for whom antifungal susceptibility testing results of blood Candida isolates were available between 2011 and 2015. Each participating centre provided both clinical and microbiological data. Non-Candida albicans Candida (NCAC) species were the mostly isolated species (89, 66.9%), which accounted for Cparapsilosis (35, 26.3%), Cglabrata (16, 12.0%), Ckrusei (14, 10.5%), Ctropicalis (13, 9.8%) and uncommon species (11, 8.3%). Calbicans caused the remaining 44 (33.1%) episodes. Excluding 2 Calbicans isolates, 23 of 25 fluconazole-resistant isolates were NCAC species (14 Ckrusei, 6 Cglabrata, 2 Cparapsilosis and 1 Ctropicalis). Fifty-six (42.1%) of 133 patients developed breakthrough candidaemia. Systemic antifungal prophylaxis consisted of azoles, especially fluconazole and posaconazole, in 50 (89.3%) of 56 patients in whom a breakthrough candidaemia occurred. Interestingly, all these patients tended to develop a Ckrusei infection (10/56, P=.02) or a fluconazole-resistant isolate's infection (14/50, P=.04) compared to patients (4/77 and 10/77, respectively) who did not have a breakthrough candidaemia. Optimisation of prophylactic strategies is necessary to limit the occurrence of breakthrough candidaemia and, importantly, the emergence of fluconazole-resistant NCAC isolates' infections in haematological malignancy patients.

A Single-Center, Open-Label Trial of Isavuconazole Prophylaxis against Invasive Fungal Infection in Patients Undergoing Allogeneic Hematopoietic Cell Transplantation.

Isavuconazole is a broad-spectrum triazole approved for treatment of invasive fungal infections (IFIs). In this open-label, single-arm study, we evaluated isavuconazole for antifungal prophylaxis after allogeneic hematopoietic cell transplantation (HCT). Adult patients admitted for first HCT received micafungin 150 mg i.v. daily from admission through day +7 (D+7) post-transplantation (±2 days) followed by isavuconazole prophylaxis (i.v./p.o. 372 mg every 8 hours for 6 doses and then 372 mg daily) through maximum D+98 post-HCT. Patients were followed through D+182. The primary endpoint was prophylaxis failure, defined as discontinuation of prophylaxis for proven/probable IFI; systemic antifungal therapy for >14 days for suspected IFI; toxicity leading to discontinuation; or an adverse event. Between June 2017 and October 2018, 99 patients were enrolled in the study, of whom 95 were included in our analysis. The median patient age was 57 years (interquartile range [IQR], 50 to 66 years). Sixty-four (67%) patients received peripheral blood, 17(18%) received bone marrow, and 14 (15%) received a cord blood allograft for acute leukemia (55%), lymphoma (17%), myelodysplastic syndrome (16%), or another hematologic disease (14%). One-third (n=31; 33%) of patients underwent CD34+-selected HCT. Isavuconazole prophylaxis was given for a median of 90 days (IQR, 87 to 91 days). Ten patients (10.7%) met the primary endpoint. Candidemia occurred in 3 patients (3.1%), 1 of whom had grade III skin acute graft-versus-host disease (GVHD). Toxicity leading to discontinuation occurred in 7 patients (7.4%). The most common toxicity was liver function abnormalities in 5 patients, including grade 1 transaminitis in 2 patients and grade 3 hyperbilirubinemia in 3 patients. Four patients (4.2%) had early discontinuation of isavuconazole for reasons not meeting the primary study endpoint. Six patients died during the study period, including 3 during prophylaxis and 3 during follow-up. No deaths were attributed to isavuconazole. The majority (85%) of allogeneic HCT recipients completed isavuconazole prophylaxis according to protocol. The rate of breakthrough candidemia was 3.1%, and there were no invasive mold infections. Our data support the utility of isavuconazole for antifungal prophylaxis after HCT.

Susceptibility profiles and clinical efficacy of antifungals against candida bloodstream isolates from critically ill patients: Focus on intravenous itraconazole

In vitro and clinical data were analysed to evaluate the susceptibility profile of itraconazole in light of the new cut-off points. The in vitro activity of itraconazole was compared with that of eight comparators against 119 Candida bloodstream isolates from 2015 to 2018. Minimum inhibitory concentrations (MICs) were measured by the colorimetric MICRONAUT-S assay. The content of wells without any color change was sub-cultured to measure killing efficacy. No major differences were found against Candida albicans. Itraconazole, posaconazole and amphotericin B were the most active agents against Candida parapsilosis. Of the 32 isolates of C. parapsilosis that were resistant to fluconazole, 96.9%, 78.1% and 93.8% were susceptible to itraconazole, voriconazole and posaconazole, respectively. The ratio of the minimum fungicidal concentration (MFC) to the MIC of itraconazole was lower than for the other azoles against C. parapsilosis and C. glabrata. Itraconazole achieved greater inhibition over-time of the growth of C. parapsilosis than fluconazole. Seventy-three critically ill patients who were unresponsive to antibiotics received intravenous empirical treatment with itraconazole (n = 28) or comparators (n = 45). Case-control matching was conducted for severity, comorbidities, risk factors for candidemia, administered antibiotics and days of antifungal treatment. Breakthrough candidemia was found in 3.6% of patients treated with itraconazole and in 32.1% of patients treated with comparators (P: 0.020); breakthrough candidemia by C. parapsilosis was found in 3.6% and 28.6% of patients, respectively. Results indicate that itraconazole retains a valuable susceptibility profile against Candida isolates, particularly C. parapsilosis. This superior profile may explain the clinical efficacy in the occurrence of breakthrough candidemia and warrants further clinical investigation.

Nutritional risk index as a risk factor for breakthrough candidemia in allogeneic hematopoietic stem cell transplantation

Nutritional risk index as a risk factor for breakthrough candidemia in allogeneic hematopoietic stem cell transplantation

Breakthrough Candidemia In Children On Micafungin

We identified 8 pediatric patients on micafungin (MCFG; ≥3 doses) at our institution who had breakthrough candidemia (BC). The causative strains of the BC were Candida parapsilosis in 7 patients. The minimum inhibitory concentration of MCFG was ≤1 µg/mL (susceptible) in all 8 isolates. Immunocompromised patients may develop BC caused by MCFG-susceptible strains.

Risk factors for noncatheter-related Candida bloodstream infections in intensive care units: A multicenter case-control study.

Candida bloodstream infections are associated with high mortality among critically ill patients in intensive care units (ICUs). Studies that explore the risk factors for candidemia may support better patient care in intensive care units. We conducted a retrospective, multicenter case-control study to investigate the risk factors for noncatheter-related Candida bloodstream infections (CBSI) in adult ICUs. Participants selected controls randomly on a 1:1 basis among all noncase patients stayed during the same period in ICUs. Data on 139 cases and 140 controls were deemed eligible. Among the controls, 69 patients died. The stratified Fine-Gray model was used to estimate the subdistribution Hazard ratios. The subdistribution hazards and 95% confidence intervals for final covariates were as follows: prior exposure to antimycotic agents, 2.21 (1.56-3.14); prior exposure to N-acetylcysteine, 0.11 (0.03-0.34) and prior surgical intervention, 1.26 (0.76-2.11). Of the patients, those exposed to antimycotic drugs, 87.1% (54/62) had breakthrough candidemia. Serious renal, hepatic, or hematologic side effects were comparable between patients those exposed and not-exposed to systemic antimycotic drugs. Untargeted administration of antimycotic drugs did not improve survival among candidemic patients (not-exposed, 63.6% [49/77]; exposed % 66.1 [41/62]; P = .899). This study documented that exposure to an antifungal agent is associated with increased the risk of subsequent development of CBSIs among nonneutropenic adult patients admitted to the ICU. Only two centers regularly prescribed N-acetylcysteine. Due to the limited number of subjects, we interpreted the positive effect of N-acetylcysteine on the absolute risk of CBSIs with caution.

Usefulness of guideline recommendations for prognosis in patients with candidemia.

We aimed to analyze whether the lack of inclusion of specific recommendations for the management of candidemia is an independent risk factor for early and overall mortality. Multicenter study of adult patients with candidemia in 13 hospitals. We assessed the proportion of patients on whom nine specific ESCMID and IDSA guidelines recommendations had been applied, and analyzed its impact on mortality. 455 episodes of candidemia were documented. Patients who died within the first 48 hours were excluded. Sixty-two percent of patients received an appropriate antifungal treatment. Either echinocandin or amphotericin B therapy were administered in 43% of patients presenting septic shock and in 71% of those with neutropenia. Sixty-one percent of patients with breakthrough candidemia underwent a change in antifungal drug class. Venous catheters were removed in 79% of cases. Follow-up blood cultures were performed in 72% of cases. Ophthalmoscopy and echocardiogram were performed in 48% and 50% of patients, respectively. Length of treatment was appropriate in 78% of cases. Early (2-7 days) and overall (2-30 days) mortality were 8% and 27.7%, respectively. Inclusion of less than 50% of the specific recommendations was independently associated with a higher early (HR = 7.02, 95% CI: 2.97-16.57; P < .001) and overall mortality (HR = 3.55, 95% CI: 2.24-5.64; P < .001). In conclusion, ESCMID and IDSA guideline recommendations were not performed on a significant number of patients. Lack of inclusion of these recommendations proved to be an independent risk factor for early and overall mortality.

Epidemiology, practice patterns, and prognostic factors for candidemia; and characteristics of fourteen patients with breakthrough Candida bloodstream infections: a single tertiary hospital experience in Japan.

BackgroundCandidemia is associated with high mortality, and its prognostic factors need to be examined in more detail in order to improve its management. A case of breakthrough (BT) candidemia is defined as the development of candidemia during antifungal therapy. The microbiological characteristics of and appropriate clinical practices for BT candidemia remain unclear.ObjectivesThe primary objective of the present study was to identify the prognostic factors of candidemia, while the secondary objective was to elucidate the microbiological characteristics of patients with BT candidemia.Materials and methodsA total of 121 patients diagnosed with candidemia between January 2007 and December 2016 were enrolled in this study. The primary outcome was the 30-day mortality rate.ResultsThe overall incidence of candidemia was 0.056 cases/1000 inpatients. Among the 126 Candida isolated, C. albicans accounted for 36%, C. parapsilosis 26%, C. glabrata 12%, C. guilliermondii 14%, C. tropicalis 3%, C. pelliculos 1%, and other unidentifiable Candida species 8%. The 30-day mortality rate was 33%. In a multivariate Cox hazard analysis, C. albicans, the absence of antifungal therapy, age, lung disease, and mechanical ventilation were associated with a high mortality rate, whereas C. parapsilosis, the removal of a central venous catheter, and surgical wards were associated with a lower mortality rate. Fourteen patients had BT candidemia. A significant difference was observed in the proportion of C. guilliermondii and other Candida species exhibiting resistance to fluconazole and voriconazole, between patients with and without BT candidemia. Resistance to fluconazole was prominent in patients that developed candidemia with a history of azole antifungal agents.ConclusionThe prompt initiation of antifungal therapy and removal of central venous catheter were essential for better outcomes. A class switch to other antifungal agents needs to be considered in empirical antifungal therapy for BT candidemia with a history of exposure to azole antifungal agents.

Candida auris: A systematic review and meta-analysis of current updates on an emerging multidrug-resistant pathogen.

From 2009, Candida auris has emerged as a multidrug‐resistant ascomycete yeast pathogen with the capacity for easy transmission between patients and hospitals, as well as persistence on environmental surfaces. Its association with high mortalities, breakthrough and persistent candidaemia, inconsistencies in susceptibility testing results, misidentification by available commercial identification systems and treatment failure, complicates its management and detection. Within the last nine years, C. auris has been increasingly reported from far‐Eastern Asia, the Middle East, Africa, Europe, South and North America with substantial fatalities and misidentification. Herein, I provide a systematic and thorough review of this emerging pathogen. Meta‐analysis showed that at least 742 C. auris isolates have been reported in 16 countries, with most of these being from India (≥243), USA (≥232) and UK (≥103) (p‐value = .0355) within 2013–2017. Most isolates were from males (64.76%) (p‐value = .0329) and blood (67.48%) (p‐value < .0001), with substantial crude mortality (29.75%) (p‐value = .0488). Affected patients presented with other comorbidities: diabetes (≥52), sepsis (≥48), lung diseases (≥39), kidney diseases (≥32) etc. (p‐value < .0001). Resistance to fluconazole (44.29%), amphotericin B (15.46%), voriconazole (12.67%), caspofungin (3.48%) etc. were common (p‐value = .0059). Commonly used diagnostic tools included PCR (30.38%), Bruker MALDI‐TOF MS (14.00%), Vitek 2 YST ID (11.93%), AFLP (11.55%) and WGS (10.04%) (p‐value = .002). Multidrug resistance, high attributable mortality and persistence are associated with C. auris infections. Two novel drugs, SCY‐078 and VT‐1598, are currently in the pipeline. Contact precautions, strict infection control, periodic surveillance and cleaning with chlorine‐based detergents, efficient, faster and cheaper detection tools are necessary for prevention, containment and early diagnosis of C. auris infections.

Breakthrough candidemia after the introduction of broad spectrum antifungal agents: A 5-year retrospective study.

Candidemia is the main invasive fungal disease among hospitalized patients. Several breakthrough candidemia (BrC) cases have been reported, but few studies evaluate the epidemiology, risk factors, molecular characterization, antifungal susceptibility profile and outcome of those patients, especially in developing countries and including patients using broad spectrum antifungals. We conducted a retrospective study from 2011 to 2016, including patients aged 12 years or older with candidemia. Epidemiological characteristics and risk factors for candidemia were evaluated and compared with patients with BrC using univariate and multivariate analysis. Sequential Candida isolates from BrC were identified by internal transcribed spacer sequencing, genotyped with amplified fragment length polymorphism fingerprinting (AFLP), and tested for antifungal susceptibility. From 148 candidemia episodes, 27 breakthrough episodes (18%) were identified, with neutropenia and mucositis being independent risk factors for BrC. Candida non-albicans was more frequent in the BrC group (P < .001). AFLP showed high correlation with conventional methods of identification among breakthrough isolates and a high genetic similarity among isolates from the same patient was observed. C. albicans was the most susceptible species with low MIC values for all antifungal agents tested. In contrast, we found isolates of C. glabrata, C. parapsilosis and C. tropicalis resistant to triazoles and echinocandins. In conclusion, BrC occurred mainly in severely immunosuppressed patients, with neutropenia and mucositis. Mortality did not differ between the groups. Candida non-albicans species were more recovered from BrC, with C. albicans being the most susceptible to antifungals.

Candida parapsilosis Candidemia Resistance Patterns and Treatment Outcomes: An Opportunity for Antifungal Stewardship

Background Candida parapsilosis has emerged as an important fungal pathogen with mortality rates up to 30%. Recent studies show no difference in treatment outcomes for patients treated both empirically and definitively with either echinocandins or fluconazole. However, the impact of antifungal susceptibility testing and opportunities for antifungal stewardship are less clear in this patient population. The purpose of this study was to assess antifungal susceptibility rates, treatment patterns, and outcomes among patients with C. parapsilosis candidemia.Methods This was a single-center, retrospective cohort review of adult patients with a positive blood culture for C. parapsilosis hospitalized at Baylor St. Luke’s Medical Center, between 2006 and 2016. Patients with mixed or breakthrough candidemia were excluded as well as patients who expired within 3 days of candidemia onset.ResultsEighty patients with C. parapsilosis candidemia were identified of which 48 met inclusion criteria. Nine patients had infections caused by fluconazole non-susceptible isolates (19%). The most common empiric treatment choice was an echinocandin (33/48, 69%), followed by fluconazole (9/48, 19%), and combination therapy (6/48, 13%). Of the 39 patients with fluconazole susceptible isolates, only 17 were treated with fluconazole definitively (44%). Among patients who received empiric echinocandin vs. fluconazole therapy, there was no difference in 14-day mortality (9% vs. 11%, P = 1.00) or in-hospital mortality (12% vs. 11%, P = 1.00). Empiric combination therapy was the only independent risk factor for treatment failure (OR, 13.8; 95% CI, 1.4–138.3; P = 0.03).Conclusion Treatment outcomes for patients receiving echinocandins were similar for those receiving fluconazole. At our institution, the increased incidence of fluconazole non-susceptible isolates warrants the use of echinocandins empirically. Patients were more likely to remain on echinocandin therapy even when fluconazole susceptible isolates were identified. This study reinforces the guideline suggestion that neither echinocandins nor fluconazole treatment leads to superior outcomes, but also identifies a cohort of patients in need of antifungal stewardship.Disclosures N. Beyda, Astellas: Grant Investigator and Scientific Advisor, Research grant

Mosquitoes can harbour yeasts of clinical significance and contribute to their environmental dissemination.

There is still a lack of studies on fungal microbiota in mosquitoes, compared with the number available on bacterial microbiota. This study reports the identification of yeasts of clinical significance in laboratory mosquito species: Anopheles gambiae, Anopheles stephensi, Culex quinquefasciatus, Aedes albopictus and Aedes aegypti. Among the yeasts isolated, they focused on the opportunistic pathogen Candida parapsilosis, since there is a need to better understand breakthrough candidaemia with resistance to the usual antifungals, which requires careful consideration in the broad-spectrum therapy, as documented in many clinical reports. C. parapsilosis occurs widely and has been isolated from diverse sources, including insects, which may contribute to its dissemination. In this study, it was isolated from the gut of An. gambiae and its presence in developmental stages and organs of different mosquito species was studied. Our results indicated that there was a stable association between C. parapsilosis and reared mosquitoes during the entire life cycle, and in adult male and female gut and gonads. A wide occurrence of C. parapsilosis was also documented in several populations of wild mosquitoes. Based on these findings, it can be said that mosquitoes might participate in the spreading of this opportunistic pathogen, not only as a carrier.