Rare Molds Research Articles

Rare mold infections from a tertiary care institute in South India: A case series

Rare mold infections from a tertiary care institute in South India: A case series

Successful Treatment of Disseminated Fusariosis in a 15-Month-Old Boy With Refractory Acute Lymphoblastic Leukemia Using High-Dose Voriconazole.

Infections due to rare molds, such as Fusarium spp., cause severe and difficult-to-control diseases with increasing frequency. Data on fusariosis in children and on the use of voriconazole (VCZ), considered a drug of choice, are scarce in infants and children <2 years of age. We present the first, to our knowledge, pediatric case of disseminated mycosis due to Fusarium musae in a 15-month-old boy with relapsed/refractory acute lymphoblastic leukemia, diagnostics and outcome. Herein, at this severely immunocompromised patient, after prompt diagnosis, disseminated fusariosis was successfully treated with high-dose VCZ at a final dose of 15 mg/kg of body weight twice a day. This occurred by achieving adequate drug exposures as determined by drug susceptibility testing and followed by therapeutic drug monitoring without observed toxicity. Appropriate diagnostic approach and timely administration of optimal antifungal therapy with VCZ were important for the successful treatment of disseminated fusariosis. Therapeutic drug monitoring, especially in <2-year-old children, is necessary to achieve sufficient drug exposure for optimal therapeutic response without toxicity.

Fusarium, Scedosporium and Other Rare Mold Invasive Infections: Over Twenty-Five-Year Experience of a European Tertiary-Care Center.

Invasive mold infections (IMD) are an emerging concern due to the growing prevalence of patients at risk, encompassing but not limited to allogeneic hematopoietic stem cell transplant recipients, hematological malignancies patients, solid organ transplant recipients and intensive care unit patients. In contrast with invasive aspergillosis and mucormycosis, other hyalohyphomycoses and phaeohyphomycoses remain poorly known. We conducted a retrospective analysis of the clinical, biological, microbiological and evolutive features of 92 IMD having occurred in patients in our tertiary-care center over more than 25 years. A quarter of these infections were due to multiple molds. Molds involved were Fusarium spp. (36.2% of IMD with a single agent, 43.5% of IMD with multiple agents), followed by Scedosporium spp. (respectively 14.5% and 26.1%) and Alternaria spp. (respectively 13.0% and 8.7%). Mortality at day 84 was higher for Fusarium spp., Scedosporium spp. or multiple pathogens IMD compared with Alternaria or other pathogens (51.7% vs. 17.6%, p < 0.05). Mortality at day 84 was also influenced by host factor: higher among hematology and alloHSCT patients than in other patients (30.6% vs. 20.9% at day 42 and 50.0% vs. 27.9% at day 84, p = 0.041). Better awareness, understanding and treatments are awaited to improve patient prognosis.

Scedosporiosis and lomentosporiosis: modern perspectives on these difficult-to-treat rare mold infections.

SUMMARYAlthough Scedosporium species and Lomentospora prolificans are uncommon causes of invasive fungal diseases (IFDs), these infections are associated with high mortality and are costly to treat with a limited armamentarium of antifungal drugs. In light of recent advances, including in the area of new antifungals, the present review provides a timely and updated overview of these IFDs, with a focus on the taxonomy, clinical epidemiology, pathogenesis and host immune response, disease manifestations, diagnosis, antifungal susceptibility, and treatment. An expansion of hosts at risk for these difficult-to-treat infections has emerged over the last two decades given the increased use of, and broader population treated with, immunomodulatory and targeted molecular agents as well as wider adoption of antifungal prophylaxis. Clinical presentations differ not only between genera but also across the different Scedosporium species. L. prolificans is intrinsically resistant to most currently available antifungal agents, and the prognosis of immunocompromised patients with lomentosporiosis is poor. Development of, and improved access to, diagnostic modalities for early detection of these rare mold infections is paramount for timely targeted antifungal therapy and surgery if indicated. New antifungal agents (e.g., olorofim, fosmanogepix) with novel mechanisms of action and less cross-resistance to existing classes, availability of formulations for oral administration, and fewer drug-drug interactions are now in late-stage clinical trials, and soon, could extend options to treat scedosporiosis/lomentosporiosis. Much work remains to increase our understanding of these infections, especially in the pediatric setting. Knowledge gaps for future research are highlighted in the review.

Invasive Scedosporium and Lomentospora prolificans Infections in Australia: A Multicenter Retrospective Cohort Study.

Management of Scedosporium/Lomentospora prolificans infections remains challenging. We described predisposing factors, clinical manifestations, and outcomes of these rare mold infections, including predictors of early (1-month) and late (18-month) all-cause mortality and treatment failure. We conducted a retrospective Australian-based observational study of proven/probable Scedosporium/L prolificans infections from 2005 to 2021. Data on patient comorbidities, predisposing factors, clinical manifestations, treatment, and outcomes up to 18 months were collected. Treatment responses and death causality were adjudicated. Subgroup analyses, multivariable Cox regression, and logistic regression were performed. Of 61 infection episodes, 37 (60.7%) were attributable to L prolificans. Forty-five of 61 (73.8%) were proven invasive fungal diseases (IFDs), and 29 of 61 (47.5%) were disseminated. Prolonged neutropenia and receipt of immunosuppressant agents were documented in 27 of 61 (44.3%) and 49 of 61 (80.3%) episodes, respectively. Voriconazole/terbinafine was administered in 30 of 31 (96.8%) L prolificans infections, and voriconazole alone was prescribed for 15 of 24 (62.5%) Scedosporium spp infections. Adjunctive surgery was performed in 27 of 61 (44.3%) episodes. Median time to death post-IFD diagnosis was 9.0 days, and only 22 of 61 (36.1%) attained treatment success at 18 months. Those who survived beyond 28 days of antifungal therapy were less immunosuppressed with fewer disseminated infections (both P < .001). Disseminated infection and hematopoietic stem cell transplant were associated with increased early and late mortality rates. Adjunctive surgery was associated with lower early and late mortality rates by 84.0% and 72.0%, respectively, and decreased odds of 1-month treatment failure by 87.0%. Outcomes associated with Scedosporium/L prolificans infections is poor, particularly with L prolificans infections or in the highly immunosuppressed population.

2043. In Vitro Activity of Manogepix Against 2,810 Fungal Isolates from the SENTRY Surveillance Program (2020-2021) Stratified by Infection Type

Abstract Background Manogepix is a new antifungal with a novel mechanism of action and potent in vitro activity against Candida (except C. krusei), Aspergillus, and rare mold isolates. The manogepix prodrug fosmanogepix is in Phase 2 development for the treatment of invasive mold infections caused by Aspergillus and rare molds (NCT04240886) and has completed Phase 2 studies for candidemia (NCT03604705) and C. auris (NCT04148287) infections. We evaluated the in vitro activity of manogepix and comparators against 2,810 geographically diverse fungal isolates collected in the SENTRY Surveillance Program during 2020-2021 and stratified them by infection type. Methods Antifungal susceptibility testing of manogepix and comparator agents was conducted according to CLSI M27 (2017) and M38 (2017) guidelines. Fungal surveillance isolates were collected from medical centers located in North America (30 sites; 37.9%), Europe (30 sites; 38.4%), Asia-Pacific (11 sites; 14.7%), and Latin America (6 sites; 9.0%). Infection sites included bloodstream infections (BSI; 48.3%), pneumonia in hospitalized patients (PIHP; 19.9%), skin and skin structure infections (SSSI; 7.8%), urinary tract infections (UTI; 3.1%), intra-abdominal infections (IAI; 1.6%), and other infection types (19.3%). Results Manogepix demonstrated potent in vitro activity against Candida spp. isolates (MIC50/90, 0.004-0.03/0.008-0.06 mg/L) regardless of infection type (Table). Similarly, manogepix was highly active against 534 Aspergillus spp. isolates (MEC50/90, 0.015/0.03 mg/L). Manogepix was active against 53 Cryptococcus neoformans var. grubii (MIC50/90, 0.25/1 mg/L), 19 Fusarium spp. (MEC50/90, 0.015/0.06 mg/L), 12 Lomentospora prolificans (MEC50/90, 0.03/0.06 mg/L), and 17 Scedosporium spp. isolates (MEC50/90, 0.06/0.12 mg/L). Conclusion Manogepix showed potent in vitro activity against Candida spp., Aspergillus spp., C. neoformans var. grubii, and rare molds, including Fusarium spp., L. prolificans, and Scedosporium spp. isolates. Notable activity was also demonstrated by manogepix against C. auris isolates. Further clinical development of fosmanogepix in difficult-to-treat, resistant fungal infections is warranted. Disclosures Michael D. Huband, BS, AbbVie: Grant/Research Support|Melinta: Grant/Research Support Cecilia G. Carvalhaes, MD, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support Mariana Castanheira, PhD, AbbVie: Grant/Research Support|Cidara: Grant/Research Support|GSK: Grant/Research Support|Melinta: Grant/Research Support|Pfizer: Grant/Research Support|Shionogi: Grant/Research Support.

An Update on the Diagnosis and Treatment of Invasive Mold Disease of the Central Nervous System in Children.

Epidemiological data of CNS IMD in pediatrics are limited. Aspergillus is the most frequently identified species, followed by other rare molds. Prompt diagnosis is of importance to define the optimal therapeutic management with respect to antifungal agent, dose, and evaluation of surgical intervention. The mortality rate of CNS IMD remains high. In this mini review we summarize the current knowledge on diagnosis and treatment of CNS IMD in pediatrics.

Liposomal amphotericin B-the future.

Advances in medicine have led to a growing number of people with compromised or suppressed immune systems who are susceptible to invasive fungal infections. In particular, severe fungal infections are becoming increasingly common in ICUs, affecting people within and outside of traditional risk groups alike. This is exemplified by the emergence of severe viral pneumonia as a significant risk factor for invasive pulmonary aspergillosis, and the recognition of influenza-associated pulmonary aspergillosis and, more recently, COVID-19-associated pulmonary aspergillosis. The treatment landscape for haematological malignancies has changed considerably in recent years, and some recently introduced targeted agents, such as ibrutinib, are increasing the risk of invasive fungal infections. Consideration must also be given to the risk of drug-drug interactions between mould-active azoles and small-molecule kinase inhibitors. At the same time, infections caused by rare moulds and yeasts are increasing, and diagnosis continues to be challenging. There is growing concern about azole resistance among both moulds and yeasts, mandating continuous surveillance and personalized treatment strategies. It is anticipated that the epidemiology of fungal infections will continue to change and that new populations will be at risk. Early diagnosis and appropriate treatment remain the most important predictors of survival, and broad-spectrum antifungal agents will become increasingly important. Liposomal amphotericin B will remain an essential therapeutic agent in the armamentarium needed to manage future challenges, given its broad antifungal spectrum, low level of acquired resistance and limited potential for drug-drug interactions.

P137 Remote inoculation mycosis: Rip Van Winkle wakes up

Poster session 2, September 22, 2022, 12:30 PM - 1:30 PMObjectiveAfter immunosuppression, a remotely inoculated organism may be activated to produce clinical disease. We describe such a case with infection due to Medicopsis romeroi, a rare mold.Patient and MethodsA 54-year-old male, diabetic, hypertensive, status post-live related donor renal transplantation, done in February 2021. The patient was on standard triple immunosuppressant regimen. He developed a painless nodule on his thumb over 5 months which did not respond to multiple courses of antibiotics. The swelling was excised and sent for various tests. Review of USG after infectious disease referral, showed a small foreign body, like a wooden splinter in the wall of the lesion (Fig. 1). On inquiry, a 3 mm wooden splinter in the lesion was noted during surgery and there was an injury at the same site, 20 years ago when the patient used to work on a farm. Organisms derived from soil or thorn injury including bacterial and fungal organisms were considered in the differential diagnosis. Bacterial organisms were considered less likely as there was no response to antibiotics.ResultsHistopathology showed brownish septate hyphae with constrictions at the areas of septations (Fig. 2). The excised tissue grew a dematiaceous mold. In Lactophenol Cotton Blue (LPCB) mount branched, septate hyphae with sparse conidia were seen. MALDI- TOF MS was unable to identify the mold. Sequencing identified it as M. romeroi. There are no ECOFFs or break points (BP) available for M. romeroi. Minimum inhibitory concentration (MIC) of Voriconazole (VCZ) is reportedly low and hence was chosen for treatment with an appropriate dose adjustment of Tacrolimus.ConclusionThis case underscores that remote inoculation, when the patient was immunocompetent, could have introduced a mold, which remained latent and reactivated after immunosuppression. Sending excised tissue for appropriate tests is rewarding. Medicopsis romeroi is a rare mold with only 12 cases reported so far. It is difficult to identify except with sequencing. There is no standard guidance on treatment. Surgical excision along with prolonged treatment with one of the new azoles is beneficial.

S4.1a Fusariosis: MICs, mono versus combination therapy and fosmanogepix

S4.1 Treatment of rare mold infections in 2021: the role of new and old antifungals, September 22, 2022, 10:30 AM - 12:00 PM Fusarium is one of the most clinically prevalent rare molds causing superficial infections such as keratitis in immunocompetent hosts and severe disseminated infections frequently presenting as fungemia in the immunocompromised. These fungi are ubiquitous in nature and are found in soil and air. Only a few of the ˃ 70 Fusarium spp. are opportunistic pathogens in humans. F. solani and F. oxysporum species complexes are specifically important, causing ˃50% and about 20% of severe fusariosis cases, respectively. Although galactomannan and also beta D glucan may result positive in fusariosis, fungal culture from either blood, BAL, or skin biopsy remains the most frequently utilized test for diagnosing fusariosis. Susceptibility testing of isolates recovered in culture should be used for epidemiologic purposes in defining the range of minimal inhibitory concentrations (MIC) distribution of Fusarium spp., however, studies that prove that susceptibility testing results should be utilized to inform antifungal drug choice are lacking. Although there are no interpretive breakpoints for antifungal agents against Fusarium spp., compounds with MICs that are off-scale, such as >16 μg/ml, at the highest range of concentrations are unlikely to be active in vivo or in patients. Initial combination therapy with a lipid formulation of amphotericin B plus voriconazole, deescalated to monotherapy once MICs come back, is, therefore, a frequently chosen management pathway. A number of drugs in the antifungal pipeline will present additional treatment options for Fusarium, including Fosmanogepix and Olorofim.

S2.3c High-resolution digital DNA melting: a breakthrough in diagnosing IMI?

S2.3 Novel diagnostic tools for invasive mold infection, September 21, 2022, 3:00 PM - 4:30 PMInvasive mold infections (IMIs) such as Aspergillosis, Mucormycosis, Fusariosis, and Lomentosporiosis have emerged as important pathogens in immunocompromised patients, with mortality rates as high as 50% to nearly 80% for these infections. Outcomes can be substantially improved with early initiation of appropriate antifungal therapy, yet early diagnosis remains difficult to establish and often requires multidisciplinary teams evaluating clinical and radiological findings plus supportive microbiologic findings. Conventional fungal culture and PCR techniques are limited by low sensitivity, long turn-around time, and are insufficient for differentiating between infection and colonization. Other non-culture-based tests, such as the Galactomannan test, are available only for invasive aspergillosis and are limited by imperfect test performance. Better and more rapid diagnostics are needed to enable early diagnosis and targeted treatment of IMIs and improve survival. We have developed a new technology called digital high resolution melting analysis (dHRM) to enable a rapid and robust diagnosis of IMI. This technology accomplishes fast genotyping of fungal genomic sequences in clinical samples by: (1) conducting broad-based amplification of fungal genes in a digital PCR format, and (2) conducting high-resolution melting of the DNA amplicons in each digital reaction. High resolution melting measures the fluorescence of a saturating intercalating dye as dPCR-amplified fungal DNA fragments are rapidly heated and disassociated, producing sequence-defined melt curves in a closed reaction format. These melt curves serve as unique fungal ‘fingerprints’, which allows us to correctly identify disease-causing pathogen(s) with an accuracy of 99%-100% through the use of machine learning methods trained to tolerate variations in reaction conditions. This approach provides a simple, low-cost, fast, and robust method for pathogen identification. Here, we will present the performance of this new technology on clinical bronchoalveolar lavage (BAL) samples from patients with and without IMI. A total of 75 patient BAL samples were tested, coming from 30 patients with proven (n = 1), probable (n = 25), or putative (n = 4) invasive pulmonary aspergillosis (IPA) infections, and from 45 patients classified as not having IPA (n = 4 possible IPA and n = 41 no IPA). Our results show that dHRM was able to reliably differentiate between different Aspergillus spp. and was also able to identify Aspergillus spp. in BAL samples from patients with probable IPA where qPCR had resulted in negative. In a few instances, it also detected rare molds in culture-negative samples and multiple Aspergillus spp. within one BAL sample, a phenomenon that has been previously described in cultures. Interestingly, there was no clear correlation between dHRM results and BAL galactomannan levels, suggesting that dHRM may serve as an independent method allowing for a combined diagnostic approach. While further validation and optimization are needed, these results suggest that dHRM is a promising new diagnostic technology capable of providing clinically relevant information within 2-3 h.

S4.1d In vitro activity of eight antifungals against 3343 filamentous pathogenic fungi collected during 18 years at the French National Reference Center for invasive mycosis and antifungals

S4.1 Treatment of rare mold infections in 2021: the role of new and old antifungals, September 22, 2022, 10:30 AM - 12:00 PM Background & ObjectivesThe NRCMA oversees the surveillance of invasive fungal diseases in France. As part of our expertise, we perform antifungal susceptibility testing based on European Committee on Antimicrobial Susceptibility Testing (EUCAST) methodology on all isolates. The antifungal profiles help us monitor the emergence of resistant isolates, determine the susceptibility pattern of wild-type strains to new antifungals, and in specific cases, determine the relationship between clinical failure and selection/emergence of a less susceptible isolate.We review the Minimum inhibitory concentrations (MIC) distribution of eight antifungals on clinical isolates of filamentous fungi identified at the NRCMA from 2003 to 2021.MethodsSpecies identification was performed by a combination of morphological features and multilocus sequencing. Only strains that produced enough conidia or spores were tested. In vitro susceptibility testing was performed according to the EUCAST procedure. Eight antifungal agents were used: triazoles [itraconazole, voriconazole, posaconazole, isavuconazole (since 2015)], echinocandins (caspofungin, micafungin), amphothericin B, and terbinafine. The concentrations inhibiting 50% (MIC50) and 90% (MIC90) of the isolates were determined for species with at least 5 and 10 isolates, respectively. For Aspergillus fumigatus isolates exhibiting high azole MICs, we sequenced the cyp51A gene for mutation screening.ResultsMICs were obtained for 3343 pathogenic strains. We identified Aspergillus spp. including cryptic species (32%), Fusarium spp. (21%), Mucorales (18%), phaeohyphomycetes (10%), i.e., Alternaria spp., Curvularia spp., Fonsecaea, Exophiala, Phaeoacremonium, rare hyphomycetes (9%), i.e., Rasamsonia, Paecilomyces, Trichoderma, Scopulariopsis. Scedosporium spp. (7%) and emergent pathogens such as Nannizziopsis obscura (1%), dimorphic fungi (1%), or to a less extent basidiomycetous molds. Examples of MIC results are presented in Table 1.For the nine genera of the order Mucorales, amphotericin B (AmB) exhibited low MICs except for Cunninghamella species and Saksenaea vasiformis. Posaconazole had variable activity depending on the species (high MIC values were observed for Mucor species) while voriconazole and echinocandins had none.In section Fumigati, amphotericin B MIC values were high due to the intrinsic resistance of cryptic species Aspergillus lentulus and A. udagawae. Other cryptic species were identified such as A. hiratsukae isolates which exhibited low MICs to all antifungals.Members of Aspergillus section Nidulantes such as A. nidulans and A. quadrilineatus showed variable MICs to caspofungin and amphotericin B.Among melanized fungi, Alternaria infectoria and A. alternata species group displayed low MICs of all azoles with the exception of voriconazole.Four Exophiala species were analyzed and had similar azole MICs, E. spinifera being the species with the lowest values.Multi-drug resistant profiles were observed especially in species belonging to Microascales such as Lomentospora prolificans, Microascus cirrosus, and Scopulariopsis brevicaulis. Members of Fusarium species complexes had predictably high MIC values to all antifungals including isavuconazole. Only Fusarium dimerum species complex had low MICs to amphotericin B.Further distribution analysis is ongoing. These large datasets provide a baseline for monitoring the emergence of antifungal resistance in our country and supports the fact that MIC determination should be performed for rare/emergent species and also in case of infections due to cryptic species, which would benefit patient management.

Severe pulmonary mucorales superinfection in three influenzapatients with and without influenza-associated aspergillosis

Mucormycosisis an opportunistic fungal disease which affects immunocompromised hosts including patients with haematologic malignancies and poorly controlled diabetes mellitus. Mucorales grow invasively and are associated with high mortality even if promptly diagnosed. Viral infection like influenza can cause severe pneumonia and is associated with pulmonary aspergillosis. Here we report three separate cases of Mucorales super infection in critically-ill patients with influenza infection, one of them histologically confirmed. Two patients also had influenza-associated pulmonary aspergillosis. Two patients had fatal clinical outcome despite intensive care. The simultaneous detection of these two rare mold infections in patients with severe influenza is highly remarkable and calls for increased awareness.

Antifungals advance

Pharmaceutical firms are making progress in addressing the need for new antifungal therapies. F2G, which specializes in the treatment of rare fungal diseases, says it will receive $100 million from the Japanese firm Shionogi in a deal to develop olorofim, an antifungal agent for invasive aspergillosis and other rare mold infections. This news follows Mycovia Pharmaceuticals’ statement April 28 that the US Food and Drug Administration approved its azole antifungal Vivjoa (oteseconazole) for chronic yeast infections. The announcements reflect efforts to fill gaps in treating fungal infections, which have limited treatment options and increasing resistance . Olorofim is part of the first new class of antifungals to be developed in 20 years, according to F2G. Chief Operating Officer Mike Birch says the firm is preparing a new drug application to submit to the FDA later this year. The deal with Shionogi is focused on Europe and Asia. Olorofim works by

Mycoses due to Rare Moulds in Our Country: A Systematic Review

An increase is observed in the frequency and diversity of fungal infections in the world and in our country. Improving the quality of patient care in infections due to rare moulds depends on early diagnosis and appropriate treatment. Raising awareness about these infections will facilitate taking the necessary steps for diagnosis and treatment in similar cases. In addition to 165 cases out of 96 studies included in this review article, 28 studies reporting rare mould isolation with limited case information were examined. The number of studies reporting cases that meet the criteria has increased over the years. The most frequently reported mould was Fusarium spp. (n= 74), followed by Scedosporium/Pseudallescheria spp. (n= 20). In 25 of the cases, dematiaceous fungi were isolated. Eye (n= 44), skin/soft tissue (n= 35), disseminated (n= 34) peritoneum (n= 13), respiratory tract (n= 13), sinus (n= 12), central nervous system (n= 10), nail (n= 3) and urinary system (n= 1) involvement was detected in the cases. Two cases due to Scedosporium apiospermum and Fonsecaea pedrosoi started locally but spread over time. Among eye involvements, two outbreak reports in which Fusarium spp. was the causative agent drew attention. Of the patients with disseminated involvement, only two who developed Exophiala dermatitidis infection did not have any conditions affecting the immune system. In all peritoneal infections, the patient had a peritoneal catheter (12 for continuous ambulatory peritoneal dialysis and one for drainage). In seven out of 10 cases with central nervous system involvement, dematiaceous fungi were isolated. Appropriate diagnosis and treatment of cases due to rare mould infections can be improved by providing knowledge on the subject in the world and in our country. In these infections where treatment success is limited, correct identification of the causative agent and application of appropriate treatment provides an advantage for clinical success. In this review article, publications from Turkey in Pubmed, Scopus and TR Directory records were searched based on The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) rules and the situation of rare mould infections in our country have been discussed.

Cladosporium spp. endogenous endophthalmitis simulating the classic “headlight-in-the-fog” appearance of active toxoplasmosis

Endogenous fungal endophthalmitis caused by an unusual fungus poses both diagnostic and therapeutic challenges. We report a case of endogenous endophthalmitis caused by a rare mold, namely Cladosporium spp., which presented with a foveal abscess. A 52-year-old male patient who was diagnosed with rectal carcinoma presented with pain, redness, and a loss of vision in the right eye. He had been experiencing the symptoms for 1 week. The patient had undergone gastrointestinal surgery 2 weeks before experiencing the eye complaint. His best-corrected visual acuity was hand movements. Fundus examination revealed a foveal abscess of around a half-disc diameter in size that simulated retinochoroiditis with vitritis. Optical coherence tomography of the macula revealed a hyperreflective lesion in the fovea, which breached the full thickness of the fovea and extended into the preretinal space. Ocular toxoplasmosis was considered. On that basis, oral trimethoprim/sulfamethoxazole was given for 1 week, although the patient's condition worsened. A vitreous tap and an intravitreal combination of vancomycin, ceftazidime, and amphotericin B were administered twice but did not improve the patient's condition. Pars plana vitrectomy was performed and the vitreous biopsy results revealed the presence of Cladosporium spp. Intravitreal voriconazole was given three times and the foveal abscess resolved into a scar. Endophthalmitis caused by Cladosporium spp. is uncommon and published case reports are extremely limited. The present case may provide insight into the variable presentation of fungal endophthalmitis and, therefore, assist with the early diagnosis and appropriate management of the condition.

Antimicrobial activity of manogepix, a first-in-class antifungal, and comparator agents tested against contemporary invasive fungal isolates from an international surveillance programme (2018–2019)

Manogepix, the active moiety of the prodrug fosmanogepix, is a novel antifungal with activity against major fungal pathogens including Candida (except Candida krusei), Aspergillus and difficult-to-treat/rare moulds. We tested manogepix and comparators against 2669 contemporary (2018-2019) fungal isolates collected from 82 medical centres in North America (42.3%), Europe (37.9%), Asia-Pacific (12.3%) and Latin America (7.6%). Of these, 70.7% were Candida spp., 3.6% were non-Candida yeasts including 49 Cryptococcus neoformans var. grubii, 21.7% were Aspergillus spp. and 4.1% were other moulds. Isolates were tested for antifungal susceptibility by the CLSI reference broth microdilution method. Manogepix (MIC50/90, 0.008/0.06 mg/L) was the most active agent tested against Candida spp. isolates; corresponding anidulafungin, micafungin and fluconazole MIC90 values were 16- to 64-fold higher. Similarly, manogepix (MIC50/90, 0.5/2 mg/L) was ≥4-fold more active than anidulafungin, micafungin and fluconazole against C. neoformans var. grubii. Against Aspergillus spp., manogepix (MEC50/90, 0.015/0.03 mg/L) had comparable activity to anidulafungin and micafungin. Low manogepix concentrations inhibited uncommon species of Candida, non-Candida yeasts, and rare moulds including Scedosporium spp. and Lomentospora (Scedosporium) prolificans. Manogepix exhibited potent activity against contemporary fungal isolates, including echinocandin- and azole-resistant strains of Candida and Aspergillus spp., respectively. Although rare, Candida strains that were non-wild type for manogepix demonstrated resistance to fluconazole. However, the clinical relevance of this finding is unknown. The extended spectrum of manogepix is noteworthy for its activity against many less-common yet antifungal-resistant strains. Clinical studies are underway to evaluate the utility of fosmanogepix against difficult-to-treat resistant fungal infections.

Scedosporium and Lomentospora infections in lung transplant recipients

Infections caused by uncommon or rare mould pathogens often complicate the management of lung transplant (Tx) recipients contributing to high mortality. This review explores the epidemiology, diagnosis, and management of Scedosporium and Lomentospora (S/L) infections in lung Tx recipients as well as highlighting constraints in the current management and areas for future research. The number of reported S/L infections remains low among lung Tx recipients whilst the diagnosis and treatment of S/L infections remains challenging. The very few studies which evaluated clinical characteristics, prognostic factors and treatment outcomes of lung Tx patients with lomentosporiosis and/or scedosporiosis were limited by single-centre and observational study design. The requirement to standardise surveillance and culture procedure for S/L infections in lung Tx remains. Better diagnostic tools and antifungal agents are needed to manage S/L infection in this patient cohort. Prospective clinical registries or online databases for lung Tx recipients with these rare mould infections are essential to refine disease management and to improve clinical outcomes in the future.

All You Need to Know and More about the Diagnosis and Management of Rare Mold Infections

ABSTRACTInvasive mold infections caused by molds other than Aspergillus spp. or Mucorales are emerging. The reported prevalences of infection due to these rare fungal pathogens vary among geographic regions, driven by differences in climatic conditions, susceptible hosts, and diagnostic capabilities. These rare molds—Fusarium, Lomentospora, and Scedosporium species and others—are difficult to detect and often show intrinsic antifungal resistance. Now, international societies of medical mycology and microbiology have joined forces and created the “Global guideline for the diagnosis and management of rare mould infections: an initiative of the European Confederation of Medical Mycology in cooperation with the International Society for Human and Animal Mycology and the American Society for Microbiology” (published in Lancet Infect Dis, https://doi.org/10.1016/S1473-3099(20)30784-2), with the goal of improving the diagnosis, treatment, prevention, and survival of persons with rare mold infections. The guideline provides cutting-edge guidance for the correct utilization and application of established and new diagnostic and therapeutic options.

Fosmanogepix: A Review of the First-in-Class Broad Spectrum Agent for the Treatment of Invasive Fungal Infections.

Fosmanogepix is a first-in-class antifungal currently in Phase 2 clinical trials for the treatment of invasive fungal infections caused by Candida, Aspergillus and rare molds. Fosmanogepix is the N-phosphonooxymethylene prodrug of manogepix, an inhibitor of the fungal enzyme Gwt1. Manogepix demonstrates broad spectrum in vitro activity against yeasts and molds, including difficult to treat pathogens. Because of its novel mechanism of action, manogepix retains potency against many resistant strains including echinocandin-resistant Candida and azole-resistant Aspergillus. Manogepix is also active against pathogens that demonstrate intrinsic resistance to other drug classes, such as Scedosporium, Lomentospora prolificans, and Fusarium with variable activity against Mucorales. Fosmanogepix demonstrates significant in vivo efficacy in mouse and rabbit disseminated infection models due to C. albicans, C. glabrata, C. auris, C. tropicalis, Coccidioides immitis, and F. solani as well as pulmonary infection models of A. fumigatus, A. flavus, S. prolificans, S. apiospermum and Rhizopus arrhizus. Clinical trials demonstrated high oral bioavailability (>90%), enabling switching between fosmanogepix intravenous and oral formulations without compromising blood levels. Favorable drug-drug interaction, tolerability, and wide tissue distribution profiles are observed making fosmanogepix an attractive option for the treatment of invasive fungal infections. This systematic review summarizes the findings of published data on fosmanogepix.