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A 56-year-old Hispanic man with a history of disseminated coccidioidomycosis was diagnosed with persistent glucocorticoid insufficiency and pseudohyperaldosteronism secondary to posaconazole toxicity. This case was notable for unexpected laboratory findings of both pseudohyperaldosteronism and severe glucocorticoid deficiency due to posaconazole’s mechanism of action on the adrenal steroid synthesis pathway. Transitioning to fluconazole and starting hydrocortisone resolved the hypokalemia but not his glucocorticoid deficiency. This case highlights the importance of recognizing iatrogenic glucocorticoid deficiency with azole antifungal agents and potential long term sequalae.
Alejandro Villar-Prados; Julia Chang; David Stevens; Gary Schoolnik; Samantha Wang. Severe Posaconazole-Induced Glucocorticoid Deficiency with Concurrent Pseudohyperaldosteronism: An Unfortunate Two-for-One Special. Journal of Fungi 2021, 7, 620 .
AMA StyleAlejandro Villar-Prados, Julia Chang, David Stevens, Gary Schoolnik, Samantha Wang. Severe Posaconazole-Induced Glucocorticoid Deficiency with Concurrent Pseudohyperaldosteronism: An Unfortunate Two-for-One Special. Journal of Fungi. 2021; 7 (8):620.
Chicago/Turabian StyleAlejandro Villar-Prados; Julia Chang; David Stevens; Gary Schoolnik; Samantha Wang. 2021. "Severe Posaconazole-Induced Glucocorticoid Deficiency with Concurrent Pseudohyperaldosteronism: An Unfortunate Two-for-One Special." Journal of Fungi 7, no. 8: 620.
A virus-free (VF) A. fumigatus isolate has been shown to be resistant in competition with Pseudomonas as compared to the isogenic line infected with Aspergillus fumigatus polymycovirus 1 (AfuPmV-1), and this phenotype was apparently related to alterations in iron metabolism. Here we investigated further the mechanisms underpinning this phenotype. The extracellular siderophore profiles of five isogenic VF and virus-infected (VI) strains were sampled at 24, 31, 48, 54, and 72 h in submerged cultures and quantitatively examined by liquid chromatography and mass spectrometry. Intracellular profiles of conidia and cultures at the stationary growth phase were defined. VF A. fumigatus demonstrated the best fitness represented by the fastest onset of its exponential growth when grown on an iron-limited mineral medium. The exponential phase and transitional production phase of the extracellular triacetylfusarinine C (TafC) were achieved at 24 and 31 h, respectively, contrary to VI strains, which acted more slowly. As a result, the TafC reservoir was consumed sooner in the VF strain. Additionally, the VF strain had lower ferricrocin and higher hydroxyferricrocin content in the pellet during the stationary phase. All of these differences were significant (Kruskal–Wallis, p< 0.01). In our study, the siderophore reservoir of a VF strain was consumed sooner, improving the fitness of the VF strain in competition with P. aeruginosa.
Rutuja Patil; Ioly Kotta-Loizou; Andrea Palyzová; Tomáš Pluháček; Robert Coutts; David Stevens; Vladimír Havlíček. Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics. Journal of Fungi 2021, 7, 497 .
AMA StyleRutuja Patil, Ioly Kotta-Loizou, Andrea Palyzová, Tomáš Pluháček, Robert Coutts, David Stevens, Vladimír Havlíček. Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics. Journal of Fungi. 2021; 7 (7):497.
Chicago/Turabian StyleRutuja Patil; Ioly Kotta-Loizou; Andrea Palyzová; Tomáš Pluháček; Robert Coutts; David Stevens; Vladimír Havlíček. 2021. "Freeing Aspergillus fumigatus of Polymycovirus Infection Renders It More Resistant to Competition with Pseudomonas aeruginosa Due to Altered Iron-Acquiring Tactics." Journal of Fungi 7, no. 7: 497.
The Pseudomonas quinolone signal (PQS) is an important quorum-sensing molecule for Pseudomonas aeruginosa that regulates virulence factors, chelates iron, and is an important factor in interactions with eukaryotes, including fungi and mammalian hosts. It was previously shown to inhibit or boost Aspergillus, depending on the milieu iron concentration. We studied several molecular modifications of the PQS molecule, and their effects on Aspergillus biofilm metabolism and growth in vitro, and the effects of iron supplementation. We found that most molecules inhibited Aspergillus at concentrations similar to that of PQS, but with relatively flat dose-responses, and all were less potent than PQS. The inhibition was reversible by iron, suggesting interference with fungal iron metabolism. Stimulation of Aspergillus was not noted. We conclude that the critical Aspergillus-inhibiting moeities of the PQS molecule were partially, but not completely, interfered with by molecular modifications at several sites on the PQS molecule. The mechanism, as with PQS, appears to relate to fungal iron metabolism.
Hasan Nazik; Gabriele Sass; Paul Williams; Eric Déziel; David Stevens. Molecular Modifications of the Pseudomonas Quinolone Signal in the Intermicrobial Competition with Aspergillus. Journal of Fungi 2021, 7, 343 .
AMA StyleHasan Nazik, Gabriele Sass, Paul Williams, Eric Déziel, David Stevens. Molecular Modifications of the Pseudomonas Quinolone Signal in the Intermicrobial Competition with Aspergillus. Journal of Fungi. 2021; 7 (5):343.
Chicago/Turabian StyleHasan Nazik; Gabriele Sass; Paul Williams; Eric Déziel; David Stevens. 2021. "Molecular Modifications of the Pseudomonas Quinolone Signal in the Intermicrobial Competition with Aspergillus." Journal of Fungi 7, no. 5: 343.
Pseudomonas aeruginosa and Aspergillus fumigatus are pathogens that are associated with deterioration of lung function, e.g., in persons with cystic fibrosis (CF). There is evidence that co-infections with these pathogens cause airway inflammation and aggravate pathology in CF lungs. Intermicrobial competition of P. aeruginosa and A. fumigatus has been described, but it is unknown how anti-fungal therapy is affected. The anti-fungal azole voriconazole (VCZ), supernatants of P. aeruginosa laboratory isolates PA14 or PAO1, or clinical isolate Pa10 independently inhibited biofilm metabolism of A. fumigatus isolates 10AF and AF13073. When VCZ and supernatants were combined at their IC50s, synergistic effects on A. fumigatus were found. Synergistic effects were no longer observed when P. aeruginosa supernatants were prepared in the presence of iron, or when P. aeruginosa mutants were lacking the ability to produce pyoverdine and pyochelin. Combination of pure P. aeruginosa products pyoverdine, pyochelin, and pyocyanin with VCZ showed synergistic anti-fungal effects. Combining VCZ with P. aeruginosa supernatants also improved its MIC and MFC against planktonic A. fumigatus. In summary, in the case of P. aeruginosa–A. fumigatus co-infections, it appeared that the P. aeruginosa co-infection facilitated therapy of the Aspergillus; lower concentrations of VCZ might be sufficient to control fungal growth.
Gabriele Sass; Pallabi Shrestha; David Stevens. Pseudomonas aeruginosa Virulence Factors Support Voriconazole Effects on Aspergillus fumigatus. Pathogens 2021, 10, 519 .
AMA StyleGabriele Sass, Pallabi Shrestha, David Stevens. Pseudomonas aeruginosa Virulence Factors Support Voriconazole Effects on Aspergillus fumigatus. Pathogens. 2021; 10 (5):519.
Chicago/Turabian StyleGabriele Sass; Pallabi Shrestha; David Stevens. 2021. "Pseudomonas aeruginosa Virulence Factors Support Voriconazole Effects on Aspergillus fumigatus." Pathogens 10, no. 5: 519.
Aspergillus and Pseudomonas compete in nature, and are the commonest bacterial and fungal pathogens in some clinical settings, such as the cystic fibrosis lung. Virus infections of fungi occur naturally. Effects on fungal physiology need delineation. A common reference Aspergillus fumigatus strain, long studied in two (of many) laboratories, was found infected with the AfuPmV-1 virus. One isolate was cured of virus, producing a virus-free strain. Virus from the infected strain was purified and used to re-infect three subcultures of the virus-free fungus, producing six fungal strains, otherwise isogenic. They were studied in intermicrobial competition with Pseudomonas aeruginosa. Pseudomonas culture filtrates inhibited forming or preformed Aspergillus biofilm from infected strains to a greater extent, also seen when Pseudomonas volatiles were assayed on Aspergillus. Purified iron-chelating Pseudomonas molecules, known inhibitors of Aspergillus biofilm, reproduced these differences. Iron, a stimulus of Aspergillus, enhanced the virus-free fungus, compared to infected. All infected fungal strains behaved similarly in assays. We show an important consequence of virus infection, a weakening in intermicrobial competition. Viral infection may affect the outcome of bacterial–fungal competition in nature and patients. We suggest that this occurs via alteration in fungal stress responses, the mechanism best delineated here is a result of virus-induced altered Aspergillus iron metabolism.
Hasan Nazik; Ioly Kotta-Loizou; Gabriele Sass; Robert Coutts; David Stevens. Virus Infection of Aspergillus fumigatus Compromises the Fungus in Intermicrobial Competition. Viruses 2021, 13, 686 .
AMA StyleHasan Nazik, Ioly Kotta-Loizou, Gabriele Sass, Robert Coutts, David Stevens. Virus Infection of Aspergillus fumigatus Compromises the Fungus in Intermicrobial Competition. Viruses. 2021; 13 (4):686.
Chicago/Turabian StyleHasan Nazik; Ioly Kotta-Loizou; Gabriele Sass; Robert Coutts; David Stevens. 2021. "Virus Infection of Aspergillus fumigatus Compromises the Fungus in Intermicrobial Competition." Viruses 13, no. 4: 686.
The One Health context considers health based on three pillars: humans, animals, and environment. This approach is a strong ally in the surveillance of infectious diseases and in the development of prevention strategies. Aspergillus spp. are fungi that fit substantially in this context, in view of their ubiquity, as well as their importance as plant pathogens, and potentially fatal pathogens for, particularly, humans and avian species. In addition, the emergence of azole resistance, mainly in Aspergillus fumigatus sensu stricto, and the proven role of fungicides widely used on crops, reinforces the need for a multidisciplinary approach to this problem. Avian species are involved in short and long distance travel between different types of landscapes, such as agricultural fields, natural environments and urban environments. Thus, birds can play an important role in the dispersion of Aspergillus, and of special concern, azole-resistant strains. In addition, some bird species are particularly susceptible to aspergillosis. Therefore, avian aspergillosis could be considered as an environmental health indicator. In this review, aspergillosis in humans and birds will be discussed, with focus on the presence of Aspergillus in the environment. We will relate these issues with the emergence of azole resistance on Aspergillus. These topics will be therefore considered and reviewed from the “One Health” perspective.
Aryse Martins Melo; David A. Stevens; Lisa A. Tell; Cristina Veríssimo; Raquel Sabino; Melissa Orzechowski Xavier. Aspergillosis, Avian Species and the One Health Perspective: The Possible Importance of Birds in Azole Resistance. Microorganisms 2020, 8, 2037 .
AMA StyleAryse Martins Melo, David A. Stevens, Lisa A. Tell, Cristina Veríssimo, Raquel Sabino, Melissa Orzechowski Xavier. Aspergillosis, Avian Species and the One Health Perspective: The Possible Importance of Birds in Azole Resistance. Microorganisms. 2020; 8 (12):2037.
Chicago/Turabian StyleAryse Martins Melo; David A. Stevens; Lisa A. Tell; Cristina Veríssimo; Raquel Sabino; Melissa Orzechowski Xavier. 2020. "Aspergillosis, Avian Species and the One Health Perspective: The Possible Importance of Birds in Azole Resistance." Microorganisms 8, no. 12: 2037.
The 9th meeting of Advances Against Aspergillosis in beautiful Lugano, Switzerland clearly had the most drama of any of the previous meetings, exceeding even the 1st one, in San Francisco, when we, the Co-Organizers, weren’t sure that although we had a great educational idea, and had put together a great list of speakers and topics, we might have few attendees, and go bankrupt! (The story of the birth efforts in initiating these meetings is described, for the historical record
David A. Stevens. Advances against Aspergillosis and Mucormycosis. Journal of Fungi 2020, 6, 358 .
AMA StyleDavid A. Stevens. Advances against Aspergillosis and Mucormycosis. Journal of Fungi. 2020; 6 (4):358.
Chicago/Turabian StyleDavid A. Stevens. 2020. "Advances against Aspergillosis and Mucormycosis." Journal of Fungi 6, no. 4: 358.
Meningitis is the most devastating form of coccidioidomycosis. A convenient, rapid diagnostic method could result in early treatment and avoid many meningitis complications. We studied cerebrospinal fluid (CSF) samples in patients with documented coccidioidal meningitis, and controls, with complement fixation (CF), immunodiffusion (ID) (the “classical” assays), lateral flow assays (LFA; one-strip and two-strip), and two enzyme immunoassays (EIA). The two-strip LFA and EIAs not only enabled separate testing for IgG and IgM antibodies separately, but also could aggregate results for each method. CF with ID or the aggregate use of IgG and IgM tests were considered optimal test uses. LFAs and EIAs were evaluated at 1:21 and 1:441 dilutions of specimens. All assays were compared to true patient status. With 49 patient specimens and 40 controls, this is the largest comparative study of CSF coccidioidal diagnostics. Sensitivity of these tests ranged from 71–95% and specificity 90–100%. IgM assays were less sensitive. Assays at 1:441 were similarly specific but less sensitive, suggesting that serial dilutions of samples could result in assays yielding titers. Agreement of positive results on cases was 87–100%. When kits are available, hospital laboratories in endemic areas can perform testing. LFA assays do not require a laboratory, are simple to use, and give rapid results, potentially even at the bedside.
David A. Stevens; Marife Martinez; Gabriele Sass; Demosthenes Pappagianis; Brian Doherty; Hannah Kutsche; Meredith McGuire. Comparative Study of Newer and Established Methods of Diagnosing Coccidioidal Meningitis. Journal of Fungi 2020, 6, 125 .
AMA StyleDavid A. Stevens, Marife Martinez, Gabriele Sass, Demosthenes Pappagianis, Brian Doherty, Hannah Kutsche, Meredith McGuire. Comparative Study of Newer and Established Methods of Diagnosing Coccidioidal Meningitis. Journal of Fungi. 2020; 6 (3):125.
Chicago/Turabian StyleDavid A. Stevens; Marife Martinez; Gabriele Sass; Demosthenes Pappagianis; Brian Doherty; Hannah Kutsche; Meredith McGuire. 2020. "Comparative Study of Newer and Established Methods of Diagnosing Coccidioidal Meningitis." Journal of Fungi 6, no. 3: 125.
Background: Pseudomonas aeruginosa (Pa) and Aspergillus fumigatus (Af) compete with each other for nutrients and survival in natural environments, and have been extensively studied because of their intermicrobial interactions in the human microbiome. These are the principal microbes infecting immunocompromised patients and persons with cystic fibrosis, particularly the airways. These intermicrobial studies have largely been conducted in liquid medium or on agar, and thus focus on soluble or diffusible microbial products. Several key inhibitory molecules were defined in such studies. Methods: in the present report, we examine several methodologies which can be conveniently used to study the interaction of microbial volatiles, including capture methods and kinetics. Results: Pa volatiles inhibit Af, and the inhibitory mechanism appears to be the incorporation of the inhibitory molecules into the substrate nourishing the Af, rather than directly onto Af structures. We define by mass spectroscopy some specific volatile Pa products that can inhibit Af. Some of these molecules are selected for interest by the study of gene deletion mutants, producing a few Pa strains that were impaired in inhibition. We presumed the volatiles of these latter strains could be excluded from the search for inhibitors. Conclusion: the Pa inhibition of Af via a gaseous phase could be critical components in their competition, particularly in airways, where more direct contact may not be extensive.
Hasan Nazik; Gabriele Sass; Eric Déziel; David A. Stevens. Aspergillus Is Inhibited by Pseudomonas aeruginosa Volatiles. Journal of Fungi 2020, 6, 118 .
AMA StyleHasan Nazik, Gabriele Sass, Eric Déziel, David A. Stevens. Aspergillus Is Inhibited by Pseudomonas aeruginosa Volatiles. Journal of Fungi. 2020; 6 (3):118.
Chicago/Turabian StyleHasan Nazik; Gabriele Sass; Eric Déziel; David A. Stevens. 2020. "Aspergillus Is Inhibited by Pseudomonas aeruginosa Volatiles." Journal of Fungi 6, no. 3: 118.
Pseudomonas aeruginosa is one of the most prominent opportunistic bacteria in airways of cystic fibrosis patients and in immunocompromised patients. These bacteria share the same polymicrobial niche with other microbes, such as the opportunistic fungus Aspergillus fumigatus. Their inter-kingdom interactions and diverse exchange of secreted metabolites are responsible for how they both fare in competition for ecological niches. The outcomes of their contests likely determine persistent damage and degeneration of lung function. With a myriad of virulence factors and metabolites of promising antifungal activity, P. aeruginosa products or their derivatives may prove useful in prophylaxis and therapy against A. fumigatus. Quorum sensing underlies the primary virulence strategy of P. aeruginosa, which serves as cell–cell communication and ultimately leads to the production of multiple virulence factors. Understanding the quorum-sensing-related pathogenic mechanisms of P. aeruginosa is a first step for understanding intermicrobial competition. In this review, we provide a basic overview of some of the central virulence factors of P. aeruginosa that are regulated by quorum-sensing response pathways and briefly discuss the hitherto known antifungal properties of these virulence factors. This review also addresses the role of the bacterial secretion machinery regarding virulence factor secretion and maintenance of cell–cell communication.
Paulami Chatterjee; Gabriele Sass; Wieslaw Swietnicki; David A. Stevens. Review of Potential Pseudomonas Weaponry, Relevant to the Pseudomonas–Aspergillus Interplay, for the Mycology Community. Journal of Fungi 2020, 6, 81 .
AMA StylePaulami Chatterjee, Gabriele Sass, Wieslaw Swietnicki, David A. Stevens. Review of Potential Pseudomonas Weaponry, Relevant to the Pseudomonas–Aspergillus Interplay, for the Mycology Community. Journal of Fungi. 2020; 6 (2):81.
Chicago/Turabian StylePaulami Chatterjee; Gabriele Sass; Wieslaw Swietnicki; David A. Stevens. 2020. "Review of Potential Pseudomonas Weaponry, Relevant to the Pseudomonas–Aspergillus Interplay, for the Mycology Community." Journal of Fungi 6, no. 2: 81.
Due to the difficulty in the access to free-ranging birds, data regarding Aspergillus infections in wild avian species is rare compared to captive wild and domestic birds. Objective: report three cases of Aspergillus section Fumigati causing fungal disease in free-ranging aquatic birds, with the identification of the causal agent to the species level. Case reports: The diagnosis of aspergillosis was performed by macroscopic lesions found during the necropsy and confirmed by culture. Molecular identification by partial sequencing of the calM and benA genes allowed to confirm Aspergillus fumigatus sensu stricto as the etiological agent of aspergillosis in Procellaria aequinoctialis (White-chinned petrel) (n = 1), Nannopterum brasilianus (Neotropical cormorant) (n = 1) and Chroicocephalus maculipennis (Brown-hooded gull) (n = 1). Conclusion: Larger studies regarding the importance of aspergillosis in free-ranging aquatic birds are necessary, as well as it potential role in the One Heath context.
Aryse Martins Melo; Rodolfo Pinho da Silva-Filho; Vanice Rodrigues Poester; Andrea von Groll; Cristina Gevehr Fernandes; David A. Stevens; Raquel Sabino; Melissa Orzechowski Xavier. Aspergillosis in free-ranging aquatic birds. Medical Mycology Case Reports 2020, 28, 36 -38.
AMA StyleAryse Martins Melo, Rodolfo Pinho da Silva-Filho, Vanice Rodrigues Poester, Andrea von Groll, Cristina Gevehr Fernandes, David A. Stevens, Raquel Sabino, Melissa Orzechowski Xavier. Aspergillosis in free-ranging aquatic birds. Medical Mycology Case Reports. 2020; 28 ():36-38.
Chicago/Turabian StyleAryse Martins Melo; Rodolfo Pinho da Silva-Filho; Vanice Rodrigues Poester; Andrea von Groll; Cristina Gevehr Fernandes; David A. Stevens; Raquel Sabino; Melissa Orzechowski Xavier. 2020. "Aspergillosis in free-ranging aquatic birds." Medical Mycology Case Reports 28, no. : 36-38.
We report a case of fungal and mycobacterial co-infection in an immunosuppressed patient from Southern Brazil. Histoplasmosis was diagnosed in an AIDS patient admitted to the hospital with nonspecific respiratory signs. However, 4 months post hospital discharge, the patient worsened and a co-infection with Mycobacterium avium was detected. Physicians must consider and investigate a broad spectrum of diseases which can occur as co-infections and which share the same clinical symptoms and signs in immunosuppressed patients.
Rossana Patricia Basso; Vanice Rodrigues Poester; Jussara Maria Silveira; Roseli Stone Vieira; Luisa Dias Da Mota; Gabriel Baracy Klafke; Jéssica Nunes Müller; Crislaine Padilha Penna; Júlia Silveira Vianna; Caroline Busatto; Pedro Eduardo Almeida Da Silva; Ivy Bastos Ramis; David A. Stevens; Melissa Orzechowski Xavier. Histoplasma capsulatum and Mycobacterium avium co-infection in an immunocompromised patient: Case report and literature review. Medical Mycology Case Reports 2020, 28, 29 -32.
AMA StyleRossana Patricia Basso, Vanice Rodrigues Poester, Jussara Maria Silveira, Roseli Stone Vieira, Luisa Dias Da Mota, Gabriel Baracy Klafke, Jéssica Nunes Müller, Crislaine Padilha Penna, Júlia Silveira Vianna, Caroline Busatto, Pedro Eduardo Almeida Da Silva, Ivy Bastos Ramis, David A. Stevens, Melissa Orzechowski Xavier. Histoplasma capsulatum and Mycobacterium avium co-infection in an immunocompromised patient: Case report and literature review. Medical Mycology Case Reports. 2020; 28 ():29-32.
Chicago/Turabian StyleRossana Patricia Basso; Vanice Rodrigues Poester; Jussara Maria Silveira; Roseli Stone Vieira; Luisa Dias Da Mota; Gabriel Baracy Klafke; Jéssica Nunes Müller; Crislaine Padilha Penna; Júlia Silveira Vianna; Caroline Busatto; Pedro Eduardo Almeida Da Silva; Ivy Bastos Ramis; David A. Stevens; Melissa Orzechowski Xavier. 2020. "Histoplasma capsulatum and Mycobacterium avium co-infection in an immunocompromised patient: Case report and literature review." Medical Mycology Case Reports 28, no. : 29-32.
Trypanosoma cruzi is the etiologic agent of Chagas disease (CD), which can result in severe cardiomyopathy. Trypanosoma cruzi is endemic to the Americas, and of particular importance in Latin America. In the United States and other non-endemic countries, rising case numbers have also been observed. The currently used drugs are benznidazole (BNZ) and nifurtimox, which have limited efficacy during chronic infection. We repurposed itraconazole (ICZ), originally an antifungal, in combination with amiodarone (AMD), an antiarrhythmic, with the goal of interfering with T. cruzi infection. Human pluripotent stem cells (hiPSCs) were differentiated into cardiomyocytes (hiPSC-CMs). Vero cells or hiPSC-CMs were infected with T. cruzi trypomastigotes of the II or I strain in the presence of ICZ and/or AMD. After 48 hours, cells were Giemsa stained, and infection and multiplication were evaluated microscopically. Trypanosoma cruzi infection and multiplication were evalutated also by electron microscopy. BNZ was used as a reference compound. Cell metabolism in the presence of test substances was assessed. Itraconazole and AMD showed strain- and dose-dependent interference with T. cruzi infection and multiplication in Vero cells or hiPSC-CMs. Combinations of ICZ and AMD were more effective against T. cruzi than the single substances, or BNZ, without affecting host cell metabolism, and better preserving host cell integrity during infection. Our in vitro data in hiPSC-CMs suggest that a combination of ICZ and AMD might serve as a treatment option for CD in patients, but that different responses due to T. cruzi strain differences have to be taken into account.
Gabriele Sass; Roy T. Madigan; Lydia-Marie Joubert; Adriana Bozzi; Nazish Sayed; Joseph C. Wu; David A. Stevens. A Combination of Itraconazole and Amiodarone Is Highly Effective against Trypanosoma cruzi Infection of Human Stem Cell–Derived Cardiomyocytes. The American Journal of Tropical Medicine and Hygiene 2019, 101, 383 -391.
AMA StyleGabriele Sass, Roy T. Madigan, Lydia-Marie Joubert, Adriana Bozzi, Nazish Sayed, Joseph C. Wu, David A. Stevens. A Combination of Itraconazole and Amiodarone Is Highly Effective against Trypanosoma cruzi Infection of Human Stem Cell–Derived Cardiomyocytes. The American Journal of Tropical Medicine and Hygiene. 2019; 101 (2):383-391.
Chicago/Turabian StyleGabriele Sass; Roy T. Madigan; Lydia-Marie Joubert; Adriana Bozzi; Nazish Sayed; Joseph C. Wu; David A. Stevens. 2019. "A Combination of Itraconazole and Amiodarone Is Highly Effective against Trypanosoma cruzi Infection of Human Stem Cell–Derived Cardiomyocytes." The American Journal of Tropical Medicine and Hygiene 101, no. 2: 383-391.
Purpose of review Aspergillus fumigatus is a ubiquitous saprophytic fungus that can cause life-threatening invasive aspergillosis in immunocompromised patients. Apart from the immune status of the host only a few characterized virulence factors have been identified. In this review, we describe the role of iron in the manifestation of A. fumigatus virulence. Recent findings We gathered recent clinical evidence suggesting that tissue iron overload increases the risk of invasive aspergillosis occurrence. Furthermore, we summarize the mechanisms that A. fumigatus employs to achieve iron homeostasis and their importance in A. fumigatus proliferation in vitro. We describe two recent in-vivo models that clearly demonstrate the importance of iron in A. fumigatus growth and invasion. Summary Based on these recent findings, therapy aimed at managing A. fumigatus iron homeostasis locally could make conditions more favorable to the host.
Efthymia I. Matthaiou; Gabriele Sass; David A. Stevens; Joe L. Hsu. Iron. Current Opinion in Infectious Diseases 2018, 31, 506 -511.
AMA StyleEfthymia I. Matthaiou, Gabriele Sass, David A. Stevens, Joe L. Hsu. Iron. Current Opinion in Infectious Diseases. 2018; 31 (6):506-511.
Chicago/Turabian StyleEfthymia I. Matthaiou; Gabriele Sass; David A. Stevens; Joe L. Hsu. 2018. "Iron." Current Opinion in Infectious Diseases 31, no. 6: 506-511.
Invasive pulmonary aspergillosis (IPA) is classically considered an illness of severely immunocompromised patients with limited host defenses. However, IPA has been reported in immunocompetent but critically ill patients. This report describes two fatal cases of pathologically confirmed IPA in patients with influenza in the intensive care unit. One patient had influenza B infection, whereas the other had influenza A H1N1. Both patients died despite broad-spectrum antimicrobials, mechanical ventilation, and vasopressor support. Microscopic and histologic postmortem examination confirmed IPA. Review of the English language and foreign literature indicates that galactomannan antigen testing and classic radiologic findings for IPA may not be reliable in immunocompetent patients. Respiratory cultures which grow Aspergillus species in critically ill patients, particularly those with underlying influenza infection, should not necessarily be disregarded as contaminants or colonizers. Further research is needed to better understand the immunological relationship between influenza and IPA for improved prevention and treatment of influenza and Aspergillus co-infections.
Melisa M. Shah; Eric I. Hsiao; Carl M. Kirsch; Amit Gohil; Supriya Narasimhan; David A. Stevens. Invasive pulmonary aspergillosis and influenza co-infection in immunocompetent hosts: case reports and review of the literature. Diagnostic Microbiology and Infectious Disease 2018, 91, 147 -152.
AMA StyleMelisa M. Shah, Eric I. Hsiao, Carl M. Kirsch, Amit Gohil, Supriya Narasimhan, David A. Stevens. Invasive pulmonary aspergillosis and influenza co-infection in immunocompetent hosts: case reports and review of the literature. Diagnostic Microbiology and Infectious Disease. 2018; 91 (2):147-152.
Chicago/Turabian StyleMelisa M. Shah; Eric I. Hsiao; Carl M. Kirsch; Amit Gohil; Supriya Narasimhan; David A. Stevens. 2018. "Invasive pulmonary aspergillosis and influenza co-infection in immunocompetent hosts: case reports and review of the literature." Diagnostic Microbiology and Infectious Disease 91, no. 2: 147-152.
Pseudomonas aeruginosa and Aspergillus fumigatus are common opportunistic bacterial and fungal pathogens, respectively. They often coexist in airways of immunocompromised patients and individuals with cystic fibrosis, where they form biofilms and cause acute and chronic illnesses. Hence, the interactions between them have long been of interest and it is known that P. aeruginosa can inhibit A. fumigatus in vitro . We have approached the definition of the inhibitory P. aeruginosa molecules by studying 24 P. aeruginosa mutants with various virulence genes deleted for the ability to inhibit A. fumigatus biofilms. The ability of P. aeruginosa cells or their extracellular products produced during planktonic or biofilm growth to affect A. fumigatus biofilm metabolism or planktonic A. fumigatus growth was studied in agar and liquid assays using conidia or hyphae. Four mutants, the pvdD pchE , pvdD , lasR rhlR , and lasR mutants, were shown to be defective in various assays. This suggested the P. aeruginosa siderophore pyoverdine as the key inhibitory molecule, although additional quorum sensing-regulated factors likely contribute to the deficiency of the latter two mutants. Studies of pure pyoverdine substantiated these conclusions and included the restoration of inhibition by the pyoverdine deletion mutants. A correlation between the concentration of pyoverdine produced and antifungal activity was also observed in clinical P. aeruginosa isolates derived from lungs of cystic fibrosis patients. The key inhibitory mechanism of pyoverdine was chelation of iron and denial of iron to A. fumigatus . IMPORTANCE Interactions between human pathogens found in the same body locale are of vast interest. These interactions could result in exacerbation or amelioration of diseases. The bacterium Pseudomonas aeruginosa affects the growth of the fungus Aspergillus fumigatus . Both pathogens form biofilms that are resistant to therapeutic drugs and host immunity. P. aeruginosa and A. fumigatus biofilms are found in vivo , e.g., in the lungs of cystic fibrosis patients. Studying 24 P. aeruginosa mutants, we identified pyoverdine as the major anti- A. fumigatus compound produced by P. aeruginosa . Pyoverdine captures iron from the environment, thus depriving A. fumigatus of a nutrient essential for its growth and metabolism. We show how microbes of different kingdoms compete for essential resources. Iron deprivation could be a therapeutic approach to the control of pathogen growth.
Gabriele Sass; Hasan Nazik; John Penner; Hemi Shah; Shajia Rahman Ansari; Karl V. Clemons; Marie-Christine Groleau; Anna-Maria Dietl; Paolo Visca; Hubertus Haas; Eric Déziel; David A. Stevens. Studies of Pseudomonas aeruginosa Mutants Indicate Pyoverdine as the Central Factor in Inhibition of Aspergillus fumigatus Biofilm. Journal of Bacteriology 2018, 200, e00345-17 .
AMA StyleGabriele Sass, Hasan Nazik, John Penner, Hemi Shah, Shajia Rahman Ansari, Karl V. Clemons, Marie-Christine Groleau, Anna-Maria Dietl, Paolo Visca, Hubertus Haas, Eric Déziel, David A. Stevens. Studies of Pseudomonas aeruginosa Mutants Indicate Pyoverdine as the Central Factor in Inhibition of Aspergillus fumigatus Biofilm. Journal of Bacteriology. 2018; 200 (1):e00345-17.
Chicago/Turabian StyleGabriele Sass; Hasan Nazik; John Penner; Hemi Shah; Shajia Rahman Ansari; Karl V. Clemons; Marie-Christine Groleau; Anna-Maria Dietl; Paolo Visca; Hubertus Haas; Eric Déziel; David A. Stevens. 2018. "Studies of Pseudomonas aeruginosa Mutants Indicate Pyoverdine as the Central Factor in Inhibition of Aspergillus fumigatus Biofilm." Journal of Bacteriology 200, no. 1: e00345-17.
Acute and chronic infection with Trypanosoma cruzi affects millions of people. The current therapeutic options are highly toxic and often not effective. Liposomal amphotericin B (LAMB) has been demonstrated previously to have some activity in murine models. In our studies, higher dosages given multiple times were tested for activity against acute or chronic disease, exploring whether intermittent and brief regimens could be effective, as might then prove useful in human, particularly outpatient, therapy. For acute infection, LAMB 25 mg/kg intravenously (i.v.) given one to three times prolonged survival and caused a rapid disappearance of Y strain trypomastigotes from the blood. However, even four or six doses of LAMB 30 mg/kg i.v., did not result in the cure of Y strain infection, with all mice relapsing after being immunosuppressed with cyclophosphamide. Similarly, chronic infection due to the CL strain was found to be unaltered by 1–3 treatments with LAMB 25 mg/kg. All surviving mice had histopathological evidence of infection in one or more tissues and equivalent antibody titers regardless of treatment regimen. Overall, LAMB at doses up to 30 mg/kg i.v. prolonged survival, but these doses were not curative in the regimens studied.
Karl V. Clemons; Raymond A. Sobel; David A. Stevens; Marife Martinez; Rodrigo Correa-Oliveira. Lack of Efficacy of Liposomal Amphotericin B Against Acute and Chronic Trypanosoma cruzi Infection in Mice. The American Journal of Tropical Medicine and Hygiene 2017, 97, 1141 -1146.
AMA StyleKarl V. Clemons, Raymond A. Sobel, David A. Stevens, Marife Martinez, Rodrigo Correa-Oliveira. Lack of Efficacy of Liposomal Amphotericin B Against Acute and Chronic Trypanosoma cruzi Infection in Mice. The American Journal of Tropical Medicine and Hygiene. 2017; 97 (4):1141-1146.
Chicago/Turabian StyleKarl V. Clemons; Raymond A. Sobel; David A. Stevens; Marife Martinez; Rodrigo Correa-Oliveira. 2017. "Lack of Efficacy of Liposomal Amphotericin B Against Acute and Chronic Trypanosoma cruzi Infection in Mice." The American Journal of Tropical Medicine and Hygiene 97, no. 4: 1141-1146.
The paucity of effective antifungals against Aspergillus and increasing resistance, the recognition of the importance of Aspergillus biofilm in several clinical settings, and reports of verapamil—a calcium channel blocker—efficacy against Candida biofilm and hyphal growth, and synergy with an azole antifungal in vitro, led to a study of verapamil ± voriconazole against Aspergillus. Broth macrodilution methodology was utilized for MIC (minimum inhibitory concentration) and MFC (minimum fungicidal concentration) determination. The metabolic effects (assessed by XTT [2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt]) on biofilm formation by conidia were studied upon exposure to verapamil, verapamil plus voriconazole, or voriconazole alone. For biofilm formation, we found less inhibition from the combinations than with either drug alone, or less inhibition from the combination than that of the more potent drug alone. For preformed biofilm, we found no significant change in activity comparing voriconazole alone compared to added verapamil, and no significant alteration of activity of the more potent voriconazole, at any concentration in the range tested, by addition of a concentration of verapamil that is inhibitory alone. In full checkerboard assays with planktonic fungus, there was no indication of any effect of one drug on the other (indifference). Although verapamil was similarly inactive against planktonic Aspergillus, as with Candida, verapamil was indeed active against Aspergillus biofilm. However, indifference and antagonism was found with voriconazole.
Hasan Nazik; Varun Choudhary; David A. Stevens. Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole. Journal of Fungi 2017, 3, 50 .
AMA StyleHasan Nazik, Varun Choudhary, David A. Stevens. Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole. Journal of Fungi. 2017; 3 (3):50.
Chicago/Turabian StyleHasan Nazik; Varun Choudhary; David A. Stevens. 2017. "Verapamil Inhibits Aspergillus Biofilm, but Antagonizes Voriconazole." Journal of Fungi 3, no. 3: 50.
Pseudomonas aeruginosa and Aspergillus fumigatus are major microbes in cystic fibrosis (CF). We reported non-mucoid P. aeruginosa isolates more inhibitory to A. fumigatus than mucoid ones. Another CF P. aeruginosa phenotype, small colony variants (SCVs), is an unknown factor in intermicrobial competition with A. fumigatus. Clinical SCV isolates and reference CF non-mucoid isolate (Pa10, producing normal-sized colonies) were compared. Live cells of P. aeruginosa or filtrates from P. aeruginosa planktonic or biofilm cultures were co-incubated with A. fumigatus growing under conditions allowing biofilm formation or with preformed biofilm. Metabolic activity of A. fumigatus biofilm was then measured. When necessary, assays were done after adjustment for growth differences by adding fresh medium to the planktonic culture filtrate. Pyoverdine determinations were performed spectrophotometrically on the planktonic culture filtrates. In all experimental conditions (live cells and planktonic or biofilm culture filtrates of P. aeruginosa versus A. fumigatus biofilm formation or preformed biofilm), three SCV isolates were less inhibitory than Pa10, two equal or more inhibitory. Adjusting planktonic culture filtrates for growth differences showed SCV inhibition differences variably related to growth or deficient inhibitor production. Studies suggested the principal P. aeruginosa inhibitor to be pyoverdine. SCV isolates appear heterogeneous in their capacity to inhibit A. fumigatus biofilm. SCV isolates can be important in the CF microbiome, because they are capable of intermicrobial inhibition.
Rajesh Anand; Richard B. Moss; Gabriele Sass; Niaz Banaei; Karl V. Clemons; Marife Martinez; David A. Stevens. Small Colony Variants of Pseudomonas aeruginosa Display Heterogeneity in Inhibiting Aspergillus fumigatus Biofilm. Mycopathologia 2017, 183, 263 -272.
AMA StyleRajesh Anand, Richard B. Moss, Gabriele Sass, Niaz Banaei, Karl V. Clemons, Marife Martinez, David A. Stevens. Small Colony Variants of Pseudomonas aeruginosa Display Heterogeneity in Inhibiting Aspergillus fumigatus Biofilm. Mycopathologia. 2017; 183 (1):263-272.
Chicago/Turabian StyleRajesh Anand; Richard B. Moss; Gabriele Sass; Niaz Banaei; Karl V. Clemons; Marife Martinez; David A. Stevens. 2017. "Small Colony Variants of Pseudomonas aeruginosa Display Heterogeneity in Inhibiting Aspergillus fumigatus Biofilm." Mycopathologia 183, no. 1: 263-272.
Aspergillosis is a fungal infection that primarily affects the respiratory tract. Amphotericin B has broad antifungal activity and is commonly used to treat aspergillosis, a fungal pneumonia that is a common sequela in oiled waterfowl as well as other birds in wildlife rehabilitation. Pharmacokinetic parameters of nebulized amphotericin B in an avian model have been reported, but those of direct intratracheal delivery have yet to be established. The objective of this study was to evaluate if a single 3 mg/kg dose of liposomal amphotericin B delivered intratracheally using a commercial atomizer would achieve plasma and lung tissue concentrations exceeding targeted minimum inhibitory concentrations (MIC) for Aspergillus species in adult mallard ducks (Anas platyrhynchos). Following intratracheal delivery, amphotericin B was present in lung parenchyma at concentrations above the targeted MIC of 1 μg/g for up to 9 days post-administration; however, distribution of the drug was uneven, with the majority of the drug concentrated in one lung lobe. Concentrations in the contralateral lung lobe and the kidneys were above the targeted MIC 1 day after administration but declined exponentially with a half-life of approximately 2 days. Plasma concentrations were never above the targeted MIC. Histological examination of the trachea, bronchi, lungs, heart, liver, and kidneys did not reveal any toxic changes. Using a commercial atomizer, intratracheal delivery of amphotericin B at 3 mg/kg resulted in lung parenchyma concentrations above 1 μg/ml with no discernable systemic effects. Further studies to establish a system of drug delivery to both sides of the pulmonary parenchyma need to be performed, and the efficacy of this treatment for disease prevention remains to be determined.
Ashley Phillips; Christine V Fiorello; Rachel M Baden; Jack H Liu; Nathaniel C Burmas; Carlos A Ruvalcaba; Roger Monroy; F Charles Mohr; Ronette Gehring; Jean-Pierre Delplanque; Karl V Clemons; David A Stevens; Lisa A Tell. Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer. Medical Mycology 2017, 56, 322 -331.
AMA StyleAshley Phillips, Christine V Fiorello, Rachel M Baden, Jack H Liu, Nathaniel C Burmas, Carlos A Ruvalcaba, Roger Monroy, F Charles Mohr, Ronette Gehring, Jean-Pierre Delplanque, Karl V Clemons, David A Stevens, Lisa A Tell. Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer. Medical Mycology. 2017; 56 (3):322-331.
Chicago/Turabian StyleAshley Phillips; Christine V Fiorello; Rachel M Baden; Jack H Liu; Nathaniel C Burmas; Carlos A Ruvalcaba; Roger Monroy; F Charles Mohr; Ronette Gehring; Jean-Pierre Delplanque; Karl V Clemons; David A Stevens; Lisa A Tell. 2017. "Amphotericin B concentrations in healthy mallard ducks (Anas platyrhynchos) following a single intratracheal dose of liposomal amphotericin B using an atomizer." Medical Mycology 56, no. 3: 322-331.