Association between nirmatrelvir/ritonavir treatment and antibiotic prescribing in the outpatient setting among patients with COVID-19

Coronavirus disease 2019 (COVID-19) has complicated the management of acute respiratory infections and impacted antibiotic use. We assessed the relationship between nirmatrelvir/ritonavir (NMV/r) receipt and outpatient antibiotic prescribing among patients with COVID-19 in a large national health system. We conducted a retrospective cohort study among outpatients enrolled in the Veterans Affairs Healthcare System who had a positive severe acute respiratory syndrome coronavirus 2 test or COVID-19 diagnosis and were eligible for NMV/r treatment between 1 April 2022 and 31 March 2024. NMV/r-treated patients were compared with those who did not receive NMV/r and were considered unexposed until NMV/r was dispensed. We assessed the relationship between NMV/r receipt and being prescribed an outpatient antibiotic in the 30 days after a COVID-19 diagnosis using adjusted Cox proportional hazards regression. We included 302,600 NMV/r-eligible outpatients with COVID-19, of whom 67,649 received NMV/r and 234,951 did not receive NMV/r. NMV/r-treated patients were less likely to receive outpatient antibiotics compared to those who did not receive NMV/r (7.2% [4,901/67,649] vs 9.2% [21,533/234,951], respectively; adjusted hazard ratio [HR] 0.65, 95% CI: 0.63‒0.68). After excluding patients who received an antibiotic prescription upon COVID-19 diagnosis (i.e., likely empiric therapy), this relationship was attenuated (HR: 0.91, 95% CI: 0.87‒0.95). NMV/r-eligible patients with COVID-19 who received NMV/r were 35% less likely to be prescribed outpatient antibiotics compared to patients who did not receive NMV/r, possibly driven by a diminished perceived need for empiric antibiotic therapy. Treatment with NMV/r may reduce unnecessary outpatient antibiotic use. Antibiotics should be reserved for patients with a high suspicion of bacterial co-infection.IMPORTANCEAntimicrobial resistance, driven by the overuse of antibiotics, is a major global health threat. The coronavirus disease 2019 (COVID-19) pandemic has complicated this issue, with antibiotics often prescribed to patients with COVID-19 despite being ineffective against viruses. These practices, typically aimed at preventing or empirically treating rare bacterial co-infections, have raised concerns about accelerating resistance. The antiviral nirmatrelvir/ritonavir (NMV/r), widely used in high-risk patients with COVID-19 to prevent severe illness, offers an opportunity to reassess antibiotic use in patients with respiratory infections. Our study of over 300,000 patients in a national healthcare system found that those treated with NMV/r for COVID-19 were 35% less likely to receive antibiotics than those who did not receive the antiviral. Lower antibiotic use among patients treated with NMV/r may reflect a reduction in unnecessary outpatient antibiotic use. These findings highlight the potential role of antivirals in supporting antibiotic stewardship and addressing a critical public health challenge.