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Background.Treatment of invasive mold infection in immunocompromised patients remains challenging. Voriconazole has been shown to have efficacy and survival benefits over amphotericin B deoxycholate, but its utility is limited by drug interactions. Liposomal amphotericin B achieves maximum plasma levels at a dosage of 10 mg/kg per day, but clinical efficacy data for higher doses are lacking. Methods.In a double-blind trial, patients with proven or probable invasive mold infection were randomized to receive liposomal amphotericin B at either 3 or 10 mg/kg per day for 14 days, followed by 3 mg/kg per day. The primary end point was favorable (i.e., complete or partial) response at the end of study drug treatment. Survival and safety outcomes were also evaluated. Results.Of 201 patients with confirmed invasive mold infection, 107 received the 3-mg/kg daily dose, and 94 received the 10-mg/kg daily dose. Invasive aspergillosis accounted for 97% of cases. Hematological malignancies were present in 93% of patients, and 73% of patients were neutropenic at baseline. A favorable response was achieved in 50% and 46% of patients in the 3- and 10-mg/kg groups, respectively (difference, 4%; 95% confidence interval, -10% to 18%; P > .05); the respective survival rates at 12 weeks were 72% and 59% (difference, 13%; 95% confidence interval, -0.2% to 26%; P > .05). Significantly higher rates of nephrotoxicity and hypokalemia were seen in the high-dose group. Conclusions.In highly immunocompromised patients, the effectiveness of 3 mg/kg of liposomal amphotericin B per day as first-line therapy for invasive aspergillosis is demonstrated, with a response rate of 50% and a 12-week survival rate of 72%. The regimen of 10 mg/kg per day demonstrated no additional benefit and higher rates of nephrotoxicity.

Chronic granulomatous disease (CGD) is characterized by life-threatening bacterial and fungal infections. Treatment with posaconazole led to a complete response in 7 of 8 patients with CGD with invasive mold infections (7 proven cases and 1 possible case) after failure or intolerance of treatment with standard antifungal agents. In this preliminary study, salvage treatment with posaconazole was safe and effective.

Background. Coccidioidomycosis can be difficult to treat with available therapies, particularly in patients with progressive or disseminated disease. Posaconazole is a new azole antifungal with potent activity against Coccidioides species, the causative agent of coccidioidomycosis. Methods. Twenty patients with chronic pulmonary or nonmeningeal disseminated coccidioidomycosis were enrolled in a multicenter trial to study the safety and tolerability of posaconazole therapy, with efficacy as a secondary end point. Patients received posaconazole (400 mg/day) in capsule formulation for up to 6 months. Safety was evaluated on the basis of the occurrence of adverse events. A satisfactory efficacy response was defined as a ⩾50% reduction in the Mycoses Study Group score from baseline. Results. Seventeen (85%) of 20 patients had a satisfactory response to treatment. The median duration of treatment was 173 days. Paired baseline and end-of-treatment culture results for Coccidioides species were available for 4 patients, all of whom converted from being positive to being negative for Coccidioides species. Relapse was experienced by 3 of 9 patients who did not receive antifungal therapy during the follow-up period. In general, posaconazole therapy was well tolerated, with 12 of 20 patients reporting adverse events that were possibly or probably related to treatment. The most common adverse events were dry mouth (in 5 patients [25%]) and headache (in 3 patients [15%]). Conclusions. Courses of posaconazole therapy that were up to 6 months in duration were well tolerated in patients with coccidioidomycosis. Although this study was limited by the number of patients enrolled, it clearly demonstrates that posaconazole shows promise in the treatment of patients with coccidioidomycosis and warrants additional investigation in a full-scale clinical trial.

Introduction Fungal airway infection (airway mycosis) is increasingly recognized as a cause of asthma and related disorders. However, prior controlled studies of patients treated with antifungal antibiotics have produced conflicting results. Our objective is to measure the effect of antifungal therapy in moderate to severe adult asthmatics with positive fungal sputum cultures in a single center referral‐based academic practice. Methods We retrospectively evaluated 41 patients with asthma and culture‐proven airway mycosis treated with either terbinafine, fluconazole, itraconazole, voriconazole, or posaconazole for 4 to >12 weeks together with standard bronchodilator and anti‐inflammatory agents. Asthma control (1 = very poorly controlled; 2 = not well controlled; and 3 = well controlled), peak expiratory flow rates (PEFR), serum total IgE, and absolute blood eosinophil counts before and after antifungal therapy were assessed. In comparison, we also studied nine patients with airway mycosis and moderate to severe asthma who received standard therapy but no antifungals. Results Treatment with azole‐based and allylamine antifungals was associated with improved asthma control (mean change in asthma control 1.72–2.25; p = 0.004), increased PEFR (69.4% predicted to 79.3% predicted, p = 0.0011) and markedly reduced serum IgE levels (1,075 kU/L to 463 kU/L, p = 0.0005) and blood eosinophil counts (Mean absolute count 530–275, p = 0.0095). Reduction in symptoms, medication use, and relapse rates decreased as duration of therapy increased. Asthmatics on standard therapy who did not receive antifungals showed no improvement in asthma symptoms or PEFR. Antifungals were usually well tolerated, but discontinuation (12.2%) and relapse (50%) rates were relatively high. Conclusion Antifungals help control symptoms in a subset of asthmatics with culture‐proven airway mycosis. Additional randomized clinical trials are warranted to extend and validate these findings. Fungal airway infection (airway mycosis) is increasingly recognized as a cause of asthma and related disorders, but existing clinical trials fail to clarify the utility of antifungal antibiotics in severe asthma. Our retrospective analysis of patients receiving antifungal therapy at a single institution indicate that azole‐based and allylamine antifungal antibiotics improve asthma control and lung function while decreasing serum IgE levels and blood eosinophil counts. Additional randomized clinical trials are warranted to extend and validate these findings.

Combination antifungal therapy is increasingly used in the treatment of invasive aspergillosis. Whether the interaction between amphotericin B and triazoles is antagonistic against invasive aspergillosis is a controversial issue that is not likely to be resolved through a randomized clinical trial. Here, we found both in vitro and in vivo antagonism between liposomal amphotericin B and ravuconazole in simultaneous treatment of experimental invasive pulmonary aspergillosis in persistently neutropenic rabbits. Bliss independence–based drug-interaction modeling showed significant antagonism in vitro and in vivo, with the observed drug effects being 20%–69% lower than would be expected if the drugs were acting independently. These in vitro and in vivo findings of antagonism were consistent with the findings from Loewe additivity–based drug-interaction modeling. No pharmacokinetic interaction was found. The combination of a triazole and polyene may be antagonistic in the treatment of invasive pulmonary aspergillosis

Background: Stroke-associated pneumonia (SAP) has been implicated in the morbidity, mortality and increased medical cost after acute ischemic stroke. The annual cost of SAP during hospitalization in the United States approaches USD 459 million. The incidence and prognosis of SAP among intensive care unit (ICU) patients have not been thoroughly investigated. We reviewed the pathophysiology, microbiology, incidence, risk factors, outcomes and prophylaxis of SAP with special attention to ICU studies. Methods: To determine the incidence, risk factors and prognosis of acute SAP, PubMed was searched using the terms ‘pneumonia' AND ‘neurology intensive unit' and the MeSH terms ‘stroke' AND ‘pneumonia'. Non-English literature, case reports and chronic SAP studies were excluded. Studies were classified into 5 categories according to the setting they were performed in: neurological intensive care units (NICUs), medical intensive care units (MICUs), stroke units, mixed studies combining more than one setting or when the settings were not specified and rehabilitation studies. Results: The incidences of SAP in the following settings were: NICUs 4.1-56.6%, MICUs 17-50%, stroke units 3.9-44%, mixed studies 3.9-23.8% and rehabilitation 3.2-11%. The majority of NICU and MICU studies were heterogeneous including different neurovascular diseases, which partly explains the wide range of SAP incidence. The higher incidence in the majority of ICU studies compared to stroke units or acute floor studies is likely explained by the presence of mechanical ventilation, higher stroke severity causing higher rates of aspiration and stroke-induced immunodepression among ICU patients. The short-term mortality of SAP was increased among the mixed and stroke unit studies ranging between 10.1 and 37.3%. SAP was associated with worse functional outcome in the majority of stroke unit and floor studies. Mortality was less consistent among NICU and MICU studies. This difference could be due to the heterogeneity of ICU studies and the effect of small sample size or other independent risk factors for mortality such as the larger neurological deficit, mechanical ventilation, and age, which may simultaneously increase the risk of SAP and mortality confounding the outcomes of SAP itself. The pathophysiology of SAP is likely explained by aspiration combined with stroke-induced immunodepression through complex humeral and neural pathways that include the hypothalamic-pituitary-adrenal axis, parasympathetic and sympathetic systems. Conclusions: A unified definition of SAP, strict inclusion criteria, and the presence of a long-term follow-up need to be applied to the future prospective studies to better identify the incidence and prognosis of SAP, especially among ICU patients.

We report 3 cases of probable invasive pulmonary disease caused by Bjerkandera spp. fungi in immunocompromised patients in Germany. Accurate identification required internal transcribed spacer sequencing. Response to antifungal treatment varied. Our report underlines the pathogenic potential of Bjerkandera spp. and the importance of molecular diagnostics in rare fungal infections.

Early diagnosis of invasive mucormycosis is important for timely therapeutic intervention, improved survival, and reduced morbidity. Given the importance of an accurate and rapid diagnosis of invasive mucormycosis to guide the timely initiation of amphotericin B and possible surgical intervention, a coordinated multidisciplinary approach of clinical assessment, diagnostic imaging, and laboratory assessment is necessary. Laboratory assessment for mucormycosis includes the conventional methods of direct examination and culture of tissue, respiratory secretions, bronchoalveolar lavage fluid, and other fluids. However, because conventional diagnostic tools are limited in their sensitivity, advanced molecular amplification systems, antigen detection assays, proteomic profiles, and metabolite detection may complement existing approaches to improve the rate of early diagnosis of invasive mucormycosis.

Purpose Mucormycosis encompasses a group of opportunistic fungal infections caused by Zygomycetes, order Mucorales. Mucormycosis can manifest as rhino-orbito-cerebral, pulmonary, gastrointestinal, cutaneous, and disseminated infections. Pulmonary mucormycosis is the second most common presentation. This manuscript characterizes the demographics, clinical presentation, diagnostic procedures, radiologic findings, therapeutic interventions, and outcome in pulmonary mucormycosis. Methods We retrospectively reviewed clinical data of 35 patients with pulmonary mucormycosis from 2000 to 2015. Microbiologic diagnosis was based on positive culture from a sterile site or findings on histopathology consistent with mucormycosis. Independent predictors of 28-day mortality were assessed using logistic regression. Survival curves were estimated using Kaplan–Meier method. Results There was male predominance with a mean age of 55 ± 15 years. Analysis of predisposing conditions revealed the prevailing presence of malignancy. Sixty-six percent of patients were receiving immunosuppressive agents. Common presenting clinical findings were fever, neutropenia, dyspnea, and cough. Radiologic findings included pleural effusion and nodules. All patients received medical therapy and 43% underwent additional surgical intervention. Twenty eight day mortality was 29% with concurrent bacteremia found as the sole independent predictor. Similar survival from pulmonary mucormycosis was noted over time. Conclusions Pulmonary mucormycosis is an opportunistic angioinvasive fungal infection. Physicians must have a high level of suspicion in immunocompromised patients with fever and respiratory symptoms refractory to antibiotics. A low threshold should be had for performing an invasive procedure to gain reliable diagnosis, as early, aggressive medical and surgical interventions are needed for successful treatment.