A model of cerebral aspergillosis in non-immunosuppressed nursing rats

Central nervous system aspergillosis is an often fatal complication of invasive Aspergillus infection. Relevant disease models are needed to study the pathophysiology of cerebral aspergillosis and to develop novel therapeutic approaches. This study presents a model of central nervous system aspergillosis that mimics important aspects of human disease. Eleven-day-old non-immunosuppressed male Wistar rats were infected by an intracisternal injection of 10μl of a conidial suspension of Aspergillus fumigatus. An inoculum of 7.18log10 colony-forming units (CFU) consistently produced cerebral infection and resulted in death of all animals (n=25) within 3-10days. Median survival time was 3days. Histomorphologically, all animals developed intracerebral abscesses (2-26per brain) containing abundant fungal hyphae and neutrophils. Fungal culture of cortical homogenates yielded maximal growth on day 3 after infection (5.4log10CFU/g, n=15) that declined over time. Galactomannan concentrations in cortical homogenates, assessed as an index for hyphal burden, peaked on days 3-5. Fungal infection spread to peripheral organs in 83% of animals. Fungal burden in lung, liver, spleen and kidney was two orders of magnitude lower than in the brain. The successful establishment of a model of cerebral aspergillosis in a non-immunosuppressed host provides the opportunity to investigate mechanisms of disease and to develop novel treatment regimens for this commonly fatal infectio

Caspofungin Cerebral Penetration and Therapeutic Efficacy in Experimental Cerebral Aspergillosis.

Despite best available therapy, cerebral aspergillosis is an often-lethal complication of disseminated aspergillosis. There is an urgent need to expand the currently limited therapeutic options. In this study, we assessed cerebral drug exposure and efficacy of caspofungin (CAS) using a lethal infant rat model of cerebral aspergillosis. Eleven-day-old Wistar rats were infected by intracisternal injection of Aspergillus fumigatus conidia. Treatment started after 22 h and was continued for 10 days. Regimens were CAS 1 mg/kg/day intraperitoneally (i.p.), liposomal amphotericin B (L-AmB) 5 mg/kg/day i.p., and both drugs combined at the same dose i.p. Infected controls were given NaCl 0.85% i.p. Primary endpoints assessed were survival, cerebral fungal burden, galactomannan index, and drug concentrations in brain homogenate at 2, 3, 5, and 11 days after infection. Compared to those of controls (4.4 ± 2.7 days), survival times were increased by treatment with CAS alone (10.3 ± 1.7 days; P < 0.0001) and CAS combined with L-AmB (9.3 ± 2.8 days; P < 0.0001). In contrast, survival time of L-AmB-treated animals (4.3 ± 3.1 days) was not different from that of controls. Cerebral fungal burden and galactomannan index declined in all animals over time, without significant differences between controls and treated animals. CAS trough levels in brain tissue were between 0.84 and 1.4 μg/g, concentrations we show to be associated with efficacy. AmB trough levels in brain tissue were higher than the MIC of the A. fumigatus isolate. In summary, CAS concentrations in brain tissue suggest it may be therapeutically relevant and it significantly improved survival in this lethal model of cerebral aspergillosis in nonneutropenic rats. The clinical efficacy of CAS treatment for cerebral aspergillosis merits further study. IMPORTANCE Treatment options for cerebral aspergillosis, an often-lethal disease, are limited. The echinocandins (caspofungin is one of them) are not recommended treatment because their brain tissue penetration is often considered insufficient. In a nursing rat model of cerebral aspergillosis that mimics human disease, we found potentially therapeutically relevant concentrations of caspofungin in brain tissue and prolonged survival of caspofungin-treated animals. The efficacy of caspofungin in the treatment of cerebral aspergillosis documented here, if confirmed in other animal models (especially immunosuppressed murine models) and by using additional Aspergillus isolates across a range of CAS minimal effective concentrations (MECs), would suggest that caspofungin merits further study as a treatment option for patients suffering from aspergillosis disseminated to the brain

Ocular penetration of caspofungin in a rabbit uveitis model

Background: Little is known about the ocular penetration of echinocandin antifungals. We studied the ocular distribution of systemically administered caspofungin in a rabbit uveitis model. Methods: Caspofungin (1mg/kg per day) was given intravenously to rabbits as a single dose or as repeated daily doses on 7days starting 24h after induction of unilateral uveitis by intravitreal endotoxin injection. Caspofungin concentrations were determined by high-performance liquid chromatography in the cornea, aqueous humor, vitreous humor, and serum 4, 8, 16, and 24h after administration of a single dose and 24h after the last of seven doses. Results: The mean caspofungin concentration in the aqueous of the inflamed eye 4 and 8h after single-dose administration was 1.30 ± 0.39μg/ml and 1.12 ± 0.34μg/ml, respectively. Drug concentrations decreased to 0.24 ± 0.09μg/ml at 16h and 0.26 ± 0.14μg/ml at 24h. In the vitreous of inflamed eyes drug levels were undetectable at all time points. No drug was found in the aqueous of inflamed eyes 24h after the last of seven repeated doses, and the vitreous only contained trace amounts. In the corneas of inflamed eyes concentrations reached 1.64 ± 0.48μg/g at 4h, peaked at 2.16 ± 1.14μg/g at 8h, and declined to 1.87 ± 0.52μg/g and 1.49 ± 0.48μg/g at 16and 24h, respectively. After repeated dosing, corneal concentrations of caspofungin were 0.8 and 1.0μg/g and below the limit of detection in two of four animals. In non-inflamed eyes no drug was detectable in the aqueous and vitreous humor, and the corneas at any time point. Conclusions: In our model, caspofungin reached therapeutically relevant levels in the aqueous and cornea but not in the vitreous humor of inflamed eyes. Intraocular drug deposition was critically dependent on a disrupted blood-eye barrier. These findings suggest a limited role for caspofungin in the treatment of fungal endophthalmiti

Travel related histoplasmosis - a diagnostic challenge in a patient with tumor necrosis factor alpha (TNF-α) inhibitor therapy.

INTRODUCTION In a non-endemic setting, disseminated histoplasmosis is a rare travel-related health problem of immunosuppressed returnees from endemic regions. METHODS We describe the case of a 68-year-old man with rheumatoid arthritis and tumor necrosis factor alpha (TNF-α) inhibitor treatment-related immunodeficiency, who suffered from disseminated histoplasmosis after traveling to Brazil. Based on this case, we discuss challenges and pitfalls associated with the diagnosis of disseminated histoplasmosis in a non-endemic setting. RESULTS The disease mimicked a hemophagocytic lymphohistiocytosis (HLH) like syndrome. Histoplasma capsulatum was microscopically detected in bronchoalveolar fluid and bone marrow aspirate smears, but was initially misclassified as Leishmania spp., another class of pathogens, which may cause HLH like syndromes in immunocompromised individuals. DISCUSSION Since the clinical symptoms of histoplasmosis are nonspecific and physicians in non-endemic regions might not be familiar with this disease pattern, there is a risk of delayed diagnosis of travel related cases. Taking a thorough travel history is key in unclear cases of illness in immunocompromised patients

Travel related histoplasmosis – a diagnostic challenge in a patient with tumor necrosis factor alpha (TNF-α) inhibitor therapy

INTRODUCTION In a non-endemic setting, disseminated histoplasmosis is a rare travel-related health problem of immunosuppressed returnees from endemic regions. METHODS We describe the case of a 68-year-old man with rheumatoid arthritis and tumor necrosis factor alpha (TNF-α) inhibitor treatment-related immunodeficiency, who suffered from disseminated histoplasmosis after traveling to Brazil. Based on this case, we discuss challenges and pitfalls associated with the diagnosis of disseminated histoplasmosis in a non-endemic setting. RESULTS The disease mimicked a hemophagocytic lymphohistiocytosis (HLH) like syndrome. Histoplasma capsulatum was microscopically detected in bronchoalveolar fluid and bone marrow aspirate smears, but was initially misclassified as Leishmania spp., another class of pathogens, which may cause HLH like syndromes in immunocompromised individuals. DISCUSSION Since the clinical symptoms of histoplasmosis are nonspecific and physicians in non-endemic regions might not be familiar with this disease pattern, there is a risk of delayed diagnosis of travel related cases. Taking a thorough travel history is key in unclear cases of illness in immunocompromised patients

Revisiting systemic treatment of bacterial endophthalmitis: a review of intravitreal penetration of systemic antibiotics

Adjunctive systemic antibiotic therapy for treatment of bacterial endophthalmitis is controversial but common practice due to the severity of the disease. In absence of guidance documents, several antibiotic regimens are being used without applying evidence-based prescribing, thus leading to inappropriate treatment of this serious eye condition.; To summarize available data on intravitreal penetration of systemically administered antibiotics and to discuss their usefulness from a microbiological and pharmacological point of view.; We performed a systematic PubMed search of studies investigating antibiotic concentrations in the vitreous after systemic administration in humans, and selected animal models.; The best-documented agents achieving therapeutic levels in the vitreous are meropenem, linezolid and moxifloxacin. Vancomycin, cefazoline, ceftriaxone, ceftazidime, imipenem and trimethoprim-sulfamethoxazole reach levels justifying their use in specific situations. Available data do not support the use of ciprofloxacin, levofloxacin, aminoglycosides, aminopenicillins, piperacillin, cefepime, and clarithromycin. With very limited but available promising data, the use of daptomycin and rifampicin deserves further investigation.; The choice of the adjunctive systemic antibiotic agent - in situations where considered relevant for treatment - must to date be made on an individual base, considering microbiological aspects as well as operative status and inflammation of the eye. This review gives a systematic overview of antibiotic options and provides guidance to the clinician striving for optimal systemic antibiotic treatment of bacterial endophthalmitis

Improved survival rates of AML patients following admission to the intensive care unit.

Induction chemotherapy in AML patients may have life-threatening side effects requiring intensive care unit (ICU) treatment. We analyzed all AML patients receiving intensive chemotherapy at a single academic center between 01/2006-12/2016. At least one ICU admission was observed in 32% (76/240) patients, and 33% of those died following ICU admission. Whereas the ICU admission proportion remained stable, mortality after ICU admission decreased from 14% (2006-2008) to 3% (2014-2016; p = .056). The number of failing organ systems inversely correlated with surviving ICU admission (p 50% even after 14 days of ICU treatment. Progression-free and overall survival were comparable between ICU surviving patients and patients never needing ICU support. In conclusion, outcome after ICU admission of AML patients has substantially improved in recent years

Distribution of Aspergillus Species and Prevalence of Azole Resistance in Respiratory Samples From Swiss Tertiary Care Hospitals

Among 400 Aspergillus species from respiratory samples in Switzerland, Aspergillus fumigatus was the most frequent species. Non-fumigatus Aspergillus spp were more prevalent among solid organ transplant recipients and after azole exposure. Azole resistance was detected in 4 A fumigatus isolates, 3 of them with the "environmental" mutation TR$_{34}$/L98H in the cyp51A gene