Maged Muhammed

The challenge of managing fusariosis.

Fusarium is the second most frequent mold involved in fungal infections and is particularly important among immunocompromised patients. Culture methods and microscopy are still routinely used in clinical laboratories to identify Fusarium spp, and more sophisticated, timely, and effective methods for detecting Fusarium spp. in laboratory samples could improve the outcome of the patient. These investigational diagnostic approaches include serological assays and specific nested PCR assays that can yield positive and negative predictive values of over 90%. Other assays in development, such as mass spectroscopy techniques, can provide accurate and consistent results. The treatment of fusariosis in immunocompromised patients remains a challenge and the prognosis of systemic fusariosis in this population remains poor. Successful treatment is highly dependent on the particular Fusarium species involved in the infection. High dose intravenous amphotericin B formulation is recommended as the first line of therapy in management of fusariosis in patients. Voriconazole is also effective in treating fusariosis. Intolerance, contraindication, or failure of the amphotericin B formulation warrants the use of voriconazole as an alternative agent, and posaconazole is licensed as salvage therapy against invasive fusariosis. Adjunctive therapies such as surgical debridement of infected tissue, granulocyte colony stimulating factor (G-CSF) or granulocyte-macrophage colony stimulating factor (GM-CSF) infusions, or granulocyte transfusions are also tools for managing fusariosis. In conclusion, Fusarium infection is considered an emerging problem and should be suspected in immunocompromised patients experiencing systemic infection and should be treated accordingly.

Of Model Hosts and Man: Using Caenorhabditis elegans, Drosophila melanogaster and Galleria mellonella as Model Hosts for Infectious Disease Research

The use of invertebrate model hosts has increased in popularity due to numerous advantages of invertebrates over mammalian models, including ethical, logistical and budgetary features. This review provides an introduction to three model hosts, the nematode Caenorhabditis elegans, the fruit fly Drosophila melanogaster and the larvae of Galleria mellonella, the greater wax moth. It highlights principal experimental advantages of each model, for C. elegans the ability to run high-throughput assays, for D. melanogaster the evolutionarily conserved innate immune response, and for G. mellonella the ability to conduct experiments at 37°C and easily inoculate a precise quantity of pathogen. It additionally discusses recent research that has been conducted with each host to identify pathogen virulence factors, study the immune response, and evaluate potential antimicrobial compounds, focusing principally on fungal pathogens.

Central nervous system aspergillosis: a series of 14 cases from a general hospital and review of 123 cases from the literature.

AbstractCentral nervous system (CNS) aspergillosis is a highly fatal infection. We review the clinical presentation, diagnosis, and outcome of this infection and present a case series of 14 consecutive patients with CNS aspergillosis admitted to Massachusetts General Hospital (MGH) from 2000 to 2011. We also review 123 cases reported in the literature during that time. We included only proven CNS aspergillosis cases conforming to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) definitions of invasive fungal infections. In the MGH case series, neutropenia, hematologic malignancies, autoimmune diseases requiring steroid treatment, and solid organ transplantation were the predominant comorbid conditions. Notably, all MGH patients were immunosuppressed, and more than half (n = 8) had a history of previous brain injury, unrelated to their index hospitalization. For most MGH patients (11 of 14), the lung was the primary focus of aspergillosis, while 2 had paranasal sinus involvement, and 1 had primary Aspergillus discitis. Among reported cases, paranasal sinuses (27.6%) and the lung (26.8%) were the primary foci of infection, whereas 22% of those cases had no obvious primary organ involvement. Although a selection bias should be considered, especially among published cases, our findings suggest that patients who underwent neurosurgery had improved survival, with MGH and literature patients having 25% and 28.6% mortality, respectively, compared to 100% and 60.4%, respectively, among patients who received only medical treatment. Although this was not the case among MGH patients, CNS aspergillosis can affect patients without significant immune suppression, as indicated by the high number of reported immunocompetent cases. In conclusion, mortality among CNS aspergillosis patients remains high, and the infection may be more common among patients with previous brain pathology. When indicated, neurosurgical procedures may improve prognosis.

Fusarium infection: report of 26 cases and review of 97 cases from the literature.

AbstractFusarium species is a ubiquitous fungus that causes opportunistic infections. We present 26 cases of invasive fusariosis categorized according to the European Organization for Research and Treatment of Cancer/Mycoses Study Group (EORTC/MSG) criteria of fungal infections. All cases (20 proven and 6 probable) were treated from January 2000 until January 2010. We also review 97 cases reported since 2000. The most important risk factors for invasive fusariosis in our patients were compromised immune system, specifically lung transplantation (n = 6) and hematologic malignancies (n = 5), and burns (n = 7 patients with skin fusariosis), while the most commonly infected site was the skin in 11 of 26 patients. The mortality rates among our patients with disseminated, skin, and pulmonary fusariosis were 50%, 40%, and 37.5%, respectively. Fusarium solani was the most frequent species, isolated from 49% of literature cases. Blood cultures were positive in 82% of both current study and literature patients with disseminated fusariosis, while the remaining 16% had 2 noncontiguous sites of infection but negative blood cultures. Surgical removal of focal lesions was effective in both current study and literature cases.Skin lesions in immunocompromised patients should raise the suspicion for skin or disseminated fusariosis. The combination of medical monotherapy with voriconazole or amphotericin B and surgery in such cases is highly suggested.

Oral Candida albicans isolates from HIV-positive individuals have similar in vitro biofilm-forming ability and pathogenicity as invasive Candida isolates

BackgroundCandida can cause mucocutaneous and/or systemic infections in hospitalized and immunosuppressed patients. Most individuals are colonized by Candida spp. as part of the oral flora and the intestinal tract. We compared oral and systemic isolates for the capacity to form biofilm in an in vitro biofilm model and pathogenicity in the Galleria mellonella infection model. The oral Candida strains were isolated from the HIV patients and included species of C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. krusei, C. norvegensis, and C. dubliniensis. The systemic strains were isolated from patients with invasive candidiasis and included species of C. albicans, C. glabrata, C. tropicalis, C. parapsilosis, C. lusitaniae, and C. kefyr. For each of the acquired strains, biofilm formation was evaluated on standardized samples of silicone pads and acrylic resin. We assessed the pathogenicity of the strains by infecting G. mellonella animals with Candida strains and observing survival.ResultsThe biofilm formation and pathogenicity in Galleria was similar between oral and systemic isolates. The quantity of biofilm formed and the virulence in G. mellonella were different for each of the species studied. On silicone pads, C. albicans and C. dubliniensis produced more biofilm (1.12 to 6.61 mg) than the other species (0.25 to 3.66 mg). However, all Candida species produced a similar biofilm on acrylic resin, material used in dental prostheses. C. albicans, C. dubliniensis, C. tropicalis, and C. parapsilosis were the most virulent species in G. mellonella with 100% of mortality, followed by C. lusitaniae (87%), C. novergensis (37%), C. krusei (25%), C. glabrata (20%), and C. kefyr (12%).ConclusionsWe found that on silicone pads as well as in the Galleria model, biofilm formation and virulence depends on the Candida species. Importantly, for C. albicans the pathogenicity of oral Candida isolates was similar to systemic Candida isolates, suggesting that Candida isolates have similar biofilm-forming ability and virulence regardless of the infection site from which it was isolated.

Diversity, evolution and medical applications of insect antimicrobial peptides

Antimicrobial peptides (AMPs) are short proteins with antimicrobial activity. A large portion of known AMPs originate from insects, and the number and diversity of these molecules in different species varies considerably. Insect AMPs represent a potential source of alternative antibiotics to address the limitation of current antibiotics, which has been caused by the emergence and spread of multidrug-resistant pathogens. To get more insight into AMPs, we investigated the diversity and evolution of insect AMPs by mapping their phylogenetic distribution, allowing us to predict the evolutionary origins of selected AMP families and to identify evolutionarily conserved and taxon-specific families. Furthermore, we highlight the use of the nematode Caenorhabditis elegans as a whole-animal model in high-throughput screening methods to identify AMPs with efficacy against human pathogens, including Acinetobacter baumanii and methicillin-resistant Staphylococcus aureus. We also discuss the potential medical applications of AMPs, including their use as alternatives for conventional antibiotics in ectopic therapies, their combined use with antibiotics to restore the susceptibility of multidrug-resistant pathogens, and their use as templates for the rational design of peptidomimetic drugs that overcome the disadvantages of therapeutic peptides. The article is part of the themed issue ‘Evolutionary ecology of arthropod antimicrobial peptides’.

Fusarium pathogenesis investigated using Galleria mellonella as a heterologous host

Members of the fungal genus Fusarium are capable of manifesting in a multitude of clinical infections, most commonly in immunocompromised patients. In order to better understand the interaction between the fungus and host, we have developed the larvae of the greater wax moth, Galleria mellonella, as a heterologous host for fusaria. When conidia are injected into the haemocoel of this Lepidopteran system, both clinical and environmental isolates of the fungus are able to kill the larvae at 37 °C, although killing occurs more rapidly when incubated at 30 °C. This killing was dependent on several other factors besides temperature, including the Fusarium strain, the number of conidia injected, and the conidia morphology, where macroconidia are more virulent than their microconidia counterpart. There was a correlation in the killing rate of Fusarium spp. when evaluated in G. mellonella and a murine model. In vivo studies indicated G. mellonella haemocytes were capable of initially phagocytosing both conidial morphologies. The G. mellonella system was also used to evaluate antifungal agents, and amphotericin B was able to confer a significant increase in survival to Fusarium-infected larvae. The G. mellonella-Fusarium pathogenicity system revealed that virulence of Fusarium spp. is similar, regardless of the origin of the isolate, and that mammalian endothermy is a major deterrent for Fusarium infection and therefore provides a suitable alternative to mammalian models to investigate the interaction between the host and this increasingly important fungal pathogen.

Discrepancy between financial disclosures of authors of clinical practice guidelines and reports by industry

Abstract There is a substantial effort to increase the accuracy of conflicts of interest (COI) reporting, and reduce the influence of COI between physicians and industry, especially as it relates to clinical practice guidelines. We used the newly implemented Open Payments dataset to evaluate the accuracy of COI disclosures of authors of clinical practice guidelines that were either newly published or revised within 2014 and were included in the National Guideline Clearinghouse (NGC) website (maintained by the U.S. Department of Health and Human Services). Authors were considered as having inaccurate COI disclosure if they had not reported all companies from which they had received funds >

Caenorhabditis elegans : A Nematode Infection Model for Pathogenic Fungi

5000 in the 12 months preceding the guidelines publication. We identified 223 guidelines that were either newly published (109/223; 48.9%) or revised (114/223; 51.1%) within 2014 and were included in the NGC website. Among the 1329 guideline authors with available Open Payments data, 523 received >

The role of mycelium production and a MAPK-mediated immune response in the C. elegans-Fusarium model system

5000 from at least 1 healthcare-associated entity. However, only 56 out of the 523 authors (10.7%) were found to have accurate COI disclosure. The percentage of authors with accurate COI disclosure in revised guidelines was significantly lower than in newly published guidelines (6.8% vs 14.3%; P < 0.01) and was also found to differ between specialties. Furthermore, authors were less likely to inaccurately disclose “research payments” (37/49, 75.5%) compared to “general payments” (488/559, 87.3%, P = 0.02) as well as “other/associated research funding” (430/506, 85.0%, P = 0.08). No statistically significant association was detected between funding amount and disclosure accuracy. The majority of guideline authors lacked significant COIs, but among authors that received significant funds from at least 1 healthcare-associated entity the frequency of accurate disclosure was low. These findings indicate that the current process of disclosing COIs may be suboptimal and a proactive approach should be adopted in order to minimize COI reporting discrepancies. Furthermore, every effort should be undertaken to ensure the completeness and accuracy of the data recorded in the Open Payments database.