National laboratory-based surveillance system for antimicrobial resistance: a successful tool to support the control of antimicrobial resistance in the Netherlands

An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the

[Tetrahydrobiopterin as putative mediator in septic shock.]

Enhanced serum levels neopterin are associated with various immune-related diseases like septic shock and vascular leakage syndrome. Tetrahydrobiopterin (THB, 100 muM) but not bioterin induces appreciable endothelium-dependent vasodilatation and enhances cGMP-level (95% increase) to the same extent as arecoline. NG-methyl-L-arginine (L-NAME) does not antagonize the tetrahydrobiopterin effects. In addition, tetrahydrobiopterin enhances cGMP-level in tracheal smooth muscle (+28%) and artery pulmonalis (+57%). Present results show that tetrahydrobiopterin being precursor of biopterin and co-factor of NO-synthase, induces vasodilatation by increasing intracellular cyclic GMP level and suggest a prominent role for tetrahydrobiopterin in immune-triggered hypotension.GH

Pharmacokinetic/pharmacodynamic target attainment of ciprofloxacin in adult patients on general wards with adequate and impaired renal function

Limited prospective data on pharmacokinetic/pharmacodynamic (PK/PD) target attainment of ciprofloxacin in patients with adequate and impaired renal function (eGFR <30 mL/min/1.73m2) are available in the literature. We aimed to investigate whether the PK/PD target (AUC/MIC ≥125) is attained in patients with adequate and impaired renal function receiving regular and reduced ciprofloxacin doses. This prospective observational cohort study included adult patients on general wards treated with ciprofloxacin. Three blood samples per patient were obtained for ciprofloxacin concentration measurement. Individual AUCs were calculated using a population PK model developed by non-linear mixed-effects modelling. Forty patients were included, of whom eight had impaired renal function and were treated with a guideline-recommended reduced dose. Using the clinical breakpoint MIC of the most isolated bacteria (Escherichia coli, 0.25 mg/L), AUC0–24/MIC ≥125 was attained in 13/32 (41%) patients with adequate renal function receiving regular doses and in 1/8 (13%) patients with impaired renal function receiving reduced doses. Median drug exposure (AUC0–24) for patients with impaired renal function was 19.0 [interquartile range (IQR) 14.2–23.3] mg/L•h, which was statistically significantly lower than that for patients with adequate renal function [29.3 (IQR 25.0–36.0) mg/L•h] (P < 0.01). AUC0–24/MIC ≥125 is not attained in the majority of adult patients on general wards for clinically relevant bacteria with MICs at or just below the clinical breakpoint. The risk of not attaining the target appears to be highest in patients with impaired renal function receiving guideline-recommended reduced doses, as drug exposure is significantly lower in these patients

National laboratory-based surveillance system for antimicrobial resistance:a successful tool to support the control of antimicrobial resistance in the Netherlands

An important cornerstone in the control of antimicrobial resistance (AMR) is a well-designed quantitative system for the surveillance of spread and temporal trends in AMR. Since 2008, the Dutch national AMR surveillance system, based on routine data from medical microbiological laboratories (MMLs), has developed into a successful tool to support the control of AMR in the Netherlands. It provides background information for policy making in public health and healthcare services, supports development of empirical antibiotic therapy guidelines and facilitates in-depth research. In addition, participation of the MMLs in the national AMR surveillance network has contributed to sharing of knowledge and quality improvement. A future improvement will be the implementation of a new semantic standard together with standardised data transfer, which will reduce errors in data handling and enable a more real-time surveillance. Furthermore, the scientific impact and the possibility of detecting outbreaks may be amplified by merging the AMR surveillance database with databases from selected pathogen-based surveillance programmes containing patient data and genotypic typing data.</p

The effect of low pH on breast cancer resistance protein (ABCG2)-mediated transport of methotrexate, 7-hydroxymethotrexate, methotrexate diglutamate, folic acid, mitoxantrone, topotecan, and resveratrol in in vitro drug transport models

Some cellular uptake systems for (anti)folates function optimally at acidic pH. We have tested whether this also applies to efflux from cells by breast cancer resistance protein (BCRP; ABCG2), which has been reported to transport folic acid, methotrexate, and methotrexate di- and triglutamate at physiological pH. Using Spodoptera frugiperda-BCRP membrane vesicles, we showed that the ATP-dependent vesicular transport of 1 muM methotrexate by BCRP is 5-fold higher at pH 5.5 than at physiological pH. The transport of methotrexate was saturable at pH 5.5, with apparent Km and Vmax values of 1.3 +/- 0.2 mM and 44 +/- 2.5 nmol/mg of protein/min, respectively, but was linear with drug concentration at pH 7.3 up to 6 mM methotrexate. In contrast to recent reports, we did not detect transport of methotrexate diglutamate at physiological pH, but we did find transport at pH 5.5. We also found that 7-hydroxy-methotrexate, the major metabolite of methotrexate, is transported by BCRP both at physiological pH and (more efficiently) at low pH. The pH effect was also observed in intact BCRP-overexpressing cells: we found a 3-fold higher level of resistance to both methotrexate and the prototypical BCRP substrate mitoxantrone at pH 6.5 as at physiological pH. Furthermore, with MDCKII-BCRP monolayers, we found that resveratrol, which is a neutral compound at pH < or = 7.4, is efficiently transported by BCRP at pH 6.0, whereas we did not detect active transport at pH 7.4. We conclude that BCRP transports substrate drugs more efficiently at low pH, independent of the dissociation status of the substrate