SUPPLEMENTARY MATERIAL.

S1. Study design and setting

Inclusion criteria in the study:

-Patients older than 18 years with MSSA-CRB diagnosed according to standard criteria [1] with a life expectancy of 7 days or more.

-No use of daptomycin within the three months preceding the incident MSSA-CRB episode.

-Removal of the intravascular catheter suspected as being the source of MSSA-CRB within a maximum of 72 hours from the sampling of the first blood cultures yielding MSSA.

-A maximum of 72 hours of treatment with glycopeptides.

-At least the first blood culture isolate available for microbiological analysis.

All included patients signed a study-specific informed consent. The study was approved by the Ethics Research Boards in all the participating centers.

Management of MSSA-CRB

Although the study was not interventional regarding the management of MSSA-CRB, adherence to a bundle of recommendations according to the main aspects selected as quality of care interventions in MSSA bacteremia [2] was highly advised (follow-up blood cultures, echocardiography and/or venous Doppler ultrasound examination in patients with clinical indication, early use of intravenous cloxacillin or other highly effective antibiotics for MSSA as definitive therapy, and adjustment of treatment duration according to the complexity of the infection).

Study definitions

Patients: Recorded clinical variables were age, acquisition of infection comorbidity burden as assessed by the Charlson Comorbidity Index [3], prognosis of the underlying disease (classified according to the McCabe and Jackson modified criteria as rapidly fatal [when death was expected within 3 months], ultimately fatal [when death was expected within a period of >3 months but <5 years] and non-fatal [when life expectancy was >5 years]) [17], type of intravenous catheter, timing of catheter withdrawal, treatmentreceived, duration of fever, duration of bacteremia, Pitt bacteremia score [4], development of septic shock, development of endovascular infection or complicated bacteremia, late complication, and both crude and attributable mortality.

Antibiotics used as treatment of MSSA bacteremia were classified within one of the following categories: glycopeptides, daptomycin, anti-staphylococcal beta-lactams (parenteral cloxacillin, cefazolin or other active beta-lactams including parenteral amoxicillin-clavulanate, piperacillin-tazobactam, imipenem or meropenem), non-beta-lactam agents with in vitro activity against MSSA (anti-staphylococcal quinolones, tigecicline or linezolid), and non-effective agents. Timing to initiation of antibiotic therapy and duration of treatment were also recorded.

We also calculated the crude mortality within the first 30 days after the first blood culture yielding MSSA (all-cause 30-day mortality) and the mortality attributable to S. aureus bacteremia according to the investigator criteria (attributable 30-day mortality).

1.Mermel LA, Allon M, Bouza E, Craven DE, Flynn P, O'Grady NP, et al. Clinical practice guidelines for the diagnosis and management of intravascular catheter-related infection: 2009 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2009;49(1):1-45. doi: 10.1086/599376. PubMed PMID: 19489710; PubMed Central PMCID: PMC4039170.

2.Lopez-Cortes LE, Del Toro MD, Galvez-Acebal J, Bereciartua-Bastarrica E, Farinas MC, Sanz-Franco M, et al. Impact of an evidence-based bundle intervention in the quality-of-care management and outcome of Staphylococcus aureus bacteremia. Clin Infect Dis. 2013;57(9):1225-33. doi: 10.1093/cid/cit499. PubMed PMID: 23929889.

3.Charlson ME, Sax FL, MacKenzie CR, Braham RL, Fields SD, Douglas RG, Jr. Morbidity during hospitalization: can we predict it? J Chronic Dis. 1987;40(7):705-12. PubMed PMID: 3110198.

4.Chow JW, Yu VL. Combination antibiotic therapy versus monotherapy for gram-negative bacteraemia: a commentary. International journal of antimicrobial agents. 1999;11(1):7-12. PubMed PMID: 10075272.

Supplementary Table 1. Demographics and clinical characteristics of the study cohort (n = 83).

Variable
Age (years) : Mean (SD) / 60 (1.9)
Male/Female (%) / 59/41
Center of origin of included cases; n (%)
Center 1
Center 2
Center 3
Center 4
Center 5 / 32 (38.6)
19 (22.9)
2 (2.4)
12 (14.5)
18 (21.7)
Prognosis of the underlying disease (McCabe modified criteria) n (%)
Non-fatal
Finally fatal.
Rapidly fatal / 31 (37.3)
44 (53)
8 (9.6)
Charlson Comorbidity Index : Mean (SD) / 3.72 (2.28)
Previous conditions, n (%)
Diabetes / 32 (38.6)
Malignancy / 45 (54.2)
Valvular prosthesis / 1 (1.2)
Osteoarticular prosthesis / 3 (3.6)
Renal failure requiring hemodyalisis / 10 (12)
Type of intravascular catheter as the source of bacteremia (%)
Peripheral venous catheter
Non-tunneled (temporary) central venous catheter
Peripherally inserted central catheter
Permanent central venous catheter / 32 (38.6)
25 (30.1)
10 (12)
16 (19.3)
Pitt score at bacteremia onset: Mean (SD) / 1.25 (1.4)
Severe sepsis/ Septic shock: n (%) / 17 (20.5)
Empirical treatment including:
Glycopeptides / 32 (38.5)
Anti-staphylococcal beta-lactams / 43 (51.8)
Other anti-staphylococcal antibiotics. / 4 (4.8)
Daptomycin / 17 (20.4)
No empirical treatment or non-effective antibiotics / 12 (14.5)
Global antimicrobial scheme
Glycopeptides followed by anti-staphylococcal beta-lactama
Only anti-staphylococcal beta-lactams
Daptomycin followed by anti-staphylococcal beta-lactama
Only daptomycin
Glycopeptides followed by daptomycin plus anti-staphylococcal beta-lactama
Daptomycin plus anti-staphylococcal beta-lactama
Other / 25 (30.1)
30 (36.1)
12 (14.5)
1 (1.2)
7 (8.4)
7 (8.4)
1 (1.2)
Timing of catheter removal, n (%)
The same day or previous to first blood cultures / 47 (56.6)
One day after first blood cultures (%) / 12 (14.5)
Two days after first blood cultures (%) / 17 (20.5)
Three days after first blood cultures (%) / 7 (8.4)
Venous Doppler ultrasound examination, n (%) / 41 (49.5)
Echocardiogram, n(%) / 61 (73.5)
Complicated MSSA-CRB : n (%)
Total
Persistent fever after 4 daysb
Persistent positive blood cultures after 72 hoursc
Septic thrombophlebitis
Endocarditis
Hematogenous osteoarticular infection
Pulmonary emboli / 26 (31.3)
11 (13.3)
6 (7.2)
10 (12)
2 (2.4)
2 (2.4)
2 (2.4)
All-cause 30-day mortality: n (%) / 10 (12)
Attributable mortality: n (%) / 2 (2.4)
CVC: central venous catheter; MSSA-CRB: methicillin-susceptible S. aureus catheter-related bacteremia; SD: standard deviation.
a Anti-staphylococcal beta-lactams refer to parenteral cloxacillin, cefazolin, amoxicillin-clavulanate, piperacillin-tazobactam or imipenem/meropenem.
b Coincident with other forms of complicated bacteremia in 5 cases.
c Coincident with other forms of complicated bacteremia in 5 cases.

Supplementary Table 2. Comparative analysis of 83 patients with catheter-related MSSA blood stream infection with or without complicated bacteremia (CB).

TOTAL
83 / Without CB
n=57 / With CB
n=26 / P*
Age (years): Mean (SD) / 60 (1.9) / 61.4 (16) / 59.3 (21) / 0.14
Male/Female (%) / 59/41 / 56.1/43.9 / 65.4/34.6
Center of origin of included cases; n (%)
Center 1
Center 2
Center 3
Center 4
Center 5 / 32 (38.6)
19 (22.9)
2 (2.4)
12 (14.5)
18 (21.7) / 15 (26.3)
14 (24.6)
2 (3.5)
11 (19.3)
15 (26.3) / 17 (65.4)
5 (19.2)
0
1 (3.8)
3 (11.5) / 0.01
0.2
0.2
Prognosis of the underlying disease (McCabe and Jackson modified criteria): n (%)
Non- fatal
Finally fatal.
Rapidly fatal / 31 (37.3)
44 (53)
8 (9.6) / 24 (42.1)
29 (50.9)
4 (7) / 7 (26.9)
15 (57.7)
4 (15.4) / 0.2
Charlson Co-morbidity Index: Mean (SD) / 3.72 (2.28) / 3.61 (2.4) / 1.86 (1.86) / 0.3
Diabetes; n (%) / 32 (38.6) / 20 (35.1) / 12 (46.2)
Neoplasia: n (%) / 45 (54.2) / 29 (50.9) / 16 (61.5)
Previous valvular prosthesis : n (%) / 1 (1.2) / 1 (1.8) / 0
Previous ostheoarticular prosthesis: n (%) / 3 (3.6) / 1 (1.8) / 2 (7.7)
Previous renal failure requiring hemodyalisis: n (%) / 10 (12) / 7 (12.3) / 3 (11.5)
Type of vascular catheter as the source of bacteremia (%)
Peripheral venous catheter
Transitory central catheter
Transitory peripherally inserted central catheter
Permanent central catheter / 32 (38.6)
25 (30.1)
10 (12)
16 (19.3) / 23 (40.4)
17 (29.8)
7 (12.3)
10 (17.5) / 9 (34.6)
8 (30.8)
3 (11.5)
6 (23.1)
Pitt score: Mean (SD) / 1.25 (1.4) / 1.1 (1.4) / 1.68 (1.9) / 0.1
Development of severe sepsis/septic shock: n (%) / 17 (20.5) / 12 (19.7) / 5 (22.7)
Empirical treatment including glycopeptides / 32 (38.5) / 24 (42) / 8 (30.7)
Empirical treatment including ASBL1 / 43 (51.8) / 31 (54.3) / 12 (46.1)
Empirical treatment including other anti-staphylococcal antibiotics / 4 (4.8) / 1 (1.7) / 3 (11.5) / 0.17
Empirical treatment including daptomycin / 17 (20.4) / 8 (14) / 9 (34.6) / 0.06
Empirical treatment with daptomycin monotherapy / 13 (15.6) / 5 (8.8) / 8 (30.8) / 0.02
No empirical treatment or non-effective antibiotics / 12 (14.5) / 10 (17.5) / 2 (7.7) / 0.4
Global antimicrobial scheme
Glycopeptides followed by ASBL1.
Only anti-staphylococcal betalactams
Daptomycin followed by ASBL1
Only daptomycin
Glycopeptides followed by daptomycin plus ASBL1
Daptomycin plus ASBL1.
Other / 25 (30.1)
30 (36.1)
12 (14.5)
1 (1.2)
7 (8.4)
7 (8.4)
1 (1.2) / 19 (33.3)
23 (40.4)
4 (7)
1 (1.8)
6 (10.5)
3 (5.3)
1 (1.8) / 6 (23.1)
7 (26.9)
8 (30.8)
0
1 (3.8)
4 (15.4)
0 / 0.34
0.01
0.26
Timing of catheter removal: n (%)
The same day or previous to first blood cultures / 47 (56.6) / 36 (63.2) / 11 (42.3) / 0.1
One day after first blood cultures / 12 (14.5) / 6 (10.5) / 6 (23)
Two days after first blood cultures / 17 (20.5) / 10 (17.5) / 7 (26.9)
Three days after first blood cultures / 7 (8.4) / 5 (8.8) / 2 (7.7)
Development of severe sepsis/septic shock: n (%) / 17 (20.5) / 11 (19.3) / 6 (23.1) / 0.34
Venous Doppler ultrasound examination: n (%) / 41 (49.5) / 21 (36.8) / 20 (76.9) / 0.001
Echocardiogram: n (%) / 61 (73.5) / 36 (63.2) / 25 (96.2) / 0.01
Crude 30-day mortality: n (%) / 10 (12) / 7 (12.3) / 3 (11.5)
Attributable mortality: n (%) / 2 (2.4) / 0 / 2 (7.7) / 0.12

1Antistaphylococcal betalactams refer to parenteral cloxacillin, cefazolin, amoxicillin-clavulanate, piperacillin-tazobactam or imipenem/meropenem. * Only p values <0.5 are shown.