Predictors of community-associated Staphylococcus aureus, methicillin-resistant and methicillin-susceptible Staphylococcus aureus skin and soft tissue infections in primary-care settings.

Skin and soft tissue infections (SSTIs) due to Staphylococcus aureus have become increasingly common in the outpatient setting; however, risk factors for differentiating methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) SSTIs are needed to better inform antibiotic treatment decisions. We performed a case-case-control study within 14 primary-care clinics in South Texas from 2007 to 2015. Overall, 325 patients [S. aureus SSTI cases (case group 1, n = 175); MRSA SSTI cases (case group 2, n = 115); MSSA SSTI cases (case group 3, n = 60); uninfected control group (control, n = 150)] were evaluated. Each case group was compared to the control group, and then qualitatively contrasted to identify unique risk factors associated with S. aureus, MRSA, and MSSA SSTIs. Overall, prior SSTIs [adjusted odds ratio (aOR) 7·60, 95% confidence interval (CI) 3·31-17·45], male gender (aOR 1·74, 95% CI 1·06-2·85), and absence of healthcare occupation status (aOR 0·14, 95% CI 0·03-0·68) were independently associated with S. aureus SSTIs. The only unique risk factor for community-associated (CA)-MRSA SSTIs was a high body weight (⩾110 kg) (aOR 2·03, 95% CI 1·01-4·09).

Impact of empiric weight-based vancomycin dosing on nephrotoxicity and mortality in geriatric patients with methicillin-resistant Staphylococcus aureus bacteraemia.

WHAT IS KNOWN AND OBJECTIVE: Few studies have evaluated the effect of vancomycin dosing on the health outcomes in geriatric patients. Data are needed to determine whether higher vancomycin dosing strategies are more effective in geriatric patients and/or lead to excessive rates of adverse events. METHODS: This study used a subset of patients aged ≥65 years from a multicentre, retrospective, cohort study of methicillin-resistant Staphylococcus aureus (MRSA) bacteraemia. Patients received ≥ 48 h of empiric vancomycin between 1 July 2002 and 30 June 2008. We compared the incidence of nephrotoxicity and in-hospital mortality in patients who received guideline-recommended dosing (at least 15 mg/kg/dose) to patients who received lower dosing. Multivariable generalized mixed-effect models were constructed to determine independent risk factors for nephrotoxicity and in-hospital mortality. RESULTS AND DISCUSSION: Half of the cohort (46% of 92 patients) received guideline-recommended dosing. Empiric use of weight-based dosing did increase the percentage of patients achieving a vancomycin trough ≥ 15 mg/L (57% vs. 42%). Nephrotoxicity occurred in 32% of patients and 26% died during their hospitalization. Guideline-recommended dosing was not associated with significant changes in nephrotoxicity (OR 1·13; 95% CI 0·40-3·19) or in-hospital mortality (OR 1·14; 95% CI 0·41-3·18) in the multivariable analysis. WHAT IS NEW AND CONCLUSION: In this study of geriatric patients, guideline-recommended dosing was not associated with significant changes in nephrotoxicity or mortality. As 40% of the patients who received guideline-recommended dosing failed to achieve a target vancomycin trough of ≥ 15 mg/L, future studies should focus on dosing strategies to increase target attainment rate.

Supervised Machine-Learning Reveals That Old and Obese People Achieve Low Dapsone Concentrations.

The human species is becoming increasingly obese. Dapsone, which is extensively used across the globe for dermatological disorders, arachnid bites, and for treatment of several bacterial, fungal, and parasitic diseases, could be affected by obesity. We performed a clinical experiment, using optimal design, in volunteers weighing 44-150 kg, to identify the effect of obesity on dapsone pharmacokinetic parameters based on maximum-likelihood solution via the expectation-maximization algorithm. Artificial intelligence-based multivariate adaptive regression splines were used for covariate selection, and identified weight and/or age as predictors of absorption, systemic clearance, and volume of distribution. These relationships occurred only between certain patient weight and age ranges, delimited by multiple hinges and regions of discontinuity, not identified by standard pharmacometric approaches. Older and obese people have lower drug concentrations after standard dosing, but with complex patterns. Given that efficacy is concentration-dependent, optimal dapsone doses need to be personalized for obese patients.

Fractal Geometry-Based Decrease in Trimethoprim-Sulfamethoxazole Concentrations in Overweight and Obese People.

Trimethoprim-sulfamethoxazole (TMP-SMX) is one of the most widely drugs on earth. The World Health Organization recommends it as an essential basic drug for all healthcare systems. Dosing is inconsistently based on weight, assuming linear relationships. Given that obesity is now a global "pandemic" it is vital that we evaluate the effect of obesity on trimethoprim-sulfamethoxazole concentrations. We conducted a prospective clinical experiment based on optimized design strategies and artificial intelligence algorithms and found that weight and body mass index (BMI) had a profound effect on drug clearance and volume of distribution, and followed nonlinear fractal geometry-based relationships. The findings were confirmed by demonstrating decreased TMP-SMX peak and area under the concentration-time curves in overweight patients based on standard regression statistics. The nonlinear relationships can now be used to identify new TMP-SMX doses in overweight and obese patients for each of the infections caused by the >60 pathogens for which the drug is indicated.

In silico-derived bedside formula for individualized micafungin dosing for obese patients in the age of deterministic chaos.

There are 2.1 billion people worldwide who are overweight or obese. However, most current doses of drugs were derived for normal weight patients. For several drugs, the relationship between clearance and patient weight follows fractal geometry rules. Clearance directly determines the area under the concentration time curve (AUC) after i.v. infusion. For micafungin, AUC-to-minimum inhibitory concentration (AUC/MIC) ratios have a close deterministic relationship with efficacy in candidiasis; an AUC/MIC ≥3,000 is associated with 98% efficacy. We performed computer-aided clinical trial simulations of 100,000 patients with candidiasis to identify the lowest micafungin dose able to achieve AUC/MIC ≥3,000 in patients weighing up to 200 kg. We used the cumulative fraction of response to derive the formula "Dose (mg) = patient weight + 42" for use by the clinician at the bedside to individualize micafungin doses for overweight and obese patients. This paradigm for dose individualization could be used to optimize efficacy for many classes of anti-infective agents in obese patients.

Phosphinic acid analogues of GABA. 1. New potent and selective GABAB agonists.

The antispastic agent and muscle relaxant baclofen 1 is a potent and selective agonist for bicuculline-insensitive GABAB receptors. For many years efforts to obtain superior GABAB agonists were unsuccessful. We describe the syntheses and biological properties of two new series of GABAB agonists, the best compounds of which are more potent than baclofen in vitro and in vivo. They were obtained by replacing the carboxylic acid group of GABA or baclofen derivatives with either the phosphinic acid or the methylphosphinic acid residue. Surprisingly, ethyl- and higher alkylphosphinic acid derivatives of GABA yielded novel GABAB antagonists, which are described in part 2 of this series. Structure-activity relationships of the novel GABAB agonists are discussed with respect to their affinities to GABAB receptors as well as to their effects in many functional tests in vitro and in vivo providing new muscle relaxant drugs with significantly improved side effect profiles.

Phosphinic acid analogues of GABA. 2. Selective, orally active GABAB antagonists.

In 1987, 25 years after the synthesis of the potent and selective GABAB agonist baclofen (1), Kerr et al. described the first GABAB antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABAB antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABAB antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABAB receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABAB antagonists interacted also with postsynaptic GABAB receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABAB antagonists showed also protective effects in various animal models of absence epilepsy.

3-Aminopropanephosphinic acid is a potent agonist at peripheral and central presynaptic GABAB receptors.

The actions of the GABA analog 3-aminopropanephosphinic acid (3-APA) were studied in the guinea-pig isolated ileal preparation and at synapses between cultured rat hippocampal neurons. Like the GABAB receptor agonist, baclofen, 3-APA inhibited the electrically evoked ileal twitch. The EC50 for 3-APA was 0.8 microM; the EC50 for baclofen was 9 microM. In addition, the depressant responses to 3-APA and baclofen were blocked by the GABAB receptor antagonists phaclofen, saclofen, 2-hydroxy-saclofen and delta-aminovaleric acid. 3-APA also mimicked the presynaptic action of baclofen at GABAergic synapses between embryonic rat hippocampal neurons in culture. 3-APA reduced the amplitude of inhibitory postsynaptic potentials (IPSPs) and currents (IPSCs) by greater than 50% at a concentration of 1 microM, while baclofen reduced synaptic transmission to a similar degree at 10 microM. 3-APA did not alter membrane conductance, nor did the drug alter postsynaptic responses to GABA. These data show that 3-APA is a potent agonist at presynaptic GABAB receptors in the periphery and on GABAergic neurons from the central nervous system. The activity of 3-APA at central postsynaptic GABAB receptors remains to be studied.

GABAA and GABAB receptors in locus coeruleus: effects of blockers.

Racemic baclofen, (-)-baclofen and muscimol depressed all spontaneously firing locus coeruleus neurons tested in a slice preparation. Racemic phaclofen (100 microM; 1 mM) moderately antagonized the effects of racemic baclofen without antagonizing those of muscimol. Bicuculline (10, 30, 100 microM) potently antagonized the action of muscimol without affecting the inhibition of baclofen. Phaclofen and bicuculline had no pronounced effect on the spontaneous discharge rate of cells. The results suggests that there are GABAA and GABAB receptors in the locus coeruleus.

CGP 35348: a centrally active blocker of GABAB receptors.

The biochemical, electrophysiological and pharmacological properties of the new GABAB receptor blocker CGP 35348 are described. In a variety of receptor binding assays CGP 35348 showed affinity for the GABAB receptor only. CGP 35348 had an IC50 of 34 microM at the GABAB receptor. The compound antagonized (100, 300, 1000 microM) the potentiating effect of L-baclofen on noradrenaline-induced stimulation of adenylate cyclase in rat cortex slices. In electrophysiological studies CGP 35348 (10, 100 microM) antagonized the effect of L-baclofen in the isolated rat spinal cord. In the hippocampal slice preparation CGP 35348 (10, 30, 100 microM) blocked the membrane hyperpolarization induced by D/L-baclofen (10 microM) and the late inhibitory postsynaptic potential. CGP 35348 appeared to be 10-30 times more potent than the GABAB receptor blocker phaclofen. Ionophoretic and behavioural experiments showed that GABAB receptors in the brain were blocked after i.p. administration of CGP 35348. This compound may be of considerable value in elucidating the roles of brain GABAB receptors.

Differing actions of baclofen and 3-amino-propylphosphinic acid in rat neocortical slices.

Rat neocortical slices maintained in Mg2(+)-free Krebs medium developed spontaneous paroxysmal discharges which were attenuated or suppressed by the gamma-aminobutyric acid-B (GABAB) receptor agonist baclofen, occasionally accompanied by a slight hyperpolarisation, and antagonised by the specific GABAB-receptor antagonist, 2-OH-saclofen. Over the same dose range, the GABA-analogue 3-amino-propylphosphinic acid (3-APA) caused a marked, prompt hyperpolarisation with little or no effect on the frequency of the discharges, although their amplitude was attenuated. In the presence of 2-OH-saclofen, 3-APA still induced a hyperpolarisation but the amplitude of the discharges was no longer affected. This marked difference in action between baclofen and 3-APA in the rat neocortical slices suggests there may be a heterogeneity of GABAB-receptors.

Drugs, insecticides and other agents from Artemisia.

Essential oils from Artemisia (wormwood) are of botanical and pharmaceutical interest. They are used in traditional remedies in many parts of the world. In pure form the oil is a narcotic poison. Nearly all species are intensively bitter and strongly aromatic. Extracted substances from the plant have an antibacterial action and some of these substances have potential use in mosquito control. Other properties include toxicity to nematodes and inhibition of seedling growth of. Several chemical compounds have been isolated and identified.

A scale for the comparison of the sexual attitudes of adolescents and their parents.

We developed a 14-item Attitudes Toward Sexuality Scale (ATSS) to compare the sexual attitudes of early, middle, and late adolescents and their parents. One hundred forty-one adolescents between the ages of 12 and 20 and their parents completed a questionnaire consisting of the ATSS and demographic information. The Cronbach alpha reliability coefficient for the adolescents was .75, and for the parents it was .84. A principal components analysis revealed four major dimensions of the scale: a large General factor, Legality/Morality, Alternative Modes of Sexual Expression, and Individual Rights. The correlation pattern between the ATSS and subscales of the Sex Knowledge and Attitudes Test, as well as with certain demographic variables, supports the construct validity of the ATSS. This is, therefore, a scale which may be used for research in which the sexual attitudes of adults and adolescents of various ages are to be measured and compared.

Synthesis and structure-activity relationships of benzophenone hydrazone derivatives with insecticidal activity.

A broad range of benzophenone hydrazone derivatives was prepared and tested against selected chewing insect pests, allowing the analysis of structure-activity relationships. Good activity was found only when the aromatic rings were substituted at the 4-positions with an halogen atom and a triflate or perhaloalkoxy group. In contrast, a number of substituents on the hydrazone part led to active compounds, the best results being achieved with acyl-type substituents. The excellent laboratory and greenhouse activity of the best representatives was confirmed in semi-field trials against Spodoptera littoralis.

Age, pattern of consultation, and functional disability in elderly patients in one general practice.

OBJECTIVE: To examine how functional disability varies with sex, age, and other variables in patients aged 75 and over living in the community and to ascertain whether a statistical model derived from the variables in this population usefully predicted functional disability in another of similar age. DESIGN: Retrospective study of data collected by interview and by examination of medical records. SETTING: An urban general practice with five partners and a list of 15,000 patients, very few of whom belonged to ethnic minorities. PATIENTS: 775 Patients (252 men, 523 women) aged 75 and over living in the community between September 1985 and August 1986; 13 other patients considered to be unsuitable and 14 who declined an interview were excluded. Also 94 patients who became 75 or joined the practice after August 1986. MAIN OUTCOME MEASURE: The proportions of fit, partially disabled, and severely disabled (housebound) patients. RESULTS: 90 Men (35.7%) and 128 women (24.5%) were fit, and 27 men (10.7%) and 116 women (22.2%) were housebound; in all age groups women were significantly more likely to be disabled than men. A significant trend towards greater disability was shown with increasing age and, more noticeably, with pattern of consultation when patients were divided into three categories based on the number of times they had attended the surgery and been visited at home over about two years. Statistical models gave the forecast percentage of fit and severely disabled patients for each sex, age group, and pattern of consultation, and a simple scheme was derived to identify from information wholly contained in medical records most of those patients most prone to severe disability. The scheme was verified applying it to a population of 94 elderly patients in 1988-9. CONCLUSION: Sex, age, and pattern of consultation together provide a quick indication of elderly patients' tendency to severe disability, which can help in screening and in day to day consultations.