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Community antibiotic prescriptions during COVID-19 era: a population-based cohort study among adults

Objectives This study investigated the association between the COVID-19 pandemic and antibiotic prescription ratios and the determinants of antibiotic prescription in the community. Methods The study was based on a retrospective population cohort of adults in a community setting. Antibiotic prescription ratios from March 1, 2020 to February 28, 2021 (COVID-19 period) were compared to similar months in previous years. Differences in visit type, infectious disease–related visit, and antibiotic prescription ratios during these visits were compared. A logistic regression model was used to identify independent determinants of antibiotic prescription during the study period. Results The cohort included almost 3 million individuals with more than 33 million community medical encounters per year. In the COVID-19 period, the antibiotic prescription ratio decreased 45% (from 34.2 prescriptions/100 patients to 19.1/100) compared to the previous year. Visits due to an infectious disease etiology decreased by 10% and prescriptions per visit decreased by 39% (from 1 034 425 prescriptions/3 764 235 infectious disease visits to 587 379/3 426 451 respectively). This decrease was observed in both sexes and all age groups. Telemedicine visits were characterized by a 10% lower prescription ratio compared to in-person visits. Thus, a threefold increase in telemedicine visits resulted in a further decrease in prescription ratios. The COVID-19 period was independently associated with a decrease in antibiotic prescription, with an OR of 0.852 (95% CI 0.848–0.857). Discussion We describe a significant decrease in antibiotic prescription ratios during the COVID-19 periods that was likely related to a decrease in the incidence of certain infectious diseases, the transfer to telemedicine, and a change in prescription practices among community-based physicians.


Introduction
The COVID-19 pandemic changed the landscape of healthcare services worldwide. At the beginning of the pandemic, there were concerns regarding antibiotic overuse due to possible coinfection, superinfection, or misdiagnosis with other infections. Another uncertainty was related to the effect of SARS-CoV-2 on seasonal viral infections, such as influenza and respiratory syncytial virus.
The COVID-19 pandemic completely changed social norms and behaviours, with the addition of lockdowns and other social distancing methods, enhanced handwashing, and mask wearing. Universal masking and social distancing were implemented in Israel throughout the entire year (March 2020 through February 2021). These dramatic changes were expected to decrease other transmissible infectious diseases and antibiotic use. Moreover, many visits that were previously conducted in-person were transferred to telemedicine encounters because of infection control policies. The effect of this change in patientephysician interactions on antibiotic prescription was unknown.
Reports from hospitals around the world described increased antibiotic use, which was driven mainly by severe COVID-19 cases [1,2]. This effect could not be extrapolated to the community because patient characteristics and antibiotic use differ. Initial reports from the community described decreased prescription of antibiotics, but those reports encompassed only the first few months of the pandemic, thereby missing a possible effect of seasonal variations [3e5].
This study describes community antibiotic prescription ratios over a full year during the COVID-19 pandemic, compared to the previous 2 years, among the population of the largest health maintenance organization (HMO) in Israel, categorized by patient demographics, visit type, and infectious diagnoses.

Study design
This retrospective, population-based, cohort study was conducted from March 1, 2018 to February 28, 2021. Three periods were defined: 2018, 2019, and 2020, each starting on March 1 and ending February 28 the following year.

Setting and population
The study was based on community electronic medical record (EMR) data from Clalit Health Services (CHS), the largest of four nationally mandated HMOs in Israel, which serves 4.5 million persons (54% of the Israeli population). All adults >18 years of age who were insured through CHS for the duration of the study were included. Data were collected based on medical encounters; thus, a patient could be included more than once.

Data source and variables
The CHS electronic database contains nearly two decades of detailed, person-level inpatient and outpatient clinical data (diagnoses, medication prescription, and laboratory tests) [6]. The following information for each patient was retrieved from the database: date of birth, sex, and population sector. Of note, SARS-CoV-2 tests performed in any of national laboratories were captured in the EMR. In our study, a SARS-CoV-2 test was linked to a specific visit if performed up to 72 hours after the visit. The following information was retrieved for each encounter: date of visit, visit type (in-person vs. telemedicine), and diagnosis (based on International Classification of Diseases, Ninth Revision and International Classification of Primary Care). Any antibiotic dispensed to the patient in the week following the infectious disease (ID) visit was retrieved from the HMO community pharmacy database. In Israel, antibiotics are dispensed only with a physician's prescription. Definitions of infectious diagnoses subgroups appear in Table S1.
COVID-19 visits included only medical encounters with a definite diagnosis of COVID-19 or a visit due to patient exposure to COVID-19, necessitating referral for a SARS-CoV-2 test. The CHS Research Ethics Committee approved this retrospective study and waived the requirement for informed consent.

Statistical analysis
The antibiotic prescription event ratio per 100 registered patients was calculated for each year. Because there was some variability in the number of registered patients over the months, the denominator included the number of registered patients mid-year as a proxy for the number of patients registered in each year. In addition to the annual ratios, monthly antibiotic prescription ratios were calculated to check for seasonal variations and to identify main time points of change. Overall and subgroup-specific ratios were calculated for certain age groups (18e65, 66e75, and 76þ), sex, and population sector.
The proportions of ID-related visits among all visits and the proportions of visits with antibiotic prescription among ID-related visits were calculated for each period and stratified according to demographic characteristics; c 2 tests were used to compare categorical variables.
The overall change in antibiotic prescription ratios before and after the pandemic began in Israel (March 2020), controlling for seasonality and age, was assessed using an interrupted time series Poisson regression model. The data included the number of prescriptions summarized by age group and month across the investigated periods. Interrupted time series analysis was used as described by Bernal et al. [7] to evaluate the effect of the COVID-19 period on the prescription rate [8]. A quasi-Poisson model, which controls for overdispersion by allowing the variable to be proportional to the mean, was fit, with the prescription count as the dependent variable and the natural log of the insured population count as offset. The independent variables included the time since the start of the study, an indicator for the COVID-19 period, and the age group. In addition, a harmonic term, representing a sine-cosine trend across the two periods, was added to adjust for seasonality.
To assess the association between periods (COVID-19 vs. pre-COVID 2018e2019) and antibiotic prescription adjusted for potential intermediate determinants for antibiotic prescription, a generalized estimating equation multivariate logistic regression model was designed. The generalized estimating equation procedure allows for dependence within clusters of visits of the same patient. The model included a random sample of 50% of all visits with ID diagnosis during the study period of 2018e2020. The covariates included in the model were demographics (age, sex, and population sector), visit type (in-person vs. telemedicine), and the specific infectious diagnosis. Adjusted ORs for antibiotic prescription by period and for each covariate in the model were calculated. The 95% CIs of the adjusted ORs and the p values are presented.
Data were analyzed using SPSS, version 23 (IBM Corp., Armonk, NY). Results were considered significant when the p value was <0.05 in a two-sided test.

Results
The study cohort included 2 978 515 insured adults in 2018, which increased by less than 2% annually to 3 055 180 in 2020. The median age was 53 years (interquartile range 35e69), and 48% were male. Population sectors included 72.2% general Jewish population, 24% Arabs, and 4.1% ultra-orthodox Jews.

Antibiotic prescription
A 45.4% and 45.9% decrease in the antibiotic prescription ratio was observed in 2020 compared to 2018 and 2019 respectively ( Table 1). This marked decrease was observed in both sexes, across age groups, and in the different population sectors. The decrease in antibiotic prescription over time according to age group is shown in Fig. 1. The monthly ratios show that the major decrease in antibiotic prescriptions occurred in April 2020, 1 month after the first COVID-19 cases appeared in Israel. The usual seasonal winter peaks did not appear in 2020. The interrupted time series analysis revealed adjusted age and season risk ratio of 0.6 (95% CI 0.545e0.665).

ID visits
ID visits represented 10.9% and 11% of total community medical visits in 2018 and 2019 respectively, which decreased to 9.8% in 2020. (p < 0.001; Table 2). Prior to 2020, the most common reasons for ID visits were upper respiratory tract infection (URTI), pharyngitis, and urinary tract infection (UTI). Although in 2020 COVID-19 diagnosis was added to the ID diagnoses and became the leading cause among them (859 842 visits [25%]), the total number of visits for an ID-related disease decreased by 10%. The change was mainly due to decreases in other respiratory diseases: URTI decreased from 3.38% of all visits in 2019 to 1.39% of all visits in 2020, pharyngitis from 1.4% to 0.8%, sinusitis from 0.47% to 0.23%, lower respiratory tract infection (LRTI) from 0.34% to 0.15%. A decrease in acute gastroenteritis was noted as well (from 0.45% in 2019 to 0.26% in 2020). The only aetiology that increased in frequency was fever (from 0.24% to 0.28%) (p < 0.001 for all comparisons).

Antibiotic prescription per ID visit
As seen in Table 3, visits due to an ID aetiology decreased, as did antibiotic prescription per ID visit, from 28.7% in 2019 to 17.0% in 2020. The largest decrease in antibiotic prescription per visit was observed in respiratory diseases: URTI from 23.1% to 16.4%, pharyngitis from 54.3% to 40.2%, LRTI from 41.2% to 28.2%, and fever from 14.7% to 9.5% (p < 0.001 for all). Although COVID-19 was the leading ID diagnosis, only 1% of those visits led to an antibiotic prescription. The decrease appeared among all population sectors.

Independent predictors of antibiotic prescriptions
Antibiotic prescription for infectious diseases decreased significantly from the 2018 and 2019 baseline periods to the 2020 COVID-19 period (OR 0.852, 95% CI 0.848e0.857; Table 4). The independent associations of the different explanatory variables influencing antibiotic prescription are presented in Table 4. Advanced age (OR 1.009; 95% CI 1.009e1.009) and female sex (OR 1.062; 95% CI 1.056e1.068) were related to increased antibiotic prescription. Telemedicine (OR 0.540; 95% CI 0.536e0.544) and Table 1 Antibiotic prescription ratio per 100 registered patients by period and demographic characteristics Variable belonging to the general Jewish sector (OR 0.812; 95% CI 0.807e0.818) were related to increases in antibiotic prescriptions. All clinical diagnoses independently influenced antibiotic prescription. Compared to acute gastroenteritis, most diagnoses were related to increased antibiotic prescription. COVID-19 diagnosis was associated with a marked decrease in antibiotic prescription, with an OR 0.219 (95% CI 0.211e0.227) compared to acute gastroenteritis (Table 4).

Discussion
In this population-based study, a 45% decrease in community antibiotic prescription was observed in 2020 during the COVID-19 pandemic. This decrease was observed across age groups, sexes, and population sectors. We investigated possible explanatory factors that could have influenced antibiotic prescription. Several changes occurred in parallel and were found as drivers of this decline: (a) a new viral disease that did not require antibiotic treatment; (b) a decrease in visits due to ID aetiology, in particular transmissible diseases; and (c) a shift toward telemedicine, in which lower antibiotic prescription was traditionally the common practice in Israel.
A clear decline was observed in respiratory diseases, a known driver of antibiotic consumption [9e11]. This decline was witnessed worldwide, both in the southern and northern hemispheres [8,12]. One possible explanation for the decrease was social distancing, compulsory mask usage, and enhanced hand hygiene [13]. The concurrent decrease in other transmissible diseases, such as acute gastroenteritis, supports this explanation. Another explanation is that the biological niche occupied by SARS-CoV-19 displaced traditional viral diseases such as influenza and respiratory syncytial virus. This explanation is supported by the near disappearance of these diseases, even in countries in which social distancing was not enforced, such as Brazil [14].
In addition to the decline in the number of ID visits, fewer visits resulted in antibiotic prescription. This phenomenon was more pronounced in viral-related aetiologies, such as URTIs, as reported by Mamun et al. [15]. A possible explanation is greater awareness of  viral pathogens, which increased physician and public acceptance of the inefficacy of antibiotics against viruses. This is supported by the extremely low antibiotic prescription for COVID-19erelated visits (1%), whereas little change was noted in the antibiotic prescription ratio for UTI, a bacterial disease. Of note, this is in sharp contrast to a report from London, England, where 31% of patients diagnosed with COVID-19 received an antibiotic prescription within 14 days of diagnosis [16]. In Israel, a country with highly accessible primary care, telemedicine for ID aetiologies traditionally comprised less than 15% of visits, with a lower antibiotic prescription ratio compared to inperson visits ( Table 2). This is in contrast to many reports from other health systems [17,18]. During 2020, telemedicine visits became more frequent than in-person visits, changing the composition of the range and severity of diseases managed through telemedicine encounters. The uncertainty of the diagnosis during virtual visits could potentially increase antibiotic prescription [19], but unexpectedly, the opposite was observed in our study.
Fever was the only ID diagnosis that increased in 2020. In our adult population, fever with no focal signs was an uncommon reason to seek formal medical advice (2.2%). At the beginning of the pandemic, a SARS-CoV-2 test required referral from a physician. We assumed that the increase in fever complaints was driven by the need to exclude the diagnosis of COVID-19. In support of this assumption is an observation that 26% of visits due to fever resulted in SARS-CoV-2 testing, with 23.6% positive results. Thus, the increase observed in visits due to fever in 2020 can be attributed to concern regarding COVID-19 (Table S2).
In multivariable analysis, all explanatory variables tested (age, sex, population sector, visit type, ID diagnosis, and the period) remained independently significant. After accounting for all variables studied, the COVID-19 period was responsible for a 14.8% decrease in antibiotic prescription. This is attributed to the change in physician prescribing habits and to unmeasured residual confounders.
A few papers on decreases in community antibiotic prescription have been published recently. Reports from the United States, Spain, South Korea, Italy, and the Netherlands describe a decrease in the first 3 to 4 months of the COVID-19 pandemic. These did not include the winter months and thus did not assess the full scale of the pandemic's effect on trends in antibiotic prescription  [3e5, 20,21]. Moreover, some only evaluated the seasons as explanatory variables [3,4,20,22] and others assessed a limited number of explanatory variables [5,21]. The current study had several limitations. It was a retrospective, population-level study, based on secondary use of routine EMR data. Thus, some diagnoses might have been misclassified and could differ between periods. Based on the number of visits in each category, however, we do not believe this had a major effect on the results. Although COVID-19 could have potentially been mislabelled during a primary care visit as URTI or gastroenteritis, the percent positivity of SARS-CoV-2 among those ID aetiologies was extremely low (about 0.5% or less), which excludes the likelihood of these misdiagnoses (Table S2). The study included only community antibiotic prescriptions that were given during an ID-related visit. Therefore, antibiotics given in hospitals and other medical facilities were not included. However, the community is the major impetus behind antibiotic use as a whole [23]. A possible concern is that difficulty accessing care during the COVID-19 era might contribute to the observed decrease in antibiotic prescriptions. However, there was no change in primary care physician office hours during the COVID-19 era. Moreover, antibiotics in Israel are prescribed via a computerized system connected directly to the pharmacy, regardless of visit type. Another concern is failure to capture purchase of antibiotics in private pharmacies or through the internet. This is unlikely, because antibiotics can be purchased through HMOs at a minimal fixed rate. Over-the-counter purchase is illegal and, to the best of our knowledge, nearly non-existent. Lastly, we cannot exclude the presence of unexamined determinants explaining the decrease in antibiotic prescription.
In conclusion, this population-level study describes a major decrease in antibiotic prescription from March 1, 2020 to February 28, 2021dduring the COVID-19 pandemic period. This was driven by a decrease in the incidence of ID, changes in their relative distribution, and a decrease in antibiotic prescriptions among physicians in the community. The effect of such a major change on antimicrobial resistance is still to be explored. Another unanswered question is whether the observed decrease in antibiotic prescription for diseases with viral aetiology will be maintained.