We present a case of cutaneous protothecosis caused by Prototheca wickerhamii infection. The patient was a 72-year-old man with hypoalbuminemia. He responded well to fluconazole treatment. We reviewed this case along with 17 other cases of cutaneous protothecosis reported from mainland China, Hong Kong, and Taiwan. Of the 18 cases, 7 each occurred in mainland China and Taiwan, and 4 occurred in Hong Kong. Thirteen cases were caused by P. wickerhamii (72.2%), and three were caused by P. zopfii (16.7%); in two cases, the species was not identified (11.1%). In all, 9 (50%) patients were immunocompromised, and 10 (55.5%) patients denied having a history of trauma. All patients presented with polymorphic skin lesions, and erythematous papules, plaques, or nodules was the most common presentation (15/18, 83.3%). Genotyping was performed in five cases, mostly by means of small subunit ribosomal DNA amplification (four cases). Susceptibility tests (6 patients) showed that P. wickerhamii was sensitive to amphotericin B and voriconazole but resistant to fluconazole or itraconazole. Treatment succeeded in 15 (83.3%) patients and failed in 3 (16.7%). Our data indicate that the number of cutaneous protothecosis cases is underestimated in China, and the skin lesions have some diagnostic value.

A 41-year-old man from the emergency department presented with fever for 2 weeks, sore throat, dry cough and generalized umbilicated skin lesions (face (Fig. 1), and chest (Fig. 2)). HIV antibody was positive, CD4+ count was 2/μL. His skin swab, sputum and blood culture all yielded Talaromyces (Penicillium) marneffei (Fig. 3). Talaromyces marneffei is an important cause of morbidity and mortality in HIV-infected and other immunosuppressed patients who live in or are from endemic areas especially Southeast Asia. Amphotericin B or Itraconazole should be initiated as soon as possible for patients with talaromycosis.

Invasive candidiasis occurs frequently in hospitalized patients, and is associated with high mortality rates due to delays in recognition and initiation of appropriate antifungals. Management of invasive candidiasis must take into account multiple host, pathogen, and drug-related factors, including the site of infection, host immune status, severity of sepsis, resistance and tolerance to antifungal agents, biofilm formation, and pharmacokinetic/pharmacodynamic considerations. Recent treatment directives have been shaped by the widespread introduction of echinocandins, highly potent and safe antifungals, into clinical use, as well as important changes in drug susceptibility patterns and the emergence of known and novel drug-resistant Candida species. Advances in molecular diagnostics have the potential to guide early targeted treatment of high-risk patients.

Candida parapsilosis is an incredibly rare cause of ventriculoperitoneal (VP) shunt infections, with only one adult case reported in the literature to date. We describe the case of a 45-year-old man admitted for a traumatic fall and subsequently treated with VP shunt placement for obstructive hydrocephalus secondary to a cerebellar contusion and intraventricular hemorrhage. Eight months following VP shunt placement, the patient presented with a two-month history of clear fluid leakage through a dehiscent surgical abdominal wound overlying the distal VP shunt. CSF cultures were obtained and grew C. parapsilosis. The patient subsequently underwent VP shunt externalization and began antifungal treatment with intravenous liposomal amphotericin B. CSF studies continued to re-demonstrate C. parapsilosis infection, for which VP shunt removal and EVD placement was performed. Three days into treatment with amphotericin B, he endured significant nephrotoxicity necessitating a switch to oral fluconazole. Following three weeks of oral fluconazole treatment with negative serial CSF cultures, the patient underwent EVD removal and VP shunt insertion. Following the procedure and 22 total days of oral fluconazole treatment, our patient recovered well and was discharged to a rehabilitation facility in stable condition. In our report, we describe the clinical course of our patient and offer a review and analysis of the most up to date literature concerning C. parapsilosis shunt infections as well as treatment guidelines for CNS candidiasis.

The occurrence of invasive fungal diseases, particularly in immunocompromised patients, is life-threatening and increases the economic burden. The rising problem of multi-drug resistance is becoming a major concern for clinicians. In addition, a repertoire of antifungal agents is far less in number than antibacterial drugs. To combat these problems, combination therapy has gained a lot of interest. We previously reported the synergistic interaction of some mono- and bis-dihydropyrimidinone and thione derivatives with fluconazole and amphotericin B for combination antifungal therapy. In this study we used the same approach and synthesized different azole and non-azole derivatives of mono-(M) and bis-(B) chalcones and evaluated their antifungal activity profile alone and in combination with the most commonly used antifungal drug - fluconazole (FLC) - against seven FLC susceptible and three FLC resistant clinically isolated Candida albicans strains. Based on the minimum inhibitory concentration results, the bis-derivatives showed lower MIC values compared to their mono-analogues. Both fractional inhibitory concentration index and isobologram results revealed mostly synergistic, additive or indifferent interactions between the tested compounds and FLC against different Candida isolates. None of the tested compounds showed any effect on energy dependent R6G efflux, revealing that they do not reverse the mechanism of drug efflux. However, surprisingly, these compounds profoundly decreased ergosterol biosynthesis and showed down regulation of ERG11 gene expression, which is the possible mechanism of reversal of azole drug resistance by these compounds. These results provide a platform for further research to develop pyrimidinone/thione ring containing compounds as promising new antifungal agents, which could be used in antifungal combination therapy.

Liposomal amphotericin B (L-AMB) is widely used for empirical or preemptive therapy and treatment of invasive fungal infection after cord blood transplantation (CBT). We retrospectively examined the efficacy and safety of low-dose L-AMB in 48 adult patients of CBT from between 2006 and 2017 in our institute. Among the entire cohort, 42 (88%) patients received L-AMB as an empirical or preemptive therapy. The median daily dose of L-AMB and the median cumulative dose of L-AMB were 1.20 mg/kg/day (range, 0.62-2.60 mg/kg/day) and 30.6 mg/kg (range, 0.7-241.5 mg/kg), respectively. The median duration of L-AMB administration was 21.5 days (range, 1-313 days). Documented breakthrough fungal infection occurred in 1 patient during L-AMB treatment, and 43 (90%) patients survived for at least 7 days after the end of L-AMB treatment. Grade 3 or higher hypokalemia and hepatotoxicity were frequently observed during L-AMB treatment. However, no patients developed an increase in serum creatinine of grade 3 or higher. In the univariate analysis using a logistic regression model, a duration of L-AMB treatment of more than 21 days and a cumulative dose of L-AMB more than 30 mg/kg were significantly associated with nephrotoxicity and grade 3 hypokalemia. These data suggest that low-dose L-AMB may be safe and effective in adult patients undergoing CBT.

Since its original isolation in 2009, Candida auris has spread across the globe as a causative agent of invasive candidiasis. C. auris is usually intrinsically resistant to fluconazole and can also be resistant to echinocandins and even amphotericin B. Thus, finding new treatment options against this emerging pathogen is urgent. To address this growing problem, we have performed a screen of the Prestwick Chemical Library, a repurposing library of 1,280 small molecules, consisting mostly of approved off-patent drugs, in search for those with activity against a multidrug resistant C. auris isolate. Our initial screen, using standardized susceptibility testing methodologies, identified nine miscellaneous compounds with no previous clinical indication as antifungals or antiseptics that displayed activity against C. auris Confirmation and follow-up studies identified ebselen as the drug displaying the most potent activity, with 100% inhibition of growth detected at concentrations as low as 2.5 μM. We further evaluated the ability of ebselen to inhibit C. auris biofilm formation and examined the effects of combination therapy of ebselen with clinically used antifungals. We extended our studies to different C. auris strains with varying susceptibility patterns and also confirmed its antifungal activity against C. albicans and clinical isolates of multiple other Candida species. Furthermore, ebselen displays broad antifungal spectrum of action based on its activity against a variety of medically important fungi, including yeasts and molds. Overall our results indicate the promise of ebselen as a repositionable agent for the treatment of candidiasis and possibly other mycoses, and in particular for the treatment of infections refractory to conventional treatment with current antifungals.

APX001A is the active moiety of the first-in-class drug candidate APX001. So far, most susceptibility testing studies have examined ≤30 isolates/species, and only one with the EUCAST method. We investigated the in vitro activity of APX001A and five comparators against 540 candidaemia and 122 C. auris isolates.Isolates (17 Candida and 3 yeast species) were identified using CHROMagar, MALDI-TOF and when needed ITS-sequencing. EUCAST E.Def 7.3.1 susceptibility testing included APX001A, amphotericin B, anidulafungin, micafungin, fluconazole, and voriconazole. Wild-type upper limits (WT-UL) were established following the EUCAST-principles for Epidemiological cut off value setting for APX001A allowing classification as WT or non-WT.APX001A MIC50 values (mg/L) were: C. albicans, C. dubliniensis and C. tropicalis 0.004-0.008, C. parapsilosis and C. auris 0.016, C. glabrata 0.06 and C. krusei >0.5. APX001A MICs varied against the rare species from C. pelliculosa ≤0.0005 to C. norvegensis >0.5. APX001A was equally or more in vitro active than the comparators against all species except C. krusei and C. norvegensis Four isolates were APX001A non-WT, all of which were fluconazole resistant. A correlation was observed between APX001A and fluconazole MICs across all species except C. guilliermondii and C. auris, and when comparing high and low fluconazole MIC isolates of C. albicans, C. dubliniensis, C. glabrata, C. tropicalis and C. aurisAPX001A showed promising in vitro activity against most Candida and other yeast species including C. auris when compared to five comparators. WT-ULs were suggested for the common species and a new and un-explained correlation to fluconazole susceptibility was observed.