AbstractBackgroundEmpiric Gram-negative antibiotics are frequently changed in response to new information. To inform antibiotic stewardship, we sought to identify predictors of antibiotic changes using information knowable before microbiological test results.MethodsWe performed a retrospective cohort study. Survival-time models were used to evaluate clinical factors associated with antibiotic escalation and de-escalation (defined as an increase or decrease, respectively, in the spectrum or number of Gram-negative antibiotics within 5 days of initiation). Spectrum was categorized as narrow, broad, extended or protected. Tjur’s D statistic was used to estimate the discriminatory power of groups of variables.ResultsIn 2019, 2 751 969 patients received empiric Gram-negative antibiotics at 920 study hospitals. Antibiotic escalation occurred in 6.5%, and 49.2% underwent de-escalation; 8.8% were changed to an equivalent regimen. Escalation was more likely when empiric antibiotics were narrow-spectrum (HR 19.0 relative to protected; 95% CI: 17.9–20.1), broad-spectrum (HR 10.3; 95% CI: 9.78–10.9) or extended-spectrum (HR 3.49; 95% CI: 3.30–3.69). Patients with sepsis present on admission (HR 1.94; 95% CI: 1.91–1.96) and urinary tract infection present on admission (HR 1.36; 95% CI: 1.35–1.38) were more likely to undergo antibiotic escalation than patients without these syndromes. De-escalation was more likely with combination therapy (HR 2.62 per additional agent; 95% CI: 2.61–2.63) or narrow-spectrum empiric antibiotics (HR 1.67 relative to protected; 95% CI: 1.65–1.69). Choice of empiric regimen accounted for 51% and 74% of the explained variation in antibiotic escalation and de-escalation, respectively.ConclusionsEmpiric Gram-negative antibiotics are frequently de-escalated early in hospitalization, whereas escalation is infrequent. Changes are primarily driven by choice of empiric therapy and presence of infectious syndromes.