Antimicrobial prescription practices for outpatients with uncomplicated cystitis in Japan

In this multi-centered study, we examined the antimicrobial prescriptions for patients diagnosed with uncomplicated cystitis. In comparison with the administrative database study reporting that more than 90% of the antimicrobials prescribed for uncomplicated cystitis were either fluoroquinolones or third-generation cephalosporins12, the proportion of broad-spectrum antimicrobials in our cohort was lower at neraly two-thirds of the cases. The broad-spectrum agents were prescribed frequently in the older group (≥ 50 years), male patients, and by internists. Of note, neither age, sex, nor antimicrobial types were associated with the recurrence of uncomplicated cystitis.

The primary aim of this study was to elucidate the prescribing rates of the antimicrobials for uncomplicated cystitis by directly drawing clinical data from medical records. Based on the health insurance claims data12, fluoroquinolones (52.7%) and third-generation cephalosporins (36.9%) accounted for most of the prescriptions for female patients aged ≥ 15 years with uncomplicated cystitis. This result indicates that the prescription rates of broad-spectrum antimicrobial agents for cystitis in female patients reach nearly 90% in Japan. However, our clinical database demonstrated that the overall prescription rates of fluoroquinolones and third-generation cephalosporins were comparatively lower at 36.0% and 29.9%, respectively. Focusing on female patients, those were prescribed to 30.4% and 31.4% of the cases, respectively. Including faropenem, the prescription rate of broad-spectrum antimicrobials for uncomplicated cystitis in females was 65.4%, which is still high but much lower than the data described in the administrative database study12. A potential explanation for the differences in the prescription rates of broad-spectrum antimicrobials includes a discrepancy in patient demographics. To collect data for patients with uncomplicated cystitis, however, we used ICD-10 code N300 similar to that employed in the previous study12. Thus, we believe that patients with similar clinical backgrounds were recruited. Upon examination of the patient age, more than 80% of the patients in our cohort were aged ≥ 50 years, while more than half of the patients in the administrative data were aged <50 years. However, the high proportion of elderly patients could have resulted in more prescriptions of broad-spectrum antimicrobial agents, but this was not the case. While the previous study included teenagers (patients aged ≥ 15 years), our study involved only those aged 20 years and more. This difference, however, would rather not influence the manner of prescriptions remarkably, because fluoroquinolones are typically not recommended for pediatric patients by package inserts in Japan. Another possible factor for fewer prescriptions of the broad-antimicrobials in the present study may be an advancement in AMS at the participating medical institutes, although it was not fully measured.

Our study suggested that age factor potentially affects antimicrobial prescribing. In the previous study12, the broad-spectrum antimicrobial prescription rates for uncomplicated cystitis were almost same; 91.1% in the younger group (<50 years) and 90.1% in the older group (≥ 50 years). In contrast, the proportions of broad-spectrum antimicrobial prescriptions among the younger and older groups were 57.1% and 71.9% (OR, 95% CI 1.83 [1.23–2.71]) in our data, indicating that aged patients were more likely to be prescribed broad-spectrum drugs, which has also been observed in other studies15. This could be rationalized by the fact that aged people tend to have underlying diseases frequently, which are conceivably associated with development of complicated or severe UTIs.

Our data corroborated that the prescription of broad-spectrum drugs was significantly more frequent in males than in females; 86.6% versus 65.4% (OR, 95% CI 4.68 [2.66–8.25]). Owing to the anatomical advantage, UTIs infrequently occur in males16.17. Male patients with UTIs generally have any of underlying urological abnormalities such as urinary tract stones / malignancy, neurogenic bladder, and benign prostatic hyperplasia18,19,20. Our observations may be attributed to this dissimilarity between the sexes in terms of vulnerability to UTIs. Considering the limitations of the feasibility of the study, we did not collect detailed data of patient characteristics, and hence, could not adjust their backgrounds.

A single-facility study suggested that organisms isolated from patients visiting the urology department with uncomplicated cystitis tend to show resistance to various antibiotics compared to hospital-wide antibiograms21. Thus, we speculated that a higher number of broad-spectrum drugs would be prescribed by urologists in our study. However, our investigation found fewer prescriptions by the urologists, while more usages by internists. This can merely be inter-facility or inter-physician differences, which should be evaluated by future study.

Importantly, our multivariate analysis suggested that prescriptions of the broad-spectrum antimicrobials were not associated with the prevention of the recurrence of cystitis. Given AMS, broad-spectrum drugs, particularly fluoroquinolones, should not be prescribed for common diseases like uncomplicated cystitis. A recent meta-analysis based on the systematic review of 47 randomized controlled trials demonstrated the superiority of fluoroquinolones compared to that of other antimicrobial agents in terms of clinical remission rates, bacteriological eradication, emergence of drug resistance, and relapsing rates22. A retrospective population-based cohort study based on administrative health data extracted from six Canadian provinces also verified the advantages of fluoroquinolone prescriptions, such as fewer revisits of outpatients and emergency patients, hospital admission, and re-prescription of antimicrobials within 30 days23. However, fluoroquinolones have a variety of adverse drug effects, including QT elongation, glucose intolerance, retinal detachment, tendinitis, aortic aneurysm, and neurologic disorders.24. Also, the increasing trend of clinical isolations of fluoroquinolone-resistant organisms in UTIs has been suggested by recent surveillance studies in Japan13,14,21,25,26. Although these facts would make us reluctant to treat patients with uncomplicated cystitis with fluoroquinolones, our data demonstrated that many such cases are still treated with the broad-spectrum drugs. Our analysis indicated that the administration of narrow-spectrum antimicrobials, including AMPC, first- or second-generation cephalosporins, and sulfamethoxazole-trimethoprim, is not associated with the recurrence, supporting the safety of these treatments for patients with uncomplicated cystitis.

Usages of antimicrobials for uncomplicated cystitis vary greatly from country to country. Accoding to national ambulatory datasets of the United States, almost half (49%) of female patients with uncomplicated cystitis was treated with fluoroquinolones, followed by sulfonamides (27%) and nitrofurantoin (19%)27. A population-based retrospective cohort study in England found that 73.8% of elderly patients with UTIs were prescribed either trimethoprim (54.7%) or nitrofurantoin (19.8%), while cephalosporins (11.5%), AMPC / CVA (9.5%), and fluoroquinolones (4.4%) were prescribed in fewer cases28. In a national registry-based study in Denmark, pivmecillinam (45.8%) was the most common antibiotic for acute lower UTIs, followed by sulfonamide (27.0%)29. These differences could partly be attributed to the discrepancy of recommendations in national guidelienes in each country. In fact, although the Japanese guideline suggested fluoroquinolones as the first choice11the Infectious Diseases Society of America guideline recommended nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, and pivmecillinam for acute uncomplicated cystitis8. Moreover, national guidelines in 15 European countries have great variability in the selection of antibiotics30; eg, 10 different antimicrobials were recommended as the first-line therapy. This discrepancy in national guidelines may be due in part to the unavailability of drugs in each nation; in fact, nitrofurantoin and pivmecillinam are currently unavailable in Japan31. Difference of antibiogram in each region should also influence on the recommendation and selection of the drugs. To promote AMS and reduce the use of broad-spectrum antibiotics such as fluoroquinolones, review and reconsideration of the antimicrobials approved and distributed in each country is warranted.

The strength of the present study lies in the direct collection of clinical data from medical records. Previous larger studies were based on health insurance claims data12, and therefore, the validity of its clinical diagnosis was unreliable. However, there are several limitations to this study. First, despite the multi-centered database, the data of our cohorts were derived merely from six medical institutes. Thus, the generalizability of the study should be evaluated by larger investigations. Second, the ages of the patients were higher for cystitis in this study. This could be attributed to the fact that we primarily collected data from regional hospitals in rural areas where the population is aging rapidly. Third, information essential to the selection of antimicrobials, such as the history of medication allergies, was not collected. Fourth, the ICD-10 codes given in the medical records may be labeled just for convenience to not interrupt their antimicrobial orders. Finally, we did not investigate the duration of antimicrobial prescriptions, which should also be evaluated as a parameter for AMS. Despite these downsides, our data was of help in comprehending the current practice of antimicrobial prescriptions for uncomplicated cystitis, which can be one of the cornerstones of AMS promotion in Japan.

In summary, amid the promotion of AMS to combat AMR, nearly two-thirds of antimicrobials prescribed for uncomplicated cystitis were broad-spectrum agents, primarily fluoroquinolones and third-generation cephalosporins. Male gender, higher age, and visits to the internal medicine department were statistically associated with such prescriptions. Notably, prescriptions of broad-spectrum antimicrobials were not related to the prevention of recurrence. Our present findings would be an indicator for monitoring the antimicrobial prescriptions for patients with uncomplicated cystitis in Japan, which, we expect, can be useful data for health policymakers.

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