Comparing antimicrobial exposure based on sales data

This paper explores the possibilities of making meaningful comparisons of the veterinary use of antimicrobial agents among countries, based on national total sales data. Veterinary antimicrobial sales data on country level and animal census data in both Denmark and the Netherlands were combined with information about estimated average dosages, to make model calculations of the average number of treatment days per average animal per year, at first based on the assumption that the treatment incidence is the same in all species and production types. Secondly, the exposure in respectively animals for meat production and dairy and other cattle (excluding veal and young beef) was estimated, assuming zero use in the dairy and other cattle, and thirdly by assuming respectively 100% oral and 100% parenteral administration. Subsequently, the outcomes of these model calculations were compared with treatment incidences calculated from detailed use data per animal species from the national surveillance programmes in these two countries, to assess their accuracy and relevancy. In Denmark and in the Netherlands, although the computed antimicrobial exposure would seem to be a reasonable estimation of the exposure for all animals as a whole, it differs significantly from the measured exposure for most species. The differences in exposure among animal species were much higher than the overall difference between the two countries. For example, the overall model estimate of 9 treatment days per year for Denmark is a severe overestimation of the true use in poultry (i.e. 3 days), and the overall model estimate of 13 treatment days per year for the Netherlands is a severe underestimation of the true use in veal calves (i.e. 66 days). The conclusion is that simple country comparisons, based on total sales figures, entail the risk of serious misinterpretations, especially if expressed in mg per kg. The use of more precise model calculations for making such comparisons, taking into account differences in dosages and in farm animal demographics, only slightly reduces this risk. Overall model estimates are strongly influenced by animal demographics and a very inaccurate indication of the true differences in exposure, per animal species. To get an appropriate certainty about the true differences in antimicrobial exposure between countries it is an absolute necessity to have reliable information about the use per animal species

Tramadol Steady-State Pharmacokinetics of Immediate-Release Capsules and Sustained-Release Tablets in Dogs

Tramadol is a veterinary analgesic for dogs. In this study, the steady-state pharmacokinetics of a sustained-release (SR) tablet (Tramagetic OD®) and immediate-release capsules (IR) were compared. In a crossover design, six dogs received five doses of IR 50 mg four times a day (qid), or two doses of SR 200 mg once a day (sid). Eight blood samples were collected per dog, per formulation, up to 6 and 24 h after the last dose, respectively. Serum concentrations of tramadol and its metabolites were measured with LC-MS/MS. Metabolite M1 levels were below the lower limit of quantification (LLOQ) in all samples. The non-compartmental analysis of the time–concentration data showed a later Tmax with the SR formulation (median 6.00 h (3.00–9.00)) and a lower Cmax/D (median 7.74 µg/L/mg/kg (0.09–25.3)) compared to the IR formulation (median Tmax 1.75 h (0.75–2.00) and median Cmax/D 11.1 µg/L/mg/kg (4.8–70.4)). AUCtau/D after SR administration was 55.5 h × kg × µg/L/mg (0–174.1) compared to 29.8 h × kg × µg/L/mg (12.2–140.8) after IR administration. The terminal elimination half-lives were 2.38 h (1.77–6.22) and 1.70 h (0.95–2.11) for the SR and IR formulations, respectively. Strong conclusions cannot be drawn from this study because of the high percentage of samples that were below LLOQ and the great interindividual variability, but these results suggest that Tramagetic OD can be administered less frequently in dogs

Influence of applying different units of measurement on reporting antimicrobial consumption data for pig farms

Background: Antimicrobial use in livestock is one of the factors contributing to selection and spread of resistant microorganisms in the environment. National ve

Comparing human and animal antimicrobial usage: a critical appraisal of the indicators used is needed

Comparisons between antimicrobial usage (AMU) in humans and food-producing animals are regularly made. The accuracy of such comparisons depends on the indicators used to quantify AMU. Indicators for AMU quantitatively relate use data (the numerator) to population data (the denominator). The denominator should be a proxy for the population at risk in a certain period when comparing the exposure of different populations to antimicrobials. Denominators based on numbers of animals slaughtered, such as the commonly used population correction unit, do not consider the time at risk of antimicrobial treatment. Production-based indicators underestimate animal AMU. Additionally, production-based indicators are fundamentally different from indicators used to quantify human AMU. Using such indicators to compare human and animal AMU therefore leads to biased results. More caution should be taken in selecting the indicator to quantify AMU when comparing AMU in food-producing animals and humans

Comparing human and animal antimicrobial usage: a critical appraisal of the indicators used is needed

Comparisons between antimicrobial usage (AMU) in humans and food-producing animals are regularly made. The accuracy of such comparisons depends on the indicators used to quantify AMU. Indicators for AMU quantitatively relate use data (the numerator) to population data (the denominator). The denominator should be a proxy for the population at risk in a certain period when comparing the exposure of different populations to antimicrobials. Denominators based on numbers of animals slaughtered, such as the commonly used population correction unit, do not consider the time at risk of antimicrobial treatment. Production-based indicators underestimate animal AMU. Additionally, production-based indicators are fundamentally different from indicators used to quantify human AMU. Using such indicators to compare human and animal AMU therefore leads to biased results. More caution should be taken in selecting the indicator to quantify AMU when comparing AMU in food-producing animals and humans

Use of a new antimicrobial consumption monitoring system (Vet-AMNet): Application to Dutch dairy sector over a 9-year period

INTRODUCTION: The urgency of preventing the increase of antimicrobial resistance has been emphasized by international authorities such as the World Health Organization, European Medicines Agency, and World Organization for Animal Health. Monitoring systems capable of reporting antimicrobial consumption data are regarded as a crucial pillar of this fight. The Vet-AMNet system was developed to collect and analyze national antimicrobial consumption data in Portuguese dairy farms to support the veterinary authority in stewardship actions and to assist both veterinarians and farmers in daily decisions related to antimicrobials. METHODS: To evaluate the robustness of the system and other identified critical success factors, it was used to analyze antimicrobial consumption data available from the Dutch dairy cow sector over the period from 2012 to 2020. The data previously used for publications by the Netherlands Veterinary Medicines Institute (SDa) were imported and pre-processed by the Vet-AMNet system according to the SDa's standard operating procedure and the Dutch metrics to measure antimicrobial consumption were calculated. RESULTS: By comparing the outputs with the figures generated by the system established in the Netherlands, the Portuguese system was validated. Antimicrobial consumption data from the Dutch dairy sector during the 9-year period will be presented in unpublished graphs and tables, where each molecule's pharmaceutical formulation, pharmacotherapeutic group and line of choice will be related and discussed, illustrating the evolution of sectorial antimicrobial consumption against a background of a strong national antimicrobial policy initiated by public-private cooperation and supported by legislation

Quantifying Antimicrobial Use in Dutch Companion Animals

Antimicrobial resistance (AMR) is an increasing threat, both in human and in veterinary medicine. To reduce the selection and spread of AMR, antimicrobial use (AMU) should be optimized, also in companion animals. To be able to optimize AMU, a feasible method to quantify AMU and information on current AMU are needed. Therefore, a method to quantify AMU was developed, using the number of Defined Daily Doses Animal (DDDA). This method was used to explore applied antimicrobial classes and to identify differences in prescribing patterns in time and between veterinary clinics. Antimicrobial procurement data of the years 2012–2014 were collected retrospectively from 100 Dutch veterinary clinics providing care for companion animals. The mean number of DDDAs per clinic per year decreased significantly from 2012 to 2014. A shift in used classes of antimicrobials (AMs) was seen as well, with a significant decrease in use of third choice AMs (i.e., fluoroquinolones and third generation cephalosporins). Large differences in total AMU were seen between clinics ranging from 64-fold in 2012 to 20-fold in 2014. Despite the relative low and decreasing AMU in Dutch companion animal clinics during the study, the substantial differences in antimicrobial prescribing practices between clinics suggest that there is still room for quantitative and qualitative optimization of AMU

Seasonality of antimicrobial use in Dutch food-producing animals

Due to globally increasing antimicrobial resistance (AMR), it is pivotal to understand factors contributing to antimicrobial use (AMU) to enable development and implementation of AMR-reducing interventions. Therefore, we explored seasonal variations of systemic AMU in food-producing animals in the Netherlands. Dutch surveillance data from January 2013 to December 2018 from cattle, pig, and broiler farms were used. AMU was expressed as the number of Defined Daily Dosages Animal per month (DDDA/animal-month) per farm by animal sector, antimicrobial line (first, second, and third), antimicrobial class, and farm type. Seasonality of AMU was analyzed using Generalized Additive Models (GAMs) with DDDA/animal-month as outcome variable, and year and month as independent variables. Year and month were modelled as smooth terms represented with penalized regression splines.Significant seasonality of AMU was found in the cattle and pig sectors, but not in broilers. Significant seasonality of AMU was found mainly for first-line antimicrobials. In the cattle sector, a significant increase during winter was found for the use of amphenicols (an increase of 23.8%) and long-acting macrolides (an increase of 3.4%). In the pig sector, seasonality of AMU was found for pleuromutilins (p < 0.001) with an increase of 20% in October-November. The seasonality of pleuromutilins was stronger in sows/piglets (an increase of 47%) than in fattening pigs (16% increase). Only in fattening pigs, the use of amphenicols showed a significant seasonality with an increase of 11% during winter (P < 0.001). AMU in cattle and pig sectors shows seasonal variations likely caused by seasonality of diseases. In broilers, no AMU seasonality was observed, possibly due to the controlled environment in Dutch farms. In the context of the one health concept, future studies are necessary to explore whether this seasonality is present in other populations and whether it has implications for antimicrobial resistance in humans through the food chain

Evaluation of PEG-L-asparaginase in asparagine suppression and anti-drug antibody development in healthy Beagle dogs: A multi-phase preclinical study

L-asparaginase is a frequently used drug in the treatment of canine malignant lymphoma. Since production and availability of native E. coli-derived L-asparaginase are limited, PEG-L-asparaginase (PEG-ASP) is an alternative. However, recommended doses and dosing intervals are mainly empirically determined. A multi-phase clinical dose-finding study with seven healthy Beagle dogs was conducted to find the minimum effective dose and, potentially, a dosing interval for PEG-ASP in dogs. Plasma concentrations of amino acids and PEG-ASP activity were measured at various time points after administration of different doses of PEG-ASP. Anti-PEG and anti-asparaginase antibody titres were measured. Administration of 10 IU/kg PEG-ASP resulted in asparagine depletion in all dogs, albeit for various durations: for 9 days in all dogs, 15 days in five dogs, 21 days in three dogs and 29 days in one dog. Asparagine suppression occurred at PEG-ASP plasma concentrations < 25 IU/L. Subsequent administrations of a second and third dose of 20 IU/kg and 40 IU/kg PEG-ASP resulted in asparagine suppression at < 9 days in five dogs, accompanied by the development of antibodies against PEG and L-asparaginase. Two dogs with prolonged asparagine suppression after the second and third administration did not develop antibodies. Marked individual variation in the mechanism and duration of response to PEG-ASP was noted. Antibody formation against PEG-ASP was frequently observed and sometimes occurred after one injection. This study suggests that PEG-ASP doses as high as the currently used dose of 40 IU/kg might not be needed in treatment of canine malignant lymphoma

Quantifying topical antimicrobial use before and during participation in an antimicrobial stewardship programme in Dutch companion animal clinics

The emergence of bacterial strains resistant to topical antimicrobials in both human and veterinary medicine has raised concerns over retaining the efficacy of these preparations. Yet, little information is available regarding the use of topical antimicrobials in either sector for planning targeted interventions. This study aims to quantify the use of topical antimicrobials in 44 Dutch companion animal clinics before and during their participation in an antimicrobial stewardship programme (ASP), to explore the effect of the intervention on topical antimicrobial use (AMU). Hence, prescription and clinic animal population data, collected from July 2012 until June 2018 were used. Specifically, the period from July 2012 until June 2015 was defined as pre-intervention period, whereas clinics started to participate in the ASP from March 2016 onwards. As quantification metric, the Defined Daily Dose for Animals (DDDA) was used and a mixed effect times series model with auto-regression was applied to monthly topical AMU data. The intervention effect was modelled using a step function with a change in (linear) time trend and clinic characteristics, as potential determinants of topical AMU, were assessed using a multivariable regression model. A seasonal pattern was identified, in the pre-intervention period, where topical AMU was highest in July-August and lowest in February-March. In addition, total topical AMU appeared to significantly decrease over time in the pre-intervention period and the proportion of dogs in the clinic was positively associated with topical AMU. The intervention effect was significant only for second line and for skin product AMU. This study demonstrates that during participation in an ASP, second line and skin product AMU decreased in Dutch companion animal clinics. Additionally, this study demonstrates the existence of a seasonal effect and a decrease in topical AMU over time already before introduction of a targeted intervention