Association Between Minimum Inhibitory Concentration, Beta-lactamase Genes and Mortality for Patients Treated With Piperacillin/Tazobactam or Meropenem From the MERINO Study.

INTRODUCTION: This study aims to assess the association of piperacillin/tazobactam and meropenem minimum inhibitory concentration (MIC) and beta-lactam resistance genes with mortality in the MERINO trial. METHODS: Blood culture isolates from enrolled patients were tested by broth microdilution and whole genome sequencing at a central laboratory. Multivariate logistic regression was performed to account for confounders. Absolute risk increase for 30-day mortality between treatment groups was calculated for the primary analysis (PA) and the microbiologic assessable (MA) populations. RESULTS: In total, 320 isolates from 379 enrolled patients were available with susceptibility to piperacillin/tazobactam 94% and meropenem 100%. The piperacillin/tazobactam nonsusceptible breakpoint (MIC >16 mg/L) best predicted 30-day mortality after accounting for confounders (odds ratio 14.9, 95% confidence interval [CI] 2.8-87.2). The absolute risk increase for 30-day mortality for patients treated with piperacillin/tazobactam compared with meropenem was 9% (95% CI 3%-15%) and 8% (95% CI 2%-15%) for the original PA population and the post hoc MA populations, which reduced to 5% (95% CI -1% to 10%) after excluding strains with piperacillin/tazobactam MIC values >16 mg/L. Isolates coharboring extended spectrum ß-lactamase (ESBL) and OXA-1 genes were associated with elevated piperacillin/tazobactam MICs and the highest risk increase in 30-day mortality of 14% (95% CI 2%-28%). CONCLUSIONS: After excluding nonsusceptible strains, the 30-day mortality difference from the MERINO trial was less pronounced for piperacillin/tazobactam. Poor reliability in susceptibility testing performance for piperacillin/tazobactam and the high prevalence of OXA coharboring ESBLs suggests that meropenem remains the preferred choice for definitive treatment of ceftriaxone nonsusceptible Escherichia coli and Klebsiella.

Parallel, solution phase synthesis of dihydropyridine miticides via a versatile multicomponent reaction.

A novel class of highly active dihydropyridine miticides was prepared using a multicomponent reaction process. The initial lead was rapidly optimized using solution phase parallel synthesis techniques and a positional scanning approach. Detailed structure-activity relationships were developed for the amino and carbonyl components of the molecule and used to select the best candidates for broad field testing. The chemistry, biology and toxicology of these compounds will be presented along with numerous structural variants of the reaction products.

Spectroscopy and fluorescence quenching of tyrosine in lima bean trypsin/chymotrypsin inhibitor and model peptides.

The effects of citrate ion concentration and pH on the optical spectra and fluorescence decay have been measured for several tyrosine model compounds and lima bean trypsin/chymotrypsin inhibitor, a protein containing one tyrosine at position 69 and seven disulfides but no tryptophan, in order to determine the location and environment of Tyr 69. Tyrosine in the protein is protected from citrate collisional quenching, as indicated by the dynamic quenching constant 9 to 15 times smaller than those for the model peptides. Static quenching remains, with a Stern-Volmer constant of about 1.0 M-1, somewhat smaller than those of L-tyrosine, tyrosine-glutamate, and leucine-tyrosine-leucine. The elevated pKa of Tyr 69, greater than or equal to 11.6, also indicates protein protection from solvent ions. Though Coulomb repulsion of the Glu 70/citrate pair may play a role in the shielding of Tyr 69 from citrate, our measurements indicate that steric effects of the protein structure are more important. Tyrosinate emission in the protein at neutral pH is minimal.

Innovations making CME more clinically relevant, attractive.

Educators are rising to the challenge of making continuing medical education relevant, valuable and enjoyable for physicians. Lectures are being replaced by small-group, interactive sessions that try to ensure physicians come away with clinically relevant information that will affect daily practice. Community-based programs also allow physicians to fit learning into their busy lifestyles.

Count the cost of day cases.

Admitting surgical patients as day cases rather than for overnight stays is one way of improving the use of resources and cutting waiting lists. But the way bed-use statistics are now presented can be misleading, and Kevin Cottrell, regional statistician, North Western RHA, suggests ways in which the treatment of day cases could be standardised and an accurate picture of hospital activity achieved.

Experts discuss cost-effective treatment of hypertension during world conference in Canada.

Even though an estimated 3.5 million Canadians are affected by hypertension, speakers at a World Conference on Hypertension Control questioned whether it is generally cost effective to treat younger men and women who have mild hypertension. Nonpharmacologic treatment via weight loss and lifestyle modification should be the first-line treatment, speakers stated. They looked at the basic principles for evaluating the economics of hypertension management and made recommendations on the cost effectiveness of treating various patient groups according to age and severity of their hypertension, and on the selection of diagnostic-evaluation procedures and antihypertensive medications.

Herbal products begin to attract the attention of brand-name drug companies.

Many Canadians are interested in alternative medicine, and burgeoning public interest in herbal remedies has not gone unnoticed by Canada's drug companies. McNeil Consumer Products recently began selling a migraine prophylaxis made from the plant feverfew. Physicians who would like to see herbal medications subjected to outcome studies and quality-control standards, with evidence of risks and benefits being made available to consumers, welcome the interest the companies are showing. Meanwhile, physicians and pharmacists are trying to respond to consumer demand by increasing their own knowledge about herbal medications.

Changes in health care system reflected in way medical students are chosen, Queen's alumni learn.

Society expects today's physicians to be expert clinicians, effective communicators, resource managers and health care advocates, all rolled into one. This is changing both medical school curricula and the way medical students are selected. During a homecoming weekend at Queen's University, faculty brought medical alumni up to date on the selection process. "I remember writing a little not saying that I wanted to come into medicine and sending it off with my transcript, and that was it," noted Dr. Robert Madsley, the vice-dean. Today, the situation is much different.

Catchment populations.

A method of estimating catchment populations which is easily understood and calculable is described by Kevin Cottrell, North Western RHA statistician. It is based on traditional statistical theory and as such is robust in its application. It can give fairly accurate determinations of the population served by various services.

Health planning: putting the weight where it belongs.

With the advent of such far reaching developments as national formulae for revenue and capital allocations, it is becoming increasingly important that full account is taken of the demographic structure of populations creating demands and using services. K. M. Cottrell, regional statistician, North Western RHA, describes the derivation and application of an age-sex index.

Serum oestradiol-17 beta in normal women.

Serum concentrations of oestradiol-17ß were measured by radio-immunoassay during 40 menstrual cycles from 38 normal premenopausal women. Repeated samples were studied from 25 normal postmenopausal women. The method was highly specific and extremely sensitive. In premenopausal women the pattern of serum oestradiol-17ß was remarkably constant but the concentrations varied with age. Women in the fourth decade of life had significantly higher concentrations of oestradiol-17ß than either younger or older women. In postmenopausal women the concentration of oestradiol-17ß was consistently very low.

Serum oestradiol-17 beta in women with benign and malignant breast disease.

Serum concentrations of oestradiol-17ß were measured daily throughout one menstrual cycle in 32 normal women, 31 women with benign disease of the breast and 10 with cancer of the breast. The concentrations were found to differ significantly from normal in women with cysts and to a lesser extent in those with cancer of the breast. In 25 normal post-menopausal and in 27 post-menopausal women with cancer repeated assays disclosed consistently low levels of oestradiol-17ß.

Sex hormones in breast disease.

Serum concentrations of oestradiol 17beta and progesterone were measured daily throughout one menstrual cycle in 32 normal women, 32 women with benign disease of the breast and 10 women with cancer of the breast. In normal women concentrations varied with age. Women with cysts had concentrations of oestradiol 17beta which were significantly higher than normal. In women with cancer the concentrations of oestradiol 17beta and progesterone were significantly higher than normal, but the difference was very small and much larger numbers of patients need to be studied. Concentrations of oestradiol 17beta and progesterone in postmenopausal women were consistently very low.

Synthesis and enzymatic evaluation of a P1 arginine aminocoumarin substrate library for trypsin-like serine proteases.

A method for the solid-phase synthesis of P1 arginine containing peptides via attachment of the arginine side-chain guanidine group is described. This procedure is applied to the preparation of a tetrapeptide, P1 arginine aminocoumarin PS-SCL. This library was validated by using it to determine the P4-P2 specificity for thrombin and comparing the results to the known thrombin subsite specificity. This is the first reported example of a PS-SCL library containing a P1 arginine.