Aspergilosis pulmonar en un paciente crítico no inmunodeprimido

BackgroundIn non-immunocompromised patients admitted to intensive care departments or units (ICU), it is difficult to establish a definitive diagnosis of pulmonary aspergillosis because the signs and symptoms of this infectious disease are non-specific, and serological techniques are not very specific as well. For this reason, a diagnosis of possible pulmonary aspergillosis is initially established, and the starting of the treatment is controversial.Case reportAn immunocompetent subject had a work-related accident after a fall, which resulted in multiple injuries (head, thorax, lower extremities). The patient required mechanical ventilation since admission. On the second week of ICU admission, he showed a clinical presentation of respiratory infection with fever, purulent secretions, bilateral pulmonary infiltrates and repeated isolation of Mucor and Aspergillus fumigatus in bronchial secretions and pharyngeal swabs. The patient was treated with amphotericin B lipid complex and voriconazole with an excellent clinical and radiological outcome.ConclusionsCombined treatment of antifungal agents, in this case amphotericin B lipid complex and voriconazole, is a therapeutic possibility to be considered in patients who failed to respond to initial antifungal monotherapy.     

Breakthrough pulmonary Aspergillus fumigatus infection with multiple triazole resistance in a Spanish patient with chronic myeloid leukemia

BackgroundAn allogeneic hematopoietic cell transplantation (allo-HCT) patient presented with chronic pulmonary aspergillosis associated to pulmonary graft versus host disease (GVHD) and was treated for a long time with several antifungal agents that were administered as prophylaxis, combination therapies, and maintenance treatment. The patient suffered from a breakthrough invasive pulmonary aspergillosis due to Aspergillus fumigatus after long-term antifungal therapy.Material and methodsSeveral isolates were analyzed. First isolates were susceptible in vitro to all azole agents. However, after prolonged treatment with itraconazole and voriconazole a multiple azole resistant A. fumigatus isolate was cultured from bronchoalveolar lavage (BAL) when the patient was suffering from an invasive infection, and cavitary lesions were observed.ResultsAnalysis of the resistant mechanisms operating in the last strain led us to report the first isolation in Spain of an azole resistant A. fumigatus strain harboring the L98H mutation in combination with the tandem repeat (TR) alteration in CYP51A gene (TR-L98H). Long-term azole therapy may increase the risk of resistance selecting strains exhibiting reduced susceptibility to these compounds. However, since the isolates were genetically different the suggestion that could be made is that the resistance was not induced during the prolonged azole therapy but the patient might simply have acquired this resistant isolate from the environment, selected by the therapy.ConclusionsThese findings suggest that in all long-term treatments with antifungal agents, especially with azoles, repeated sampling and regular susceptibility testing of strains isolated is necessary as resistant isolates could be selected.     

Invasive aspergillosis with extrapulmonary involvement: pathogenesis, clinical characteristics and prognosis

BackgroundThe incidence of invasive aspergillosis has increased worldwide. Information regarding the clinical characteristics of patients with extrapulmonary involvement is scarce.ObjectiveWe aimed to describe the pathogenesis, characteristics and outcomes of patients with invasive aspergillosis and extrapulmonary disease.MethodsA retrospective study conducted in a university hospital in Barcelona, Spain (1995-2011).ResultsA total of 12 cases of invasive aspergillosis and extrapulmonary involvement were found. The most common clinical manifestations were invasive sinusitis, early postoperative prosthetic valve endocarditis, fungaemia, postoperative meningitis, multiple brain abscesses and lumbar spondylitis with epidural abscess. Sinusitis occurred frequently in patients without immunosuppression and had invasive brain involvement in one case. Endocarditis was associated with multiple septic metastases. Concomitant lung involvement was documented in 5 cases. The strains isolated were Aspergillus fumigatus (5), Aspergillus flavus (3), and Aspergillus niger (2). The species of Aspergillus was not established for 3 isolates. All patients were treated with antifungals and surgery was performed in 8 cases. Outcome was related with the source of infection; all patients with invasive sinusitis survived, while the remaining patients had a high mortality rate (88%).ConclusionsInvasive aspergillosis with extrapulmonary involvement is rare. The most common presentation is invasive sinusitis, which has a lower mortality. Other clinical forms with extrapulmonary involvement were associated with severe immunosuppression or previous surgery, and had a poor outcome.     

Azole Resistance in <Emphasis Type="Italic">Aspergillus fumigatus</Emphasis> in Patients with Cystic Fibrosis: A Matter of Concern?

Aspergillus fumigatus is the most frequent filamentous fungus isolated from respiratory specimens from patients with cystic fibrosis (CF). Triazoles are the most widely used antifungals in the treatment of allergic bronchopulmonary aspergillosis (ABPA) and invasive aspergillosis (IA) in CF patients. Treatment success could be severely compromised by the occurrence of azole-resistant A. fumigatus (ARAf), which is increasingly reported worldwide from both clinical samples and the environment. In previous studies, ARAf has been detected in up to 8% of CF patients. Isolates from CF patients requiring antifungal treatment should therefore be routinely subjected to antifungal susceptibility testing. The optimal treatment of ABPA or IA in CF patients with azole-resistant isolates has not been established; treatment options include liposomal amphotericin B i.v. and/or echinocandins i.v.     

Chemosensitization prevents tolerance of Aspergillus fumigatus to antimycotic drugs

Tolerance of human pathogenic fungi to antifungal drugs is an emerging medical problem. We show how strains of the causative agent of human aspergillosis, Aspergillus fumigatus, tolerant to cell wall-interfering antimycotic drugs become susceptible through chemosensitization by natural compounds. Tolerance of the A. fumigatus mitogen-activated protein kinase (MAPK) mutant, sakAΔ, to these drugs indicates the osmotic/oxidative stress MAPK pathway is involved in maintaining cell wall integrity. Using deletion mutants of the yeast, Saccharomyces cerevisiae, we first identified thymol and 2,3-dihydroxybenzaldehyde (2,3-D) as potent chemosensitizing agents that target the cell wall. We then used these chemosensitizing agents to act as synergists to commercial antifungal drugs against tolerant strains of A. fumigatus. Thymol was an especially potent chemosensitizing agent for amphotericin B, fluconazole or ketoconazole. The potential use of natural, safe chemosensitizing agents in antifungal chemotherapy of human mycoses as an alternative to combination therapy is discussed.     

TR34/L98H Mutation in <Emphasis Type="Italic">CYP51A</Emphasis> Gene in <Emphasis Type="Italic">Aspergillus fumigatus</Emphasis> Clinical Isolates During Posaconazole Prophylaxis: First Case in Korea

Azole resistance in Aspergillus fumigatus is an emerging problem, especially in immunocompromised patients. It has been reported worldwide, including in Asia, but has not yet been reported in Korea. Here, we report a case of invasive pulmonary aspergillosis (IPA) caused by azole-resistant A. fumigatus that developed in a hematopoietic stem cell transplantation recipient during posaconazole prophylaxis for immunosuppressive therapy of graft-versus-host diseases. We identified TR34/L98H/S297T/F495L mutation in the CYP51A gene of A. fumigatus clinical isolate obtained from bronchial washing fluid. Minimal inhibitory concentrations for itraconazole, voriconazole, and posaconazole were >?16, 1, and 4 μg/mL, respectively. While IPA improved partially under voriconazole treatment, the patient died from carbapenemase-producing Klebsiella pneumoniae bacteremia. Further epidemiological surveillance studies are warranted.     

Management of allergic aspergillosis

Treatment of allergic bronchopulmonary aspergillosis depends on accurate diagnosis, which is difficult because of multiple clinical, radiographic, and immunologic criteria; unstandardized immunoassays; and its similarity to cystic fibrosis. Advances in chest CT interpretation, measuring serum Aspergillus fumigatus-specific antibodies and the T_H2 chemokine thymusactivated-and-regulated chemokine, recognizing risk factors, should improve diagnostic accuracy. Oral glucocorticosteroids remain the mainstay of treatment. Dose regimen and duration are not standardized, so expert recommendations are used. Inhaled steroids have not been proven to be effective. Due to relapse and toxicity, itraconazole has been added as second-tier therapy, supported by randomized, placebo-controlled trials in asthma and open-label trials in cystic fibrosis. Itraconazole is steroid sparing with anti-inflammatory aspects and poor bioavailability. Despite combination steroid-itraconazole therapy, relapses and steroid toxicity have led to open-label use of voriconazole, nebulized amphotericin B, monthly high-dose intravenous methylprednisolone, and omalizumab. Controlled trials are needed to evaluate these and other antifungal or immunomodulatory interventions.     

Successful Antifungal Combination Therapy and Surgical Approach for A<Emphasis Type="Italic">spergillus fumigatus</Emphasis> Suppurative Thyroiditis Associated with Thyrotoxicosis and Review of Published Reports

In immunocompromised patients, Aspergillus infections are important causes of morbidity and mortality. We describe a patient with cryoglobulinemic vasculitis who developed disseminated invasive aspergillosis with thyrotoxicosis caused by Aspergillus fumigatus. The diagnosis was based upon radiological, microbiological and pathological findings. The patient was treated successfully with voriconazole and caspofungin treatment followed by total thyroidectomy. We provide an overview of published reports on Aspergillus thyroiditis with an emphasis on therapeutic approaches.     

Micafungina en el tratamiento de la infección fúngica en modelos animales

BackgroundMicafungin is an echinocandin antifungal drug recently approved for the treatment of candidiasis. The possibility of its clinical use against other invasive mycoses, has aroused the interest of numerous investigators in evaluating its efficacy in different animal models.ObjectivesTo critically review the current data on the use of micafungin in the treatment of invasive mycoses in animal models.MethodsWe searched the PubMed/Medline data base (National Library of Medicine) from 2005 to 2008, both inclusive, on the use of micafungin in the experimental treatment of the fungal infection.Results and conclusionsSeven, of a total of 18 articles reviewed, were done in animal models of candidiasis and six in animal models of pulmonary or SNC aspergillosis. Similarly to the other echinocandins, caspofungin and anidulafungin, micafungin seems to exert a fungicidal activity against Candida albicans and Candida glabrata and a fungistatic activity against Aspergillus fumigatus. The paradoxical effect observed in lung tissue the experimental caspofungin treatment of aspergillosis has not been seen in the case of micafungin. The available data demonstrate a higher efficacy of micafungin versus fluconazole in the experimental treatment of C. albicans infections caused by strains susceptible in vitro to both drugs. To improve the efficacy of micafungin in the treatment of C. glabrata and A. fumigatus infections, several authors have tested different combined therapies, the combination of micafungin with amphotericin B being that showed the best results.     

Phaeohyphomycosis caused by Cladophialophora bantiana

BackgroundCladophialophora bantiana is the most frequent cause of central nervous system phaeohyphomycosis.AimsWe report a case of phaeohyphomycosis by C. bantiana in a patient with underlying lung disease on steroid therapy.MethodsAn 81-year-old male was admitted in August 2011 with a history of difficulty speaking and deflection of the oral commeasure to the left side with a brain abscess. Brain tissue was cultured on Sabouraud media and sequence analysis of the internal transcribed spacer region of the ribosomal DNA was done for identification purposes. Susceptibility testing to various antifungal agents was performed using the microdilution test.ResultsHistopathological examination of the brain tissue ruled out malignancy and the presence of dematiaceous hyphae was observed. Culture showed the presence of a single black fungus, identified as C. bantiana. It was susceptible to all antifungals, except to caspofungin. The patient was treated with voriconazole plus liposomal amphotericin B. Cerebral cranial computed tomography [CCT] scans demonstrated persistence of the intraparenchymal abscess collection. Despite surgical and medical treatment with antifungal drugs, the patient died 5 months after the first diagnosis of the cerebral occupying lesion was made.ConclusionsPhaeohyphomycosis is an uncommon infection with severe limitations on the clinical clues that can help in early diagnosis. Fungal species identification is mandatory for epidemiological and therapeutic reasons. The MICs could be useful in selecting the appropriate antifungal agent. Avoiding the unnecessary exposure to soil or other media potentially contaminated with fungal spores should be recommended to any immunosuppressed patient.     

Liver abscess caused by Candida haemulonii var. vulnera. First case report in Peru

BackgroundLiver abscesses caused by Candida species are mainly found in immunocompromised hosts, associated with conditions (such as neutropenia and mucositis) that facilitate the spreading of microorganisms from the gastrointestinal tract.Case reportWe present the case of a non-immunocompromised 72-year-old woman with a liver abscess caused by Candida haemulonii var. vulnera, in whom potential associated conditions could be polycystic kidney disease and renal replacement therapy. The patient experienced clinical resolution after percutaneous drainage and treatment with caspofungin.ConclusionsTo our knowledge, this is the first case reported in Peru of a liver abscess due to Candida haemulonii var. vulnera, a clinical presentation that has not been described previously. This finding should prompt us to establish active surveillance of causal agents of systemic candidiasis.     

In vitro interaction between glabridin and voriconazole against Aspergillus fumigatus isolates

BackgroundVoriconazole (VRC) is widely recommended as the first-line therapy for invasive aspergillosis. However, surveillance studies have demonstrated that there is an increase in the frequency of azole resistance among Aspergillus fumigates isolates. In recent years, more studies on effective synergisms between natural agents and antifungal drugs have been published.AimsTo evaluate the synergistic antifungal effect of glabridin (Gla) and VRC against A. fumigatus isolates.MethodsPotential interactions between Gla and VRC were studied by using a microdilution checkerboard method based on the CLSI reference technique. To assess the interaction of drugs the fractional inhibitory concentration index (FICI) was calculated based on the Loewe Additivity model.ResultsThe minimum inhibitory concentrations (MIC) obtained with Gla alone were relatively high (MIC₅₀ 16 μg/ml). However, our results showed synergistic interaction between Gla and VRC against A. fumigatus strains, with FICI range values between 0.15 and 0.5.ConclusionsSynergistic activity of Gla and VRC against both VRC-sensitive and -resistant A. fumigatus isolates may lead to design new antifungal agents, especially for inhibiting those azole-resistant strains.     

Osteomyelitis of the rib cage by Aspergillus flavus

BackgroundAspergillus osteomyelitis of the ribs is relatively uncommon. It is a debilitating and severe form of invasive aspergillosis.Case reportA 61year-old female presented with spontaneous chest pain on the right side of the rib cage and a palpable soft-tissue mass. FDG-PET/CT scan identified activity in the infected site. The lesion was punctured, and purulent material was sent to the laboratory. Aspergillus complex Flavi was isolated. An antifungal treatment with voriconazole was started. The lesion healed, and no recurrence was observed at 8-month follow-up. Molecular identification of the isolate was based on PCR amplification and sequencing of β-tubulin gene. Aspergillus flavus was identified.ConclusionsOur case highlights the relevance of microbiological studies in patients with osteomyelitis and the involvement of soft tissue. The FDG-PET/CT scan was found to be a useful tool for revealing the extent of the disease and evaluating the response to the antifungal therapy.     

The Pathogenesis of Aspergillus fumigatus,Host Defense Mechanisms,and the Development of AFMP4 Antigen as a Vaccine

Aspergillus fumigatus is one of the ubiquitous fungi with airborne conidia, which accounts for most aspergillosis cases. In immunocompetent hosts, the inhaled conidia are rapidly eliminated. However, immunocompromised or immunodeficient hosts are particularly vulnerable to most Aspergillus infections and invasive aspergillosis (IA), with mortality from 50% to 95%. Despite the improvement of antifungal drugs over the last few decades, the therapeutic effect for IA patients is still limited and does not provide significant survival benefits. The drawbacks of antifungal drugs such as side effects, antifungal drug resistance, and the high cost of antifungal drugs highlight the importance of finding novel therapeutic and preventive approaches to fight against IA. In this article, we systemically addressed the pathogenic mechanisms, defense mechanisms against A. fumigatus, the immune response, molecular aspects of host evasion, and vaccines’ current development against aspergillosis, particularly those based on AFMP4 protein, which might be a promising antigen for the development of anti-A. fumigatus vaccines.     

Lethal destructive sinusopathy due to amphotericin B-resistant Aspergillus flavus: A case report

BackgroundThe prevalence of pulmonary aspergillosis and the importance of its early diagnosis are recognized. However, non-pulmonary involvement, including the sinuses region, is not frequently reported, and an infection in this area can affect all paranasal sinuses (pansinusopathy), being a rare pathology that affects immunocompromised hosts. Recent studies have highlighted the occurrence of Aspergillus flavus resistant to antifungal therapy. Therefore, a nasal sinus infection by resistant Aspergillus strains in immunocompromised patients may be linked to a high risk of lethality.Case reportWe are reporting a resistant A. flavus infection in an allogeneic hematopoietic stem cell transplant recipient with episodes of febrile neutropenia, and prolonged use of various antibacterial drugs and antifungal prophylaxis. The patient underwent brain magnetic resonance, which showed the presence of pansinusopathy, and presented necrosis in the left nasal region. Direct microscopic examination of a sample taken from the nasal mucosa revealed the presence of septate hyphae and conidiophores resembling those of A. flavus, that species being the identification achieved with MALDI-TOF MS. Antifungigram was performed by microdilution in broth (EUCAST-E.DEF. 9.3.2) and E-test, and resistance to amphotericin B was shown in both tests. The patient died after septic shock and hemorrhage.ConclusionsInvasive fungal infections due to amphotericin-B resistant A. flavus may lead to the death of the patient due to an ineffective therapeutic management. Therefore, antifungal susceptibility testing are of utmost importance for administering the proper treatment.     

Aspergillosis by cryptic Aspergillus species: A case series and review of the literature

BackgroundThe cryptic Aspegillus species are rare, these microorganisms are usually more resistant to common antifungal therapies. Therefore, a correct identification is important when evaluating the impact of such species in aspergillosis.AimsWe aimed to describe the frequency, clinical and microbiological characteristics, and the outcomes of those cases of aspergillosis caused by cryptic species in a tertiary hospital.MethodsWe retrospectively identified all microbiologically documented cases of aspergillosis between January 2013 and December 2018. Definitive species identification of clinically significant isolates was achieved via sequencing methods. The polymerase chain reaction (PCR) products were sequenced, and the results obtained were compared to sequences deposited in GenBank. Antifungal susceptibility testing was performed using the Sensititre® YeastOne® panel.ResultsA total of 679 Aspergillus isolates were recovered from 489 patients, of which 109 were clinically relevant. Ten (9.2%) isolates were identified as cryptic species: Aspergillus arcoverdensis (2), Aspergillus lentulus (2), Aspergillus ellipticus (2), Aspergillus alliaceus (1), Aspergillus nomius (1), Aspergillus tubingensis (1) and Aspergillus montevidensis (1). Most patients already suffered some type of immunosuppression. Half of these patients had required intensive care before the infection showed up, and most of them had a pulmonary infection. Mortality at the 100-day follow-up was 40%. Antifungal susceptibility testing was performed on three of the isolates (A. arcoverdensis, A. tubingensis and A. nomius), which showed high minimum inhibitory concentrations (MIC) for azoles and amphotericin B.ConclusionsThe frequency of cryptic species in our centre was 9.2%. Most patients had some degree of immunosuppression, and the mortality rate was 40%.     

以反复多发脓肿为表现的播散型隐球菌病1例

报道以反复多发脓肿为表现的播散型隐球菌病患者1例。患者男,68岁,因＂全身反复多发性脓肿1a,伴低热2个月余＂入院,该患者以背部脓肿起病,反复发作累及肺部、骨骼、皮肤等多部位,多次组织及血标本病原学检查、隐球菌乳胶凝集试验均阴性,给予多种抗菌药物治疗无效,后在右髂部脓肿切开组织物中培养到新生隐球菌。经脓肿切开引流及静脉滴注两性霉素B脂质体联合伊曲康唑治疗后,脓肿消退,症状消失,改用氟康唑联合氟胞嘧啶治疗4个月后停药,并已随访至今7个月,患者未有发热及新的脓肿出现。     

Fungal cerebral abscess in a diabetic patient successfully treated with surgery followed by prolonged antifungal therapy

BackgroundIntracranial fungal masses are uncommon diseases, but their incidence is increasing, most often due to the prolonged survival of patients with different immunodeficiencies. The management of patients with intracranial fungal masses included stereotactic biopsy for diagnosis, partial or radical surgery excision and prolonged antifungal therapy.AimsWe report the case of a 51-year-old diabetic man with a history of psoas abscess due to Candida albicans 1 year before the onset of neurological symptoms, including headache and generalized tonoclonic seizures.MethodsMagnetic resonance imaging showed a single lesion located in the right parietal lobe with mass effect, surrounding edema and enhancement after injection of gadolinium. The material was purulent.ResultsDirect microscopic examination showed hyaline, branched and septate hyphae compatible with fungal elements.ConclusionsFungal infections, especially due to Candida species, should be considered in diabetic patients with parenchymal brain abscesses. Radical excision followed by prolonged antifungal therapy based on fluconazole or amphotericin B is necessary to improve the prognosis of this type of patients.     

Scaffold hopping of sampangine: Discovery of potent antifungal lead compound against Aspergillus fumigatus and Cryptococcus neoformans

Discovery of novel antifungal agents against Aspergillus fumigatus and Cryptococcus neoformans remains a significant challenge in current antifungal therapy. Herein the antifungal natural product sampangine was used as the lead compound for novel antifungal drug discovery. A series of D-ring scaffold hopping derivatives were designed and synthesized to improve antifungal activity and water solubility. Among them, the thiophene derivative S2 showed broad-spectrum antifungal activity, particularly for Aspergillus fumigatus and Cryptococcus neoformans. Moreover, compound S2 also revealed better water solubility than sampangine, which represents a promising antifungal lead compound for further structural optimization.