We developed a national population level cost estimation about the unnecessary cost of antibiotic prescription for URI. To our knowledge, the present study is the first to assess physicians’ antibiotic prescription behaviour not only in view of the proportion of antibiotic prescriptions but also the associated additional costs. By adding the viewpoint of cost, our findings show novel characteristics of inappropriate antibiotic prescription in ambulatory care settings.
First, both the proportion and cost of unnecessary antibiotic prescription for URI have decreased in recent years. The proportion of URI cases to which physicians prescribed antibiotics was 32·41% in 2013 but only 29·36% in 2016. The cost of antibiotic prescriptions for URI cases was 423·6 million USD in 2013 and decreased to 297·1 million USD in 2016. The proportion of URI cases to which physicians prescribed unnecessary antibiotics demonstrated a gradually decreasing trend every year and the total annual cost of antibiotic prescriptions for URI in 2016 was about 30% lower than that in 2013. According to a previous study, Japanese physicians had prescribed antibiotics for 60% of URI cases in 2005. It is difficult to compare the results of the present study and that of the previous study because of sample size (the previous study analysed only 2,577 claims), sampling period (the previous study collected claims from January to March 2005 only), and other factors. Nevertheless, this decreasing trend of unnecessary antibiotic use might have already existed in Japan early in this century.
As mentioned above, the Japanese government established the National Action Plan on AMR in 2016. While it will take a few more years to assess the impact of this plan because it is newly established, our findings might reflect physicians’ alteration in awareness on AMR rather than behavioural change in antibiotic prescription.
Conversely, the proportion of antibiotic prescriptions for URI is difficult to compare with previous studies from foreign countries due to differences in settings and conditions. For example, Barnett and Linder reported that the antibiotic prescribing rate dropped from roughly 80% to 70% around 1993 and decreased again around 2000 to 60%. However, their study was limited to adults and ‘sore throat’ cases; therefore, a large number of bacterial pharyngitis cases were likely included. Finkelstein and colleagues examined the effect of an educational outreach intervention in ambulatory care but only evaluated paediatric cases. Fleming-Dutra and colleagues conducted a more extensive analysis, however, their focus was on whole ambulatory care, which includes diagnoses sometimes appropriate for antibiotic prescription (e.g. otitis media and sinusitis).
Furthermore, we must take the differences in healthcare system between Japan and other countries into consideration. The Japanese healthcare system generally secures ‘free access’ to healthcare services, regardless of facility level, and there is no limitation on the frequency of ambulatory care visit. This implies that a larger number of URI patients tends to visit ambulatory care although URI is basically a self-limited disease and there are substantial numbers of URI patients amongst patients admitted to healthcare facilities[19, 20]. This fact makes it more difficult to compare the proportion of URI cases prescribed antibiotics prescribed. While decreasing trends in the proportion and cost of antibiotic prescription for URI are favourable findings, the main driver of this trend and the current situation of Japanese ambulatory care in global society are still not clear.
Second, our results demonstrated the importance of appropriate antibiotic use, especially in paediatric ambulatory care. Despite the comparatively low rate of antibiotic prescription in children and the ratio of children to the total population, the additional cost in children under 15 years accounted for over 30% of total additional costs annually. This finding likely reflects the frequency of healthcare facility visits attributed to URI by children. Additionally, most Japanese nursery schools and kindergartens require caregivers to bring their children to healthcare facilities when they catch a cold. As a result, children are exposed to the risk of unnecessary antibiotic prescription more frequently than adults are in Japanese ambulatory care. Therefore, children should be an appropriate target population for interventions to promote appropriate antibiotic use.
Third, it is noteworthy that broad-spectrum oral antibiotics accounted for the majority of additional antibiotic prescription costs for URI. Three antibiotic classes (third-generation cephalosporins, macrolides, and fluoroquinolones) comprised almost 95% of total additional antibiotic prescription costs for URI in Japan. Our finding of a high prescription rate of third-generation cephalosporins and macrolides is compatible with findings from a previous study. The fluoroquinolone prescription rate was comparatively low, however, it can be attributed to the clinical contraindication of fluoroquinolones for children. We observed an extremely low prescription rate of fluoroquinolones in children under 5 years and a high rate in adults (Supplementary file 3). Considering these findings with the difference in drug prices between these broad-spectrum antibiotics and other narrow-spectrum antibiotics (e.g. penicillins), we can understand the significance of appropriate use of broad-spectrum antibiotics more profoundly. Compared with other high-income countries, Japan demonstrated higher consumption rates of these three antibiotic classes. Namely, these broad-spectrum antibiotics could be an appropriate target for antimicrobial stewardship in ambulatory care in Japan, not only from the standpoint of antimicrobial resistance but also that of economic burden.
Strengths and limitations
A major strength of the present study is the use of a large number of individual patient-level claims data, which cover both children and adults. Conversely, our data did not include claims of patients 65 years of age or older.
While millions of individual claims are included in the dataset, its representativeness is not completely assured because our data are based on information from health insurance purchased by enterprises. Nevertheless, a low proportion of self-employed people (8·48% in 2017) and low unemployment rate (3·1% in 2016) in Japan enable us to justify the result of our analyses. Because self-employed and unemployed people are also covered by other types of national health insurance in the Japanese healthcare system and out-of-pocket costs are reimbursed according to each individual’s income, we can expect that healthcare-seeking behaviour would not be greatly different among employed, self-employed, and unemployed individuals. Nonetheless, further study would be desirable to examine the difference in healthcare-seeking behaviour brought by employment status.
In addition, diagnoses in the dataset are sometimes unreliable. It is often the case that physicians make different diagnosis in the claims on purpose to justify their examinations and prescriptions. Nevertheless, physicians never make a fake diagnosis of “URI” when they would like to prescribe antibiotics, but make a diagnosis of other bacterial infections in order to justify their antibiotic prescriptions. Then therefore unreliable diagnoses might not overemphasize the cost of inappropriate antibiotic prescription.
Another strength is that we introduced the concept of cost. Although the rate of antibiotic prescription or defined daily dose are indicators understood intuitively, our findings added another aspect of broad-spectrum antibiotics. As one important limitation, our present analyses showed conservative results because we did not consider any additional cost of adverse effects of antibiotics. For example, rush, diarrhoea, and anaphylaxis are general adverse effects sometimes observed with systemic use of oral antibiotics. Of course, these adverse events might impose additional medical costs, however, there is no appropriate information about costs and the probability of such events is unclear in Japan thus far. Furthermore, broad-spectrum antibiotics have their own adverse effects. For example, oral third-generation cephalosporins can cause hypocarnitinaemia on rare occasions. Azithromycin is associated with a slightly increased risk of cardiovascular death. Fluoroquinolones uncommonly cause tendon rupture and QT prolongation and the US Food and Drug Administration updated its drug safety information for fluoroquinolone due to the rare but serious risk of aortic ruptures or tears in certain patient. If we can take these adverse events into consideration as a form of medical cost, then the estimated economic burden of antibiotic prescription for URI might be more precise.