Advertisement
Browse Subject Areas
?

Click through the PLOS taxonomy to find articles in your field.

For more information about PLOS Subject Areas, click here.

  • Loading metrics

Characteristics of Staphylococcus aureus Bacteraemia and Predictors of Early and Late Mortality

  • Matteo Bassetti ,

    mattba@tin.it

    Current address: Matteo Bassetti: Clinica Malattie Infettive, Azienda Ospedaliera Universitaria Santa Maria della Misericordia, Udine, Italy

    Affiliation Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy

  • Maddalena Peghin,

    Affiliation Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy

  • Enrico Maria Trecarichi,

    Affiliation Institute of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy

  • Alessia Carnelutti,

    Affiliation Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy

  • Elda Righi,

    Affiliation Infectious Diseases Division, Santa Maria Misericordia University Hospital, Udine, Italy

  • Paola Del Giacomo,

    Affiliation Institute of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy

  • Filippo Ansaldi,

    Affiliation IRCCS AOU San Martino IST, Department of Health Sciences, University of Genoa; Genoa, Italy

  • Cecilia Trucchi,

    Affiliation IRCCS AOU San Martino IST, Department of Health Sciences, University of Genoa; Genoa, Italy

  • Cristiano Alicino,

    Affiliation IRCCS AOU San Martino IST, Department of Health Sciences, University of Genoa; Genoa, Italy

  • Roberto Cauda,

    Affiliation Institute of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy

  • Assunta Sartor,

    Affiliation Microbiology Unit, Santa Maria Misericordia University Hospital, Udine, Italy

  • Teresa Spanu,

    Affiliation Institute of Microbiology, Catholic University of the Sacred Heart, Rome, Italy

  • Claudio Scarparo,

    Affiliation Microbiology Unit, Santa Maria Misericordia University Hospital, Udine, Italy

  • Mario Tumbarello

    Affiliation Institute of Infectious Diseases, Catholic University of the Sacred Heart, Rome, Italy

Characteristics of Staphylococcus aureus Bacteraemia and Predictors of Early and Late Mortality

  • Matteo Bassetti, 
  • Maddalena Peghin, 
  • Enrico Maria Trecarichi, 
  • Alessia Carnelutti, 
  • Elda Righi, 
  • Paola Del Giacomo, 
  • Filippo Ansaldi, 
  • Cecilia Trucchi, 
  • Cristiano Alicino, 
  • Roberto Cauda
PLOS
x

Abstract

We aimed to describe the characteristics of patients with Staphylococcus aureus bacteremia and to evaluate the risk factors associated with early (7-day) and late (30-day) mortality. We performed an observational study including all consecutive episodes of Staphylococcus aureus bacteremia diagnosed at two Italian university hospitals during 2010–2014. A total of 337 patients were included. Mean age was 69 years (range, 57–78) and 65% were males. Methicillin-resistant S. aureus (MRSA) was identified in 132/337 (39%)cases. Overall 7- and 30-day mortality were 13% and 26%, respectively. Early mortality was associated with increased Charlson scores (OR 1.3, 95% CI 1.1–1.5), MRSA bacteremia (OR 3.2, 95% CI 1.4–8.1), presentation with septic shock (OR 13.5, 95% CI 5.4–36.4), and occurrence of endocarditis (OR 4.5, 95%CI 1.4–14.6). Similar risk factors were identified for late mortality, including increased Charlson scores (OR 1.2, 95% CI 1.1–1.4), MRSA bacteremia (OR 2.1, 95% CI 1.2–3.9), presentation with septic shock (OR 4, 95%CI 1.7–9.7), occurrence of endocarditis (OR 3.8, 95% CI 1.4–10.2) as well as Child C cirrhosis (OR 3.9, 95% CI 1.1–14.4) and primary bacteremia (OR 2.5, 95%CI 1.3–5). Infectious disease consultation resulted in better outcomes both at 7 (OR 0.1, 95% CI 0.05–0.4) and at 30 days (OR 0.4, 95% CI 0.2–0.7). In conclusion, our study highlighted high rates of MRSA infection in nosocomial Staphylococcus aureus bacteremia. Multiple comorbidities, disease severity and methicillin-resistance are key factors for early and late mortality in this group. In patients with Staphylococcus aureus bacteremia, infectious disease consultation remains a valuable tool to improve clinical outcome.

Introduction

The distribution of methicillin-sensitive (MSSA) and methicillin-resistant S. aureus (MRSA) bacteremia varies substantially by geographical region [1] [2] [3] [4] [5]. Staphylococcus aureus, however, remains a leading cause of community- and healthcare-associated bacteremia worldwide [3] [5]. Despite efforts to reduce its incidence, S. aureus bacteremia (SAB) remains frequent and associated with mortality rates up to 25% [3]. SAB acquisition and outcome are affected by patients’ comorbidities, infection site, and methicillin-resistance [6] [7]. In this patient population, evidence-based bundle interventions demonstrated to have a positive impact in clinical management and outcome [8]. In particular, results from a recent metanalysis suggested that infectious diseases (ID) consultation might improve clinical care and impact hospital survival in patients with SAB [8]. Most of the studies, however, focused on predictors of 30- and 60 day-mortality even if high early (≤ 7 day) mortality rates have been reported among patients with SAB [6] [7] [8] [9] [10, 11] [12].Aim of the study was to describe the epidemiology and clinical characteristics of patients with SAB and assess the prognostic factors for early (7-day) and late (30-day) mortality.

Material and Methods

Study design, setting and patients

A retrospective, observational, cohort study was performed in two tertiary care university hospitals in Italy that admit approximately 90,000 patients per year. All episodes of clinically significant SAB in adult patients (aged 18 years and older) between January 2011 and December 2014 were included. Patients were followed in the participant centers until discharge or death. Cases were detected through electronic databases, using a standardized protocol including age, sex, comorbidities, source of infection, setting of acquisition, antimicrobial susceptibility, antibiotic treatment, and clinical outcome. This study was approved by the local institutional review board (Comitato Etico Regionale Unico). Because of the retrospective nature of the study, the requirement for informed consent was waived.

Definitions

SAB was defined as the presence of ≥1 positive blood culture for S. aureus in patients with signs and symptoms consistent with an infection [7]. Onset of SAB was defined as the date of collection of the first blood culture yielding positivity for S.aureus. Only the first clinically significant episode of infection with SAB for each patient was included in the analysis.

SAB was defined as hospital-acquired (HA) if the first positive blood culture was performed more than 48 hours after admission either to the intensive care unit (ICU) or to another hospital ward [13]. Other SAB were classified as HCA or CA according to previously reported definitions [14].

In the presence of a laboratory-confirmed bloodstream infection, bacteremia of unknown source or primary bacteremia was defined when its origin could not been established after careful examination of clinical signs, microbiological findings, and imaging results. Otherwise, 72 hours from blood culture collection or by the presence of an ID physician responsible for the patient’s management. At both hospitals, ID service consultation was available and optional.

Empirical therapy was defined as adequate when at least one active antimicrobial agent was administered at recommended doses according to susceptibility data within the first 48 hours after the blood cultures were performed. Antibiotic de-escalation was defined as switch to a narrower spectrum agent [15]. Targeted antibiotic therapy was considered adequate when at least one active antimicrobial agent was administered, according to susceptibility data, at recommended doses after 96 hours following blood cultures collection. Regimens were classified as monotherapy or combination therapy depending on the number of active drugs included. Overall mortality was determined at 7 days (early mortality) and at 30 days (late mortality) after the first blood culture.

Blood cultures and microbiology analysis

Identification of isolates and antimicrobial susceptibility profiles were obtained through VITEK 2 (bioMérieux Inc., Hazelwood, MO, USA). The Aris Sensititre instrument for incubating and reading susceptibility plates (Trek Diagnostic Systems Inc., Independence, OH) was used according to European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints, and Etest strips (BioMerieux) were used to confirm antibiotic resistance [16]

Statistical analysis

Continuous and categorical data were reported as median, 25th and 75th percentile and frequency distributions, respectively. The Wilcoxon test was used to determine if differences existed between groups for continuous variables, respectively. Categorical variables were evaluated using chi-square or, when appropriate, the two-tailed Fisher’s exact test. Multiple logistic regression analysis was performed to identify risk factors that were associated with 7- and 30-day hospital mortality [JMP, SAS, NC, USA). Covariates that were significant at 0.10 in the univariate analysis and therapy-related variables were further evaluated for inclusion in multivariable regression models, using a backward stepwise algorithm. Given the high number of potential independent variables, a backward stepwise algorithm was used to identify the best-fitting subset of variables for use in the final multivariable regression model. In particular, Akaike’s Information Criterion (AIC) was used to assess the models’ fit and the model with the lowest AIC was selected for the multivariable analysis. All tests were two-tailed, and a P value less than 0.05 was determined to represent statistical significance.

Results and Discussion

Population characteristics

During the four-year study period, 337 episodes of SAB were diagnosed (see the database in S1 and S2 Data). The demographic characteristics and underlying conditions of these patients are summarised in Table 1.

thumbnail
Table 1. Characteristics of patients with staphylococcal bacteremia caused by MRSA compared with patients with staphylococcal bacteremia caused by MSSA.

https://doi.org/10.1371/journal.pone.0170236.t001

Of all cases of SAB, 9.2% were CA, 27.6% HCA and 63.2% were nosocomial. Among nosocomial infections, the majority was acquired in a medical ward (63.9%). Most common sites of infection were skin and soft tissue (12.5%), CVC-related infections (11.6%), endocarditis (10.9%), respiratory tract infections (5.9%), surgical site (5.3%), urinary tract (3.9%) and bone infections (2.4%). In 144 (42.7%) patients a clear source of infection was not identified.

Antimicrobial resistance and therapeutic management

MRSA isolates were identified in 132/337 cases (39.2%), mostly among HCA (43%, 40/93) and HA (42.3%, 90/213) (Table 1). MRSA isolates were more common among patients with indwelling devices (e.g., CVC and abdominal drainage catheter), recent surgery, and antimicrobial therapy compared to MSSA (Table 1). Patients with MRSA bacteremia had higher severity at presentation (e.g., septic shock) and greater proportion of pulmonary and CVC-related infections compared to MSSA bacteremia. Adequate empiric and definitive antibiotic therapy, as well as use of empiric daptomycin, were lower in patients with MRSA isolates compared to MSSA isolates. The comparison between patients with MRSA and MSSA SAB is reported in Table 1.

An ID specialist was consulted in 51.6% of cases within 72 hours of the onset of bacteremia. Once the diagnosis of SAB was suspected, 90.8% (306/337) of patients received empiric systemic antibiotic therapy. An empiric combination therapy was prescribed in 37.9% (116/306). A beta-lactam represented the most used empiric regimen (189/306, 61.8%), followed by glycopeptides (53/306, 17.3%) and fluoroquinolones (40/306, 13.1%). Empirical therapy was considered adequate in 219 (64.9%) episodes, and in 43.3% of cases included a combination treatment. Overall, definitive antibiotic therapy was appropriate in 96.4% (325/337).

Outcome

Twenty-one patients (6.2%) were admitted to the ICUs ≤ 72 hours after the first positive blood culture. Seven- and 30-day mortality were 13.1% (44 out of 337) and 25.5% (86 out of 337), respectively, and were significantly higher for patients with MRSA infections compared to MSSA infections at both time-periods (Table 2). Compared to survivors, patients with SAB who died within 7 or 30 days after first positive blood culture were more likely to be older, have a higher age-adjusted Charlson score, have a pulmonary or cardiac source of infection, present with septic shock, and be admitted to the ICU within 72 hours from SAB diagnosis. In contrast, mortality was lower in patients with a urinary tract source of infection and undergoing catheter removal. Lower mortality rates were also reported in patients receiving adequate therapy, patients treated with daptomycin or undergoing de-escalation therapy, and those evaluated by an ID specialist. Risk factors for mortality at univariate analysis of are shown in Table 2.

thumbnail
Table 2. Univariate analysis of risk factors for mortality at 7 and 30 days in patients with Staphylococcus aureus bacteremia.

https://doi.org/10.1371/journal.pone.0170236.t002

Multivariate analysis identified as risk factors independently associated to both early and late fatal outcome a high age-adjusted Charlson score, the occurrence of endocarditis, septic shock at clinical presentation, and infections caused by MRSA. Other risk factors, only for 30-day mortality, included Child C cirrhosis and primary bacteremia. Consultation with an ID specialist and de-escalation therapy represented factors associated with a decreased risk of mortality at both timepoint and at 7-days, respectively (Table 3). ID consultation was associated to higher rates of adequate initial antibiotic regimen (71.8% vs. 57.6%, P = 0.006) and more frequent recommendation for the use of daptomycin in empiric therapy (53.2% vs. 30.5%, P = 0.001) (Table 4).

thumbnail
Table 3. Multivariate analysis of risk factors for mortality due to Staphylococcus aureus bacteremia at 7 and 30 days.

https://doi.org/10.1371/journal.pone.0170236.t003

thumbnail
Table 4. Univariate analysis of SAB with infectious disease consultation VS. SAB without ID consultation.

https://doi.org/10.1371/journal.pone.0170236.t004

Discussion

The proportion of MRSA has declined in the United States and in some European countries, including Italy, over the past years, but still remains a concern for public health and a major cause of nosocomial infections [1] [2]. In our study, we observed methicillin-resistance rates of about 40%, slightly higher than 34% reported for Italy by the European Antimicrobial Resistance Surveillance Network in 2014 [1]. In our study, MRSA accounted for most nosocomial and healthcare-associated infections but only for a limited proportion of community-acquired infections, stressing the importance of the clinical setting in defining patient populations at risk for MRSA bacteremia [17] [18]. Previous studies showed higher mortality rates among patients with MRSA bacteremia compared to MSSA, but the results are conflicting [7] [12] [19] [20] [21]. In our study, methicillin resistance was an independent risk factor for both early and late mortality survival. One reason could be represented by higher rates of inadequate treatment associated with MRSA compared to MSSA or by other potential confounding factors (e.g., disease severity, risk factors) associated with MRSA infections [10] [20] [22] [23]. Our study, in particular, showed lower rates of appropriate empiric and definitive therapy in patients with MRSA compared to MSSA infections.

We reported a significant survival benefit in SAB when ID service was involved. Specifically, ID consultation impacted long term as well as short-term mortality. ID consultation was also associated with an adequate initial therapy and empiric use of daptomycin. Our data support the growing body of evidence that ID consultation improves patients’ outcomes [8] [9] [24]. ID consultation can be optional or mandatory, depending on hospital policies, and its rate can vary from 33 to 88% [24] [25]. In our cohort, an ID specialist was consulted within 72 hours of the onset of bacteremia in only half of cases. The need to increase ID stewardship as part of hospital bundle interventions to positively impact patient care decisions and reduce SAB mortality should be carefully considered by all hospitals [8] [9] [11].

As previously reported, SAB mortality in our cohort increased with older age and presence of multiple comorbidities, including Child C cirrhosis [6] [7] [26] [27] [28] [29]. Severity at presentation also influenced SAB prognosis, being septic shock an independent risk factor for both early and late mortality [23].

We confirmed the occurrence of endocarditis as an independent risk factor for poor outcomes, including early mortality [6] [10]. Moreover, a relationship between death and the absence of an identified focus emerged for late mortality. In these instances, a better diagnostic definition of the source of infection could help to reach a better source control and improve patients’ management [30]

De-escalation therapy was also associated with reduced 7-days mortality. A reason could be represented by overall better clinical evolution or absence of multidrug resistance in patients undergoing de-escalation therapy [15].

Interestingly, combination therapy (mainly association of beta-lactams and glycopeptides) was often prescribed in our study (40% of all SAB) but did not impact the mortality. A reason could be that combination therapy was preferred to widen the antibacterial spectrum or to increase the synergistic bactericidal activity of the treatment in severe infections, this representing a confounding factor. The role of combined treatment in the setting of MSSA and MRSA bacteremia, however, appears promising but is yet to be defined [31]

Considerable early and late mortality rates were reported in our study (13% and 26%, respectively). Previous studies that analysed risk factors associated with SAB early mortality (e.g. within 2 to 9 days from the onset of the infection) showed mortality rates around 35% [10, 11] [12] [26]. Hence, early mortality represents a significant timepoint to analyse in SAB.

Our study presents several limitations. First, its retrospective, observational nature can limit the considerations on patient treatments. Second, we considered overall mortality rather than SAB-related mortality. We tried to overcome this bias using two timepoints for mortality, assuming that early mortality could have been more likely associated with SAB. Third, while not specific criteria for requesting an ID consultation have been established and followed, this option could be more likely requested in patients with more severe infections. To minimize the selection bias, we adjusted the data for confounders using multivariate analysis. Furthermore, molecular testing of S.aureus was not performed, but because of the retrospective nature of our study, this information was not available.

Conclusions

In conclusion, S.aureus bacteremia represents a serious infection, associated with significant both early and late mortality. Methicillin resistance is associated mostly to nosocomial and health-care associated infections and may be a risk factor for mortality in patients with SAB. Clinicians should be aware of the severity of patients with S. aureus bacteremia, and infectious disease consultation should be always considered to improve patients’ outcomes.

Supporting Information

S1 Data. Anonymised database of Udine Hospital.

https://doi.org/10.1371/journal.pone.0170236.s001

(XLS)

S2 Data. Anonymised database of Roma Hospital.

https://doi.org/10.1371/journal.pone.0170236.s002

(XLS)

Author Contributions

  1. Conceptualization: MB MT FA.
  2. Data curation: AS CS.
  3. Formal analysis: AS CS TS MB MT.
  4. Funding acquisition: MB MT.
  5. Investigation: MP AC PDG ER.
  6. Methodology: MB MT ER MP AC FA CA CT PDG EMT RC.
  7. Project administration: MB.
  8. Resources: MB MT FA.
  9. Software: FA CT CA MB MT.
  10. Supervision: MB MT.
  11. Validation: MB MT FA.
  12. Visualization: MB.
  13. Writing – original draft: MB MT ER MP AC EMT RC.
  14. Writing – review & editing: MB.

References

  1. 1. 2014. EAArotEARSNE-N.
  2. 2. Center for Disease Dynamics EP. State of the World’s Antibiotics CW, DC 2015.
  3. 3. Laupland KB, Lyytikainen O, Sogaard M, Kennedy KJ, Knudsen JD, Ostergaard C et al. The changing epidemiology of Staphylococcus aureus bloodstream infection: a multinational population-based surveillance study. Clin Microbiol Infect 2013;19:465–471. pmid:22616816
  4. 4. Rhee Y, Aroutcheva A, Hota B, Weinstein RA, Popovich KJ. Evolving Epidemiology of Staphylococcus aureus Bacteremia. Infect Control Hosp Epidemiol 2015; 36:1417–1422. pmid:26372679
  5. 5. Tom S, Galbraith JC, Valiquette L, Jacobsson G, Collignon P, Schonheyder HC et al. Case fatality ratio and mortality rate trends of community-onset Staphylococcus aureus bacteraemia. Clin Microbiol Infect 2014; 20:O630–632. pmid:24461038
  6. 6. Kaasch AJ, Barlow G, Edgeworth JD, Fowler VG Jr., Hellmich M, Hopkins S et al. Staphylococcus aureus bloodstream infection: a pooled analysis of five prospective, observational studies. J Infect 2014; 68:242–251. pmid:24247070
  7. 7. Yilmaz M, Elaldi N, Balkan II, Arslan F, Batirel AA, Bakici MZ et al. Mortality predictors of Staphylococcus aureus bacteremia: a prospective multicenter study. Ann Clin Microbiol Antimicrob 2016; 15:7. pmid:26860463
  8. 8. 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; 57:1225–1233. pmid:23929889
  9. 9. Vogel M, Schmitz RP, Hagel S, Pletz MW, Gagelmann N, Scherag A, Schlattmann P, Brunkhorst FM. Infectious disease consultation for Staphylococcus aureus bacteremia—A systematic review and meta-analysis. J Infect 2016; 72:19–28. pmid:26453841
  10. 10. Gasch O, Camoez M, Dominguez MA, Padilla B, Pintado V, Almirante B et al. Predictive factors for early mortality among patients with methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2013; 68:1423–1430. pmid:23404193
  11. 11. Tissot F, Calandra T, Prod'hom G, Taffe P, Zanetti G, Greub G, Senn L. Mandatory infectious diseases consultation for MRSA bacteremia is associated with reduced mortality. J Infect 2014; 69:226–234. pmid:24844825
  12. 12. Cosgrove SE, Sakoulas G, Perencevich EN, Schwaber MJ, Karchmer AW, Carmeli Y. Comparison of mortality associated with methicillin-resistant and methicillin-susceptible Staphylococcus aureus bacteremia: a meta-analysis. Clin Infect Dis 2003, 36:53–59. pmid:12491202
  13. 13. Garner JS, Jarvis WR, Emori TG, Horan TC, Hughes JM. CDC definitions for nosocomial infections, 1988. Am J Infect Control 1988; 16:128–140. pmid:2841893
  14. 14. Friedman ND, Kaye KS, Stout JE, McGarry SA, Trivette SL, Briggs JP, Lamm W, Clark C, MacFarquhar J, Walton AL, Reller LB, Sexton DJ. Health care—associated bloodstream infections in adults: a reason to change the accepted definition of community-acquired infections. Ann Intern Med 2002; 137:791–797. pmid:12435215
  15. 15. Tabah A, Cotta MO, Garnacho-Montero J, Schouten J, Roberts JA, Lipman J, Tacey M, Timsit JF, Leone M, Zahar JR, De Waele JJ, Working Group for Antimicrobial Use in the ICU. A Systematic Review of the Definitions, Determinants, and Clinical Outcomes of Antimicrobial De-escalation in the Intensive Care Unit. Clin Infect Dis 2016, 62:1009–1017. pmid:26703860
  16. 16. (EUCAST). TECoAST. Breakpoint tables for interpretation of MICs and zone diameters. 2016 Version 6.0. Available at http://www.eucast.org/clinical_breakpoints/. Accessed May 16.
  17. 17. Epstein L, Mu Y, Belflower R, Scott J, Ray S, Dumyati G et al. Risk Factors for Invasive Methicillin-Resistant Staphylococcus aureus Infection After Recent Discharge From an Acute-Care Hospitalization, 2011–2013. Clin Infect Dis 2016; 62:45–52. pmid:26338787
  18. 18. Bassetti M, Trecarichi EM, Mesini A, Spanu T, Giacobbe DR, Rossi M et al. Risk factors and mortality of healthcare-associated and community-acquired Staphylococcus aureus bacteraemia. Clin Microbiol Infect 2012; 18:862–869. pmid:21999245
  19. 19. de Kraker ME, Wolkewitz M, Davey PG, Koller W, Berger J, Nagler Jet al. Clinical impact of antimicrobial resistance in European hospitals: excess mortality and length of hospital stay related to methicillin-resistant Staphylococcus aureus bloodstream infections. Antimicrob Agents Chemother 2011; 55:1598–1605. pmid:21220533
  20. 20. Kullar R, McKinnell JA, Sakoulas G. Avoiding the perfect storm: the biologic and clinical case for reevaluating the 7-day expectation for methicillin-resistant Staphylococcus aureus bacteremia before switching therapy. Clin Infect Dis 2014; 59:1455–1461. pmid:25048852
  21. 21. Wolkewitz M, Frank U, Philips G, Schumacher M, Davey P, Group BS. Mortality associated with in-hospital bacteraemia caused by Staphylococcus aureus: a multistate analysis with follow-up beyond hospital discharge. J Antimicrob Chemother 66:381–386. pmid:21098543
  22. 22. Soriano A, Martinez JA, Mensa J, Marco F, Almela M, Moreno-Martinez A, Sanchez F, Munoz I, Jimenez de Anta MT, Soriano E. 2000. Pathogenic significance of methicillin resistance for patients with Staphylococcus aureus bacteremia. Clin Infect Dis 2011; 30:368–373.
  23. 23. Paul M, Kariv G, Goldberg E, Raskin M, Shaked H, Hazzan R, Samra Z, Paghis D, Bishara J, Leibovici L. Importance of appropriate empirical antibiotic therapy for methicillin-resistant Staphylococcus aureus bacteraemia. J Antimicrob Chemother 2010; 65:2658–2665. pmid:20947620
  24. 24. Bai AD, Showler A, Burry L, Steinberg M, Ricciuto DR, Fernandes T et al. Impact of Infectious Disease Consultation on Quality of Care, Mortality, and Length of Stay in Staphylococcus aureus Bacteremia: Results From a Large Multicenter Cohort Study. Clin Infect Dis 2015; 60:1451–1461. pmid:25701854
  25. 25. Honda H, Krauss MJ, Jones JC, Olsen MA, Warren DK. The value of infectious diseases consultation in Staphylococcus aureus bacteremia. Am J Med 2010; 123:631–637. pmid:20493464
  26. 26. Lamagni TL, Potz N, Powell D, Pebody R, Wilson J, Duckworth G. Mortality in patients with meticillin-resistant Staphylococcus aureus bacteraemia, England 2004–2005. J Hosp Infect 2011; 77:16–20. pmid:21030112
  27. 27. Tacconelli E, Pop-Vicas AE, D'Agata EM. Increased mortality among elderly patients with meticillin-resistant Staphylococcus aureus bacteraemia. J Hosp Infect 2006; 64:251–256. pmid:16978733
  28. 28. Kang CI, Song JH, Ko KS, Chung DR, Peck KR, Asian Network for Surveillance of Resistant Pathogens Study G. Clinical features and outcome of Staphylococcus aureus infection in elderly versus younger adult patients. Int J Infect Dis 2011; 15:e58–62. pmid:21111647
  29. 29. Lesens O, Methlin C, Hansmann Y, Remy V, Martinot M, Bergin C, Meyer P, Christmann D. Role of comorbidity in mortality related to Staphylococcus aureus bacteremia: a prospective study using the Charlson weighted index of comorbidity. Infect Control Hosp Epidemiol 2003; 24:890–896. pmid:14700403
  30. 30. Vos FJ, Kullberg BJ, Sturm PD, Krabbe PF, van Dijk AP, Wanten GJ, Oyen WJ, Bleeker-Rovers CP. Metastatic infectious disease and clinical outcome in Staphylococcus aureus and Streptococcus species bacteremia. Medicine (Baltimore) 2012; 91:86–94.
  31. 31. Davis JS, Sud A, O'Sullivan MV, Robinson JO, Ferguson PE, Foo H et al. Combination of Vancomycin and beta-Lactam Therapy for Methicillin-Resistant Staphylococcus aureus Bacteremia: A Pilot Multicenter Randomized Controlled Trial. Clin Infect Dis 2016; 62:173–180. pmid:26349552
  32. 32. Singal HK, Kamath PS. Model for End- Stage Liver Disease. J Clin Exp Hepatol 2013; 3:50–60 pmid:25755471