Validation of the Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) quality assessment tool.

BACKGROUND: The Antifungal National Antimicrobial Prescribing Survey (AF-NAPS) was developed to undertake streamlined quality audits of antifungal prescribing. The validity and reliability of such tools is not characterized. OBJECTIVES: To assess the validity and reliability of the AF-NAPS quality assessment tool. METHODS: Case vignettes describing antifungal prescribing were prepared. A steering group was assembled to determine gold-standard classifications for appropriateness and guideline compliance. Infectious diseases physicians, antimicrobial stewardship (AMS) and specialist pharmacists undertook a survey to classify appropriateness and guideline compliance of prescriptions utilizing the AF-NAPS tool. Validity was measured as accuracy, sensitivity and specificity compared with gold standard. Inter-rater reliability was measured using Fleiss' kappa statistics. Assessors' responses and comments were thematically analysed to determine reasons for incorrect classification. RESULTS: Twenty-eight clinicians assessed 59 antifungal prescriptions. Overall accuracy of appropriateness assessment was 77.0% (sensitivity 85.3%, specificity 68.0%). Highest accuracy was seen amongst specialist (81%) and AMS pharmacists (79%). Prescriptions with lowest accuracy were in the haematology setting (69%), use of echinocandins (73%), mould-active azoles (75%) and for prophylaxis (71%). Inter-rater reliability was fair overall (0.3906), with moderate reliability amongst specialist pharmacists (0.5304). Barriers to accurate classification were incorrect use of the appropriateness matrix, knowledge gaps and lack of guidelines for some indications. CONCLUSIONS: The AF-NAPS is a valid tool, assisting assessors to correctly classify appropriate prescriptions more accurately than inappropriate prescriptions. Specialist and AMS pharmacists had similar performance, providing confidence that both can undertake AF-NAPS audits to a high standard. Identified reasons for incorrect classification will be targeted in the online tool and educational materials.

Establishing essential metrics for antifungal stewardship in hospitals: the results of an international Delphi survey.

BACKGROUND: Guidance on assessment of the quantity and appropriateness of antifungal prescribing is required to assist hospitals to interpret data effectively and structure quality improvement programmes. OBJECTIVES: To achieve expert consensus on a core set of antifungal stewardship (AFS) metrics and to determine their feasibility for implementation. METHODS: A literature review was undertaken to develop a list of candidate metrics. International experts were invited to participate in sequential web-based surveys to evaluate the importance and feasibility of metrics in the area of AFS using Delphi methodology. Three surveys were completed. Consensus was predefined as ≥80% agreement on the importance of each metric. RESULTS: Eighty-two experts consented to participate from 17 different countries. Response rate for each survey was >80%. The panel included adult and paediatric physicians, microbiologists and pharmacists with diverse content expertise. Consensus was achieved for 38 metrics considered important to routinely include in AFS programmes, and related to antifungal consumption (n = 5), quality of antifungal prescribing and management of invasive fungal infection (IFI) (n = 24), and clinical outcomes (n = 9). Twenty-one consensus metrics were considered to have moderate to high feasibility for routine collection. CONCLUSIONS: The identified core AFS metrics will provide a framework to comprehensively assess the quantity and quality of antifungal prescribing within hospitals to develop quality improvement programmes aimed at improving IFI prevention, management and patient-centred outcomes. A standardized approach will support collaboration and benchmarking to monitor the efficacy of current prophylaxis and treatment guidelines, and will provide important feedback to guideline developers.

FDG PET/CT imaging in detecting and guiding management of invasive fungal infections: a retrospective comparison to conventional CT imaging.

PURPOSE: Invasive fungal infections (IFIs) are common in immunocompromised patients. While early diagnosis can reduce otherwise high morbidity and mortality, conventional CT has suboptimal sensitivity and specificity. Small studies have suggested that the use of FDG PET/CT may improve the ability to detect IFI. The objective of this study was to describe the proven and probable IFIs detected on FDG PET/CT at our centre and compare the performance with that of CT for localization of infection, dissemination and response to therapy. METHODS: FDG PET/CT reports for adults investigated at Peter MacCallum Cancer Centre were searched using keywords suggestive of fungal infection. Chart review was performed to describe the risk factors, type and location of IFIs, indication for FDG PET/CT, and comparison with CT for the detection of infection, and its dissemination and response to treatment. RESULTS: Between 2007 and 2017, 45 patients had 48 proven/probable IFIs diagnosed prior to or following FDG PET/CT. Overall 96% had a known malignancy with 78% being haematological. FDG PET/CT located clinically occult infection or dissemination to another organ in 40% and 38% of IFI patients, respectively. Of 40 patients who had both FDG PET/CT and CT, sites of IFI dissemination were detected in 35% and 5%, respectively (p < 0.001). Of 18 patents who had both FDG PET/CT and CT follow-up imaging, there were discordant findings between the two imaging modalities in 11 (61%), in whom normalization of FDG avidity of a lesion suggested resolution of active infection despite a residual lesion on CT. CONCLUSION: FDG PET/CT was able to localize clinically occult infection and dissemination and was particularly helpful in demonstrating response to antifungal therapy.

Emerging infections caused by non-Aspergillus filamentous fungi.

There are three broad groups of non-Aspergillus moulds: the mucormycetes, the hyalohyphomycetes and the phaeohyphomycetes. Infections with these pathogens are increasingly reported, particularly in the context of increasing use of immunosuppressant agents and improved diagnostics. The epidemiology of non-Aspergillus mould infections varies with geography, climate and level of immunosuppression. Skin and soft-tissue infections are the predominant presentation in the immunocompetent host and pulmonary and other invasive infections in the immunocompromised host. The more common non-Aspergillus moulds include Rhizopus, Mucor, Fusarium and Scedosporium species; however, other emerging pathogens are Rasamsonia and Verruconis species, which are discussed in this article. Outbreaks of non-Aspergillus mould infections have been increasingly reported, with contaminated medical supplies and natural disasters as common sources. Currently culture and other conventional diagnostic methods are the cornerstone of diagnosis. Molecular methods to directly detect and identify mould pathogens in tissue and body fluids are increasingly used.

Fabrication of low loss dispersion engineered chalcogenide photonic crystals.

We demonstrate low loss photonic crystal waveguides in chalcogenide (Ge(33)As(12)Se(55)) glasses. The measured losses are as low as 21 dB/cm. We experimentally determine the refractive index of the thin film chalcogenide glass to be n = 2.6 and demonstrate that dispersion engineering can be performed up to a group index of ng = 40 in this relatively low refractive index contrast system.

Photowritten high-Q cavities in two-dimensional chalcogenide glass photonic crystals.

We demonstrate a high-Q(approximately 125,000) photonic crystal (PhC) cavity formed using a postprocessing optical exposure technique where the refractive index of a photosensitive chalcogenide PhC is modified locally. The evolution of the cavity resonances was monitored in situ during writing using a tapered fiber evanescent coupling system, and the Q of 125,000 represents 1 order of magnitude increase over previously reported cavities in two-dimensional chalcogenide glass PhC.

Multiple-cladding fibers with reduced bend loss.

We demonstrate that a highly bend-resistant fiber can be realized. It is shown theoretically that, by introducing both depressed and elevated rings into the cladding, bending loss can be reduced significantly. A fiber based on this design has been fabricated and characterized as a first step toward achieving this goal. The results show that a multiple-cladding fiber is highly bend resistant when compared with the standard telecom single-mode fiber.

Deposition and characterization of silica-based films by helicon-activated reactive evaporation applied to optical waveguide fabrication.

Planar silicon dioxide optical waveguides were deposited by use of a plasma-activated reactive evaporation system, at a low deposition temperature and with reduced hydrogen contamination, on thermally oxidized silicon wafers. The deposited films show a refractive-index inhomogeneity of less than 0.1%, a thickness nonuniformity of less than 5%, and a material birefringence of approximately 5 x 10(-4). Rib-type channel waveguides were formed on the deposited films by means of hydrofluoric acid etching. The transmission loss of the rib waveguides is determined to be as low as 0.3 dB/cm at a wavelength of 1310 nm for TE polarization, after subtraction of the calculated leakage and scattering losses. Owing to the presence of the OH vibrational overtone band, an additional loss peak of 1 dB/cm is found near the 1385-nm wavelength. The experimental results of transmission loss at wavelengths of 1310 and 1550 nm are compared with analytic expressions for interface scattering and leakage loss.

Effects of scorpion and rattlesnake venoms on the canine pancreas following pancreaticoduodenal arterial injections.

Three scorpion venoms caused a transitory decrease in the rate of fluid secretion and increases in the concentration, in pancreatic juice, of total protein and individual enzymes. Protein and enzyme elevations 4-7 fold over the basal levels were produced by the venom of Tityus bahiensis and 6-7 fold by venoms from Tityus serrulatus and Buthus quinquestriatus. Although these increases were smaller than those stimulated by the C-terminal octapeptide of cholecystokin (OP-CCK; 8-9 fold), the secretory responses were of longer duration, so that the total output of protein caused by each of the three venoms was significantly greater than that observed with OP-CCK. Although electron microscopy revealed evidence of widespread degeneration of acinar cells at 1 hr and more extensive damage at 2 hr following injection of scorpion venom, no free protease was detected in pancreatic secretion collected during this period. The scorpion venoms also caused hypersecretion of viscid saliva. In contrast, rattlesnake venom, had no detectable effect on salivation, pancreatic secretion or morphology of the pancreas.

Tiotidine, a new H2-receptor antagonist, is a potent inhibitor of nocturnal acid secretion in duodenal ulcer patients.

The efficacy of tiotidine, a new H2-receptor antagonist, in reducing nocturnal acid secretion of duodenal ulcer patients (N = 12, ages 21-60 years) was investigated. Different doses of tiotidine, 25, 50, 100, and 150 mg or placebo, were given as a single oral dose and acid secretion collected overnight. Tiotidine produced a significant, prolonged, and dose-related reduction of the nocturnal acid secretion without important side effects. The inhibition of cumulative H+ secretion after 25, 50, 100, and 150 mg tiotidine was 80, 89, 96, and 98% of that observed after placebo, while 300 mg of cimetidine caused an 87% inhibition. Compared to cimetidine, tiotidine appears to be approximately eight times more potent on a molar basis than cimetidine as an inhibitor of acid secretion, and the tiotidine effect is more prolonged. This strong and safe H2-receptor antagonist may be an important addition to the treatment of acid hypersecretory states.

Studies of pure pancreatic secretions in chronic alcoholic subjects without pancreatic insufficiency.

To determine the role alcohol might play in altering pancreatic function, we have examined pure pancreatic juice, obtained by endoscopic cannulation of the pancreatic duct, from a group of 10 chronic alcoholic subjects without history or clinical or laboratory evidence of pancreatic disease and compared the results with those obtained from 15 healthy, non-alcoholic subjects. These findings confirm observations in experimental animals made by others and support the hypothesis that chronic alcohol abuse may damage the pancreas via a sequence of events involving protein hypersecretion. Increase in concentration was not uniform for all proteins measured. Unexpectedly, chronic alcoholics exhibited a highly significant elevation (two- to three-fold over normal) in trypsinogen, in contrast to statistically insignificant increases of other zymogens and trypsin inhibitor. The strikingly increased ratio of trypsinogen to trypsin inhibitor observed in all our alcoholic patients may indicate a weakening of the defence mechanism provided by the trypsin inhibitor against premature intraductal activation of zymogens and explain the predisposition of these patients to pancreatitis.

alpha-Amylase of human pure pancreatic juice: effects of pancreatic disease and the occurrence of variant forms in pancreatic juice from healthy volunteers.

Pure pancreatic juice (PPJ) from healthy human volunteers and from patients with pancreatic or liver disease was subjected to isoelectric focussing (IEF) and assayed for alpha-amylase activity. In PPJ from most normals, a single predominant form of amylase was found, comprising congruent to 83% of the total activity recovered, and having pIapp congruent to pH 6.8. In PPJ from six normals, variant principal forms of amylase were found at pH congruent to 6.4 or pH congruent to 7.3, in addition to the peak at pH 6.8. IEF patterns of PPJ from individuals with pancreatic or liver disease were indisquishable from patterns obtained with PPJ from the control group of healthy volunteers.

Highly purified basal lateral plasma membranes from rat duodenum. Physical criteria for purity.

Preparations of intestinal epithelial cell basal lateral plasma membranes were analyzed with free flow electrophoresis and density perturbation with digitonin. The initial basal lateral membrane preparations were obtained by equilibrium density gradient centrifugation after two different schemes of homogenization and differential sedimentation (A.K. Mircheff, C.H. van Os, and E.M. Wright. 1978. Membr. Biochem. 1:177, and A.K. Mircheff, S.D. Hanna, M.W. Walling, and E.M. Wright. 1979. Prep. Biochem. 9:33. In these preparations, Na,K-ATPase, a marker for the basal lateral mambrane, was purified 16- to 18-fold over the initial homogenate. The preparations were also enriched in NADPH-cytochrome c reductase, alkaline phosphatase, acid phosphatase, and galactosyltransferase. Both free-flow electrophoresis, which separates on the basis of surface charge, and density perturbation with digitonin, which depends on a specific interaction of digitonin with cholesterol-rich membranes, resolved the preparation into three populations of particles. The major population, which represented basal lateral membranes purified 20- to 32-fold with respect to the initial homogenate, contained Na,K-ATPase, alkaline phosphatase, adenylate cyclase, and acid phosphatase. A second population was defined by its content of NADPH-cytochrome c reductase, and the third was defined by its content of galactosyltransferase. Guanylate cyclase appeared to be partitioned between the Na,K-ATPase-rich and NADPH-cytochrome c reductase-rich populations. Galactosyltransferase is also present in fractions which contain the Na,K-ATPase-rich membranes, but the present data cannot exclude the possibility of spillover by the adjacent, galactosyltransferase-rich population. This work emphasizes the importance of multiple, physical criteria for purity in the isolation of subcellular components.

Profiles of pure pancreatic secretions in patients with acute pancreatitis: the possible role of proteolytic enzymes in pathogenesis.

Studies have been performed on pure pancreatic juice obtained by direct cannulation of the pancreatic duct in 2 patients with acute pancreatitis. The striking abnormalities observed, which were in marked contrast to our observations in 15 normal subjects, were high concentrations of protein throughout the period of secretin stimulation and the sporadic appearance of free proteolytic activity in many 1-min specimens throughout the collection period. In 1 subject repeat studies were performed after resolution of the pancreatitis when the profile observed was normal. Our findings are consistent with the hypothesis that obstruction of ductules and intraductal activation of zymogens may be important in the pathogenesis of acute pancreatitis.

Choledochal cyst presenting as acute pancreatitis: evaluation with endoscopic retrograde cholangiopancreatography.

A unusual case of choledochal cyst in an adult presenting as acute pancreatitis is described. Subsequent evaluation by ERCP revealed two atypical features, involvement of the cystic duct (proximal dilatation) and a long (six times normal) intrapancreatic common channel, which may be etiologically related to the pancreatitis.

The spectrum of paracetamol (acetaminophen) overdose: clinical and epidemiological studies.

In a regional survey of paracetamol overdose, 201 patients were admitted to hospital over 12 months. Chronic alcoholism was present in 10% of cases. Over 25% of patients were females aged 20 years or less. Initial blood paracetamol levels were in the toxic range in 16% and histologically severe liver damage eventually found in 20% of those biopsied. This finding corresponded to a serum aspartate aminotransferase of 600 i.u./l or more. Renal failure severe enough to require peritoneal dialysis developed in 1%. Elevated serum amylase was recorded in 22% of a 108-patient subset. Evidence of myocardial damage was found in 11.6% of an eighty-six patient subset. An unfavourable prognosis was indicated by a prothrombin ratio of 20% or less and hepatic coma, the overall mortality being 3.5%. The apparent safety of this useful analgesic is compromized by its widespread employment in parasuicide. This, the insidious and delayed onset of toxicity in overdose and ineffectiveness of late treatment argues for controlling availability to the general public.

Paracetamol (acetaminophen) kinetics in patients with Gilber's syndrome.

The pahrmacokinetics of paracetamol after intravenous and oral administration has been studied in 6 patients with Gilbert's syndrome, and 6 healthy controls. Paracetamol clearance was significantly less in the patients (255 ml/min SE +/- 23 ml/min) than in the normal subjects (352 ml/min SE +/- 40 ml/min). Moreover, whilst paracetamol concentrations declined monoexponentially in the patients, the decline was biexponential in the controls. No difference in the bioavailability of 500 mg paracetamol given orally was observed between the two groups. The results suggest that not only is paracetamol elimination impaired in Gilbert's syndrome, but that its distribution kinetics are also abnormal. Both these findings could be attributed to a decrease in hepatic glucuronyl transferase activity.

A comparative study of double contrast and single contrast barium meals with endoscopic arbitration in the diagnosis of peptic ulcer.

The study compares the ability of a simple double contrast technique with our standard single contrast barium meal to diagnose peptic ulceration. Two hundred and six patients were randomly allocated to either examination. Endoscopy was used as the definitive diagnostic procedure. Deformity of the duodenal cap was more accurately detected by the double contrast technique (P less than 0.01). There was no significant difference in the detection rates for duodenal ulcer. False positive or false negative diagnoses of duodenal pathology were similar by both techniques. The incidence of gastric ulceration in the series was too low for statistical analysis.