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

Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals(1,2) and 44% of deaths in a cohort of HIV-seropositive South African miners.(3) This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.(4,6) In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to. use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced! More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.(8) We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible

Treatment of HIV-associated cryptococcal meningitis in South Africa: The case for amphotericin B over conventional dose fluconazole for initial therapy

Cryptococcal meningitis is a major cause of morbidity and mortality in African AIDS patients, accounting for between 13% and 17% of deaths in Ugandan HIV-infected individuals1,2 and 44% of deaths in a cohort of HIV-seropositive South African miners.3 This burden of disease is a result of high incidence, especially in southern and East Africa, and high acute mortality.4-6 In much of Africa, fluconazole rather than amphotericin B was, and still is, widely used as initial therapy, for a variety of reasons. These include the availability of fluconazole through free access programmes and in generic form, and the attractiveness of an easy to use, safe oral regimen over a difficult to administer intravenous drug with significant side-effects, requiring inpatient admission and close laboratory monitoring. In addition, in the absence of antiretroviral therapy, treatment of cryptococcal meningitis has in the recent past been palliative rather than curative, reducing the rationale for more aggressive therapy, if this is associated with increased side-effects. However, what data there are suggest that outcomes with fluconazole at conventional dosage (up to 400 mg/d) as initial therapy are poor. In addition, the cost of amphotericin B, previously considerable in South Africa, has been reduced.7 More importantly, increasing access to antiretroviral therapy (ART) now means that the long-term prognosis of patients with cryptococcal meningitis is good, provided they survive the acute infection.8 We summarise the evidence that a factor contributing to high acute mortality in cryptococcal meningitis is the inadequacy of fluconazole at up to 400 mg/d as an induction regimen, and present the case for initial treatment with amphotericin B in South Africa, where feasible. Southern African Journal of HIV Medicine Vol. 8 (3) 2007: pp. 36-3

The Stability of Polar Oxide Surfaces

The structures of the polar surfaces of ZnO are studied using ab initio calculations and surface x-ray diffraction. The experimental and theoretical relaxations are in good agreement. The polar surfaces are shown to be very stable; the cleavage energy for the (0001)-Zn and (0001̅ )-O surfaces is 4.0J/m2 comparable to 2.32J/m2 for the most stable nonpolar (1010) surface. The surfaces are stabilized by an electronic mechanism involving the transfer of 0.17 electrons between them. This leads to 2D metallic surface states, which has implications for the use of the material in gas sensing and catalytic applications

Fungal infections in HIV/AIDS.

Fungi are major contributors to the opportunistic infections that affect patients with HIV/AIDS. Systemic infections are mainly with Pneumocystis jirovecii (pneumocystosis), Cryptococcus neoformans (cryptococcosis), Histoplasma capsulatum (histoplasmosis), and Talaromyces (Penicillium) marneffei (talaromycosis). The incidence of systemic fungal infections has decreased in people with HIV in high-income countries because of the widespread availability of antiretroviral drugs and early testing for HIV. However, in many areas with high HIV prevalence, patients present to care with advanced HIV infection and with a low CD4 cell count or re-present with persistent low CD4 cell counts because of poor adherence, resistance to antiretroviral drugs, or both. Affordable, rapid point-of-care diagnostic tests (as have been developed for cryptococcosis) are urgently needed for pneumocystosis, talaromycosis, and histoplasmosis. Additionally, antifungal drugs, including amphotericin B, liposomal amphotericin B, and flucytosine, need to be much more widely available. Such measures, together with continued international efforts in education and training in the management of fungal disease, have the potential to improve patient outcomes substantially

Nanodiamond surface redox chemistry: influence of physicochemical properties on catalytic processes

Modification of an electrode with an immobilised layer of nanodiamond is found to significantly enhance the recorded currents for reversible oxidation of ferrocene methanol (FcMeOH). Current enhancement is related to nanodiamond diameter, with enhancement increasing in the order 1000 nm < 250 nm < 100 nm < 10 nm < 5 nm. We attribute the current enhancement to two catalytic processes: i) electron transfer between the solution redox species and redox-active groups on the nanodiamond surface; ii) electron transfer mediated by FcMeOH(+) adsorbed onto the nanodiamond surface. The first process is pH dependent as it depends on nanodiamond surface functionalities for which electron transfer is coupled to proton transfer. The adsorption-mediated process is observed most readily at slow scan rates and is due to self-exchange between adsorbed FcMeOH(+) and FcMeOH in solution. FcMeOH(+) has a strong electrostatic affinity for the nanodiamond surface, as confirmed by in situ infrared (IR) experiments

A prospective study of mortality from cryptococcal meningitis following treatment induction with 1200 mg oral fluconazole in Blantyre, Malawi.

OBJECTIVE: We have previously reported high ten-week mortality from cryptococcal meningitis in Malawian adults following treatment-induction with 800 mg oral fluconazole (57% [33/58]). National guidelines in Malawi and other African countries now advocate an increased induction dose of 1200 mg. We assessed whether this has improved outcomes. DESIGN: This was a prospective observational study of HIV-infected adults with cryptococcal meningitis confirmed by diagnostic lumbar puncture. Treatment was with fluconazole 1200 mg/day for two weeks then 400mg/day for 8 weeks. Mortality within the first 10 weeks was the study end-point, and current results were compared with data from our prior patient cohort who started on fluconazole 800 mg/day. RESULTS: 47 participants received fluconazole monotherapy. Despite a treatment-induction dose of 1200 mg, ten-week mortality remained 55% (26/47). This was no better than our previous study (Hazard Ratio [HR] of death on 1200 mg vs. 800 mg fluconazole: 1.29 (95% CI: 0.77-2.16, p = 0.332)). There was some evidence for improved survival in patients who had repeat lumbar punctures during early therapy to lower intracranial pressure (HR: 0.27 [95% CI: 0.07-1.03, p = 0.055]). CONCLUSION: There remains an urgent need to identify more effective, affordable and deliverable regimens for cryptococcal meningitis

Investigating the specificity of the neurologic pain signature against breathlessness and finger opposition

Brain biomarkers of pain, including pain-predictive “signatures” based on brain activity, can provide measures of neurophysiological processes and potential targets for interventions. A central issue relates to the specificity of such measures, and understanding their current limits will both advance their development and explore potentially generalizable properties of pain to other states. Here, we used 2 data sets to test the neurologic pain signature (NPS), an established pain neuromarker. In study 1, brain activity was measured using high-field functional magnetic resonance imaging (7T fMRI, N = 40) during 5 to 25 seconds of experimental breathlessness (induced by inspiratory resistive loading), conditioned breathlessness anticipation, and finger opposition. In study 2, we assessed anticipation and breathlessness perception (3T, N = 19) under blinded saline (placebo) and remifentanil administration. The NPS responded to breathlessness, anticipation, and finger opposition, although no direct comparisons with painful events were possible. Local NPS patterns in anterior or midinsula, S2, and dorsal anterior cingulate responded to breathlessness and finger opposition and were reduced by remifentanil. Local NPS responses in the dorsal posterior insula did not respond to any manipulations. Therefore, significant global NPS activity alone is not specific for pain, and we offer insight into the overlap between NPS responses, breathlessness, and somatomotor demand

Multiplicity adjustments in parallel-group multi-arm trials sharing a control group: Clear guidance is needed

Multi-arm, parallel-group clinical trials are an efficient way of testing several new treatments, treatment regimens or doses. However, guidance on the requirement for statistical adjustment to control for multiple comparisons (type I error) using a shared control group is unclear. We argue, based on current evidence, that adjustment is not always necessary in such situations. We propose that adjustment should not be a requirement in multi-arm, parallel-group trials testing distinct treatments and sharing a control group, and we call for clearer guidance from stakeholders, such as regulators and scientific journals, on the appropriate settings for adjustment of multiplicity