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.

Histoplasmosis in Inflammatory Bowel Disease with Tumor Necrosis Factor-Alpha Inhibitors: Safe to Continue Biologics?

BACKGROUND: The advent of tumor necrosis factor-α (TNF-α) inhibitor therapy has transformed inflammatory bowel disease management; however, these medications carry a boxed warning for risk of serious infections, including invasive fungal infections. AIMS: We aimed to study the clinical features, severity, and outcomes of histoplasmosis in patients on TNF-α inhibitors for IBD. METHODS: We performed a retrospective review of IBD patients receiving TNF-α inhibitors who developed histoplasmosis from January 1, 2001, to May 31, 2018. Patients with drug indications other than ulcerative colitis or Crohn's disease were excluded. IBD was diagnosed histologically, radiographically, or endoscopically. RESULTS: We identified 49 patients (median age 44 years; range 19-76) with histoplasmosis on TNF-α inhibitors. Patients with disseminated disease had a median urine antigen of 10.76 ng/mL compared with pulmonary disease alone 0.375 ng/mL (p < 0.001). Charlson Comorbidity Index and urine antigen levels showed a trend toward predicting disease severity (p > 0.05). Median length of stay was 9.5 days. Itraconazole was used for maintenance in all patients. Median follow-up was 4.7 years. Total treatment duration ranged from 3 to 15 months. TNF-α inhibitor therapy was continued in nine and resumed in ten patients after completing antifungals. Three deaths occurred (6%). CONCLUSIONS: Histoplasmosis outcomes were mostly favorable. Many patients were young with few comorbidities; however, those with more comorbidities experienced more severe histoplasmosis. Compared to prior studies, many of these patients resumed or continued biologic therapy. There were no histoplasmosis recurrences after resuming TNF-α inhibitor therapy. Vigilance for disseminated fungal infections in this patient population is essential.

A Rare Diagnosis: Recognizing and Managing Fungal Tenosynovitis of the Hand and Upper Extremity.

PURPOSE: Fungal infections involving the tenosynovium of the upper extremity are uncommon and are often misdiagnosed. This study evaluates the epidemiology, diagnosis, treatment, and outcomes of patients with fungal tenosynovitis of the upper extremity over a 20-year period. METHODS: A retrospective review of all culture-confirmed cases of fungal tenosynovitis of the upper extremity treated between 1990 and 2013 at a single institution was performed. Clinical data included patient and epidemiologic risk factors, causative fungal organism, surgical management, antimicrobial regimen, recurrence rates, and outcomes. RESULTS: There were 10 patients (9 female, 1 male) who met the inclusion criteria. The mean patient age was 60 years (range, 47-76 y). Identified pathogens included Histoplasmacapsulatum (7), Coccidioides posadasii/immitis (2), and Cryptococcus neoformans (1). Eight patients were on immunosuppressant medications at the time of diagnosis. The most common clinical presentation was subacute localized pain, swelling, and erythema consistent with tenosynovitis. The diagnosis was delayed by a median of 6 months (range, 0-48 mo). The most helpful diagnostic imaging studies included magnetic resonance imaging and ultrasound. All patients were treated with extensive surgical synovectomy and debridement. Seven patients were treated by a single surgery, whereas 3 required multiple consecutive debridements (2, 7, and 10 surgeries). The mean course of initial antimicrobial therapy was 8.2 months (range, 3-12 mo). Clinical recurrence was noted in 3 patients (30%) during a median follow-up period of 46 months (range, 7-250 mo). Both patients with Coccidioides infection incurred recurrence. CONCLUSIONS: Although uncommon, surgeons and clinicians should consider a diagnosis of fungal tenosynovitis among immunocompromised patients with signs of mild tenosynovitis and should consider operative debridement and biopsy. Although the majority of patients were successfully treated with surgical debridement and antimicrobial therapy, a recurrence rate of 30% highlights the need for close post-treatment follow-up. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V.

Evaluation of impact of statin use on development of CPK elevation during daptomycin therapy.

BACKGROUND: Because both daptomycin and statins may increase creatine phosphokinase (CPK) levels, the manufacturer of daptomycin suggests considering holding statins during daptomycin therapy. Published evidence suggests potential detrimental effects of withdrawing statin therapy. OBJECTIVES: The objectives of this study were to determine the impact of concurrent statin therapy on peak CPK values, incidence of CPK elevation in patients receiving daptomycin therapy, and clinical factors associated with increased risk of developing CPK elevation. METHODS: This was a single-center, retrospective cohort study of patients ≥18 years of age who received daptomycin for ≥72 hours and had ≥1 follow-up CPK during a 5-year period. A Kaplan-Meier curve was used to evaluate time to CPK elevation. Cox regression analyses were used to compare the risk of developing elevated CPK between 3 study groups: those receiving daptomycin alone, daptomycin with concurrent statin therapy, and statin therapy held while on daptomycin. RESULTS: 498 patients were included in the study-384 received daptomycin alone, 63 received daptomycin concurrent with statin, and 51 with statin held during daptomycin therapy. Cumulative incidence of CPK elevation was 5.1% and 12% at 7 and 14 days. Those on daptomycin and statin concurrent therapy demonstrated an approximately 2-fold risk of CPK elevation compared with those having their statin therapy held, but the overall group effect was not statistically significant (P = .17). CONCLUSIONS: Our findings suggest that holding statin during daptomycin therapy may not be necessary, but may indicate need for increased frequency of CPK monitoring when these medications are used concurrently.

COVID-19 outcome is not affected by anti-CD20 or high-titer convalescent plasma in immunosuppressed patients.

The role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) convalescent plasma in the treatment of Coronavirus Disease 2019 (COVID-19) in immunosuppressed individuals remains controversial. We describe the course of COVID-19 in patients who had received anti-CD20 therapy within the 3 years prior to infection. We compared outcomes between those treated with and those not treated with high titer SARS-CoV2 convalescent plasma. We identified 144 adults treated at Mayo clinic sites who had received anti-CD20 therapies within a median of 5.9 months prior to the COVID-19 index date. About one-third (34.7%) were hospitalized within 14 days and nearly half (47.9%) within 90 days. COVID-19 directed therapy included anti-spike monoclonal antibodies (n = 30, 20.8%), and, among those hospitalized within 14 days (n = 50), remdesivir (n = 45, 90.0%), glucocorticoids (n = 36, 72.0%) and convalescent plasma (n = 24, 48.0%). The duration from receipt of last dose of anti-CD20 therapy did not correlate with outcomes. The overall 90-day mortality rate was 14.7%. Administration of convalescent plasma within 14 days of the COVID-19 diagnosis was not significantly associated with any study outcome. Further study of COVID-19 in CD20-depleted individuals is needed focusing on the early administration of new and potentially combination antiviral agents, associated or not with vaccine-boosted convalescent plasma.

Meningeal coccidioidomycosis diagnosed by real-time polymerase chain reaction analysis of cerebrospinal fluid.

We describe two cases of coccidioidal meningitis (CM) diagnosed using real-time polymerase chain reaction (PCR) analysis of cerebrospinal fluid. These cases highlight the promise of PCR as a diagnostic method to assist in the rapid diagnosis of CM.

Left hand extensor tenosynovitis due to Histoplasma capsulatum complicated by immune reconstitution inflammatory syndrome.

We describe a case of left hand extensor tenosynovitis due to histoplasmosis in a patient with dermatomyositis on chronic immunosuppression. Treatment involved surgical debridement and antifungal therapy. The patient experienced paradoxical worsening of tenosynovial inflammation during de-augmentation of immunosuppression felt to be immune reconstitution inflammatory syndrome.

Diagnostic Methods and Risk Factors for Severe Disease and Mortality in Blastomycosis: A Retrospective Cohort Study.

Background: Blastomycosis can cause severe disease with progressive respiratory failure and dissemination even in immunocompetent individuals. We sought to evaluate risk factors for severe disease and mortality using clinical and laboratory data within a large health system in an endemic area. Methods: We performed a retrospective cohort study of patients diagnosed with blastomycosis at all Mayo Clinic sites from 1 January 2004 through 31 March 2020. Diagnosis was established by culture, histopathology/cytopathology, serology, antigen testing, or PCR. Disease was categorized as mild for patients treated in the outpatient setting, moderate for hospitalized patients who did not require intensive care, and severe for patients admitted to the intensive care unit. Logistic regression was used to evaluate risk factors for severe disease. A Cox proportional hazards model was constructed to evaluate mortality. Findings: We identified 210 patients diagnosed with blastomycosis. Mean age was 51 years (range, 6-84). Most subjects were male (71.0%). Extrapulmonary disease was confirmed in 24.8%. In this cohort, 40.5% of patients had mild disease, 37.6% had moderate disease, and 21.9% had severe disease. Independent risk factors for severe disease were neutrophilia (odds ratio (OR) 3.35 (95% CI 1.53-7.35), p = 0.002) and lymphopenia (OR 3.34 (95% CI 1.59-7.03), p = 0.001). Mortality at 90 days was 11.9%. Median time from diagnosis to death was 23 days (interquartile range 8-31 days). Independent risk factors for mortality were age (OR 1.04 (95% CI 1.01-1.08), p = 0.009), neutrophilia (OR 2.84 (95% CI 1.04-7.76), p = 0.041), and lymphopenia (OR 4.50 (95% CI 1.67-12.11), p = 0.003). Blastomyces immunodiffusion had an overall sensitivity of 39.6% (95% CI 30.1-49.8). Sensitivity was higher among those who were tested 4 weeks or longer after the onset of symptoms. Urine Blastomyces antigen had a significantly higher sensitivity of 80.8% (95% CI 68.1-89.2) compared to serology. There was a trend towards higher antigen concentration in patients with severe disease. The sensitivity of PCR from respiratory specimens was 67.6% (95% CI 50.1-85.5). Conclusion: In this cohort, we did not find an association between pharmacologic immunosuppression and disease severity. Lymphopenia at diagnosis was an independent risk factor for mortality. This simple marker may aid clinicians in determining disease prognosis.

Outcomes of COVID-19 With the Mayo Clinic Model of Care and Research.

OBJECTIVE: To report the Mayo Clinic experience with coronavirus disease 2019 (COVID-19) related to patient outcomes. METHODS: We conducted a retrospective chart review of patients with COVID-19 diagnosed between March 1, 2020, and July 31, 2020, at any of the Mayo Clinic sites. We abstracted pertinent comorbid conditions such as age, sex, body mass index, Charlson Comorbidity Index variables, and treatments received. Factors associated with hospitalization and mortality were assessed in univariate and multivariate models. RESULTS: A total of 7891 patients with confirmed COVID-19 infection with research authorization on file received care across the Mayo Clinic sites during the study period. Of these, 7217 patients were adults 18 years or older who were analyzed further. A total of 897 (11.4%) patients required hospitalization, and 354 (4.9%) received care in the intensive care unit (ICU). All hospitalized patients were reviewed by a COVID-19 Treatment Review Panel, and 77.5% (695 of 897) of inpatients received a COVID-19-directed therapy. Overall mortality was 1.2% (94 of 7891), with 7.1% (64 of 897) mortality in hospitalized patients and 11.3% (40 of 354) in patients requiring ICU care. CONCLUSION: Mayo Clinic outcomes of patients with COVID-19 infection in the ICU, hospital, and community compare favorably with those reported nationally. This likely reflects the impact of interprofessional multidisciplinary team evaluation, effective leveraging of clinical trials and available treatments, deployment of remote monitoring tools, and maintenance of adequate operating capacity to not require surge adjustments. These best practices can help guide other health care systems with the continuing response to the COVID-19 pandemic.

The Many Faces of Itraconazole Cardiac Toxicity.

Itraconazole is well known for carrying a black-box warning for new or worsening congestive heart failure. Single cases of other cardiac- and fluid-related disturbances have been reported periodically since its issuance. We describe a large cohort of patients on itraconazole experiencing a breadth of cardiac- and fluid-related toxicities, ranging from new-onset hypertension to cardiac arrest. A retrospective, single-center, large case series at a large tertiary medical center was conducted. Patients with itraconazole and cardiac toxicity-including hypertension, cardiomyopathy, reduced ejection fraction, and edema-in medical record between January 1, 1999, and May 21, 2019, were identified and assigned a Naranjo score; 31 patients were included with a Naranjo score of 5 or higher. There were slightly more male subjects than female subjects, average age was 66, and all subjects were Caucasian. Median time until presentation of adverse effects was 4 weeks (range: 0.3 to 104 weeks). Most common symptom was edema (74% of patients), followed by heart failure without and with preserved ejection fraction (19.4% and 22.6% of patients, respectively). Worsening or new hypertension was also common (25.8% of patients). Rarer were pulmonary edema, pericardial effusion, and cardiac arrest that occurred in 1 patient. In most cases, clinicians stopped itraconazole (74%) or decreased itraconazole dose (19%), resulting in improvement or resolution of symptoms. In 4 cases, the adverse effect did not resolve. Itraconazole can cause a range of possible serious cardiac and fluid-associated adverse events. Dose decrease or cessation usually resulted in symptomatic improvement or reversal.

Severe reversible left ventricular dysfunction associated with multiple cardiac myxomata.

A 22-year-old Caucasian woman presented with acrocyanosis of fingers and toes and dyspnea on exertion. Initial echocardiography showed multiple right and left atrial myxomata, mild enlargement of the left ventricle and severely depressed left ventricular systolic function. Resection of the tumors and replacement of the myxomatous mitral valve led to a complete resolution of echocardiographic evidence of left ventricular dysfunction, and was accompanied by disappearance of skin findings and symptoms of asthma.

Catheter Salvage After Catheter-Related Bloodstream Infection During Home Parenteral Nutrition.

BACKGROUND: Catheter-related bloodstream infection (CRBSI) is a common complication in patients receiving home parenteral nutrition (HPN). Data regarding catheter salvage after a CRBSI episode are limited. We aimed to determine the incidence of CRBSI and rates of catheter salvage in adult patients receiving HPN. MATERIALS AND METHODS: We retrospectively searched our prospectively maintained HPN database for the records of all adult patients receiving HPN from January 1, 1990, to December 31, 2013, at our tertiary referral center. Data abstracted from the medical records included demographics, diseases, treatments, and outcomes. The incidence of CRBSI and rates of catheter salvage were determined. RESULTS: Of 1040 patients identified, 620 (59.6%) were men. The median total duration on HPN was 124.5 days (interquartile range, 49.0-345.5 days). Mean (SD) age at HPN initiation was 53.3 (15.3) years. During the study period, 465 CRBSIs developed in 187 patients (18%). The rate of CRBSI was 0.64/1000 catheter days. Overall, 70% of catheters were salvaged (retained despite CRBSI) during the study period: 78% of infections with coagulase-negative staphylococci, 87% with methicillin-sensitive Staphylococcus aureus, and 27% with methicillin-resistant S aureus. The percentage of catheters salvaged was 63% from 1990 to 1994, 63% from 1995 to 1999, 61% from 2000 to 2004, 72% from 2005 to 2009, and 76% from 2010 to 2013. CONCLUSION: Catheter salvage is possible after a CRBSI episode. Since most episodes of CRBSI are caused by skin commensals, effective treatment without removal of the central venous catheter is possible in most cases.

Clinical Study of an Online Tool for Standardizing Hospital Care.

We assessed if use of an online clinical decision support tool improved standardization and quality of care in hospitalized patients with lower extremity cellulitis (LEC). This was a 14-month preintervention and postintervention study of 85 LEC admissions. There was significantly higher usage of the online LEC care process model (CPM) in the postintervention phase (p < .001). There was a trend toward higher rates of appropriate antibiotic regimen in the postintervention group both initially and at discharge (p = .063 for both). A sensitivity analysis of CPM users versus nonusers demonstrated a significantly higher rate of appropriate initial antibiotics prescribed when the CPM was used (p < .001). Use of this online CPM was associated with improved standardization, as demonstrated by increased ordering of an appropriate initial antibiotic regimen for hospitalized patients with LEC.