Biomarkers to guide antibiotic timing and administration in infected patients presenting to the emergency department.

Antibiotics are often prescribed in the emergency department (ED) to patients presenting with a suspected infection before any definitive diagnosis can be made [1]. However, increasing antibiotic resistance and detrimental effects on the microbiota require their use to be limited to those with a high likelihood of bacterial infection or the potential for further clinical deterioration. Conversely, withheld or delayed treatment in higher severity patients may lead to increased morbidity and mortality rates [2]. Thus, an accurate assessment of antibiotic requirement and speed of administration is crucial.

Current tools to aid clinical decision-making include the use of procalcitonin (PCT) and C-reactive protein (CRP). However, recent interventional evidence in the ED has shown few differences between conventional biomarker-guided therapy and standard practice [1, 3], despite protocol compliance, patient selection and cut-off concerns. This post hoc analysis of a patient subset (Malmö, Sweden) from our previous investigation [4] compared the use of PCT, CRP and lactate to the novel biomarker mid-regional proadrenomedullin (MR-proADM) in guiding antibiotic administration during treatment within the ED.

Within this subset (N = 213), 26 (12.2%), patients were prescribed antibiotics < 48 h prior to presentation, whilst 187 (87.8%) were administered antibiotics during ED assessment. Of these patients, 164 (77.0%) were treated with intravenous (i.v.) and 23 (10.8%) with oral antibiotics. The median time to initial administration was 93 [28-160] min, with 71 (43.8%) patients receiving therapy within 60 min. Univariate and multivariate logistic regression found that MR-proADM had the strongest association with the requirement for antibiotic administration during ED treatment (Table 1). Interestingly, MR-proADM (Spearman ρ = − 0.31, p < 0.001) and lactate (Spearman ρ = − 0.25, p = 0.002) were the only parameters to be significantly negatively correlated with the time to antibiotic administration, with significant differences found at optimised MR-proADM cut-offs for antibiotic administration (1.27 nmol/L: 139 [76-211] vs 43 [26-135] min; p < 0.001) or pre-established [4] cut-offs for mortality prediction (1.54 nmol/L: 124 [33-199] vs 42 [26-122] min; p = 0.002). Similar results were also found for MR-proADM within previously established PCT concentration ranges [5] (Table 2), with an absence of ICU admission or 28-day mortality in patients with low MR-proADM concentrations, despite lower antibiotic administration rates and a significantly longer time to administration.

Table 1

Univariate and Multivariate analyses found that MR-proADM had the strongest correlation with the requirement for antibiotic administration during ED treatment

Biomarker	Patient population (N)	Antibiotic administration (N)	p value	C index	Univariate OR [95% CI]	Multivariate OR [95% CI]
MR-proADM	213	164	< 0.001	0.76	3.1 [1.9–4.9]	3.3 [1.9–5.9]
PCT	213	164	< 0.001	0.74	2.7 [1.7–4.3]	2.7 [1.7–4.5]
CRP	207	159	< 0.001	0.68	1.8 [1.3–2.5]	1.9 [1.4–2.8]
Lactate	204	158	0.002	0.66	1.8 [1.2–2.6]	1.6 [1.1–2.5]

Age, cardiovascular, neurological, renal and malignancy comorbidities were used as adjusting variables within the multivariate regression analysis, as previously outlined [4]. Univariate and multivariate odds ratios were expressed per 1 SD increment of the log-transformed value for each respective biomarker. CI confidence interval, CRP C-reactive protein, DF degrees of freedom, MR-proADM mid-regional proadrenomedullin, N number, OR odds ratio, PCT procalcitonin

Table 2

Low MR-proADM concentrations resulted in an absence of ICU admission or 28-day mortality, despite lower antibiotic administration rates and a significantly longer time to administration, irrespective of corresponding PCT concentration

Patient subgroups	MR-proADM concentration
	< 1.27 (nmol/L)	≥ 1.27 (nmol/L)
Subgroup 1: PCT concentration: < 0.25 μg/L (N = 106)
Patients (N)	65	41
Antibiotic administration (N, %)	35 (53.8%)	34 (82.9%)
Time to antibiotic administration (min) (median, Q1-Q3)	127 [45.0–220]	42 [25.8–116]
Composite of 28-day mortality and ICU admission (N, %)	0 (0.0%)	7 (17.1%)
Subgroup 2: PCT concentration: ≥ 0.25 and < 0.50 μg/L (N = 24)
Patients (N)	8	16
Antibiotic administration (N, %)	7 (87.5%)	15 (93.8%)
Time to antibiotic administration (min) (median, Q1–Q3)	165 [88–305]	50 [19.3–186]
Composite of 28-day mortality and ICU admission (N, %)	0 (0.0%)	1 (6.3%)
Subgroup 3: PCT concentration: ≥ 0.50 μg/L (N = 83)
Patients (N)	21	62
Antibiotic administration (N, %)	15 (71.4%)	59 (95.2%)
Time to antibiotic administration (min) (median, Q1–Q3)	131 [92.8–166]	45 [26–136.5]
Composite of 28-day mortality and ICU admission (N, %)	0 (0.0%)	15 (24.2%)

MR-proADM mid-regional proadrenomedullin, N number, PCT procalcitonin, Q quartile

Results suggest that delayed antibiotic administration in patients with low MR-proADM concentrations may result in few adverse effects, potentially allowing for a more detailed clinical assessment prior to any subsequent initiation. Further studies in larger patient populations are required to confirm these initial findings.