June 10, 2021

Improving Second-Dose Antibiotic Administration in Admitted Patients

The timely administration of antibiotics has a well-established benefit in serious bacterial infections, including sepsis, bacteremia and meningitis (1-4). Although the control of bacterial infections is dependent on the maintenance of sufficient antibiotic pharmacokinetic and pharmacodynamic parameters, the majority of studies evaluating antibiotic delay focus only on the first dose. Recent evidence from studies evaluating septic patients suggests that delays in antibiotic redosing may also be associated with worse clinical outcomes (5,6). In light of the increasing burden of boarding in Emergency Departments (ED) and subsequent need to often redose antibiotic in the ED, we examined the association between delayed second antibiotic dose administration and mortality among patients admitted from the ED (7). We also evaluated potential risk factors for delay to elucidate obstacles to timely administration. 

In this retrospective cohort study of patients admitted through five EDs in a single healthcare system, we evaluated patients with a broad array of infections who received two intravenous antibiotic doses of the same antibiotic within a 30-hour period, with the first dose administered in the ED. Delay of the second dose was defined as administration of this dose at a time-point greater than 125% of the recommended dosing interval, based on antibiotic type and indication. A total of 5605 second antibiotic doses, occurring during 4904 visits, met study criteria, and delayed administration of a second dose occurred during 21.1% of ED visits. After adjustment for patient characteristics, delayed second dose administration was associated with increased odds of in-hospital mortality (OR 1.50, 95% CI 1.05-2.13).  

Our assessment of potential risk factors for delay identified several significant associations, including independent associations with ED boarding (> 4 hours), frequent recommended antibiotic redosing frequency, multiple patient comorbidities (CCI ≥ 2), high acuity ED presentation (ESI 1 or 2), elevated lactate level in the ED, and ICU admission from the ED. Interestingly, these latter three associations suggest that patients with greater illness severity may be more susceptible to delays in redosing. Notably, we did not see a significant association between delay of second dose administration and the use of individual orders for first and second doses, as opposed to a standing order for repeat dosing, in our primary analysis model. However, a significant association was seen between these two factors in a sensitivity analysis, suggesting that further evaluation is needed to determine if the standardized utilization of standing orders might be one tool for promoting timely redosing. 

The findings of this study both support the critical importance of expanding the focus of quality improvement programs beyond initial antibiotic administration and begin to shed light on potential target populations and interventions to more efficiently improve timely administration of second antibiotic doses. 

Learn More Here


(1) Seymour CW, Gesten F, Prescott HC, Friedrich ME, Iwashyna TJ, Phillips GS, et al. Time to Treatment and Mortality during Mandated Emergency Care for Sepsis. N  Engl  J  Med 2017;376:2235-2244. 

(2) Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, et al. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N  Engl  J  Med 2001;345:1368-1377. 

(3) Corl KA, Zeba F, Caffrey AR, Hermenau M, Lopes V, Phillips G, et al. Delay in Antibiotic Administration Is Associated With Mortality Among Septic Shock Patients With Staphylococcus aureus Bacteremia. Crit Care Med 2020;48:525-532. 

(4) Brouwer MC, van de Beek D. Management of bacterial central nervous system infections. Handb Clin Neurol 2017;140:349-364. 

(5) Leisman D, Huang V, Zhou Q, Gribben J, Bianculli A, Bernshteyn M, et al. Delayed Second Dose Antibiotics for Patients Admitted From the Emergency Department With Sepsis: Prevalence, Risk Factors, and Outcomes. Crit Care Med 2017;45:956-965. 

(6) Andersson M, Östholm-Balkhed Å, Fredrikson M, Holmbom M, Hällgren A, Berg S, et al. Delay of appropriate antibiotic treatment is associated with high mortality in patients with community-onset sepsis in a Swedish setting. Eur  J  Clin  Microbiol  Infect  Dis 2019;38:1223-1234. 

(7) Kemmler CB, Sangal RB, Rothenberg C, Li SX, Shofer FS, Abella BS, Venkatesh AK, Foster SD. Delays in antibiotic redosing: Association with inpatient mortality and risk factors for delay. Am J Emerg Med 2021: Mar 1;46:63-69

Charles B. Kemmler, MD, PhD
Department of Emergency Medicine, Prisma Health-Upstate
Instructor, University of South Carolina School of Medicine Greenville