Flucytosine and cryptococcosis: time to urgently address the worldwide accessibility of a 50-year-old antifungal.

Current, widely accepted guidelines for the management of HIV-associated cryptococcal meningoencephalitis (CM) recommend amphotericin B combined with flucytosine (5-FC) for ≥2 weeks as the initial induction treatment of choice. However, access to flucytosine in Africa and Asia, where disease burden is greatest, is inadequate at present. While research into identifying effective and well-tolerated antifungal combinations that do not contain flucytosine continues, an ever-increasing body of evidence from in vitro, in vivo and clinical studies points to the benefits of flucytosine in the treatment of CM in both intravenous combinations with amphotericin B and oral combinations with high-dose fluconazole. This article provides an up-to-date review of this evidence, and the current issues and challenges regarding increasing access to this key component of combination antifungal therapy for cryptococcosis

Determinants of Disease Presentation and Outcome during Cryptococcosis: The CryptoA/D Study

BACKGROUND: Cryptococcosis is a life-threatening opportunistic fungal infection in both HIV-positive and -negative patients. Information on clinical presentation and therapeutic guidelines, derived mostly from clinical trials performed before introduction of highly active antiretroviral therapy in patients with cryptococcal meningoencephalitis, is missing data on extrameningeal involvement and infections by serotype D as opposed to serotype A of Cryptococcus neoformans. METHODS AND FINDINGS: The prospective multicenter study CryptoA/D was designed in France (1997–2001) to analyse the factors influencing clinical presentation and outcome without the bias of inclusion into therapeutic trials. Of the 230 patients enrolled, 177 (77%) were HIV-positive, 50 (22%) were female, and 161 (72.5%) were infected with serotype A. Based on culture results at baseline, cryptococcosis was more severe in men, in HIV-positive patients, and in patients infected with serotype A. Factors independently associated with mycological failure at week 2 independent of HIV status were initial dissemination (OR, 2.4 [95% confidence interval (CI), 1.2–4.9]), high (>1:512) serum antigen titre (OR, 2.6 [1.3–5.4]), and lack of flucytosine during induction therapy (OR, 3.8 [1.9–7.8]). The three-month survival was shorter in patients with abnormal neurology or brain imaging at baseline, and in those with haematological malignancy. CONCLUSIONS: Thus sex, HIV status, and infecting serotype are major determinants of presentation and outcome during cryptococcosis. We propose a modification of current guidelines for the initial management of cryptococcosis based on systematic fungal burden evaluation

Cryptococcal meningitis in HIV-infected patients: a longitudinal study in Cambodia.

To describe the frequency of diagnosis of cryptococcosis among HIV-infected patients in Phnom Penh, Cambodia, at programme entry, to investigate associated risk factors, and to determine the incidence of cryptococcal meningitis

Recent advances in managing HIV-associated cryptococcal meningitis

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

Comparison of albicans vs. non-albicans candidemia in French intensive care units

The AmarCand Study Group (ICU physicians): Drs. Allaouchiche (Lyon), Amigues (Montpellier), Ausseur (Saint Herblain), Azoulay (Paris), Badet (Lyon), Baldesi (Aix-en-Provence), Bastien (Bron), Baudin (Paris), Bayle (Lyon), Bazin (Clermont-Ferrand), Benayoun (Clichy), Blondeau (Roubaix), Bodin (Paris), Bollaert (Nancy), Bonadona (La Tronche), Bonnaire (Aulnay Sous Bois), Bonnivard (Montauban), Borne (Paris), Brabet (Montpellier), Branche (Lyon), Braud (Rouen), Bret (Lyon), Bretonnière (Nantes), Brocas (Evry), Brun (Bron), Bruneel (Versailles), Canevet (Armentières), Cantais (Toulon Armées), Carlet (Paris), Charbonneau (Caen), Charles (Dijon), Chastagner (Chamberry), Corne (Montpellier), Courte (Saint-Brieuc), Cousson (Reims), Cren (Morlaix), Diconne (Saint Etienne), Drouet (Saint-Denis), Dube (Angers), Duguet (Paris), Dulbecco (Antibes), Dumenil (Clamart), Dupont (Amiens), Durand (Grenoble), Durand-Gasselin (Toulon), Durocher (Lille), Fangio (Poissy), Fattouh (Mulhouse), Favier (Metz Armées), Fieux (Paris), Fleureau (Pessac), Freys (Strasbourg), Fulgencio (Paris), Gally (Mulhouse), Garnaud (Orléans), Garot (Tours), Gilhodes (Créteil), Girault (Rouen), Gouin (Marseille), Gouin (Rouen), Guidon (Marseille), Hérault (Grenoble), Hyvernat (Nice), Jobard (Monaco), Jospe (Saint Etienne), Kaidomar (Fréjus), Karoubi (Bobigny), Kherchache (Agen), Lacherade (Poissy), Lakermi (Paris), Lambiotte (Maubeuge), Lamia (Le Kremlin-Bicêtre), Lasocki (Paris), Launoy (Strasbourg), Le Guillou (Paris), Lefort (Saint-Denis), Lefrant (Nîmes), Lemaire (Roubaix), Lepape (Pierre-Bénite), Lepoutre (Lomme), Leroy (Lille), Leroy (Tourcoing), Loriferne (Bry-sur-Marne), Mahe (Nantes), Mandin (Gap), Marighy (Saint- Denis), Mathieu (Lille), Mathonnet (Paris), Megarbane (Paris), Mercat (Angers), Michel (Saint Herblain), Michelet (Marseille), Mimoz (Poitiers), Mohammedi (Lyon), Mouquet (Paris), Mourvillier (Paris), Navellou (Besançon), Novara (Paris), Obadia (Montreuil), Perrigault (Montpellier), Perrin (Marseille), Petit (Valence), Poussel (Metz), Rahmani (Strasbourg), Renard (La Roche sur Yon), Robert (Poitiers), Robert (Lyon), Saliba (Villejuif ), Sannini (Marseille), Santré (Annecy), Seguin (Rennes), Souweine (Clermont-Ferrand), Trouillet (Paris), Valentin (Besançon), Volatron (Rennes), Voltz (Vandoeuvre les Nancy), Winer (Saint Pierre), and Winnock (Bordeaux).International audienceINTRODUCTION: Candidemia raises numerous therapeutic issues for intensive care physicians. Epidemiological data that could guide the choice of initial therapy are still required. This analysis sought to compare the characteristics of intensive care unit (ICU) patients with candidemia due to non-albicans Candida species with those of ICU patients with candidemia due to Candida albicans. METHODS: A prospective, observational, multicenter, French study was conducted from October 2005 to May 2006. Patients exhibiting candidemia developed during ICU stay and exclusively due either to one or more non-albicans Candida species or to C. albicans were selected. The data collected included patient characteristics on ICU admission and at the onset of candidemia. RESULTS: Among the 136 patients analyzed, 78 (57.4%) had candidemia caused by C. albicans. These patients had earlier onset of infection (11.1 +/- 14.2 days after ICU admission vs. 17.4 +/- 17.7, p = 0.02), higher severity scores on ICU admission (SOFA: 10.4 +/- 4.7 vs. 8.6 +/- 4.6, p = 0.03; SAPS II: 57.4 +/- 22.8 vs. 48.7 +/- 15.5, P = 0.015), and were less often neutropenic (2.6% vs. 12%, p = 0.04) than patients with candidemia due to non-albicans Candida species. CONCLUSIONS: Although patients infected with Candida albicans differed from patients infected with non-albicans Candida species for a few characteristics, no clinical factor appeared pertinent enough to guide the choice of empirical antifungal therapy in ICU

Major Role for Amphotericin B–Flucytosine Combination in Severe Cryptococcosis

BACKGROUND: The Infectious Diseases Society of America published in 2000 practical guidelines for the management of cryptococcosis. However, treatment strategies have not been fully validated in the various clinical settings due to exclusion criteria during therapeutic trials. We assessed here the optimal therapeutic strategies for severe cryptococcosis using the observational prospective CryptoA/D study after analyzing routine clinical care of cryptococcosis in university or tertiary care hospitals. METHODOLOGY/PRINCIPAL FINDINGS: Patients were enrolled if at least one culture grew positive with Cryptococcus neoformans. Control of sterilization was warranted 2 weeks (Wk2) and 3 months (Mo3) after antifungal therapy onset. 208 HIV-positive or -negative adult patients were analyzed. Treatment failure (death or mycological failure) at Wk2 and Mo3 was the main outcome measured. Combination of amphotericin B+flucytosine (AMB+5FC) was the best regimen for induction therapy in patients with meningoencephalitis and in all patients with high fungal burden and abnormal neurology. In those patients, treatment failure at Wk2 was 26% in the AMB+5FC group vs. 56% with any other treatments (p<0.001). In patients treated with AMB+5FC, factors independently associated with Wk2 mycological failure were high serum antigen titer (OR [95%CI] = 4.43[1.21-16.23], p = 0.025) and abnormal brain imaging (OR = 3.89[1.23-12.31], p = 0.021) at baseline. Haematological malignancy (OR = 4.02[1.32-12.25], p = 0.015), abnormal neurology at baseline (OR = 2.71[1.10-6.69], p = 0.030) and prescription of 5FC for less than 14 days (OR = 3.30[1.12-9.70], p = 0.030) were independently associated with treatment failure at Mo3. CONCLUSION/SIGNIFICANCE: Our results support the conclusion that induction therapy with AMB+5FC for at least 14 days should be prescribed rather than any other induction treatments in all patients with high fungal burden at baseline regardless of their HIV serostatus and of the presence of proven meningoencephalitis

β-Glucan Antigenemia Assay for the Diagnosis of Invasive Fungal Infections in Patients With Hematological Malignancies: A Systematic Review and Meta-Analysis of Cohort Studies From the Third European Conference on Infections in Leukemia (ECIL-3)

This Third European Conference on Infections in Leukemia meta-analysis of high-quality hemato-oncological cohort studies shows that 2 consecutive positive 1,3-β-D-glucan assays have high specificity and both positive and negative predictive values but low sensitivity for diagnosis of invasive fungal infectio