Global Analysis of the Evolution and Mechanism of Echinocandin Resistance in Candida glabrata

The evolution of drug resistance has a profound impact on human health. Candida glabrata is a leading human fungal pathogen that can rapidly evolve resistance to echinocandins, which target cell wall biosynthesis and are front-line therapeutics for Candida infections. Here, we provide the first global analysis of mutations accompanying the evolution of fungal drug resistance in a human host utilizing a series of C. glabrata isolates that evolved echinocandin resistance in a patient treated with the echinocandin caspofungin for recurring bloodstream candidemia. Whole genome sequencing identified a mutation in the drug target, FKS2, accompanying a major resistance increase, and 8 additional non-synonymous mutations. The FKS2-T1987C mutation was sufficient for echinocandin resistance, and associated with a fitness cost that was mitigated with further evolution, observed in vitro and in a murine model of systemic candidemia. A CDC6-A511G(K171E) mutation acquired before FKS2-T1987C(S663P), conferred a small resistance increase. Elevated dosage of CDC55, which acquired a C463T(P155S) mutation after FKS2-T1987C(S663P), ameliorated fitness. To discover strategies to abrogate echinocandin resistance, we focused on the molecular chaperone Hsp90 and downstream effector calcineurin. Genetic or pharmacological compromise of Hsp90 or calcineurin function reduced basal tolerance and resistance. Hsp90 and calcineurin were required for caspofungin-dependent FKS2 induction, providing a mechanism governing echinocandin resistance. A mitochondrial respiration-defective petite mutant in the series revealed that the petite phenotype does not confer echinocandin resistance, but renders strains refractory to synergy between echinocandins and Hsp90 or calcineurin inhibitors. The kidneys of mice infected with the petite mutant were sterile, while those infected with the HSP90-repressible strain had reduced fungal burden. We provide the first global view of mutations accompanying the evolution of fungal drug resistance in a human host, implicate the premier compensatory mutation mitigating the cost of echinocandin resistance, and suggest a new mechanism of echinocandin resistance with broad therapeutic potential

Migration to western industrialised countries and perinatal health: A systematic review

Influxes of migrant women of childbearing age to receiving countries have made their perinatal health status a key priority for many governments. The international research collaboration Reproductive Outcomes And Migration (ROAM) reviewed published studies to assess whether migrants in western industrialised countries have consistently poorer perinatal health than receiving-country women. A systematic review of literature from Medline, Health Star, Embase and PsychInfo from 1995 to 2008 included studies of migrant women/infants related to pregnancy or birth. Studies were excluded if there was no cross-border movement or comparison group or if the receiving country was not western and industrialised. Studies were assessed for quality, analysed descriptively and meta-analysed when possible. We identified 133 reports (>20,000,000 migrants), only 23 of which could be meta-analysed. Migrants were described primarily by geographic origin; other relevant aspects (e.g., time in country, language fluency) were rarely studied. Migrants' results for preterm birth, low birthweight and health-promoting behaviour were as good or better as those for receiving-country women in >=50% of all studies. Meta-analyses found that Asian, North African and sub-Saharan African migrants were at greater risk of feto-infant mortality than 'majority' receiving populations, and Asian and sub-Saharan African migrants at greater risk of preterm birth. The migration literature is extensive, but the heterogeneity of the study designs and definitions of migrants limits the conclusions that can be drawn. Research that uses clear, specific migrant definitions, adjusts for relevant risk factors and includes other aspects of migrant experience is needed to confirm and understand these associations.Emigration and immigration Women Perinatal health Refugee Review

The European perinatal health report: Delivering comparable data for examining differences in maternal and infant health

In December 2008, the first-ever European Perinatal Health Report was released by EURO-PERISTAT. Part of the EU Health Programme for health surveillance and reporting, this landmark report presents indicators of perinatal health and care derived from routine statistical data in 25 EU Member States and Norway. It also includes chapters from three other European projects with perinatal data: SCPE on cerebral palsy, EUROCAT on congenital anomalies and EURONEOSTAT on very preterm babies admitted to intensive care. © 2009 Elsevier Ireland Ltd. All rights reserved

FKS Mutations and Elevated Echinocandin MIC Values among Candida glabrata Isolates from U.S. Population-Based Surveillance ▿

Candida glabrata is the second leading cause of candidemia in the United States. Its high-level resistance to triazole antifungal drugs has led to the increased use of the echinocandin class of antifungal agents for primary therapy of these infections. We monitored C. glabrata bloodstream isolates from a population-based surveillance study for elevated echinocandin MIC values (MICs of ≥0.25 μg/ml). From the 490 C. glabrata isolates that were screened, we identified 16 isolates with an elevated MIC value (2.9% of isolates from Atlanta and 2.0% of isolates from Baltimore) for one or more of the echinocandin drugs caspofungin, anidulafungin, and micafungin. All of the isolates with elevated MIC values had a mutation in the previously identified hot spot 1 of either the glucan synthase FKS1 (n = 2) or FKS2 (n = 14) gene. No mutations were detected in hot spot 2 of either FKS1 or FKS2. The predominant mutation was mutation of FKS2-encoded serine 663 to proline (S663P), found in 10 of the isolates with elevated echinocandin MICs. Two of the mutations, R631G for FKS1 and R665G for FKS2, have not been reported previously for C. glabrata. Multilocus sequence typing indicated that the predominance of the S663P mutation was not due to the clonal spread of a single sequence type. With a rising number of echinocandin therapy failures reported, it is important to continue to monitor rates of elevated echinocandin MIC values and the associated mutations

Migration to western industrialised countries and perinatal health: a systematic review

Influxes of migrant women of childbearing age to receiving countries have made their perinatal health status a key priority for many governments. The international research collaboration Reproductive Outcomes And Migration (ROAM) reviewed published studies to assess whether migrants in western industrialised countries have consistently poorer perinatal health than receiving-country women. A systematic review of literature from Medline, Health Star, Embase and PsychInfo from 1995 to 2008 included studies of migrant women/infants related to pregnancy or birth. Studies were excluded if there was no cross-border movement or comparison group or if the receiving country was not western and industrialised. Studies were assessed for quality, analysed descriptively and meta-analysed when possible. We identified 133 reports (>20,000,000 migrants), only 23 of which could be meta-analysed. Migrants were described primarily by geographic origin; other relevant aspects (e.g., time in country, language fluency) were rarely studied. Migrants' results for preterm birth, low birthweight and health-promoting behaviour were as good or better as those for receiving-country women in >or=50% of all studies. Meta-analyses found that Asian, North African and sub-Saharan African migrants were at greater risk of feto-infant mortality than 'majority' receiving populations, and Asian and sub-Saharan African migrants at greater risk of preterm birth. The migration literature is extensive, but the heterogeneity of the study designs and definitions of migrants limits the conclusions that can be drawn. Research that uses clear, specific migrant definitions, adjusts for relevant risk factors and includes other aspects of migrant experience is needed to confirm and understand these association

The European Perinatal Health Report: Comparing the health and care of pregnant women and newborn babies in Europe

EditorialResearch Support, Non-U.S. Gov'tinfo:eu-repo/semantics/publishe

The European perinatal health report: delivering comparable data for examining differences in maternal and infant health

In December 2008, the first-ever European Perinatal Health Report was released by EURO-PERISTAT. Part of the EU Health Programme for health surveillance and reporting, this landmark report presents indicators of perinatal health and care derived from routine statistical data in 25 EU Member States and Norway. It also includes chapters from three other European projects with perinatal data: SCPE on cerebral palsy, EUROCAT on congenital anomalies and EURONEOSTAT on very preterm babies admitted to intensive care.info:eu-repo/semantics/publishe