Study findings and implications
This is one of the first studies to look at outpatient antibiotic prescriptions among children in the bordering regions of two countries. Considering the importance of appropriate antibiotic use, the ability for patients to seek healthcare services abroad, and the large differences between healthcare systems and guidelines, a cross-border comparison is of great interest. Furthermore, these comparisons may be beneficial to inform healthcare providers and to discuss best clinical practice. We observed considerable differences between the two countries. This may indicate that improvements can be achieved. Mainly on the distribution of substances, differences were profound: second generation cephalosporins (i.e., mostly oral cefuroxime) were prescribed in 25 % of the cases for the German patients, while almost none of the Dutch children received this type (<0.1 %). Given the low rate of oral bioavailability and the high selective pressure due to these substances, they are avoided wherever possible in ambulatory paediatric care in the Netherlands. It would be highly interesting and relevant to perform further research into the reasons for prescribing second generation cephalosporins in Germany and its long term effects.
These differences in prescriptions of antibiotics for outpatients between European countries have been reported earlier, although not for bordering regions. There are however comparisons showing differences between Germany and the Netherlands in general , as well as for children . In the Netherlands, guideline adherence is higher compared to Germany , which might also be a reason for different distributions of substances between both countries. In 7–17 years old children, nitrofurantoin was among the top 5 antibiotics in the Netherlands but not in Germany. In Germany, there may still be hesitance to prescribe nitrofurantoin due to a history of warnings in the past (pulmonary fibrosis, neuropathy and liver damage) .
In addition, the occurrence of resistant bacteria such as MRSA differs also significantly between the bordering regions of the Netherlands and Germany, with up to 32-fold higher MRSA incidence in the German border region compared to the adjacent Dutch border region . In addition, higher resistance rates were also observed for classical community-acquired pathogens such as pneumococci where penicillin-resistance involved 1.9 % of invasive isolates in Germany vs. 0.2 % in the Netherlands in 2013 . The Dutch prevalence data observed in this study are comparable to earlier studies, indicating a quite stable use and also corroborating the fact that the IADB database can be considered as representative for the whole county [9, 17]. Comparing various German studies there is a bit more variation, but it is known that there is a quite large regional variation of outpatient antibiotic prescriptions within the country. The north-western part of Germany, which is included in this study, is one of the higher prescribing regions [18, 19].
For both datasets, clinical indications for the prescriptions analyzed were not known. For the Netherlands, a large survey showed that the primary diagnosis for children coming to general practitioners is lower respiratory tract infections . Antibiotic prescriptions by general practitioners for children in the Netherlands are mainly for acute otitis media and bronchitis, and especially broad-spectrum antibiotics are still prescribed inappropriately . Dutch guidelines regarding antibiotic treatment are very strict. Otitis media guidelines recommend antibiotics only when there are other risk factors for complications or with severe general symptoms . For respiratory tract infections, antibiotics are only recommended in the case of pneumonia . In Germany most diagnoses for children (0–15 years) in an outpatient setting were upper respiratory tract infections without a focus, fever without a focus and acute bronchitis . Antibiotic prescriptions for this group are mainly given for acute tonsillitis, bronchitis and otitis media, for all of which appropriateness of antibiotics is debatable . The German guideline for otitis media recommends antibiotic treatment only to be started after two days, thereby being less conservative than the Dutch counterpart . The general guideline for bronchitis states that when uncomplicated, antibiotics are not recommended and should be avoided .
Influence of parents on the prescribed antibiotic treatment seems to be relatively small. A European survey, although not performed in the Netherlands or Germany, showed that patients tend to adhere to the decision of the general practitioner even when they disagree . When they disagree, they have a tendency to be more conservative than the physician . A survey in Germany confirms this and shows that the large majority of patients understand the limitations of antibiotic treatment for indications like the common cold . The influence of the family practitioner or paediatrician thus seems to be often underestimated, whereas they show indeed a high inter-individual variation in their prescription pattern . Perceptions of antibiotic resistance among general practitioners also differs between countries , probably also leading to different prescription behaviour. A combination of these aspects is most likely leading to the differences between the Netherlands and Germany.
Strengths and limitations
The major strength of this study is the unique dataset of two bordering regions coming from countries with different healthcare systems and antibiotic prescribing policies. Other studies compared nationwide data (either from a subset of databases or up to 100 % coverage such as most of ESAC). However, as shown here for the first time, there are also large small area variations among and between bordering regions from two different countries. Studies comparing national consumption data, aggregate these data and variations within a country are then lost, making it impossible to effectively compare bordering regions. We were able to include about 37,000 children and adolescents living in the northern Netherlands as well as 18,000 living in north-west Germany. However, especially in the Netherlands our cohort size differs relevantly per area (depending on the distribution of pharmacies included in the IADB.nl database). Therefore, in some areas several postal codes were combined. Age distribution and drug utilization of the patients included in the database is, however, representative for the total Dutch population . For Germany, the sample size was somewhat smaller than for the Netherlands. German data were derived from a large health insurance fund and we know that differences exist regarding socioeconomic status and morbidity between these insurance funds . Such differences were found in children and adolescents, too, but the utilization of medications within the specific fund we used was quite comparable to the complete German population . Unfortunately, we had no access to diagnoses and indications for which antibiotics were prescribed. These data would be relevant in determining the appropriateness of the (antibiotic) treatments, and also could shed light on the question if some patients might even be undertreated. It seems, that coming closer to the border increases antibiotic consumption in both countries. One explanation might be, that these parts of the country are furthest away from an academic centre. These (rural) parts of the countries are also socio-economically weaker compared to the more densely populated parts. Such a lower socio-economic status appears to influence antibiotic prescribing, although it is unclear to which extent [34, 35]. However, more precise information is not available within the datasets used. This study should form a starting point for (regional) antimicrobial stewardship programs focusing on general practitioners and outpatients. This group is still somewhat neglected in stewardship programs, but these data show that there is a lot to gain.
It is important to keep in mind that the structures and organization of the two healthcare systems differ substantially between the Netherlands and Germany. In the former, there are only family practitioners in private practice, whereas nearly all specialists are working in outpatient clinics in (larger) hospitals. Hence, the data analyzed in this study primarily contain prescription data for these family physicians. In Germany, the majority of medical specialists, including paediatricians, is working in private practice (or consortiums). The German data set comprised also the data from these specialists. Previous analysis for the whole of Germany showed that 49 % of the prescriptions came from paediatricians and 35 % from general practitioners . This may also influence individual prescribing patterns due to a variety of reasons and cause a bias due to more severe cases treated by specialists on the German side of the border, although we hypothesize that severe cases are most likely send to a hospital and are thus not included in this dataset. One may speculate that the more individualized healthcare system for primary care in Germany might lead to a more heterogeneous healthcare behaviour than the more peer group-dependent gatekeeper system in the Netherlands. Prescribing patterns are influenced by many different factors. Other differences between the Netherlands and Germany (e.g. medical education, performing microbiological diagnostics or healthcare insurance system) are most likely also of influence, however to which degree is uncertain and should be subject to further investigation.