Test plates were automatically read and results were recorded with the BIOMIC Vision Image Analysis System. Species, drug, zone diameter, susceptibility category, and quality control results were collected quarterly via e-mail for analysis. Duplicate (the same patient, same species, and same susceptible-resistant biotype profile during any 7-day period) and uncontrolled test results were not analyzed. The 10 most common species of yeasts all showed less resistance to voriconazole than to fluconazole. Candida krusei showed the largest difference, with over 70% resistance to fluconazole and less than 8% to voriconazole. All species of yeasts tested were more susceptible to voriconazole than to fluconazole, assuming proposed interpretive breakpoints of >17 mm (susceptible) and <13 mm (resistant) for voriconazole. MICs reported in this study were determined from the zone diameter in millimeters from the continuous agar gradient around each disk, which was calibrated with MICs determined from the standard CLSI M27-A2 broth dilution method by balanced-weight regression analysis. The results from this investigation demonstrate the broad spectrum of the azoles for most of the opportunistic yeast pathogens but also highlight several areas where resistance may be progressing and/or where previously rare species may be "emerging."

BackgroundThere is increasing evidence that invasive fungal disease (IFD) is more likely to occur in non-neutropenic patients in critical care units. A number of randomised controlled trials (RCTs) have evaluated antifungal prophylaxis in non-neutropenic, critically ill patients, demonstrating a reduction in the risk of proven IFD and suggesting a reduction in mortality. It is necessary to establish a method to identify and target antifungal prophylaxis at those patients at highest risk of IFD, who stand to benefit most from any antifungal prophylaxis strategy.ObjectivesTo develop and validate risk models to identify non-neutropenic, critically ill adult patients at high risk of invasiveCandidainfection, who would benefit from antifungal prophylaxis, and to assess the cost-effectiveness of targeting antifungal prophylaxis to high-risk patients based on these models.DesignSystematic review, prospective data collection, statistical modelling, economic decision modelling and value of information analysis.SettingNinety-six UK adult general critical care units.ParticipantsConsecutive admissions to participating critical care units.InterventionsNone.Main outcome measuresInvasive fungal disease, defined as a blood culture or sample from a normally sterile site showing yeast/mould cells in a microbiological or histopathological report. For statistical and economic modelling, the primary outcome was invasiveCandidainfection, defined as IFD-positive forCandidaspecies.ResultsSystematic review: Thirteen articles exploring risk factors, risk models or clinical decision rules for IFD in critically ill adult patients were identified. Risk factors reported to be significantly associated with IFD were included in the final data set for the prospective data collection.Data collection: Data were collected on 60,778 admissions between July 2009 and March 2011. Overall, 383 patients (0.6%) were admitted with or developed IFD. The majority of IFD patients (94%) were positive forCandidaspecies. The most common site of infection was blood (55%). The incidence of IFD identified in unit was 4.7 cases per 1000 admissions, and for unit-acquired IFD was 3.2 cases per 1000 admissions.Statistical modelling: Risk models were developed at admission to the critical care unit, 24 hours and the end of calendar day 3. The risk model at admission had fair discrimination (c-index 0.705). Discrimination improved at 24 hours (c-index 0.823) and this was maintained at the end of calendar day 3 (c-index 0.835). There was a drop in model performance in the validation sample.Economic decision model: Irrespective of risk threshold, incremental quality-adjusted life-years of prophylaxis strategies compared with current practice were positive but small. Incremental costs of the prophylaxis strategies compared with current practice were positive for most strategies, although a few strategies were cost saving. Incremental net benefits of each prophylaxis strategy compared with current practice were positive for most, but not all, of the strategies. Cost-effectiveness acceptability curves showed that risk assessment and prophylaxis at the end of calendar day 3 was the strategy most likely to be cost-effective when the risk threshold was 1% or 2%. At a lower risk threshold (0.5%) it was most cost-effective to assess risk at each time point; this led to a relatively high proportion of patients receiving antifungal prophylaxis (30%), which may lead to additional burden from increased resistance. The estimates of cost-effectiveness were highly uncertain and the value of further research for the whole population of interest is high relative to the research costs.ConclusionsThe results of the Fungal Infection Risk Evaluation (FIRE) Study, derived from a highly representative sample of adult general critical care units across the UK, indicated a low incidence of IFD among non-neutropenic, critically ill adult patients. IFD was associated with substantially higher mortality, more intensive organ support and longer length of stay. Risk modelling produced simple risk models that provided acceptable discrimination for identifying patients at ‘high risk’ of invasiveCandidainfection. Results of the economic model suggested that the current most cost-effective treatment strategy among non-neutropenic, critically ill adult patients admitted to NHS adult general critical care units is a strategy of risk assessment and antifungal prophylaxis at the end of calendar day 3, but this finding is highly uncertain and future studies should consider the potential impact of increased resistance.FundingFunding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research.A previous version of this report was published in February 2013. The report was subsequently modified to reflect a substantial reduction in the unit cost of fluconazole that took place between the original analysis being conducted and the publication of the report.

Bone marrow transplantation and stem cell transplantation have become standard therapies offering potential cures for a number of hematologic malignancies and immunologic disorders. Severe infection remains a life threatening complication after transplantation, contributes significantly to morbidity, and may necessitate admission to the ICU. It is estimated that between 20 and 40% of patients receiving bone marrow transplant will require ICU admission in the initial posttransplantation phase. Historically, survival rates after admission to the ICU are dismal, particularly if mechanical ventilation is required for respiratory failure. Other organ involvement worsens the prognosis still further and has led to proposals for rationing or restricting access to critical care units and supportive measures. Recent studies have reported small but significant improvements in outcome after critical illness. Whether this improvement is a result of changes in levels of supportive care or a more defined patient selection is uncertain. Moreover, risk factors identifying patients who will benefit most from intensive support are poorly defined. However, it is generally accepted that respiratory failure requiring invasive mechanical ventilation is associated with a poor prognosis in this patient group. Early involvement of intensivists in the management of critical illness in transplant recipients is likely to continue to improve survival in this group of patients.

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Meningococcal meningitis and septicemia are serious infections with significant morbidity and mortality. A sensitive affordable test is required to provide evidence of meningococcal disease at the earliest opportunity to improve local management and give early warning of potential outbreaks of disease. Culture of organisms is considered the gold standard for diagnosis but is slow (24 h or more) and increasingly influenced by prior antibiotic treatment. Recently, the development of polymerase chain reaction (PCR) has improved diagnosis but this sensitive assay is costly, is not available at most primary care institutions and is not feasible for developing countries. Conventional latex agglutination (LA) enables rapid detection of bacterial antigen in cerebrospinal fluid (CSF) (1,2) and can also be used to test specimens of blood (3,4) or urine (5) and for serogroup determinations on primary cultures (6,7). We discuss here test-card agglutination and also describe a new technique based upon LA in an ultrasonic standing wave that retains the speed of direct antigen testing while significantly increasing sensitivity.