Concerns about antibiotic overuse were first raised by Alexander Fleming, who worried in 1945 that availability of oral penicillin would lead to “self-medication and all its abuses.”¹ Fleming’s prescience was confirmed just a decade later by a study of a small community in South Dakota. Residents received an average of 3.9 antibiotic prescriptions over the 5-year period, and the investigators estimated that 52.5% of those prescriptions were not indicated.²

While early antimicrobial stewardship programs have focused primarily on the inpatient setting, ˜80%-90% of total human antibiotic consumption occurs in the ambulatory setting.³ Ambulatory medical practice includes primary care, outpatient subspecialty care, urgent care, ambulatory surgery centers, emergency care, and telemedicine; the broad range of settings is accompanied by substantial variability in antibiotic utilization. Acute respiratory tract infections (ARTIs) are the most frequent indications for antibiotics in ambulatory care, followed by skin and soft tissue infections, genitourinary infections, and gastrointestinal infections.⁴ In the United States, patients with respiratory infections not requiring antibiotics are much more likely to receive antibiotic prescriptions from urgent care centers and emergency departments (EDs) than from medical offices and retail clinics.⁵ In direct-toconsumer telemedicine visits, a growing healthcare sector, antibiotics are prescribed more frequently than in medical offices, and antibiotic selections are broader spectrum in the telemedicine visits.^6,7 These diverse settings present unique challenges for antimicrobial stewardship efforts.

In the United States, ˜506 outpatient antibiotic courses are prescribed per 1000 person-years or about half of an antibiotic prescription per person per year.⁸ While similar antibiotic utilization rates are observed in England as in the United States,⁹ Swedes receive just 318 antibiotic courses per person-year.¹⁰ Regional variation in antibiotic prescribing rates suggests overuse. In the United States, it is estimated that 30% of total antibiotic prescriptions and 50% of prescriptions for ARTIs are likely unnecessary.^4,11 There is substantial, mostly unexplained, regional variation in antibiotic utilization within the United States, with a nearly fourfold difference in per capita antibiotic prescribing rates between the lowest- and highest-prescribing states.⁸ In addition to gross overuse of antibiotics, inappropriate antibiotic selections are also common, with large proportions of patients receiving antibiotics not recommended as first line by broadly accepted prescribing guidelines.^12,13,14,15 Non-first-line antibiotics are generally broader spectrum, more expensive, and more likely to cause adverse effects than first-line antibiotics.

The drivers of antibiotic overuse in the ambulatory setting are manifold. While direct requests for antibiotics appear to be rare, providers often perceive patients’ desire for antibiotics and prescribe out of concern for patient satisfaction.^16,17,18,19 Patients report practicing antibiotic shopping strategies, and clinicians report that other clinicians’ willingness to prescribe antibiotics unnecessarily results in greater prescribing pressure.^18,19 Lack of familiarity with antibiotic prescribing guidelines also plays a role, as providers express a desire for local evidence-based guidance.¹⁹ Diagnostic uncertainty presents a substantial challenge to frontline providers, with less use of diagnostic testing and more limited ability to follow up compared to the hospital setting.

Although antibiotic prescribing patterns are less well studied outside North America and Europe, it is clear that antibiotic overuse in outpatient settings is a global issue.²⁰ In fact, it is likely an even greater concern in low- and middle-income countries (LMIC) as compared to resourcerich contexts because of limited access to diagnostic tests, less regulation of antimicrobial dispensing, and a lack of antibiotic stewardship programs. In an analysis of 71 countries, antibiotic use increased from 54 billion to 73 billion units between 2000 and 2010 with 76% of the increase attributable to only five developing countries: Brazil, Russia, India, China, and South Africa.²¹

In LMIC, outpatient antibiotics are commonly prescribed for respiratory and gastrointestinal complaints and acute undifferentiated febrile illnesses. In sub-Saharan Africa, in particular, the wide availability of malaria rapid diagnostic tests that allow for accurate and timely diagnosis or exclusion of malaria has increased awareness that a majority of pediatric fever episodes are due to other
causes.^22,23,24 Although many of these illnesses are viral and do not require antibiotic treatment, these febrile patients are nonetheless often treated empirically with antibiotics, in part because of the lack of other diagnostic tools.^25,26,27 Globally, this diagnostic uncertainty often leads to empiric treatment with drugs that are of broader spectrum than necessary.²⁸ Outpatient antibiotic overuse is also rampant in Southeast Asia and India, especially in the context of respiratory infections.^{29,30,31,32,33} In China, a large study of outpatient clinics found that more than 60% of antibiotic prescriptions were inappropriate, with 78%-93% of respiratory infections being treated with antibiotics. Drivers of overuse included inadequate training and clinics’ reliance on direct antibiotic sales.³⁴ Reports such as these suggest that antibiotic overuse in LMICs is a complex, growing challenge that will require a much different set of solutions from those used in high-income countries.