Pharmacology and metabolism of anidulafungin, caspofungin and micafungin in the treatment of invasive candidosis - review of the literature

Echinocandins represent the newest class of antifungal agents. Currently, three echinocandins, anidulafungin, caspofungin and micafungin are licensed for clinical use in various indications. They act as inhibitors of β-(1,3)-glucan synthesis in the fungal cell wall and have a favorable pharmacological profile. They have a broad spectrum of activity against all Candida species. Higher MIC's have been observed against C. parapsilosis and C. guilliermondii. Data from clinical trials for invasive Candida infections/candidaemia suggest that the clinical outcome of patients treated with either drug may be very similar. A comparison has been done between caspofungin and micafungin but for anidulafungin a comparative trial with another echinocandin is still lacking. All three drugs are highly effective if not superior to treatment with either fluconazole or Amphotericin B, particularly in well-defined clinical settings such as invasive Candida infections, Candida oesophagitis and candidaemia. Differences between the three echinocandins with regard to the route of metabolism, requirement for a loading dose, dose adjustment in patients with moderate to severe hepatic disease and different dosing schedules for different types of Candida infections have to be considered. Relevant drug-drug interactions of Caspofungin and Micafungin are minimal. Anidulafungin has no significant drug interactions at all. However, echinocandins are available only for intravenous use. All three agents have an excellent safety profile

Trends in Mortality and Medical Spending in Patients Hospitalized for Community-Acquired Pneumonia: 1993–2005

Background: Community-acquired pneumonia (CAP) is the most common infectious cause of death in the United States. To understand the impact of efforts to improve quality and efficiency of care in CAP, we examined trends in mortality and costs among hospitalized CAP patients. Methods: Using the National Inpatient Sample from 1993–2005, we studied 569,524 CAP admissions. The primary outcome was mortality at discharge. We used logistic regression to evaluate the mortality trend, adjusting for age, gender, and comorbidities. To account for the impact of early discharge practices, we also compared daily mortality rates and performed a Cox proportional-hazards model. We used a generalized linear model to analyze trends in hospitalization costs, which were derived using cost-to-charge ratios. Results: Over time, length of stay (LOS) declined, while more patients were discharged to other facilities. The frequency of many comorbidities increased. Age/gender-adjusted mortality decreased from 8.9% to 4.1% (P < 0.001). In multivariable analysis, the mortality risk declined through 2005 (odds ratio, 0.50; 95% confidence interval [CI], 0.48–0.53), compared to reference year 1993. The daily mortality rates demonstrated that most of the mortality reduction occurred early during hospitalization. After adjusting for early discharge practices, the risk of mortality still declined through 2005 (hazard ratio, 0.74, 95% CI 0.70–0.78). Median hospitalization costs exhibited a modest reduction over time, mostly due to reduced LOS. Conclusions: Mortality among patients hospitalized for CAP has declined. Lower in-hospital mortality at a reduced cost suggests that pneumonia is a case of improved productivity in health care.Economic

Randomised, multicentre trial of micafungin vs. an institutional standard regimen for salvage treatment of invasive aspergillosis.

Invasive aspergillosis remains associated with significant morbidity and mortality, necessitating new options for salvage therapy. The objective of this study was to evaluate the efficacy and safety of micafungin as salvage monotherapy in patients with invasive aspergillosis. Patients with proven or probable invasive aspergillosis, who were refractory or intolerant to previous systemic antifungal therapy, were randomised 2 : 1 to receive 300 mg day 121 intravenous micafungin monotherapy or an intravenous control monotherapy [lipid amphotericin B (5 mg kg 121 day 121), voriconazole (8 mg kg 121 day 121) or caspofungin (50 mg day 121)] for 3\u201312 weeks. Patients underwent final assessment 12 weeks after treatment start. Seventeen patients with invasive aspergillosis (proven, n = 2; probable, n = 14; not recorded, n = 1) participated in the study (micafungin arm, n = 12; control arm, n = 5). Three patients each in the micafungin (25.0%; 95% CI: 5.5\u201357.2) and control arm (60.0%; 95% CI: 14.7\u201394.7) had successful therapy at end of treatment as assessed by an Independent Data Review Board. Eleven patients died; six due to invasive aspergillosis. No deaths were considered related to study treatment. During this study it became increasingly common to use combination treatment for salvage therapy. Consequently, enrolment was low and the study was discontinued early. No clear trends in efficacy and safety can be concluded

Subtropical trace gas profiles determined by ground-based FTIR spectroscopy at Izaña (28° N, 16° W): Five-year record, error analysis, and comparison with 3-D CTMs

International audienceWithin the framework of the NDSC (Network for the Detection of Stratospheric Change) ground-based FTIR solar absorption spectra have been routinely recorded at Izaña Observatory (28° N, 16° W) on Tenerife Island since March 1999. By analyzing the shape of the absorption lines, and their different temperature sensitivities, the vertical distribution of the absorbers can be retrieved. Unique time series of subtropical profiles of O3, HCl, HF, N2O, and CH4 are presented. The effects of both dynamical and chemical annually varying cycles can be seen in the retrieved profiles. These include enhanced upwelling and photochemistry in summer and a more disturbed atmosphere in winter, which are typical of the subtropical stratosphere. A detailed error analysis has been performed for each profile. The output from two different three-dimensional (3-D) chemical transport models (CTMs), which are forced by ECMWF analyses, are compared to the measured profiles. Both models agree well with the measurements in tracking abrupt variations in the atmospheric structure, e.g. due to tropical streamers, in particular for the lower stratosphere. Simulated and measured profiles also reflect similar dynamical and chemical annual cycles. However, the differences between their mixing ratios clearly exceed the error bars estimated for the measured profiles. Possible reasons for this are discussed

Global stratospheric hydrogen peroxide distribution from MIPAS-Envisat full resolution spectra compared to KASIMA model results

MIPAS-ENVISAT full resolution spectra were analyzed to obtain a global distribution of hydrogen peroxide (H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt;) in the stratosphere. H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; acts as reservoir gas for the HO&lt;sub&gt;x&lt;/sub&gt; family (= H+OH+HO&lt;sub&gt;2&lt;/sub&gt;) and thus, observations of H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; provide a better understanding of the HO&lt;sub&gt;x&lt;/sub&gt; chemistry in the atmosphere. A retrieval approach based on constrained least squares fitting was developed and applied to small dedicated spectral analysis windows with maximum H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; information and minimum contribution of interfering gases. Due to a low signal to noise ratio in the measured spectra single profiles cannot be used for scientific interpretation and about 100 profiles have to be averaged temporally or spatially. Our retrievals of H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; from MIPAS measurements provide meaningful results between approximately 20 and 60 km. A possible impact by the high uncertainty of the reaction rate constant for HO&lt;sub&gt;2&lt;/sub&gt; + HO&lt;sub&gt;2&lt;/sub&gt;→H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; + O&lt;sub&gt;2&lt;/sub&gt; in our 3D-CTM KASIMA is discussed. We find best agreement between model and observations for applying rate constants according to Christensen et al. (2002) however, a mismatch in vertical profile shape remains. The observations were compared to the model results of KASIMA focusing on low to mid latitudes. Good agreement in spatial distribution and in temporal evolution was found. Highest vmr of H&lt;sub&gt;2&lt;/sub&gt;O&lt;sub&gt;2&lt;/sub&gt; in the stratosphere were observed and modeled in low latitudes shortly after equinox at about 30 km. The modelled diurnal cycle with lowest vmr shortly after sunrise and highest vmr in the afternoon is confirmed by the MIPAS observations

Denitrification, dehydration and ozone loss during the 2015/2016 Arctic winter

The 2015/2016 Arctic winter was one of the coldest stratospheric winters in recent years. A stable vortex formed by early December and the early winter was exceptionally cold. Cold pool temperatures dropped below the nitric acid trihydrate (NAT) existence temperature of about 195 K, thus allowing polar stratospheric clouds (PSCs) to form. The low temperatures in the polar stratosphere persisted until early March, allowing chlorine activation and catalytic ozone destruction. Satellite observations indicate that sedimentation of PSC particles led to denitrification as well as dehydration of stratospheric layers. Model simulations of the 2015/2016 Arctic winter nudged toward European Centre for Medium-Range Weather Forecasts (ECMWF) analysis data were performed with the atmospheric chemistry–climate model ECHAM5/MESSy Atmospheric Chemistry (EMAC) for the Polar Stratosphere in a Changing Climate (POLSTRACC) campaign. POLSTRACC is a High Altitude and Long Range Research Aircraft (HALO) mission aimed at the investigation of the structure, composition and evolution of the Arctic upper troposphere and lower stratosphere (UTLS). The chemical and physical processes involved in Arctic stratospheric ozone depletion, transport and mixing processes in the UTLS at high latitudes, PSCs and cirrus clouds are investigated. In this study, an overview of the chemistry and dynamics of the 2015/2016 Arctic winter as simulated with EMAC is given. Further, chemical–dynamical processes such as denitrification, dehydration and ozone loss during the 2015/2016 Arctic winter are investigated. Comparisons to satellite observations by the Aura Microwave Limb Sounder (Aura/MLS) as well as to airborne measurements with the Gimballed Limb Observer for Radiance Imaging of the Atmosphere (GLORIA) performed aboard HALO during the POLSTRACC campaign show that the EMAC simulations nudged toward ECMWF analysis generally agree well with observations. We derive a maximum polar stratospheric O3 loss of ∼ 2 ppmv or 117 DU in terms of column ozone in mid-March. The stratosphere was denitrified by about 4–8 ppbv HNO3 and dehydrated by about 0.6–1 ppmv H2O from the middle to the end of February. While ozone loss was quite strong, but not as strong as in 2010/2011, denitrification and dehydration were so far the strongest observed in the Arctic stratosphere in at least the past 10 years