Abstract
Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. Some hospitals have intervened in the inappropriate use of third-generation oral cephalosporins. However, there have been no such studies in community pharmacy settings. This study aimed to investigate how the use of oral third-generation cephalosporins in community pharmacies affects the amount of antimicrobials used. Patients who visited Nakanomaru Pharmacy after being prescribed antimicrobials at target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use, number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for the proper use of oral third-generation cephalosporins were retrospectively investigated based on the patients’ medication history and prescription receipts. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased. There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use. By working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use.
INTRODUCTION
Proper use of antimicrobials in hospital and outpatient settings is critical for minimizing the occurrence of antimicrobial resistance. From the results of the Japan Surveillance of Antimicrobial Consumption, it has become clear that the use of antimicrobial drugs is higher in clinics than in hospitals.1) Ninety percent of the prescriptions were for outpatients, and many antimicrobials were used for upper respiratory tract infections and diarrhea, for which antimicrobials were originally considered unnecessary.2–4) The breakdown of the oral antimicrobials used by type was as follows: macrolides, 33%; cephalosporins (of which 80% were third-generation cephalosporins), 27%; and fluoroquinolones, 19%. These three types account for approximately 80% of the total antimicrobials used.1) A comparison of the use of antimicrobials in Japan and other countries revealed that the frequency of use of broad-spectrum antimicrobials, such as oral third-generation cephalosporins, fluoroquinolones, and macrolides, was higher in Japan. Furthermore, the drug resistance rate of Escherichia coli to third-generation cephalosporins is higher in Japan.5) Therefore, the National Action Plan on Antimicrobial Resistance 2023–2027 was introduced to implement practices for the proper use of antimicrobials.5)
Third-generation oral cephalosporins have a wide antimicrobial spectrum and are safe; therefore, they are frequently used.6) However, in some cases, they are used unnecessarily for infections against which narrow-spectrum antimicrobials are effective given the assumed causative bacteria. Additionally, third-generation oral cephalosporins are associated with low bioavailability and low blood concentrations.7) The increase in drug-resistant bacteria such as extended-spectrum β-lactamase-producing bacteria is owing to the overuse of oral third-generation cephalosporins.8) Therefore, some hospitals have intervened in the inappropriate use of drugs, and efforts have been made to address the proper use of oral third-generation cephalosporins.9,10) However, there have been no such studies in community pharmacy settings.
Given this background, it is important to promote the proper use of third-generation oral cephalosporins in community pharmacy settings. Therefore, in February 2022, Nakanomaru Pharmacy began efforts to adhere to the proper use of third-generation oral cephalosporins. This study investigated the effects of suggestions regarding changes in oral third-generation cephalosporin antimicrobial use in community pharmacies.
PATIENTS AND METHODS
Outline of Activities for Proper Use of AntimicrobialsWe conducted a single-center quasi-experimental study on the effectiveness of antimicrobial resistance (AMR) activities. The flowchart of our experimental scheme was described in Fig. 1. In February 2022, Nakanomaru Pharmacy initiated an initiative aimed at ensuring the proper use of third-generation oral cephalosporins. Before the start of the initiative, targeting the two clinics with the highest number of prescriptions received, infectious diseases that did not have oral third-generation cephalosporins were listed as first-line drugs in the Japanese Association for Infectious Diseases (JAID)/Japanese Society of Chemotherapy (JSC) Infection Treatment Guide 2019.11) The pharmacist suggested changing the antimicrobial. Among the cases in which third-generation cephalosporins were prescribed, we did not perform interventions for infectious diseases for which third-generation cephalosporins are recommended as first-line drugs in the guidelines (JAID/JSC Guide 2019). However, we administered interventions for cases in which third-generation cephalosporins, including acute sinusitis and hordeolum, were not recommended as first-line drugs. All pharmacists were educated on proper use of antimicrobial agents by JAID/JSC. However, interventions could not be performed in all cases because not all working pharmacists are familiar with infectious diseases or have the knowledge to make suggestions and change prescriptions. All pharmacists could intervene as long as they were under the supervision of a pharmacist with expertise in antimicrobial chemotherapy. However, in the absence of a pharmacist with expertise, prescriptions for which it was difficult to determine whether they were correct were excluded from the analysis.
Patients who visited the Nakanomaru Pharmacy after being prescribed antimicrobials by the target medical institutions between February 2021 and January 2023 were identified. The number of oral antimicrobials used, duration of use (number of days), number of prescriptions, patient age and sex, and infectious diseases in the target patients before and after the intervention for proper use of oral third-generation cephalosporins (February 2021 to January 2022 and February 2022 to January 2023, respectively) were retrospectively investigated based on the patients’ medication history and prescription receipts. The identified infectious diseases were classified according to the JAID/JSC Infection Treatment Guide, 2019.
Survey on the Amount of Antimicrobials UseThe number of third-generation oral cephalosporins used was calculated monthly as antimicrobial use density (AUD), days of therapy (DOT), and daily doses/prescription/month (DPM).12) These factors were compared before and after intervention. Values from the Anatomical Therapeutic Chemical (ATC)/Defined Daily Dose (DDD) index of 2023 were used. The calculation formulas for AUD, DOT, and DPM are as follows:
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Formula (1)
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AUD (DDDs/1000 outpatients) = (monthly antimicrobial use [g] × 1000)/(DDD [g] × total number of monthly outpatients from target medical institutions)
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Formula (2)
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DOT (DOTs/1000 outpatients) = (total number of days of antimicrobial administration per month [d] × 1000)/(DDD [g] × total number of monthly outpatients from the target medical institutions).
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Formula (3)
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DPM (DDDs/1000 prescriptions/month) = (monthly amount of antimicrobials used [g] × 1000) (DDD [g] × number of prescriptions received from target medical institutions)
The ratios of the prescriptions containing each type of antimicrobial to those containing antimicrobials were calculated. In addition, the acceptance rate of the prescription suggestions after the intervention was determined. The observation period was three months after the start of antimicrobial administration. Antimicrobial changes and recurrence rates associated with treatment failure were calculated. Recurrence rate was defined as the occurrence of the same infection within three following the end of the three-months observation period. Treatment failure was defined as a change in antibiotic therapy between the first and second visits, or later. At that time, we asked the prescribing physician about the reason for the change and then, we defined treatment failure as “insufficient efficacy or no response.”
Statistical AnalysisThe Mann–Whitney U test was used to analyze continuous variables, and Fisher’s exact test was used to analyze categorical variables. In both cases, a significance level of less than 5% was considered significant. EZR (v1.35)13) statistical software, which extends the functions of R and R Commander, was used for the statistical analysis.
Ethical ConsiderationsThis study complied with the “Ethical Guidelines for Medical Research Involving Human Subjects” and was approved by the Ethics Review Committee of the Kagoshima Pharmaceutical Association (Rokuken Pharmaceutical Ethics No. 2302).
RESULTS
Patient BackgroundThe number of target patients for whom antimicrobials were prescribed was 92 and 90 before and after the intervention, respectively, and the corresponding numbers of prescriptions were 111 and 106, respectively. There were no significant differences in age, sex, or infectious disease classification between before or after the intervention (Table 1). Third-generation cephalosporins prescribed in this study were cefdinir and cefcapene pivoxil.
Table 1. Patient Background
| Before intervention | After intervention | p-Value |
|---|
| Patients, n | 92 | 90 | — |
| Prescriptions, n | 111 | 106 | — |
| Age (mean ± S.D.) | 62.8 ± 20.3 | 61.6 ± 23.2 | 0.722a) |
| Sex (male/female) | 43/49 | 35/55 | 0.298b) |
| Pediatrics (<12 years old) | 5 | 6 | — |
| Age ≥65 years old | 59 | 50 | — |
| Infectious disease classification |
| Urinary tract infection | 10 | 8 | 0.807b) |
| Respiratory infections | 5 | 11 | 0.122b) |
| Otitis media and rhinosinusitis | 3 | 5 | 0.491b) |
| Skin infections | 1 | 2 | 0.615b) |
| Dental infections | 0 | 1 | 0.488b) |
| Eye infections | 92 | 79 | 0.139b) |
a) Mann–Whitney U test or b) Fisher’s exact test. S.D., standard deviation.
Figure 2 and Table 2 show the number of antimicrobials used before and after the intervention. The monthly use of antimicrobials, as calculated by the AUD, DOT, and DPM, decreased after the intervention (February 2022). The median AUD significantly decreased from 10.0 to 2.6 and DOT from 19.5 to 6.2 after the intervention compared with the corresponding values before the intervention. The median DPM decreased significantly from 9.1 to 2.6.
Table 2. Changes in Antimicrobial Use before and after Intervention
| Before intervention | After intervention | p-Value |
|---|
| AUD, median (interquartile range) | 10.0 (8.8–11.2) | 2.6 (1.2–3.5) | <0.001a) |
| DOT, median (interquartile range) | 19.5 (18.2–24.4) | 6.2 (0–7.7) | <0.001a) |
| DPM, median (interquartile range) | 9.1 (7.5–10.5) | 2.6 (1.1–3.4) | <0.001a) |
The proportion of prescriptions for oral third-generation cephalosporins to the number of prescriptions containing antimicrobials significantly decreased from 84.7% to 19.8% after the intervention compared with that before the intervention (Table 3). In contrast, oral penicillin prescriptions increased from 0 to 4.7%, and oral first-generation cephalosporins increased significantly from 0.9 to 56.6%. There were no significant differences in the prescriptions of new quinolones and macrolide antimicrobials before and after the intervention.
Table 3. Proportion of Each Antimicrobial Drug in the Numbers of Antimicrobial Drug Prescriptions before and after the Intervention
| Before intervention (n = 111) | After intervention (n = 106) | p-Value |
|---|
| Penicillin antimicrobials | 0% | 4.7% | 0.027a) |
| First-generation cephalosporins | 0.9% | 56.6% | <0.001a) |
| Third-generation cephalosporins | 84.7% | 19.8% | <0.001a) |
| New quinolone antimicrobials | 11.7% | 13.2% | 0.838a) |
| Macrolide antimicrobials | 0.9% | 0% | 1.0a) |
| Others | 1.8% | 5.7% | — |
There was no significant difference between the pre- and post-intervention rates of antimicrobial changes due to treatment difficulties (Table 4). Furthermore, there was no significant difference in the recurrence rates before and after the intervention during the observation period.
Table 4. Efficacy Evaluation of Oral Antimicrobials before and after the Intervention
| Before intervention (n = 92) | After intervention (n = 90) | p-Value |
|---|
| Proportion of changes in antibiotics owing to treatment failure | 0% | 0% | 1.0a) |
| Recurrence rate of infections during the observation period | 14.1% | 6.7% | 0.145a) |
DISCUSSION
We undertook efforts to ensure the proper use of oral third-generation cephalosporins in community pharmacies and clinics and focused on the amount of antimicrobials to evaluate the effectiveness of our intervention. Through efforts to ensure the proper use of oral third-generation cephalosporins, the amount of oral third-generation cephalosporins used has decreased, and the use of penicillins and oral first-generation cephalosporins has increased.
Before initiation, oral third-generation cephalosporins were used to manage acute sinusitis and infections caused by Staphylococcus aureus. However, after the initiation of the initiative, these drugs were used only for the management of acute sinusitis. In contrast, S. aureus is considered the cause of increased opportunities for the use of oral first-generation cephalosporins. The Sanford guidelines also recommend the use of first-generation cephalosporins and penicillins when targeting Gram-positive cocci, including S. aureus. The use of third-generation cephalosporins, which have an antimicrobial spectrum that includes enterobacteria, is considered inappropriate in these cases.7) There was no increase in the antimicrobial change or relapse rates associated with treatment failure before and after the initiation of appropriate antimicrobial use.
Antimicrobial resistance is recognized as a serious health threat worldwide. The WHO has undertaken measures to manage antimicrobial resistance as part of its important policy agenda,14) and the appropriate use of antimicrobials is an urgent issue. Given that more than 90% of the antimicrobials used in Japan are prescribed by clinics, proper use of antimicrobials is important not only in hospitals but also in clinics and community pharmacies.5) Judicious use of oral third-generation cephalosporins in hospitals has already been reported. Shinoda et al. reported that the use of third-generation oral cephalosporins in emergency departments was reduced by reviewing hospital-adopted oral antibiotics and providing information on proper use.9) Tsuchimoto et al. reported that the use of oral third-generation cephalosporins in outpatient clinics decreased owing to antimicrobial stewardship activities based on relevant guidelines and antimicrobial drug manuals.10)
This study has some limitations. Most infections in this study were ophthalmic infections. This was attributed to the concentration of prescriptions at our pharmacy for neurosurgery (69.5% pre-intervention and 70.4% post-intervention) and ophthalmology (27.1% pre-intervention and 26.1% post-intervention). We believe that the proportion of ophthalmological infections was high because neurosurgeons do not often prescribe antimicrobial agents. Because most of the patients who visited the neurosurgery were those with stroke, dementia, migraine and other headache disorders, epilepsy, etc., and few patients visited due to infectious diseases. Further studies are needed to determine whether this intervention is applicable to the treatment of outpatient infectious diseases at other institutions. Next, the prescribing physicians did not evaluate the effectiveness of antimicrobial treatment for all patients in this study. However, we demonstrated that this intervention was effective, at least in certain areas.
In this study, by working toward the proper use of oral third-generation cephalosporins in community pharmacies, we were able to reduce the doses of oral third-generation cephalosporins without compromising their therapeutic efficacy. We believe that recommending the selection of narrow-spectrum antimicrobials based on these guidelines will contribute to their proper use. Within the framework of community pharmacies, we aimed to achieve proper use of third-generation oral cephalosporins. Reducing the inappropriate use of oral third-generation cephalosporins may reduce the number of resistant strains. However, we were unable to demonstrate any changes in the resistant strains, an issue that needs to be addressed in the future.
Author Contributions
Yuki Enoki, the corresponding author of the work, certifies that all authors have participated sufficiently in the conception and design of the work and were involved in the acquisition of data. All of them also participated in the analysis and interpretation of the data, as well as in drafting the work. All authors revised the manuscript and approved the final version for publication. Each author agreed to be accountable for all aspects of the work, ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. All authors meet the ICMJE authorship criteria.
Conflict of Interest
The Laboratory of Community Healthcare Pharmacy received donations from WELCIA YAKKYOKU Co., Ltd. The Laboratory of Home Team Care Pharmacy received donations from the Yuu YAKKYOKU GROUP. KM received Grant support funding from Meiji Seika Pharma Co., Ltd. and Sumitomo Pharma Co., Ltd., and speaker honoraria from Meiji Seika Pharma Co., Ltd. The authors declare no conflict of interest.
Data Availability
The datasets generated or analyzed in the current study are available from the corresponding author upon reasonable request.
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