Comparative population plasma and tissue pharmacokinetics of micafungin in critically ill patients with severe burn injuries and patients with complicated intra-abdominal infection

Severely burned patients have altered drug pharmacokinetics (PKs), but it is unclear how different they are from those in other critically ill patient groups. The aim of the present study was to compare the population pharmacokinetics of micafungin in the plasma and burn eschar of severely burned patients with those of micafungin in the plasma and peritoneal fluid of postsurgical critically ill patients with intra-abdominal infection. Fifteen burn patients were compared with 10 patients with intra-abdominal infection; all patients were treated with 100 to 150 mg/day of micafungin. Micafungin concentrations in serial blood, peritoneal fluid, and burn tissue samples were determined and were subjected to a population pharmacokinetic analysis. The probability of target attainment was calculated using area under the concentration-time curve from 0 to 24 h/MIC cutoffs of 285 for Candida parapsilosis and 3,000 for non-parapsilosis Candida spp. by Monte Carlo simulations. Twenty-five patients (18 males; median age, 50 years; age range, 38 to 67 years; median total body surface area burned, 50%; range of total body surface area burned, 35 to 65%) were included. A three-compartment model described the data, and only the rate constant for the drug distribution from the tissue fluid to the central compartment was statistically significantly different between the burn and intra-abdominal infection patients (0.47 +/- 0.47 versus 0.15 +/- 0.06 h(-1), respectively; P< 0.05). Most patients would achieve plasma PK/pharma-codynamic (PD) targets of 90% for non-parapsilosis Candida spp. and C. parapsilosis with MICs of 0.008 and 0.064 mg/liter, respectively, for doses of 100 mg daily and 150 mg daily. The PKs of micafungin were not significantly different between burn patients and intra-abdominal infection patients. After the first dose, micafungin at 100 mg/day achieved the PK/PD targets in plasma for MIC values of < 0.008 mg/liter and < 0.064 mg/liter for non-parapsilosis Candida spp. and Candida parapsilosis species, respectively

Magnitude and determinants of antibiotic dispensing without prescription in Spain: a simulated patient study

Objectives: Excessive and inappropriate use of antibiotics increases antimicrobial resistance. The aim of this study was to determine the magnitude and determinants of antibiotic dispensing without prescription in Spain by the simulated patient technique. Methods: A cross-sectional study was conducted with all the pharmacies in a region of north-west Spain (n = 977), between December 2016 and January 2017. Four actors visited the pharmacies simulating a respiratory infection. Four incremental levels of pressure were used to obtain an antibiotic. The education and sex of the person who was dispensing and the area where the pharmacy was located were recorded. The effect of these independent variables on the dispensing of an antibiotic without prescription (1 = yes, 0 = no) was modelled by logistic regression. Results: An antibiotic was obtained in 18.83% (95% CI = 16.5%-21.41%) of the visits. The area influenced the dispensing of antibiotics without a medical prescription, with a greater likelihood of dispensing in rural (OR = 1.79; 95% CI = 1.20-2.68) or semi-rural (OR = 1.66; 95% CI = 1.13-2.44) areas than in urban areas. No association was found with the sex or the training of the person who dispensed the antibiotic. In the pharmacies in urban areas, a lower level of pressure was needed to obtain the antibiotic. Conclusions: This study shows that one-fifth of the pharmacies still dispense antibiotics without prescription, especially under patient pressure. A rural setting has been identified as a risk factor for dispensing without prescription, so it must be taken into account for future interventions

Influence of Polymorphisms Involved in Platelet Activation and Inflammatory Response on Aspirin-Related Upper Gastrointestinal Bleeding: A Case-Control Study

Background: Despite the wide benefits of aspirin and its cost-effectiveness, aspirin prescriptions have been reduced due to idiosyncratic responses in susceptible individuals. Low-dose aspirin and single-nucleotide polymorphisms (SNPs) are independently associated with increased risk of gastrointestinal hemorrhage; however, to-date, no studies investigated the SNP-aspirin interaction effect on upper gastrointestinal hemorrhage (UGIH). Therefore, we aimed to evaluate the role of 25 SNPs in multiple genes involved in platelet activation, angiogenesis and inflammatory response in aspirin-related UGIH. Methods: A multicenter, full case-control study was conducted in patients exposed and unexposed to aspirin. Three hundred twenty-six cases diagnosed with UGIH were matched with 748 controls (1:3) by age, gender, health center, and recruitment date. Only adults of European origin were included. Participants were stratified by aspirin exposure and genotype [(Aspirin(-), wild-type), (Aspirin(+), wild-type), (Aspirin(+), genetic variation), (Aspirin(-), genetic variation)]. For each SNP, the Odds Ratio of UGIH and their 95% confidence intervals were estimated in each subgroup by using the generalized linear mixed models for dependent binomial variables. SNP-aspirin interaction effect was estimated through Relative Excess Risk due to Interaction (RERI) measures. Results: We observed two categories of SNPs that might modify the risk magnitude of UGIH in aspirin consumers. Seven SNPs (rs1387180 A > G, rs2238631 T > C, rs1799964 T > C, rs5050 T > C/T > G, rs689466 T > C, rs1799983 T > A/T > G, and rs7756935 C > A) were "positive modifiers" associated with an excess of risk from aspirin exposure and carrying that genetic variation (1.75 T, rs1131882 G > A, rs4311994 C > T, rs10120688 G > A, rs4251961 T > C, rs3778355 G > C, rs1330344 C > T, rs5275 A > G/A > T, and rs3779647 C > T) were "negative modifiers" and associated with a reduced risk in aspirin users (-2.74 </= RERI </= -0.95). Conclusion: This preliminary study suggests that polymorphisms in genes involved in platelets activity, angiogenesis and inflammatory response might modify the risk of aspirin-related UGIH. Further studies with larger sample size and in different populations are needed to confirm our findings. If confirmed, this might have great impact on public health, thanks to aspirin's prophylactic properties in diseases of high incidence and severity

Pharmaceutical companies information and antibiotic prescription patterns: A follow-up study in Spanish primary care

OBJECTIVES: To assess the impact of sources of drug information on antibiotic prescribing patterns (quantity and quality) among primary care physicians. METHODS: We conducted a cohort study on primary care physicians who were actively engaged in medical practice in 2010 in a region in north-west Spain (Galicia), fulfilling inclusion criteria (n = 2100). As the independent variable, we took the perceived utility of 6 sources of information on antibiotics, as measured by the validated KAAR-11 questionnaire. As dependent variables, we used: (1) a quality indicator (appropriate quality, defined as any case where 6 of the 12 indicators proposed by the European Surveillance of Antimicrobial Consumption Network [ESAC-Net] were better than the mean values for Spain); and, (2) a quantity indicator (high prescribing), defined as any case where defined daily doses (DDD) per 1 000 inhabitants per day of antibacterials for systemic use were higher than the mean values for Spain. The adjusted odds ratio for a change in the interquartile range (IqOR) for each sources of information on antibiotics was calculated using Generalized Linear Mixed Models. RESULTS: The questionnaire response rate was 68%. Greater perceived utility of pharmaceutical sales representatives increases the risk of having high prescribing (1/IqOR = 2.50 [95%CI: 1.63-3.66]) and reduces the probability of having appropriate quality (1/IqOR = 2.28 [95%CI: 1.77-3.01]). Greater perceived utility of clinical guidelines increases the probability of having appropriate quality (1/IqOR = 1.25 [95%CI: 1.02-1.54]) and reduces the probability of high prescribing (1/IqOR = 1.25 [95%CI: 1.02-1.54]). CONCLUSIONS: Sources of information on antibiotics are an important determinant of the quantity and quality of antibiotic prescribing in primary care. Commercial sources of information influence prescribing negatively, and clinical guidelines are associated with better indicators.Instituto de Salud Carlos IIIThe European Regional Development Fund (ERDF)Mutua Madrileñ