Vergidis, Paschalis

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 The aim of this study was to evaluate the frequency of unnecessary antibiotic prescribing for Tier 3 upper respiratory infection (URI) syndromes across the Mayo Clinic Enterprise before and after a multifaceted antimicrobial stewardship intervention, and to determine ongoing factors associated with antibiotic prescribing and repeat respiratory healthcare contact in the postintervention period. Methods This was a quasi-experimental, pre/post, retrospective cohort study from 1 January 2019 through 31 December 2022, with 12-month washout during implementation from 1 July 2020 through 30 June 2021. All outpatient encounters, adult and pediatric, from primary care, urgent care, and emergency medicine specialties with a Tier 3 URI diagnosis were included. The intervention was a multifaceted outpatient antibiotic stewardship bundle. The primary outcome was the rate of antibiotic prescribing in Tier 3 encounters. Secondary outcomes included 14-day repeat healthcare contact for respiratory indications and factors associated with persistent unnecessary prescribing. Results A total of 165 658 Tier 3 encounters, 96 125 in the preintervention and 69 533 in the postintervention period, were included. Following intervention, the prescribing rate for Tier 3 encounters decreased from 21.7% to 11.2% (P &lt; .001). Repeat 14-day respiratory healthcare contact in the no antibiotic group was lower postintervention (9.9.% vs 9.4%; P = .004). Multivariable models indicated that increasing patient age, Charlson comorbidity index, and primary diagnosis selected were the most important factors associated with persistent unnecessary antibiotic prescribing. Conclusions Outpatient antibiotic stewardship initiatives can reduce unnecessary antibiotic prescribing for Tier 3 URIs without increasing repeat respiratory healthcare contact. Advancing age and number of comorbidities remain risk factors for persistent unnecessary antibiotic prescribing.

ABSTRACT The rapid pace of name changes of medically important fungi is creating challenges for clinical laboratories and clinicians involved in patient care. We describe two sources of name change which have different drivers, at the species versus the genus level. Some suggestions are made here to reduce the number of name changes. We urge taxonomists to provide diagnostic markers of taxonomic novelties. Given the instability of phylogenetic trees due to variable taxon sampling, we advocate to maintain genera at the largest possible size. Reporting of identified species in complexes or series should where possible comprise both the name of the overarching species and that of the molecular sibling, often cryptic species. Because the use of different names for the same species will be unavoidable for many years to come, an open access online database of the names of all medically important fungi, with proper nomenclatural designation and synonymy, is essential. We further recommend that while taxonomic discovery continues, the adaptation of new name changes by clinical laboratories and clinicians be reviewed routinely by a standing committee for validation and stability over time, with reference to an open access database, wherein reasons for changes are listed in a transparent way.

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 Pancreatic fungal infection (PFI) in patients with necrotizing pancreatitis can lead to significant morbidity and mortality. The incidence of PFI has increased during the past decade. Our study aimed to provide contemporary observations on the clinical characteristics and outcomes of PFI in comparison to pancreatic bacterial infection and necrotizing pancreatitis without infection. We conducted a retrospective study of patients with necrotizing pancreatitis (acute necrotic collection or walled-off necrosis), who underwent pancreatic intervention (necrosectomy and/or drainage) and had tissue/fluid culture between 2005 and 2021. We excluded patients with pancreatic procedures prior to hospitalization. Multivariable logistic and Cox regression models were fitted for in-hospital and 1-year survival outcomes. A total of 225 patients with necrotizing pancreatitis were included. Pancreatic fluid and/or tissue was obtained from endoscopic necrosectomy and/or drainage (76.0%), CT-guided percutaneous aspiration (20.9%), or surgical necrosectomy (3.1%). Nearly half of the patients had PFI with or without concomitant bacterial infection (48.0%), while the remaining patients had either bacterial infection alone (31.1%) or no infection (20.9%). In multivariable analysis to assess the risk of PFI or bacterial infection alone, only previous pancreatitis was associated with an increased odds of PFI vs. no infection (OR 4.07, 95% CI 1.13-14.69, p = .032). Multivariable regression analyses revealed no significant differences in in-hospital outcomes or one-year survival between the 3 groups. Pancreatic fungal infection occurred in nearly half of necrotizing pancreatitis. Contrary to many of the previous reports, there was no significant difference in important clinical outcomes between the PFI group and each of the other two groups.

Objective: Our study aimed to assess the impact of pharmacogenomic panel testing in people with HIV (PWH). Design: Prospective, observational intervention assessment Methods: One hundred PWH were provided a comprehensive pharmacogenomic panel during routine care visits within the HIV specialty clinic of a large academic medical center. The panel determined the presence of specific genetic variants that could predict response or toxicity to commonly prescribed antiretroviral therapy (ART) and non-ART medications. An HIV specialty pharmacist reviewed the results with participants and the care team. The pharmacist (1) recommended clinically actionable interventions based on the participants’ current drug therapy, (2) assessed for genetic explanations for prior medication failures, adverse effects, or intolerances, and (3) advised on potential future clinically actionable care interventions based on individual genetic phenotypes. Results: Ninety-six participants (median age 53 years, 74% white, 84% men, 89% viral load <50 copies/ml) completed panel testing, yielding 682 clinically relevant pharmacogenomic results (133 major, 549 mild–moderate). Ninety participants (89 on ART) completed follow-up visits with 65 (72%) receiving clinical recommendations based on current medication profiles. Of the 105 clinical recommendations, 70% advised additional monitoring for efficacy or toxicity, and 10% advised alteration of drug therapy. Panel results offered explanation for prior ART inefficacy in one participant and ART intolerance in 29%. Genetic explanation for non-ART toxicity was seen in 21% of participants, with genetic contributors to inefficacy of non-ART therapy identified in 39% of participants. Conclusion: Preliminary data in a small cohort of PWH demonstrates benefit of routine pharmacogenomic panel testing.

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 The field of transplant infectious diseases is rapidly evolving, presenting a challenge for clinical practice and trainee education. Here we describe the construction of transplantid.net, a free online library, crowdsourced and continuously updated for the dual purpose of point-of-care evidence-based management and teaching.

AbstractBackgroundItraconazole is the recommended first‐line treatment for mild‐to‐moderate blastomycosis and consolidation treatment of moderate‐to‐severe disease. Itraconazole is metabolised into three metabolites, including an active metabolite hydroxy‐itraconazole. Literature provides little evidence indicating whether therapeutic drug monitoring targets should be based on itraconazole parent compound alone or a sum of itraconazole and hydroxy‐itraconazole serum concentrations.ObjectivesThis study aims to compare clinical outcomes and adverse drug events (ADEs) of combined itraconazole and hydroxy‐itraconazole concentrations versus itraconazole parent compound alone in patients with blastomycosis.Patients/MethodsThis study was a retrospective cohort review of patients ≥18 years with probable or proven Blastomyces infection who received itraconazole with at least one documented serum itraconazole concentration. The primary outcome was rate of partial or complete treatment response across three patient groups: (1) Itraconazole parent compound >1.0 mcg/ml (parent), (2) parent compound <1.0 mcg/ml, but a combined itraconazole and hydroxy‐itraconazole >1.0 mcg/ml (combined) and (3) failure to achieve a combined or parent concentration >1.0 mcg/ml (subtherapeutic) for >75% of the duration of itraconazole therapy.ResultsA total of 80 patients were included (parent = 32, combined = 36, subtherapeutic = 12). No statistically significant difference was observed for rate of partial or complete treatment response (97% parent vs 94% combined, p = .99). Significantly higher mortality due to blastomycosis was observed in patients in the subtherapeutic group (0% parent vs 3% combined vs 25% subtherapeutic, p = .01).ConclusionsThis study supports an itraconazole therapeutic target combining itraconazole and hydroxy‐itraconazole >1.0 mcg/ml for blastomycosis treatment.