Comparison with literature
Previously conducted studies regarding consecutive antibiotic use report high treatment failure rates [
11,
12]. A study performed in the United States of America reports unadjusted failure rates ranging from 20 to 24% for antibiotics prescribed for treatment of community-acquired pneumonia [
11]. A study from the United Kingdom reports an overall treatment failure rate of 15% for antibiotics prescribed for the treatment of upper and lower respiratory tract infections, skin and soft tissue infections, and acute otitis media [
12]. The vast majority of treatment failures include antibiotic switches as is demonstrated in the study of Currie et al. reporting a switch in 94% of failures [
12]. A recent study from Norway reports an average switch rate of 6% for doxycycline, amoxicillin, phenoxymethylpenicillin and macrolides [
13]. A Danish study evaluated prescribing patterns of antibiotics among Danish children and found switch percentages of 5 and 1% for phenoxymethylpenicillin and amoxicillin [
14]. Although we cannot directly compare our results with these data, due to different settings and studies, differences in switch rates between countries is apparent. Switch rates in the Netherlands seems to be low in comparison with US, UK and Norway.
We found the highest switch percentages for trimethoprim and nitrofurantoin. These antibiotics are predominantly used to treat urinary tract infections and the switch percentages indicate that initial treatment with these antibiotics is quite often followed by another antibiotic. According to the Dutch national guidelines, nitrofurantoin is the first choice treatment for uncomplicated urinary tract infections in the outpatient setting [
17]. Fosfomycin should be used as second choice and trimethoprim as third [
17]. The total use of nitrofurantoin significantly increased from 1.0 defined daily dose (DDD) /1000 inhabitant-days to 1.4 DDD/1000 inhabitant-days [
5], and the switch percentage for nitrofurantoin showed a minor yearly increase. Trimethoprim showed a relatively high switch percentage of 7.6%. This might be explained by high resistance to trimethoprim among urine-isolated
E. coli, K.
pneumonia and
P. mirabilis, the predominant species causing urinary tract infections in the Netherlands [
5]. It was shown that fosfomycin, trimethoprim and ciprofloxacin are often used as second prescription after initial treatment with nitrofurantoin. This is in line with the Dutch guidelines for the treatment of urinary infections [
17]. However, the vast majority of prescriptions for fosfomycin, trimethoprim and ciprofloxacin concern first prescriptions in a treatment, which is not in line with guidelines. A decrease in the switch percentage for sulfamethoxazole/trimethoprim is in line with a decreasing resistance for this agent in the primary care setting in the Netherlands [
5]. In the Netherlands, presentation of urological indications has been increasing, with 148 episodes per 1000 patient-years in 2010; the prescribing rate for urological indications remained about 50% [
18].
For ciprofloxacin we found a yearly increase in total use and a corresponding annual increase of 0.08% in its switch percentage. This is worrisome as it could reflect increased bacterial resistance to ciprofloxacin. Ciprofloxacin often is a 3rd choice treatment in Dutch primary care and reserved for severe infections and hospitalised patients, and resistance in primary care jeopardises this aim.
Not surprisingly, amoxicillin/clavulanic acid is the drug that is most often used as second antibiotic in a switch. It is used after a wide variety of first prescriptions, including nitrofurantoin, amoxicillin, doxycycline, flucloxacillin, a macrolide and ciprofloxacin. A second prescription of either azithromycin or clarithromycin, amoxicillin/clavulanic acid or doxycycline after initial amoxicillin are all plausible changes in treatment strategy.
Our data indicate that fosfomycin and ciprofloxacin are increasingly used as second drug in an antibiotic treatment course. This could be the result of high switching from trimethoprim and nitrofurantoin and the increase in cystitis episodes [
18]. Treatment failure due to resistance to first choice antibiotics could also be (partly) responsible for this observation, however, as we do not know the reason for a switch firm conclusions cannot be drawn. The increase in fosfomycin being used as a second agent might be the result of changes in the Dutch guidelines for urinary tract infections. Since 2005 fosfomycin is considered the second option to treat cystitis, making it plausible that fosfomycin use (as first and second prescriptions) increases in the following years.
Strengths and limitations of the study
The main strength of the study is the use of a nationwide database containing over 90% of total dispensed antibiotics. The use of a database containing pharmacy dispensing data instead of prescription data results in more valid estimations of consumed antibiotics. Because patients in the Netherlands are often linked to one pharmacy, it is possible to monitor subsequent antibiotic use based on pharmacy data. A recent study showed that only 2% of patients regularly switch between pharmacies [
19]. In contrast to earlier antibiotic switch studies that report data on specific diagnoses, or specific groups of antibiotics [
11‐
13], our study gives an overview of the total outpatient antibiotic use. The greatest value of our approach is the analysis and visualisation of consecutive antibiotic use and distinguishing between prolongations and switches. In contrast to other studies that define switches as a prescription of a new antibiotic within 1 month after index date [
11‐
13], our study uses a calculated end date of the first antibiotic to define antibiotic switches. The chance of including treatment for new or unrelated infections instead of prolonged treatment of the initial one is largely reduced by this method. Furthermore, we excluded patients on (nearly) chronic antibiotics because these could distort the data. In these patients antibiotics are mainly used for the prevention of recurrent infections instead of treating acute infectious disease episodes.
However, there are also limitations to our study that need to be addressed. First, the indication for prescription was not available. With the indication it would have been possible to specifically identify those switches that deviate from national treatment guidelines. Second, the data only contains outpatient pharmacy data. Data on treatment failures leading to hospital admission, visits to the emergency department, or antibiotics previously used in the hospital setting were not available and could not be incorporated. Finally, we were not able to determine the actual reason for the antibiotic switches. Although we speculate that an antibiotic switch reflects ineffectiveness of the treatment, possibly as a result of bacterial resistance, there can be several other explanations. Switches can also be a result of doctors’ behaviour (wrong diagnosis, inappropriate prescribing), patients’ behaviour (non-compliance, inappropriate expectations and re-counselling), or progression of the infection itself (including complications), or availability of the results of in vitro antimicrobial susceptibility testing. The evidence linking antibiotic treatment failure and antibiotic resistance is considered to be weak [
20,
21]. Therefore, we cannot expect that bacterial resistance is the major cause of treatment failure and antibiotic switches.
Future challenges
The dataset could be enriched by linking pharmacy data with clinical patient data, the antibiotic indication, outcomes of antimicrobial susceptibility tests, clinical outcomes and complications. However, there are security, privacy and technical issues that need to be addressed before such linking can be performed. Another challenge is to study seasonal and demographic differences in switch percentages for antibiotics. For European comparison studies, we encourage others to also evaluate trends in consecutive antibiotic use and switching patterns. These issues can provide even more detailed information that can help policymaking.