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To our knowledge, this is the first case report of a transudative pleural effusion with positive Cryptococcal antigen and culture. We describe a 32-year-old male with end-stage liver disease (ESLD) who presented to an outside hospital with dyspnea and a large pleural effusion. An initial pleural fluid analysis was positive for Cryptococcal Ag. However, the infection was eventually found to be widespread as he had positive Cryptococcal Ag and cultures in his pleural fluid, serum, and cerebrospinal fluid (CSF). His antimicrobial regiment was escalated from fluconazole to amphotericin B and flucytosine. His medical condition deteriorated, and the patient passed away. Due to its rarity and range of clinical severity, diagnosis of disseminated Cryptococcosis can be delayed. We present this case to bring awareness of this diagnosis as a differential in immunocompromised patients regardless of a transudative pleural effusion.

We previously reported a 39-year-old man who presented with pulmonary and cerebral Cryptococcus gattii (genotype VGIIa) infection and was successfully treated with liposomal amphotericin B and flucytosine induction therapy. Following induction therapy, oral fluconazole treatment was initiated as consolidation therapy. However, the patient complained of progressively worsening headache, presenting an elevated cerebrospinal fluid (CSF) cell count. The minimum inhibitory concentrations of the CSF isolate were 8 and 0.12 μg/mL for fluconazole and voriconazole, respectively. The oral administration of voriconazole for more than 18 months alleviated his symptoms. Voriconazole might be useful for controlling refractory cases of C. gattii infection.

Fungal skin infections are on the rise in India, and pregnant women are not immune to them. They are one of the commonest causes of secondary pruritus in pregnancy and can worsen the quality of life. Cutaneous dermatophytic infections have seen a recent emergence as a public health problem in India with increasing incidence as well as failure to appropriately respond to treatment. Vaginal candidiasis may cause obstetric and perinatal complications such as chorioamnionitis, premature rupture of membranes, preterm labor and neonatal candidiasis. Antifungal drugs are commonly prescribed in pregnancy. The common oral antifungals used are fluconazole, ketoconazole, itraconazole, terbinafine and griseofulvin; whereas the common topical antifungals are azoles, ciclopirox oleamine, terbinafine, amongst others. There have been reports of congenital abnormalities in the fetus and spontaneous abortions attributed to oral antifungals. Prescribing antifungal drugs in pregnancy needs careful consideration. In this article, we discuss the safety profile and recommendations regarding the use of these drugs during gestation. We have performed a literature search of recent large-scale cohort, case-control, and meta-analysis studies and presented them in this review. Antifungals such as echinocandins, amphotericin B, flucytosine, etc. which are indicated for systemic mycoses are beyond the scope of this article. Finally, we have given authors’ perspective regarding the justifiable use of these antifungals in pregnant women.

Candida glabrata is the second frequent etiologic agent of mucosal and invasive candidiasis. Based on the recent developments in molecular methods, C. glabrata has been introduced as a complex composed of C. glabrata, Candida nivariensis, and Candida bracarensis. The four main classes of antifungal drugs effective against C. glabrata are pyrimidine analogs (flucytosine), azoles, echinocandins, and polyenes. Although the use of antifungal drugs is related to the predictable development of drug resistance, it is not clear why C. glabrata is able to rapidly resist against multiple antifungals in clinics. The enhanced incidence and antifungal resistance of C. glabrata and the high mortality and morbidity need more investigation regarding the resistance mechanisms and virulence associated with C. glabrata; additional progress concerning the drug resistance of C. glabrata has to be further prevented. The present review highlights the mechanism of resistance to antifungal drugs in C. glabrata.

Background: Candida species are responsible for causing many health care associated and central line associated infections. They are responsible for causing opportunistic infection in human beings. Genus of Candida is composed of a heterogeneous group of organsims.Invasive infections of Candida mainly caused by Candida albicans, Candida glabrata, Candida parapsilosis & Candida tropicalis. Aim and objective: The main objective of this study was to isolates candida albicans and Non- albicans candida and their antifungal susceptibility testing. Materials and Methods: The study was carried out in the Department of Microbiology, in Tmu Hospital Moradabad. Total numbers of 806 clinical samples were processed in which 206 isolates were taken for candida. Isolation and antifungal susceptibility testing done by Vitek-2 system. Result: Out of 206 samples 77(37%) were C.albicans and 129(63%) were Non-albicans candida (NAC). Maximum isolated species were C.albicans 77(37%), followed by C.tropicalis 70(34%), C. parapsilosis 24(12%), C. glabrata 19(9%), C. dubliniensis 12(6%), C. krusei 3(1%), C.african 1(1%). Conclusion: Infection caused by NAC species have increased. C.tropicalis was the most common isolated species. Candida albicans, C.glabrata and C.krusei were shown high susceptibility to fluconazole and voriconazole. Amphotericin B, Caspofungin, Micafungin and Flucytosine shows high susceptibility towards other candida species. Keywords: Candida species, Non-albicans candida, Antifungal Susceptibility Testing

Background Cryptococcal meningitis is a leading cause of mortality in advanced HIV disease. A positive cerebrospinal fluid cryptococcal antigen (CrAg) test defines cryptococcal meningitis. Herein, we present a patient with serum and cerebrospinal fluid CrAg negative cryptococcal meningitis, despite a positive cerebrospinal fluid India ink examination and quantitative culture. Case Details A 56-year-old HIV-positive Ugandan woman, with an undetectable HIV RNA viral load and CD4+ T-cell count of 766 cells per microlitre presented with signs and symptoms consistent with cryptococcal meningitis. Her serum and cerebrospinal fluid CrAg tests were negative despite having a positive cerebrospinal fluid India ink and quantitative culture. On day 1, she was commenced on intravenous amphotericin B deoxycholate (1mg/kg) for 3 days (considering 10 CFU growth of Cryptococcus spp) in combination with oral flucytosine (100mg/kg) for 7 days and then fluconazole 1200mg once daily for the next 11 days. By day 7, she was symptom free and quantitative cerebrospinal fluid culture was negative for Cryptococcus spp. She was discharged on day 9. At 10 weeks (day +40) and 18 weeks (day +72), she was well and adherent to her antiretroviral therapy and on maintenance phase of cryptococcal meningitis on fluconazole at a dose of 400mg once daily. Conclusion This report alerts clinicians managing patients with HIV-associated cryptococcal meningitis to four uncommon clinical scenarios; first, the possibility of negative serum and cerebrospinal fluid CrAg lateral flow assay results in the context of low cerebrospinal fluid fungal burden in a symptomatic patient. Second, possible occurrence of cryptococcal meningitis in a patient with high CD4 T-cell lymphocyte counts. Third, an early seroconversion of cryptococcal antigenaemia following effective fluconazole therapy. Fourth, an early symptomatic relapse of cryptococcal meningitis albeit negative serum CrAg.

Cryptococcal meningoencephalitis was first described over a century ago. This fungal infection is preventable and treatable yet continues to be associated with excessive morbidity and mortality. The largest burden of disease resides in people living with HIV in low-income and middle-income countries. In this group, mortality with the best antifungal induction regimen (7 days of amphotericin B deoxycholate [1·0 mg/kg per day] and flucytosine [100·0 mg/kg per day]) in a clinical trial setting was 24% at 10 weeks. The world is now at an inflection point in terms of recognition, research, and action to address the burden of morbidity and mortality from cryptococcal meningoencephalitis. However, the scope of interventional programmes needs to increase, with particular attention to implementation science that is specific to individual countries. This Review summarises causes of excessive mortality, interventions with proven survival benefit, and gaps in knowledge and practice that contribute to the ongoing high death toll from cryptococcal meningoencephalitis. TRANSLATIONS: For the Vietnamese and Chichewa translations of the abstract see Supplementary Materials section.

Mortality rates due to Cryptococcus neoformans var. grubii fungemia remain significant despite treatment with antifungal drugs. The predictive function of antifungal susceptibility and its correlation with treatment outcome remains controversial. A retrospective study was conducted from January 1, 2009, to December 31, 2016, on 85 patients with C. neoformans var. grubii fungemia confirmed by matrix-assisted laser desorption ionization-time-of-flight mass spectrometry. Antifungal drug susceptibility was determined using the YeastONE™ colorimetric broth microdilution method coupled with Vizion™ System following the Clinical and Laboratory Standards Institute guidelines. Six antifungal agents-amphotericin B, fluconazole, flucytosine, itraconazole, posaconazole, and voriconazole-were tested. The patients' demographic data and clinical information were abstracted for further analyses. Antifungal regimens consisting of amphotericin B with or without fluconazole or flucytosine were administered for induction treatment of these patients, followed with intravenous or oral fluconazole for maintenance therapy. Clinical outcomes were defined by 14- and 30-day mortality rates. Risk factors associated with outcomes were fitted in a logistic regression model by univariate or multivariate method. Eighty-five patients with C. neoformans var. grubii fungemia were enrolled in the study. The Sequential Organ Failure Assessment Score, Glasgow Coma Scale, Charlson comorbidity score, and adequate duration of therapy for amphotericin B were predictors for mortality in univariate analysis. Antifungal susceptibility testing with YeastONE™ does not predict clinical outcomes of C. neoformans var. grubii fungemia. Greater disease severity, high comorbidities, poor consciousness level, and inappropriate treatment were associated with increased mortality in cryptococcemia cases. Lay abstract Cryptococcus neoformans is an encapsulated yeast living in both plants and animals that is composed of three main serotypes: C. neoformans var. grubii, C. neoformans var. gattii, and C. neoformans var. neoformans. C. neoformans var. grubii is the most common disease-causing Cryptococcus species worldwide. C. neoformans var. gattii is more prevalent than C. neoformans var. neoformans in both tropical and subtropical regions of Asia. C. neoformans causes severe, even fatal, diseases such as pulmonary infection, bloodstream infection, skin and soft tissue infection, bone and joint infection, central nervous system infection, and disseminated infection, regardless of host immunocompetence. We conducted a retrospective study on 85 patients who contracted cryptococcemia from January 1, 2009, to December 31, 2016. This work conducted both microbiological and clinical studies involving in vitro susceptibility testing, demographic data, comorbidities, treatment modalities, and treatment outcomes. We utilized a modern medical technique-based instrument, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-ToF MS; Biotyper, Bruker Daltonics, Inc.), which determines the unique proteomic fingerprint of an organism, to identify the C. neoformans serotype. We utilized Thermo Fisher Scientific™ Sensititre™ YeastONE™ colorimetric broth microdilution plates coupled with a Vizion™ Digital MIC Viewing System (a computer-assisted optical reading machine) to determine the in vitro susceptibility of amphotericin B, flucytosine, fluconazole, itraconazole, posaconazole, and voriconazole against 85 C. neoformans var. grubii blood isolates. In conclusion, the susceptibility patterns of these antifungal agents did not correlate significantly with treatment outcomes. However, a lower disease severity score, a lower Glasgow Coma Scale score, fewer comorbidities, and adequate amphotericin B treatment duration were predictors for treatment success in univariate analysis.

Cryptococcal meningitis, which has a high mortality rate, is rare in immunocompetent children. Although many immunocompromised conditions are identified as predisposing factors, congenital heart disease in children is not well recognized as a predisposing factor for the disease. A 12-year-old female child presented with a progressively increasing headache for one month. There was history of vomiting and fever off and on. On examination, she had a pansystolic murmur and meningeal signs. Lumbar puncture was done; opening pressure was high (27 cm H2O) and white blood cell (WBC) count in cerebrospinal fluid (CSF) was slightly high. Gram staining, India ink preparation, and culture of CSF were negative. Cryptococcal antigen (CrAg) test was not available. Echocardiography showed a 12 mm ventricular septal defect (VSD). The patient was diagnosed as meningitis with VSD and treated with intravenous ceftriaxone and vancomycin; however, she did not improve after 7 days of antimicrobial treatment. She was then transferred to another hospital where India ink and culture of CSF showed cryptococcus; CrAg test was done, and it was positive. Despite the treatment with lyposomal amphotericin B and flucytosine, she died on 9th day of admission in pediatric intensive care unit. It is necessary for global advocacy for need of availability of CrAg test in resource-limited regions. Treating doctors should consider VSD, a congenital heart disease, as a predisposing factor for cryptococcal meningitis in children. As CrAg is more sensitive than India ink and culture, it should be the first line of investigation in suspected cases.

Two cases of disseminated cryptococcosis are described. The first was an HIV-infected patient where cryptococcosis was diagnosed as “unmasking immune reconstitution syndrome”; the second was an immunosuppressed patient with multiple myeloma. In both cases, a definitive healing could not be reached despite long therapeutic approaches. This review summarizes both the most recent and relevant studies about disseminated and refractory form of cryptococcal infections and identifies research gaps. Given the limited data, we draw some conclusions with respect to management from literature: not clear and accepted indication are available regarding disseminated cryptococcosis, no specific schemes were identified, and the duration of therapy is usually decided case by case and supported only by case reports. In this perspective, usually standard therapeutic schemes and duration of induction depend on multiple factors (e.g., neurologic deficit, non-HIV/non transplant status, CSF culture positivity at 2 weeks, etc.). We found that there are no empiric and literature data that support a role of cryptococcal serum antigen (CRAG) in guiding the antifungal therapy; with the data collected, we think that although is possible, it is very rare to find disseminated cryptococcosis with negative CRAG. We looked also for the more important risk factor of recurrence. Some possible causes explored are risk of azole resistant strains, pre-existent conditions of patients that play a permissive role and the common situation where flucytosine is unavailable that led to suboptimal induction phase of therapy. Herein, we discuss disseminated cryptococcosis with a particular attention to antifungal therapy, role of cryptococcal antigen, and risk factors for recurrence of disease.

Over the past 15 years, there has been an increase in the development and utilization of newer antifungal agents. The ideal antifungal, however, in regard to spectrum of activity, pharmacokinetic/pharmacodynamic properties, development of resistance, safety, and drug interaction profile remains elusive. This article reviews pharmacologic aspects of Food and Drug Administration-approved polyenes, flucytosine, azoles, and echinocandins as well as promising pipeline antifungal agents. Unique properties of these newer agents are highlighted. The clinical role of established and investigational antifungal agents as treatment and/or prevention of invasive fungal infections is discussed.

Cryptococcal infection has been documented in 2.8% of solid-organ transplant recipients, with the median time to disease onset being 21 months. Renal transplant recipients account for the majority of cases. Most patients present with central nervous system or disseminated disease, with only a minority having cutaneous manifestations. We present the case of a 47-year-old female renal transplant recipient who presented with refractory acute cellulitis 7 months after transplant. She had received thymoglobulin induction and was on a maintenance immunosuppressive regimen of tacrolimus, mycophenolic acid, and prednisone (5 mg/d). She did not respond to broad-spectrum antibacterial therapy for presumed bacterial cellulitis. Skin and soft tissue biopsies subsequently showed the presence of yeast; Cryptococcus neoformans was recovered in culture. Blood cultures, chest radiography, and cerebrospinal fluid sampling were negative, which resulted in a diagnosis of multifocal soft tissue cryptococcosis, a form of disseminated disease. Serum cryptococcal antigen testing was strongly positive (≥ 1:2560). The patient's immunosuppression was reduced, and she received treatment with liposomal amphotericin B and flucytosine for 2 weeks, which resulted in symptomatic improvement. This was followed by 1 year of consolidation and subsequent maintenance therapy with fluconazole. This case should increase awareness of the broader differential diagnosis of soft tissue infection in immunocompromised patients. Her case mimicked bacterial cellulitis, which delayed administration of effective therapy. Although our patient was initially diagnosed via biopsy, early clinical suspicion and serum cryptococcal antigen testing can lead to the correct diagnosis more rapidly. As transplant patients return to their community providers, heightened vigilance for unusual infections and presentations is warranted. The possibility of a cryptococcal cause for acute soft tissue infection should be considered, even in the absence of pulmonary or central nervous system involvement.

Cryptococcosis is the third most common invasive fungal infection in solid organ transplant recipients. We describe three cases of neuro-meningeal cryptococcosis occurring among kidney transplant (KT) patients, and discuss the diagnostic and therapeutic challenges in this context. Median time from KT to infection was 6 months [range: 3-9]. The most common clinical manifestations at diagnosis were fever (2/3), headache (2/3), and confusion (2/3); none had extra-neurological involvement. CrAg was positive in all cases at diagnosis both in serum and cerebrospinal fluid (CSF). For two patients, analysis of previous samples showed that CrAg was detected in plasma up to 4 weeks before diagnosis. All patients received induction treatment with liposomal amphotericin-B (L-AmB) and flucytosine for a median duration of 10 days [range: 7-14], followed by fluconazole maintenance therapy. Acute kidney injury secondary to L-AmB therapy was observed in only one case, but all patients had a tacrolimus overdose following initiation of maintenance therapy due to drug-drug interactions between fluconazole and tacrolimus. Among KTR, early detection of Cryptococcus meningitis using serum CrAg is possible. Close monitoring of renal function during treatment is essential due to the nephrotoxicity of L-AmB, but also drug-drug interactions between fluconazole and calcineurin inhibitors.

Objective: The aim of this study is to determine the distribution of samples exhibiting Candida growth among the blood cultures, and the antifungal susceptibility. Methods: The retrospective study was conducted in Samsun Training and Research Hospital, Samsun, Turkey from January to December, 2018 and comprised immunosuppressed patients with sepsis. Ethical approval was obtained and consent was taken from all patients. Yeast growths were typed by means of colony morphology, germ tube formation and the VITEK 2 system. Their susceptibilities tests were determined using the same automatized system. Resistance strains were also tested using the dilution method. Results: Of the 50 patients, 19(38%) were females and 31(62%) were males. The overall mean age was 60.84 ± 22.05 years. 31 (62%) of the samples were received from intensive care units, 14 (28%) from the palliative care unit, and five from other inpatients. In our study, most common among our isolates was C. albicans, and C. parapsiosis was most common among non-albicans species. Resistance to antifungals was observed in 28% of Candida isolates. Of the total isolates, %10 were found to be naturally resistant to fluconazole, 8% to voriconazole, 4% to flucytosine, and amphotericin B. The high resistance rate for fluconazole in Candida species is noteworthy. The findings obtained through both the dilution method and the automatized system were consistent. Continuou....

The upsurge of candidemia in the past years has been an immense encumbrance on public health and the number of deaths caused by candidemia particularly in critical care unit patients is devastating. Candida species harbor a 30% - 60% mortality rate and compared to stable people or those with less serious illnesses, this ranges from 60% to 80% of those who are chronically ill patients. Grounded on a recent report from a tertiary care hospital in Kenya showing the emergence of previously unobserved species: Candida auris, this study aimed to determine the prevalence, species distribution, and antifungal susceptibility profile of candidemia in critical care unit patients of the hospital. 378 Critical Care Unit patients were enrolled for the study from January 2019 to January 2020. Positive archived isolates were sub-cultured using Saboraud Dextrose Agar. Candida species were identified utilizing API20C AUX and Vitek-2. Antifungal susceptibility testing was conducted using the Liofilchem MIC Test strip. Out of 378 patients, thirty-one presented a positive culture for Candida species. The prevalence of Candidemia was 8.2% with 9 (29.03%) Candida auris, 8 (25.81%) Candida albicans, 6 (19.35%) Candida parapsilosis, 3 (9.68%) Candida famata, 3 (9.68%) Candida tropicalis, 1 (3.23%) Candida duobushaemolumonii, and 1 (3.23%) Candida lusitaniae. A resistance pattern to Fluconazole was observed among Candida auris and Candida parapsilosis, and resistance to Flucytosine was observed in Candida tropicalis, whereas susceptible MIC values were obtained for the other drugs. There is an increase in candidemia among critical care unit patients in the health facility posing a public health challenge. Moreover, the onset of new species Candida auris which is unprecedented in Kenya warrants enhanced infection control, and the uniform resistance of Candida auris, Candida parapsilosis, and Candida tropicalis towards Fluconazole and Flucytosine necessitate constant drug monitoring for empirical treatment regime. In contrast, the high potency of Echinocandins and Amphotericin-B demonstrate them as the drug of choice.

Background: Despite an increasing trend of onychomycosis caused by Candida species in recent years, there is a scarcity of published data. Objective: To determine the epidemiological and clinical characteristics of Candida onychomycosis, to identify the prevalent, and perform in-vitro antifungal susceptibility testing (AFST) of the isolates. Methodology: A total of 506 consecutive patients with a clinical suspicion of onychomycosis were included in a cross-sectional clinical study. Nail scrapings and clippings were subjected to KOH examination and culture. Species identification and antifungal drug sensitivity testing were done for Candida isolates using Vitek 2YST Compact system using Vitek 2 cards. Results: Out of 384 (75.88%) culture-positive cases, dermatophytes were isolated in 58.08%, yeast in 26.30%, and NDM in 12.24%. Of the yeast, Candida albicans was isolated in 59.4% and non-albicans species in 40.59%. AFST showed that most of Candida species exhibited 100% susceptibility to most of the antifungal drugs tested, while intermediate resistance to fluconazole and flucytosine was seen in some non-albicans species (C. krusei, C. glabrata, and C. guilliermondii). Time taken for species identification was 14–18 h (average 15.5 h), while determination of minimum inhibitory concentration took 9–27 h (average 13 h). Conclusions: Our study showcases the present scenario of Candida distribution and the resistance patterns of various species afflicting the nail unit. Furthermore, our findings clearly indicate that the carriage of this pathogenic yeast is seen in both healthy individuals as well as with immunosuppression.

Purpose: High-grade gliomas (HGGs) are central nervous system tumors with poor prognoses and limited treatment options. Vocimagene amiretrorepvec (Toca 511) is a retroviral replicating vector encoding cytosine deaminase, which converts extended release 5-fluorocytosine (Toca FC) into the anticancer agent, 5-fluorouracil. According to preclinical studies, this therapy kills cancer cells and immunosuppressive myeloid cells in the tumor microenvironment, leading to T-cell–mediated antitumor immune activity. Therefore, we sought to elucidate this immune-related mechanism of action in humans, and to investigate potential molecular and immunologic indicators of clinical benefit from therapy. Patients and Methods: In a phase I clinical trial (NCT01470794), patients with recurrent HGG treated with Toca 511 and Toca FC showed improved survival relative to historical controls, and some had durable complete responses to therapy. As a part of this trial, we performed whole-exome DNA sequencing, RNA-sequencing, and multiplex digital ELISA measurements on tumor and blood samples. Results: Genetic analyses suggest mutations, copy-number variations, and neoantigens are linked to survival. Quantities of tumor immune infiltrates estimated by transcript abundance may potentially predict clinical outcomes. Peak values of cytokines in peripheral blood samples collected during and after therapy could indicate response. Conclusions: These results support an immune-related mechanism of action for Toca 511 and Toca FC, and suggest that molecular and immunologic signatures are related to clinical benefit from treatment.

Introduction Cryptococcal meningoencephalitis is a life-threatening disease affecting mainly immunocompromised hosts. Case report We present a case of a 64-year-old immunocompetent patient, who initially developed a traumatic scalp skin infection due to Cryptococcus neoformans. The patient received oral fluconazole and subsequently liposomal amphotericin B due to the development of resistance with resolution of the infection. Two years later, during chemotherapy for newly diagnosed gastric and lung cancer, he developed fulminant cryptococcal meningoencephalitis, which did not respond to liposomal amphotericin B and flucytosine. Conclusions To our knowledge, this is the first case of fulminant cryptococcal meningoencephalitis following long latency after adequately treated primary cutaneous infection.

Background: Invasive Trichosporon infections are rarely seen opportunistic fungal infections in children and mainly affect immunocompromised patients. This multicenter retrospective study has rewieved the characteristics, risk factors, treatment modalities and outcomes of bloodstream infections caused by Trichosporon species in children diagnosed over the past ten years in Turkey. Methods: The study was performed with the participation of 12 of 55 hospitals invited from Turkey. In each center, the patients with bloodstream infections caused by Trichosporon spp. between January 2010 and December 2020 were retrospectively ascertained and the results were reported to the study coordinator by means of a simple case report. Data were collected on patient demographics, underlying condition(s), treatment of.infections caused by Trichosporon spp, and 7 and 30- day mortality rates. Results: A total of 28 cases with fungemia caused by Trichosporon spp. were included in the study. The most common underlying disease was paediatric cancers (39.3%). T. asahii infections were detected in 78.5 % (n=22) of patients. A various spectrum of antifungal treatment regimens were used including intravenous amphotericin B monotherapy in 35.7%, intravenous amphotericin B and voriconazole combination in 32.1% and intravenous voriconazole monotherapy in 28.6% of the patients. The overall mortality rate was 28.5 %. The mortality rates were 12.5% in the voricanozole, 30% in the amphotericin B and 33.3% in combined voriconazole -amphotericin B arms Conclusions: Invasive Trichosporon infections with an important impact of patients quality of life are almost related to underlying diseases with an overall mortality rate of 28.5%. Voriconazole was found to be associated with lower mortality rates when compared with other treatment regimens. (c) 2021 SFMM. Published by Elsevier Masson SAS. All rights reserved.

A 49- year old immunocompetent male presented with a right flank abscess and was found to have disseminated cryptococcal disease. Treatment was initiated with a one-week intravenous regime of amphotericin B and flucytosine based on recent trial data that this is as effective, and less toxic, than the standard two weeks. After completion of intravenous treatment he was discharged with oral anti-fungals and is making a good recovery with ongoing follow up.

Background: Candida species are among the most common fungal pathogens. They are ubiquitous yeasts found on plants and form the microbiota of the alimentary tract of mammals and the mucocutaneous membranes in humans. Methods: A total of 90 clinical samples were collected from Mahatma Gandhi Medical College & Hospital, Jaipur over a period of one year. Primary identification is done by the direct smear examination by Gram’s staining and KOH mount and then further sub-cultured on SDA media. Results: Out of 90 clinical specimens collected, most common form of Candidiasis seen was Candiduria type followed by blood cultures, swab, Endotracheal tube, sputum and Bronchialveolar lavage. The maximum number of patients were found in the age group of 21-30 years, followed by 51-60 years. Out of 90 patients, 48 (53.3%) were males and 42 (46.6%) were females. C. tropicalis (44.4%) was the predominant species followed by C. albicans and other species of Candida. Among 90 samples, 32% were Candida albicans and remaining 68% were Non albicans Candida species. Conclusion: The study found that C. tropicalis was sensitive against Micafungin & Caspofungin, showing a 100% sensitivity. Candida albicans showed 100% sensitivity against Flucytosine.

Purpose of review HIV-associated cryptococcal meningitis remains a significant public health problem in parts of Africa and Asia and a major cause of AIDS-related mortality, accounting for 15% of all AIDS-related deaths worldwide. Cryptococcal meningitis is uniformly fatal if untreated, and access to antifungal therapy in regions with the highest burden is often limited. Outcomes with fluconazole monotherapy are poor, and induction treatment with amphotericin B and high-dose fluconazole for 2 weeks is associated with significant drug-related toxicities and prolonged hospital admissions. This review focuses on the potential of novel short-course and oral combination therapies for cryptococcal meningitis. Recent findings Recent clinical trials have shown that shorter courses of amphotericin, if paired with oral flucytosine, rather than fluconazole, can achieve non-inferior mortality outcomes. In addition, an oral combination of fluconazole and flucytosine is a potential alternative. Liposomal amphotericin B may further simplify treatment; it is associated with fewer drug-related toxicities, and a recent phase II randomised controlled trial demonstrated that a single, high dose of liposomal amphotericin is non-inferior to 14 standard daily doses at clearing Cryptococcus from cerebrospinal fluid. This has been taken forward to an ongoing phase III, clinical endpoint study. Summary The incidence and mortality associated with cryptococcal meningitis is still unacceptably high. There is evidence supporting the use of short-course amphotericin B and oral combination antifungal treatment regimens for cryptococcal meningitis (CM). Ongoing research into short-course, high-dose treatment with liposomal amphotericin may also help reduce the impact of this devastating disease.

Background Raised intracranial pressure (ICP) and insufficient antifungal regimens are the two main factors result to unsatisfactory outcomes in non-HIV cryptococcal meningitis (CM) patients. In this study, we try to discuss that whether triple therapy of amphotericin B (AmB), fluconazole, 5-flucytosine (5-FC) plus ventriculoperitoneal shunts (VPS) is superior to AmB, 5-FC, fluconazole plus intermittent lumbar puncture in induction therapy in non-HIV CM patients with increased ICP. Methods We reviewed 66 clinical records from non-HIV CM patients with increased ICP. The demographic and clinical characteristics, BMRC staging, cerebrospinal fluid profiles (CSF), brain magnetic resonance imaging, treatment, and outcomes of these individuals were retrospectively analyzed. All non-HIV CM patients with increased ICP (≥ 25 cmH2O) were divided into two groups, including 27 patients treated with triple antifungal agents and 39 patients treated with the same triple therapy plus VPS. Results Triple therapy plus VPS group had more satisfactory outcomes, more CSF sterilization at 10 weeks follow-up, lower CSF opening pressure, lower BMRC staging scores one week after VPS, less CSF C. neoformans counts and CSF culture positive. Besides, these patients had shorter hospital stay than triple therapy group. Conclusions Triple antifungal agents combined with VPS could effectively reduce ICP, had faster rate of clearance of C. neoformans counts, more improved neurological function, shorten hospitalization time and better outcomes in non-HIV CM patients with increased ICP. Our study indicated that triple therapy plus early VPS may be an optimal treatment for non-HIV CM patients with increased ICP.

BACKGROUND: Determining the extent of Cryptococcal disease (CD) is key to therapeutic management. Treatment with fluconazole is only recommended for localized pulmonary disease. Induction therapy with amphotericin B (AmB) and flucytosine is recommended for disease at other sites, irrespective of central nervous system (CNS) involvement, but this is not often followed in patients without meningitis. In this study, we compared treatment and mortality between patients with CD of the CNS and other extrapulmonary (OE) sites. METHODS: This is a retrospective, single-center study of all hospitalized patients with non-pulmonary Cryptococcal infection from 2002 to 2015 who underwent lumbar puncture. Demographics, predisposing factors, comorbidities, clinical presentation, laboratory values, antifungal treatment, and mortality data were collected to evaluate 90-day mortality and treatment differences between patients with OE and CNS CD. Survival analysis was performed using multivariable Cox Regression analysis. RESULTS: Of 193 patients analyzed, 143 (74%) had CNS CD and 50 (26%) had OE CD. Ninety-day mortality was 23% and similar between the OE and CNS CD groups (22% vs 23%, P=0.9). In the comorbidity adjusted multivariable Cox Regression model, mortality risk was similar in the OE and CNS groups. Fewer patients with OE CD received induction therapy with AmB and flucytosine compared to those with CNS disease (28% vs 71.3%, P

We investigated the value of susceptibility testing in predicting response in AIDS-associated cryptococcal meningitis using clinical isolates from a randomized controlled trial of antifungal treatment (amphotericin monotherapy, amphotericin with flucytosine, or amphotericin with fluconazole). We found no correlation between antifungal susceptibility and either early or late survival, or fungal clearance.

Invasive fungal infections are an important cause of morbidity and mortality in infants, particularly in extreme prematurity. Successful systemic treatment requires consideration of antifungal efficacy, safety, and pharmacokinetics, including optimization of dosing in this population.This review summarizes published pharmacokinetic data on four classes of antifungal agents used in the neonatal population. Alterations in absorption, distribution, drug metabolism and clearance in infants compared to adult populations are highlighted. Additionally, pharmacodynamics, safety, and therapeutic drug monitoring are discussed. Recent advancements in neonatal antifungal pharmacotherapies are examined, with emphasis on clinical application.Over the last two decades, published studies have provided increased knowledge on pharmacokinetic considerations in the neonatal population. Future research should focus on filling in the knowledge gaps that remain regarding the benefits and risks of combination antifungal therapy, the rising use of micafungin for invasive candidiasis given its fungicidal activity against polyene and azole-resistant Candida species and its minimal adverse effect profile, and the need for pharmacokinetic and safety data of broad spectrum triazoles, like voriconazole and posaconazole, in infants. Furthermore, efforts should focus on well-designed trials, including population pharmacokinetic studies, to develop dosing recommendations with subsequent implementation into clinical practice.

The more common manifestations of cryptococcal infections are restricted to the central nervous system and lungs. A young man, suffering from idiopathic dilated cardiomyopathy with a left ventricular ejection fraction of 20%, presented with subacute, painful tender swelling in both legs initially attributed to congestive cardiac failure. No response to diuretics was achieved. Metabolically active lesions in the muscles of both lower limbs suggestive of muscle abscesses were found. A diagnosis of tropical pyomyositis was therefore made, but aspiration surprisingly revealed gram-positive yeast cells, staining of which on India ink and culture confirmed Cryptococcus. A good response to a combination of liposomal amphotericin B and flucytosine was obtained, but nevertheless the patient died from heart failure after induction of antifungal therapy.

Background: Opportunistic infections are the leading cause of morbidity and mortality among immuno-compromised patients. Oropharyngeal candidiasis (OPC) dominates opportunistic fungal infections associated with HIV/AIDS. Objective:We determined the distribution and prevalence of antifungal resistance in Candida isolates recovered from patients infected with HIV and presenting with OPC. Methods: HIV-infected patients with provisional diagnosis of OPC were consecutively enrolled between May 2017 and June 2018. After patient data collection, oral swabs and blood specimens were collected for culture and CD4 T-lymphocyte estimation, respectively. Presumptive Candida isolates were speciated and their antifungal susceptibilities to fluconazole, flucytosine and amphotericin B, including minimum inhibitory concentration was determined using the E-test. Results: Of 286 patients enrolled, 67.8% (194) cultured positive for Candidaspp. The mean age of culture positive patients was 40.7 ±15.2 with more female enrollment (63.4%,123/194). The CD4 counts ofculture positive patients were low (211.1 ±235.6 cells/μL) and 68.6% (133) of them were on anti-retroviral therapy (ART) with 10.3% (20/194) having previous exposure to fluconazole. Seven different Candidaspecies, with the following distributions were isolated: C. albicans (69.1%, 134), C. tropicalis (10.3%, 20), C. glabrata (6.7%, 13), C. parapsilosis (5.7%, 11), C. krusei(4.1%, 8), C. dubliniensis(2.6%, 5),and C. lusitaniae (1.5%, 3). Of all C. albicans isolates tested, 29.1%, 1.5% and 2.3% were resistant to fluconazole, amphotericin B and flucytosine, respectively. Non-C. albicans isolates showed 45%, 3.3% and 8.3% resistance to fluconazole, amphotericin B and flucytosine, respectively. Conclusion: C. albicans accounted for majority of oropharyngeal candidiasis(OPC), with non-C. albicans showing significantly higher resistance to fluconazole. Positive culture was independent of gender, previous exposure to antifungal drugs, ART status and duration. Without any contraindication, flucytosine and Amphotericin B may be considered for OPC not responding to fluconazole therapy

The management of fungal infections is challenging, especially given the continued increase in fluconazole resistance and prevalence of non-albicans Candida spp. Urinary tract infections due to non-albicans and fluconazole-resistant Candida are particularly problematic given the uncertainty in determining true infection from colonization and the limited number of antifungal agents with adequate penetration to the site of infection. While our understanding of mechanisms of resistance and pharmacokinetics and pharmacodynamics continues to improve, it is combatted by the emergence of novel, difficult-to-manage pathogens such as C. auris. The purpose of this review is to summarize recent data regarding the management of urinary tract infections due to non-albicans and fluconazole-resistant Candida spp. with a focus on mechanisms of resistance, pharmacokinetics and pharmacodynamics, and treatment strategies. Advances in molecular techniques have improved our understanding of the mechanisms responsible for antifungal resistance, especially to the echinocandins and azole antifungal classes. Additionally, increased knowledge of the pharmacokinetic and pharmacodynamic properties that govern available antifungal agents has enhanced the ability to optimize dosing, especially for extravascular fungal infections. Unfortunately, these developments in the pre-clinical arena have not been matched by additional high-quality clinical data, and therefore, the optimal management strategies for fungal UTIs remain elusive. The lack of adequate new clinical data to guide optimal management of UTIs due to fluconazole-resistant and non-albicans Candida, combined with the dearth of novel antifungal agents, leaves fluconazole, amphotericin B deoxycholate, and flucytosine as the drugs of choice for these infections. Further data regarding urinary concentrations and optimal urinary PK/PD parameters may allow for the use of other agents, such as the echinocandins, in certain situations. Several novel antifungal agents are currently in clinical development with adequate in vitro activity against fluconazole-resistant and non-albicans Candida, although their utility in the treatment of UTIs requires further investigation.

Purpose To describe the pharmacokinetics of flucytosine in a critically ill patient undergoing continuous venovenous hemodiafiltration (CVVHDF) treated for cryptococcal meningitis. Summary A 20-year-old female weighing 93.4 kg with a body mass index of 34.3 kg/m2 with a past medical history of systemic lupus erythematous with diffuse proliferative lupus nephritis (class IV) was admitted to the hospital after several months of worsening dyspnea, fatigue, myalgia, vomiting, and diarrhea. The patient developed worsening renal function and volume overload requiring CVVHDF on hospital day 7. She was diagnosed with cryptococcal meningitis on hospital day 8, and flucytosine 2,500 mg enterally every 12 hours and liposomal amphotericin B 500 mg intravenously every 24 hours were initiated. Flucytosine serum concentrations were collected on day 4 of therapy, and pharmacokinetics were performed on 2 sequential levels. Pharmacokinetic calculations displayed an elimination rate constant of 0.0338 h-1, a volume of distribution between 0.42 and 0.43 L/kg, a half-life of 20.5 hours, and a total drug clearance between 1.32 and 1.36 L/h while on CVVHDF. The nonsequential levels displayed good correlation, and no further monitoring or dosage adjustment was required. The patient completed therapy, with clinical resolution of her infection, and no toxicities due to flucytosine were noted. Conclusion Flucytosine dosed at 25 mg/kg of actual body weight every 12 hours during CVVHDF conferred therapeutic levels with no appreciable toxicities. Because of its narrow therapeutic index and risk of toxicity, additional pharmacokinetic studies are needed to determine optimal drug dosing of this medication in patients requiring renal replacement therapy.

Cryptococcal meningitis is being increasingly described in immunocompetent adults. We describe here a young immuncompetent adult of Indian origin from Ghana, West Africa with cryptococcal meningitis who had several ups and downs during his treatment. First he developed neurologic worsening due to premature transition from intensive to consolidation phase therapy. Subsequently he deteriorated due to “immune reconstitution inflammatory syndrome (IRIS)” like phenomenon that necessitated the prolonged use of steroids. Additionally he suffered serious adverse effects due to antifungal drugs including liposomal amphotericin B and flucytosine. He recovered after 16 months of treatment. The case highlights the possible difficulties in management of cryptococcal meningitis in immunocompetent host including ‘immune reconstitution like syndrome’. There is need for new trial data and guidelines about treatment of cryptococcosis in the non HIV host. Keywords: Cryptococcus, Meningitis, Immunocompetent, Paradoxical upgrading reaction

The purpose of this review is to summarize and evaluate relevant literature on combination antifungal therapy for invasive fungal infections (IFIs). Cryptococcal meningitis has the largest body and highest quality in support of combination therapy with amphotericin B and flucytosine. More recent data in treatment of invasive aspergillosis suggest combination therapy with voriconazole and echinocandins may be effective in select patients. Quality studies are needed to define combination therapy in rare mold infections. Multiple strategies have been employed to optimize treatment of the growing incidence of IFIs. With exceptions as noted above, justification for the use of combination antifungal therapy is most often based on uncontrolled and/or underpowered studies, in vitro data, and case reports.

International audience; BackgroundAt the dermatology service of the General Hospital of Mexico City, Mexico, two patients, father and son, with black-grain mycetoma were seen. The grains were isolated, and the cultured fungi were identified as Madurella mycetomatis based on morphology. Using the M. mycetomatis specific PCR, amplicons of a different size than that of the M. mycetomatis type strain were obtained.ObjectiveTo determine the causative agent of the two black-grain mycetoma cases and develop non-culture-based diagnostic tools to identify them to the species level.MethodsThe M. mycetomatis specific, the internal transcribed spacer (ITS) region, β-tubulin (BT) and ribosomal binding protein 2 (RBP2) PCRs were used to confirm the identity of the isolates. Genetic variation was established by amplification fragment length polymorphisms. To determine the antifungal susceptibility profile, the Sensititre™ YeastOne™ assay was used. To develop a species-specific PCR primers were designed on the sequenced PCR amplicon from the M. mycetomatis specific PCR.ResultsBy analyzing the ITS, BT and RBP2 regions the isolates were identified as Madurella pseudomycetomatis. The isolates from father and son were similar but not identical to M. pseudomycetomatis from Venezuela and one from an unknown origin. Madurella pseudomycetomatis isolates were inhibited by itraconazole, posaconazole and voriconazole but showed increased MIC values for amphotericin B and fluconazole. They were not inhibited by the echinocandins and five flucytosine. The two patients were treated with itraconazole resulting in cure for the father while the son was lost to follow-up. The species-specific PCR developed for M. pseudomyceotmatis was discriminative and specific.ConclusionMadurella pseudomycetomatis is genetically diverse with same susceptibility profile as M. mycetomatis and causes eumycetoma in Latin America. The M. pseudomycetomatis specific PCR can be used to identify this causative agent to the species level; however, this needs to be validated in an endemic setting.

Background Cryptococcal prostatitis is a rare clinical disease and has never been reported in China. Case presentation We report on a male HIV-infected patient with pulmonary and prostate cryptococcosis that was misdiagnosed (as tuberculosis) and delayed diagnosed. Although the patients accepted anti-fungal treatment and anti-retroviral treatment finally, the physician’s mistakes reflect the rarity of this condition in China. Conclusion Cryptococcal prostatitis is a rare disease that unusually presents in immunodeficient patients. Physicians should have a heightened awareness of this particular infection in the immunodeficient population.

Purpose To evaluate treatment options for candida keratitis and endopthalmitis after corneal transplantation. Methods Case reports and literature review. Results Two patients with keratitis due to Candida glabrata/ parapsilosis after corneal transplantation were successfully treated with a combination of topical voriconazole, intracameral voriconazole and amphotericin B, and systemic treatment with flucytosine. Conclusions Natamycine and voriconazole topically are preferred therapeutic options for the treatment of fungal keratitis. Systemic flucytosine is a useful alternative additive, particularly for countries where natamycine is not registered as a pharmaceutical agent.

Wickerhamomyces anomalus is an emerging pathogen, which has been associated with clonal outbreaks and poor clinical outcomes. Despite being an important emerging yeasts species, our understanding concerning the microbiological and clinical characteristics of infections due to this species is limited. Herein, we are reporting a retrospective analysis of fungemia patients with W. anomalus from a 2,100-bed hospital in Shanghai during 2014–2016. Moreover, we conducted an extensive literature review to gain a deeper clinical and microbiological insights. Detailed clinical data were recorded. Antifungal susceptibility testing (AFST) followed CLSI M27-A3, and isolates were identified using MALDI-TOF MS. In total, 13 patients were identified with a mortality rate of 38.5% (5/13). Central venous catheter (CVC), broad-spectrum antibiotic therapy, total parenteral nutrition (TPN), surgery, and mechanical ventilation were the most frequently observed risk factors. Eight patients (61.5%) experienced mixed bacterial/Candida bloodstream infections, and four patients developed mixed candidemia (MC). W. anomalus isolates showed high minimum inhibitory concentrations (MICs) against all azoles tested and flucytosine, while AMB showed the highest in vitro activity. Azoles were used for 84.6% (11/13) of the cases, while 36.4% (4/11) of them died. When combining with the AFST data and the literature review, our study highlights the poor efficacy of azoles and optimal efficacy of AMB and LAMB against infections caused by W. anomalus. In conclusion, our study highlights the emerging threat of W. anomalus affecting both neonates and adults. Furthermore, our results advocate the use of AMB formulations rather than azoles among patients infected with W. anomalus. Future studies are warranted to reach a definitive consensus regarding the utility of echinocandins among such patients.

Cytopenia is a common complication in patients with human immunodeficiency virus (HIV) infection. Identifying the cause is demanding because of the wide range of possible diagnoses. We herein report an HIV-infected patient with disseminated cryptococcosis involving multiple organs including the blood, brain, lungs, and bone marrow, who developed progressive pancytopenia after initiation of anti-fungal treatment with liposomal amphotericin-B (L-AMB) and flucytosine (5FC). The pancytopenia persisted despite early 5FC discontinuation. A bone marrow biopsy revealed cryptococcal infiltration and the blood examination findings recovered quickly after resuming L-AMB. Thus, this HIV-infected patient's pathological findings and clinical course suggested that the primary cause of the pancytopenia was bone marrow cryptococcosis.

Background Cirrhosis is an end-stage liver disease and is reported as an independent risk factor for cryptococcosis. Information about cryptococcosis in patients with cirrhosis remains sparse. Methods Human immunodeficiency virus–uninfected patients with cryptococcosis and cirrhosis admitted to Huashan Hospital from July 2005 to June 2020 were reviewed. Efficacy and safety of antifungal treatments, clinical outcome, and prognostic factors of mortality were evaluated. Results A total of 49 cryptococcosis patients with cirrhosis were included. Sites of infection involved central nervous system (n = 38), lung (n = 21), bloodstream (n = 11), skin (n = 1), and bone (n = 1). Nine patients (18.4%) had pulmonary cryptococcosis alone. Viral hepatitis B infection (57.1%) was the most common cause of cirrhosis. Patients with decompensated cirrhosis (Child-Pugh class B and C) were more likely to have extrapulmonary cryptococcosis than those with compensated cirrhosis (90.7% vs 64.7%; P = .049). In patients with cryptococcal meningitis (CM), 7 were treated with amphotericin B with/without flucytosine, 5 with amphotericin B plus fluconazole with/without flucytosine, and 12 with fluconazole with/without flucytosine. Fluconazole (>400 mg/day) was well tolerated and only 1 patient had a mild adverse drug reaction. At 1-year follow-up, all patients treated with fluconazole with or without flucytosine survived, whereas the mortality rate was 14.3%–20.0% in the remaining groups. In addition, Child-Pugh class C cirrhosis (hazard ratio [HR], 7.555 [95% confidence interval {CI}, 1.393–40.971]) and time to diagnosis >120 days (HR, 18.619 [95% CI, 2.117–163.745]) were independent factors for 1-year mortality in patients with CM. Conclusions Severity of cirrhosis was associated with developing extrapulmonary cryptococcosis and mortality in CM. Early diagnosis and intervention of cryptococcosis are key for outcome., This study shows a higher rate of extrapulmonary cryptococcosis and higher mortality of cryptococcal meningitis in patients with more advanced cirrhosis, which calls on early recognition and timely intervention of cryptococcosis in patients with cirrhosis.

Aims: The aim of this study was to identify C. parapsilosis complex strains isolated from various clinical samples by sequence analysis and to investigate whether there are any differences between the species in terms of virulence factors and antifungal susceptibility. Methods: The study included a total of 42 isolates identified as C. parapsilosis complex based on the color they formed in chromogenic medium, colony morphology, and microscopic appearance in Corn Meal-Tween 80 Agar and they were confirmed with API 20 C AUX. For the DNA sequence analysis of clinical isolates, V9G forward and LS reverse primers were used as well as internal transcribed spacers (ITS1 and ITS4). Biofilm formation, esterase, phospholipase, and protease activities were evaluated as virulence factors. Antifungal susceptibility was investigated via colorimetric microdilution method. Results: A total of 75 non-C. albicans isolates were obtained from various clinical samples between 2016 and 2017 in a Turkish Tertiary Care Hospital. Of them, 42 were identified as members of the C. parapsilosis complex. Of the 42 strains, 41 were identified as C. parapsilosis sensu stricto (CpSS), while only one was identified as C. orthopsilosis. Of the CpSS strains, 31 (75.6%) were biofilm-positive, six (14.6%) were esterase-positive, nine (21.9%) were positive for phospholipase activity, and 31 (75.6%) were positive for protease formation, whereas all virulence factors of C. orthopsilosis strain were found to be negative. All CpSS strains were found susceptible to amphotericin B, echinocandins, and flucytosine. Conclusions: It has been concluded that the use of molecular methods to identify CpSS would not be effective in routine laboratory practices as it is the most commonly isolated species from the C. parapsilosis complex and there are no significant differences between species in terms of antifungal susceptibility.

Background Cryptococcal meningitis (CM) is estimated to cause 181 000 deaths annually, with the majority occurring in Sub-Saharan Africa. Flucytosine is recommended by the World Health Organization as part of the treatment for CM. Widespread use of flucytosine could reduce mortality in hospital by as much as 40% compared to the standard of care, yet due to market failure, quality-assured flucytosine remains unregistered and largely inaccessible throughout Africa. Methods The recently established South African flucytosine clinical access programme is an attempt to address the market failure that led to a lack of public sector access to flucytosine for CM, by making the medicine freely available to tertiary hospitals in South Africa. Results Between November 2018 and September 2019, 327 CM patients received flucytosine through this programme, with efforts to support sustainable national scale-up presently ongoing. We describe why this programme was needed, its catalytic potential, what is still required to ensure widespread access to flucytosine, and observations from this experience that may have wider relevance. Conclusions The South African flucytosine access programme illustrates how access programmes may be one part of the solution to addressing the vicious cycle of perceived low demand, limiting manufacturer interest in specific product markets.

Context: Candidiasis still remains as a common opportunistic infection in patients with human immunodeficiency virus (HIV). Drug resistance has become a serious health concern because of indiscriminate usage and dosage. Aim: To determine the antifungal resistance pattern of Candida albicans and non-albicans Candida (NAC) from HIV patients. Subjects and Methods: The study was carried out in the department of microbiology at a tertiary care hospital. Candida isolates obtained from HIV patients were tested for drug susceptibility by Vitek-2 automated system. Results: Antifungal susceptibility pattern (n=109) revealed that 15% of the isolates were resistant to at-least one and 85% were sensitive to all the drugs tested. About 10% and 19% of C. albicans showed resistance to fluconazole and flucytosine respectively. Among non-albicans tested, only C. tropicalis (14%) exhibited resistance to flucytosine. Conclusions: Knowledge on epidemiology, species prevalence, and drug resistance pattern may guide for effective therapy. This reduces morbidity and also improves the quality of life.

Cryptococcemia is a life-threatening fungal infection. Sometimes, it is hard to diagnose. The studies to describe the characteristics of cryptococcemia specifically were limited. We performed this retrospective analysis in a Chinese hospital during 2002–2015, including 85 cryptococcemia cases and 52 Cryptococcus spp. isolates. The species, mating type, antifungal susceptibility and multilocus sequence typing of Cryptococcus spp. were determined. C. neoformans var. grubii MATα of sequence type (ST) 5 is the representative strain of cryptococcemia, accounting for 51 isolates. The MIC50/90 values were 0.5/0.5, 1.0/1.0, 2.0/4.0, ≤0.06/0.25, and ≤0.06/≤0.06 μg/ml for amphotericin B, flucytosine, fluconazole, itraconazole, and voriconazole, respectively. Cryptococcemia was the first diagnostic proof of cryptococcosis in 37 patients (43.5%, 37/85). Compared with the patients initially diagnosed of cryptococcosis in other sites (mainly cerebrospinal fluid), the patients firstly diagnosed by blood culture had prolonged time from admission to diagnosis of cryptococcosis (9 days vs. 2 days, P < .001) and higher 30-day mortality (54.1% vs. 20.8%, P = .003), while fewer symptoms of meningitis (45.9% vs. 100%, P < .001). For the patients receiving lumbar puncture, the occurrence of meningitis was similar between the patients firstly diagnosed by blood culture and those firstly diagnosed in other sites (94.1% vs. 100%, P = .26). However, the patients first diagnosed by blood culture had lower baseline intracranial pressure (250 mm H2O vs. 342.5 mm H2O, P = .001). In conclusion, patients with cryptococcemia as the first diagnostic proof of cryptococcosis usually had neglected subtle symptoms of meningitis, which may result in delayed diagnosis and catastrophic outcome.

Vulvovaginal candidiasis (VVC) is a common infection of the genital tract affecting millions of women worldwide. Data on epidemiological trends of VVC in Greece are scarce. This study was undertaken to evaluate the prevalence of VVC among symptomatic women in Crete, Greece, identify the Candida species involved and determine their susceptibility to antifungals. Over a 6-year period (2012-2017), 10 256 symptomatic women with vaginitis were evaluated. Isolation of yeasts was performed on Sabouraud dextrose agar with chloramphenicol, and the isolates were identified using the API 20 C AUX and/or the Vitek 2 YST card. Susceptibility of the isolates to amphotericin, fluconazole, voriconazole and flucytosine was determined by the Vitek 2 automated system. The results were interpreted according to Clinical and Laboratory Standards criteria. Vaginal swab cultures of 1217 (11.9%) women yielded Candida species. Recurrent VVC was documented in 62 (5.1%) of them. Candida albicans was the most frequently isolated species (75.6%), followed by Candida glabrata (13.6%). Overall, resistance rates to amphotericin B, fluconazole, voriconazole and flucytosine were 0.2%, 6.6%, 1.4% and 2.1%, respectively. Fluconazole resistance of C. albicans significantly increased in the second period of the study (2015-2017) (P = 0.031). This study demonstrated that VVC is a common infection among women in our region, with C. albicans being the predominant species involved. Although resistance to antifungals was infrequent, resistance to fluconazole among C. albicans isolates was found to significantly increase with time. Continued surveillance of changes in species distribution and susceptibility to antifungals are necessary to guide treatment.

We provide a review of current literature and report on a case of electronic device infective endocarditis with C. tropicalis. A 64-year-old man presented for revision of his implantable cardioverter defibrillator. Echocardiography revealed extensive vegetations attached to the Eustachian valve and in the right ventricular apex. Microbiological findings presented C. tropicalis on the explanted material. The patient refused additional surgical intervention. We successfully treated the patient with liposomal Amphotericin B and Flucytosine for 8 weeks. Keywords: Candida tropicalis, Implantable electronic device, Endocarditis, Eustachian valve

Fungal infections, especially invasive types, have become a serious healthcare problem as the immunocompromised population increases. There are five main classes of antifungal drugs: polyenes, flucytosine, allylamines, azoles, and echinocandins. Therapeutic drug monitoring (TDM) is justified for flucytosine and triazoles due to their large inter- and intra-individual pharmacokinetic variability and their high tendency for drug-drug interactions. Available methods for measuring these drugs include bioassay, liquid chromatography and liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). The LC-MS/MS approach is preferred due to its superior analytic sensitivity and specificity. In this review, we highlight TDM methods by LC-MS/MS for these antifungal drugs searchable in PubMed by December 1, 2018. LC-MS/MS methods that were developed for other purposes such as pharmacokinetics or toxicokinetics were also included. We have critically analyzed these methods with an emphasis on sensitivity, specificity, simplicity, throughput and robustness.

Background: Patients with Cushing's disease (CD) with hypercortisolism have an increased risk of opportunistic infection. However, most CD patients exposed to infections are diagnostic latency, leading to a poor prognosis. Methods: Six patients in our hospital and an additional six patients in the literature were included in this study. Clinical information of CD patients with pulmonary Cryptococcus neoformans are reviewed. Results: The average baseline total cortisol and ACTH in serum at 8 am of all the patients was 44.85 μg/dL (normal range 4.0–22.3 μg/dL) and 200.3 pg/mL (normal range 0–46 pg/mL), respectively. Lymphopenia was found in 2 out of 6 patients in our hospital. The pulmonary radiologic findings included nodules (4/12), masses with or without a cavity (5/12), infiltration (5/12), and consolidation (4/12). The diagnosis of C. neoformans was established by lung pathology results (7/12), microorganism culture (3/12), and serum cryptococcal polysaccharide antigen (4/12). Lung lobectomy was performed in two patients who had a nodule in one lung lobe. Antifungal drugs were administered, including amphotericin-B (7/12), fluconazole (4/12), flucytosine (2/12) and liposomal amphotericin (1/12). Additional therapies for CD included trans-sphenoidal pituitary adenoma surgery (9/12), adrenalectomy (1/12) and ketoconazole (2/12). Seven patients survived, and five patients died. Conclusion: Pulmonary C. neoformans is an uncommon but fatal opportunistic infection in CD patients. Pulmonary nodules or masses should be aggressively investigated to exclude the C. neoformans among CD patients. The infiltration lesions in chest CT scan and lymphopenia are associated with poor prognosis. Keywords: Cushing's disease, Lung, Cryptococcus neoformans

Background This case report emphasizes the need to recognize cryptococcus as a possible cause of meningitis in non-HIV patients in Sub-Saharan Africa and to highlight the possibility of grave outcomes due to the paradoxical immune response in diabetic patients with cryptococcus meningitis. It also highlights the need for widespread availability of amphotericin-B and flucytosine in hospitals in Sub-Saharan Africa. Case presentation A 27 year old African lady was admitted with generalized tonic clonic seizures lasting 5 to 10 min. These seizures were preceded by severe frontal headaches radiating to the occiput and neck and associated with chills, photophobia and loss of consciousness. She was tachycardic and had tongue bites on the lateral aspects of her tongue. Kernig’s and Brudzinski’s signs were positive. India ink was positive on two cerebrospinal fluid (CSF) samples. She had hyperglycemia and glucosuria as well. She was diagnosed with cryptococcal meningitis in diabetes and had a remarkable response to fluconazole monotherapy. She went home on maintenance dose of fluconazole having made full recovery. and is currently on prophylactic doses of fluconazole. Conclusions With the rising prevalence of diabetes in Sub-Saharan Africa, coupled with the low levels of adequate glucose control, cryptococcal meningitis should be considered in the differential diagnosis for diabetic patients presenting with chronic headache, fever and neurologic deficits.

Background Paediatric Cryptococcus gattii disease is rare, with only two previous cases recorded in the Northern Territory (NT) over the last 54 years. Immune reconstitution inflammatory syndrome (IRIS) is a recognised complication of C. gattii infection, even in the absence of an identified immunodeficiency syndrome; however, limited paediatric data exist. We present a series of three paediatric patients treated for C. gattii infection in the NT during 2016/2017. Case discussions All three cases were males aged 8-13 years at the time of presentation. Two were Aboriginal Australians from remote NT communities, and the third was a Timorese child from a remote district in Timor-Leste. All cases had evidence of brain cryptococcomas, and two had associated pulmonary lesions. Each child was treated with a 6-week induction phase of intravenous liposomal amphotericin and flucytosine and then continued on a 2-year course of eradication oral fluconazole. Persistent high intracranial pressure (ICP) complicated each case, requiring serial lumbar punctures and, in two cases, insertion of ventriculoperitoneal shunts. All three cases were diagnosed with IRIS between 5 and 10 weeks after commencement of antifungal treatment and were managed with high-dose corticosteroids, which were weaned slowly (6-20 months post-commencement). Conclusions Paediatric C. gattii disease is rare, although three recent cases in the NT highlight some of the challenges involved in managing the infection, including persistent raised ICP and complications such as IRIS. There is a need for further collaborative research into paediatric C. gattii disease.

Background The 2010 Infectious Diseases Society of America (IDSA) guidelines for management of cryptococcal diseases recommend high dose fluconazole (≥ 800 mg/day), either alone or with other antifungal drugs, as alternative anticryptococcal choices. But evidence for its use in the treatment of HIV-uninfected cryptococcal meningitis (CM) remains sparse. Methods A retrospective analysis of HIV-uninfected CM patients who received fluconazole 800 mg/day for salvage therapy from January 2011 to December 2016 at Huashan Hospital, Shanghai, China was performed. Efficacy and safety were assessed, and mortality and prognostic factors evaluated. Results A total of 44 patients were studied including 19 refractory to amphotericin B induction therapy, 8 refractory to fluconazole consolidation therapy (400 mg/d), and 17 intolerant of antifungal drugs. For salvage, 11 patients received triple therapy of high dose fluconazole, amphotericin B and flucytosine, 20 received dual therapy of high dose fluconazole and flucytosine, 13 received monotherapy of high dose fluconazole. Median duration of high dose fluconazole in salvage regimens was 136.5 days (range, 1–667 days). Clinical response rates were 72.1% (31/43) and 83.7% (36/43) when assessed at 2 weeks and the end of salvage therapy, respectively. Adverse events possibly related to high dose fluconazole occurred in 54.5% (24/44) of the patients, and all were mild or moderate. From the initiation of salvage therapy, 1-year all-cause mortality was 13.6% (6 of 44 patients) among the study population with no significant difference in refractory or intolerant patients. Conclusions Adherence to guideline recommendations of high dose fluconazole, alone or in combination with other antifungals, was safe and often effective for salvage therapy of HIV-uninfected CM patients.

Disseminated cryptococcosis in children is a classic affliction associated with human immunodeficiency virus (HIV) infection or primary inherited immunodeficiency disorders (PID) with central nervous system being the most common site of dissemination. We report a rare case of disseminated cryptococcosis in an 11-year-old girl who presented with pulmonary involvement, hepatosplenomegaly, and generalized lymphadenopathy. No known inherited or acquired immune deficiencies were identified after a comprehensive laboratory work-up including genetic sequencing. She responded well to anti-fungal therapy (flucytosine and amphotericin followed by fluconazole) and is on regular follow-up.