flucytosine
Sources réglementaires consultées
Indications approuvées
- Infections sévères sensibles à Candida ou Cryptococcus, habituellement en association avec l’amphotéricine B pour limiter la résistance.
Contre-indications
Absolues
- Hypersensibilité à la flucytosine.
- Déficit complet en dihydropyrimidine déshydrogénase.
Mises en garde cliniques
- L’insuffisance rénale peut entraîner une accumulation potentiellement mortelle ; surveiller la fonction rénale, la numération, la fonction hépatique et les concentrations avant et pendant le traitement. Des concentrations supérieures à 100 microgrammes/ml sont associées à une toxicité accrue. — DailyMed, set_id 01d874f9-e073-4092-94ad-da361551d4bf
- Elle peut provoquer leucopénie, thrombopénie, agranulocytose, aplasie médullaire et hépatotoxicité ; réduire ou arrêter selon la toxicité. — DailyMed, set_id 01d874f9-e073-4092-94ad-da361551d4bf
Interactions médicamenteuses
- ModéréeAmphotéricine B
Mécanisme: L’association améliore l’activité mais peut augmenter la toxicité rénale et l’exposition à la flucytosine.
Recommandation: Utiliser l’association sous surveillance rénale, hématologique et pharmacologique.
DailyMed, set_id 01d874f9-e073-4092-94ad-da361551d4bf
Effets indésirables
Communs (≥1%)
Nausées, vomissements, diarrhée, éruption et élévation des enzymes hépatiques
Rares mais graves
Aplasie médullaire, agranulocytose, thrombopénie sévère et hépatotoxicité
Grossesse et allaitement
Utiliser pendant la grossesse uniquement si le bénéfice l’emporte sur le risque. Décider d’interrompre soit l’allaitement, soit le traitement.
Bibliographie récente (PubMed)
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. 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. 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 log10 colony-forming units (CFU) per milliliter per day in the liposomal amphotericin B group and -0.42 log10 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%). Single-dose liposomal amphotericin B combined with flucytosine and fluconazole was noninferior to the WHO-recommended treatment for HIV-assoc
Cryptococcus neoformans and Cryptococcus gattii species complexes cause meningoencephalitis with high fatality rates and considerable morbidity, particularly in persons with deficient T cell-mediated immunity, most commonly affecting people living with HIV. Whereas the global incidence of HIV-associated cryptococcal meningitis (HIV-CM) has decreased over the past decade, cryptococcosis still accounts for one in five AIDS-related deaths globally due to the persistent burden of advanced HIV disease. Moreover, mortality remains high (~50%) in low-resource settings. The armamentarium to decrease cryptococcosis-associated mortality is expanding: cryptococcal antigen screening in the serum and pre-emptive azole therapy for cryptococcal antigenaemia are well established, whereas enhanced pre-emptive combination treatment regimens to improve survival of persons with cryptococcal antigenaemia are in clinical trials. Short courses (≤7 days) of amphotericin-based therapy combined with flucytosine are currently the preferred options for induction therapy of cryptococcal meningitis. Whether short-course induction regimens improve long-term morbidity such as depression, reduced neurocognitive performance and physical disability among survivors is the subject of further study. Here, we discuss underlying immunology, changing epidemiology, and updates on the management of cryptococcal meningitis with emphasis on HIV-associated disease.
CNS candidiasis typically occurs in patients with candidemia, especially immunocompromised hosts or patients with neurosurgical CNS devices. The gold standard for diagnosis is identification of Candida growth in CSF culture. For initial treatment, liposomal amphotericin B with or without flucytosine is recommended. If the isolate is susceptible to initial treatment, fluconazole is added. When possible, CNS devices should be removed. Autosomal recessive CARD9 deficiency is a primary immunodeficiency disorder associated with chronic mucocutaneous or invasive candidiasis, especially drug-resistant or recurrent candidal meningitis. In patients presenting with primary candidal meningitis in the absence of known immunodeficiency, CARD9 deficiency should be considered. A history of chronic mucocutaneous candidiasis provides an important diagnostic clue.
Cryptococcal meningitis is a leading cause of morbidity and mortality globally, especially in people with advanced HIV disease. Cryptococcal meningitis is responsible for nearly 20% of all deaths related to advanced HIV disease, with the burden of disease predominantly experienced by people in resource-limited countries. Major advancements in diagnostics have introduced low-cost, easy-to-use antigen tests with remarkably high sensitivity and specificity. These tests have led to improved diagnostic accuracy and are essential for screening campaigns to reduce the burden of cryptococcosis. In the last 5 years, several high-quality, multisite clinical trials have led to innovations in therapeutics that have allowed for simplified regimens, which are better tolerated and result in less intensive monitoring and management of medication adverse effects. One trial found that a shorter, 7-day course of deoxycholate amphotericin B is as effective as the longer 14-day course and that flucytosine is an essential partner drug for reducing mortality in the acute phase of disease. Single-dose liposomal amphotericin B has also been found to be as effective as a 7-day course of deoxycholate amphotericin B. These findings have allowed for simpler and safer treatment regimens that also reduce the burden on the healthcare system. This review provides a detailed discussion of the latest evidence guiding the clinical management and special circumstances that make cryptococcal meningitis uniquely difficult to treat.
Pulmonary cryptococcosis describes an invasive lung mycosis caused by Cryptococcus neoformans or Cryptococcus gattii complex. It is often a high-consequence disease in both immunocompromised and immunocompetent populations, and may be misdiagnosed as pulmonary malignancy, leading to a delay in therapy. Epidemiology follows that of cryptococcal meningoencephalitis, with C. gattii infection more common in certain geographic regions. Diagnostic tools include histopathology, microscopy and culture, and the detection of cryptococcal polysaccharide antigen or Cryptococcus-derived nucleic acids. All patients with lung cryptococcosis should have a lumbar puncture and cerebral imaging to exclude central nervous system disease. Radiology is key, both as an adjunct to laboratory testing and as the initial means of detection in asymptomatic patients or those with non-specific symptoms. Pulmonary cryptococcomas (single or multiple) may also be associated with disseminated disease and/or cryptococcal meningitis, requiring prolonged treatment regimens. Optimal management for severe disease requires extended induction (amphotericin B and flucytosine) and consolidation therapy (fluconazole) with close clinical monitoring. Susceptibility testing is of value for epidemiology and in regions where relatively high minimum inhibitory concentrations to azoles (particularly fluconazole) have been noted. Novel diagnostic tools and therapeutic agents promise to improve the detection and treatment of cryptococcosis, particularly in low-income settings where the disease burden is high.