Pseudallescheria boydii with Aspergillus fumigatus and Aspergillus terreus in a Critically Ill Hematopoietic Stem Cell Recipient with ARDS.

Pseudallescheria boydii is a fungal organism known to affect immunocompromised patients. This organism is known to cause, in severe cases, invasive infection of various organs such as the central nervous, cardiovascular, and respiratory systems. We report an unusual case of pulmonary P. boydii pneumonia in an immunocompromised critically ill patient with a co-infection of Aspergillus fumigatus and Aspergillus terreus with ARDS. This case highlights the importance of a high index of suspicion for superimposed fungal infections in patients who are critically ill and immunocompromised. Uncommon fungal pathogens should be considered in the differential diagnosis of respiratory failure, especially if diagnostic markers such as galactomannan (from BAL and serum) or 1,3-beta-D-glucan are elevated. Further diagnostic interventions are warranted when insufficient clinical improvement is observed to prevent treatment failure and adverse outcomes.

In vitro antifungal activity of antipsychotic drugs and their combinations with conventional antifungals against Scedosporium and Pseudallescheria isolates.

In the present study, in vitro antifungal activities of five antipsychotic drugs (i.e., chlorpromazine hydrochloride, CPZ; trifluoperazine hydrochloride, TPZ; amantadine hydrochloride; R-(-)-deprenyl hydrochloride, and valproic acid sodium salt) and five conventional antifungal drugs (i.e., amphotericin B, AMB; caspofungin, CSP; itraconazole; terbinafine, TRB and voriconazole, VRC) were investigated in broth microdilution tests against four clinical and five environmental Scedosporium and Pseudallescheria isolates. When used alone, phenothiazines CPZ and TPZ exerted remarkable antifungal effects. Thus, their in vitro combinations with AMB, CSP, VRC, and TRB were also examined against the clinical isolates. In combination with antifungal agents, CPZ was able to act synergistically with AMB and TRB in cases of one and two isolates, respectively. In all other cases, indifferent interactions were revealed. Antagonism was not observed between the tested agents. These combinations may establish a more effective and less toxic therapy after further in vitro and in vivo studies for Scedosporium and Pseudallescheria infections.

Susceptibility and diversity in the therapy-refractory genus scedosporium.

Scedosporium species show decreased susceptibility to the majority of systemic antifungal drugs. Acquired resistance is likely to disseminate differentially with the mode of exchange of genetic material between lineages. Inter- and intraspecific diversities of Scedosporium species were analyzed for three partitions (rDNA internal transcribed spacer gene [ITS], partial ß-tubulin gene, and amplified fragment length polymorphism profiles), with the aim to establish distribution of resistance between species, populations, and strains. Heterogeneity of and recombination between lineages were determined, and distances between clusters were calculated using a centroid approach. Clinical, geographic, and antifungal data were plotted on diversity networks. Scedosporium minutisporum, Scedosporium desertorum, and Scedosporium aurantiacum were distinguished unambiguously in all partitions and had differential antifungal susceptibility profiles (ASP). Pseudallescheria fusoidea and Pseudallescheria ellipsoidea were indistinguishable from Scedosporium boydii. Pseudallescheria angusta took an intermediate position between Scedosporium apiospermum and S. boydii. Scedosporium boydii and S. apiospermum had identical ASP. Differences in (multi)resistance were linked to individual strains. S. apiospermum and S. boydii showed limited interbreeding and were recognized as valid, sympatric species. The S. apiospermum/S. boydii group, comprising the main clinically relevant Scedosporium species, consists of separate lineages and is interpreted as a complex undergoing sympatric evolution with incomplete lineage sorting. In routine diagnostics, the lineages in S. apiospermum/S. boydii are indicated with the umbrella descriptor "S. apiospermum complex"; individual species can be identified with rDNA ITS with 96.3% confidence. Voriconazole is recommended as the first-line treatment; resistance against this compound is rare.

Cell wall modifications during conidial maturation of the human pathogenic fungus Pseudallescheria boydii.

Progress in extending the life expectancy of cystic fibrosis (CF) patients remains jeopardized by the increasing incidence of fungal respiratory infections. Pseudallescheria boydii (P. boydii), an emerging pathogen of humans, is a filamentous fungus frequently isolated from the respiratory secretions of CF patients. It is commonly believed that infection by this fungus occurs through inhalation of airborne conidia, but the mechanisms allowing the adherence of Pseudallescheria to the host epithelial cells and its escape from the host immune defenses remain largely unknown. Given that the cell wall orchestrates all these processes, we were interested in studying its dynamic changes in conidia as function of the age of cultures. We found that the surface hydrophobicity and electronegative charge of conidia increased with the age of culture. Melanin that can influence the cell surface properties, was extracted from conidia and estimated using UV-visible spectrophotometry. Cells were also directly examined and compared using electron paramagnetic resonance (EPR) that determines the production of free radicals. Consistent with the increased amount of melanin, the EPR signal intensity decreased suggesting polymerization of melanin. These results were confirmed by flow cytometry after studying the effect of melanin polymerization on the surface accessibility of mannose-containing glycoconjugates to fluorescent concanavalin A. In the absence of melanin, conidia showed a marked increase in fluorescence intensity as the age of culture increased. Using atomic force microscopy, we were unable to find rodlet-forming hydrophobins, molecules that can also affect conidial surface properties. In conclusion, the changes in surface properties and biochemical composition of the conidial wall with the age of culture highlight the process of conidial maturation. Mannose-containing glycoconjugates that are involved in immune recognition, are progressively masked by polymerization of melanin, an antioxidant that is commonly thought to allow fungal escape from the host immune defenses.

KB425796-A, a novel antifungal antibiotic produced by Paenibacillus sp. 530603.

The novel antifungal macrocyclic lipopeptidolactone, KB425796-A (1), was isolated from the fermentation broth of bacterial strain 530603, which was identified as a new Paenibacillus species based on morphological and physiological characteristics, and 16S rRNA sequences. KB425796-A (1) was isolated as white powder by solvent extraction, HP-20 and ODS-B column chromatography, and lyophilization, and was determined to have the molecular formula C79H115N19O18. KB425796-A (1) showed antifungal activities against Aspergillus fumigatus and the micafungin-resistant infectious fungi Trichosporon asahii, Rhizopus oryzae, Pseudallescheria boydii and Cryptococcus neoformans.

Comparison of in vitro antifungal activities of efinaconazole and currently available antifungal agents against a variety of pathogenic fungi associated with onychomycosis.

Onychomycosis is a common fungal nail infection in adults that is difficult to treat. The in vitro antifungal activity of efinaconazole, a novel triazole antifungal, was evaluated in recent clinical isolates of Trichophyton rubrum, Trichophyton mentagrophytes, and Candida albicans, common causative onychomycosis pathogens. In a comprehensive survey of 1,493 isolates, efinaconazole MICs against T. rubrum and T. mentagrophytes ranged from ≤ 0.002 to 0.06 µg/ml, with 90% of isolates inhibited (MIC90) at 0.008 and 0.015 µg/ml, respectively. Efinaconazole MICs against 105 C. albicans isolates ranged from ≤ 0.0005 to >0.25 µg/ml, with 50% of isolates inhibited (MIC50) by 0.001 and 0.004 µg/ml at 24 and 48 h, respectively. Efinaconazole potency against these organisms was similar to or greater than those of antifungal drugs currently used in onychomycosis, including amorolfine, ciclopirox, itraconazole, and terbinafine. In 13 T. rubrum toenail isolates from onychomycosis patients who were treated daily with topical efinaconazole for 48 weeks, there were no apparent increases in susceptibility, suggesting low potential for dermatophytes to develop resistance to efinaconazole. The activity of efinaconazole was further evaluated in another 8 dermatophyte, 15 nondermatophyte, and 10 yeast species (a total of 109 isolates from research repositories). Efinaconazole was active against Trichophyton, Microsporum, Epidermophyton, Acremonium, Fusarium, Paecilomyces, Pseudallescheria, Scopulariopsis, Aspergillus, Cryptococcus, Trichosporon, and Candida and compared favorably to other antifungal drugs. In conclusion, efinaconazole is a potent antifungal with a broad spectrum of activity that may have clinical applications in onychomycosis and other mycoses.

Species-specific antifungal susceptibility patterns of Scedosporium and Pseudallescheria species.

Since the separation of Pseudallescheria boydii and P. apiosperma in 2010, limited data on species-specific susceptibility patterns of these and other species of Pseudallescheria and its anamorph Scedosporium have been reported. This study presents the antifungal susceptibility patterns of members affiliated with both entities. Clinical and environmental isolates (n = 332) from a wide range of sources and origins were identified down to species level and tested according to CLSI M38-A2 against eight antifungal compounds. Whereas P. apiosperma (geometric mean MIC/minimal effective concentration [MEC] values of 0.9, 2.4, 7.4, 16.2, 0.2, 0.8, 1.5, and 6.8 µg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) and P. boydii (geometric mean MIC/MEC values of 0.7, 1.3, 5.7, 13.8, 0.5, 1.4, 2.3, and 11.8 µg/ml for voriconazole, posaconazole, isavuconazole, itraconazole, micafungin, anidulafungin, caspofungin, and amphotericin B, respectively) had similar susceptibility patterns, those for S. aurantiacum, S. prolificans, and S. dehoogii were different from each other. Voriconazole was the only drug with significant activity against S. aurantiacum isolates. The MIC distributions of all drugs except voriconazole did not show a normal distribution and often showed two subpopulations, making a species-based prediction of antifungal susceptibility difficult. Therefore, antifungal susceptibility testing of all clinical isolates remains essential for targeted antifungal therapy. Voriconazole was the only compound with low MIC values (MIC(90) of ≤ 2 µg/ml) for P. apiosperma and P. boydii. Micafungin and posaconazole showed moderate activity against the majority of Scedosporium strains.

Severe prosthetic joint infection in an immunocompetent male patient due to a therapy refractory Pseudallescheria apiosperma.

Prosthetic joint infections (PJI) are rarely due to fungal agents and if so they are mainly caused by Candida strains. This case represents a PJI caused by a multi-drug resistant Pseudallescheria apiosperma, with poor in vivo response to itraconazole and voriconazole. This case differs also by the way of infection, since the joint infection did not follow a penetrating trauma. In the majority of cases, Scedosporium extremity infections remain local in immunocompetent individuals. We report a persistent joint infection with multiple therapeutic failures, and subsequent amputation of the left leg. Detailed clinical data, patient history, treatment regime and outcome of a very long-lasting (>4 years) P. apiosperma prosthetic knee infection in an immunocompetent, 61-year-old male patient are presented with this case. The patient was finally cured by the combination of multiple and extensive surgical interventions and prolonged antifungal combination therapy with voriconazole and terbinafine.

In vitro activity of E1210, a novel antifungal, against clinically important yeasts and molds.

E1210 is a new antifungal compound with a novel mechanism of action and broad spectrum of antifungal activity. We investigated the in vitro antifungal activities of E1210 compared to those of fluconazole, itraconazole, voriconazole, amphotericin B, and micafungin against clinical fungal isolates. E1210 showed potent activities against most Candida spp. (MIC(90) of ≤0.008 to 0.06 µg/ml), except for Candida krusei (MICs of 2 to >32 µg/ml). E1210 showed equally potent activities against fluconazole-resistant and fluconazole-susceptible Candida strains. E1210 also had potent activities against various filamentous fungi, including Aspergillus fumigatus (MIC(90) of 0.13 µg/ml). E1210 was also active against Fusarium solani and some black molds. Of note, E1210 showed the greatest activities against Pseudallescheria boydii (MICs of 0.03 to 0.13 µg/ml), Scedosporium prolificans (MIC of 0.03 µg/ml), and Paecilomyces lilacinus (MICs of 0.06 µg/ml) among the compounds tested. The antifungal action of E1210 was fungistatic, but E1210 showed no trailing growth of Candida albicans, which has often been observed with fluconazole. In a cytotoxicity assay using human HK-2 cells, E1210 showed toxicity as low as that of fluconazole. Based on these results, E1210 is likely to be a promising antifungal agent for the treatment of invasive fungal infections.

Successful treatment of Pseudallescheria boydii keratitis with topical natamycin as monotherapy.

PURPOSE: To report a case of Pseudallescheria boydii keratitis successfully treated with topical natamycin as monotherapy. METHODS: Interventional case report describing the clinical presentation, histopathologic findings, course, and treatment of a patient with P. boydii keratitis. RESULTS: A 50-year-old male electrician with a 4-day history of right eye pain and blurring of vision was referred. There was history of right eye injury while hammering and examining a hole in the ceiling. Examination showed a corneal abscess with overlying epithelial defect measuring 2 mm in diameter. Histopathologic investigation revealed septate hyaline cylindrical hyphae with acute angle branching and formation of oval to pyriform conidia truncated at the base, compatible with P. boydii. The patient was treated with topical natamycin 5%, which eradicated the infection, resulting in a final best-corrected visual acuity of 6/7.5. CONCLUSION: The fungus P. boydii can cause keratitis. The success rate for treatment was generally thought to be poor. Early detection and treatment is important in improving the outcome. This is believed to be the first reported case of P. boydii keratitis successfully treated with topical natamycin as monotherapy.

Estimation of the biodegradation rate of 2,3,7,8-tetrachlorodibenzo-p-dioxin by using dioxin-degrading fungus, Pseudallescheria boydii.

We are developing a bioreactor system for treating dioxin-contaminated soil or water using the dioxin-degrading fungus, Pseudallescheria boydii (P. boydii). In order to design the bioreactor system, this study estimated the rate at which P. boydii degraded 2,3,7,8-tetrachlorodibenzo-p-dioxin (2,3,7,8-TCDD), which is the most toxic of the dioxins. The experimental results showed that P. boydii degraded 2,3,7,8-TCDD during its logarithmic growth phase, using glucose as a carbon source for growth, and that the growth of P. boydii was not affected by 2,3,7,8-TCDD concentrations usually found at contaminated sites. These results were then used to apply successfully an existing mathematical model to the degradation of 2,3,7,8-TCDD by P. boydii. This allowed an estimation of the rate of degradation of 2,3,7,8-TCDD by P. boydii that can be used in the design of the bioreactor system.

Re-identification of clinical isolates of the Pseudallescheria boydii-complex involved in near-drowning.

Fungal infections caused by the members of the genera Pseudallescheria and/or Scedosporium are important complications in patients after near-drowning. As the taxonomy of Pseudallescheria and Scedosporium has been revised, clinical isolates from 11 patients, after near-drowning, previously identified as P. boydii or S. apiospermum had to be re-identified. S. apiospermum, now separated from P. boydii as a distinct species, was found most frequently (n = 8), while S. aurantiacum, recently described as new species and P. boydii were less common (n = 2 and n = 1, respectively). Three patients near-drowned during the Tsunami 2004 were infected by different species of the P. boydii complex. In vitro testing resulted in lowest minimal inhibitory concentration (MICs) for voriconazole (range 0.25-2.0 microg ml(-1)).

Prevalence and susceptibility testing of new species of pseudallescheria and scedosporium in a collection of clinical mold isolates.

The prevalence of new species of Pseudallescheria and Scedosporium in a collection of 46 clinical isolates was analyzed. Strain identification was done by morphological and molecular methods. Four Scedosporium aurantiacum isolates were detected among the panel of clinical strains. The susceptibility profile of S. aurantiacum was similar to that of Scedosporium apiospermum.

Pseudallescheria boydii keratitis.

A case of Pseudallescheria boydii keratitis is presented. The patient was successfully treated with topical natamycin and systemic itraconazole in conjunction with penetrating keratoplasty, leading to visual acuity of 20/40.

Antifungal susceptibilities of the species of the Pseudallescheria boydii complex.

Eighty-four isolates belonging to eight species that constitute the Pseudallescheria boydii complex were tested against 11 antifungal agents by using the microdilution method. There were significant differences among the species, with Scedosporium aurantiacum being the most resistant. In general, voriconazole was the most active drug, followed by posaconazole.

Extracellular peptidase in the fungal pathogen Pseudallescheria boydii.

Pseudallescheria boydii is a ubiquitous filamentous fungus capable of causing invasive disease in humans. In the present study, using sodium dodecyl sulfate-polyacrylamide gels containing bovine serum albumin as co-polymerized substrate, we identified a 28-kDa proteolytic activity released to the extracellular environment by mycelia of P. boydii. This peptidase was detected during the growth of P. boydii in Sabouraud-dextrose medium for 13 days and reached its maximal production on day 7. The 28-kDa peptidase was active in acidic pH (5.5) and had its activity completely blocked by 1,10-phenanthroline, a potent zinc-metallopeptidase inhibitor. Two other metallopeptidase inhibitors, EDTA and EGTA, were also tested and no alterations were observed in the activity of the 28-kDa extracellular peptidase. Likewise, E-64 (a cysteine peptidase inhibitor), phenylmethylsulphonyl fluoride (a serine peptidase inhibitor), and pepstatin A (an aspartyl peptidase inhibitor) did not significantly alter the enzymatic behavior. Collectively, we described for the first time the expression of an extracellular metallopeptidase in the human opportunistic fungal pathogen P. boydii.

Pseudallescheriasis in the 21st century.

Since its discovery as an agent of mycetoma nearly a century ago, Pseudallescheria boydii with its asexual (synanamorphic) form, Scedosporium apiospermum, is now recognized as an important emerging opportunistic pathogen causing invasive mycosis in immunocompromised patients. The clinical spectrum of pseudallescheriasis is wide. Invasive disease of the lung, CNS and dissemination are serious manifestations in immunocompromised patients. This organism responds poorly to amphotericin B, and its histopathologic resemblance to aspergillosis often results in a delay in diagnosis. In vitro data, animal models and accumulating clinical experience support the use of voriconazole as a primary treatment for pseudallescheriasis. This paper reviews the microbiology, ecology, epidemiologic trends, clinical manifestations and current treatment options of pseudallescheriasis.

Pseudallescheria boydii cranial osteomyelitis and subdural empyema successfully treated with voriconazole: a case report and literature review.

Described here is a case of Pseudallescheria boydii cranial osteomyelitis and subdural empyema following craniotomy, which was successfully treated with surgical debridement and voriconazole. Other reported cases of Pseudallescheria boydii osteomyelitis are reviewed. The reported case suggests that voriconazole may represent a new therapeutic option for this infection.