• PET-Scanner
• biomarkers
• invasive fungal diseases therapy duration

• Humans
• Antifungal Agents/therapeutic use
• Antifungal Agents/administration & dosage
• Invasive Fungal Infections/drug therapy
• Invasive Fungal Infections/microbiology
• Immunocompromised Host
• Duration of Therapy
• Mycoses/drug therapy

• Cryptococcosis
• Fungal disease
• HIV
• Transplant

• Humans
• Cryptococcosis/diagnosis
• Cryptococcosis/drug therapy
• Cryptococcosis/epidemiology
• Cryptococcosis/microbiology
• Antifungal Agents/therapeutic use
• Cryptococcus
• Immunocompromised Host

• Antifungal Agents/pharmacology
• Microbial Sensitivity Tests
• Drug Resistance, Fungal
• Candida auris/drug effects
• Candida auris/genetics
• Candidiasis/microbiology
• Candidiasis/drug therapy
• Humans
• Models, Theoretical
• Candida/drug effects
• Candida/genetics

• 945352 EC | Horizon 2020 Framework Programme (EU Framework Programme for Research and Innovation H2020)

• Amphotericin B/pharmacology
• Amphotericin B/therapeutic use
• Antifungal Agents/pharmacology
• Antifungal Agents/therapeutic use
• HIV Protease Inhibitors/therapeutic use
• HIV Protease Inhibitors/pharmacology
• Animals
• Drug Synergism
• Cryptococcosis/drug therapy
• Humans
• Caenorhabditis elegans/microbiology
• Caenorhabditis elegans/drug effects
• Microbial Sensitivity Tests
• Cryptococcus neoformans/drug effects
• Drug Therapy, Combination
• Ritonavir/therapeutic use
• Ritonavir/pharmacology
• Cryptococcus/drug effects

• National Institutes of Health

• Cryptococcal meningitis
• Cryptococcosis
• Fungaemia
• HIV-seronegative
• Malignancy
• Solid-organ transplantation

• Humans
• France/epidemiology
• Female
• Male
• Cryptococcosis/epidemiology
• Cryptococcosis/mortality
• Middle Aged
• Adult
• Cross-Sectional Studies
• Antifungal Agents/therapeutic use
• Aged
• Flucytosine/therapeutic use
• HIV Seronegativity
• Polyenes/therapeutic use
• Young Adult
• Immunocompromised Host

• Amphotericin B
• Cryptococcosis
• Fluconazole
• Immunosuppression
• Kidney transplant recipients

• Amphotericin B
• Case report
• Choroiditis
• Cryptococcal infection
• Double filtration plasmapheresis
• Fluconazole
• Immunosuppressant
• Kidney transplant
• Solid organ transplant
• Uveitis

• Humans
• Female
• Antifungal Agents/therapeutic use
• Kidney Transplantation/adverse effects
• Cryptococcosis/diagnosis
• Cryptococcosis/drug therapy
• Cryptococcosis/microbiology
• Immunosuppressive Agents/therapeutic use
• Kidney

• Cryptococcus neoformans
• antifungal drug
• flucytosine

• HHS | NIH | National Institute of Allergy and Infectious Diseases (NIAID)

Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by adulthood, but symptomatic infection only occurs in a minority, in most cases, months or years after exposure. Disease has been described in almost all tissues, but it is the organism’s tropism for the central nervous system that results in the most devastating illness. While invasive disease can occur in the immunocompetent, the greatest burden by far is in immunocompromised individuals, particularly people living with human immunodeficiency virus (HIV), organ transplant recipients and those on glucocorticoid therapy or other immunosuppressive drugs. Clinical presentation is variable, but diagnosis is usually straightforward, with cerebrospinal fluid microscopy, culture, and antigen testing proving significantly more sensitive than diagnostic tests for other brain infections. Although disease incidence has reduced since the advent of effective HIV therapy, mortality when disease occurs remains extremely high, and has changed little in recent decades. This Therapy in Practice review is an update of a talk first given by JND at the European Congress on Clinical Microbiology and Infectious Diseases in 2019 in the Netherlands. The review contextualizes the most recently published World Health Organization (WHO) guidelines for the treatment of HIV-associated cryptococcal meningitis in terms of the data from large, randomized, controlled trials published between 1997 and 2022. We discuss the rationale for induction and maintenance therapy and the efficacy and undesirable effects of the current therapeutic armamentarium of amphotericin, flucytosine and fluconazole. We address recent research into repurposed drugs such as sertraline and tamoxifen, and potential future treatment options, including the novel antifungals fosmanogepix, efungumab and oteseconazole, and non-pharmaceutical solutions such as neurapheresis cerebrospinal fluid filtration.

• Adult
• Amphotericin B/adverse effects
• Antifungal Agents
• Fluconazole/adverse effects
• Flucytosine/therapeutic use
• Glucocorticoids/therapeutic use
• HIV Infections/drug therapy
• Humans
• Meningitis, Cryptococcal/diagnosis
• Meningitis, Cryptococcal/drug therapy
• Meningitis, Cryptococcal/microbiology
• Sertraline/therapeutic use
• Tamoxifen/therapeutic use

• Amphotericin B
• anti-fungal therapy
• aspergillosis
• post-COVID-19 mucormycosis

The multidrug-resistant Candida auris often defies treatments and presently represents a worldwide public health threat. Currently, the ergosterol-targeting Amphotericin B (AmB) and the DNA/RNA-synthesis inhibitor 5-flucytosine (5-FC) are the two main drugs available for first-line defense against life-threatening Candida auris infections. However, important aspects of their mechanisms of action require further clarification, especially regarding metabolic reactions of yeast cells. Here, we applied Raman spectroscopy empowered with specifically tailored machine-learning algorithms to monitor and to image in situ the susceptibility of two Candida auris clades to different antifungal drugs (LSEM 0643 or JCM15448T, belonging to the East Asian Clade II; and, LSEM 3673 belonging to the South African Clade III). Raman characterizations provided new details on the mechanisms of action against Candida auris Clades II and III, while also unfolding differences in their metabolic reactions to different drugs. AmB treatment induced biofilm formation in both clades, but the formed biofilms showed different structures: a dense and continuous biofilm structure in Clade II, and an extra-cellular matrix with a “fluffy” and discontinuous structure in Clade III. Treatment with 5-FC caused no biofilm formation but yeast-to-hyphal or pseudo-hyphal morphogenesis in both clades. Clade III showed a superior capacity in reducing membrane permeability to the drug through chemically tailoring chitin structure with a high degree of acetylation and fatty acids networks with significantly elongated chains. This study shows the suitability of the in situ Raman method in characterizing susceptibility and stress response of different C. auris clades to antifungal drugs, thus opening a path to identifying novel clinical solutions counteracting the spread of these alarming pathogens.

• HIV
• antifungal treatment
• cryptococcal meningitis
• cryptococcus

• MR/N006364/2 Medical Research Council
• MR/V033417/1 Medical Research Council

• Aspergillus
• Cryptococcus
• Fungal pneumonia
• Histoplasma
• Mucormycetes
• Pneumocystis

• Cryptococcosis
• Cryptococcus gattii
• Cryptococcus neoformans
• HIV/AIDS
• Immune reconstitution inflammatory syndrome (IRIS)
• Meningitis
• Solid organ transplantation

• Cryptococcus neoformans infection
• Cryptococcus-associated immune reconstitution inflammatory syndrome
• HIV infection
• infectious diseases consultation
• mortality
• solid organ transplant recipients

• Aspergillus fumigatus
• Candida glabrata
• Cryptococcus neoformans
• candidiasis
• fungicide
• mistranslation

Over the past few decades advances in modern medicine have resulted in a global increase in the prevalence of fungal infections. Particularly people undergoing organ transplants or cancer treatments with a compromised immune system are at an elevated risk for lethal fungal infections such as invasive candidiasis, aspergillosis, cryptococcosis, etc. The emergence of drug resistance in fungal pathogens poses a serious threat to mankind and it is critical to identify new targets for the development of antifungals. Calcineurin and TOR proteins are conserved across eukaryotes including pathogenic fungi. Two small molecules FK506 and rapamycin bind to FKBP12 immunophilin and the resulting complexes (FK506-FKBP12 and rapamycin-FKBP12) target calcineurin and TOR, respectively in both humans and fungi. However, due to their immunosuppressive nature these drugs in the current form cannot be used as an antifungal. To overcome this, it is important to identify key differences between human and fungal FKBP12, calcineurin, and TOR proteins which will facilitate the development of new small molecules with higher affinity toward fungal components. The current review highlights FK506/rapamycin-FKBP12 interactions with calcineurin/TOR kinase in human and fungi, and development of non-immunosuppressive analogs of FK506, rapamycin, and novel small molecules in inhibition of fungal calcineurin and TOR kinase.

• FK506
• FKBP12
• TOR
• antifungal
• calcineurin
• fungi
• rapamycin

• AIDS-related opportunistic infections
• acquired immunodeficiency syndrome
• autopsy
• cryptococcus
• meningitis

• Antigens, Fungal
• CD4 Lymphocyte Count
• Cohort Studies
• Cryptococcus
• Fluconazole/therapeutic use
• HIV Infections/complications
• Humans
• Meningitis, Cryptococcal/diagnosis
• Meningitis, Cryptococcal/drug therapy
• South Africa/epidemiology

• IIR 16-003 HSRD VA
• R01 AI118511 NIAID NIH HHS
• National Institutes of Health
• South African Medical Research Council
• National Institute for Health Research
• St George’s Hospital Research Charity
• National Institute of Allergy and Infectious Diseases
• Ratanji Dalal Research Scholarship
• South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation of South Africa
• Meningitis Research Foundation
• Bill and Melinda Gates Foundation
• Centers for Disease Control and Prevention

Central nervous system (CNS) cryptococcosis in non-HIV infected patients affects solid organ transplant (SOT) recipients, patients with malignancy, rheumatic disorders, other immunosuppressive conditions and immunocompetent hosts. More recently described risks include the use of newer biologicals and recreational intravenous drug use. Disease is caused by Cryptococcus neoformans and Cryptococcus gattii species complex; C. gattii is endemic in several geographic regions and has caused outbreaks in North America. Major virulence determinants are the polysaccharide capsule, melanin and several ‘invasins’. Cryptococcal plb1, laccase and urease are essential for dissemination from lung to CNS and crossing the blood–brain barrier. Meningo-encephalitis is common but intracerebral infection or hydrocephalus also occur, and are relatively frequent in C. gattii infection. Complications include neurologic deficits, raised intracranial pressure (ICP) and disseminated disease. Diagnosis relies on culture, phenotypic identification methods, and cryptococcal antigen detection. Molecular methods can assist. Preferred induction antifungal therapy is a lipid amphotericin B formulation (amphotericin B deoxycholate may be used in non-transplant patients) plus 5-flucytosine for 2–6 weeks depending on host type followed by consolidation/maintenance therapy with fluconazole for 12 months or longer. Control of raised ICP is essential. Clinicians should be vigilant for immune reconstitution inflammatory syndrome.

• Cryptococcosis
• Cryptococcus gattii
• Cryptococcus neoformans
• HIV-negative patients
• antifungal therapy
• central nervous system
• cerebral infection
• epidemiology
• meningo-encephalitis

• Cryptococcus
• amphotericin
• clinical therapeutics
• fungus

• antibiotic
• antifungal
• complication
• fungal
• infection and infectious agents
• infectious

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.

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.

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.

• Cryptococcal meningitis
• Diabetes
• Fluconazole
• HIV negative

Cryptococcocis is an opportunistic fungal infection with high morbidity and mortality. Guidelines to aid clinicians regarding diagnosis, management, and treatment can be extensive and challenging to comply with. There is no tool to measure guideline adherence. To create such a tool, we reviewed current guidelines from the Infectious Diseases Society of America, the World Health Organization, the American Society of Transplantation, and recent significant publications to select the strongest recommendations as vital components of our scoring tool. Items included diagnostic tests (blood, tissue, and cerebrospinal fluid cultures, Cryptococcus antigen, India ink, histopathology with special fungal stains, central nervous system imaging), pharmacological (amphotericin B, flucytosine, azoles) and nonpharmacological treatments (intracranial pressure management, immunomodulation, infectious disease consultation), and follow-up of central nervous system complications. The EQUAL Cryptococcus Score 2018 weighs and aggregates the recommendations for the optimal management of cryptococcosis. Providing a tool that could measure guideline adherence or facilitate clinical decision-making.

• Cryptococcus
• fungal infection
• guideline adherence
• score
• therapy

• Cryptococcus neoformans
• VT-1129
• cryptococcal meningitis
• in vivo efficacy
• loading dose
• maintenance dose
• murine model

• Animals
• Antifungal Agents/pharmacology
• Brain/microbiology
• Cryptococcus neoformans/drug effects
• Male
• Meningitis, Cryptococcal/drug therapy
• Meningitis, Cryptococcal/microbiology
• Mice
• Mice, Inbred ICR
• Microbial Sensitivity Tests/methods
• Pyridines/pharmacology
• Tetrazoles/pharmacology

• HHSN261200800001C NCI NIH HHS
• HHSN261200800001E NCI NIH HHS
• HHS | NIH | National Cancer Institute (NCI)

• antibiofilm material coating
• antifungal susceptibility testing
• biofilm eradication
• biofilm inhibition
• in vivo models

• R35 GM124594 NIGMS NIH HHS
• R01 DE026600 NIDCR NIH HHS
• R01 AI124566 NIAID NIH HHS
• R21 AI125801 NIAID NIH HHS
• MR/N006364/1 Medical Research Council
• Wellcome Trust
• R01 DE010641 NIDCR NIH HHS

• cryptococcus neoformans
• cryptococcal meningo-encephalitis
• cryptococcal antigen
• hiv infection
• advanced aids disease
• screening

• AIDS-Related Opportunistic Infections/diagnosis
• AIDS-Related Opportunistic Infections/drug therapy
• Antifungal Agents/administration & dosage
• Cryptococcosis/diagnosis
• Cryptococcosis/drug therapy
• Drug Therapy, Combination
• Humans
• Immunologic Tests
• Meningitis, Cryptococcal/diagnosis
• Meningitis, Cryptococcal/drug therapy

• 5-FC: flucytosine
• AmB: amphotericin B
• CM:cryptococcal meningitis
• CSF: cerebrospinal fluid
• Flu: fluconazole
• SD: standard deviation
• Triple therapy
• WBC: white blood cell
• clinical outcome
• cryptococcal meningitis
• fungal clearance

Cryptococcal meningitis is the most common central nervous system infection in the world today. It occurs primarily, but not exclusively, in immunocompromised individuals and despite substantial improvement in management of clinical events like AIDS, the numbers of cases of cryptococcosis remain very high. Unfortunately, despite several antifungal agents available for treatment, morbidity and mortality rates remain high with this fungal infection. In this Review, we will describe the treatments and strategies for success, identify the failures, and provide insights into the future developments / improvements for management. This sugar-coated yeast can play havoc within the human brain. Our goals must be to either prevent or diagnose disease early and treat aggressively with all our clinical tools when disease is detected.

• Cryptococcosis
• Cryptococcus
• Endemic mycoses
• Fungal lung infection
• Treatment

• Adult
• Cryptococcus
• Infectious Disease Consult
• Mortality
• Prognosis
• Therapy

Cryptococcosis has been one of the most common opportunistic infections and causes of mortality among HIV-infected patients, especially in resource-limited countries. Cryptococcal meningitis is the most common form of cryptococcosis. Laboratory diagnosis of cryptococcosis includes direct microscopic examination, isolation of Cryptococcus from a clinical specimen, and detection of cryptococcal antigen. Without appropriate treatment, cryptococcosis is fatal. Early diagnosis and treatment is the key to treatment success. Treatment of cryptococcosis consists of three main aspects: antifungal therapy, intracranial pressure management for cryptococcal meningitis, and restoration of immune function with antiretroviral therapy (ART). Optimal integration of these three aspects is crucial to achieving successful treatment and reducing the mortality. Antifungal therapy consists of three phases: induction, consolidation, and maintenance. A combination of two drugs, i.e. amphotericin B plus flucytosine or fluconazole, is preferred in the induction phase. Fluconazole monotherapy is recommended during consolidation and maintenance phases. In cryptococcal meningitis, intracranial pressure rises along with CSF fungal burden and is associated with morbidity and mortality. Aggressive control of intracranial pressure should be done. Management options include therapeutic lumbar puncture, lumbar drain insertion, ventriculostomy, or ventriculoperitoneal shunt. Medical treatment such as corticosteroids, mannitol, and acetazolamide are ineffective and should not be used. ART has proven to have a great impact on survival rates among HIV-infected patients with cryptococcosis. The time to start ART in HIV-infected patients with cryptococcosis has to be deferred until 5 weeks after the start of antifungal therapy. In general, any effective ART regimen is acceptable. Potential drug interactions between antiretroviral agents and amphotericin B, flucytosine, and fluconazole are minimal. Of most potential clinical relevance is the concomitant use of fluconazole and nevirapine. Concomitant use of these two drugs should be cautious, and patients should be monitored closely for nevirapine-associated adverse events, including hepatotoxicity. Overlapping toxicities of antifungal and antiretroviral drugs and immune reconstitution inflammatory syndrome are not uncommon. Early recognition and appropriate management of these consequences can reinforce the successful integrated therapy in HIV-infected patients with cryptococcosis.

• Cryptococcosis
• HIV
• Integrated therapy
• Treatment

Disseminated cryptococcal infection carries a high risk of morbidity and mortality. Typical patients include HIV individuals with advanced immunosuppression or solid organ or hematopoietic transplant recipients. We report a case of disseminated cryptococcal disease in a 72-year-old male who was immunocompromised with chronic lymphocytic leukemia and ongoing chemotherapy. The patient presented with a subacute history of constitutional symptoms and headache after he received five cycles of FCR chemotherapy (fludarabine/cyclophosphamide/rituximab). Diagnosis of disseminated cryptococcal disease was made based on fungemia in peripheral blood cultures with subsequent involvement of the brain, lungs, and eyes. Treatment was started with liposomal amphotericin, flucytosine, and fluconazole as induction. He was discharged after 4 weeks of hospitalization on high dose fluconazole for consolidation for 2 months, followed by maintenance therapy.

• Central nervous system (CNS) infection
• Cryptococcosis
• HIV/AIDS
• Immune reconstitution inflammatory syndrome (IRIS)
• Opportunistic mycoses
• Solid organ transplantation (SOT)

Recent investigations have yielded both profound insights into the mechanisms required by pathogenic fungi for virulence within the human host, as well as novel potential targets for antifungal therapeutics. Some of these studies have resulted in the identification of novel compounds that act against these pathways and also demonstrate potent antifungal activity. However, considerable effort is required to move from pre-clinical compound testing to true clinical trials, a necessary step toward ultimately bringing new drugs to market. The rising incidence of invasive fungal infections mandates continued efforts to identify new strategies for antifungal therapy. Moreover, these life-threatening infections often occur in our most vulnerable patient populations. In addition to finding completely novel antifungal compounds, there is also a renewed effort to redirect existing drugs for use as antifungal agents. Several recent screens have identified potent antifungal activity in compounds previously indicated for other uses in humans. Together, the combined efforts of academic investigators and the pharmaceutical industry is resulting in exciting new possibilities for the treatment of invasive fungal infections.

• amphotericin
• aspergillosis
• azole
• candidiasis
• cryptococcosis
• echinocandin
• flucytosine
• fungal infection
• mycosis
• polyene

• P01 AI104533 NIAID NIH HHS
• R01 AI074677 NIAID NIH HHS

• AIDS
• Cryptococcosis
• Immune reconstitution inflammatory syndrome (IRIS)
• Increased intracranial pressure
• Meningoencephalitis

• HIV
• amphotericin B
• anaemia
• cryptococcal meningitis

• AIDS
• Criptococosis meníngea
• Cryptococcal meningitis
• Cryptococcal meningoencephalitis
• Meningoencefalitis criptocócica
• Sida

Background. Amphotericin-based combination antifungal therapy reduces mortality from human immunodeficiency virus (HIV)-associated cryptococcal meningitis. However, 40%–50% of individuals have positive cerebrospinal fluid (CSF) fungal cultures at completion of 2 weeks of amphotericin induction therapy. Residual CSF culture positivity has historically been associated with poor clinical outcomes. We investigated whether persistent CSF fungemia was associated with detrimental clinical outcomes in a contemporary African cohort.

Methods. Human immunodeficiency virus-infected individuals with cryptococcal meningitis in Uganda and South Africa received amphotericin (0.7–1.0 mg/kg per day) plus fluconazole (800 mg/day) for 2 weeks, followed by “enhanced consolidation” therapy with fluconazole 800 mg/day for at least 3 weeks or until cultures were sterile, and then 400 mg/day for 8 weeks. Participants were randomized to receive antiretroviral therapy (ART) either 1–2 or 5 weeks after diagnosis and observed for 6 months. Survivors were classified as having sterile or nonsterile CSF based on 2-week CSF cultures. Mortality, immune reconstitution inflammatory syndrome (IRIS), and culture-positive relapse were compared in those with sterile or nonsterile CSF using Cox regression.

Results. Of 132 participants surviving 2 weeks, 57% had sterile CSF at 2 weeks, 23 died within 5 weeks, and 40 died within 6 months. Culture positivity was not significantly associated with mortality (adjusted 6-month hazard ratio, 1.2; 95% confidence interval, 0.6–2.3; P = .28). Incidence of IRIS or relapse was also not significantly related to culture positivity.

Conclusions. Among patients, all treated with enhanced consolidation antifungal therapy and ART, residual cryptococcal culture positivity was not found to be associated with poor clinical outcomes.

• HIV
• amphotericin
• clinical outcome
• cryptococcal meningitis

• Cryptococcus gattii
• antifungals
• immunosuppression
• organ transplantation

• Antigens, Fungal/cerebrospinal fluid
• Cryptococcosis/diagnosis
• Cryptococcosis/microbiology
• Cryptococcus gattii/classification
• Cryptococcus gattii/drug effects
• Cryptococcus gattii/immunology
• Cryptococcus gattii/isolation & purification
• Disease Outbreaks
• Female
• Fluconazole/pharmacology
• Humans
• Male
• Microbial Sensitivity Tests
• Middle Aged
• Oregon/epidemiology
• Organ Transplantation/adverse effects
• Retrospective Studies
• Transplant Recipients