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

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

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

Long term mortality and disability in Cryptococcal Meningitis: a systematic literature review.

Cryptococcal meningitis (CM) is the primary cause of meningitis in HIV-infected adults and an emerging disease in HIV-seronegative individuals. No literature review has studied the long-term outcome of CM. We performed a systematic review on the long-term (≥3 months) impact of CM (C. neoformans and C. gattii) on mortality and disability in HIV-infected and non-HIV-infected adults. Though the quality of current evidence is limited, the long-term impact of CM on survival and disability appears to be high. One-year mortality ranged from 13% in an Australian non-HIV C.gattii infected cohort to 78% in a Malawian HIV-infected cohort treated with fluconazole monotherapy. One-year impairment proportions among survivors ranged from 19% in an Australian C.gattii cohort to more than 70% in a Taiwanese non-HIV and HIV-infected cohorts. Ongoing early therapeutic interventions, early detection of impairments and access to rehabilitation services may significantly improve patients' survival and quality of life

Impact of routine cryptococcal antigen screening and targeted pre-emptive fluconazole therapy in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL: a systematic review and meta-analysis.

Cryptococcal antigen (CrAg) screening and targeted pre-emptive fluconazole in antiretroviral naive HIV-infected adults with less than 100 CD4 cells/μL seems promising to reduce the burden of cryptococcal meningitis (CM). We searched MEDLINE, EMBASE, and Web of Science and used random-effect meta-analysis to assess the prevalence of blood CrAg-positivity (31 studies; 35,644 participants) and asymptomatic CM in CrAg-positives, incidence of CM and all-cause mortality in screened participants. Pooled prevalence of blood CrAg-positivity was 6% (95%CI: 5 - 7) and asymptomatic CM in CrAg-positives was 33% (95%CI: 21 - 45). Incidence of CM without pre-emptive fluconazole was 21.4% (95%CI: 11.6 - 34.4) and 5.7% (95%CI: 3.0 - 9.7) with pre-emptive fluconazole initiated at 800 mg/day. In CrAg-positives, post-screening lumbar puncture prior to initiating pre-emptive fluconazole at 800 mg/day further reduced incidence of CM to null and showed some survival benefits. However, all-cause mortality remained significantly higher in CrAg-positives than CrAg-negatives: RR: 2.2 (95%CI: 1.7 - 2.9, p<0.001)

The incidence of tuberculosis in patients treated with certolizumab pegol across indications: impact of baseline skin test results, more stringent screening criteria and geographic region

Objectives We report the incidence of tuberculosis (TB) across certolizumab pegol (CZP) clinical trials in rheumatoid arthritis (RA), psoriasis, psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), before and after the introduction of stricter TB screening. Methods TB incidence rates (IRs) were assessed and stratified according to screening guidelines used at the time of CZP trials. Before 2007 (original trials), purified protein derivative (PPD) tuberculin skin test positivity varied according to local standards (induration ≥5 up to ≥20 mm). Since 2007, all CZP trial protocols have been amended, including trials spanning (intermediate) and initiated after 2007 (current), mandating that any patient with PPD≥5 mm receives treatment for latent TB infection (LTBI). All cases of suspected TB or PPD≥5 mm, in pooled data from 5402 CZP patients across all CZP trials up to 2012, underwent blinded central review by independent experts. Results 44 TB cases were confirmed in pooled CZP RA trials (IR 0.47/100PY, patient-years) with no cases in Japanese RA trials (J-RAPID, HIKARI). Single TB cases were confirmed in psoriasis and axSpA trials (RAPID-axSpA), and no cases in the PsA trial (RAPID-PsA). IR of TB was 0.51/100PY across original or intermediate RA trials and 0.18/100PY in current trials. The majority of TB cases in RA occurred in Eastern (IR 1.02/100PY) and Central Europe (IR 0.58/100PY). Of 242/370 PPD≥5 mm patients who received 9 months isoniazid (INH) treatment for latent TB infection (LTBI), none developed TB, versus 7.8% of 128 untreated PPD≥5 mm patients. Conclusions Implementation of more stringent LTBI screening, plus treatment for LTBI, reduced the IR of TB, even when INH was administered after starting CZP therapy.This study was funded by UCB PharmaS

Evidence of triggered star formation in G327.3-0.6. Dust-continuum mapping of an infrared dark cloud with P-ArT\'eMiS

Aims. Expanding HII regions and propagating shocks are common in the environment of young high-mass star-forming complexes. They can compress a pre-existing molecular cloud and trigger the formation of dense cores. We investigate whether these phenomena can explain the formation of high-mass protostars within an infrared dark cloud located at the position of G327.3-0.6 in the Galactic plane, in between two large infrared bubbles and two HII regions. Methods: The region of G327.3-0.6 was imaged at 450 ? m with the CEA P-ArT\'eMiS bolometer array on the Atacama Pathfinder EXperiment telescope in Chile. APEX/LABOCA and APEX-2A, and Spitzer/IRAC and MIPS archives data were used in this study. Results: Ten massive cores were detected in the P-ArT\'eMiS image, embedded within the infrared dark cloud seen in absorption at both 8 and 24 ?m. Their luminosities and masses indicate that they form high-mass stars. The kinematical study of the region suggests that the infrared bubbles expand toward the infrared dark cloud. Conclusions: Under the influence of expanding bubbles, star formation occurs in the infrared dark areas at the border of HII regions and infrared bubbles.Comment: 4 page

Plasmodium falciparum malaria and Parvovirus B19; a case of acute co-infection

<p>Abstract</p> <p>Background</p> <p>Co-infection with Plasmodium falciparum malaria and Parvovirus B19 in adults is an extremely rare occurrence and, apparently, only one case has been previously reported. Herein we describe a case of acute co-infection with severe anemia and renal failure.</p> <p>Case presentation</p> <p>The patient was a 34-year-old African man presenting myalgia, fatigue, headache, anemia and hepatosplenomegaly. A thin peripheral smear showed Plasmodium falciparum trophozoites and the patient was treated with oral mefloquine. After an initial amelioration, fever, fatigue and myalgia reappeared, the anemia worsened and there was evidence of acute renal failure. No malarial parasites were found with a blood smear. A bone marrow aspiration showed marked erythroid hypoplasia. Parvovirus B19-specific IgM and IgG and viremia were positive. The patient was treated with steroids and blood cell transfusions. After ten days, anemia and renal failure progressively decreased. When last seen, the patient was asymptomatic and the blood values were within the normal range.</p> <p>Conclusions</p> <p>The diagnosis of Parvovirus B19 acute infection should be considered in any case of persistent severe anemia and/or renal failure, even in clinical conditions that are well-known causes of anemia and renal failure, such as malaria.</p