Reevaluation of the impact of methicillin-resistance on outcomes in patients with Staphylococcus aureus bacteremia and endocarditis

Article information

Korean J Intern Med. 2018;.kjim.2017.098
Publication date (electronic) : 2018 January 20
doi : https://doi.org/10.3904/kjim.2017.098
1Division of Infectious Diseases, Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea
2Office of Health Technology Evaluation, National Evidence-based Healthcare Collaboration Agency, Seoul, Korea
3Division of Infectious Diseases, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Correspondence to Kyong Ran Peck, M.D. Division of Infectious Diseases, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-0329 Fax: +82-2-3410-0064 E-mail: krpeck@skku.edu
*

These authors contributed equally to this work.

Received 2017 February 13; Revised 2017 June 12; Accepted 2017 July 8.

Abstract

Background/Aims

Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals, and has recently emerged in the community. The impact of methicillin-resistance on mortality and medical costs for patients with S. aureus bacteremia (SAB) requires reevaluation.

Methods

We searched studies with SAB or endocarditis using electronic databases including Ovid-Medline, Embase-Medline, and Cochrane Library, as well as five local databases for published studies during the period January 2000 to September 2011.

Results

A total of 2,841 studies were identified, 62 of which involved 17,563 adult subjects and were selected as eligible. A significant increase in overall mortality associated with MRSA, compared to that with methicillin-susceptible S. aureus (MSSA), was evidenced by an odds ratio (OR) of 1.95 (95% confidence interval [CI], 1.73 to 2.21; p < 0.01). In 13 endocarditis studies, MRSA increased the risk of mortality, with an OR of 2.65 (95% CI, 1.46 to 4.80). When three studies, which compared mortality rates between CA-MRSA and CA-MSSA, were combined, the risk of methicillin-resistance increased 3.23-fold compared to MSSA (95% CI, 1.25 to 8.34). The length of hospital stay in the MRSA group was 10 days longer than that in the MSSA group (95% CI, 3.36 to 16.70). Of six studies that reported medical costs, two were included in the analysis, which estimated medical costs to be $9,954.58 (95% CI, 8,951.99 to 10,957.17).

Conclusions

MRSA is still associated with increased mortality, longer hospital stays and medical costs, compared with MSSA in SAB in studies published since the year 2000.

INTRODUCTION

Hospital-acquired (HA) methicillin-resistant Staphylococcus aureus (MRSA) infections are a major cause of illness and death and impose serious economic costs on patients and hospitals. The estimated number of S. aureus-related hospitalizations increased by 62% from 294,570 to 477,927, and the estimated number of MRSA-related hospitalizations more than doubled, from 127,036 to 278,203, from 1999 through 2005 in the United States [1]. Published studies on mortality for patients with S. aureus bacteremia (SAB) indicated an increased risk of mortality for patients with MRSA compared to those with methicillin-susceptible S. aureus (MSSA) bacteremia [2]. Thus bacteremia due to HA-MRSA results in increased direct medical costs and hospital stays, compared with that due to MSSA [3].

Cases of MRSA have been documented among healthy community-dwelling persons without established risk factors for MRSA acquisition, lately defined as community-associated (CA)-MRSA [4]. Community-genotype strains carrying SCCmec type IV have now emerged as a significant cause of healthcare-associated (HCA) and hospital associated (HA) infections in the USA and European countries [5-9]. Despite the epidemiologic changes in hospital MRSA strains with the encroachment of CA-MRSA into healthcare settings [9,10], whether methicillin resistance adversely affects outcomes in patients with community-associated S. aureus bacteremia is unclear [11,12]. After the year 2000, newer antimicrobial agents active against MRSA have become available to treat MRSA and are in use as alternatives for treating serious MRSA infections. The efficacy of new antibiotics in terms of reducing mortality in patients infected with S. aureus, especially MRSA, has not been verified. Furthermore, progress in high-quality clinical management has been made in the last few years as evidenced by the fact that case fatality can be reduced by hospital infection control systems [13]. These factors, including the emergence of MRSA strains with reduced vancomycin susceptibility, enhanced the controversy regarding the clinical impact of methicillin resistance on outcomes in SAB [14].

Meta-analyses by Cosgrove et al. [2] and Whitby et al. [15] comparing the mortality rate of MRSA and MSSA bacteremia found that methicillin resistance was associated with an increased mortality. In a recent meta-analysis, a significant increase in mortality associated with MRSA bacteremia was evident in the odds ratio (OR) of 1.93 (95% confidence interval [CI], 1.54 to 2.42), when 31 articles were combined with data regarding mortality associated with both MSSA and MRSA bacteremia [2]. There were also worse outcomes in studies that involve nosocomial SAB, compared to those involving a significant proportion of CA-SAB [2]. However, in the era of the emergence of CA-MRSA and the advent of newer antimicrobial agents active against MRSA, the impact of methicillin-resistance on mortality and medical costs for patients with SAB needs to be reevaluated. Therefore, we performed a systematic review and meta-analysis to investigate the effect of methicillin-resistance on mortality, length of hospital stay and medical costs of patients with SAB based on reports published after the year 2000.

METHODS

Literature search and selection of eligible studies

We searched studies of SAB or endocarditis using electronic databases including Ovid-Medline, Embase-Medline, and the Cochrane Library, as well as five local databases providing information on Korean medical research, published from January 1, 2000 to September 15, 2011. We used the search filter recommended by the Scottish Intercollegiate Guidelines Network to efficiently identify cohort studies. We also reviewed the bibliographies of relevant articles to identify additional publications. A full-text search of eight databases in English or Korean were reviewed using the terms “Staphylococcus aureus” AND “bacteremia” OR “endocarditis.” Two reviewers (D.A.P. and S.M.L.) independently evaluated titles, abstracts and citations to assess relevance for full review. We applied no language restriction in the electronic database search, which was limited to studies involving humans.

The inclusion criteria were as follows: studies (1) targeting SAB or S. aureus endocarditis (SAE); (2) comparison of outcomes of MRSA and MSSA; (3) evaluating any type of mortality, the length of hospital stay (LOS) or medical costs; and (4) involving adults 18 years older. The exclusion criteria were as follows: (1) not original research; (2) animal or pre-clinical studies; (3) not cohort studies; (4) only an abstract; (5) studies not published in Korean or English; and (6) duplicate reports. Therefore, all cohort studies in adults with SAB or endocarditis were included if they compared outcomes of MRSA to those of MSSA. Outcomes of methicillin-resistance were analyzed in terms of all-cause mortality, in-hospital mortality, SAB-related mortality, and 30-day mortality. The LOS and medical costs were also compared between the MRSA and MSSA groups. Studies involving children or neonates and those of a case-control design were excluded. We also excluded studies involving the same population during an overlapping 1-year study period.

Data extraction

Using a standardized form developed in advance, two independent reviewers extracted the following pre-specified data: first author, publication year, country, study period, study setting, study design, total number of study participants, the number and proportion of individuals in the MRSA and MSSA groups, age, proportion of males, cases with nosocomial- and community-acquired bacteremia, SAE, and results of predetermined outcomes during the follow-up period. We also collected the adjusted estimates of mortality in SAB and endocarditis and confounding variables considered in the statistical models of each study. Agreement was obtained after discussion between the two reviewers. We did not assess the methodological quality of included studies because most did not differ in design or in the methods used for recruiting participants.

Data synthesis and analysis

We employed a random-effects model using the method described by DerSimonian and Laird [16] to synthesize data from included studies. For the outcome data on mortality, we calculated the OR and 95% CI as summary statistics. For continuous outcomes, such as the length of hospital stay and medical costs, weighted mean differences (WMDs) and 95% CIs were calculated.

We assessed statistical heterogeneity using the Cochrane Q-test (p < 0.10) and I2 statistic, with I2 > 50% indicating at least moderate heterogeneity [17]. To assess the potential explanations for heterogeneity, we performed subgroup analyses using pre-specified criteria including disease characteristics (bacteremia including mixed populations and endocarditis) and the type of infection (community-acquired infections and ≥ 70% vs. < 70% nosocomial infection). We also performed sensitivity analyses using summary estimates in studies adjusted for confounding variables. First, we used a funnel plot asymmetry approach to assess publication bias qualitatively, and then we confirmed the symmetry of the funnel plot using Begg and Mazumdar’s rank correlation test (Supplementary Fig. 1) [18,19]. If publication bias was suspected, we performed the Trim and Fill method to obtain symmetry in the funnel plot and to determine the effect of hypothetical studies on the pooled estimate [20]. Statistical analysis was performed using Review Manager version 5.0 (RevMan, The Cochrane Collaboration, Oxford, UK) and Stata software version 10.0 (SE, Stata Corp., College Station, TX, USA). A p value of 0.05 was regarded as statistically significant.

RESULTS

Study populations

A total of 2,841 studies were searched from January 2000 through September 2011. Of 2,075 studies from which duplicated reports were eliminated, 92 (eight studies in Korea and 84 in other countries) were selected after the first and second literature review. A flow diagram of identification of eligible studies is shown in Fig. 1. Of these, 62 cohort studies were selected as eligible that reported any outcome regarding mortality, LOS and medical costs after review of the full-text of articles (Table 1) [21-82]. Pooled data for 17,563 patients (6,390 MRSA and 11,173 MSSA) were included in the analysis. All were cohort studies, comprising 41 retrospective, 20 prospective and one both retro- and prospective study. The characteristics of the selected studies are shown in Table 1 according to year of publication.

Figure 1.

Flow diagram detailing reviewed articles and exclusion. DB, database.

Characteristics of the studies of Staphylococcus aureus bacteremia or endocarditis included in the systematic review

Mortality in patients with methicillin-resistant and methicillin-susceptible SAB and endocarditis

Of the 62 studies, 60 reported all-cause mortality including in-hospital mortality, 14- and 30-day mortality and SAB-related mortality. The clinical characteristics of all patients with MRSA and MSSA in the 62 studies are summarized in Table 1. A significant increase in all-cause mortality associated with MRSA was evident with a pooled OR of 1.95 (95% CI, 1.73 to 2.21; I2 = 44%) compared to that of MSSA (Fig. 2) [21-82]. The pooled OR for 40 studies that reported in-hospital mortality was 1.90 (95% CI, 1.57 to 2.28; I2 = 51%). In 13 studies that compared 30-day mortality rates in SAB, MRSA increased the odds of death 1.89-fold compared to MSSA (95% CI, 1.58 to 2.26; I2 = 40%). In the 16 studies that documented SAB or infection-related mortality, generic inverse variance methods were used. The pooled OR was 2.04 (95% CI, 1 63 to 2.55; I2 = 40%).

Figure 2.

Forest plot summary of the results of 60 studies which reported all-cause mortality. MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; CI, confidence interval.

Of the 62 selected studies, 13 reported the outcomes of SAE, among which 10 involved a population with SAE [30,35,40,47,55,61,64,65,68,71], and the remaining three reported outcomes of SAE as part of SAB episodes [26,31,82]. Methicillin-resistance increased the risk of mortality by 2.65-fold in those patients (95% CI, 1.46 to 4.80; I2 = 50%). There was no significant heterogeneity among the results of these studies. Further analysis primarily involving the SAE population showed a pooled OR of 3.32 (95% CI, 1.68 to 6.59).

Mortality in patients with methicillin-resistant and methicillin-susceptible SAB and endocarditis in the Korean population

In a meta-analysis of eight studies which reported all-cause mortality in SAB and endocarditis in the Korean population, methicillin-resistance was associated with increases in mortality with a pooled OR of 3.14 (95% CI, 1.48 to 6.67) (Fig. 3) [24,26,35,51,52,64,69,71]. There was significant heterogeneity among the results of these studies (I2 = 76%). Of eight studies, three studies analyzed the outcomes of SAE in Korean populations [35,64,71]; in these, the mortality risk of MRSA increased 14.19-fold compared to that of MSSA (95% CI, 3.84 to 52.41).

Figure 3.

Forest plot summary of results of eight which reported all-cause mortality in Staphylococcus aureus bacteremia and endocarditis in the Korean population. MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; CI, confidence interval.

Community- and hospital-acquired SAB

Twenty-two studies reported outcomes of CA-SAB; of these, only three studies compared mortality rates between CA-MRSA and CA-MSSA. MRSA increased the odds 3.23-fold, compared to MSSA (95% CI, 1.25 to 8.34) when the three studies were combined (Fig. 4) [31,39,74]. Forty-one studies reported the outcomes in patients of nosocomial SAB. In the 13 selected studies in which ≥ 70% of the cases of SAB were hospital-acquired, the pooled OR was 1.70 (95% CI, 1.29 to 2.25). In contrast, in 28 studies in which less than 70% were nosocomial, the OR was 1.95 (95% CI, 1.66 to 2.29).

Figure 4.

Forest plot summary of results of three studies which reported mortality rates between community-associated (CA)-methicillin-resistant Staphylococcus aureus (MRSA) and CA-methicillin-susceptible S. aureus (MSSA). CI, confidence interval.

LOS, ICU stay, and medical costs

LOS was divided into two categories for analysis—the total LOS and the length of stay after the onset of bacteremia. Eight studies reported total LOS (Table 2) [29,37,45,63,66,67,75,82]. Of them, four studies were combined for the meta-analysis of total LOS [37,63,67,75]. The average total LOS in the MRSA group was 10.03 days longer than that in the MSSA group; this difference was significant (WMD, 10.03; 95% CI, 3.36 to 16.70; I2 = 83%). The result of a sensitivity analysis, excluding the heterogeneous studies, indicated that patients with MRSA bacteremia stayed 6.72 days longer (WMD, 6.72; 95% CI, 3.38 to 10.0) than those with MSSA bacteremia without heterogeneity (I2 = 31%). Among six studies that reported length of stay after the onset of bacteremia, data from two studies [62,63] were included in the analysis and showed that the average stay was 5.02 days longer in the MRSA group than the MSSA group (WMD, 5.02; 95% CI, 2.66 to 7.38), with homogeneity (I2 = 0%). Four studies described the length of intensive care unit (ICU) stay. Patients with MRSA bacteremia stayed in the ICU 6.46 days longer (WMD, 6.46; 95% CI, 0.87 to 12.04), with heterogeneity among combined studies (I2 = 86%) than those with MSSA. Of six studies that reported medical costs (Table 3) [33,37,46,62,63,76], two were included in the analysis, and the estimated medical costs were $9,954.58 (WMD, 9,954.58; 95% CI, 8,951.99 to 10,957.17) with a statistically significant difference between groups and homogeneity between the two studies (I2 = 0%) [62,63].

Length of hospital stay

Medical costs

Publication bias

We generated contour-enhanced funnel plots to evaluate the presence of potential publication bias for the meta-analyses performed in our review (Supplementary Fig. 1). No evidence of publication bias was noted in the funnel plots and the adjusted rank correlation tests in the meta-analyses for all-cause mortality (p = 0.10), in-hospital mortality (p = 0.056), 30-day mortality (p = 0.714), or SAB-related mortality (p = 0.557).

DISCUSSION

This systematic review of 62 relevant reports published since 2000 that evaluated the outcomes of SAB and endocarditis in adults, suggested that methicillin-resistant isolates is associated with increased mortality, hospital stay and medical costs, compared with susceptible isolates. A significant increase in all-cause mortality associated with MRSA, compared to that with MSSA compromised of 17,565 patients from 62 combined studies was evident with a pooled OR of 1.95. This is consistent with the report in 2003 by Cosgrove et al. [2] which had combined 31 studies with a total of 3,962 patients of an OR of mortality associated with MRSA of 1.93, compared with MSSA. In 60 studies that reported mortality outcomes, the relative risk (RR) was estimated to be 1.59 based on the mean mortality rate of 33.1% (2,101/6,338) in the MRSA group and 18.2% (2,014/11,075) in the MSSA group. In studies of in-hospital mortality, the RR was estimated at 1.54. This is also similar to the RR of 1.42 reported by Cosgrove et al. [2]. In the analysis involving SAB-related mortality, the pooled OR was 2.04 (95% CI, 1.63 to 2.55; I2 = 40%). This was compatible with the OR of 2.2 (95% CI, 1.2 to 3.8) reported by Cosgrove et al. [2]. In this analysis reevaluating the impact of methicillin-resistance on mortality in the era of the changing epidemiology and treatment of MRSA infections, a similar trend for a strong association between methicillin-resistance and a significantly increased mortality risk was identified through a review of the literature. Through a systematic review using a database published since the year 2000, two studies reported length of stay after the onset of bacteremia; patients in the MRSA group stayed 5.02 days longer than those in the MSSA group (95% CI, 2.66 to 7.38).

We also intended to evaluate the risk of mortality in endocarditis by comparing the groups with MRSA and MSSA. Interestingly, methicillin resistance increased the risk of mortality in SAE by 2.65 (95% CI, 1.46 to 4.80). Further analysis, involving primarily the SAE population, showed a pooled OR of 3.32 (95% CI, 1.68 to 6.59), which is higher than that reported by Cosgrove et al. [2] 1.79 (95% CI, 0.84 to 3.81). This is different than our expectation that mortality would be lower among patients with MRSA endocarditis as a consequence of better management with new antibiotics. Although glycopeptides were the only treatment option for MRSA infections before 2000, new treatment agents, including daptomycin and linezolid, for MRSA have been introduced since that time. Hence, the outcomes in the MRSA group were expected to be better than those in the past, especially in SAE, which is a severe form of SAB. The increased risk of mortality in the SAE group is attributable in part to the delay between data collection and publication. More than half of the study population was collected before 2000. Besides, only fifteen studies specified the treatment regimens for SAB; the mainstay of therapy for these was limited to glycopeptides. There was no study evaluating the clinical outcomes of SAB according to the treatment regimens between glycopeptides and the new anti-MRSA agents among the 62 relevant studies. Thus, the estimated risk in our analysis does not fully reflect changes in treatment of MRSA infections using new antibiotics as alternatives to glycopeptides. Further studies are required to evaluate the risk of methicillin-resistance for mortality in the SAE population under treatments with antibiotics other than glycopeptides.

Traditionally, bacteremia and endocarditis are classified as either CA or HA (nosocomial). CA-MRSA infections have emerged in the past few years as an important medical problem, especially in children without traditional risk factors for healthcare-associated MRSA. To evaluate the risk for emergence of methicillin-resistance in the community, we examined the outcomes of 22 studies reporting outcomes for CA-SAB as part of SAB; of these, three studies reported outcomes by comparing CA-MRSA and CA-MSSA. Interestingly, methicillin-resistance increased the risk of death by 3.23 (95% CI, 1.25 to 8.34). Furthermore, in nosocomial SAB, methicillin-resistance had a relatively low risk of morality in adults with ≥ 70% HA-SAB, compared to those with < 70% HASAB. These findings are opposed to previous reports in adults, which have described non-severe outcomes in CA-SAB compared to those in HA-SAB with a few notable exceptions. Given the different distribution pattern of CA- and HA-SAB, empiric antimicrobial therapy for CA-SAB could be less appropriate than for patients with HA-SAB. Since clinical practice guidelines for the treatment of MRSA often do not recommend coverage for CA-MRSA, the association between the presence of CA-MRSA and mortality in SAB suggests that patients with CA-MRSA were more likely to have received antibiotics not effective against methicillin-resistant strains [83]. Heterogeneity among study results, however, was detected in subgroup analyses; thus, further studies are required to determine the impact of methicillin-resistance on outcomes in adults with CA-SAB.

This study had several limitations. First, we included all adult subjects irrespective of disease patterns and severity of illness in this meta-analysis; this wide distribution of subject characteristics may result in heterogeneity between the combined studies. In this study, however, the heterogeneity test results were considerably lower than those in the general meta-analysis by Cosgrove et al. [2]. When we assessed the statistical heterogeneity with I2 > 50% as the indication of at least moderate heterogeneity, between-study statistical heterogeneity was not found in this meta-analysis (I2 statistic, 44%). Twenty-two studies were selected as high-quality in the assessment of bias risk of 62 relevant papers; with these, the sensitivity analysis showed a pooled OR of 2.12 (95% CI, 1.76 to 2.55), a significantly increased risk of mortality of methicillin- resistance in SAB. Heterogeneity in the combined studies was not identified (I2 = 46%). Thus heterogeneity did not have a major impact on the results. Therefore, a wide distribution of subject characteristics between studies in this meta-analysis is not considered to have had a huge impact on the results. Second, this analysis included data in part collected before the year 2000. Given that our data were collected around 2000, the mainstay of therapy for MRSA in this analysis was confined to glycopeptides; this may not fully reflect current medical treatment, in which newer antimicrobial agents active against MRSA have become available. Further study of the effect of new antimicrobial agents on mortality of patients with SAB is required.

Despite these limitations, the present systematic review of studies published since 20 suggests that methicillin-resistance is associated with increased mortality and hospital stay compared with susceptible isolates in SAB and endocarditis. In the SAE and CA-SAB infection subgroups, methicillin-resistance was associated with increased mortality.

KEY MESSAGE

1. Methicillin-resistance is still associated with increased mortality and hospital stay, compared with susceptible isolates in Staphylococcus aureus bacteremia.

2. In comparison of outcome between community-acquired methicillin-resistant and methicillin-susceptible S. aureus bacteremia, methicillin-resistance increased the risk for mortality.

Notes

No potential conflict of interest relevant to this article was reported.

Acknowledgements

This study was supported by a grant from the Korean Healthcare Technology R&D Project, Ministry of Health and Welfare, Republic of Korea (A102065).

Supplementary Materials

Supplementary Figure 1.

Contour-enhanced funnel plot and Begg & Mazumdar’s rank correlation test for exploring publication bias for all-cause mortality (A), in-hospital mortality (B), 30-day mortality (C), and Staphylococcus aureus bacteremia-related mortality (D).

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Article information Continued

Figure 1.

Flow diagram detailing reviewed articles and exclusion. DB, database.

Figure 2.

Forest plot summary of the results of 60 studies which reported all-cause mortality. MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; CI, confidence interval.

Figure 3.

Forest plot summary of results of eight which reported all-cause mortality in Staphylococcus aureus bacteremia and endocarditis in the Korean population. MRSA, methicillin-resistant S. aureus; MSSA, methicillin-susceptible S. aureus; CI, confidence interval.

Figure 4.

Forest plot summary of results of three studies which reported mortality rates between community-associated (CA)-methicillin-resistant Staphylococcus aureus (MRSA) and CA-methicillin-susceptible S. aureus (MSSA). CI, confidence interval.

Table 1.

Characteristics of the studies of Staphylococcus aureus bacteremia or endocarditis included in the systematic review

No. Author Year Study period Country Total no. of cases Proportion of HAMRSA/CAMRSA/MSSAa,b,c Population IE (% of cases) Types of outcomes Mortality rate, %
Crude OR (95% CI)
MRSA MSSA
1 Holmes [21] 2011 2007.1–2008.11 Australia 532 22.2/15.8/62.0b SAB 30-Day mortality 22.1 14.2 1.72 (1.09–2.71)
New Zealand
2 Kao [22] 2011 2004.1–2004.12 Taiwan 137 42.3/5.8/51.8a SAB Hospital mortality 43.9 21.1 2.93 (1.38–6.19)
3 Lubart [23] 2011 2004.1–2005.12 Israel 68 66.2/33.8c SAB 14-Day mortality 40.0 13.0 4.44 (1.15–17.18)
4 Park [24] 2011 2003.1–2008.12 Korea 266 46.6/7.9/45.5a SAB 30-Day mortality 21.4 28.9 0.67 (0.38–1.17)
5 Big [25] 2010 2004.1–2008.7 USA 76 60.5/39.5c SAB Hospital mortality 34.8 20.0 2.13 (0.72–6.29)
6 Kang [26] 2010 2004.9–2006.8 Korea 709 46.4/53.6c SAB/SAE 31 (4.4) 30-Day mortality 33.1 17.1 2.40 (1.69–3.41)
7 Khan [27] 2010 2007.7–2008.6 Qatar 53 13.2/86.8c SAB Hospital mortality 28.6 28.3 1.02 (0.17–5.91)
8 Kim [28] 2010 2006.7–2008.12 Canada 684 27.9/72.1c SAB 30-Day mortality 25.1 15.4 1.84 (1.22–2.77)
9 Ponce-de-Le-on [29] 2010 2003.1–2007.12 Mexico 172 45.9/0/54.1b SAB 30-Day mortality, hos- pital mortality, 7-day mortality, LOS 21.5 21.5 1.0 (0.48–2.08)
10 Takayama [30] 2010 1990.1–2006.12 Japan 33 30.3/0/69.7b SAE 33 (100) Hospital mortality 70.0 34.8 4.38 (0.88–21.71)
11 Wehrhahn [31] 2010 2-Year period Australia 81 0/22.2/77.8b SAB/SAE 15 (18.5) 30-Day mortality 22.2 11.1 2.29 (0.59–8.91)
12 Ammerlaan [32] 2009 2007.1–2007.12 Europe 334 23.1/76.9c SAB 30-Day mortality 26.0 23.3 1.15 (0.64–2.07)
13 Ben-David [33] 2009 2000.1–2003.8 Israel 182 52.2/0/47.8b SAB Hospital mortality, LOS, total medical cost 25.3 18.4 1.5 (0.74–3.06)
14 Khatib [34] 2009 2002.1–2003.6 USA 78 78.2/21.8c SAB Hospital mortality 34.4 5.9 8.4 (1.04–67.79)
15 Kim [35] 2009 1995.1.–2006.12 Korea 73 16.4/26.0/57.5b SAE 73 (100) Hospital mortality, 35.5 2.4 22.55 (2.72–187.07)
16 Rieg [36] 2009 2002–2007 Germany 521 12.9/0/87.1a SAB Hospital mortality 41.8 18.7 3.12 (1.82–5.35)
17 Rubio-Terres [37] 2009 2005.1–2005.12 Spain 366 26.8/6.3/66.9b SAB Hospital mortality, LOS (in wards), ICU stay, cost per episode bacteremia 39.7 25.3 1.94 (1.22–3.09)
18 Turnidge [38] 2009 2007.6–2008.5 Australia 1865 24.1/75.9c SAB 30-Day mortality 30.0 17.7 2.0 (1.57–2.55)
New Zealand
19 Allard [39] 2008 1991–2005 Canada 815 8.3/0.1/91.5a SAB 30-Day mortality 33.3 23.1 1.67 (0.98–2.83)
20 Baroudi [40] 2008 1990.1–2006.1 USA 27 55.6/44.4c SAE 27 (100) Hospital mortality 40.0 50.0 0.67 (0.14–3.09)
21 Libert [41] 2008 2002.1–2004.12 Belgium 140 31.4/12.9/55.7b SAB Hospital mortality 54.8 35.9 1.90 (0.97–3.76)
22 Malani [42] 2008 2004–2005 USA 68 52.9/47.1c SAB Hospital mortality 25.0 12.5 3.88 (1.29–11.68)
23 Bader [43] 2007 2003.1–2004.12 USA 135 23.0/31.8/45.2b SAB Hospital mortality 33.8 18.0 2.32 (1.03–5.22)
24 Cagatay [44] 2007 2001.10–2002.12 Turkey 57 80.7/19.3c SAB SAB-related mortality (30-day) 54.3 63.6 0.68 (0.17–2.65)
25 Das [45] 2007 2001–11–2002–12 UK 140 49.3/10.7/40.0b SAB SAB-related mortality (within 10-day), LOS 33.3 16.1 2.61 (1.12–6.08)
26 Greiner [46] 2007 1999.12–2005.5 Germany 109 18.3/7.4/74.3b SAB Total hospital cost NR NR NR
27 Hsu [47] 2007 1995–2005 Taiwan 123 39.0/61.0c SAE 123 (100) Hospital mortality 41.7 16.0 3.75 (1.61–8.71)
28 Wang [48] 2007 1990–2004 Taiwan 1148 74.1/25.9c SAB 30-Day mortality 49.8 27.6 2.60 (1.95–3.47)
29 Depuydt [49] 2006 1992–2002 Belgium 32 59.4/40.6c Bacteremic SAP Hospital mortality 72.2 NR NR
30 Guilarde [50] 2006 2000.1–2001.12 Brazil 111 55.0/45.0c SAB SAB-related mortality 47.5 20.0 3.63 (1.54–8.53)
31 Heo [51] 2006 2000.1–2005.8 Korea 231 0/27.3/72.7b SAB Hospital mortality 30.2 19.6 1.77 (0.91–3.41)
32 Kim [52] 2006 1999.1–2003.5 Korea 96 64.6/3.1/32.3a SAB Hospital mortality 26.2 0.0 22.73 (1.32–391.68)
33 Lesse [53] 2006 1997.1–2003.12 USA 38 63.2/36.8c SAB Hospital mortality 33.3 21.4 1.83 (0.4–8.49)
34 Marra [54] 2006 2003.12.15–2004.12.31 USA 91 46.2/53.8c SAB Hospital mortality 26.2 4.1 8.69 (1.80–41.88)
35 Nori [55] 2006 1999.1–2004.2 USA 22 50.0/50.0c SAE 22 (100) Hospital mortality 54.5 45.5 1.44 (0.27–7.71)
36 Perovic [56] 2006 1999.11–2002.10 South Africa 449 18.7/4.7/76.6b SAB SAB-related mortality (14-day) 33.3 20.1 1.99 (1.23–3.23)
37 Shorr [57] 2006 2002–2003 USA 1540 21.2/6.2/72.6a SAB Hospital mortality 23.5 16.4 1.57 (1.19–2.06)
38 Wyllie [58] 2006 1997.4–2004.3 UK 441 51.5/0/48.5b SAB 30-Day mortality 33.5 27.1 1.35 (0.90–2.04)
39 Cassettari [59] 2005 1999.5–1999.8 Brazil 163 58.9/0/41.1b SAB Hospital mortality, SAB-related mortality (15-day) 44.8 29.9 1.91 (0.99–3.69)
40 DeRyke [60] 2005 1999.1–2004.4 USA 60 70.0/0/30.0b Bacteremic SAP Hospital mortality, SAB-related mortality, infection-related LOS 54.8 55.6 0.97 (0.32–2.94)
41 Fowler [61] 2005 2000.6–2003.12 USA 424 26.7/6.7/66.7a SAE 424 (100) Hospital mortality 29.8 23.3 1.39 (0.89–2.20)
Multicontinent
42 Lodise [62] 2005 1999.1–2001.1 USA 353 39.9/8.2/51.8b SAB SAB-related mortality, 30-day mortality, SAB-related LOS and hospital cost 30.6 15.3 2.44 (1.45–4.10)
43 Reed [63] 2005 1996.7.–2001.8 USA 143 37.8/62.2 SAB Hospital-mortality, LOS, ICU stay, total hospital cost 14.8 9.0 1.76 (0.62–5.01)
44 Yoon [64] 2005 1986.3–2004.3 Korea 32 18.8/12.5/68.8b SAE 32 (100) Hospital mortality 50.0 9.1 10.0 (1.48–67.55)
45 Chang [65] 2004 1988.1–2002.12 Taiwan 12 66.7/33.3c SAE 12 (100) Hospital mortality 100 0 153.0 (2.58–9,077.05)
46 Cordova [66] 2004 1997.7–1999.6 Australia 501 7.8/3.2/89.0a SAB Hospital mortality (within 16-day), 7-day mortality, LOS 27.3 16.8 1.86 (0.98–3.53)
47 Osmon [67] 2004 2001.12–2002.9 USA 265 36.2/19.6/44.2a SAB Hospital mortality, LOS, ICU stay 13.5 16.2 0.81 (0.41–1.59)
48 Chang [68] 2003 1994.8–1996.3 USA 64 15.6/15.6/68.8a SAE 64 (100) 30-Day mortality, 14-Day mortality 50.0 22.7 3.40 (1.10–10.47)
49 Kim [69] 2003 1998.1–2002.3 Korea 29 48.3/51.7c SAB SAB-related mortality 57.1 20.0 5.33 (1.02–27.76)
50 Melzer [70] 2003 1995.1–2000.12 UK 815 46.9/0/53.1b SAB SAB-related mortality, overall mortality 29.6 13.6 2.66 (1.87–3.79)
51 Na [71] 2003 1990.1–2000.5 Korea 10 20.0/80.0c SAE 10 (100) Hospital mortality 100 25 13.00 (0.45–377.47)
52 Blot [72] 2002 1992.1.–1998.12 Belgium 85 55.3/0/44.7b SAB Hospital mortality, 15-day mortality, 30-day mortality, ICU stay 53.2 18.4 5.03 (1.85–13.69)
53 Campillo [73] 2002 1996.1–2001.3 France 83 90.4/0/9.6b SAB/peritonitis Hospital mortality 60.0 75.0 0.5 (0.09–2.64)
54 Talon [74] 2002 1997.1–1998.12 France 99 11.1/19.2/69.7b SAB 51.7 SAB-related mortality (14-day) 43.3 20.3 3.00 (1.18–7.62)
55 Tumbarello [75] 2002 1991.1–2000.12 Italy 129 24.8/7.0/68.2b SAB Hospital mortality, LOS 34.1 11.4 4.04 (1.61–10.17)
56 Cosgrove [76] 2001 1997.7–2000.6 USA 348 27.6/72.4c SAB Hospital mortality, SAB-related mortality, SAB-related LOS and hospital charge 22.9 19.8 1.20 (0.68–2.12)
57 Morin [77] 2001 1998.1–1998.12 USA 192 9.9/5.2/84.9a SAB Hospital mortality 13.8 10.4 1.37 (0.43–4.42)
58 Wisplinghoff [78] 2001 1995.12–1997.5 USA 82 48.8/0/51.2b SAB Hospital mortality 25.0 23.8 1.07 (0.39–2.92)
59 Ibrahim [79] 2000 1997.6–1999.7 USA 94 48.9/51.1c SAB Hospital mortality 37.0 25.0 1.76 (0.73–4.27)
60 Roghmann [80] 2000 1995.10–1998.1 USA 125 22.7/7.0/70.3b SAB 30-Day mortality 32.4 23.9 1.53 (0.66–3.57)
61 Selvey [81] 2000 1992–1997 Australia 504 37.3/0/62.7b SAB Hospital mortality, SAB-related mortality 18.6 13.0 1.53 (0.94–2.51)
62 Soriano [82] 2000 1991.1–1998.12 Spain 908 19.9/4.8/75.2b SAB/SAE 31 (3.4) SAB-related mortality (30-day), LOS 21.8 8.9 2.84 (1.88–4.28)

HA, hospital-acquired; MRSA, methicillin-resistant S. aurues; CA, community-acquired; MSSA, methicillin-susceptible S. aureus; IE, infective endocarditis; OR, odds ratio; CI, confidence interval; SAB, S. aureus bacteremia; SAE, S. aureus-associated infective endocarditis; LOS, length of hospital stay; ICU, intensive care unit; SAP, S. aureus-associated pneumonia.

a

Represents the proportion of cases which were epidemiologically defined according to CA- and HA-MRSA.

b

Represents the proportion of cases which were classified into community-onset and hospital-onset MRSA without definition of CA-MRSA.

c

Indicates the proportion of cases with MRSA, when onset of bacteremia was not defined according to the epidemiologic definition.

Table 2.

Length of hospital stay

No. Author Year Populations LOS, day
p value
MRSA MSSA
1 Ponce-de-Leon [29] 2010 SAB 31 (1–585)a 21 (0–140)a 0.003
2 Rubio-Terres [37] 2009 SAB 24.8 (19.9–29.9)b 22.66 (18.8–26.5)b NR
3 Das [45] 2007 SAB 14c 8c 0.004
4 Reed [63] 2005 SAB 16.6 ± 12.7d 9.3 ± 8.5d < 0.0001
5 Cordova [66] 2004 SAB 16 (6–25, 1–211)e 14 (7–30, 1–273)e NR
6 Osmon [67] 2004 SAB 22.1 ± 24.9d 13.2 ± 13.5d 0.001
7 Tumbarello [75] 2002 SAB 49 ± 27d 24 ± 16d < 0.001
8 Soriano [82] 2000 SAB 18f 8f < 0.00001

LOS, length of hospital stay; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; SAB, S. aureus bacteremia; NR, not recorded.

a

Mean (range).

b

Mean (95% confidence interval).

c

Median.

d

Mean ± SD.

e

Median (interquartile range, range),

f

Mean.

Table 3.

Medical costs

No Author Year Medical costs
p value
MRSA MSSA
1 Rubio-Terres [37] 2009 €11,044.59/episodea €9839.25/episodea -
2 Ben-David [33] 2009 ICU origin: $113,852 (48,961–55,001)b ICU origin: $42,137 (32,388–74,781)b ICU origin: < 0.001
General origin: $53,409 (32,945–84,053)b General origin: $35,131 (18,340–50,896)b General origin: 0.005
3 Greiner [46] 2006 €24,931a €10,573a < 0.05
4 Lodise [62] 2005 $21,577 (17,061–27,290)c $11,668 (9,550–14,223)c 0.001
5 Reed [63] 2005 $28,297 ± 23,619d $16,066 ± 16,337d < 0.0001
6 Cosgrove [76] 2001 $26,424 (14,006–50,484)b $19,212 (9,999–36,548)b 0.008

MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillin-susceptible S. aureus; ICU, intensive care unit.

a

Mean.

b

Median (interquartile range).

c

Mean (95% confidence interval).

d

Mean ± SD.