Wengenack, Nancy L.

Abstract Background Central nervous system (CNS) infections are significant causes of morbidity and mortality, especially when diagnosis is delayed. Traditional cerebrospinal fluid diagnostic methods for CNS infections have limited sensitivity. Metagenomic next-generation sequencing of cerebrospinal fluid (MSCSF) is a newer diagnostic tool capable of detecting a broad range of pathogens in a single assay. Methods This retrospective cohort study evaluated the first-year experience with MSCSF at Mayo Clinic. A total of 422 tests performed during calendar year 2024 on adult patients at Mayo Clinic facilities and those tested through Mayo Clinic Laboratories were analyzed, with a subcohort analysis of the 210 Mayo Clinic patients performed to define patient characteristics associated with positive results and clinical outcomes. Results The sensitivity of MSCSF for detecting neuroinfection in the subcohort was 64%, with 43% of confirmed neuroinfections diagnosed by MSCSF only. Subjects who were immunosuppressed (odds ratio [OR]: 3.5, P = .008) and those with a high pretest probability of CNS infection (OR: 20.1, P < .001) were more likely to have positive results. Also, those who tested positive were more likely to die within the ensuing 30 days than those who tested negative (OR: 5.2, P = .001). Conclusions MSCSF can be a valuable tool for diagnosing CNS infection but should not be used indiscriminately. It appears to be most beneficial when there is a high clinical suspicion of CNS infection and conventional diagnostics, and available molecular tests, yield negative results. Its integration into clinical practice should be guided by diagnostic stewardship to maximize cost-effectiveness and clinical utility.

Abstract Antifungal susceptibility testing among 1740 Candida parapsilosis blood isolates submitted to a United States reference laboratory (2015–2024) revealed a significant increase in fluconazole resistance from 8.2% to 20.3% (odds ratio [OR] per year, 1.13 [95% confidence interval {CI}, 1.06–1.20]; P < .001), with notable acceleration since 2021. Voriconazole resistance remained stable over this period. Micafungin resistance was rare, but intermediate susceptibility significantly increased, especially after 2021 (OR per year, 1.42 [95% CI, 1.25–1.63]; P < .001). These findings highlight important recent shifts in antifungal susceptibility among C parapsilosis isolates, emphasizing the need for ongoing surveillance and stewardship.

Abstract Background Invasive mold infections (IMI) lead to significant morbidity and mortality in patients with hematologic malignancies. We provide patients deemed at higher risk mold active prophylaxis but still observe breakthrough IMIs. The purpose of this study was to evaluate risk factors associated with these breakthrough infections. Methods We conducted a retrospective cohort study of adult hematologic patients at 3 tertiary care medical centers from November 19, 2011 - August 6, 2021. Only IMI cases defined as proven or probable per EORTC/MSG criteria were included. Patients with IMIs who received a minimum of 7 days of mold active prophylaxis were classified as breakthrough infection. We performed logistical regression analysis to identify risk factors associated with breakthrough IMI. Results Majority of cases were probable IMIs, with 16 (28.6%) and 25 (15.7%) proven cases amongst breakthrough and non-breakthrough IMIs, respectively. Many variables indicative of weakened host immune system, including neutropenia and hypogammaglobulinemia, were associated with breakthrough IMIs, albeit not statistically significant (Table 1). Multivariate analysis revealed history of AML (OR 4.20, 95% CI 2.03-8.88; p < 0.001) and receipt of HCT (OR 3.37, 95% CI 1.46-8.11; p = 0.003) to be independent host risk factors for breakthrough IMI. Of all the pathogens, Fusarium (OR 4.38, 95% CI 1.56-12.56; p = 0.005) and Mucorales (OR 5.59, 95% CI 2.11-15.61; p < 0.001) were significantly likely to lead to breakthrough IMIs. 26 (47.3%) of the breakthrough IMIs were on appropriately dosed prophylaxis at the time of infection, with only 9 (16.4%) found to be subtherapeutic (Table 2). Overall, mortality was slightly higher amongst the breakthrough IMIs (51.8% vs 45.9%) but not significantly different (Figure 1). Conclusion In our cohort of probable/proven IMIs, we did not observe any significant difference in mortality between patients with breakthrough IMIs and those not on mold active prophylaxis. Even with appropriate prophylactic dosing, breakthrough infections occurred, irrespective of agent. Our study demonstrates that host risk factors and the causative pathogen are clinically more pertinent than the prophylaxis regimen in breakthrough IMIs. Disclosures Paschalis Vergidis, MD, MSc, AbbVie: Advisor/Consultant|Ansun Biopharma: Grant/Research Support|Cidara Therapeutics: Grant/Research Support|F2G: Grant/Research Support|Scynexis: Advisor/Consultant|Scynexis: Grant/Research Support

Abstract Nocardiosis is an uncommon yet potentially devastating infection. Nocardia tends to affect individuals with chronic lung disease or immunocompromising conditions, 2 groups increasing in number. Incidence of nocardiosis is likely to increase as well, and it is vital to have an approach to this complex disease. Here, we aim to review the presentation, diagnosis, and management of Nocardia in the modern era. We will also highlight areas of uncertainty in our understanding of nocardiosis and propose a general approach to nocardiosis therapy, accounting for response and tolerance of Nocardia treatment.

ABSTRACT Medically important pathogenic fungi invade vertebrate tissue and are considered primary when part of their nature life cycle is associated with an animal host and are usually able to infect immunocompetent hosts. Opportunistic fungal pathogens complete their life cycle in environmental habitats or occur as commensals within or on the vertebrate body, but under certain conditions can thrive upon infecting humans. The extent of host damage in opportunistic infections largely depends on the portal and modality of entry as well as on the host’s immune and metabolic status. Diseases caused by primary pathogens and common opportunists, causing the top approximately 80% of fungal diseases [D. W. Denning, Lancet Infect Dis, 24:e428–e438, 2024, https://doi.org/10.1016/S1473-3099(23)00692-8 ], tend to follow a predictive pattern, while those by occasional opportunists are more variable. For this reason, it is recommended that diseases caused by primary pathogens and the common opportunists are named after the etiologic agent, for example, histoplasmosis and aspergillosis, while this should not be done for occasional opportunists that should be named as [causative fungus] [clinical syndrome], for example, Alternaria alternata cutaneous infection. The addition of a descriptor that identifies the location or clinical type of infection is required, as the general name alone may cover widely different clinical syndromes, for example, “rhinocerebral mucormycosis.” A list of major recommended human and animal disease entities (nomenclature) is provided in alignment with their causative agents. Fungal disease names may encompass several genera of etiologic agents, consequently being less susceptible to taxonomic changes of the causative species, for example, mucormycosis covers numerous mucormycetous molds.

ABSTRACT The prevalence of invasive candidiasis caused by non- albicans Candida species is increasing. Candida guilliermondii is an infrequent cause of candidemia but has been associated with decreased susceptibility to triazoles. Clinical data related to the infection with C. guilliermondii are sparse. Our study evaluated the antifungal susceptibility testing (AST) for C. guilliermondii isolates submitted to a reference laboratory over a 12-year period (2012–2023). AST patterns were examined using Clinical and Laboratory Standards Institute (CLSI) and European Committee on Antimicrobial Susceptibility Testing (EUCAST) epidemiological cutoff values (ECVs) and breakpoints. Where isolates were identified from patients treated at our institution, retrospective chart review was performed to describe patient risk factors, treatment approaches, and outcomes associated with C. guilliermondii fungemia. One hundred twelve blood culture isolates of C. guilliermondii were identified, and clinical data were available for 21 fungemic patients. A significant number of isolates (9.8–20.5%) were observed to be non-wild type for various triazoles. All isolates were susceptible to micafungin. A majority (76.2%) of cases of C. guilliermondii fungemia treated at our tertiary care center were hospital-acquired, and two-thirds of patients were immunocompromised at the time of diagnosis. Ten of the 21 patients died within 60 days of fungemia, although mortality was directly or partially attributed to C. guilliermondii fungemia in only four cases (19.0%). Echinocandins may be used for empiric therapy for C. guilliermondii until the results of AST are available. Further research is required to determine appropriate clinical breakpoints for triazoles. IMPORTANCE Our study addresses a significant knowledge gap in the clinical management of this non- Candida albicans species. Our retrospective review includes comprehensive AST data for 112 Candida guilliermondii isolates, which is the largest number of isolates reported from the United States to date. Susceptibility data are supplemented by clinical outcomes, where isolates were identified for patients treated at Mayo Clinic. Key findings from our study include the observation that a notable proportion of C. guilliermondii isolates exhibit non-wild-type profiles for various triazoles. Importantly, all isolates remained susceptible to echinocandins, suggesting their efficacy as first-line therapy in the absence of timely susceptibility results. Furthermore, our study highlights the high mortality associated with C. guilliermondii fungemia in immunocompromised patients, emphasizing the urgent need for optimized treatment strategies.

Abstract Background Nocardia tends to cause infection in immunocompromised patients or those with chronic pulmonary disease. Nocardia is known to recur, prompting the practice of secondary prophylaxis in patients perceived at high risk. However, few data exist regarding the epidemiology of recurrent nocardiosis or the effectiveness of secondary prophylaxis. Methods We performed a multicenter, retrospective cohort study of adults diagnosed with nocardiosis from November 2011 to April 2022, including patients who completed primary treatment and had at least 30 days of posttreatment follow-up. Propensity score matching was used to analyze the effect of secondary prophylaxis on Nocardia recurrence. Results Fifteen of 303 (5.0%) patients developed recurrent nocardiosis after primary treatment. Most recurrences were diagnosed either within 60 days (N = 6/15, 40.0%) or between 2 to 3 years (N = 4/15, 26.7%). Patients with primary disseminated infection tended to recur within 1 year, whereas later recurrences were often nondisseminated pulmonary infection. Seventy-eight (25.7%) patients were prescribed secondary prophylaxis, mostly trimethoprim-sulfamethoxazole (N = 67/78). After propensity-matching, secondary prophylaxis was not associated with reduced risk of recurrence (hazard ratio, 0.96; 95% confidence interval, .24–3.83), including in multiple subgroups. Eight (53.3%) patients with recurrent nocardiosis required hospitalization and no patients died from recurrent infection. Conclusions Recurrent nocardiosis tends to occur either within months because of the same Nocardia species or after several years with a new species. Although we did not find evidence for the effectiveness of secondary prophylaxis, the confidence intervals were wide. However, outcomes of recurrent nocardiosis are generally favorable and may not justify long-term antibiotic prophylaxis for this indication alone.