Antibiotic Stewardship Related to Delayed Diagnosis and Poor Prognosis of Critically Ill Patients with Vancomycin-Resistant Enterococcal Bacteremia: A Retrospective Cohort Study

Figures & data

Figure 1 Flow chart of patients enrolled in this study. We screened 5144 cases with blood culture data and excluded 3582 cases of GNB bacteremia. After further exclusion of 452 contaminated cultures, 233 single set blood cultures, and 2 cases of out-of-hospital cardiac arrest (OHCA) without return of spontaneous circulation (ROSC), 875 cases of GPC bacteremia remained. Furthermore, 191 Enterococcus bacteremia cases were analyzed after excluding 450 Staphylococcus and 231 Streptococcus cases. A total of 191 patients with enterococcal bacteremia (55 patients with VRE bacteremia [case group] and 136 patients with VSE bacteremia [control group]) were included in the analysis.

Abbreviations: GPC, Gram-positive cocci; GNB, Gram-negative bacteria; VRE, vancomycin-resistant Enterococcus; VSE, vancomycin-sensitive Enterococcus.

Table 1 Comparisons of Demographic Characteristics Between Critically Ill Patients with VRE Bacteremia and Those with VSE Bacteremia

Demographic Characteristics	VRE Bacteremia (N=55)	VSE Bacteremia (N=136)	p value
Sex			NS
Female	15 (27.3%)	53 (39%)
Male	40 (72.7%)	83 (61%)
Age	72.1±9.9	72.4±15.9	NS
Comorbidities
Charlson comorbidity index	6.9±2.5	6.3±3.2	NS
Any cancer	22 (40%)	37 (27.2%)	NS
Solid organ tumor	15 (27.3%)	37 (27.2%)	NS
Hematological malignancy	7 (12.7%)	0 (0%)	<0.001^a
DM	17 (30.9%)	57 (41.9%)	NS
COPD	7 (12.7%)	16 (11.8%)	NS
Chronic renal failure	24 (43.6%)	54 (39.7%)	NS
Heart disease	30 (54.5%)	62 (45.6%)	NS
Liver cirrhosis	7 (12.7%)	7 (5.1%)	NS
Gastrointestinal disease	29 (52.7%)	40 (29.4%)	0.002^a
Hepatobiliary disease	13 (23.6%)	29 (21.3%)	NS
Bone marrow transplant	0 (0%)	0 (0%)	NS
Solid organ transplant	5 (9.1%)	1 (0.7%)	0.003^a
Catheter
Catheter total number	2.4±1.8	1.0±1.3	<0.001^a
Central venous catheter	29 (52.7%)	22 (16.2%)	<0.001^a
Urinary catheter	30 (54.5%)	38 (27.9%)	0.001^a
NG tube	31 (56.4%)	36 (26.5%)	<0.001^a
Drainage tube	11 (20%)	6 (4.4%)	0.001^a
Endo tube	16 (29.1%)	9 (6.6%)	<0.001^a
Tracheostomy	2 (3.6%)	6 (4.4%)	NS
Double lumen (or perm)	15 (27.3%)	19 (14%)	0.03^a
Antibiotic experiences
Antibiotic exposure within 3 months	46 (83.6%)	64 (47.1%)	<0.001^a
Vancomycin	5 (9.1%)	5 (3.7%)	NS
Glycopeptide	27 (49.1%)	10 (7.4%)	<0.001^a
Carbapenem	26 (47.3%)	17 (12.5%)	<0.001^a
Cephalosporin	40 (72.7%)	49 (36%)	<0.001^a
Penicillin	30 (54.5%)	27 (19.9%)	<0.001^a
Colimycin	9 (16.4%)	5 (3.7%)	0.002^a
Fluoroquinolones	23 (41.8%)	28 (20.6%)	0.003^a
Baktar	6 (10.9%)	2 (1.5%)	0.003^a
Metronidazole	4 (7.3%)	2 (1.5%)	0.037^a
Clindamycin	0 (0%)	2 (1.5%)	NS
Macrolides	0 (0%)	0 (0%)	NS
Aminoglycosides	2 (3.6%)	4 (2.9%)	NS
Tetracycline	4 (7.3%)	2 (1.5%)	0.037^a
Infection events
Other sites of Enterococcus infection	17 (30.9%)	43 (31.6%)	NS
Other bacteremia coinfections	35 (63.6%)	74 (54.4%)	NS
Others
Rectal swab test result positive for VRE	14 (25.5%)	6 (4.4%)	<0.001^a
Antacid use	34 (61.8%)	52 (38.2%)	0.003^a
Probiotic use	1 (1.8%)	7 (5.1%)	NS
History of surgery within 6 months	24 (43.6%)	30 (22.1%)	0.003^a
From long-term care facility	5 (9.1%)	19 (14%)	NS
Septic shock	8 (14.5%)	13 (9.6%)	NS
Mechanical ventilation use	27 (49.1%)	37 (27.2%)	0.004^a
Initial antibiotic during confirmed GPC bacteremia
First line antibiotics	4 (7.3%)	14 (10.3%)	NS
Vancomycin	8 (14.5%)	17 (12.5%)	NS
Teicoplanin	43 (78.2%)	105 (77.2%)	NS
Linezolid	0	0	NS
Daptomycin	0	0	NS
Tigecycline	0	0	NS
Antibiotic change rate	55 (100%)	14 (10.3%)	<0.001^a
Time to appropriate antibiotic administration after GPC bacteremia diagnosis	3.3±2.1	1.5±1.8	<0.001^a

Notes: ^aStatistically significant, p<0.05.

Abbreviations: VRE, vancomycin-resistant Enterococcus; VSE, vancomycin-sensitive Enterococcus; NG, nasogastric; DM, diabetes mellitus; COPD, chronic obstructive pulmonary disease; GPC, Gram-positive cocci; NS, non-significant.

Table 2 Univariate and Multivariate Logistic Regression Analyses to Identify Variables Associated with Vancomycin-Resistant Enterococcus (VRE) Bacteremia in Critically Ill Patients with Enterococcus Bacteremia

	Univariate		Multivariate
	OR (95% CI)	p	Adjusted OR (95% CI)	p
Gastrointestinal disease	2.677 (1.404–5.103)	0.003^a
Solid organ transplant	13.5 (1.539–118.404)	0.019^a
Total bilirubin	1.085 (1.004–1.171)	0.038^a
Albumin	0.496 (0.306–0.802)	0.004^a
Lactate (mmol/L)	0.784 (0.632–0.974)	0.028^a
HCO3	1.088 (1.006–1.177)	0.036^a
A-a DO2	1.002 (1–1.004)	0.03^a
Overall catheter use	1.801 (1.437–2.256)	<0.001^a
Central venous catheter	5.78 (2.873–11.627)	<0.001^a	3.116 (1.386–7.008)	0.006^a
Urinary catheter	3.095 (1.616–5.926)	0.001^a
NG tube	3.588 (1.864–6.908)	<0.001^a
Drainage tube	5.417 (1.892–15.507)	0.002^a
Endo tube	5.789 (2.373–14.126)	<0.001^a
Double lumen (or perm)	2.309 (1.073–4.969)	0.032^a
Antibiotic exposure within 3 months	5.575 (2.61–12.666)	<0.001^a
Glycopeptide	12.150 (5.281–27.951)	<0.001^a	5.734 (2.297–14.312)	<0.001^a
Carbapenem	6.276 (3.013–13.072)	<0.001^a
Cephalosporin	4.735 (2.377–9.43)	<0.001^a	2.923 (1.346–6.345)	0.007^a
Penicillin	4.844 (2.46–9.54)	<0.001^a
Colimycin	5.126 (1.633–16.087)	0.005^a
Fluoroquinolones	2.772 (1.407–5.462)	0.003^a
Baktar	8.204 (1.602–42.016)	0.012^a
Antacid use	2.615 (1.373–4.983)	0.003^a
History of surgery within 6 months	2.735 (1.400–5.343)	0.003^a
Rectal swab test result positive for VRE	7.398 (2.671–20.492)	<0.001^a
Mechanical ventilation use	3.314 (1.604–6.850)	0.001^a

Notes: Dependent variable: VRE bacteremia. ^aStatistically significant, p<0.05. All significant univariate variables were included and adjusted for in the final multivariate model.

Abbreviations: OR, odds ratio; CI, confidence interval; NS, non-significant.

Table 3 Comparisons of Clinical Outcomes Between Patients with VRE Bacteremia and Those with VSE Bacteremia

	VRE Bacteremia (N=55)	VSE Bacteremia (N=136)	RR (95% CI)	p value
All-cause hospital mortality	30 (54.5%)	43 (31.6%)	2.595 (1.366–4.933)	0.004^a
All-cause 28-day mortality	24 (43.6%)	38 (27.9%)	1.997 (1.041–3.830)	0.037^a
AAU ≤3 D	9/33 (27.3%)	29/107 (27.1%)	0.991(0.413–2.382)	0.985
AAU >3 D	15/22 (68.2%)	9/29 (31%)	4.762 (1.444–15.703)	0.01^a
Length of stay in hospital	25.1±26.8	15.0±14.5	1.025 (1.009–1.041)	0.002^a
Ventilator use days	29.8±29.1	15.9±20.2	1.024 (1.001–1.047)	0.04^a

Notes: ^aStatistically significant, p<0.05.

Abbreviations: VRE, vancomycin-resistant Enterococcus; VSE, vancomycin-sensitive Enterococcus; RR, relative risk; ICU, intensive care unit; NS, non-significant; AAU, appropriate antibiotic use.

Table 4 Cox Regression Model to Determine Factors Associated with All-Cause 28-Day Mortality

	Univariate		Multivariate
	HR (95% CI)	p value	Adjusted HR (95% CI)	p value
VSE with AAU ≤3 D	Reference	0.047	Reference	0.048
VSE with AAU >3 D	0.948 (0.449–2.005)	NS	1.053 (0.493–2.249)	NS
VRE with AAU ≤3 D	0.744 (0.35–1.58)	NS	0.679 (0.308–1.498)	NS
VRE with AAU >3 D	2.096 (1.123–3.913)	0.02^a	2.045 (1.089–3.84)	0.026^a
APACHE II	1.04 (1.009–1.072)	0.011^a	1.040 (1.009–1.072)	0.011^a
SOFA score	1.083 (1.014–1.158)	0.018^a	1.057 (0.962–1.16)	NS
Central venous catheter use	1.452 (0.872–2.418)	NS
Antibiotic exposure for 3 days within 3 months	1.474 (0.839–2.589)	NS
Glycopeptide	0.89 (0.496–1.595)	NS
Cephalosporin	1.299 (0.78–2.164)	NS
Septic shock	1.995 (1.062–3.748)	0.032	1.249 (0.604–2.585)	NS
Mechanical ventilation use	1.207 (0.700–2.083)	NS	0.796 (0.400–1.585)	NS

Notes: Events: all-cause 28-day mortality. Time: days since enterococcal bacteremia diagnosis to 28 days. ^aStatistically significant, p<0.05.

Abbreviations: AAU, appropriate antibiotic use; HR, hazard ratio; CI, confidence interval; NS, non-significant.

Figure 2 Survival curves according to VRE or VSE bacteremia and the time to appropriate antibiotic administration after GPC bacteremia diagnosis (four groups). The Kaplan–Meier survival analysis was adopted for patients with (1) VSE bacteremia with time to appropriate antibiotic administration ≤3 days, (2) VSE bacteremia with time to appropriate antibiotic administration >3 days, (3) VRE bacteremia with time to appropriate antibiotic administration ≤3 days, and (4) VRE bacteremia with time to appropriate antibiotic administration >3 days during their hospital stay (cut-off point: 28 days). Log rank test: p<0.05.