Risk factors for and consequences of positive valve cultures in patients who undergo cardiac surgery while receiving antimicrobial treatment for infective endocarditis

Figures & data

Table 1. Characteristics of episodes with negative and positive valve culture.

	Total (345) Median (IQR) or n (%)	NVC (267) Median (IQR) or n (%)	PVC (78) Median (IQR) or n (%)	P-value
Patient characteristics
Age *	66 (52–73)	66 (53–73)	64 (50–74)	0.57^2
Sex (Male)	252 (73)	197 (74)	55 (71)	0.57^1
Immunosuppression *	28 (8.3)	22 (8.2)	6 (7.7)	0.88^1
Charlson score *				0.06^1
0–1	260 (75)	208 (78)	52 (67)
2–4	77 (22)	52 (19)	25 (32)
5–9	8 (2.3)	7 (2.6)	1 (1.3)
Predisposing factors	191 (55)	152 (57)	39 (50)	0.28^1
Prosthetic valve *	94 (27)	71 (27)	23 (30)	0.61^1
Previous IE	32 (9.3)	25 (9.4)	7 (9.0)	0.92^1
Valvular heart disease	106 (31)	88 (33)	18 (23)	0.10^1
Intravenous drug use	17 (4.9)	11 (4.1)	6 (7.7)	0.20^1
Indications for surgery
Heart failure	175 (51)	135 (51)	40 (51)	0.91^1
Uncontrolled infection	158 (46)	128 (48)	30 (39)	0.14^1
Prevention of embolism	152 (44)	112 (42)	40 (51)	0.14^1
Infection characteristics
Definite IE *	303 (88)	232 (87)	71 (91)	0.33^1
Heart abscess *	120 (35)	94 (35)	26 (33)	0.76^1
Vegetation size (mm) *	10 (5–16)	10 (5–15)	14 (7–20)	0.02^2
Preoperative fever *	92 (27)	57 (21)	35 (45)	<0.001^1
Embolic events *				0.11^1
0	183 (53)	139 (52)	44 (56)
1–3	68 (20)	59 (22)	9 (12)
4 or more	94 (27)	69 (26)	25 (32)
CRP-ratio *	0.42 (0.21–0.68)	0.36 (0.19–0.61)	0.65 (0.39–0.83)	<0.001^2
Duration of preoperative * antibiotic treatment (days)	9 (5–16)	11 (7–19)	5 (2–7)	<0.001^2
Number of affected valves *				0.04^1
1	298 (86)	225 (84)	73 (94)
2	47 (14)	42 (16)	5 (6.4)
Blood culture findings *				<0.001^1
Viridans streptococci and S. bovis	105 (30)	97 (36)	8 (10)
S. aureus	85 (25)	58 (22)	27 (35)
Enterococci	35 (10)	20 (7.5)	15 (19)
CoNS	29 (8.4)	16 (6.0)	13 (17)
Others	68 (20)	57 (21)	11 (14)
BCNE	23 (6.7)	19 (7.1)	4 (5.1)
Affected valve				0.19^1
Aortic valve	185 (54)	140 (52)	45 (58)
Mitral valve	100 (29)	76 (28)	24 (31)
Tricuspid valve	5 (1.4)	2 (0.7)	3 (3.8)
Pulmonary valve	8 (2.3)	7 (2.6)	1 (1.3)
Aortic & Mitral valve	37 (11)	34 (13)	3 (3.8)
Aortic & Tricuspid valve	6 (1.7)	5 (1.9)	1 (1.3)
Mitral & Tricuspid valve	3 (0.9)	2 (0.7)	1 (1.3)
Aortic & Pulmonic valve	1 (0.3)	1 (0.4)	0 (0)

¹Using Pearson Chi-square test.

²Using Mann–Whitney U-test.

IQR: interquartile range; CoNS: Coagulase-negative staphylococci; IE: infective endocarditis; PVC: Positive valve cultures; NVC: Negative valve cultures.

p < 0.05 was considered statistically significant.

*Were used in multivariable logistic regression.

Figure 1. Development of the study population with reasons for exclusions.

Table 2. Microbiological findings in blood and valve cultures.

	Blood cultures n = 341 n (%)	Valve cultures n = 345 n (%)
Positive result	322 (94)	78 (23)
Causative agents
Viridans streptococci	89 (28)	6 (7.7)
S. mitis-group	51	6
S. sanguinis-group	14	0
S. anginous-group	10	0
S. salivarius-group	8	0
S. mutans-group	6	0
S. aureus *	85 (26)	29 (37)
Enterococci	35 (11)	13 (17)
E. faecalis	34	13
E. faecium	1	0
CoNS	29 (9.0)	12 (15)
S. epidermidis	21	8
S. lugdunensis	4	2
S. haemolyticus	1	0
S. waneri	1	1
S. caprae	1	0
CoNS unspecified	1	1
β-hemolytic streptococci	20 (6.2)	3 (3.8)
S. agalactiae	14	2
S. dysgalactiae	3	0
S. pyogenes	1	1
Group C Streptococcus **	1	0
Group G Streptococcus **	1	0
S. bovis-group	16 (5.0)	2 (2.6)
HACEK-group	10 (3.1)	0 (0)
H. parainfluenzae	6	0
Cardiobacterium spp.	2	0
Aggregatibacter spp.	1	0
A. aphrophilius	1	0
Others	34 (11)	8 (10)
Aerococcus urinae	5	0
Streptococcus pneumoniae	5	0
Corynebacterium spp.	4	0
Abiotrophia defectiva	3	0
Candida spp.	3	2
Gemella spp.	3	1
Granulicatella adiacens	2	0
Rothia mucilaginosa	2	0
Capnocytophaga canimorsus	1	0
Cutibacterium acnes	1	1
Enterobacter cloacae	1	1
Escherichia coli	1	1
Klebsiella pneumoniae	1	0
Shewanella algae	1	0
Veillonella parvula	1	0
Neisseria spp.	0	1
Pantoea spp.	0	1
Polymicrobial	4 (1.2)	5 (6.4)

Causative agents are presented as a percentage of positive results.

CoNS: Coagulase-negative staphylococci.

*All S. aureus isolates were sensitive to methicillin. **Likely to be S. dysgalactiae.

Table 3. Episodes with follow-up blood cultures.

	Total (145) n (%)	NVC (111) n (%)	PVC (37) n (%)	P-value
Persistent bacteremia	78 (54)	52 (48)	26 (70)	0.02^1
Causative agent in episodes with persistent bacteremia				0.11^2
Viridans streptococci and S. bovis	9 (12)	8 (15)	1 (4)
S. aureus	36 (46)	27 (52)	9 (35)
Enterococci	10 (13)	4 (8)	6 (23)
CoNS	10 (13)	5 (10)	5 (19)
Others	13 (17)	8 (15)	5 (19)

Causative agents are presented as a percentage of positive results.

CoNS: Coagulase-negative staphylococci; NVC: Negative valve culture; PVC: Positive valve culture.

¹Using Pearson Chi-square test.

²Using Fisher’s exact test.

Table 4. Multivariable analysis for positive valve cultures.

	COR (95% CI)	P-value	AOR (CI 95%)	P-value
Duration of preoperative antibiotic treatment (days)
0-2	Reference		Reference
3-5	0.22 (0.09–0.55)	0.001	0.14 (0.04–0.47)	0.002
6-8	0.14 (0.06–0.36)	<0.001	0.05 (0.01–0.19)	<0.001
9-11	0.11 (0.04–0.31)	<0.001	0.03 (0.01-0.13)	<0.001
11 or above	0.02 (0.01–0.05)	<0.001	0.003 (0.001–0.02)	<0.001
Preoperative fever	3.0 (1.8–5.1)	<0.001	2.6 (1.2–5.6)	0.02
Prosthetic valve	1.2 (0.66-2.0)	0.61	3.3 (1.4–7.9)	0.01
Single affected valve	2.7 (1.0-7.1)	0.04	4.8 (1.2–20)	0.03
Blood culture findings
Viridans streptococci and S. bovis	Reference		Reference
S. aureus	5.6 (2.4–13)	<0.001	28 (7.9–99)	<0.001
Enterococci	9.1 (3.4–24)	<0.001	20 (4.8–86)	<0.001
CoNS	9.9 (3.5–28)	<0.001	48 (11–212)	<0.001
Others	2.3 (0.89–6.2)	0.09	3.5 (1.00–12)	0.05
BCNE	2.6 (0.70–9.3)	0.16	0.82 (0.11–6.1)	0.85

COR: crude odds ratio; AOR: adjusted odds ratio; CI: confidence interval. p < 0.05 was considered statistically significant. CoNS: Coagulase-negative staphylococci; BCNE: Blood culture-negative endocarditis.

Figure 2. Kaplan–Meier curves presenting survival in patients with positive and negative valve cultures until one year after surgery.

Table 5. Outcomes in episodes with negative and positive valve cultures.

	Total (345) Median (IQR) or n (%)	Negative valve cultures (267) Median (IQR) or n (%)	Positive valve cultures (78) Median (IQR) or n (%)	P-value
Length of stay (days)	37 (32-50)	39 (32-50)	35 (31-48)	0.20^2
Surgical intervention	40 (11)	35 (13)	5 (6.4)	0.10^1
Reoperation	5 (1.4)	5 (1.9)	0 (0)
Re-exploration	23 (6.7)	21 (7.9)	2 (2.6)
Other	12 (3.5)	9 (3.4)	3 (3.8)
Relapse *	7 (2.5)	5 (2.4)	2 (3.1)	0.67^3
One-year mortality	41 (13)	31 (13)	10 (14)	0.72^1

¹Using Pearson Chi-square test.

²Using Mann–Whitney U-test.

³Using Fisher’s exact test.

IQR: Interquartile range; IE: infective endocarditis.

p < 0.05 was considered statistically significant. *Valid data in 276 episodes.

Table 6. Characteristics of patients with one-year mortality and final mortality model.

	Lived through the first year (274) Median (IQR) or n (%)	One-year mortality (41) Median (IQR) or n (%)	Crude HR (CI 95%)	P-value	Adjusted HR (CI 95%)	P-value
Age	65 (52–73)	71 (62–75)	1.03 (1.0–1.1)	0.03	1.03 (1.0–1.1)	0.02
Charlson score	0 (0–1)	1 (0–3)	1.3 (1.2–1.5)	<0.001	1.3 (1.2–1.5)	<0.001
Immunosuppression	24 (8.8)	1 (2.4)	0.28 (0.04–2.0)	0.20
Heart abscess	96 (35)	16 (39)	1.2 (0.63–2.2)	0.61
Vegetation size (mm)	10 (5–16)	12 (5–19)	1.0 (0.99–1.06)	0.19
Preoperative fever	76 (28)	9 (22)	0.74 (0.35–1.5)	0.42
Embolic events
0	147 (54)	21 (51)	Reference
1–3	60 (22)	5 (12)	0.59 (0.22–1.6)	0.30
4 or more	67 (24)	15 (37)	1.5 (0.77–2.9)	0.23
CRP-ratio	0.42 (0.21–0.67)	0.45 (0.25–0.74)	1.4 (0.46–4.2)	0.56
Time to surgery (days)	8 (5–15)	12 (7–21)	1.0 (0.99–1.03)	0.19
Prosthetic valve	70 (26)	12 (29)	1.2 (0.62–2.4)	0.57
Number of affected valves
1	239 (87)	32 (78)	Reference
2	35 (13)	9 (22)	1.8 (0.89–3.9)	0.10
Positive valve cultures	60 (22)	10 (24)	1.1 (0.56–2.3)	0.72	0.99 (0.46–2.1)	0.97
Blood culture findings
Viridans streptococci and S. bovis	91 (33)	6 (15)	Reference		Reference
S. aureus	57 (21)	19 (46)	4.4 (1.7–11)	0.002	3.6 (1.4–9.2)	0.008
Enterococci	31 (11)	3 (7.3)	1.4 (0.36–5.7)	0.62	1.2 (0.29–4.9)	0.81
CoNS	20 (7.3)	7 (17)	4.6 (1.5–14)	0.006	4.1 (1.3–13)	0.01
Others	56 (20)	5 (12)	1.3 (0.4–4.4)	0.63	1.2 (0.37–4.0)	0.75
BCNE	19 (6.9)	1 (2.4)	0.81 (0.97–6.7)	0.85	1.0 (0.12–8.4)	0.99
Surgical intervention	26 (11)	10 (29)	2.5 (1.2–5.2)	0.01	2.6 (1.2–5.6)	0.01

Abbreviations used are IQR: interquartile range; HR: hazard ratio; CoNS: Coagulase-negative staphylococci. Adjusted HR are presented for variables included in the final model. HR are calculated with univariable and multivariable Cox regression.

Appendix 1. Microbiological findings in episodes with valve cultures defined as contaminated.

Blood culture	Valve culture	16S-rDNA analysis
S. mitis	Acinetobacter spp.	Not performed
H. parainfluenzae	Acinetobacter spp.	H. parainfluenzae
S. haemolyticus	Acinetobacter spp.	S. haemolyticus
S. sanguinis	Environmental bacteria	S. sanguinis
S. epidermidis	C. acnes	CoNS
E. faecalis	C. acnes	E. faecalis
S. mitis + P. aeruginosa	C. parapsilosis	S. mitis + P. aeruginosa
S. gordonii	P. oryzihabitans	S. gordonii

Appendix 2. Number of PVC in each group of duration of antibiotic treatment.

	NVC (267) n (%)	PVC (78) n (%)
Duration of preoperative antibiotic treatment (days)
0–2	9 (28)	23 (72)
3–5	40 (64)	22 (36)
6–8	53 (74)	19 (26)
9–11	33 (79)	9 (21)
11 or above	132 (97)	5 (2.6)

PVC: positive valve culture; NVC: negative valve culture. Percentage is presented as percentage of positive valve cultures within each group of duration of preoperative antibiotic treatment.

Appendix 3. Univariable and stepwise forward multivariable logistic regression with duration of preoperative antibiotic treatment as a continuous variable.

	COR (95% CI)	P-value	AOR (CI 95%)	P-value
Duration of preoperative antibiotic treatment	0.85 (0.80–0.90)	<0.001	0.74 (0.66–0.82)	<0.001
Preoperative fever	3.0 (1.8–5.1)	<0.001	2.6 (1.2–5.4)	0.01
Prosthetic valve	1.2 (0.66-2.0)	0.61	2.9 (1.2–6.8)	0.01
Single affected valve	2.7 (1.0-7.1)	0.04	4.5 (1.1-18)	0.03
Blood culture findings
Viridans streptococci and S. bovis	Reference		Reference
S. aureus	5.6 (2.4–13)	<0.001	17 (5.6–51)	<0.001
Enterococci	9.1 (3.4–24)	<0.001	13 (3.8–49)	<0.001
CoNS	9.9 (3.5–28)	<0.001	30 (7.7–119)	<0.001
Others	2.3 (0.89–6.2)	0.09	2.5 (0.81–7.0)	0.11
BCNE	2.6 (0.70–9.3)	0.16	0.69 (0.10–4.7)	0.71

COR = crude odds ratio, AOR = adjusted odds ratio, CI = confidence interval. p < 0.05 was considered statistically significant. CoNS = Coagulase negative staphylococci. BCNE = Blood culture negative endocarditis.

Appendix 4. Cases defined as relapses with case description and information about antibiotic treatment.

Case description	Days of antibiotic treatment	Days of postoperative antibiotic	Days to relapse after finished antibiotic treatment
Prosthetic aortic valve IE caused by Candida glabrata. Relapse with Candida glabrata in blood cultures and clinically verified IE.	59	43	257
Native aortic valve IE caused by S. dysgalactiae. Develops prosthetic valve IE with vegetations and abscess during antibiotic treatment. Reoperation.	68	62	Relapse during antibiotic treatment
Native aortic and mitral valve IE caused by S. aureus. Develops paravalvular leakage and a new vegetation during antibiotic treatment. Reoperation.	48	36	Relapse during antibiotic treatment
Native aortic valve IE caused by S. aureus. Relapse of S. aureus sepsis. Not confirmed IE.	47	22	206
Native mitral and tricuspid valve IE caused by E. faecalis in patient with intravenous drug use. Relapse with E. faecalis bacteraemia. Not confirmed IE.	68	31	281
Prosthetic tricuspid valve IE caused by S. aureus. Intravenous drug use. Relapse with S. aureus bacteraemia. Not confirmed IE.	90	86	213
Prosthetic aortic valve IE caused by S. bovis. Relapse with S. bovis bacteraemia. Not confirmed IE.	47	15	84