Trends in U.S. outpatient antibiotic prescriptions during the COVID-19 pandemic

Abstract Background The objective of our study was to describe trends in U.S. outpatient antibiotic prescriptions from January through May 2020 and compare with trends in previous years (2017-2019). Methods We used data from the IQVIA Total Patient Tracker to estimate the monthly number of patients dispensed antibiotic prescriptions from retail pharmacies in January 2017-May 2020. We averaged estimates from 2017-2019 and defined expected seasonal change as the average percent change from January to May 2017-2019. We calculated percentage point and volume changes in the number of patients dispensed antibiotics from January to May 2020 exceeding expected seasonal changes. We also calculated average percent change in number of patients dispensed antibiotics per month in 2017- 2019 versus 2020. Data were analyzed overall and by agent, class, patient age, state, and prescriber specialty. Results From January to May 2020, the number of patients dispensed antibiotic prescriptions decreased from 20.3 to 9.9 million, exceeding seasonally expected decreases by 33 percentage points and 6.6 million patients. The largest changes in 2017-2019 versus 2020 were observed in April (-39%) and May (-42%). The number of patients dispensed azithromycin increased from February to March 2020 then decreased. Overall, beyond-expected decreases were greatest among children (≤19 years) and agents used for respiratory infections, dentistry, and surgical prophylaxis. Conclusions From January 2020 to May 2020, the number of outpatients with antibiotic prescriptions decreased substantially more than would be expected due to seasonal trends alone, possibly related to the COVID-19 pandemic and associated mitigation measures.


Introduction
The coronavirus disease 2019 (COVID- 19) pandemic and related mitigation measures, such as school closures and stay-at-home orders, substantially impacted healthcare-and medication-seeking patterns throughout the United States. [1][2][3][4] These measures also potentially affected transmission of infections commonly managed with outpatient antibiotics. Antibiotics are among the most commonly prescribed medications in U.S. outpatient healthcare and antibiotic stewardship is a focus of nationaland state-level efforts, underscoring the importance of evaluating impacts of the COVID-19 pandemic on outpatient antibiotic prescribing. Prescribing of azithromycin, which was under exploration for treatment of COVID-19, initially increased during the pandemic; 2,3 however, examination of prescribing for other antibiotics during the COVID-19 pandemic has been limited. Outpatient antibiotic use varies by season and is typically highest in winter, likely related to the incidence of respiratory diseases, 5 with decreases during the spring. However, impacts of the COVID-19 pandemic, including associated mitigation measures and changes in healthcare delivery, on outpatient antibiotic use during spring 2020 is unknown. The objective of our analysis was to describe and compare trends in U.S. outpatient antibiotic prescriptions between January 2020 and May 2020 (the first several months of the COVID-19 pandemic) with historic trends to assess how antibiotic prescribing changed during the pandemic.

Data Source and Study Population
We used 2017-2020 data from IQVIA Total Patient Tracker (TPT), a proprietary IQVIA dataset, to estimate the number of unique patients dispensed antibiotic prescriptions from retail pharmacies in the United States. IQVIA collects data from approximately 48,900 U.S. retail pharmacies, representing over 3.5 billion transactions annually and covering 92% of all retail prescriptions, and generates national projections of numbers of unique, individual patients receiving dispensed prescriptions. IQVIA TPT data A c c e p t e d M a n u s c r i p t 4 are updated monthly and are available approximately one month after collection, with data available through May 2020 at the time of this analysis. IQVIA TPT contains data on drug active ingredient, drug class, patient age, patient sex, prescriber specialty, and state. These data have previously been used for regulatory oversight, 6 public health surveillance 7,8 and studies of medication dispensing trends. 3 We included only systemic (oral or parenteral) antibiotics and excluded antibiotics prescribed by veterinarians. IQVIA TPT data were accessed through an online portal.
We categorized antibiotic prescriptions by active ingredient and therapeutic class. We categorized patient age as: ≤19 years, 20-64 years, and ≥65 years. We further categorized the ≤19 years group into ≤4 years and 5-19 years to examine differences in trends in younger and older children.

Data analysis
We estimated the number of patients dispensed antibiotic prescriptions each month by agent, therapeutic class, and patient age group. Although estimates for all antibiotics were not available at the state and specialty level, select antibiotic information was available, thus we estimated the number of patients dispensed prescriptions for commonly-used antibiotics by prescriber specialty (for amoxicillin, amoxicillin-clavulanate, azithromycin, cefdinir, and cephalexin) and by state (for amoxicillin and azithromycin). We chose one month from each season, January (winter) and May (spring), to evaluate seasonal changes. We averaged the number of patients dispensed antibiotic prescriptions in 2017-2019 to create a historic baseline prior to the pandemic for comparison with estimates from 2020. We calculated the following endpoints for each strata (See Supplemental Table 1   Prevention as part of public health surveillance activities. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy. 1

Results
From January 2020 to May 2020, the number of patients dispensed antibiotic prescriptions decreased from 20.3 million to 9.9 million, 6.6 million fewer than seasonally expected, representing an additional decrease of 33 percentage points beyond the expected seasonal decline (Table 1). Monthly numbers of patients with antibiotic prescriptions in 2020 were only slightly lower than 2017-2019 averages in January through March, with decreases of 4% in January and February and 9% in March ( Figure 1). Much larger differences were seen in April and May; the number of patients with prescriptions was 39% and 42% lower, respectively, than 2017-2019 averages for these months.
Larger than seasonally expected decreases from January 2020 to May 2020 in the number of patients dispensed antibiotic prescriptions occurred across antibiotic classes and agents ( Table 1). The  A c c e p t e d M a n u s c r i p t 8 Among patients dispensed amoxicillin prescriptions, the greatest decreases beyond seasonally expected declines occurred in patients treated by primary care prescribers (pediatrics, emergency medicine), gastroenterologists, nurse practitioners, and physician assistants ( Table 2) (Supplemental table 3).

Discussion
From January to May 2020, over 6 million fewer outpatients were dispensed antibiotic prescriptions from retail pharmacies than would be expected based on the same timeframe in prior years. Decreases were seen across all antibiotic classes and agents, with the greatest beyond seasonally expected declines among agents commonly prescribed for respiratory diseases, dentistry, and surgical prophylaxis. Temporal and geographic azithromycin trends varied from trends in other antibiotic classes with increases in the number of patients dispensed azithromycin prescriptions. Declines beyond seasonal expectations were greatest in children, especially young children (≤4 years), followed by older adults. The greatest beyond-seasonally expected decreases during the COVID-19 pandemic period examined here were observed in prescribing by primary care, advanced practice providers, and select subspecialty and surgical providers, although monthly trends varied between these groups. found that outpatient visit rates decreased by around 50% in March. 13 However, these studies demonstrated rebounds in number of outpatient visits in April and May, 12,13 differing from trends observed in antibiotic prescribing. Pandemic-related declines in routine vaccination 14,15 and chronic disease medication dispensing 16 have also been observed. In addition, a study using a nationallyrepresentative survey found that an estimated 41% of adults in the United States have delayed medical care during the pandemic due to concerns about COVID-19. 17 Decreases in antibiotic prescriptions from dentists, surgical, and subspecialty prescribers and in agents commonly used in dentistry and surgical prophylaxis suggest that decreases in elective and sub-specialty medical care may have contributed to declines in antibiotic prescriptions. Greater decreases observed in antibiotic prescriptions for children compared with adults may be indicative of declines in respiratory disease transmission caused by daycare and school closures and other COVID-19 mitigation efforts. Overall decreases across all antibiotic classes may also be due to fewer healthcare encounters for non-COVID-19 related conditions. Further decreases in outpatient antibiotic prescribing are uncertain. Although many states began re-opening efforts in May, we observed that the number of patients prescribed antibiotics continued to decrease in May 2020 relative to previous years. This ongoing decrease appeared to be driven by primary care prescriber specialties. Among many medical subspecialty and surgical specialties Second, azithromycin is associated with QTc prolongation, a potentially life-threatening cardiac adverse event, particularly in older adults. 22,23 Due to the risk of adverse events, if azithromycin is combined with hydroxychloroquine, close monitoring by healthcare professionals is recommended. 24 Third, azithromycin use for COVID-19 may result in antibiotic resistance and diminished effectiveness for recommended indications (e.g., sexually transmitted infections, 25 community-acquired pneumonia 26 ).
Outpatient antibiotic stewardship efforts will continue to be important for ensuring patient safety during the COVID-19 pandemic and beyond. Prior to the COVID-19 pandemic, at least one-third of outpatient antibiotic prescriptions were considered unnecessary. 27,28 It is unclear how much of the A c c e p t e d M a n u s c r i p t 11 decline observed in our study may be decreases in unnecessary antibiotic prescribing due to reduced healthcare visits and how much may be due to reduced disease transmission. It is also unknown how much of this decrease may represent needed care that was not received. Ongoing surveillance of complications of common bacterial infections (e.g., mastoiditis as a complication of acute otitis media) and antibiotic-associated adverse events may be needed to evaluate the impact of reductions on both necessary and unnecessary antibiotic prescribing. Additionally, ongoing surveillance of vaccination rates and vaccine-preventable disease incidence may inform antibiotic stewardship efforts. Encouraging routine vaccination uptake, especially influenza vaccination, may be especially important during the COVD-19 pandemic to prevent increases in non-COVID respiratory infections. 29 Large healthcare delivery changes due to COVID-19 may create new challenges and opportunities for antibiotic stewardship in outpatient settings. The Centers for Medicare & Medicaid Services has substantially expanded coverage of telehealth opportunities during the public health emergency. 30 A market research company estimated that telehealth visits increased by 50% during the pandemic and are expected to top 1 billion by the end of 2020, with primary care visits projected at 200 million. 31 Continued coverage of telehealth services for low-and intermediate-acuity healthcare needs will be relevant to antibiotic stewardship because these types of encounters may include evaluation and management of common outpatient infections, such as sinusitis and acute otitis media. Telehealth has been used during the pandemic to triage patients to home monitoring or appropriate medical settings. Similar approaches may be beneficial for triaging common outpatient respiratory infections and identifying cases that may require additional diagnostic evaluation or in-office testing (e.g., acute otitis media, pharyngitis) versus those that may be more appropriate for home care without antibiotics (e.g., viral upper respiratory infections). Antibiotic use in telemedicine has not been widely studied, and it is not clear from previous studies how well guideline-concordant care is delivered in telemedicine as A c c e p t e d M a n u s c r i p t 12 compared with in-person visits. [32][33][34] Concerted stewardship efforts may be needed in this new and growing setting to ensure appropriate antibiotic use and patient safety.
Our study has limitations. First, as these data do not include visit information, we cannot determine the relative contributions of factors such as decreased infection incidence, decreased healthcare utilization, or shifts in healthcare settings (e.g., telemedicine versus in-person) to reductions in antibiotic dispensing. Second, we could not evaluate the impact of prescribing changes on disease complications or adverse health outcomes. Third, the IQVIA TPT dataset does not contain diagnosis information; therefore, we could not evaluate indications or appropriateness of antibiotic prescriptions included in this study. Fourth, for prescriber specialty and state, the IQVIA TPT dataset does not contain aggregated data for all antibiotic classes. Therefore, we selected commonly-used agents to examine major trends. Fifth, in this dataset, nurse practitioners, physician assistants, and osteopathic medicine physicians are categorized by provider type rather than specialty. Sixth, this analysis did not include antibiotics dispensed by mail-order; however, we expect few antibiotics to be dispensed via mail-order pharmacy, as most are one-time prescriptions for an acute illness. Finally, we were unable to separate whether changes observed in our study were due solely to the COVID-19 pandemic or influenced by other secular trends, such as general decreases in outpatient antibiotic prescribing. 35 However, a study of national outpatient antibiotic prescriptions showed only a 5% decrease in dispensed prescriptions from 2011 to 2016, 36 suggesting that changes observed in 2020 exceed previously-observed secular trends.
A c c e p t e d M a n u s c r i p t 13

Conclusion
During the early period of the COVID-19 pandemic, the number of outpatients with antibiotic prescriptions dispensed from retail pharmacies decreased substantially more than would be expected due to seasonal trends alone. Decreases were greatest among children and agents frequently prescribed for respiratory infections, dentistry, and surgical prophylaxis.  A c c e p t e d M a n u s c r i p t      A c c e p t e d M a n u s c r i p t 31 Figure 3