80 research outputs found

    C脫MO OPTIMIZAR LA FARMACODINAMIA ANTIMICROBIANA: UNA GU脥A PARA UN PROGRAMA DE OPTIMIZACI脫N DEL USO DE ANTIMICROBIANOS

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    RESUMENLos conceptos de farmacodin谩mica deber铆an aplicarse para optimizar los reg铆menes de dosificaci贸n antibi贸tica, especialmente de cara a algunas infecciones bacterianas resistentes a m煤ltiples drogas. A pesar de que la farmacodinamia de la mayor铆a de las clases de antibi贸ticos utilizadas en el 谩mbito hospitalario est谩 bien descrita, las pautas acerca de c贸mo seleccionar reg铆menes y su implementaci贸n en un programa de administraci贸n antimicrobiana en la propia instituci贸n, son m谩s limitadas. La funci贸n del antibi贸tico en concentraciones m铆nimas inhibitorias (MIC) es primordial para entender qu茅 reg铆menes podr铆an beneficiarse de la implementaci贸n como un protocolo o como uso en los pacientes individuales. Este art铆culo destaca la farmacodin谩mica de aminogluc贸sidos, betalact谩micos, fluoroquinolonas, tigeciclina, vancomicina, polimixinas, con el objetivo de proporcionar una base estrat茅gica para seleccionar un r茅gimen antibi贸tico optimizado en vuestro 谩mbito hospitalario

    Expression of the MexXY-OprM efflux system in Pseudomonas aeruginosa with discordant cefepime/ceftazidime susceptibility profiles

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    While MIC distributions and percent susceptibility for cefepime and ceftazidime are generally similar among Pseudomonas aeruginosa, we noted an increasing discordance in susceptibility favoring ceftazidime at our hospital. Quantitative reverse transcriptase-polymerase chain reaction was utilized to explore overexpression of the MexXY-OprM efflux as the mechanism for this phenotype profile. Thirteen of 15 (87%) randomly selected isolates had mexY gene expression levels of 5.8鈥40.8-fold relative to the wild-type reference strain. While mexY overexpression was noted in the majority of isolates, other resistance mechanisms appear to contribute to the observed phenotypic profile of the Pseudomonas aeruginosa studied. Clinicians must understand not only the magnitude of difference in the MIC profiles between agents, but also the mechanism(s) responsible for these observations if strategies (ie, pharmacodynamic dosing) are to be designed to optimize patient care outcomes in the face of increasing resistance

    Lung penetration, bronchopulmonary pharmacokinetic/pharmacodynamic profile and safety of 3 g of ceftolozane/tazobactam administered to ventilated, critically ill patients with pneumonia

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    Objectives: Ceftolozane/tazobactam is approved for hospital-acquired/ventilator-associated bacterial pneumonia at double the dose (i.e. 2 g/1 g) recommended for other indications. We evaluated the bronchopulmonary pharmacokinetic/pharmacodynamic profile of this 3 g ceftolozane/tazobactam regimen in ventilated pneumonia patients. Methods: This was an open-label, multicentre, Phase 1 trial (clinicaltrials.gov: NCT02387372). Mechanically ventilated patients with proven/suspected pneumonia received four to six doses of 3 g of ceftolozane/tazobactam (adjusted for renal function) q8h. Serial plasma samples were collected after the first and last doses. One bronchoalveolar lavage sample per patient was collected at 1, 2, 4, 6 or 8 h after the last dose and epithelial lining fluid (ELF) drug concentrations were determined. Pharmacokinetic parameters were estimated by noncompartmental analysis and pharmacodynamic analyses were conducted to graphically evaluate achievement of target exposures (plasma and ELF ceftolozane concentrations >4 mg/L and tazobactam concentrations >1 mg/L; target in plasma: similar to 30% and similar to 20% of the dosing interval, respectively). Results: Twenty-six patients received four to six doses of study drug; 22 were included in the ELF analyses. Ceftolozane and tazobactam T-max (6 and 2 h, respectively) were delayed in ELF compared with plasma (1h). Lung penetration, expressed as the ratio of mean drug exposure (AUC) in ELF to plasma, was 50% (ceftolozane) and 62% (tazobactam). Mean ceftolozane and tazobactam ELF concentrations remained >4 mg/L and >1mg/L, respectively, for 100% of the dosing interval. Therewere no deaths or adverse event-related study discontinuations. Conclusions: In ventilated pneumonia patients, 3 g of ceftolozane/tazobactam q8h yielded ELF exposures considered adequate to cover ceftolozane/tazobactam-susceptible respiratory pathogens

    Population Pharmacokinetics and Safety of Ceftolozane-Tazobactam in Adult Cystic Fibrosis Patients Admitted with Acute Pulmonary Exacerbation

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    ABSTRACT Ceftolozane-tazobactam has potent activity against Pseudomonas aeruginosa , a pathogen associated with cystic fibrosis (CF) acute pulmonary exacerbations (APE). Due to the rapid elimination of many antibiotics, CF patients frequently have altered pharmacokinetics. In this multicenter, open-label study, we described the population pharmacokinetics and safety of ceftolozane-tazobactam at 3 g every 8 h (q8h) in 20 adult CF patients admitted with APE. Population pharmacokinetics were determined using the nonparametric adaptive grid program in Pmetrics for R. A 5,000-patient Monte Carlo simulation was performed to determine the probability of target attainment (PTA) for the ceftolozane component at 1.5 g and 3 g of ceftolozane-tazobactam q8h across a range of MICs using a primary threshold exposure of 60% free time above the MIC ( fT >MIC). In these 20 adult CF patients, ceftolozane and tazobactam concentration data were best described by 2-compartment models, and ceftolozane clearance (CL) was significantly correlated with creatinine clearance ( r = 0.71, P MIC, ceftolozane-tazobactam regimens of 1.5 g and 3 g q8h should achieve PTAs of 鈮90% at MICs up to 4 and 8 渭g/ml, respectively. Ceftolozane-tazobactam at 3 g q8h was well tolerated. These observations support additional studies of ceftolozane-tazobactam for Pseudomonas aeruginosa APE in CF patients. (This study has been registered at ClinicalTrials.gov under identifier NCT02421120.

    Population pharmacokinetics of meropenem administered as a prolonged infusion in children with cystic fibrosis

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    OBJECTIVES: Meropenem is frequently used to treat pulmonary exacerbations in children with cystic fibrosis (CF) in the USA. Prolonged-infusion meropenem improves the time that free drug concentrations remain above the MIC (fT> MIC) in adults, but data in CF children are sparse. We describe the population pharmacokinetics, tolerability and treatment burden of prolonged-infusion meropenem in CF children. METHODS: Thirty children aged 6-17 years with a pulmonary exacerbation received 40 mg/kg meropenem every 8 h; each dose was administered as a 3 h infusion. Pharmacokinetics were determined using population methods in Pmetrics. Monte Carlo simulation was employed to compare 0.5 with 3 h infusions to estimate the probability of pharmacodynamic target attainment (PTA) at 40% fT> MIC. NCT#01429259. RESULTS: A two-compartment model fitted the data best with clearance and volume predicted by body weight. Clearance and volume of the central compartment were 0.41鈥娐扁0.23 L/h/kg and 0.30鈥娐扁0.17 L/kg, respectively. Half-life was 1.11鈥娐扁0.38 h. At MICs of 1, 2 and 4 mg/L, PTAs for the 0.5 h infusion were 87.6%, 70.1% and 35.4%, respectively. The prolonged infusion increased PTAs to >99% for these MICs and achieved 82.8% at 8 mg/L. Of the 30 children, 18 (60%) completed treatment with prolonged infusion; 5 did so at home without any reported burden. Nine patients were changed to a 0.5 h infusion when discharged home. CONCLUSIONS: In these CF children, meropenem clearance was greater compared with published values from non-CF children. Prolonged infusion provided an exposure benefit against pathogens with MICs 鈮1 mg/L, was well tolerated and was feasible to administer in the hospital and home settings, the latter depending on perception and family schedule

    Global injury morbidity and mortality from 1990 to 2017 : results from the Global Burden of Disease Study 2017

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    Correction:Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.Peer reviewe

    Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

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    A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4% (62.3 (55.1鈥70.8) million) to 6.4% (58.3 (47.6鈥70.7) million), but is predicted to remain above the World Health Organization鈥檚 Global Nutrition Target of <5% in over half of LMICs by 2025. Prevalence of overweight increased from 5.2% (30 (22.8鈥38.5) million) in 2000 to 6.0% (55.5 (44.8鈥67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic

    Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017

    Get PDF
    A double burden of malnutrition occurs when individuals, household members or communities experience both undernutrition and overweight. Here, we show geospatial estimates of overweight and wasting prevalence among children under 5 years of age in 105 low- and middle-income countries (LMICs) from 2000 to 2017 and aggregate these to policy-relevant administrative units. Wasting decreased overall across LMICs between 2000 and 2017, from 8.4 (62.3 (55.1芒锟斤拷70.8) million) to 6.4 (58.3 (47.6芒锟斤拷70.7) million), but is predicted to remain above the World Health Organization芒锟斤拷s Global Nutrition Target of <5 in over half of LMICs by 2025. Prevalence of overweight increased from 5.2 (30 (22.8芒锟斤拷38.5) million) in 2000 to 6.0 (55.5 (44.8芒锟斤拷67.9) million) children aged under 5 years in 2017. Areas most affected by double burden of malnutrition were located in Indonesia, Thailand, southeastern China, Botswana, Cameroon and central Nigeria. Our estimates provide a new perspective to researchers, policy makers and public health agencies in their efforts to address this global childhood syndemic. 脗漏 2020, The Author(s)

    Author Correction: Mapping local patterns of childhood overweight and wasting in low- and middle-income countries between 2000 and 2017 (Nature Medicine, (2020), 26, 5, (750-759), 10.1038/s41591-020-0807-6)

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    An amendment to this paper has been published and can be accessed via a link at the top of the paper. 脗漏 2020, The Author(s)
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