MSG-15: Super-Bioavailability Itraconazole Versus Conventional Itraconazole in the Treatment of Endemic Mycoses-A Multicenter, Open-Label, Randomized Comparative Trial.

Background: Invasive fungal disease caused by dimorphic fungi is associated with significant morbidity and mortality. Super-bioavailability itraconazole (SUBA-itra) is a novel antifungal agent with pharmacokinetic advantages over currently available formulations. In this prospective comparative study, we report the outcomes of patients with endemic fungal infections (histoplasmosis, blastomycosis, coccidioidomycosis, and sporotrichosis). Methods: This open-label randomized trial evaluated the efficacy, safety, and pharmacokinetics SUBA-itra compared with conventional itraconazole (c-itra) treatment for endemic fungal infections. An independent data review committee determined responses on treatment days 42 and 180. Results: Eighty-eight patients were enrolled for IFD (SUBA-itra, n = 42; c-itra, n = 46) caused by Histoplasma (n = 51), Blastomyces (n = 18), Coccidioides (n = 13), or Sporothrix (n = 6). On day 42, clinical success was observed with SUBA-itra and c-itra on day 42 (in 69% and 67%, respectively, and on day 180 (in 60% and 65%). Patients treated with SUBA-itra exhibited less drug-level variability at days 7 (P = .03) and 14 (P = .06) of randomized treatment. The concentrations of itraconazole and hydroxyitraconazole were comparable between the 2 medications (P = .77 and P = .80, respectively). There was a trend for fewer adverse events (AEs; 74% vs 87%, respectively; P = .18) and serious AEs (10% vs 26%; P = .06) in the SUBA-itra-treated patients than in those receiving c-itra. Serious treatment-emergent AEs were less common in SUBA-itra-treated patients (12% vs 50%, respectively; P < .001). Conclusions: SUBA-itra was bioequivalent, well tolerated, and efficacious in treating endemic fungi, with a more favorable safety profile than c-itra. Clinical Trials Registration: NCT03572049.

Headaches in a Horseback Rider.

An immunocompetent woman presented with headaches. She previouslyworked at a farm in upstate New York. Brain MRI noted pituitary enlargement and neurosurgerypursued trans-sphenoidal pituitary biopsy. Histopathology revealed ill-defined granulomaswith clusters of yeast, consistent with Histoplasma.

Make Sure You Have a Safety Net: Updates in the Prevention and Management of Infectious Complications in Stem Cell Transplant Recipients.

Hematopoietic stem cell transplant recipients are at increased risk of infection and immune dysregulation due to reception of cytotoxic chemotherapy; development of graft versus host disease, which necessitates treatment with immunosuppressive medications; and placement of invasive catheters. The prevention and management of infections in these vulnerable hosts is of utmost importance and a key "safety net" in stem cell transplantation. In this review, we provide updates on the prevention and management of CMV infection; invasive fungal infections; bacterial infections; Clostridium difficile infection; and EBV, HHV-6, adenovirus and BK infections. We discuss novel drugs, such as letermovir, isavuconazole, meropenem-vaborbactam and bezlotoxumab; weigh the pros and cons of using fluoroquinolone prophylaxis during neutropenia after stem cell transplantation; and provide updates on important viral infections after hematopoietic stem cell transplant (HSCT). Optimizing the prevention and management of infectious diseases by using the best available evidence will contribute to better outcomes for stem cell transplant recipients, and provide the best possible "safety net" for these immunocompromised hosts.

Severe acute respiratory distress syndrome in a liver transplant patient.

This case report presents a 46-year old man with a failed liver transplant who presented with malaise and dyspnea. Imaging studies revealed diffuse reticulonodular infiltrates and innumerable miliary nodules and a left upper lobe consolidative mass. Examination of bronchoalveolar lavage fluid demonstrated yeast cells with broad-based budding. He was diagnosed with pulmonary blastomycosis and started therapy with liposomal amphotericin. In spite of therapy, he clinically worsened, developing acute respiratory distress syndrome (ARDS) and eventually expired.

Aspergillus calidoustus case series and review of the literature.

Aspergillus calidoustus, previously classified as Aspergillus ustus, is an emerging pathogen in immunocompromised persons. We describe four recent cases of A. calidoustus and review 37 additional cases of A. calidoustus (n = 8) or A. ustus (n = 29) published through June 2016. Twenty (49%) cases occurred in patients with hematologic malignancy and/or receipt of hematopoietic cell transplantation, and 13 (32%) occurred in solid organ transplant recipients. Antifungal susceptibility was reported in 49% of cases and in 42% treatment failed. Overall mortality was 66% and, where reported, attributable mortality was 30%. A. calidoustus infection is associated with a high mortality rate and frequently displays in vitro antifungal resistance.

AST to ALT Ratio is elevated in disseminated histoplasmosis as compared to localized pulmonary disease and other endemic mycoses.

Severe pulmonary or disseminated histoplasmosis often necessitates presumptive antifungal treatment while awaiting definitive diagnosis. Histoplasma antigen assays have improved sensitivity but results may lag up to 7 days. In order to increase diagnostic certainty, "soft clues" may be looked for in laboratory and radiologic data, such as elevated alkaline phosphatase or ferritin levels and findings of mediastinal adenopathy or hepatosplenomegaly. To determine if elevated aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio is specific to histoplasmosis or a non-specific marker for disseminated fungal infection or sepsis in general, we retrospectively examined records of all patients diagnosed with an endemic fungal infection (EFI) at Rush University Medical Center from January of 1997 to October of 2012, and a cohort of septic patients with elevated liver enzymes. We identified 90 cases of EFIs during the study period that met all inclusion criteria (Histoplasma 21, Blastomyces 56, Coccidioides 12, Paracoccidioides 1). We also evaluated 10 control patients with bacterial sepsis. The mean ratio of AST to ALT in patients with disseminated histoplasmosis was 2.69 (95% CI:1.22, 4.16) while for other EFIs, the mean ratio ranged from 0.38 to 1.14 with disseminated coccidioidomycosis and blastomycosis respectively (P < 0.0001). The ratio in patients with bacterial sepsis was 0.84. We propose the use of the AST/ALT ratio as a clinical "soft clue" suggestive of disseminated histoplasmosis in the appropriate host, and to possibly distinguish cross reactivity of the Histoplasma antigen assay with other EFIs.

Disseminated Cryptococcal Disease in a Patient with Chronic Lymphocytic Leukemia on Ibrutinib.

Cryptococcus is a unique environmental fungus that can cause disease most often in immunocompromised individuals with defective cell-mediated immunity. Chronic lymphocytic leukemia (CLL) is not known to be a risk factor for cryptococcal disease although cases have been described mainly in patients treated with agents that suppress cell-mediated immunity. Ibrutinib is a new biologic agent used for treatment of CLL, mantle cell lymphoma, and Waldenstrom's macroglobulinemia. It acts by inhibiting Bruton's tyrosine kinase, a kinase downstream of the B-cell receptor critical for B-cell survival and proliferation. Ibrutinib use has not been associated previously with cryptococcal disease. However, recent evidence suggested that treatments aimed at blocking the function of Bruton's tyrosine kinase could pose a higher risk for cryptococcal infection in a mice model. Here, we report the first case of disseminated cryptococcal disease in a patient with CLL treated with ibrutinib. When evaluating possible infection in CLL patients receiving ibrutinib, cryptococcal disease, which could be life threatening if overlooked, could be considered.

Cerebrospinal fluid Coccidioides antigen testing in the diagnosis and management of central nervous system coccidioidomycosis.

The goal of this study was to report on the potential utility of cerebrospinal fluid (CSF) Coccidioides antigen testing in the diagnosis and management of Coccidioides meningitis. We retrospectively reviewed medical records of seven patients with Coccidioides meningitis who had Coccidioides antigen tests performed on CSF. In two severely immunocompromised patients, CSF Coccidioides antigen testing was helpful in the diagnosis when other testing modalities were negative. Coccidioides antigen testing was also useful in the management of patients who had progression of disease due to non-adherence, development of resistance, failure of therapy and the presence of vasculitis. Changing antigen levels helped identify disease complications in three patients that led to alterations in therapy or management. On the basis of our review of these seven patients with Coccidioides meningitis, we concluded that the Coccidioides antigen test contributed to the diagnosis and management of patients with Coccidioides meningitis.

Use of posaconazole delayed-release tablets for treatment of invasive aspergillosis.

A 65-year-old man developed Aspergillus brain abscesses following surgical resection of a sinus aspergilloma. He was treated with voriconazole for 1 year but infection recurred. We elected to treat with posaconazole delayed-release tablets, currently only indicated as antifungal prophylaxis in high-risk patients. A maintenance dose of 300 mg Q24 h resulted in a therapeutic serum concentration and appears safe and clinically effective thus far. This is the first report of successful use of posaconazole tablets for treatment of invasive aspergillosis.

Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era.

BACKGROUND: Central nervous system (CNS) involvement with Blastomyces dermatitidis is an uncommon and potentially fatal complication of blastomycosis. METHODS: We retrospectively reviewed 22 patients with CNS blastomycosis at our institutions from 1990 through 2008 (13 proven, 5 probable, and 4 possible cases). RESULTS: Magnetic resonance imaging was used in most patients, alone or in addition to computed tomography. CNS blastomycosis manifested as epidural abscess (1 of 22), meningitis (7 of 22), intracranial mass lesions (10 of 22), and concomitant intracranial mass lesions and meningitis (4 of 22). All patients received amphotericin B deoxycholate or a lipid formulation of amphotericin B as part of their treatment regimens. Most patients received amphotericin B followed by a prolonged course of oral azole therapy (voriconazole, fluconazole, or itraconazole). Four (18%) of 22 patients died during follow-up. CONCLUSIONS: On the basis of these data, we recommend initial treatment with a lipid formulation of amphotericin B followed by a prolonged course of oral azole therapy, preferably voriconazole.

Classic pyomyositis of the extremities as an unusual manifestation of Blastomyces dermatitidis: a report of two cases.

Pyomyositis is an infection of skeletal muscle that, by definition, arises intramuscularly rather than secondarily from adjacent infection. It is usually associated with bacterial infection, particularly Staphylcococcus aureus. Fungi are rare causes, and Blastomyces dermatitidis has not been reported previously. In this case series, we report two cases of pyomyositis caused by B. dermatitidis. Cases were prospectively identified through routine clinical care at a single academic referral hospital. Two patients with complaints of muscle pain and subacute cough were treated at our hospital in 2007. Both patients were found to have pyomyositis caused by B. dermatitidis- in the quadriceps muscles in one patient, and in the calf muscle in another - by radiological imaging and fungal culture. Both were also diagnosed with pneumonia caused by B. dermatitidis (presumptive in one, confirmed in the other). There was no evidence of infection of adjacent structures, suggesting that the route of infection was likely direct haematogenous seeding of the muscle. A review of the literature confirmed that although B. dermatitidis has been described as causing axial muscle infection secondary to adjacent infection such as vertebral osteomyelitis, our description of isolated muscle involvement (classic pyomyositis) caused by B. dermatitidis, particularly of the extremity muscles, is unique. We conclude that B. dermatitidis is a potential cause of classic pyomyositis.

An unusual case of Aspergillus fibrosing mediastinitis.

Fibrosing mediastinitis due to Aspergillus is rare, particularly in the immunocompetent host. Fibrosing mediastinitis due to Aspergillus species in the immunocompetent patient can be indolent and may be treated with antifungal therapy rather than surgery. We present a 78-year-old nonsmoking, nondiabetic woman with chronic fibrosing mediastinitis due to Aspergillus. Multiple attempts at securing a tissue diagnosis were inconclusive. Ultimately, Aspergillus infection was diagnosed by a video-assisted thoracoscopic surgical biopsy. The patient was started on oral voriconazole, and she remains clinically stable with radiographic improvement. A prolonged, perhaps lifelong, course of antifungal therapy is planned.

Voriconazole use for endemic fungal infections.

In a retrospective review of 24 patients with histoplasmosis, blastomycosis, or coccidioidomycosis treated with voriconazole (most for salvage therapy), the outcome was favorable (improved or stable) for 22 (95.8%) within 2 months of starting voriconazole and for 20 (83.3%) at the last follow-up. Prospective studies are required to determine its role in the treatment of endemic mycoses.

Clinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.

Evidence-based guidelines for the management of patients with blastomycosis were prepared by an Expert Panel of the Infectious Diseases Society of America. These updated guidelines replace the previous management guidelines published in the April 2000 issue of Clinical Infectious Diseases. The guidelines are intended for use by health care providers who care for patients who have blastomycosis. Since 2000, several new antifungal agents have become available, and blastomycosis has been noted more frequently among immunosuppressed patients. New information, based on publications between 2000 and 2006, is incorporated in this guideline document, and recommendations for treating children with blastomycosis have been noted.

The epidemiology of blastomycosis in Illinois and factors associated with death.

BACKGROUND: Blastomycosis is a systemic fungal disease that may be asymptomatic or progressive and may lead to death. METHODS: In response to a reported increase in the number of cases of blastomycosis in Illinois, surveillance data reported to the Illinois Department of Public Health from January 1993 to August 2003 were analyzed and the medical records of 4 patients who died were reviewed. RESULTS: Among the 500 cases reported, the median age of the patients was 43 years (range, 4-87 years), and 34 patients (7%) died. Higher rates of mortality were observed among persons who were black, who were > or =65 years of age, and who were male. The median time from onset of illness to diagnosis was 128 days (range, 12-489 days). Death was associated with a time from onset of illness to diagnosis of > or =128 days (OR, 2.1; 95% CI, 1.0-4.8). During the period from 1993 through 2002, the number of cases reported per year increased from 24 to 87 (P<.05). CONCLUSIONS: The incidence of blastomycosis has been increasing in Illinois. To reduce mortality related to delay in diagnosis and treatment, medical providers need to be educated about blastomycosis, with an emphasis on symptom recognition, methods of diagnosis, and appropriate antifungal treatment.