Emerging anti-spike monoclonal antibodies against SARS-CoV-2.

INTRODUCTION: Anti-spike monoclonal antibodies (mAbs) were previously authorized for the prevention and treatment of COVID-19 in immunocompromised patients. However, they are no longer authorized in the U.S. due to their lack of neutralizing activity against current circulating SARS-CoV-2 Omicron variants. AREAS COVERED: We summarized the available data on emergent mAbs in the early stages of clinical development. Consistent with data on prior mAbs, these novel agents have been well tolerated and demonstrated a good safety profile in early clinical trials. Additionally, many of them have been engineered to ensure prolonged half-life and combined with other mAbs to overcome the potential for emerging resistant mutants. Interestingly, one of these agents has been evaluated using an inhaled route of administration, and another agent is being evaluated for treatment of long COVID. EXPERT OPINION: Although the available data of novel mAbs holds promise, we anticipate that these agents will face similar challenges encountered by prior authorized agents, including the continued evolution of SARS-CoV-2 and emergence of new escape mutations. Strategies to potentially mitigate this are discussed. Based on prior successful experience, immunocompromised patients will certainly benefit from the utilization of mAbs for the prevention and treatment of COVID-19; thus, we need to design potential interventions to ensure the sustained activity of these agents.

Temporal trends in antifungal susceptibility of Cryptococcus neoformans isolates from a reference laboratory in the United States, 2011-2021.

BACKGROUND: There 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/METHODS: We 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. RESULTS: We 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. CONCLUSIONS: We 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.

Description of Cryptococcosis Following SARS-CoV-2 Infection: A Disease Survey Through the Mycosis Study Group Education and Research Consortium (MSG-19).

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.

"Let the Cat Out of the Heart": Clinical Characteristics of Patients Presenting With Blood Culture-Negative Endocarditis Due to Bartonella Species.

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.

The Role of Novel Antifungals in the Management of Candidiasis: A Clinical Perspective.

Mucosal and invasive candidiasis can be challenging to treat in the setting of drug intolerance, antifungal resistance, drug-drug interactions, or host immune status. Antifungals with novel mechanisms of action and distinct pharmacokinetic/pharmacodynamic properties have been developed in recent years. Rezafungin is an echinocandin with high-tissue penetration and an extended half-life that allows for once-weekly administration, making it a convenient treatment option for invasive candidiasis while obviating the need for central catheter placement. Ibrexafungerp is an oral glucan synthase inhibitor that is active against most echinocandin-resistant Candida species. At present, it is approved for the treatment of acute vulvovaginal candidiasis and is under investigation as an oral step-down therapy following initial treatment with an echinocandin for cases of invasive candidiasis. Oteseconazole is a long-acting tetrazole that exhibits a higher affinity for the fungal enzyme CYP51, resulting in a potentially lower risk of drug-drug interactions and side effects compared to other azoles. It is currently approved for the treatment of recurrent vulvovaginal candidiasis. Fosmanogepix has a novel mechanism of action and potent activity against several Candida strains resistant to other antifungals. Due to its considerable bioavailability and tissue penetration, it holds promise as a potential treatment option in patients with invasive candidiasis, including those with chorioretinitis or meningitis. Results from clinical trials and observational studies will further delineate the role of these agents in the management of candidiasis. As the usage of these novel antifungals becomes widespread, we expect to acquire a greater understanding of their efficacy and potential benefits.

Transplantation and immigration: Comparing infectious complications and outcomes between foreign-born and US-born kidney transplant recipients in Minnesota.

BACKGROUND: Foreign-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). METHODS: We 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. RESULTS: Of 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). CONCLUSION: Although 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.

Genotypic and predicted phenotypic analysis of SARS-COV-2 Omicron subvariants in immunocompromised patients with COVID-19 following tixagevimab-cilgavimab prophylaxis.

BACKGROUND: Tixagevimab-cilgavimab is used for pre-exposure prophylaxis of COVID-19 in immunocompromised patients, though in vitro data has shown reduced neutralizing activity against SARS-CoV-2 Omicron subvariants. METHODS: We performed genomic sequencing of SARS-CoV-2 isolated from patients diagnosed with COVID-19 following tixagevimab-cilgavimab. Resistance-associated substitutions were used to generate a predicted phenotypic susceptibility analysis to tixagevimab-cilgavimab and bebtelovimab. Clinical data collected from these patients included SARS-CoV-2 immunization status, COVID-19-directed therapies, and outcomes. RESULTS: SARS-CoV-2 genome sequencing was performed in 25 patients. SARS-CoV-2 Omicron BA.2 was the most common identified subvariant. All patients had viral isolates with spike codon substitutions associated with reduced susceptibility to tixagevimab-cilgavimab; their predicted phenotypic analysis showed a >2-fold reduced susceptibility to tixagevimab-cilgavimab. Two patients had viral isolates with spike codon substitutions (K444N and G446D) associated with highly reduced susceptibility to bebtelovimab, although all the viral isolates had <2-fold reduced susceptibility based on predicted phenotypic analysis. Sixteen patients received rescue therapy with bebtelovimab, but one patient with BA.2 subvariant harboring K444N mutation died of COVID-19-related complications. Five patients received other COVID-19 therapies and survived. Four had mild or asymptomatic COVID-19 with an uncomplicated course despite not receiving any additional therapy. DISCUSSION: Multiple SARS-CoV-2 Omicron spike codon substitutions that correlated with reduced susceptibility to tixagevimab-cilgavimab were identified in patients with COVID-19 after receiving this monoclonal antibody. Most patients had an uncomplicated course. The identification of spike codon substitutions conferring resistance to bebtelovimab highlights the importance of performing genomic surveillance to identify new resistant SARS-CoV-2 variants.

Real-world experience of tixagevimab-cilgavimab pre-exposure prophylaxis in orthotopic heart transplant recipients.

BACKGROUND: Pre-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) recipients METHODS: We 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. RESULTS: One 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. CONCLUSIONS: In 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.

Disseminated histoplasmosis and hemophagocytic lymphohistiocytosis in a patient receiving TNF-alpha inhibitor therapy.

Histoplasmosis commonly presents as an asymptomatic or self-limited infection in immunocompetent patients, but immunocompromised hosts may present with severe and disseminated disease. Herein, we present a 26-year-old male with history of ulcerative colitis receiving long-term TNF-alpha inhibitor therapy who presented with six months of diarrhea and recently fever and hematochezia. On admission, he was febrile and hypotensive, with initial workup revealing pancytopenia and imaging reporting pulmonary infiltrates, pancolitis, and enlarged mesenteric lymph nodes. Disseminated histoplasmosis was ultimately diagnosed after examination of the colonic biopsy. Bone marrow biopsy was also consistent with the diagnosis of histoplasmosis but also demonstrated hemophagocytic lymphohistiocytosis. The patient was ultimately treated with amphotericin B, intravenous immunoglobulin, etoposide, and corticosteroids.

Characterization of Early-Onset Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Immunocompromised Patients Who Received Tixagevimab-Cilgavimab Prophylaxis.

Tixagevimab-cilgavimab is authorized for preexposure prophylaxis against coronavirus disease 2019 (COVID-19) in immunocompromised hosts. Herein, we report the clinical characteristics of 8 patients who developed COVID-19 soon after receiving tixagevimab-cilgavimab. This study emphasizes the need to maintain additional measures to prevent COVID-19 during periods of high severe acute respiratory syndrome coronavirus 2 transmission.

Clostridium Tetani Bacteremia From a Suspected Cutaneous Source.

Bacteremia is a rare complication of Clostridium tetani infection. To our knowledge, there are only two case reports to date of C. tetani bacteremia, both hypothesized to be secondary to a gastrointestinal source. Herein, we report a case of an elderly man with genome sequence-proven C. tetani bacteremia from a possible cutaneous source without neuromuscular symptoms.

Double Trouble: A Unique Case of Hypercalcemia Caused by Two Underlying Etiologies.

Hypercalcemia has a variety of causes, with primary hyperparathyroidism and malignancies being the most frequently reported. We present the case of a patient presenting with chronic abdominal pain, constipation, and weight loss who was found to have hypercalcemia. The patient was initially diagnosed with colonic actinomycosis, but further investigations revealed an intra-abdominal diffuse large B-cell lymphoma (DLBCL). We suspect that the leading cause of hypercalcemia was the DLBCL, likely exacerbated by actinomycosis. Actinomycosis and DLBCL can have a similar presentation, so misdiagnosis or coexistence of both conditions should be suspected when a lack of response to one specific therapy is observed.

Aspergillus Osteomyelitis Secondary to Chronic Necrotizing Pulmonary Aspergillosis in a Patient With Rheumatoid Arthritis.

Aspergillus spp. are ubiquitous molds that cause a wide range of clinical syndromes depending on the immune status of the host. Herein, we present a case of a patient with rheumatoid arthritis on long-term immunosuppressive medications, with a persistent dry cough and left-sided chest pain for over a year, who presented with acute sternal drainage. Computed tomography of the chest showed chronic pulmonary abnormalities, parasternal fluid, and bone destruction of the distal sternum and left sixth rib. The patient underwent debridement; sternal biopsy tissue showed septate hyphae with acute-angled branching, and Aspergillus fumigatus grew in culture. We suspected that the patient developed chronic necrotizing pulmonary aspergillosis (CNPA) that traversed tissue planes and caused chest wall osteomyelitis. The patient received voriconazole and surgical debridement, with clinical and radiological improvement. This case demonstrates the importance of considering CNPA as a diagnosis in patients with moderate degrees of immunosuppression and chronic respiratory symptoms, and Aspergillus spp. as an etiology of osteomyelitis in such patients.

Hemophagocytic lymphohistiocytosis (HLH): Elusive diagnosis of disseminated Mycobacterium avium complex infection.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is a clinical syndrome of hyperinflammation leading to an uncontrolled and ineffective immune response, associated with high mortality. CASE REPORT: A 26-year-old woman with acute lymphoblastic leukemia, 8 months in remission, was found to have HLH. Without any improvement, stem cell transplantation was considered. Then, Mycobacterium avium complex (MAC) infection was identified as cause of her HLH. With appropriate therapy for infection, HLH improved and transplantation was averted. CONCLUSION: MAC should be included in the list of potential causes of HLH.