In this multicenter study, we examined antimicrobial prescriptions for patients diagnosed with uncomplicated cystitis. Compared to administrative database study reporting that more than 90% of antimicrobials prescribed for uncomplicated cystitis were third-generation fluoroquinolones or cephalosporins12, the proportion of broad-spectrum antimicrobials in our cohort was lower in almost two thirds of the cases. Broad-spectrum agents were frequently prescribed in the older age group (≥ 50 years), male patients, and by internists. Of note, neither age, gender, nor antimicrobial types were associated with recurrence of uncomplicated cystitis.
The main objective of this study was to elucidate antimicrobial prescription rates for uncomplicated cystitis by directly extracting clinical data from medical records. Based on health insurance claims data12, fluoroquinolones (52.7%) and third-generation cephalosporins (36.9%) accounted for the majority of prescriptions for female patients ≥15 years of age with uncomplicated cystitis. This result indicates that the prescription rates of broad-spectrum antimicrobial agents for cystitis in female patients reach almost 90% in Japan. However, our clinical database showed that the overall prescription rates for fluoroquinolones and third-generation cephalosporins were comparatively lower, 36.0% and 29.9%, respectively. Focusing on female patients, they were prescribed in 30.4% and 31.4% of cases, respectively. Including faropenem, the broad-spectrum antimicrobial prescription rate for uncomplicated cystitis in women was 65.4%, which is still high but much lower than the data described in the administrative database study12. One possible explanation for the differences in broad-spectrum antimicrobial prescription rates includes a discrepancy in patient demographics. However, to collect data from patients with uncomplicated cystitis, we used the ICD-10 N300 code similar to that used in the previous study.12. Therefore, we believe that patients with similar clinical histories were recruited. When examining the age of the patients, more than 80% of the patients in our cohort were ≥ 50 years old, while more than half of the patients in the administrative data were < 50 years old. However, the high proportion of elderly patients could have led to more prescriptions of broad-spectrum antimicrobial agents, but it did not. Whereas the previous study included adolescents (patients aged ≥15 years), our study involved only those aged 20 years or older. This difference, however, would prefer not to greatly influence the form of prescriptions, because fluoroquinolones are generally not recommended for pediatric patients by package inserts in Japan. Another possible factor for the decrease in broad antimicrobial prescriptions in the present study may be an advance in AMS in the participating medical institutes, although this was not fully measured.
Our study suggested that the age factor potentially affects the prescription of antimicrobials. In the previous study12, broad-spectrum antimicrobial prescription rates for uncomplicated cystitis were about the 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 between 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 elderly patients were more likely to receive broad-spectrum medications, which has also been observed in other studiesfifteen. This could be justified by the fact that older people tend to have frequent underlying diseases, possibly associated with the development of complicated or serious urinary tract infections.
Our data corroborated that the prescription of broad-spectrum drugs was significantly more frequent in men than in women; 86.6% versus 65.4% (OR, 95% CI 4.68 [2.66–8.25]). Due to the anatomical advantage, urinary tract infections occur infrequently in men.16,17. Male patients with UTIs usually have some underlying urologic abnormality, such as stones/malignancies in the urinary tract, neurogenic bladder, and benign prostatic hyperplasia.18,19,20. Our observations can 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 on the characteristics of the patients and, therefore, could not adjust their background.
A single facility study suggested that organisms isolated from patients visiting the urology department with uncomplicated cystitis tend to show resistance to multiple antibiotics compared with hospital-wide susceptibility testingtwenty-one. Therefore, we speculate that the urologists in our study would prescribe a greater number of broad-spectrum drugs. However, our research found fewer prescriptions by urologists, while more use by internists. This may simply be differences between centers or between clinicians, which need to be assessed in a future study.
Importantly, our multivariate analysis suggested that broad-spectrum antimicrobial prescriptions were not associated with prevention of cystitis recurrence. Given AMS, broad-spectrum drugs, particularly fluoroquinolones, should not be prescribed for common conditions such as uncomplicated cystitis. A recent meta-analysis based on the systematic review of 47 randomized controlled trials demonstrated the superiority of fluoroquinolones compared to other antimicrobial agents in terms of clinical remission rates, bacteriological eradication, development of drug resistance, and relapse rates.22. A population-based retrospective cohort study based on administrative health data drawn from six Canadian provinces also verified advantages of fluoroquinolone prescriptions, such as fewer emergency and outpatient visits, hospitalization, and antimicrobial prescription within 30 days .23. However, fluoroquinolones have a variety of adverse pharmacological effects, including QT interval prolongation, glucose intolerance, retinal detachment, tendinitis, aortic aneurysm, and neurological disorders.24. Furthermore, the increasing trend of clinical isolates of fluoroquinolone-resistant organisms in UTIs has been suggested by recent surveillance studies in Japan.13,14,21,25,26. Although these facts would make us reluctant to treat patients with uncomplicated cystitis with fluoroquinolones, our data showed that many of these cases are still treated with 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 recurrence, supporting the safety of this treatment for patients with uncomplicated cystitis.
Antimicrobial uses for uncomplicated cystitis vary widely from country to country. Based on US national outpatient data sets, almost half (49%) of patients with uncomplicated cystitis were 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 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 urinary tract infections, followed by sulfonamide (27.0%).29. These differences could be attributed in part to the discrepancy of the recommendations in the national guidelines of each country. In fact, although the Japanese guide suggested fluoroquinolones as the first optioneleventhe Infectious Diseases Society of America guideline recommended nitrofurantoin, trimethoprim-sulfamethoxazole, fosfomycin, and pivmecillinam for acute uncomplicated cystitis8. In addition, the national guidelines of 15 European countries present a great variability in the selection of antibiotics30; e.g, 10 different antimicrobials were recommended as first-line therapy. This discrepancy in national guidelines may be due in part to the lack of drug availability in each nation; in fact, nitrofurantoin and pivmecillinam are not currently available in Japan31. The difference in antibiogram in each region should also influence the recommendation and selection of 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. Larger earlier studies relied on data from health insurance claims12, and therefore the validity of his clinical diagnosis was unreliable. However, there are several limitations in this study. First, despite the multicenter database, our cohort data were derived from just six medical institutes. Therefore, the generalizability of the study needs to be evaluated by larger investigations. Second, patient ages were higher for cystitis in this study. This could be attributed to the fact that we primarily collect data from regional hospitals in rural areas where the population is rapidly ageing. Third, essential information for antimicrobial selection, such as history of drug allergies, was not collected. Fourth, ICD-10 codes provided in medical records may be labeled for convenience only so as not to disrupt your antimicrobial orders. Finally, we did not investigate the duration of antimicrobial prescriptions, which should also be evaluated as a parameter for AMS. Despite these drawbacks, our data helped understand the current practice of antimicrobial prescriptions for uncomplicated cystitis, which may be one of the cornerstones of AMS promotion in Japan.
In summary, amid the promotion of AMS to combat AMR, nearly two-thirds of the antimicrobials prescribed for uncomplicated cystitis were broad-spectrum agents, primarily fluoroquinolones and third-generation cephalosporins. Male sex, older age and visits to the internal medicine service were statistically associated with these prescriptions. Notably, broad-spectrum antimicrobial prescriptions were not associated with prevention of recurrence. Our current findings would be an indicator to monitor antimicrobial prescriptions for patients with uncomplicated cystitis in Japan, which, we hope, may be useful information for health policymakers.