Ordaya, Eloy E.

Abstract Background Despite advances in clinical microbiology, the diagnosis of invasive fungal infections remains challenging. Giant magnetoresistance (GMR) is a novel technology that enables the detection of trace amounts of cell-free DNA (cfDNA). We evaluated a high-multiplex molecular diagnostic assay coupled with GMR-enabled lab-on-a-chip technology that can detect 18 different fungal species. Methods Analytical performance was evaluated in spiked plasma samples. After amplification, cfDNA was digested. Residual single-stranded DNA was flowed over a GMR sensor that was surface-coated with probes specific to different fungal species. After hybridization, magnetic beads bound to the probe complexes produced a GMR signal that was detected by the sensors. Clinical performance was determined using residual serum samples collected before the initiation of antifungal treatment from 20 patients with infection. Results The limit of detection of the assay ranged from 5 to 50 copies per polymerase chain reaction (PCR) reaction. Nonspecific signals were not observed in the spiked samples. Fungal cfDNA was detected in 80% of patients with invasive candidiasis (3/4 with candidemia, 5/6 with invasive candidiasis without candidemia), all 3 cases of invasive pulmonary aspergillosis, and all 3 cases of disseminated histoplasmosis. cfDNA was not detected in 2 patients with cryptococcosis (both had negative blood cultures) and 2 patients with Pneumocystis pneumonia. Conclusions We developed a novel GMR-enabled multiplex PCR assay detecting fungal pathogens that have been prioritized for public health action. Clinical sensitivity was highest in cases of presumed angioinvasion and dissemination. This technology has the potential for use in the clinical microbiology laboratory setting.

AbstractBackgroundThere are no established clinical breakpoints for antifungal agents against Cryptococcus species; however, epidemiological cut‐off values can help distinguish wild‐type (WT) isolates without any acquired resistance from non‐WT strains, which may harbour resistance mechanisms.Patients/MethodsWe describe the trends of antifungal MICs and percentages of WT C. neoformans species complex (CNSC) isolates processed in our reference laboratory from November 2011 to June 2021. There were only nine isolates in 2011, thus, we included them in the year 2012 for data analysis. Clinical data is also described when available.ResultsWe identified 632 CNSC, the majority collected from blood (n = 301), cerebrospinal fluid (n = 230), and respiratory (n = 71) sources. The overall percentage of WT isolates for amphotericin B (AMB), 5‐flucytosine, and fluconazole was 77%, 98%, and 91%, respectively. We noticed a statistically significant change in the percentage of AMB WT isolates over the years, with 98% of isolates being WT in 2012 compared to 79% in 2021 (p < .01). A similar change was not observed for other antifungal agents. Clinical data was available for 36 patients, primarily non‐HIV immunocompromised patients with disseminated cryptococcosis. There were no statistically significant differences in the clinical characteristics and outcomes between patients with WT (58.3%) versus non‐WT (41.7%) isolates, but we noticed higher mortality in patients infected with an AMB non‐WT CNSC isolate.ConclusionsWe observed an increase in the percentage of AMB non‐WT CNSC isolates in the past decade. The clinical implications of this finding warrant further evaluation in larger studies.

Abstract Background Histoplasmosis is an endemic mycosis associated with a wide range of clinical presentations. Cardiovascular histoplasmosis (CVH) was rarely seen at our center before 2007 but has increased in frequency over the last 15 years. Herein, we describe the clinical characteristics of our recent CVH cases. Methods We identified all adults diagnosed with CVH at Mayo Clinic in Rochester, MN, between May 2007 and February 2023. Results Ten cases of CVH were identified, all of whom resided in the Midwest (Table). The majority were male, with a median age of 72 years. Five patients had prosthetic valves, two endovascular grafts, one a prosthetic valve and aortic graft, and one was a heart-kidney transplant recipient. Patients most frequently presented with prolonged night sweats, fever, and dyspnea. Cytopenias, pulmonary nodules, and splenomegaly were common laboratory and imaging findings. The diagnosis was suspected based on a positive Histoplasma antibody (100%) and/or antigen (80%) testing and confirmed by positive culture (blood 60%, explanted valve/graft 20%) and/or histopathology (60%). Identified clinical syndromes included: prosthetic valve endocarditis (PVE; 50%), native valve endocarditis (10%), mycotic aortic aneurysm (10%), aortic graft infection (10%), PVE and aortic graft infection (10%), and myocarditis (10%). Most patients received combined medical and surgical treatment (50%). Three patients (30%) received medical treatment only, including one patient with myocarditis. Two patients (20%) presented progressive clinical decline and were not considered antifungal treatment or surgical candidates. The overall mortality within one year of diagnosis was 50%. Patients with endocarditis and/or graft infection who received only medical treatment had higher mortality than those who received combined medical and surgical treatment (100% vs 20%, respectively).Table.Clinical characteristics of patients presenting with cardiovascular histoplasmosis (N=10) *Patient frequently had more than one comorbidity, symptom, laboratory or imaging finding, positive histoplasmosis testing, or affected valve. **Two patients did not receive treatment given their critical status, and were transitioned to comfort care. Conclusion CVH is being seen more frequently at our institution. One-year mortality of CVH was high, but combined medical and surgical management conferred better outcomes than medical treatment alone. We suggest a high index of suspicion of CVH in patients residing in Histoplasma endemic regions with a history of prior cardiac or vascular surgery presenting with prolonged fevers and/or new cardiomyopathy. Disclosures All Authors: No reported disclosures

Abstract Background Invasive fungal infections have been described throughout the COVID-19 pandemic. Cryptococcal disease after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been reported in several isolated case reports and 1 larger case series. We sought to describe cryptococcal infections following SARS-CoV-2 through establishing a database to investigate underlying risk factors, disease manifestations, and outcomes. Methods We created a crowdsourced call for cases solicited through the Mycoses Study Group Education and Research Consortium, the Centers for Disease Control and Prevention Emerging Infectious Diseases Network, and infectious diseases Twitter groups. Data were collected in a web-based and secure REDCap survey without personal identifiers. Results Sixty-nine cases were identified and submitted by 29 separate institutional sites. Cryptococcosis was diagnosed a median of 22 days (interquartile range, 9–42 days) after SARS-CoV-2 infection. Mortality among those with available follow-up was 72% (26/36) for the immunocompetent group and 48% (15/31) for the immunocompromised group (likelihood ratio, 4.01; P = .045). We observed a correlation between disease manifestation (central nervous system infection, proven/probable disseminated disease, and respiratory) and mortality (P = .002). Conclusions The mortality rate of 59% for patients with cryptococcosis following SARS-CoV-2 is higher than that of modern Cryptococcus cohorts. There was an association between immunocompromised status and cryptococcal disease manifestations as well as mortality. Moreover, our series emphasizes the need for clinical and laboratory assessment of opportunistic infections beyond 30 days when concerning symptoms develop.

Abstract Patients with blood culture-negative endocarditis due to Bartonella infection frequently presented with fever, cytopenias, kidney failure, and positive PR3-ANCA. Bartonella IgG titers were variable. Patients commonly underwent surgery with overall low mortality.

AbstractBackgroundForeign‐born kidney transplant recipients (FBKTRs) are at increased risk for reactivation of latent infections that may impact outcomes. We aimed to compare the etiology of infections and outcomes between FBKTR and United States KTRs (USKTR).MethodsWe performed a retrospective study of patients who underwent kidney transplantation between January 1, 2014 and December 31, 2018 at two transplant centers in Minnesota. Frequency and etiology of infections as well as outcomes (graft function, rejection, and patient survival) at 1‐year post‐transplant between FBKTR and USKTR were compared.ResultsOf the 573 transplant recipients, 124 (21.6%) were foreign‐born and 449 (78.4%) US‐born. At least one infection occurred in 411 (71.7%) patients (38.2% bacterial, 55% viral, 9.4% fungal). Viral infections were more frequent in FBKTR, particularly BK viremia (38.7% vs. 21.2%, p < .001). No statistical differences were found for bacterial or fungal infections; no parasitic infections were identified in either group. No geographically‐restricted infections were noted aside from a single case of Madura foot in a FBKTR. Rejection episodes were more common in USKTR (p = .037), but stable/improving graft function (p = .976) and mortality (p = .451) at 1‐year posttransplantation were similar in both groups. After adjusting for covariates, previous transplantation was associated with a higher number of infections (IRR 1.35, 95% confidence intervals 1.05–1.73, p = .020).ConclusionAlthough viral infections were more frequent in FBKTR, overall frequency and etiology of most infections and outcomes were similar between FBKTR and USKTR suggesting that comprehensive transplant care is providing timely prevention, diagnosis, and treatment of latent infections in FBKTR. image

AbstractBackgroundPre‐exposure prophylaxis with tixagevimab‐cilgavimab (tix‐cil) may be associated with cardiovascular adverse events. Also, in vitro studies have reported a reduced activity of tix‐cil against emerging SARS‐CoV‐2 Omicron subvariants. Our study aimed to report the real‐world outcomes of tix‐cil prophylaxis in orthotopic heart transplant (OHT) recipientsMethodsWe retrospectively studied all OHT recipients who received one dose of tix‐cil (150–150 mg or 300–300 mg) at Mayo Clinic in Arizona, Florida, and Minnesota, between February 5, 2022 and September 8, 2022. We collected data on cardiovascular adverse events and breakthrough COVID‐19 following tix‐cil administration.ResultsOne hundred sixty‐three OHT recipients were included. The majority were male (65.6%), and the median age was 61 years (IQR 48, 69). During the median follow‐up of 164 days (IQR 123, 190), one patient presented an episode of asymptomatic hypertensive urgency that was managed with outpatient antihypertensive treatment optimization. Twenty‐four patients (14.7%) experienced breakthrough COVID‐19 at the median of 63.5 days (IQR 28.3, 101.3) after tix‐cil administration. The majority (70.8%) completed the primary vaccine series and received at least one booster dose (70.8%). Only one patient with breakthrough COVID‐19 required hospitalization. All patients survived.ConclusionsIn this cohort of OHT recipients, no patients developed severe cardiovascular events related to tix‐cil. The high incidence of breakthrough COVID‐19 could be due to the reduced activity of tix‐cil against current circulating SARS‐CoV‐2 Omicron variants. These results emphasize the need for a multimodal prevention strategy against SARS‐CoV‐2 in these high‐risk patients. image

Abstract Background There are not established clinical breakpoints (CBP) for antifungals against Cryptococcus species; However, the analysis of their MICs using epidemiological cut-off values (ECVs) can help to distinguish wild-type (WT) isolates from non-WT strains that may harbor intrinsic or acquired resistance to antifungals. Herein, we analyze the MIC distribution of antifungals against Cryptococcus spp. isolated over the last decade at our reference laboratory. Methods We conducted a retrospective evaluation of antifungals MICs for Cryptococcus neoformans and Cryptococcus gattii complex isolates from various sources that were processed at the Mayo Clinic Laboratory from November 18, 2011 to June 7, 2021. Antifungal susceptibility testing was performed by the Clinical & Laboratory Standards Institute (CLSI) standards (CLSI M59-ED3:2020). We used recommended ECVs to define if the isolates were WT or non-WT, and described the change in the percentage of WT isolates over time. Results During the study period, C. neoformans was isolated from 632 samples collected from 533 patients. Sample sources included cultures from blood (n=301), cerebrospinal fluid (n=230), respiratory (n=71), and other sources (n=30). The overall percentage of WT isolates for amphotericin B (AMB), 5-flucytosine, and fluconazole were 77%, 98% and 91% respectively with no significant difference based on various sources (Table). We noticed an overall increase in MICs for AMB, with 100% WT isolates in 2011 compared to 79% in 2021. No such increase was seen for fluconazole or 5-Flucytosine (Figure). Irrespective of the source or the year of isolation, WT strains for itraconazole, voriconazole, and posaconazole were consistently &gt; 93%. C. gattii was isolated from 16 samples, and 94% were WT strains for AMB and 100% for the other antifungals. CLSI, Clinical and Laboratory Standard Institute; CSF, cerebrospinal fluid; ECVs, epidemiologic cut-off values. AMB, amphotericin B; FLU, fluconazole; 5FC, 5-flucytosine. Conclusion In the last decade, we have observed an overall increase in MICs of AMB for C. neoformans. The number of WT strains for other antifungals was high and not significantly changed during the study frame. Further studies are needed to identify the clinical implications of these findings. Disclosures Paschalis Vergidis, MD, AbbVie: DSMB|Cidara: Grant/Research Support|Scynexis: Grant/Research Support.