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Clinical Microbiology and Infection :... May 2018The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint...
The European Society for Clinical Microbiology and Infectious Diseases, the European Confederation of Medical Mycology and the European Respiratory Society Joint Clinical Guidelines focus on diagnosis and management of aspergillosis. Of the numerous recommendations, a few are summarized here. Chest computed tomography as well as bronchoscopy with bronchoalveolar lavage (BAL) in patients with suspicion of pulmonary invasive aspergillosis (IA) are strongly recommended. For diagnosis, direct microscopy, preferably using optical brighteners, histopathology and culture are strongly recommended. Serum and BAL galactomannan measures are recommended as markers for the diagnosis of IA. PCR should be considered in conjunction with other diagnostic tests. Pathogen identification to species complex level is strongly recommended for all clinically relevant Aspergillus isolates; antifungal susceptibility testing should be performed in patients with invasive disease in regions with resistance found in contemporary surveillance programmes. Isavuconazole and voriconazole are the preferred agents for first-line treatment of pulmonary IA, whereas liposomal amphotericin B is moderately supported. Combinations of antifungals as primary treatment options are not recommended. Therapeutic drug monitoring is strongly recommended for patients receiving posaconazole suspension or any form of voriconazole for IA treatment, and in refractory disease, where a personalized approach considering reversal of predisposing factors, switching drug class and surgical intervention is also strongly recommended. Primary prophylaxis with posaconazole is strongly recommended in patients with acute myelogenous leukaemia or myelodysplastic syndrome receiving induction chemotherapy. Secondary prophylaxis is strongly recommended in high-risk patients. We strongly recommend treatment duration based on clinical improvement, degree of immunosuppression and response on imaging.
Topics: Antibodies, Fungal; Antifungal Agents; Aspergillosis; Aspergillus; Biopsy; Bronchoalveolar Lavage; Disease Management; Early Diagnosis; Flucytosine; Galactose; Humans; Immunocompromised Host; Immunologic Tests; Invasive Pulmonary Aspergillosis; Itraconazole; Leukemia, Myeloid, Acute; Magnetic Resonance Imaging; Mannans; Microbial Sensitivity Tests; Myelodysplastic Syndromes; Nitriles; Pyridines; Tomography, X-Ray Computed; Triazoles; Voriconazole
PubMed: 29544767
DOI: 10.1016/j.cmi.2018.01.002 -
The New England Journal of Medicine Mar 2022Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Cryptococcal meningitis is a leading cause of human immunodeficiency virus (HIV)-related death in sub-Saharan Africa. Whether a treatment regimen that includes a single high dose of liposomal amphotericin B would be efficacious is not known.
METHODS
In this phase 3 randomized, controlled, noninferiority trial conducted in five African countries, we assigned HIV-positive adults with cryptococcal meningitis in a 1:1 ratio to receive either a single high dose of liposomal amphotericin B (10 mg per kilogram of body weight) on day 1 plus 14 days of flucytosine (100 mg per kilogram per day) and fluconazole (1200 mg per day) or the current World Health Organization-recommended treatment, which includes amphotericin B deoxycholate (1 mg per kilogram per day) plus flucytosine (100 mg per kilogram per day) for 7 days, followed by fluconazole (1200 mg per day) for 7 days (control). The primary end point was death from any cause at 10 weeks; the trial was powered to show noninferiority at a 10-percentage-point margin.
RESULTS
A total of 844 participants underwent randomization; 814 were included in the intention-to-treat population. At 10 weeks, deaths were reported in 101 participants (24.8%; 95% confidence interval [CI], 20.7 to 29.3) in the liposomal amphotericin B group and 117 (28.7%; 95% CI, 24.4 to 33.4) in the control group (difference, -3.9 percentage points); the upper boundary of the one-sided 95% confidence interval was 1.2 percentage points (within the noninferiority margin; P<0.001 for noninferiority). Fungal clearance from cerebrospinal fluid was -0.40 log colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log CFU per milliliter per day in the control group. Fewer participants had grade 3 or 4 adverse events in the liposomal amphotericin B group than in the control group (50.0% vs. 62.3%).
CONCLUSIONS
Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-associated cryptococcal meningitis and was associated with fewer adverse events. (Funded by the European and Developing Countries Clinical Trials Partnership and others; Ambition ISRCTN number, ISRCTN72509687.).
Topics: AIDS-Related Opportunistic Infections; Administration, Oral; Africa South of the Sahara; Amphotericin B; Antifungal Agents; Drug Administration Schedule; Drug Therapy, Combination; Fluconazole; Flucytosine; HIV Infections; Meningitis, Cryptococcal
PubMed: 35320642
DOI: 10.1056/NEJMoa2111904 -
Drugs Aug 2022Cryptococcal meningitis is a devastating brain infection cause by encapsulated yeasts of the Cryptococcus genus. Exposure, through inhalation, is likely universal by... (Review)
Review
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.
Topics: Adult; Amphotericin B; Antifungal Agents; Fluconazole; Flucytosine; Glucocorticoids; HIV Infections; Humans; Meningitis, Cryptococcal; Sertraline; Tamoxifen
PubMed: 36112342
DOI: 10.1007/s40265-022-01757-5 -
BMJ Case Reports Apr 2014A 52-year-old man with a history of HIV (CD4 count 155, and viral load 154 K), who is on antiretroviral treatment presented in the emergency room with acute onset of...
A 52-year-old man with a history of HIV (CD4 count 155, and viral load 154 K), who is on antiretroviral treatment presented in the emergency room with acute onset of headache. The patient had lumbar puncture and found to have elevated intracranial pressure and cryptococcal antigen was positive. The patient was started on flucytosine. After 10 days of treatment, the patient developed watery diarrhoea. An extensive infectious workup was carried out, which did not reveal any infectious aetiology. A colonoscopy was carried out which revealed acute colitis in the colon and the pathology confirmed the colonoscopic findings with severe colitis in the colon. At this time, the patient's diarrhoea was attributed to flucytosine and it was stopped. The patient's diarrhoea improved after 5 days of stopping flucytosine.
Topics: Antifungal Agents; Colitis; Diagnosis, Differential; Diarrhea; Flucytosine; HIV Infections; Humans; Immunocompromised Host; Male; Meningitis, Cryptococcal; Middle Aged
PubMed: 24777084
DOI: 10.1136/bcr-2013-203381 -
Clinical Infectious Diseases : An... Dec 2023Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed. (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Amphotericin B is the gold standard treatment for severe mycoses. A new orally delivered, less-toxic formulation of amphotericin has been developed.
METHODS
In our randomized clinical trial, we tested oral lipid nanocrystal (LNC) amphotericin B (MAT2203, Matinas Biopharma) vs intravenous (IV) amphotericin for human immunodeficiency virus-associated cryptococcal meningitis in 4 sequential cohorts. Two pilot cohorts assessed safety and tolerability (n = 10 each), and 2 cohorts assessed efficacy with/without 2 IV loading doses (n = 40 each). The experimental arm received 1.8 g/d oral LNC amphotericin through 2 weeks with 100 mg/kg/d flucytosine, then 1.2 g/d LNC amphotericin through 6 weeks. The randomized control arm (n = 41) received 7 days of IV amphotericin with flucytosine, then 7 days of fluconazole 1200 mg/d. The primary end point was cerebrospinal fluid (CSF) early fungicidal activity (EFA).
RESULTS
We randomized 80 participants to oral LNC amphotericin + flucytosine with (n = 40) and without (n = 40) 2 IV loading doses and 41 control participants to IV amphotericin + flucytosine. Mean EFA was 0.40 log10 colony-forming units (CFU)/mL/d for all-oral LNC amphotericin, 0.42 log10 Cryptococcus CFU/mL/d for oral LNC amphotericin with IV loading doses, and 0.46 log10 CFU/mL/d for IV amphotericin controls. LNC amphotericin groups achieved 2-week CSF sterility in 63% (44 of 70) vs 68% (23 of 34) of controls. The 18-week survival was 85% (34 of 40) with all-oral LNC amphotericin, 90% (36 of 40) with oral LNC amphotericin given IV loading doses, and 85% (35 of 41) with IV amphotericin.Grade 3-4 laboratory adverse events occurred less frequently in LNC amphotericin groups (41%) than the IV amphotericin group (61%, P = .05), particularly for anemia (21% vs 44%; P = .01) and potassium (5% vs 17%; P = .04).
CONCLUSIONS
This new oral amphotericin B LNC formulation appears promising for cryptococcal meningitis with antifungal activity, similar survival, and less toxicity than IV amphotericin.
CLINICAL TRIALS REGISTRATION
NCT04031833.
Topics: Humans; Meningitis, Cryptococcal; Amphotericin B; Flucytosine; Drug Therapy, Combination; Antifungal Agents; Fluconazole; Vaccines; Lipids
PubMed: 37606364
DOI: 10.1093/cid/ciad440 -
British Medical Journal Jul 1975A patient was admitted to hospital with an apparent psychiatric disturbance. When she became stuporous the cerebrospinal fluid was cultured but proved sterile. The latex...
A patient was admitted to hospital with an apparent psychiatric disturbance. When she became stuporous the cerebrospinal fluid was cultured but proved sterile. The latex test showed that serum was positive for cryptococcal antigens, and cryptococcal meningoencephalitis was diagnosed. Amphotericin B was given but when she developed a toxic reaction it was replaced by flucytosine. She responded well to flucytosine alone and no side effects appeared on continued treatment. Cryptococcal meningitis may present as a psychiatric disturbance, and serological tests are invaluable aids to diagnosis.
Topics: Adult; Cerebrospinal Fluid; Cryptococcosis; Cryptococcus neoformans; Female; Flucytosine; Humans; Latex Fixation Tests; Meningoencephalitis; Mental Disorders
PubMed: 1095135
DOI: 10.1136/bmj.3.5975.75 -
Cold Spring Harbor Perspectives in... Nov 2014Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including... (Review)
Review
Successful treatment of infectious diseases requires choice of the most suitable antimicrobial agent, comprising consideration of drug pharmacokinetics (PK), including penetration into infection site, pathogen susceptibility, optimal route of drug administration, drug dose, frequency of administration, duration of therapy, and drug toxicity. Antimicrobial pharmacokinetic/pharmacodynamic (PK/PD) studies consider these variables and have been useful in drug development, optimizing dosing regimens, determining susceptibility breakpoints, and limiting toxicity of antifungal therapy. Here the concepts of antifungal PK/PD studies are reviewed, with emphasis on methodology and application. The initial sections of this review focus on principles and methodology. Then the pharmacodynamics of each major antifungal drug class (polyenes, flucytosine, azoles, and echinocandins) is discussed. Finally, the review discusses novel areas of pharmacodynamic investigation in the study and application of combination therapy.
Topics: Animals; Antifungal Agents; Disease Models, Animal; Echinocandins; Flucytosine; Humans; Mice; Mycoses; Polyenes; Rabbits; Rats; Triazoles
PubMed: 25384765
DOI: 10.1101/cshperspect.a019653 -
Revista Da Sociedade Brasileira de... 2023There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an... (Review)
Review
There is a consensus that the antifungal repertoire for the treatment of cryptococcal infections is limited. Standard treatment involves the administration of an antifungal drug derived from natural sources (i.e., amphotericin B) and two other drugs developed synthetically (i.e., flucytosine and fluconazole). Despite treatment, the mortality rates associated with fungal cryptococcosis are high. Amphotericin B and flucytosine are toxic, require intravenous administration, and are usually unavailable in low-income countries because of their high cost. However, fluconazole is cost-effective, widely available, and harmless with regard to its side effects. However, fluconazole is a fungistatic agent that has contributed considerably to the increase in fungal resistance and frequent relapses in patients with cryptococcal meningitis. Therefore, there is an unquestionable need to identify new alternatives or adjuvants to conventional drugs for the treatment of cryptococcosis. A potential antifungal agent should be able to kill cryptococci and "bypass" the virulence mechanism of the yeast. Furthermore, it should have fungicidal action, low toxicity, high selectivity, easily penetrate the central nervous system, and widely available. In this review, we describe cryptococcosis, its conventional therapy, and failures arising from the use of drugs traditionally considered to be the reference standard. Additionally, we present the approaches used for the discovery of new drugs to counteract cryptococcosis, ranging from the conventional screening of natural products to the inclusion of structural modifications to optimize anticryptococcal activity, as well as drug repositioning and combined therapies.
Topics: Humans; Antifungal Agents; Amphotericin B; Flucytosine; Fluconazole; Cryptococcosis; Cryptococcus neoformans
PubMed: 37493736
DOI: 10.1590/0037-8682-0121-2023 -
F1000Research 2019The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes.... (Review)
Review
The recent development of highly sensitive and specific point-of-care tests has made it possible to diagnose HIV-associated cryptococcal meningitis within minutes. However, diagnostic advances have not been matched by new antifungal drugs and treatment still relies on old off-patent drugs: amphotericin B, flucytosine and fluconazole. Cryptococcal meningitis treatment is divided in three phases: induction, consolidation and maintenance. The induction phase, aimed at drastically reducing cerebrospinal fluid fungal burden, is key for patient survival. The major challenge in cryptococcal meningitis management has been the optimisation of induction phase treatment using the limited number of available medications, and major progress has recently been made. In this review, we summarise data from key trials which form the basis of current treatment recommendations for HIV-associated cryptococcal meningitis.
Topics: Amphotericin B; Antifungal Agents; Fluconazole; Flucytosine; HIV Infections; Humans; Meningitis, Cryptococcal
PubMed: 31275560
DOI: 10.12688/f1000research.17673.1 -
CMAJ : Canadian Medical Association... Apr 2021
Topics: Amphotericin B; Anti-Bacterial Agents; Brain; Cryptococcus neoformans; Female; Flucytosine; Humans; Kidney Transplantation; Magnetic Resonance Imaging; Meningitis, Cryptococcal; Middle Aged; Piperacillin, Tazobactam Drug Combination; Pneumonia; Polycystic Kidney Diseases; Treatment Outcome
PubMed: 33875468
DOI: 10.1503/cmaj.200825-f