Saling, Christopher

ABSTRACT Biofilm‐associated staphylococcal infections remain exceptionally difficult to treat due to the presence of resilient staphylococcal biofilms and the limited effectiveness of currently available antibiotics. To combat persistent infections, providers are often forced to use prolonged courses of combination antimicrobial therapies that have significant toxicities with limited effectiveness, leading to increased hospital stays, substantial health care costs and a rise in patient morbidity and mortality. Staphylococcus aureus is a dominant cause of recalcitrant biofilms, for which novel non‐antibiotic therapeutics are critically needed. Lysins, a class of protein‐based antimicrobials, rapidly kill staphylococci, exhibit potent anti‐biofilm activity, have a low propensity of resistance development and synergy with antibiotics. To address this unmet need, we evaluate an extracellular vesicle (EV)‐based delivery platform for the engineered anti‐staphylococcal lysin LYSG101, designed to improve stability and localization at sites of infection. Initial proof‐of‐concept work is provided here, demonstrating that human serum‐derived EVs can be loaded with LYSG101 to exert a potent in vitro antimicrobial effect against both planktonic and biofilm forms of S. aureus . EV‐mediated delivery achieved activity equivalent to free lysin, with additional translational advantages including stability and the potential for sustained intra‐articular retention. This work supports further development of the EV‐mediated lysin delivery as a broadly applicable antimicrobial platform, with potential future applications in biofilm‐associated infections, including prosthetic joint infection (PJI).

Abstract Coccidioidomycosis is an invasive fungal infection that can disseminate and cause severe disease. Fosmanogepix (“gepix”), a first-in-class antifungal available via expanded access (NCT06433128), was successful in 8/11 patients (meningitis, 6/8 [75%]; nonmeningeal dissemination, 2/3 [66%]) and was well tolerated for a median treatment duration of 208 days.

Abstract Objective: To define the incidence of donor-derived infection (DDI) in recipients of solid organ transplant (SOT) from donors with positive blood cultures and to assess the impact of shorter versus longer duration of targeted preemptive antibiotic therapy (PAT). Design: Retrospective, single-center, cohort study. Setting: Mayo Clinic Arizona. Patients: Recipients transplanted between 1/1/2019 and 7/1/2024 who received an organ from a donor with positive blood cultures. Methods: The primary outcome was incidence of DDI. Secondary outcomes included duration of PAT and incidence of donor blood culture contamination. Results: Among 199 SOT recipients from 167 unique donors with positive blood cultures, two recipients developed confirmed DDI within 30 days of SOT. Both cases were gram negative bacillary bacteremia not treated in donors and occurred immediately posttransplant prior to adequate recipient PAT. Six-month graft survival and recipient survival were 96.5% and 97.5% respectively. 139 recipients (69.8%) received PAT for a median duration of 7 days. There was no difference in rate of infections between recipients provided with ≤7 days versus 8–14 days of PAT for donor blood cultures; however, recipients who received 8–14 days had more Clostridioides difficile infections (CDIs) within 60 days of SOT (7.7% vs 1.5% ≤ 7 days, P = .040) and were more often discharged on intravenous antibiotics (32.3% vs 11.3%, P < .001). Conclusion: We observed a low rate of DDI following receipt of organs from donors with positive blood cultures. DDI occurred in cases without adequate donor/recipient treatment. Longer durations of targeted PAT resulted in more CDI and intravenous antibiotics on discharge.

AbstractBackgroundDevelopment of brain abscess following solid organ transplantation is associated with significant morbidity and mortality. We undertook a descriptive study to evaluate the etiology, clinical manifestations, diagnosis, management, and outcomes of brain abscess in solid organ transplant (SOT) recipients at three major transplant centers in the United States.MethodsThis is a retrospective study of adults with brain abscess following SOT between January 2000 and June 2021 at Mayo Clinic sites in Arizona, Minnesota, and Florida.ResultsA total of 39 patients were diagnosed with a brain abscess following SOT. The most common pathogens were Nocardia sp. (24 cases, 61.5% [Nocardia farcinica, 37.5%]), followed by fungi (12 cases, 30.7% [Aspergillus sp., 83.3%]). The majority were kidney transplant recipients (59%). Median time to brain abscess diagnosis was 1.3 years (range, 29 days–12 years) after SOT; 10 of 12 patients (83%) with fungal brain abscess were diagnosed within 1 year after SOT. Twelve patients underwent brain biopsy for diagnosis (25% Nocardia vs. 50% fungal), eight (20.5%) underwent surgical resection of the abscess, and 31 (79.5%) received antimicrobial therapy alone. Median time to brain abscess resolution was 166 days for Nocardia and 356 days for fungal pathogens. Eleven of 39 patients (28.2%) died as a result of their brain abscess, including four of 24 patients (16%) with Nocardia and six of 10 patients (60%) with Aspergillus brain abscess. All‐cause mortality was 43.6%.ConclusionBrain abscess remains an uncommon infectious complication following SOT. Nocardia and fungi accounted for 92% of pathogens in our cohort. Fungal brain abscess portends a poor prognosis. image

Abstract Deep sternal wound infection is a rare complication of cardiac surgery that is typically caused by skin resident flora, such as species of Staphylococcus and Streptococcus. Infections caused by fungi are less common and are generally caused by Candida species. Regardless of etiology, these infections are associated with significant morbidity and mortality. We present a case of postoperative mediastinitis that occurred following a 5-vessel coronary artery bypass graft and was caused by a filamentous fungus of the Rhizopus genus. The patient was treated with serial debridement, liposomal amphotericin B, and isavuconazonium and was discharged from the hospital in stable condition. Fungal mediastinitis is a rare entity, and clinicians must maintain a high level of suspicion to make the diagnosis. A fungal cause of postoperative mediastinitis should be considered in patients with negative bacterial cultures, uncontrolled diabetes, or current immunosuppression or those who present weeks after surgery with a subacute onset of symptoms.

Abstract Background Despite the endemic nature of Coccidioides sp. to the American Southwest, the incidence Coccidioides sp. infective endocarditis (CIE) is rare. Following successful treatment of a patient with CIE at our institution, we reviewed the literature to identify trends in disease presentation, patient characteristics, and outcomes. Methods We reviewed all cases of CIE reported since 1938. Details including patient demographics, underlying immunodeficiency, time to diagnosis, treatment, and outcome were collected for analysis of diagnostic challenges and survival. Results Including ours, we identified 11 published cases of CIE. The majority (7) occurred in men. 5 patients were of either African American or Hispanic descent. Of the 10 patients with reported ages, the median age was 35.5 years (range 3 weeks – 61 years). 5 patients had a previous diagnosis of coccidioidomycosis and only 3 had an immunocompromising condition. These comprised pregnancy, heart transplant, and juvenile inflammatory arthritis. Three cases had multi-valvular involvement, but the majority affected the mitral (5) and the aortic (4) valves. Only 2 of the 11 cases involved a prosthetic valve. Of the 8 cases with reported blood cultures, only 2 were positive. Ten of the 11 cases had extra-cardiac disease. Complement fixation (CF) titers were heterogenous with a median of 1:32 and a range of 1:1 to 1:2048. There was no obvious correlation between a patient’s CF titer and their survival. Average time to diagnosis was 3.5 months (range 2.5 – 36 months). Diagnosis was made post-mortem in 4 of the 11 cases. 6 patients (54%) did not survive. Notably, 2 of the fatal cases preceded the discovery of amphotericin B (1969) and 4 occurred prior to the discovery of fluconazole (1990). Of the five patients that survived, four required surgical intervention in addition to azole therapy. Conclusion CIE is a diagnostic and therapeutic challenge. The diagnosis itself is rare, culture incubation times are long, and the symptoms are often non-specific thus delaying definitive therapy. The introduction of azole therapy appears to have had significant impact on rates of survival. Despite this, successful management of CIE still requires concurrent surgical intervention with aggressive, indefinite anti-fungal therapy. Disclosures All Authors: No reported disclosures

Abstract Background More accounts of opportunistic infection in COVID-19 patients are emerging. At our institution, we identified 2 COVID-19 patients with Pneumocystis jiroveci pneumonia (PJP) opportunistic infection. This prompted a review of the literature to identify trends in patient characteristics, risk factors, and outcomes in this population. Methods A literature review was conducted using PubMed that identified 13 other patients with both COVID-19 and PJP infection. Age, gender, human immunodeficiency virus (HIV) status, other immunocompromised states, time between COVID-19 and PJP diagnosis, and clinical outcomes were captured for analysis. Results Eleven patients were male. The average age was 56 years. All but 2 patients were immunocompromised. At time of PJP diagnosis, seven patients had newly diagnosed HIV and one had known, well-controlled HIV. One patient had rheumatoid arthritis receiving leflunomide, 1 had ulcerative colitis receiving budesonide and sulfasalazine, 2 patients had multiple myeloma whereby both were on lenalidomide, 1 patient was a renal transplant recipient immunosuppressed on tacrolimus, mycophenolate, and methylprednisolone, and 1 patient had chronic lymphocytic leukemia getting fludarabine, cyclophosphamide, and rituximab. Nine patients had positive COVID-19 and PJP tests performed within 7 days of one another. One patient tested positive for PJP 54 days into admission for COVID-19. This patient received high dose steroids and tocilizumab for initial COVID-19 infection. Three patients were re-hospitalized with PJP after a recent admission for COVID-19 pneumonia, with a mean time to readmission of 25 days. One of these 3 patients had no treatment for COVID-19, while 2 received steroids. Five of the total 15 patients (33%) died. Conclusion COVID-19 treatments with high dose steroids and tocilizumab can make patients vulnerable for opportunistic infection with PJP. Furthermore, COVID-19 is known to cause lymphopenia which may further increase this risk. A diagnosis of concomitant PJP can be especially challenging due to nearly identical radiographical findings. Serum beta-D glucan and HIV testing can be especially helpful in this situation, and there should be a low threshold for performing bronchoalveolar lavage. Disclosures All Authors: No reported disclosures

Abstract Background Management of disseminated Nocardia (NC) infection in transplant recipients requires prolonged antimicrobial therapy. Treatment can be particularly challenging if NC is resistant to standard agents. Drug toxicities can further limit options. We present a series of transplant patients with multi-drug resistant, disseminated NC infection complicated by serious adverse reactions to sequential antimicrobials. Methods This is a prospective review monitoring response to treatment of disseminated NC as well as adverse events to therapies. Results The first case is a 66-year old heart transplant patient who presented with fever and cough. Investigations revealed N. otitidiscaviarum lung lesion and multiple brain abscesses. Trimethoprim-sulfamethoxazole (TMP-SMX) and linezolid were started empirically. NC was fully susceptible to linezolid only, and intermediate to quinolones and tobramycin. Linezolid was switched to ciprofloxacin due to ongoing cytopenia, and dose of TMP-SMX was reduced due to renal insufficiency. Repeat brain MRI showed enlarging abscesses; regimen was changed to linezolid and moxifloxacin. Severe peripheral neuropathy led to linezolid discontinuation and initiation of high-dose doxycycline plus moxifloxacin. One year into therapy, he presented with a large aortic dissection. His long-term quinolone therapy was felt to be contributory. He underwent aortic stent placement and remains on doxycycline monotherapy. The second case is a 74-year old female renal transplant patient who presented with fevers. A perinephric abscess was found which grew N. farcinica resistant to floroquinolones and clarithromycin, and intermediate to doxycycline. Further imaging also revealed pulmonary and brain involvement. TMP-SMX was started but soon switched to linezolid due to acute kidney injury. One month later she presented with severe thrombocytopenia and subdural hematoma thought to be secondary to linezolid. She died despite surgery. Conclusion This series illustrates challenges encountered in the treatment of disseminated NC infection in transplant recipients. Multidrug resistant NC coupled with serious toxicities of therapies often severely limits treatment options. Counseling patients and closely monitoring for adverse events is essential. Disclosures All Authors: No reported disclosures

Coccidioides is an endemic fungus of the Southwest United States that causes the disease coccidioidomycosis. Immunocompromised persons are at increased risk for severe infection and dissemination. One such population is allogeneic bone marrow transplant (allo-HCT) recipients, but accounts of coccidioidal infection in these patients have rarely been documented. We present two cases of Coccidioides in allo-HCT recipients with good outcomes: one patient who developed pulmonary coccidioidomycosis in the late post-engraftment phase and another with known controlled disseminated infection at the time of transplant. A review of the literature identified 19 allo-HCT recipients with coccidioidomycosis. Due to the limited published literature, no guidelines have yet been established regarding optimal prophylaxis and treatment of Coccidioides infection in allo-HCT recipients. Candidates for transplantation should undergo a rigorous pre-transplant assessment to identify evidence of prior or active coccidioidomycosis. In our experience, patients who visit or live in Coccidioides-endemic areas should receive primary prophylaxis for at least the first 100 days post-transplant, and duration should be extended as long as the patient remains on immunosuppression. Those with prior infection should receive secondary prophylaxis while immunosuppressed. Patients with active infection should have treatment and stabilization of infection and continue anti-fungal treatment through immunosuppression.

Herein, we report a case of a 68-year-old woman receiving ibrutinib for chronic lymphocytic leukaemia, who presented with septic shock and a progressive necrotic lesion on her nose. Surgical pathology of the nasal lesion revealed evidence of tissue necrosis, and both tissue and blood culture grew Pseudomonas aeruginosa. A diagnosis of ecthyma gangrenosum was made. Additional investigations also led to the discovery of invasive pulmonary aspergillosis. To our knowledge, this is the first case of ecthyma gangrenosum secondary to Pseudomonas sepsis and concurrent invasive pulmonary aspergillosis associated with ibrutinib use.