Background.Although the Netherlands is a country with a low endemic level, methicillin-resistant Staphylococcus aureus (MRSA) poses a significant health care problem. Therefore, high coverage... Show moreBackground.Although the Netherlands is a country with a low endemic level, methicillin-resistant Staphylococcus aureus (MRSA) poses a significant health care problem. Therefore, high coverage national MRSA surveillance has been in place since 1989. To monitor possible changes in the type-distribution and emergence of resistance and virulence, MRSA isolates are molecularly characterized.Methods.All 43,321 isolates from 36,520 persons, collected 2008-2019, were typed by multiple-locus variable number tandem repeats analysis (MLVA) with simultaneous PCR detection of the mecA, mecC and lukF-PV genes, indicative for PVL. Next-generation sequencing data of 4991 isolates from 4798 persons were used for whole genome multi-locus sequence typing (wgMLST) and identification of resistance and virulence genes.Results.We show temporal change in the molecular characteristics of the MRSA population with the proportion of PVL-positive isolates increasing from 15% in 2008-2010 to 25% in 2017-2019. In livestock-associated MRSA obtained from humans, PVL-positivity increases to 6% in 2017-2019 with isolates predominantly from regions with few pig farms. wgMLST reveals the presence of 35 genogroups with distinct resistance, virulence gene profiles and specimen origin. Typing shows prolonged persistent MRSA carriage with a mean carriage period of 407 days. There is a clear spatial and a weak temporal relationship between isolates that clustered in wgMLST, indicative for regional spread of MRSA strains.Conclusions.Using molecular characterization, this exceptionally large study shows genomic changes in the MRSA population at the national level. It reveals waxing and waning of types and genogroups and an increasing proportion of PVL-positive MRSA.A group of bacteria that cause difficult-to-treat infections in humans is methicillin-resistant Staphylococcus aureus (MRSA). The aim of this study was to monitor changes in the spread of MRSA, their disease causing potential and resistance to antibiotics used to treat MRSA infections. MRSA from patients and their contacts in the Netherlands were collected over a period of 12 years and characterized. This revealed new types of MRSA emerged and others disappeared. An increasing number of MRSA produces a protein called PVL toxin, enabling MRSA to cause more severe infections. Also, some people appear to carry MRSA without any disease for more than a year. These findings suggest an increasing disease potential of MRSA and possible unnoticed sources of infection. Consequently, it is important to maintain monitoring of these infections to minimize MRSA spread.Schouls et al. characterize 43,321 methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained between 2008 and 2019 in the Netherlands. Genomic changes occur in the MRSA population, with increases in the proportion of PVL-positive MRSA. Show less
Background: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic... Show moreBackground: Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%integral T > 1-4xMIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment.Methods: This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (integral T > MICECOFF and integral T > 4xMIC(ECOFF)) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes.Results: A total of 147 patients were included, of whom 63.3% achieved PDT of 100% integral T > MICECOFF and 36.7% achieved 100% integral T > 4xMIC(ECOFF). Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) >= 90 mL/min/1.73 m(2), and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100% integral T > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival.Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Show less
Purpose To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective... Show morePurpose To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. Methods Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an integral AUC(0-24)/MIC >= 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. Results A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m(2), and eGFR of 58.5 mL/min/1.73 m(2). The median integral AUC(0-24) and integral C-max were 29.9 mg center dot h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target integral AUC(0-24)/MIC >= 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of >= 1200 mg/day is needed to achieve sufficient integral AUC(0-24)/MIC ratios. Conclusions The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure. Show less
Prehn, J. van; Triest, M.I. van; Altorf-van der Kuil, W.; Dijk, K. van; Stuart, J.W.T.C.; Weersink, A.J.L.; ... ; Dutch Natl AMR Surveillance Study 2019
A survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a... Show moreA survey of diagnosis and treatment of invasive aspergillosis was conducted in eight University Medical Centers (UMCs) and eight non-academic teaching hospitals in the Netherlands. Against a background of emerging azole resistance in Aspergillus fumigatus routine resistance screening of clinical isolates was performed primarily in the UMCs. Azole resistance rates at the hospital level varied between 5% and 10%, although rates up to 30% were reported in high-risk wards. Voriconazole remained first choice for invasive aspergillosis in 13 out of 16 hospitals. In documented azole resistance 14 out of 16 centres treated patients with liposomal amphotericin B. Show less
Groep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle... Show moreGroep B streptokokken (GBS) zijn belangrijke veroorzakers van ernstige infecties rondom de bevalling. Ter preventie van GBS-ziekte bij het kind worden antibiotica aan ongeveer 20% van alle zwangeren toegediend. Ondanks de toediening van antibiotica worden er soms kinderen ziek. Onderzoek naar de farmacokinetiek (lotgevallen van geneesmiddelen in het lichaam) en de huidige dosering van deze antibiotica tijdens de bevalling werd nog niet eerder verricht. Antibiotica zoals amoxicilline en clindamycine, die tijdens de bevalling worden toegediend, moeten bij de moeder een voldoende tijd een werkzame bloedspiegel hebben, de moederkoek passeren en ook bij het kind een voldoende tijd een werkzame bloedspiegel bereiken. Uit ons onderzoek blijkt, dat voor amoxicilline de farmacokinetiek bij vrouwen met gebroken vliezen voor aanvang van de bevalling vergelijkbaar is met die bij niet-zwangeren. Verschillende situaties bleken geen invloed te hebben op de farmacokinetiek van amoxicilline. Wanneer gebruik wordt gemaakt van een farmacokinetisch computermodel, waarin de bloedspiegels van amoxicilline van moeder, de navelstreng en het kind verwerkt zijn, lijkt de begin dosis van 2 gram amoxicilline afdoende voor het voorkomen van GBS-ziekte. Doseringen penicilline G die gebruikt worden voor de behandeling van GBS-ziekte bij vroegtijdig geboren kinderen zijn ook afdoende. Over clindamycine kunnen geen definitieve conclusies getrokken worden. Show less
