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Invasive fungal infections continue to increase as at-risk populations expand. The high associated morbidity and mortality with fungal diseases mandate the continued investigation of novel antifungal agents and diagnostic strategies that include surrogate biomarkers. Biologic markers of disease are useful prognostic indicators during clinical care, and their use in place of traditional survival end points may allow for more rapid conduct of clinical trials requiring fewer participants, decreased trial expense, and limited need for long-term follow-up. A number of fungal biomarkers have been developed and extensively evaluated in prospective clinical trials and small series. We examine the evidence for these surrogate biomarkers in this review and provide recommendations for clinicians and regulatory authorities.

Coronavirus disease 2019 (COVID-19) can become complicated by secondary invasive fungal infections (IFIs), stemming primarily from severe lung damage and immunologic deficits associated with the virus or immunomodulatory therapy. Other risk factors include poorly controlled diabetes, structural lung disease and/or other comorbidities, and fungal colonization. Opportunistic IFI following severe respiratory viral illness has been increasingly recognized, most notably with severe influenza. There have been many reports of fungal infections associated with COVID-19, initially predominated by pulmonary aspergillosis, but with recent emergence of mucormycosis, candidiasis, and endemic mycoses. These infections can be challenging to diagnose and are associated with poor outcomes. The reported incidence of IFI has varied, often related to heterogeneity in patient populations, surveillance protocols, and definitions used for classification of fungal infections. Herein, we review IFI complicating COVID-19 and address knowledge gaps related to epidemiology, diagnosis, and management of COVID-19-associated fungal infections.

Background Diagnosis of invasive candidiasis (IC) is limited by insensitivity and slow turnaround of cultures. Our objectives were to define the performance of T2Candida, a nonculture test, under guidance of a diagnostic stewardship program, and evaluate impact on time to antifungal initiation and antifungal utilization. Methods This was a retrospective study of adult medical intensive care unit (MICU) patients with septic shock for whom T2Candida testing was performed from March 2017 to March 2020. Patients with positive T2Candida results during this period were compared to MICU patients who did not undergo T2Candida testing but had septic shock and blood cultures positive for Candida from January 2016 through March 2020. Results Overall, 155 T2Candida tests from 143 patients were included. Nine percent of T2Candida tests were positive compared to 4.5% of blood cultures. Sensitivity, specificity, positive predictive value, and negative predictive value of T2Candida for proven and probable IC were 78%, 95%, 50%, and 99%, respectively. Patients who tested positive for T2Candida (n = 14) were diagnosed earlier and initiated on antifungal therapy sooner than patients with IC (n = 14) diagnosed by blood culture alone (median, 5.6 vs 60 hours; P <.0001). Median antifungal days of therapy/1000 patient-days were 23.3/month preimplementation and 15/month postimplementation (P   =.007). Following a negative T2Candida result, empiric antifungals were either not administered in 58% or discontinued within 72 hours in 96% of patients. Conclusions Diagnostic stewardship guided T2Candida testing resulted in reduced time to IC diagnosis, faster initiation of antifungal therapy, and lower antifungal usage among MICU patients with septic shock. [ABSTRACT FROM AUTHOR]

Ocular candidiasis (OC) complicates approximately 10% of candidemia and carries potentially severe morbidity. There are conflicting recommendations about the need for routine funduscopic examinations of candidemic patients. Indirect funduscopy is accurate and safe in diagnosing OC, and positive findings change recommended treatment. However, conclusive evidence that treatment changes improve outcomes is lacking. Bringing perspectives as infectious diseases physicians and ophthalmologists, we review controversies about OC and endorse routine screening during candidemia. We acknowledge difficulties in obtaining inpatient ophthalmologic consults and recommend studies to evaluate digital fundus photography and teleophthalmology as an alternative to funduscopic examinations by ophthalmologists in asymptomatic patients. [ABSTRACT FROM AUTHOR]

Background In an investigation of hospital-acquired mucormycosis cases among transplant recipients, healthcare linens (HCLs) delivered to our center were found to be contaminated with Mucorales. We describe an investigation and remediation of Mucorales contamination at the laundry supplying our center. Methods We performed monthly RODAC cultures of HCLs upon hospital arrival, and conducted site inspections and surveillance cultures at the laundry facility. Remediation was designed and implemented by infection prevention and facility leadership teams. Results Prior to remediation, 20% of HCLs were culture-positive for Mucorales upon hospital arrival. Laundry facility layout and processes were consistent with industry standards. Significant step-ups in Mucorales and mold culture-positivity of HCLs were detected at the post-dryer step (0% to 12% [ P =.04] and 5% to 29% [ P =.01], respectively). Further increases to 17% and 40% culture-positivity, respectively, were noted during pre-transport holding. Site inspection revealed heavy Mucorales-positive lint accumulation in rooftop air intake and exhaust vents that cooled driers; intake and exhaust vents that were facing each other; rooftop and plant-wide lint accumulation, including in the pre-transport clean room; uncovered carts with freshly-laundered HCLs. Following environmental remediation, quality assurance measures and education directed toward these sources, Mucorales culture-positivity of newly-delivered HCLs was reduced to 0.3% (P =.0001); area of lint-contaminated rooftop decreased from 918 m2 to 0 m2 on satellite images. Conclusions Targeted laundry facility interventions guided by site inspections and step-wise culturing significantly reduced Mucorales-contaminated HCLs delivered to our hospital. Collaboration between infection prevention and laundry facility teams was crucial to successful remediation. [ABSTRACT FROM AUTHOR]

Background Multidrug-resistant Enterobacterales (MDR-E), including carbapenem-resistant and third-generation cephalosporin-resistant Enterobacterales (CRE, CefR-E), are major pathogens following solid organ transplantation (SOT). Methods We prospectively studied patients who underwent lung, liver, and small bowel transplant from February 2015 through March 2017. Weekly perirectal swabs (up to 100 days post-transplant) were cultured for MDR-E. Whole-genome sequencing (WGS) was performed on gastrointestinal (GI) tract–colonizing and disease-causing isolates. Results Twenty-five percent (40 of 162) of patients were MDR-E GI-colonized. Klebsiella pneumoniae was the most common CRE and CefR-E. Klebsiella pneumoniae carbapenemases and CTX-M were leading causes of CR and CefR, respectively. Thirty-five percent of GI colonizers developed MDR-E infection vs 2% of noncolonizers (P <.0001). The attack rate was higher among CRE colonizers than CefR-E colonizers (53% vs 21%, P =.049). GI colonization and high body mass index were independent risk factors for MDR-E infection (P ≤.004). Thirty-day mortality among infected patients was 6%. However, 44% of survivors developed recurrent infections; 43% of recurrences were late (285 days to 3.9 years after the initial infection). Long-term survival (median, 4.3 years post-transplant) did not differ significantly between MDR-E–infected and MDR-E–noninfected patients (71% vs 77%, P =.56). WGS phylogenetic analyses revealed that infections were caused by GI-colonizing strains and suggested unrecognized transmission of novel clonal group-258 sublineage CR- K. pneumoniae and horizontal transfer of resistance genes. Conclusions MDR-E GI colonization was common following SOT and predisposed patients to infections by colonizing strains. MDR-E infections were associated with low short- and long-term mortality, but recurrences were frequent and often occurred years after initial infections. Findings provide support for MDR-E surveillance in our SOT program. [ABSTRACT FROM AUTHOR]

Background: Clostridioides difficile infection (CDI) is a significant cause of morbidity and mortality in recipients of solid organ transplant (SOT) or hematopoietic stem cell transplant (HSCT). In retrospective single center analyses, severe disease and relapse are common. We undertook an international, prospective cohort study to estimate the response to physician determined antibiotic treatment for CDI in patients with SOT and HSCT. Methods: Adults with a first episode of CDI within the first 2 years of SOT or HSCT were enrolled. Demographics, comorbidities, and medication history were collected, and over 90 days of follow‐up clinical cure, recurrences, and complications were assessed. Logistic regression was used to study associations of baseline predictors of clinical cure and recurrence. Odds ratios (ORs) and 95% confidence intervals (CIs) are cited. Results: A total of 132 patients, 81 SOT and 51 HSCT (32 allogeneic), were enrolled with a median age of 56 years; 82 (62%) were males and 128 (97%) were hospitalized at enrollment. One hundred and six (80.3%) were diagnosed by DNA assay. CDI occurred at a median of 20 days post‐transplant (interquartile range, IQR: 6–133). One hundred and eight patients (81.8%) were on proton pump inhibitors; 126 patients (95.5%) received antibiotics within the 6 weeks before CDI. The most common initial CDI treatments prescribed, on or shortly before enrollment, were oral vancomycin alone (50%) and metronidazole alone (36%). Eighty‐three percent (95% CI: 76, 89) of patients had clinical cure; 18% (95% CI: 12, 27) of patients had recurrent CDI; global clinical cure occurred in 65.2%. Of the 11 patients who died, two (1.5% of total) were related to CDI. In multivariable logistic regression analyses, the type of initial treatment was associated with clinical cure (p =.009) and recurrence (p =.014). A history of cytomegalovirus (CMV) after transplant was associated with increased risk of recurrence (44% with versus 13% without CMV history; OR: 5.7, 95% CI: 1.5, 21.3; p =.01). Conclusions: Among adults who develop CDI after SOT or HSCT, despite their immunosuppressed state, the percentage with clinical cure was high and the percentage with recurrence was low. Clinical cure and recurrence varied by type of initial treatment, and CMV viremia/disease was associated with an increased risk of recurrence. [ABSTRACT FROM AUTHOR]

Background: Isavuconazole, administered as isavuconazonium sulfate (ISAVUSULF), is a broad‐spectrum triazole agent for the treatment of invasive fungal disease. In phase 3 studies, ISAVUSULF showed comparable efficacy to voriconazole and amphotericin B for the treatment of invasive aspergillosis (IA) and invasive mucormycosis (IM), respectively. Objectives: The objective of this study is to determine all‐cause mortality and safety outcomes among adults with IM and/or IA non‐fumigatus (nf) treated with ISAVUSULF or other antifungal therapies (AFT). Patients and methods: This multicentre, non‐interventional registry enrolled patients aged ≥18 years with IM or IA‐nf who received systemic AFT from January 2016 to November 2018. Patients received primary ISAVUSULF, non‐primary ISAVUSULF, or other AFT, as monotherapy or combination therapy. The primary end point was all‐cause mortality at Days 42 and 84; safety outcomes were adverse drug reactions (ADRs) to ISAVUSULF. Results: Of 204 patients enrolled, 74 received primary ISAVUSULF, 30 non‐primary ISAVUSULF, and 100 other AFT. All‐cause mortality through Day 42 was numerically lower in the non‐primary ISAVUSULF group than in the primary ISAVUSULF and other AFT groups, for patients with IM (20.0% vs. 33.3% and 41.3%, respectively) or IA‐nf (0% vs. 14.8% and 17.8%, respectively). All‐cause mortality tended to be lower with combination therapy than with monotherapy, except for patients with IM receiving primary ISAVUSULF. Of 111 patients receiving ISAVUSULF, 14 (12.6%) reported ADRs, of whom three (2.7%) developed serious ADRs. There were no drug‐related deaths. Conclusions: This study supports the effectiveness and tolerability of ISAVUSULF in clinical practice. Further research is required to confirm the value of ISAVUSULF combination therapy over monotherapy. [ABSTRACT FROM AUTHOR]

Background Carbapenem-resistant gram-negative bacteria (CRGNB) continue to present a global healthcare crisis. We aimed to identify emerging trends of CRGNB over nearly 2 decades and describe the impact of CRGNB on patient outcomes. Methods Patients from whom CRGNB were isolated between 2000 and 2017 were included in the study. Carbapenem resistance was defined by the most recent breakpoints and applied across the study period. Patient demographics, clinical characteristics, and outcomes were retrieved from the electronic health record. Results A total of 94 888 isolates from 64 422 patients were identified; 9882 (10%) isolates from 4038 patients were carbapenem-resistant. Pseudomonas aeruginosa was the most common CRGNB each year. The second most common CRGNB emerged in waves over time. Carbapenem daily defined doses increased in parallel with CRGNB rates (R 2 = 0.8131). The overall 30-day mortality rate was 19%, which decreased from 24% in 2000 to 17% in 2017 (P =.003; R 2 =.4330). Among patients with CRGNB bloodstream infections (n = 319), overall 30- and 90-day mortality rates were 27% and 38%, respectively. Charlson score (adjusted odds ratio [aOR], 1.11 per point), intensive care unit residence (aOR, 7.32), and severe liver disease (aOR, 4.8.4) were independent predictors of 30-day mortality, while receipt of transplantation was associated with lower rates of death (aOR, 0.39). Among patients admitted between 2011 and 2017 (n = 2230), 17% died during hospitalization, 32% were transferred to long-term care facilities, and 38% were discharged home. Conclusions CRGNB emerged in waves over time, causing high rates of mortality. Despite increasing rates of CRGNB, overall patient outcomes have improved, suggesting that recognition and novel therapeutics have made a major impact. [ABSTRACT FROM AUTHOR]

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies. [ABSTRACT FROM AUTHOR]

The article discusses ongoing research and collaboration as the basis for new guidelines that prevent vision loss and save lives for patients with candidemia. However, given the lack of specificity and a high prevalence of incidental findings noted during ocular screening, routine screening.

Carbapenem-resistant Klebsiella pneumoniae (CRKp) is a pathogen of significant concern to public health, as it has become increasingly associated with difficult-to-treat community-acquired and hospital-associated infections. Transmission of K. pneumoniae between patients through interactions with shared health care personnel (HCP) has been described as a source of infection in health care settings. However, it is not known whether specific lineages or isolates of K. pneumoniae are associated with increased transmission. Thus, we used whole-genome sequencing to analyze the genetic diversity of 166 carbapenem-resistant K. pneumoniae isolates from five U.S. hospitals in four states as part of a multicenter study examining risk factors for glove and gown contamination by carbapenem-resistant Enterobacterales (CRE). The CRKp isolates exhibited considerable genomic diversity with 58 multilocus sequence types (STs), including four newly designated STs. ST258 was the most prevalent ST, representing 31% (52/166) of the CRKp isolates, but was similarly prevalent among patients who had high, intermediate, and low CRKp transmission. Increased transmission was associated with clinical characteristics including a nasogastric (NG) tube or an endotracheal tube or tracheostomy (ETT/Trach). Overall, our findings provide important insight into the diversity of CRKp associated with transmission from patients to the gloves and gowns of HCP. These findings suggest that certain clinical characteristics and the presence of CRKp in the respiratory tract, rather than specific lineages or genetic content, are more often associated with increased transmission of CRKp from patients to HCP. IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae (CRKp) is a significant public health concern that has contributed to the spread of carbapenem resistance and has been linked to high morbidity and mortality. Transmission of K. pneumoniae among patients through interactions with shared health care personnel (HCP) has been described as a source of infection in health care settings; however, it remains unknown whether particular bacterial characteristics are associated with increased CRKp transmission. Using comparative genomics, we demonstrate that CRKp isolates associated with high or intermediate transmission exhibit considerable genomic diversity, and there were no K. pneumoniae lineages or genes that were universally predictive of increased transmission. Our findings suggest that certain clinical characteristics and the presence of CRKp, rather than specific lineages or genetic content of CRKp, are more often associated with increased transmission of CRKp from patients to HCP., Competing Interests: The authors declare no conflict of interest.