Cutaneous Lagenidium deciduum infection in a patient with relapsed acute myeloid leukemia.

BACKGROUND: Lagenidium deciduum is an oomycete that can cause infections in mammals that present similarly to pythiosis and mucormycosis. Most of the existing case reports have occurred in canines and have been fatal. In animals, medical therapy has not been successful, so surgical excision is the mainstay of treatment. Lagenidium sp. infections in humans are rare. There is only one case of a human Lagenidium sp. infection in the literature, and it presented as an ocular infection. The human ocular infection was resistant to medical therapy and required a penetrating keratoplasty for cure. Additional reports of effective therapy are needed to guide management of this emerging pathogen. We present the first case of a cutaneous Lagenidium deciduum infection in a human patient, which is also the first documented case of a Lagenidium deciduum infection in an immunocompromised host of any species. CASE PRESENTATION: An 18-year-old female with relapsed acute myeloid leukemia, awaiting a haploidentical stem cell transplant, presented with erythematous cutaneous lesions on her left hip and bilateral buttocks that enlarged and blackened over several days. About 1 week later, boil-like lesions appeared on her bilateral buttocks. The skin lesions were initially presumed to be bacterial in origin, so the patient was treated with clindamycin and cefepime with little improvement. Upon further investigation, fungal cultures and skin biopsies revealed aseptate hyphae, so the patient was switched to isavuconazole and amphotericin B due to concern for mucormycosis. Phenotypic characterization and DNA sequencing were performed by the Fungus Testing Laboratory, University of Texas Health Science Center at San Antonio, which identified the causal fungal organism as Lagenidium deciduum. All of her cutaneous lesions were surgically excised, and the patient was treated with micafungin, terbinafine, doxycycline, and azithromycin. Micafungin and terbinafine were continued until she achieved engraftment post-transplant. CONCLUSIONS: We report the first successful treatment of a human Lagenidium infection in an immunocompromised host through a combination of aggressive surgical excision and prolonged antifungal therapy during the prolonged neutropenia associated with allogeneic stem cell transplant. Prompt diagnosis and management may prevent disseminated oomycosis.

Terbinafine-Resistant Dermatophytes and the Presence of Trichophyton indotineae in North America.

Dermatophytes are common causes of skin, hair, and nail infections in humans. The most common species causing infections in humans are Trichophyton rubrum, Trichophyton mentagrophytes, and Trichophyton interdigitale. Outbreaks of recalcitrant dermatophytosis have been reported in parts of South Asia, including those caused by a hypervirulent and resistant species, Trichophyton indotineae. We evaluated the antifungal susceptibility profiles of dermatophytes received by our laboratory from institutions across North America between 2021 and 2022 and performed species identification for isolates deemed to demonstrate in vitro resistance. Susceptibility testing was performed by CLSI broth microdilution methods, and species identification was performed by DNA sequence analysis. During this 2-year period, 271 dermatophyte isolates were included, the majority of which demonstrated low MIC values for terbinafine (geometric mean [GM] and modal MIC, 0.031 µg/mL and 0.008 µg/mL, respectively) and the azoles itraconazole, posaconazole, and voriconazole (0.035 to 0.049 µg/mL and ≤0.03 µg/mL). However, 18.6% of the isolates tested were resistant to terbinafine (MIC ≥ 0.5 µg/mL), including 21 T. rubrum and 21 T. indotineae isolates. These isolates were received from several different states in the United States and two provinces in Canada. In contrast, resistance to itraconazole was relatively rare. We also searched our laboratory database for earlier isolates that were resistant to terbinafine and identified 3 additional T. indotineae isolates, the earliest of which was from 2017. These results demonstrate that terbinafine resistance in dermatophytes was relatively common over this 2-year period and that T. indotineae is present in multiple areas in North America. Continued surveillance is warranted.

Dihydroorotate dehydrogenase inhibitor olorofim has potent in vitro activity against Microascus/Scopulariopsis, Rasamsonia, Penicillium and Talaromyces species.

BACKGROUND: Treatment options against infections caused by rare but emerging moulds may be limited by their reduced susceptibility or resistance to clinically available antifungals. The investigational antifungal olorofim, which targets the biosynthesis of pyrimidines within fungi, has activity against different species of filamentous fungi, including Aspergillus and Scedosporium/Lomentospora prolificans isolates that are resistant to available antifungals. OBJECTIVE: We evaluated the in vitro activity of olorofim against 160 isolates within the genera Microascus/Scopulariopsis, Penicillium, Talaromyces and the Rasamsonia argillacea species complex. METHODS: One hundred sixty clinical isolates that had previously been identified to the species level by DNA sequence analysis were included. Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, caspofungin, posaconazole and voriconazole. RESULTS: Olorofim demonstrated in vitro activity against each of the genera tested. Overall, olorofim MICs ranged from ≤0.008 to 0.5 mg/L against all isolates tested, with MIC90 and modal MIC values ranging from ≤0.008 to 0.25 mg/L and ≤0.008 to 0.03 mg/L, respectively. This activity was also maintained against individual isolates that had reduced susceptibility to or in vitro resistance against amphotericin B, posaconazole and/or voriconazole. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against clinical isolates of emerging mould pathogens, including those with reduced susceptibility or resistance to clinically available antifungals. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy against infections caused by these fungi.

Species Distribution and Antifungal Susceptibilities of Aspergillus Section Fumigati Isolates in Clinical Samples from the United States.

Aspergillus species are capable of causing both invasive disease and chronic infections in immunocompromised patients or those with preexisting lung conditions. Aspergillus fumigatus is the most commonly cultured species, and there is increasing concern regarding resistance to the azoles, which are the mainstays of antifungal therapy against aspergillosis. We evaluated the species distribution and susceptibility profiles of isolates within Aspergillus section Fumigati in the United States over a 52-month period. Species identification was performed by combined phenotypic characteristics and DNA sequence analysis, and antifungal susceptibility testing was performed by CLSI M38 broth microdilution for amphotericin B, the azoles, and the echinocandins. The entire CYP51A gene and its promoter were also sequenced in isolates that were phenotypically resistant to the azoles. During the study time frame, 2,138 isolates were included, representing 11 different species within Aspergillus section Fumigati, of which A. fumigatus was the most prevalent (96.91%). Overall, amphotericin B and the echinocandins demonstrated consistent in vitro activity with very few isolates demonstrating reduced susceptibility to these agents. Voriconazole, isavuconazole, and posaconazole also demonstrated good in vitro activity, and the overall percentages of isolates classified as resistant or non-wild type ranged from 3.33 to 6.58%. Mutations within the CYP51A gene leading to amino acid changes associated with azole resistance were found in 75.3% of isolates that were phenotypically resistant or non-wild type and included both those associated with chronic clinical exposure and environmental exposure to the azoles. Further studies are warranted to continue to monitor for azole-resistant A. fumigatus within the United States.

Manogepix, the Active Moiety of the Investigational Agent Fosmanogepix, Demonstrates In Vitro Activity against Members of the Fusarium oxysporum and Fusarium solani Species Complexes.

We evaluated the in vitro activity of manogepix against Fusarium oxysporum and Fusarium solani species complex (FOSC and FSSC, respectively) isolates per CLSI document M38 broth microdilution methods. Manogepix demonstrated activity against both FOSC (MEC [minimum effective concentration] range, ≤0.015 to 0.03 µg/ml; MIC50 range, ≤0.015 to 0.125 µg/ml) and FSSC (MEC, ≤0.015 µg/ml; MIC50, ≤0.015 to 0.25 µg/ml). Amphotericin B was also active (MIC, 0.25 to 4 µg/ml), whereas the triazoles (MIC, 1 to >16 µg/ml) and micafungin (MEC, ≥8 µg/ml) had limited activity.

Epidemiology and Antifungal Susceptibilities of Mucoralean Fungi in Clinical Samples from the United States.

The global incidence of mucormycosis has increased in recent years owing to higher numbers of individuals at risk for these infections. The diagnosis and treatment of this aggressive fungal infection are of clinical concern due to differences in species distribution in different geographic areas and susceptibility profiles between different species that are capable of causing highly aggressive infections. The purpose of this study was to evaluate the epidemiology and susceptibility profiles of Mucorales isolates in the United States over a 52-month period. Species identification was performed by combined phenotypic characteristics and DNA sequence analysis, and antifungal susceptibility testing was performed by CLSI M38 broth microdilution for amphotericin B, isavuconazole, itraconazole, and posaconazole. During this time frame, 854 isolates were included, representing 11 different genera and over 26 species, of which Rhizopus (58.6%) was the predominant genus, followed by Mucor (19.6%). The majority of isolates were cultured from the upper and lower respiratory tracts (55%). Amphotericin B demonstrated the most potent in vitro activity, with geometric mean (GM) MICs of ≤0.25 µg/ml against all genera with the exception of Cunninghamella species (GM MIC of 1.30 µg/ml). In head-to-head comparisons, the most active azole was posaconazole, followed by isavuconazole. Differences in azole and amphotericin B susceptibility patterns were observed between the genera with the greatest variability observed with isavuconazole. Awareness of the epidemiology of Mucorales isolates and differences in antifungal susceptibility patterns in the United States may aide clinicians in choosing antifungal treatment regimens. Further studies are warranted to correlate these findings with clinical outcomes.

In vitro activity of olorofim against clinical isolates of the Fusarium oxysporum and Fusarium solani species complexes.

BACKGROUND: Invasive fusariosis is associated with marked morbidity and mortality in immunocompromised hosts, and clinical outcomes are poor with conventional therapy. Olorofim (F901318) is an investigational antifungal in the orotomide class that selectively targets fungal dihydroorotate dehydrogenase (DHODH) causing inhibition of pyrimidine biosynthesis. OBJECTIVE: We evaluated the in vitro activity of olorofim against 61 clinical isolates of the Fusarium oxysporum and F solani species complexes (FOSC and FSSC, respectively), the most prevalent causes of invasive fusariosis. METHODS: Clinical isolates of FOSC (n = 45) and FSSC (n = 16) were identified using DNA sequence analysis of the translation elongation factor 1-alpha (TEF1α) and RNA polymerase II second largest subunit (RPB2). Antifungal susceptibility testing was performed by CLSI M38 broth microdilution for olorofim, amphotericin B, isavuconazole, posaconazole, voriconazole and micafungin. RESULTS: Olorofim demonstrated good in vitro activity against both FOSC and FSSC. Against the 45 FOSC isolates, olorofim MICs ranged between 0.03-0.5 mg/L and 0.06->4 mg/L at the 50% and 100% inhibition endpoints, respectively. Against FSSC isolates, olorofim MIC ranged between 0.25-1 mg/L and 1->4 mg/L at 50% and 100% inhibition, respectively. While amphotericin B also demonstrated similar in vitro activity (MIC ranges 1-4 and 0.25-4 mg/L against FOSC and FSSC, respectively), neither the triazoles nor micafungin demonstrated consistent in vitro activity against Fusarium isolates at clinically relevant concentrations. CONCLUSIONS: The investigational agent olorofim demonstrated good in vitro activity against FOSC and FSSC clinical isolates. Further studies are warranted to determine how well this in vitro activity translates into in vivo efficacy.

Pseudocanariomyces americanus, gen. nov., sp. nov., A New Thielavia-Like Species in the Chaetomiaceae: Identification and Management of a Prosthetic Hip Infection.

This report describes the phenotypic characteristics of a novel fungal species, isolated from a prosthetic hip infection. The patient, who had undergone multiple total hip arthroplasties due to Legg-Calvé-Perthes disease, presented with continued fever and wound dehiscence. Findings upon incision and draining were notable for necrotic tissue and a sinus tract from the fluid collection. Intraoperative cultures were positive for a sterile filamentous fungus. BLASTn results following DNA sequencing placed the isolate within the family Chaetomiaceae close to the genera Madurella, Canariomyces, Stolonocarpus, Stellatospora, Ovatospora, Carteria and Melanocarpus. Phylogenetic analysis demonstrated that the isolate was a new thielavia-like species, Pseudocanariomyces americanus. Antifungal susceptibility was performed, and low minimum inhibitory concentrations were observed with amphotericin B, itraconazole, posaconazole, and voriconazole. The patient was initially treated with voriconazole but was switched to posaconazole secondary to a photosensitivity reaction. Acceptable posaconazole trough concentrations were achieved, and the patient remained stable without pain or drainage from her surgical incision.

Spiromastigoides asexualis: Phylogenetic Analysis and Evaluation as a Cause of False-Positive Blastomyces DNA Probe Test Results.

This is the first case of Spiromastigoides asexualis human infection, and it notably gave a false-positive Blastomyces DNA probe laboratory result. We further investigated other Spiromastigoides isolates as a cause of false-positive testing results, their phylogenetic relationship, and their susceptibility profiles to clinically available antifungal agents. Other S. asexualis isolates also resulted in positive Blastomyces DNA probe results, while Spiromastigoides species other than S. asexualis did not.

Novel Penicillium species causing disseminated disease in a Labrador Retriever dog.

This report describes the phenotypic characteristics of a novel Penicillium species, Penicillium labradorum, isolated from a 3-year-old male, castrated, Labrador retriever with disseminated fungal disease. The dog's presenting clinical signs included lethargy, lymphadenopathy, tachypnea, moderate pitting edema, and nonweight bearing lameness associated with the right hind limb. Fine-needle aspirate biopsies from the sublumbar and prescapular lymph nodes were initially examined. The cytologic findings were consistent with pyogranulomatous inflammation with abundant extracellular and phagocytized fungal fragments and hyphae. Based on the morphology of the organisms and lack of endogenous pigment, hyalohyphomycosis was considered most likely, with Fusarium, Penicillium, and Paecilomyces species being considerations. Fungal isolates were obtained via culture of samples from the lymph nodes, and molecular identification testing originally identified an undescribed Penicillium species belonging to the Penicillium section Exilicaulis. BLAST searches and phylogenetic analyses performed approximately 1 year and 9 months after the isolation date revealed an isolate within the Penicillium parvum clade in the Penicillium section Exilicaulis but phylogenetically distant from the other species in the section, thus representing a new species, Penicillium labradorum. Antifungal susceptibility testing was also performed on the isolate and low minimum inhibitory concentrations were observed with terbinafine, voriconazole, and posaconazole, while in vitro resistance was observed with fluconazole. The dog had been previously treated with fluconazole, itraconazole, amphotericin B lipid complex, voriconazole, and terbinafine. Approximately 587 days after the initial diagnosis, the dog was euthanized due to worsening of clinical signs and concerns for quality of life.

Novel Paranannizziopsis species in a Wagler's viper (Tropidolaemus wagleri), tentacled snakes (Erpeton tentaculatum), and a rhinoceros snake (Rhynchophis boulengeri) in a zoological collection.

We report several cases of fungal infections in snakes associated with a new species within the genus Paranannizziopsis. Three juvenile Wagler's vipers (Tropidolaemus wagleri) presented with skin abnormalities or ulcerative dermatitis, and two snakes died. Histologic examination of skin from the living viper revealed hyperplastic, hyperkeratotic, and crusting epidermitis with intralesional fungal elements. The terrestrial Wagler's vipers were housed in a room with fully aquatic tentacled snakes (Erpeton tentaculatum), among which there had been a history of intermittent skin lesions. Approximately 2 months after the biopsy of the viper, a skin sample was collected from one tentacled snake (TS1) with skin abnormalities and revealed a fungal infection with a similar histologic appearance. Fungal isolates were obtained via culture from the Wagler's viper and TS1 and revealed a novel species, Paranannizziopsis tardicrescens, based on phenotypic characterization and molecular analysis. P. tardicrescens was cultured and identified by DNA sequence analysis 8 months later from a dead tentacled snake in an exhibit in an adjacent hallway and 13 months later from a living rhinoceros snake (Rhynchophis boulengeri) with two focal skin lesions. Antifungal susceptibility testing on three of four cultured isolates demonstrated potent in vitro activity for terbinafine and voriconazole.

In Vitro Activity of Isavuconazole against Opportunistic Fungal Pathogens from Two Mycology Reference Laboratories.

Monitoring antifungal susceptibility patterns for new and established antifungal agents seems prudent given the increasing prevalence of uncommon species associated with higher antifungal resistance. We evaluated the activity of isavuconazole against 4,856 invasive yeasts and molds collected worldwide. The 4,856 clinical fungal isolates, including 2,351 Candida species isolates, 97 non-Candida yeasts, 1,972 Aspergillus species isolates, and 361 non-Aspergillus molds, including 292 Mucorales isolates collected in 2015 to 2016, were tested using CLSI methods. The MIC values for isavuconazole versus Aspergillus ranged from 0.06 to ≥16 µg/ml. The modal MIC for isavuconazole was 0.5 µg/ml (range, 0.25 [A. nidulans and A. terreus species complex] to 4 µg/ml [A. calidoustus and A. tubingensis]). Eight A. fumigatus isolates had elevated isavuconazole MIC values at ≥8 µg/ml (non-wild type). Isavuconazole showed comparable activity to itraconazole against the Mucorales The lowest modal isavuconazole MIC values were seen for Rhizopus spp., R. arrhizus var. arrhizus, and R. microsporus (all 1 µg/ml). Candida species isolates were inhibited by ≤0.25 µg/ml of isavuconazole (range, 96.1% [C. lusitaniae] to 100.0% [C. albicans, C. dubliniensis, C. kefyr, and C. orthopsilosis]). MIC values were ≤1 µg/ml for 95.5% of C. glabrata isolates and 100.0% of C. krusei isolates. Isavuconazole was active against the non-Candida yeasts, including Cryptococcus neoformans (100.0% at ≤0.5 µg/ml). Isavuconazole exhibited excellent activity against most species of Candida and Aspergillus Isavuconazole was comparable to posaconazole and voriconazole against the less common yeasts and molds. Isavuconazole was generally less active than posaconazole and more active than voriconazole against the 292 Mucorales isolates. We confirm the potentially useful activity of isavuconazole against species of Rhizopus as determined by CLSI methods.

Invasive Rhinosinusitis Caused by Lasiodiplodia theobromae in an Allogeneic Hematopoietic Cell Transplant Recipient Case Report and Review of Literature.

Lasiodiplodia theobromae is a known plant pathogen in tropical and subtropical areas. Few cases have been reported in humans (usually keratitis and endophthalmitis) with only two cases of fungal sinusitis in immunocompromised and immunocompetent patients published to date. We report a case of invasive sinusitis secondary to L. theobromae in an allogeneic hematopoietic cell transplant recipient successfully treated with surgical debridement and triazole antifungals with a review of available literature.

Effects of Treated versus Untreated Polystyrene on Caspofungin In Vitro Activity against Candida Species.

Significant interlaboratory variability is observed in testing the caspofungin susceptibility of Candida species by both the CLSI and EUCAST broth microdilution methodologies. We evaluated the influence of treated versus untreated polystyrene microtiter trays on caspofungin MICs using 209 isolates of four Candida species, including 16 C. albicans and 11 C. glabrata isolates with defined FKS mutations. Caspofungin MICs were also determined using the commercially available YeastOne and Etest assays and 102 isolates. All C. glabrata isolates had caspofungin MICs of ≥0.5 µg/ml, the clinical breakpoint for caspofungin resistance in this species, measured using trays made of treated polystyrene, regardless of the FKS status. In contrast, susceptible isolates could readily be distinguished from resistant/non-wild-type isolates when caspofungin MICs were measured using untreated polystyrene trays and both the YeastOne and Etest assays. Similar results were also observed for C. krusei isolates, as all isolates had caspofungin MICs above the threshold for resistance measured using treated polystyrene trays. In contrast, C. albicans isolates could be correctly identified as susceptible or resistant when caspofungin MICs were measured with treated or untreated trays and with the YeastOne and Etest assays. MICs falsely elevated above the resistance breakpoint were also not observed for C. tropicalis isolates. These results demonstrated that the use of treated polystyrene may be one factor that leads to falsely elevated caspofungin in vitro susceptibility results and that this may also be a greater issue for some Candida species than for others.

First Detection of TR34 L98H and TR46 Y121F T289A Cyp51 Mutations in Aspergillus fumigatus Isolates in the United States.

Azole resistance in Aspergillus fumigatus is an increasing problem. The TR34 L98H and TR46 Y121F T289A mutations that can occur in patients without previous azole exposure have been reported in Europe, Asia, the Middle East, Africa, and Australia. Here, we report the detection of both the TR34 L98H and TR46 Y121F T289A mutations in confirmed A. fumigatus isolates collected in institutions in the United States. These mutations, other mutations known to cause azole resistance, and azole MICs are reported here.

Ustilago echinata: Infection in a Mixed Martial Artist Following an Open Fracture.

Ustilago, a common fungal parasite of grains, is infrequently isolated as a pathogen in humans. We describe a case of Ustilago echinata infection following an open distal tibia fracture, review the current literature of this genus as a cause of invasive fungal infection in humans, and discuss management issues.

Morphological and Molecular Characterization of Exophiala polymorpha sp. nov. Isolated from Sporotrichoid Lymphocutaneous Lesions in a Patient with Myasthenia Gravis.

Exophiala species are capable of causing cutaneous and subcutaneous infections in immunocompromised patients. An Exophiala isolate was cultured from a biopsy specimen of a lesion on the forearm of a patient with myasthenia gravis. The patient also had lesions on the palm and distal aspects of the hand, which were successfully treated with a long-term course of itraconazole. A detailed morphological and molecular characterization of the isolate was undertaken. Phylogenetic analysis of the internal transcribed spacer region and portions of the ß-tubulin and translation elongation factor 1-alpha genes indicated that the isolate was a novel species closely related to but genetically distinct from species within the Exophiala spinifera clade; the name Exophiala polymorpha sp. nov. is proposed. Morphologically, E. polymorpha most closely resembles E. xenobiotica but it differs in possessing phialides bearing prominent, wide collarettes, and it does not produce chlamydospores.

Combat-Related Pythium aphanidermatum Invasive Wound Infection: Case Report and Discussion of Utility of Molecular Diagnostics.

We describe a 22-year-old soldier with 19% total body surface area burns, polytrauma, and sequence- and culture-confirmed Pythium aphanidermatum wound infection. Antemortem histopathology suggested disseminated Pythium infection, including brain involvement; however, postmortem PCR revealed Cunninghamella elegans, Lichtheimia corymbifera, and Saksenaea vasiformis coinfection. The utility of molecular diagnostics in invasive fungal infections is discussed.

Comparison of MICs of fluconazole and flucytosine when dissolved in dimethyl sulfoxide or water.

A total of 145 clinical strains of Candida species were tested by the Clinical and Laboratory Standards Institute M27-A3 methodology to determine if replacing water with dimethyl sulfoxide as the solvent for fluconazole and flucytosine impacted the in vitro potency. No significant differences in MIC values were observed with either antifungal between the two solvents against any Candida species, and the essential agreement for each agent between the two solvents was greater than 99%.

Phialophora chinensis fungal keratitis: An initial case report and species identification.

Purpose: To report the initial case of microbial keratitis caused by Phialophora chinensis, a rare cause of fungal keratitis. Observations: A 66-year-old gentleman with a complex right eye (OD) ocular history including herpes simplex virus infectious epithelial keratitis with subsequent neurotrophic keratopathy, and prior combined Candida albicans and parapsilosis fungal keratitis presented with pain OD in the absence of an antecedent trauma. The patient was found to have a filamentous fungal keratitis, which was subsequently cultured and identified as Phialophora chinensis by the laboratory. Despite topical and oral antifungal treatment based on sensitivities determined by the lab, the patient ultimately required intrastromal and subconjunctival antifungal injections, corneal crosslinking, and superficial keratectomy with amniotic membrane to clinically improve. The fungal keratitis recurred twice, with each occurrence rapidly progressing to corneal perforation. Months after the second penetrating keratoplasty, the patient's mental status declined due to multiorgan failure. An occult pulmonary malignancy was discovered during this hospital stay, and the patient was lost to follow-up after entering hospice. Conclusions and Importance: We report a unique case of fungal keratitis caused by Phialophora chinensis and the subsequent management, including both medical and surgical interventions. Despite a multimodal treatment regimen, this case demonstrates the recalcitrant and potentially recurrent nature of fungal keratitis caused by P. chinensis.