Risk Factors and Outcomes of Endocarditis Due to Non-HACEK Gram-Negative Bacilli: Data from the Prospective Multicenter Italian Endocarditis Study Cohort

Marco Falcone; Giusy Tiseo; Emanuele Durante-Mangoni; Veronica Ravasio; Francesco Barbaro; Maria Paola Ursi; Maria Bruna Pasticci; Matteo Bassetti; Paolo Grossi; Mario Venditti; Marco Rizzi

doi:10.1128/AAC.02208-17

DOI: 10.1128/AAC.02208-17

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FIG 1
Flow diagram of the study.
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FIG 2
Kaplan-Meier plots showing in-hospital (A) and 1-year (B) survival of patients with IE caused by GNB according to multidrug-resistant etiology.

TABLE 1

Etiologies of IE due to non-HACEK GNB

Etiology	No. of patients (% of total^a)
Enterobacteriaceae
Escherichia coli	18 (31)
Klebsiella pneumoniae	6 (10.3)
Citrobacter koseri	3 (5.2)
Proteus mirabilis	2 (3.5)
Serratia marcescens	2 (3.5)
Enterobacter spp.	2 (3.5)
Yersinia enterocolitica	1 (1.7)
Total	34 (58.6)
Nonfermenting bacteria
Pseudomonas spp.	11 (19)
Acinetobacter baumannii	1 (1.7)
Other bacteria
Campylobacter fetus	2 (3.5)
Fusobacterium spp.	2 (3.5)
Achromobacter xylosoxidans	1 (1.7)
Brucella spp.	1 (1.7)
Prevotella buccae	1 (1.7)
Raoultella spp.	1 (1.7)
Sphingomonas paucimobilis	1 (1.7)
GNB coinfections^b	3 (5.2)
MDR etiology	16 (27.6)

↵a A total of 58 patients with IE due to non-HACEK GNB were studied.
↵b Comprising one case with E. coli and Proteus mirabilis, one with Pseudomonas aeruginosa and Pseudomonas fluorescens, and one with Pseudomonas aeruginosa and Stenotrophomonas maltophilia.

TABLE 2

Comparison between patients with IE due to GNB (cases) and patients with IE due to other etiologies

Variable^a	Value^b for patients with IE due to:		P
Variable^a	GNB (n = 58)	Other etiologies (n = 174)	P
Demographic data
Males	39 (67.2)	117 (67.6)	1.0
Median (range) age (yr)	69.5 (57.75–77)	69.5 (60–76)	1.0
Type of endocarditis
NVE	34 (58.6)	118 (67.8)	0.202
PVE	16 (27.6)	48 (27.6)	1.0
Device-related IE	8 (13.8)	8 (4.6)	0.017
Comorbidities
Diabetes	19 (32.8)	30 (17.2)	0.012
Hemodialysis	1 (1.7)	5 (2.9)	0.633
Malignancies	10 (17.2)	16 (9.2)	0.093
HIV infection	2 (3.4)	4 (2.3)	0.633
Risk factors
IVDU	5 (8.6)	15 (8.6)	1.0
Dental procedures	3 (5.2)	13 (7.5)	0.537
CVC	12 (20.7)	16 (10)	0.021
CIED	15 (25.9)	19 (10.9)	0.005
Congenital heart disease	4 (6.9)	10 (5.7)	0.758
Immunosuppression	9 (15.5)	7 (4)	0.003
Pre-existing valvular disease	18 (31)	57 (32.8)	0.808
Invasive procedures within 180 days
Dental procedures	3 (5.2)	13 (7.5)	0.537
Esophagogastroscopy	1 (1.7)	5 (2.9)	0.633
Colonoscopy	4 (6.9)	6 (3.4)	0.263
Cystoscopy	3 (5.2)	3 (1.7)	0.152
Route of acquisition
Community acquired	32 (55.2)	116 (66.7)	0.115
Healthcare associated	24 (41.4)	49 (28.2)	0.060
Nosocomially acquired	2 (3.4)	9 (5.2)	0.593
Complications
Stroke	7 (12.1)	27 (15.5)	0.520
Embolism	14 (24.1)	64 (36.8)	0.078
Heart failure	15 (25.9)	72 (41.4)	0.030
Septic shock	2 (3.4)	3 (1.7)	0.434
Arrhythmias	5 (8.6)	27 (15.5)	0.187
Echocardiographic findings
Evidence of vegetation	50 (86.2)	155 (89.1)	0.555
Median (range) size of vegetation (mm)	14 (6.5–20)	10 (8–15)	0.027
Cardiac abscess	3 (5.2)	17 (9.8)	0.280
Perforation	4 (6.9)	8 (4.6)	0.494
Dehiscence	6 (10.3)	9 (5.2)	0.165
New regurgitation	10 (17.2)	63 (36.2)	0.007
Fistula	0 (0)	4 (2.3)	0.244
Presumed source of infection
Genitourinary tract	16 (27.6)	6 (3.4)	<0.001
Skin	8 (13.8)	28 (16.1)	0.675
Nonoral gastrointestinal tract	9 (15.5)	37 (21.3)	0.342
Oral	3 (5.2)	18 (10.3)	0.234
Other or unknown	24 (41.4)	81 (46.6)	0.493
Treatment (surgery plus antibiotic therapy)	25 (43.1)	79 (45.4)	0.760
Outcomes
All-cause in-hospital mortality	8 (13.8)	23 (13.2)	0.911
IE-related in-hospital mortality	8 (13.8)	21 (12.1)	0.731
Cumulative all-cause 1-yr mortality^c	15 (30.6)	NA
Cumulative IE-related 1-yr mortality^c	11 (22.4)	NA

↵a NVE, native valve endocarditis; PVE, prosthetic valve endocarditis; IVDU, intravenous drug user; CVC, central venous catheter (including any of the following: arteriovenous fistula, chronic intravenous catheter, or acute central catheter); CIED, cardiac implantable electronic device (12 permanent pacemakers and 3 cardioverter defibrillators in patients with endocarditis due to GNB; 17 permanent pacemakers and 2 cardioverter defibrillators in patients with other causes of endocarditis).
↵b Values are numbers (percentages) of patients except where otherwise indicated.
↵c Cumulative 1-year mortality was calculated for 49 patients (8 patients who died during the hospital stay and 41 patients with available follow-up after 1 year). NA, not available.

TABLE 3

Multivariate analysis of factors independently associated with Gram-negative IE

Factor^a	Univariate analysis				Multivariate analysis
	OR	95.0% CI		P	OR	95.0% CI		P
	OR	Lower	Upper	P	OR	Lower	Upper	P
Genitourinary tract	10.67	3.93	28.92	<0.001	13.60	4.63	39.93	<0.001
Immunosuppression	4.38	1.55	12.37	0.003	5.16	1.6	16.62	0.006
CIED	2.85	1.33	6.06	0.005	3.60	1.55	8.20	0.003
New regurgitation	0.37	0.17	0.77	0.007	0.39	0.17	0.90	0.027
Device-related endocarditis	3.32	1.19	9.30	0.017
CVC	2.56	1.13	5.80	0.021
Heart failure	0.48	0.25	0.94	0.003

↵a CIED, cardiac implantable electronic device; CVC: central venous catheter (including any of the following: arteriovenous fistula, chronic intravenous catheter, or acute central catheter).

TABLE 4

Treatment strategies for IE due to non-HACEK GNB

Antibiotic therapy^a	No. (% of total^b)
Noncarbapenem β-lactam^c ± aminoglycosides ± fluoroquinolones	29 (50)
Penicillin or cephalosporin only	5
Non-carbapenem β-lactam + aminoglycosides	14
Non-carbapenem β-lactam + fluoroquinolones	8
Non-carbapenem β-lactam + aminoglycosides + fluoroquinolones	2
Carbapenem ± aminoglycosides ± fluoroquinolones	8 (13.8)
Carbapenem only	3
Carbapenem + aminoglycosides	1
Carbapenem + fluoroquinolones	3
Carbapenem + aminoglycosides + fluoroquinolones	1
Noncarbapenem β-lactam +carbapenem ± aminoglycosides ± fluoroquinolones	13 (22.4)
Non-carbapenem β-lactam + carbapenem	4
Non-carbapenem β-lactam + carbapenem + aminoglycosides	3
Non-carbapenem β-lactam + carbapenem + fluoroquinolones	4
Non-carbapenem β-lactam + carbapenem + aminoglycosides + fluoroquinolones	2
Colistin-containing regimens	3 (5.2)
Colistin + carbapenem + rifampin	2
Colistin + penicillin or cephalosporin + carbapenem + rifampin	1
Other regimens	5 (8.6)
Non-carbapenem β-lactam + rifampin	1
Non-carbapenem β-lactam + tobramycin + clindamycin	1
Aminoglycosides + rifampin	1
Aminoglycosides + fluoroquinolones + rifampin	2

↵a ±, with or without.
↵b A total of 58 patients with IE due to non-HACEK GNB were studied.
↵c Includes penicillin alone, penicillin–penicillinase inhibitor combinations, and third-generation cephalosporins.

TABLE 5
Cox regression analysis investigating the effect of MDR etiology on in-hospital and 1-year mortality among patients with IE due to non-HACEK GNB
MDR etiology on: Cox regression analysis
HR 95.0% CI P
Lower Upper
In-hospital mortality 21.849 2.672 178.683 0.004
1-yr mortality 4.408 1.581 12.287 0.005