Powassan Virus Encephalitis: A Tertiary Center Experience.

BACKGROUND: Powassan virus (POWV) is an emerging arthropod-borne flavivirus, transmitted by Ixodes spp. ticks, which has been associated with neuroinvasive disease and poor outcomes. METHODS: A retrospective study was conducted at Mayo Clinic from 2013 to 2022. We included clinical and epidemiologic data of probable and confirmed neuroinvasive POWV cases. RESULTS: Sixteen patients with neuroinvasive POWV were identified; their median age was 63.2 years, and 62.5% were male. Six patients presented with rhombencephalitis, 4 with isolated meningitis, 3 with meningoencephalitis, 2 with meningoencephalomyelitis, and 1 with opsoclonus myoclonus syndrome. A median time of 18 days was observed between symptom onset and diagnosis. Cerebrospinal fluid analysis showed lymphocytic pleocytosis with elevated protein and normal glucose in the majority of patients. Death occurred within 90 days in 3 patients (18.8%), and residual neurologic deficits were seen in 8 survivors (72.7%). CONCLUSIONS: To our knowledge, this is the largest case series of patients with neuroinvasive POWV infection. We highlight the importance of a high clinical suspicion among patients who live in or travel to high-risk areas during the spring to fall months. Our data show high morbidity and mortality rates among patients with neuroinvasive disease.

Effect of Preoperative Antibiotic Therapy on Operative Culture Yield for Diagnosis of Native Joint Septic Arthritis.

BACKGROUND: Native joint septic arthritis (NJSA) is definitively diagnosed by a positive Gram stain or culture, along with supportive clinical findings. Preoperative antibiotics are known to alter synovial fluid cell count, Gram stain and culture results and are typically postponed until after arthrocentesis to optimize diagnostic accuracy. However, data on the impact of preoperative antibiotics on operative culture yield for NJSA diagnosis are limited. METHODS: We retrospectively reviewed adult cases of NJSA who underwent surgery at Mayo Clinic facilities from 2012-2021 to analyze the effect of preoperative antibiotics on operative culture yield through a paired analysis of preoperative culture (POC) and operative culture (OC) results using logistic regression and generalized estimating equations. RESULTS: Two hundred ninety-nine patients with NJSA affecting 321 joints were included. Among those receiving preoperative antibiotics, yield significantly decreased from 68.0% at POC to 57.1% at OC (p < .001). In contrast, for patients without preoperative antibiotics there was a non-significant increase in yield from 60.9% at POC to 67.4% at OC (p = 0.244). In a logistic regression model for paired data, preoperative antibiotic exposure was more likely to decrease OC yield compared to non-exposure (OR = 2.12; 95% CI = 1.24-3.64; p = .006). Within the preoperative antibiotic group, additional antibiotic doses and earlier antibiotic initiation were associated with lower OC yield. CONCLUSION: In patients with NJSA, preoperative antibiotic exposure resulted in a significant decrease in microbiologic yield of operative cultures as compared to patients in whom antibiotic therapy was held prior to obtaining operative cultures.

Impact of hypoalbuminemia on clinical outcomes among patients with obesity treated with ceftriaxone.

The use of ceftriaxone, a highly protein-bound drug, in the setting of hypoalbuminemia may result in suboptimal drug exposure. Patients with obesity also exhibit higher absolute drug clearance. We aimed to evaluate the impact of hypoalbuminemia on clinical success among hospitalized adults with obesity who were treated with ceftriaxone. This retrospective review included adult inpatients with weight >100 kg or body mass index >40 kg/m2 who received ceftriaxone 2 g intravenously every 12 hours for at least 72 hours. The primary outcome was clinical success, a composite of clinical cure and microbiologic cure. Secondary outcomes included clinical cure, microbiologic cure, length of stay, ICU length of stay, mortality, 30-day readmission, and adverse events. In all, 137 patients were included, 34 of whom had a serum albumin of ≤2.5 g/dL. In a propensity-score-weighted analysis, clinical success was significantly more common among those without hypoalbuminemia (91.2%) as compared to those with hypoalbuminemia (77.8%) (P = 0.038). Death within 30 days (13.7% vs 0%, P < 0.001) and 30-day readmission (31.6% vs 12.0%, P = 0.008) were more common in the hypoalbuminemia group. In a univariate analysis, serum albumin and indication for ceftriaxone use were found to be predictors of clinical success. Hypoalbuminemia was associated with a lower rate of clinical success among patients with obesity who were treated with ceftriaxone 2 g every 12 hours.

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.

Use of the DMAIC Lean Six Sigma quality improvement framework to improve beta-lactam antibiotic adequacy in the critically ill.

BACKGROUND: Beta-lactam antibiotics are widely used in the intensive care unit due to their favorable effectiveness and safety profiles. Beta-lactams given to patients with sepsis must be delivered as soon as possible after infection recognition (early), treat the suspected organism (appropriate), and at a dose that eradicates the infection (adequate). Early and appropriate antibiotic delivery occurs in >90% of patients, but less than half of patients with sepsis achieve adequate antibiotic exposure. This project aimed to address this quality gap and improve beta-lactam adequacy using the DMAIC Lean Six Sigma quality improvement framework. METHODS: A multidisciplinary steering committee was formed and completed a stakeholder analysis to define the gap in practice. An Ishikawa cause and effect (Fishbone) diagram was used to identify the root causes and an impact/effort grid facilitated prioritization of interventions. An intervention which included bundled education with the use of therapeutic drug monitoring (TDM; i.e., drug level testing) was projected to have the highest impact relative to the amount of effort and selected to address beta-lactam inadequacy in the critically ill. RESULTS: The education and TDM intervention were deployed through a Plan, Do, Study, Act (PDSA) cycle. In the three months after 'go-live,' 54 episodes of beta-lactam TDM occurred in 41 unique ICU patients. The primary quality metric of beta-lactam adequacy was achieved in 94% of individuals after the intervention. 94% of clinicians gauged the education provided as sufficient. The primary counterbalance of antimicrobial days of therapy, a core antimicrobial stewardship metric, was unchanged over time (favorable result; p=0.73). CONCLUSIONS: Application of the DMAIC Lean Six Sigma quality improvement framework effectively improved beta-lactam adequacy in critically ill patients. The approach taken in this quality improvement project is widely generalizable to other drugs, drug classes, or settings to increase the adequacy of drug exposure.

Melanoma Management: Exploring Staging, Prognosis, and Treatment Innovations.

Melanoma, a malignant neoplasm originating from melanocytes, stands as one of the most prevalent cancers globally, ranking fifth in terms of estimated new cases in recent years. Its aggressive nature and propensity for metastasis pose significant challenges in oncology. Recent advancements have led to a notable shift towards targeted therapies, driven by a deeper understanding of cutaneous tumor pathogenesis. Immunotherapy and tyrosine kinase inhibitors have emerged as promising strategies, demonstrating the potential to improve clinical outcomes across all disease stages, including neoadjuvant, adjuvant, and metastatic settings. Notably, there has been a groundbreaking development in the treatment of brain metastasis, historically associated with poor prognosis in oncology but showcasing impressive results in melanoma patients. This review article provides a comprehensive synthesis of the most recent knowledge on staging and prognostic factors while highlighting emerging therapeutic modalities, with a particular focus on neoadjuvant and adjuvant strategies, notably immunotherapy and targeted therapies, including the ongoing trials.

Perimyocarditis Associated with Immune Checkpoint Inhibitors: A Case Report and Review of the Literature.

Patient prognoses have been significantly enhanced by immune checkpoint inhibitors (ICIs), altering the standard of care in cancer treatment. These novel antibodies have become a mainstay of care for metastatic non-small-cell lung cancer (mNSCLC) patients. Several types of adverse events related to ICIs have been identified and documented as a result of the launch of these innovative medicines. We present here a 74-year-old female patient with a stage IV lung adenocarcinoma, treated with nivolumab plus ipilimumab, who developed perimyocarditis two weeks after receiving the third cycle of immune checkpoint inhibitor therapy. The patient was diagnosed using troponin levels, computed tomography (CT) angiography, and echocardiography. After hospitalization, her cardiac condition was successfully resolved with corticosteroids, colchicine, and symptomatic treatment. To the best of our knowledge, this is one of the rarest cases to be reported of perimyocarditis as a toxicity of immunotherapy in a patient treated for adenocarcinoma of the lung.

Failure of mecA/mecC PCR Testing to Accurately Predict Oxacillin Resistance in a Patient with Staphylococcus aureus Infective Endocarditis.

Genotypic testing for mecA/mecC is heavily relied upon for rapid optimization of antimicrobial therapy in infections due to Staphylococcus aureus. Little is known regarding optimal reporting and/or therapy for patients demonstrating lack of genotypic evidence of mecA or mecC but phenotypic oxacillin resistance. We report a case of a 77-year-old patient with S. aureus bloodstream infection and infective endocarditis with discordance between mecA/mecC genotypic results and phenotypic susceptibility testing.

Post-treatment outcomes of ceftriaxone versus antistaphylococcal penicillins or cefazolin for definitive therapy of methicillin-susceptible Staphylococcus aureus bacteremia.

Methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia is associated with poor outcomes. Ceftriaxone offers logistical advantages over other standard therapies, though in vitro studies have questioned its efficacy and clinical studies of ceftriaxone in MSSA bacteremia are conflicting.We performed a multicenter, retrospective cohort study of adult patients who received ceftriaxone, cefazolin, or antistaphylococcal penicillins as definitive therapy for MSSA bacteremia from 2018 to 2019. Definitive therapy was defined as the antibiotic used in the outpatient setting. Patients were excluded if they received less than 7 days of outpatient therapy. Follow-up started on the date of definitive therapy completion. The primary outcome was 90-day treatment failure, defined as a composite of mortality and microbiologic recurrence. This was analyzed with multivariable Cox regression. A total of 223 patients were included, 37 (16.6%) of whom received ceftriaxone. The most common ceftriaxone dose was 2 g daily (83.8%). The most common primary site of infection was skin/soft tissue (37.2%), unknown (21.1%), and catheter-related (15.2%). Twenty-six (11.7%) developed infective endocarditis. Median total duration of treatment was 31.0 days, and median outpatient duration was 24.0 days. Twenty-six (11.7%) developed 90-day treatment failure. After adjusting for Charlson comorbidity index, duration of therapy, and use of transesophageal echocardiography, definitive treatment with ceftriaxone was associated with treatment failure (hazard ratio 2.66, 95% confidence interval 1.15-6.12; p=0.022). Among patients with MSSA bacteremia, definitive treatment with ceftriaxone was associated with a higher risk of treatment failure within 90 days as compared to cefazolin or antistaphylococcal penicillins.

Clinical characteristics of central nervous system phaeohyphomycosis: A brief report of 20 years' experience.

Central nervous system (CNS) phaeohyphomycosis is a rare and often fatal fungal infection. Our study reported a case series of eight CNS phaeohyphomycosis cases at our institution over the past 20 years. We did not observe the common pattern of risk factors, abscess location, or number of abscesses among them. Most patients were immunocompetent without classic risk factors for fungal infection. Early diagnosis and aggressive management with surgical intervention and prolonged antifungal therapy can lead to a favorable outcome. The study highlights the need for further research to better understand the pathogenesis and optimal management of this challenging rare infection.

Immunomodulators for severe coronavirus disease-2019 in transplant patients: Do they increase the risk of secondary infection?

BACKGROUND: Current guidelines recommend immunomodulators, tocilizumab or baricitinib, for the management of severe coronavirus disease-2019 (COVID-19) in patients with increasing oxygen requirements. Given their immunosuppressive effects, there is a concern for higher rates of infection among transplant recipients. METHODS: A retrospective cohort study of transplant patients with severe COVID-19 between April 2020 and January 2022 was performed at the Mayo Clinic. The primary outcome was incidence of secondary infections after COVID-19 diagnosis. Secondary outcomes were 90-day mortality, ventilatory days, and thromboembolic events. RESULTS: A total of 191 hospitalized transplant patients were studied, including 77 (40.3%) patients who received an immunomodulator. Overall, 89% were solid organ transplant recipients, with kidney as the most common transplanted organ (50.3%). The majority (89.0%) required oxygen supplementation on admission, and 39.8% of these patients required mechanical ventilation during the hospital course. There was no significant difference in the incidence of secondary infections between those who received or did not receive an immunomodulator (p = .984). Likewise, there was no difference in 90-day mortality between patients who received or did not receive an immunomodulator (p = .134). However, higher mortality was observed among patients that developed a secondary infection (p < .001). CONCLUSION: The use of immunomodulators in transplant patients with severe COVID-19 was not significantly associated with an increased risk of secondary infections. Secondary infections were associated with higher risk of all-cause mortality. Future studies of larger cohorts are needed to explore the effect of immunomodulators on survival among transplant patients with COVID-19.

Does metabolite matter? Defining target itraconazole and hydroxy-itraconazole serum concentrations for blastomycosis.

BACKGROUND: Itraconazole 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. OBJECTIVES: This 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/METHODS: This 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. RESULTS: A 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). CONCLUSIONS: This study supports an itraconazole therapeutic target combining itraconazole and hydroxy-itraconazole >1.0 mcg/ml for blastomycosis treatment.

Diagnostic Value of 16S Ribosomal RNA Gene Polymerase Chain Reaction/Sanger Sequencing in Clinical Practice.

BACKGROUND: Accurate microbiologic diagnosis is important for appropriate management of infectious diseases. Sequencing-based molecular diagnostics are increasingly used for precision diagnosis of infections. However, their clinical utility is unclear. METHODS: We conducted a retrospective analysis of specimens that underwent 16S ribosomal RNA (rRNA) gene polymerase chain reaction (PCR) followed by Sanger sequencing at our institution from April 2017 through March 2019. RESULTS: A total of 566 specimens obtained from 460 patients were studied. Patients were considered clinically infected or noninfected based on final diagnosis and management. In 17% of patients, 16S rRNA PCR/sequencing was positive and in 5% of patients, this test led to an impact on clinical care. In comparison, bacterial cultures were positive in 21% of patients. Specimens with a positive Gram stain had 12 times greater odds of having a positive molecular result than those with a negative Gram stain (95% confidence interval for odds ratio, 5.2-31.4). Overall, PCR positivity was higher in cardiovascular specimens (37%) obtained from clinically infected patients, with bacterial cultures being more likely to be positive for musculoskeletal specimens (P < .001). 16S rRNA PCR/sequencing identified a probable pathogen in 10% culture-negative specimens. CONCLUSION: 16S rRNA PCR/sequencing can play a role in the diagnostic evaluation of patients with culture-negative infections, especially those with cardiovascular infections.

Prospective Validation of PREDICT and Its Impact on the Transesophageal Echocardiography Use in Management of Staphylococcus aureus Bacteremia.

BACKGROUND: Infective endocarditis (IE) is the most feared complication of Staphylococcus aureus bacteremia (SAB). Transesophageal echocardiogram (TEE) is generally recommended for all patients with SAB; however, supporting data for this are limited. We previously developed a scoring system, "PREDICT," that quantifies the risk of IE and identifies patients who would most benefit most from undergoing TEE. The current prospective investigation aims to validate this score. METHODS: We prospectively screened all consecutive adults (≥18 years) hospitalized with SAB at 3 Mayo Clinic sites between January 2015 and March 2017. RESULTS: Of 220 patients screened, 199 with SAB met study criteria and were included in the investigation. Of them, 23 (11.6%) patients were diagnosed with definite IE within 12 weeks of initial presentation based on modified Duke's criteria. Using the previously derived PREDICT model, the day 1 score of ≥4 had a sensitivity of 30.4% and a specificity of 93.8%, whereas a day 5 score of ≤2 had a sensitivity and negative-predictive value of 100%. Additional factors including surgery or invasive procedure in the past 30 days, prosthetic heart valve, and higher number of positive blood culture bottles in the first set of cultures were associated with increased risk of IE independent of the day 5 risk score. CONCLUSIONS: We validated the previously developed PREDICT scoring tools for stratifying risk of IE, and the need for undergoing a TEE, among cases of SAB. We also identified other factors with predictive potential, although larger prospective studies are needed to further evaluate possible enhancements to the current scoring system.

Disseminated blastomycosis in a kidney transplant recipient.

Disseminated blastomycosis in solid organ transplant is uncommon. The diagnosis is usually challenging due to vague clinical presentations, which could lead to a devastating outcome. We reported a unique case of disseminated blastomycosis with laryngeal involvement in a kidney transplant recipient who presented with hoarseness. The diagnosis was made by histopathology and culture of laryngeal mass.

Retrospective Analysis of Antimicrobial Susceptibility Profiles of Nocardia Species from a Tertiary Hospital and Reference Laboratory, 2011 to 2017.

Nocardia species are found worldwide and are opportunistic pathogens of both immunocompromised and immunocompetent hosts. Recent updates to the taxonomy of this genus have indicated that there are more than 90 recognized species of Nocardia with 54 species reported to be clinically relevant. In this paper, we report the species distribution, specimen source distribution, and antimicrobial susceptibility profiles of 2,091 clinical isolates recovered for the years 2011 to 2017 using the updated taxonomy. The most commonly isolated species included Nocardia nova complex, Nocardia cyriacigeorgica, and Nocardia farcinica complex, with an additional 25 species or species complexes recovered from clinical specimens. The antimicrobial susceptibility profile was highly variable between the species, but in general, amikacin, linezolid, and trimethoprim-sulfamethoxazole demonstrated good in vitro activity against most species.

Mycobacterium septicum: a 6-Year Clinical Experience from a Tertiary Hospital and Reference Laboratory.

Mycobacterium septicum is a rarely identified nontuberculous mycobacterium capable of causing infections in both healthy and immunocompromised individuals. Only a few cases of M. septicum infections have been reported, which makes recognizing corresponding clinical disease more challenging for clinicians. Antimicrobial susceptibility profiles for this organism are not well described, and corresponding optimal therapeutic regimens have not been established. We report a tertiary care center's experience with M. septicum from 2014 to 2020. Twelve adult patients with positive cultures for M. septicum were identified. Most cases were identified from sputum samples of individuals with underlying lung disease. Most cases involving M. septicum isolation in culture were not felt to be clinically significant. Two cases were considered possible infections, while only one case was considered a definite infection that required antimicrobial treatment. All M. septicum isolates were susceptible in vitro to amikacin, ciprofloxacin, imipenem, linezolid, moxifloxacin, and trimethoprim-sulfamethoxazole. Isolates were universally resistant to clarithromycin and doxycycline. The isolation of M. septicum in culture is uncommon and requires clinical correlation to determine its clinical relevance and need for treatment. Susceptibility testing should be performed to guide therapy.

Linezolid and fentanyl: An underrecognized drug-to-drug interaction.

WHAT IS KNOWN AND OBJECTIVE: Despite its frequent use in clinical practice, fentanyl's pro-serotonergic effects are underrecognized, especially in combination with linezolid. Life-threatening reactions can occur. CASE SUMMARY: We report a case of serotonin syndrome developed shortly after the initiation of linezolid in a 63-year-old patient in whom selective serotonin reuptake inhibitor therapy was discontinued for the duration of antibiotic therapy. However, fentanyl transdermal patch treatment was inadvertently continued. Noteworthy, 24 hours following discontinuation of linezolid, the patient experienced complete resolution of symptoms. WHAT IS NEW AND CONCLUSION: Fentanyl can increase the intrasynaptic release of serotonin through their effects on y-amino butyric acid and its phenylpiperidine chemical structure. We illustrate the importance of thorough medication reconciliation and review of all potential drug-to-drug interactions when indicating linezolid therapy to ensure patient safety. We believe that our case provides novel observations and insight that could help recognize similar cases in clinical practice.

Clostridium paraputrificum septic arthritis and osteomyelitis of shoulder: A case report and review of literature.

Septic arthritis due to Clostridium species is rare. We report the first case of Clostridium paraputrificum native shoulder septic arthritis and osteomyelitis. An 86-year-old woman with osteoarthritis presented with acute-onset right shoulder pain. Injection of the glenohumeral joint with methylprednisolone resulted in worsening of pain. Synovial fluid analysis was consistent with septic arthritis and culture of the synovial fluid grew C. paraputrificum. Arthroscopic irrigation and debridement of shoulder joint with 6 weeks of ertapenem was unsuccessful, with persistence of C. paraputrificum from synovial fluid and tissue culture. She underwent right shoulder resection followed by a second course of ertapenem for 6 weeks. She was pain free at 12 months follow-up visit.

Laryngeal histoplasmosis in a kidney transplant recipient.

Histoplasma capsulatum is an endemic fungus that most oftenly causes a self-limiting illness but can result in severe infections in immunocompromised patients including pulmonary or extra-pulmonary disease. Rarely it can also cause a chronic progressive infection of the larynx. Herein, we report a case of laryngeal histoplasmosis in a kidney transplant patient who presented with progressive symptoms of several weeks of hoarseness, dysphagia and odynophagia. Laryngoscopic examination revealed thick plaques in the oropharynx with surrounding hyper-erythema and histopathology showed numerous intracellular yeasts forms consistent with H capsulatum. Patient was initiated on treatment with itraconazole. Infection of the larynx due to H capsulatum is highly uncommon and therefore can result in an inappropriate or delayed diagnosis. A review of literature showed four previously reported cases of laryngeal histoplasmosis in patients with solid organ transplant. This is the first case series of laryngeal histoplasmosis in transplant recipients.