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1.  Trends in Staphylococcus aureus bacteraemia and impacts of infection control practices including universal MRSA admission screening in a hospital in Scotland, 2006–2010: retrospective cohort study and time-series intervention analysis 
BMJ Open  2012;2(3):e000797.
To describe secular trends in Staphylococcus aureus bacteraemia (SAB) and to assess the impacts of infection control practices, including universal methicillin-resistant Staphylococcus aureus (MRSA) admission screening on associated clinical burdens.
Retrospective cohort study and multivariate time-series analysis linking microbiology, patient management and health intelligence databases.
Teaching hospital in North East Scotland.
All patients admitted to Aberdeen Royal Infirmary between 1 January 2006 and 31 December 2010: n=420 452 admissions and 1 430 052 acute occupied bed days (AOBDs).
Universal admission screening programme for MRSA (August 2008) incorporating isolation and decolonisation.
Primary and secondary measures
Hospital-wide prevalence density, hospital-associated incidence density and death within 30 days of MRSA or methicillin-sensitive Staphylococcus aureus (MSSA) bacteraemia.
Between 2006 and 2010, prevalence density of all SAB declined by 41%, from 0.73 to 0.50 cases/1000 AOBDs (p=0.002 for trend), and 30-day mortality from 26% to 14% (p=0.013). Significant reductions were observed in MRSA bacteraemia only. Overnight admissions screened for MRSA rose from 43% during selective screening to >90% within 4 months of universal screening. In multivariate time-series analysis (R2 0.45 to 0.68), universal screening was associated with a 19% reduction in prevalence density of MRSA bacteraemia (−0.035, 95% CI −0.049 to −0.021/1000 AOBDs; p<0.001), a 29% fall in hospital-associated incidence density (−0.029, 95% CI −0.035 to −0.023/1000 AOBDs; p<0.001) and a 46% reduction in 30-day mortality (−15.6, 95% CI −24.1% to −7.1%; p<0.001). Positive associations with fluoroquinolone and cephalosporin use suggested that antibiotic stewardship reduced prevalence density of MRSA bacteraemia by 0.027 (95% CI 0.015 to 0.039)/1000 AOBDs. Rates of MSSA bacteraemia were not significantly affected by screening or antibiotic use.
Declining clinical burdens from SAB were attributable to reductions in MRSA infections. Universal admission screening and antibiotic stewardship were associated with decreases in MRSA bacteraemia and associated early mortality. Control of MSSA bacteraemia remains a priority.
Article summary
Article focus
This study describes the changing epidemiology of MRSA and MSSA bacteraemia in a large inpatient population from Scotland over a 5-year period.
Second, it evaluates the impact of universal MRSA admission screening, and other infection control practices, on hospital-wide rates of MRSA bacteraemia.
Key messages
Recent declines in clinical burdens from SAB in North East Scotland were attributable to a reduction in invasive MRSA infections.
Compared with a strategy of targeted screening in high-risk environments, universal admission screening may significantly reduce rates of MRSA bacteraemia and associated early mortality alongside improvements in antibiotic stewardship and infection control.
Strategies to reduce clinical burdens from MSSA bacteraemia are required if progress towards national targets for all SAB is to be sustained.
Strengths and limitations of this study
Without a contemporary control, this study did not prove causality but a temporal association between universal admission screening and rates of MRSA bacteraemia.
ARIMA modelling accounted for the non-independence of data and stochastic elements in time series of infections, and the dynamic effects of changes in other aspects of care.
Findings may be limited to large public hospitals with intensive care units and endemic MRSA but low rates of MRSA infection.
PMCID: PMC3378947  PMID: 22685226
2.  Predicting Risk of Endocarditis Using a Clinical Tool (PREDICT): Scoring System to Guide Use of Echocardiography in the Management of Staphylococcus aureus Bacteremia 
Infective endocarditis (IE) is a serious complication of Staphylococcus aureus bacteremia (SAB). We propose 2 scoring systems that can accurately predict IE in patients with SAB and complement decision-making by clinicians for optimal use of transesophageal echocardiography in these patients.
Background. Infective endocarditis (IE) is a serious complication of Staphylococcus aureus bacteremia (SAB). There is limited clinical evidence to guide use of echocardiography in the management of SAB cases.
Methods. Baseline and 12-week follow-up data of all adults hospitalized at our institution with SAB from 2006 to 2011 were reviewed. Clinical predictors of IE were identified using multivariable logistic regression analysis.
Results. Of the 757 patients screened, 678 individuals with SAB (24% community acquired, 56% healthcare associated, and 20% nosocomial) met study criteria. Eighty-five patients (13%) were diagnosed with definite IE within the 12 weeks of initial presentation based on modified Duke criteria. The proportion of patients with IE was 22% (36/166) in community-acquired SAB, 11% (40/378) in community-onset healthcare-associated SAB, and 7% (9/136) in nosocomial SAB. Community-acquired SAB, presence of cardiac device, and prolonged bacteremia (≥72 hours) were identified as independent predictors of IE in multivariable analysis. Two scoring systems, day 1 (SAB diagnosis day) and day 5 (when day 3 culture results are known), were derived based on the presence of these risk factors, weighted in magnitude by the corresponding regression coefficients. A score of ≥4 for day 1 model had a specificity of 96% and sensitivity of 21%, whereas a score of <2 for day 5 model had a sensitivity of 98.8% and negative predictive value of 98.5%.
Conclusions. We propose 2 novel scoring systems to guide use of echocardiography in SAB cases. Larger prospective studies are needed to validate the classification performance of these scoring systems.
PMCID: PMC4542912  PMID: 25810284
Staphylococcus aureus; bacteremia; echocardiography; endocarditis; risk score
3.  Treatment Duration for Uncomplicated Staphylococcus aureus Bacteremia To Prevent Relapse: Analysis of a Prospective Observational Cohort Study 
Practice guidelines recommend at least 14 days of antibiotic therapy for uncomplicated Staphylococcus aureus bacteremia (SAB). However, these recommendations have not been formally evaluated in clinical studies. To evaluate the duration of therapy for uncomplicated SAB, we analyzed data from our prospective cohort of patients with SAB. A prospective observational cohort study was performed in patients with SAB at a tertiary-care hospital in Korea between August 2008 and September 2010. All adult patients with SAB were prospectively enrolled and observed over a 12-week period. Uncomplicated SAB was defined as follows: negative results of follow-up blood cultures at 2 to 4 days, defervescence within 72 h of therapy, no evidence of metastatic infection, and catheter-related bloodstream infection or primary bacteremia without evidence of endocarditis on echocardiography. Of 483 patients with SAB, 111 met the study criteria for uncomplicated SAB. Fifty-three (47.7%) had methicillin-resistant SAB. When short-course therapy (<14 days) and intermediate-course therapy (≥14 days) were compared, the treatment failure rates (10/38 [26.3%] versus 16/73 [21.9%]) and crude mortality (7/38 [18.4%] versus 16/73 [21.9%]) did not differ significantly between the two groups. However, short-course therapy was significantly associated with relapse (3/38 [7.9%] versus 0/73; P = 0.036). In multivariate analysis, primary bacteremia was associated with a trend toward increased treatment failure (P = 0.06). Therefore, in the treatment of uncomplicated SAB, it seems reasonable to consider at least 14 days of antibiotic therapy to prevent relapse, as practice guidelines recommend. Because of its poor prognosis, primary bacteremia, even with a low risk of complication, should not be treated with short-course therapy.
PMCID: PMC3591920  PMID: 23254436
4.  Echocardiography Is Dispensable in Uncomplicated Staphylococcus aureus Bacteremia 
Medicine  2013;92(3):182-188.
Current Staphylococcus aureus bacteremia (SAB) practice guidelines stratify treatment duration according to the likelihood of complications and recommend transesophageal echocardiography (TEE) in all cases. The benefit of TEE in uncomplicated SAB has not been validated. We performed a retrospective analysis of TEE and transthoracic echocardiography (TTE) among hospitalized adults with SAB in 3 prior observational studies (2002–2003, 2005–2006, and 2008–2009). Echocardiograms were ordered at the attending physician’s discretion. SAB cases were stratified into the following types: complicated (persistent bacteremia [duration ≥3 d], relapse, and/or secondary foci); device-associated (intracardiac prosthetic devices); suspected endocarditis (the presence of murmurs or emboli); and uncomplicated (bacteremia duration ≤2 d, no device and/or secondary foci). We encountered 960 SAB cases; 83 were excluded (57 death/transfer/discharge within 48 h; 19 contaminants/no treatment; 7 care withdrawn). TEE and TTE were performed within 0–28 days of SAB onset in 177 (20.2%) and 321 (36.6%) instances, respectively. TEE was positive (with signs of endocarditis) in 42/177 (23.7%) cases: 7/39 (17.9%) community associated and 35/138 (25.4%) health care associated. It was positive in 29/120 (24.2%) complicated, 3/11 (27.3%) device-associated, 9/15 (60.0%) suspected endocarditis, and 1/31 (3.2%) uncomplicated cases of SAB. TTE was positive in 25/321 (7.8%) cases of SAB, 1 was uncomplicated; it was negative in 20/30 (66.7%) TEE-positive cases. Follow-up of ≥100 days was possible in 282/361 (78.1%) uncomplicated SAB; many (46.8%) received ≤15 days of therapy. None of them had relapses or secondary foci.
These findings suggest that echocardiography is dispensable in cases of uncomplicated community-associated and health care-associated SAB. It should be limited to subsets with clinical findings of endocarditis, persistence, intracardiac devices, secondary foci, and relapse. The cost effectiveness of TTE prior to TEE among these patients is unknown.
PMCID: PMC4553989  PMID: 23619238
5.  Staphylococcus aureus Bloodstream Infection and Endocarditis - A Prospective Cohort Study 
PLoS ONE  2015;10(5):e0127385.
To update the epidemiology of S. aureus bloodstream infection (SAB) in a high-income country and its link with infective endocarditis (IE).
All consecutive adult patients with incident SAB (n = 2008) were prospectively enrolled between 2009 and 2011 in 8 university hospitals in France.
SAB was nosocomial in 54%, non-nosocomial healthcare related in 18% and community-acquired in 26%. Methicillin resistance was present in 19% of isolates. SAB Incidence of nosocomial SAB was 0.159/1000 patients-days of hospitalization (95% confidence interval [CI] 0.111-0.219). A deep focus of infection was detected in 37%, the two most frequent were IE (11%) and pneumonia (8%). The higher rates of IE were observed in injecting drug users (IE: 38%) and patients with prosthetic (IE: 33%) or native valve disease (IE: 20%) but 40% of IE occurred in patients without heart disease nor injecting drug use. IE was more frequent in case of community-acquired (IE: 21%, adjusted odds-ratio (aOR) = 2.9, CI = 2.0-4.3) or non-nosocomial healthcare-related SAB (IE: 12%, aOR = 2.3, CI = 1.4-3.5). S. aureus meningitis (IE: 59%), persistent bacteremia at 48 hours (IE: 25%) and C-reactive protein > 190 mg/L (IE: 15%) were also independently associated with IE. Criteria for severe sepsis or septic shock were met in 30% of SAB without IE (overall in hospital mortality rate 24%) and in 51% of IE (overall in hospital mortality rate 35%).
SAB is still a severe disease, mostly related to healthcare in a high-income country. IE is the most frequent complication and occurs frequently in patients without known predisposing conditions.
PMCID: PMC4447452  PMID: 26020939
6.  Impact of routine bedside infectious disease consultation on clinical management and outcome of Staphylococcus aureus bacteraemia in adults 
Staphylococcus aureus bacteraemia (SAB) is a common, serious infection that is associated with high rates of morbidity and mortality. Evidence suggests that infectious disease consultation (IDC) improves clinical management in patients with SAB. We examined whether the introduction of a routine bedside IDC service for adults with SAB improved clinical management and outcomes compared to telephone consultation. We conducted an observational cohort study of 571 adults with SAB at a teaching hospital in the United Kingdom between July 2006 and December 2012. A telephone consultation was provided on the day of positive blood culture in all cases, but an additional bedside IDC was provided after November 2009 (routine IDC group). Compared to patients in the pre-IDC group, those in the routine IDC group were more likely to have a removable focus of infection identified, echocardiography performed and follow-up blood cultures performed. They also received longer courses of antimicrobial therapy, were more likely to receive combination antimicrobial therapy and were more likely to have SAB recorded in the hospital discharge summary. There was a trend towards lower mortality at 30 days in the routine IDC group compared to the pre-IDC group (12% vs. 22%, p 0.07). Our findings suggest that routine bedside IDC should become the standard of care for adults with SAB.
PMCID: PMC4509716  PMID: 26033668
Bacteraemia; infectious disease consultation; outcome; Staphylococcus aureus; treatment
7.  High Cell-Free DNA Predicts Fatal Outcome among Staphylococcus aureus Bacteraemia Patients with Intensive Care Unit Treatment 
PLoS ONE  2014;9(2):e87741.
Among patients with bacteraemia or sepsis the plasma cell-free DNA (cf-DNA) biomarker has prognostic value and Pitt bacteraemia scores predict outcome. We evaluated the prognostic value of plasma cf-DNA in patients with Staphylococcus aureus bacteraemia (SAB) treated in the ICU or in the general ward.
418 adult patients with positive blood culture for S. aureus were prospectively followed for 90 days. SAB patients were grouped according to ICU treatment: 99 patients were treated in ICU within 7 days of documented SAB whereas 319 patients were managed outside ICU. Pitt bacteraemia scores were assessed at hospital arrival and cf-DNA was measured at days 3 and 5 from positive blood culture.
SAB patients with high Pitt bacteraemia scores and ICU treatment presented higher cf-DNA values as compared to SAB patients with low Pitt bacteraemia scores and non-ICU treatment at both days 3 and 5. Among ICU patients cf-DNA >1.99 µg/ml at day 3 predicted death with a sensitivity of 67% and a specificity of 77% and had an AUC in receiver operating characteristic analysis of 0.71 (p<0.01). The cut-off cf-DNA >1.99 µg/ml value demonstrated a strong association to high Pitt bacteraemia scores (≥4 points) (p<0.000). After controlling for all prognostic markers, Pitt bacteraemia scores ≥4 points at hospital admission (OR 4.47, p<0.000) and day 3 cf-DNA (OR 3.56, p<0.001) were the strongest factors significantly predicting outcome in ICU patients. cf-DNA at day 5 did not predict fatal outcome.
High cf-DNA concentrations were observed among patients with high Pitt bacteraemia scores and ICU treatment. Pitt bacteraemia scores (≥4 points) and cf-DNA at day 3 from positive blood culture predicted death among SAB patients in ICU and were found to be independent prognostic markers. cf-DNA had no prognostic value among non-ICU patients.
PMCID: PMC3919733  PMID: 24520336
8.  Outcome and reinfection after Staphylococcus aureus bacteraemia in individuals with and without HIV-1 infection: a case–control study 
BMJ Open  2014;4(4):e004075.
Individuals infected with HIV-1 are at an increased risk of Staphylococcus aureus bacteraemia (SAB). The aim of this study was to investigate mortality rate and risk of reinfection associated with SAB in HIV-1-infected individuals compared to individuals without HIV-1 infection.
University hospital treating a third of the estimated 5000 individuals with HIV infection in Denmark.
HIV-1-infected (n=82) and sex-matched and age-matched uninfected (n=163) individuals with SAB in the time period 1 January 1995 to 31 December 2010.
Primary outcome measures
30-day and 365-day mortality rate ratio and relative risk of reinfection.
Individuals with HIV had an increased risk of death at day 30 (OR 11.90 (95% CI 2.15 to 65.85)) compared to individuals without HIV. Other factors associated with mortality were age, a foreign device and Pitt score. HIV-related factors did not associate to mortality. During follow-up, there were 43 episodes of reinfection; in individuals with HIV infection at an incidence rate of 7.8 (95% CI 4.7 to 10.9)/100 person-years compared with 2.2 (95% CI 1.2 to 3.2)/100 person-years for individuals without HIV. In multivariate analysis, HIV status (OR 2.91 (95% CI 1.29 to 6.58) and injection drug use (OR 3.51 (95% CI 1.06 to 11.63) were independently associated with an increased risk of reinfection.
HIV-1 infection is associated with an increased risk of 30-day mortality after SAB and a very high rate of reinfection. Age, a foreign device and Pitt score predicted outcome. For patients infected with HIV, neither CD4 T-lymphocyte counts nor plasma HIV RNA levels were associated with 30-day outcome.
Trial registration number
The study was approved by the Danish Data Protection Agency (record no. 2007-41-1196).
PMCID: PMC4010819  PMID: 24760348
9.  Clinical Management of Staphylococcus aureus Bacteremia 
JAMA  2014;312(13):1330-1341.
Several management strategies may improve outcomes in patients with Staphylococcus aureus bacteremia (SAB). The strength of evidence supporting these management strategies, however, varies widely.
To perform a systematic review of the evidence for two unresolved questions involving management strategies for SAB: 1) is transesophageal echocardiography (TEE) necessary in all cases of SAB; and 2) what is the optimal antibiotic therapy for methicillin resistant Staphylococcus aureus (MRSA) bacteremia?
Evidence acquisition
A PubMed search from inception through May 2014 was performed to find studies that addressed the role of TEE in SAB. A second search of PubMed, EMBASE, and The Cochrane Library from 1/1/1990 to 5/28/2014 was performed to find studies that addressed antibiotic treatment of MRSA bacteremia. Studies that reported outcomes of systemic antibiotic therapy for MRSA bacteremia were included. All searches were augmented by review of bibliographic references from included studies. The quality of evidence was assessed using the GRADE system by consensus of independent evaluations by at least two authors.
In 9 studies with a total of 3513 patients, use of TEE was associated with higher rates of diagnosis of endocarditis (14–25%) when compared with TTE (2–14%). Five studies proposed criteria to identify patients in whom TEE might safely be avoided. Only one high-quality trial of antibiotic therapy for MRSA bacteremia was identified from the 83 studies considered.
Conclusions and relevance
Most contemporary management strategies for SAB are based upon low quality evidence. TEE is indicated in most patients with SAB. It may be possible to identify a subset of SAB patients for whom TEE can be safely avoided. Vancomycin and daptomycin are the first-line antibiotic choices for MRSA bacteremia. Well-designed studies to address the management of SAB are desperately needed.
PMCID: PMC4263314  PMID: 25268440
10.  Impact of infectious diseases consultation on the management of Staphylococcus aureus bacteraemia in children 
BMJ Open  2014;4(7):e004659.
Infectious diseases consultation (IDC) in adults with Staphylococcus aureus bacteraemia (SAB) has been shown to improve management and outcome. The aim of this study was to evaluate the impact of IDC on the management of SAB in children.
Study design
Observational cohort study of children with SAB.
Cambridge University Hospitals National Health Service (NHS) Foundation Trust, a large acute NHS Trust in the UK.
All children with SAB admitted to the Cambridge University Hospitals NHS Foundation Trust between 16 July 2006 and 31 December 2012.
Children with SAB between 2006 and 31 October 2009 were managed by routine clinical care (pre-IDC group) and data were collected retrospectively by case notes review. An IDC service for SAB was introduced in November 2009. All children with SAB were reviewed regularly and data were collected prospectively (IDC group) until 31 December 2012. Baseline characteristics, quality metrics and outcome were compared between the pre-IDC group and IDC group.
There were 66 episodes of SAB in 63 children—28 patients (30 episodes) in the pre-IDC group, and 35 patients (36 episodes) in the IDC group. The median age was 3.4 years (IQR 0.2–10.7 years). Patients in the IDC group were more likely to have echocardiography performed, a removable focus of infection identified and to receive a longer course of intravenous antimicrobial therapy. There were no differences in total duration of antibiotic therapy, duration of hospital admission or outcome at 30 or 90 days following onset of SAB.
IDC resulted in improvements in the investigation and management of SAB in children.
PMCID: PMC4091395  PMID: 24989617
11.  Infectious Diseases Consultation Lowers Mortality From Staphylococcus aureus Bacteremia 
Medicine  2009;88(5):263-267.
Staphylococcus aureus bacteremia (SAB) is a lethal and increasingly common infection in hospitalized patients. We assessed the impact of infectious diseases consultation (IDC) on clinical management and hospital mortality of SAB in 240 hospitalized patients in a retrospective cohort study. Patients who received IDC were older than those who did not (57.9 vs. 51.7 yr; p = 0.05), and were more likely to have a health care-associated infection (63% vs. 45%; p < 0.01). In patients who received IDC, there was a higher prevalence of severe complications of SAB such as central nervous system involvement (5% vs. 0%, p = 0.01), endocarditis (20% vs. 2%; p < 0.01), or osteomyelitis (15.6% vs. 3.4%; p < 0.01). Patients who received IDC had closer blood culture follow-up and better antibiotic selection, and were more likely to have pus or prosthetic material removed. Hospital mortality from SAB was lower in patients who received IDC than in those who did not (13.9% vs. 23.7%; p = 0.05). In multivariate survival analysis, IDC was associated with substantially lower hazard of hospital mortality during SAB (hazard 0.46; p = 0.03). This mortality benefit accrued predominantly in patients with methicillin-resistant SAB (hazard 0.3; p < 0.01), and in patients who did not require ICU admission (hazard 0.15; p = 0.01). In conclusion, IDC is associated with reduced mortality in patients with staphylococcal bacteremia.
PMCID: PMC2881213  PMID: 19745684
12.  Clinical manifestations and outcome in Staphylococcus aureus endocarditis among injection drug users and nonaddicts: a prospective study of 74 patients 
Endocarditis is a common complication in Staphylococcus aureus bacteremia (SAB). We compared risk factors, clinical manifestations, and outcome in a large, prospective cohort of patients with S. aureus endocarditis in injection drug users (IDUs) and in nonaddicts.
Four hundred and thirty consecutive adult patients with SAB were prospectively followed up for 3 months. Definite or possible endocarditis by modified Duke criteria was found in 74 patients: 20 patients were IDUs and 54 nonaddicts.
Endocarditis was more common in SAB among drug abusers (46%) than in nonaddicts (14%) (odds ratio [OR], 5.12; 95% confidence interval [CI], 2.65–9.91; P < 0.001). IDUs were significantly younger (27 ± 15 vs 65 ± 15 years, P < 0.001), had less ultimately or rapidly fatal underlying diseases (0% vs 37%, P < 0.001) or predisposing heart diseases (20% vs 50%, P = 0.03), and their SAB was more often community-acquired (95% vs 39%, P < 0.001). Right-sided endocarditis was observed in 60% of IDUs whereas 93% of nonaddicts had left-sided involvement (P < 0.001). An extracardiac deep infection was found in 85% of IDUs and in 89% of nonaddicts (P = 0.70). Arterial thromboembolic events and severe sepsis were also equally common in both groups. There was no difference in mortality between the groups at 7 days, but at 3 months it was lower among IDUs (10%) compared with nonaddicts (39%) (OR, 5.73; 95% CI, 1.20–27.25; P = 0.02).
S. aureus endocarditis in IDUs was associated with as high complication rates including extracardiac deep infections, thromboembolic events, or severe sepsis as in nonaddicts. Injection drug abuse in accordance with younger age and lack of underlying diseases were associated with lower mortality, but after adjusting by age and underlying diseases injection drug abuse was not significantly associated with mortality.
PMCID: PMC1584240  PMID: 16965625
13.  Mortality predictors of Staphylococcus aureus bacteremia: a prospective multicenter study 
Staphylococcus aureus is one of the causes of both community and healthcare-associated bacteremia. The attributable mortality of S. aureus bacteremia (SAB) is still higher and predictors for mortality and clinical outcomes of this condition are need to be clarified. In this prospective observational study, we aimed to examine the predictive factors for mortality in patients with SAB in eight Turkish tertiary care hospitals.
Adult patients with signs and symptoms of bacteremia with positive blood cultures for S. aureus were included. All data for episodes of SAB including demographics, clinical and laboratory findings, antibiotics, and outcome were recorded for a 3-year (2010–2012) period. Cox proportional hazard model with forward selection was used to assess the independent effect of risk factors on mortality. A 28-day mortality was the dependent variable in the Cox regression analysis.
A total of 255 episodes of SAB were enrolled. The median age of the patients was 59 years. Fifty-five percent of the episodes were considered as primary SAB and vascular catheter was the source of 42.1 %. Healthcare associated SAB was defined in 55.7 %. Blood cultures yielded methicillin-resistant S. aureus (MRSA) as a cause of SAB in 39.2 %. Initial empirical therapy was inappropriate in 28.2 %. Although overall mortality was observed in 52 (20.4 %), 28-day mortality rate was 15.3 %. Both the numbers of initial inappropriate empirical antibiotic treatment and the median hours to start an appropriate antibiotic between the cases of fatal outcome and survivors after fever onset were found to be similar (12/39 vs 60/216 and 6 vs 12 h, respectively; p > 0.05). High Charlson comorbidity index (CCI) score (p = 0.002), MRSA (p = 0.017), intensive care unit (ICU) admission (p < 0.001) and prior exposure to antibiotics (p = 0.002) all were significantly associated with mortality. The Cox analysis defined age [Hazard Ratio (HR) 1.03; p = 0.023], ICU admission (HR 6.9; p = 0.002), and high CCI score (HR 1.32; p = 0.002) as the independent predictive factors mortality.
The results of this prospective study showed that age, ICU stay and high CCI score of a patient were the independent predictors of mortality and MRSA was also significantly associated with mortality in SAB.
PMCID: PMC4748515  PMID: 26860463
Staphylococcus aureus; Bacteremia; Risk factors; Mortality; Sepsis
14.  Usefulness of previous methicillin-resistant Staphylococcus aureus screening results in guiding empirical therapy for S aureus bacteremia 
Staphylococcus aureus bacteremia (SAB), which may be caused by methicillin-resistant S aureus (MRSA), is a leading cause of bloodstream infections. SAB and MRSA can cause an increase in mortality, result in longer hospital stays and increase medical costs. However, it is possible that MRSA colonization may predict infection. Using a retrospective cohort investigation, this study evaluated the clinical utility of past MRSA screening swabs for predicting methicillin resistance and its use in guiding empirical antibiotic therapy for SAB.
Staphylococcus aureus bacteremia (SAB) is an important infection. Methicillin-resistant S aureus (MRSA) screening is performed on hospitalized patients for infection control purposes.
To assess the usefulness of past MRSA screening for guiding empirical antibiotic therapy for SAB.
A retrospective cohort study examined consecutive patients with confirmed SAB and previous MRSA screening swab from six academic and community hospitals between 2007 and 2010. Diagnostic test properties were calculated for MRSA screening swab for predicting methicillin resistance of SAB.
A total of 799 patients underwent MRSA screening swabs before SAB. Of the 799 patients, 95 (12%) had a positive and 704 (88%) had a negative previous MRSA screening swab. There were 150 (19%) patients with MRSA bacteremia. Overall, previous MRSA screening swabs had a positive likelihood ratio of 33 (95% CI 18 to 60) and a negative likelihood ratio of 0.45 (95% CI 0.37 to 0.54). Diagnostic accuracy differed depending on mode of acquisition (ie, community-acquired, nosocomial or health care-associated infection) (P<0.0001) and hospital (P=0.0002). At best, for health care-associated infection, prior MRSA screening swab had a positive likelihood ratio of 16 (95% CI 9 to 28) and a negative likelihood ratio of 0.27 (95% CI 0.17 to 0.41).
A negative prior MRSA screening swab cannot reliably rule out MRSA bacteremia and should not be used to guide empirical antibiotic therapy for SAB. A positive prior MRSA screening swab greatly increases likelihood of MRSA, necessitating MRSA coverage in empirical antibiotic therapy for SAB.
PMCID: PMC4556181  PMID: 26361488
Antimicrobial stewardship; Empirical antimicrobial therapy; MRSA screening; Sensitivity; Specificity; Staphylococcus aureus bacteremia
15.  Heterogeneous vancomycin-intermediate susceptibility in a community-associated methicillin-resistant Staphylococcus aureus epidemic clone, in a case of Infective Endocarditis in Argentina 
Community-Associated Methicillin Resistant Staphylococcus aureus (CA-MRSA) has traditionally been related to skin and soft tissue infections in healthy young patients. However, it has now emerged as responsible for severe infections worldwide, for which vancomycin is one of the mainstays of treatment. Infective endocarditis (IE) due to CA-MRSA with heterogeneous vancomycin-intermediate susceptibility-(h-VISA) has been recently reported, associated to an epidemic USA 300 CA-MRSA clone.
Case Presentation
We describe the occurrence of h-VISA phenotype in a case of IE caused by a strain belonging to an epidemic CA-MRSA clone, distinct from USA300, for the first time in Argentina. The isolate h-VISA (SaB2) was recovered from a patient with persistent bacteraemia after a 7-day therapy with vancomycin, which evolved to fatal case of IE complicated with brain abscesses. The initial isolate-(SaB1) was fully vancomycin susceptible (VSSA). Although MRSA SaB2 was vancomycin susceptible (≤2 μg/ml) by MIC (agar and broth dilution, E-test and VITEK 2), a slight increase of MIC values between SaB1 and SaB2 isolates was detected by the four MIC methods, particularly for teicoplanin. Moreover, Sab2 was classified as h-VISA by three different screening methods [MHA5T-screening agar, Macromethod-E-test-(MET) and by GRD E-test] and confirmed by population analysis profile-(PAP). In addition, a significant increase in cell-wall thickness was revealed for SaB2 by electron microscopy. Molecular typing showed that both strains, SaB1 and SaB2, belonged to ST5 lineage, carried SCCmecIV, lacked Panton-Valentine leukocidin-(PVL) genes and had indistinguishable PFGE patterns (subtype I2), thereby confirming their isogenic nature. In addition, they were clonally related to the epidemic CA-MRSA clone (pulsotype I) detected in our country.
This report demonstrates the ability of this epidemic CA-MRSA clone, disseminated in some regions of Argentina, to produce severe and rapidly fatal infections such as IE, in addition to its ability to acquire low-level vancomycin resistance; for these reasons, it constitutes a new challenge for the Healthcare System of this country.
PMCID: PMC3111347  PMID: 21527033
16.  Persistent strong anti-HLA antibody at high titer is complement binding and associated with increased risk of antibody-mediated rejection in heart transplant recipients 
Sensitized heart transplant candidates are evaluated for donor-specific anti-HLA IgG antibody (DSA) by Luminex single-antigen bead (SAB) testing (SAB-IgG) to determine donor suitability and help predict a positive complement-dependent cytotoxicity crossmatch (CDC-XM) by virtual crossmatching (VXM). However, SAB testing used for VXM does not correlate perfectly with CDC-XM results and individual transplant programs have center-specific permissible thresholds to predict crossmatch positivity. A novel Luminex SAB-based assay detecting C1q-binding HLA antibodies (SAB-C1q) contributes functional information to SAB testing, but the relationship between SAB strength and complement-binding ability is unclear.
In this retrospective study, we identified 15 pediatric and adult heart allograft candidates with calculated panel-reactive antibody (cPRA) >50% by SAB-IgG and compared conventional SAB-IgG results with SAB-C1q testing.
Pre- and post-transplant DSA by SAB-C1q correlated with DSA by SAB-IgG and also with CDC-XM results and early post-transplant endomyocardial biopsy findings. Individual HLA antibodies by SAB-IgG in undiluted sera correlated poorly with SAB-C1q; however, when sera were diluted 1:16, SAB-IgG results were well correlated with SAB-C1q. In some sera, HLA antibodies with low mean fluorescent intensity (MFI) by SAB-IgG exhibited high SAB-C1q MFIs for the same HLA antigens. Diluting or heat-treating these sera increased SAB-IgG MFI, consistent with SAB-C1q results. In 13 recipients, SAB-C1q–positive DSA was associated with positive CDC-XM and with early clinical post-transplant antibody-mediated rejection (cAMR).
Risk assessment for positive CDC-XM and early cAMR in sensitized heart allograft recipients are correlated with SAB-C1q reactivity.
PMCID: PMC3628631  PMID: 23142561
HLA antibody; complement binding; antibody mediated rejection; heart transplantation; virtual crossmatch
17.  Genetic Variability in Beta-Defensins Is Not Associated with Susceptibility to Staphylococcus aureus Bacteremia 
PLoS ONE  2012;7(2):e32315.
Human beta-defensins are key components of human innate immunity to a variety of pathogens, including Staphylococcus aureus. The aim of the present study was to investigate a potential association between gene variations in DEFB1 and DEFB103/DEFB4 and the development of S. aureus bacteremia (SAB) employing a case-control design.
Cases were unique patients with documented SAB, identified with the National S. aureus Bacteremia Register, a comprehensive dataset of all episodes of community associated-SABs (CA-SAB) occurring in children (≤20 yrs) in Denmark from 1990 to 2006. Controls were age-matched healthy individuals with no history of SAB. DNA obtained from cases and controls using the Danish Newborn Screening Biobank were genotyped for functional polymorphisms of DEFB1 by Sanger sequencing and copy number variation of the DEFB103 and DEFB4 genes using Pyrosequencing-based Paralogue Ratio Test (P-PRT).
193 ethnic Danish SAB cases with 382 age-matched controls were used for this study. S. aureus isolates represented a variety of bacterial (i.e., different spa types) types similar to SAB isolates in general. DEFB1 minor allele frequencies of rs11362 (cases vs. controls 0.47/0.44), rs1800972 (0.21/0.24), and rs1799946 (0.32/0.33) were not significantly different in cases compared with controls. Also, DEFB4/DEFB103 gene copy numbers (means 4.83/4.92) were not significantly different in cases compared with controls.
Using a large, unique cohort of pediatric CA-SAB, we found no significant association between DEFB1 genetic variation or DEFB4/DEFB103 gene copy number and susceptibility for SAB.
PMCID: PMC3285211  PMID: 22384213
18.  Persistent Staphylococcus aureus Bacteremia 
Medicine  2013;92(2):98-108.
Persistent Staphylococcus aureus bacteremia (SAB) that fails to respond to appropriate antibiotic therapy is associated with poor outcomes. Comprehensive prospective studies on risk factors and outcomes of persistent bacteremia are limited. We investigated outcomes and risk factors encompassing clinical, pharmacokinetic, microbiologic, and genotypic characteristics associated with persistent bacteremia using a case-control study nested in a prospective cohort of patients with SAB at a tertiary-care hospital from August 2008 through September 2010. We compared the clinical characteristics, management, and outcomes of patients with persistent bacteremia (≥7 d) with controls with resolving bacteremia (<3 d). To detect associations between microbiologic and genotypic characteristics of methicillin-resistant S. aureus (MRSA) isolates and persistent bacteremia, we determined the heteroresistance phenotype, SCCmec type, agr genotype and functionality, multilocus sequence typing, and presence of 41 virulence genes. Our cohort consisted of 483 patients; 76 (15.7%) had persistent bacteremia, 212 (43.5%) had resolving bacteremia. In the multivariate analysis, independent risk factors associated with persistent bacteremia were community-onset bacteremia (odds ratio [OR], 2.91; 95% confidence interval [CI], 1.24–6.87), bone and joint infection (OR, 5.26; 95% CI, 1.45–19.03), central venous catheter-related infection (OR, 3.36; 95% CI, 1.47–7.65), metastatic infection (OR, 36.22; 95% CI, 12.71–103.23), and methicillin resistance (OR, 16.99; 95% CI, 5.53–52.15). For patients with eradicable foci, delay (>3 d) in the removal of the infection focus was significantly associated with persistent bacteremia (OR, 2.18; 95% CI, 1.05–4.55). There were no significant associations of persistent bacteremia with high vancomycin minimal inhibitory concentration, vancomycin heteroresistance, and microbiologic/genotypic characteristics of MRSA isolates. However, initial vancomycin trough level <15 mg/L was an independent risk factor for persistent MRSA bacteremia (OR, 4.25; 95% CI, 1.51–11.96) in the multivariate analysis. Clinical outcomes were significantly worse for patients with persistent bacteremia. Relapse of bacteremia and attributable mortality within 12 weeks after SAB were significantly higher in patients with persistent bacteremia than in those with resolving bacteremia (9.2% [7/76] vs. 2.4% [5/212], p = 0.02 and 21.1% [16/76] vs. 9.4% [20/212], p = 0.009, respectively).
In conclusion, patients with SAB should be given early aggressive treatment strategies, including early source control and maintenance of a vancomycin trough level ≥15 mg/L, to reduce the risk of persistent bacteremia.
PMCID: PMC4553980  PMID: 23429353
19.  Effect of Statin Therapy in the Outcome of Bloodstream Infections Due to Staphylococcus aureus: A Prospective Cohort Study 
PLoS ONE  2013;8(12):e82958.
Statins have pleiotropic effects that could influence the prevention and outcome of some infectious diseases. There is no information about their specific effect on Staphylococcus aureus bacteremia (SAB).
A prospective cohort study including all SAB diagnosed in patients aged ≥18 years admitted to a 950-bed tertiary hospital from March 2008 to January 2011 was performed. The main outcome variable was 14-day mortality, and the secondary outcome variables were 30-day mortality, persistent bacteremia (PB) and presence of severe sepsis or septic shock at diagnosis of SAB. The effect of statin therapy at the onset of SAB was studied by multivariate logistic regression and Cox regression analysis, including a propensity score for statin therapy.
We included 160 episodes. Thirty-three patients (21.3%) were receiving statins at the onset of SAB. 14-day mortality was 21.3%. After adjustment for age, Charlson index, Pitt score, adequate management, and high risk source, statin therapy had a protective effect on 14-day mortality (adjusted OR = 0.08; 95% CI: 0.01–0.66; p = 0.02), and PB (OR = 0.89; 95% CI: 0.27–1.00; p = 0.05) although the effect was not significant on 30-day mortality (OR = 0.35; 95% CI: 0.10–1.23; p = 0.10) or presentation with severe sepsis or septic shock (adjusted OR = 0.89; CI 95%: 0.27–2.94; p = 0.8). An effect on 30-day mortality could neither be demonstrated on Cox analysis (adjusted HR = 0.5; 95% CI: 0.19–1.29; p = 0.15).
Statin treatment in patients with SAB was associated with lower early mortality and PB. Randomized studies are necessary to identify the role of statins in the treatment of patients with SAB.
PMCID: PMC3871563  PMID: 24376617
20.  Incidence and Risk Factors of Ocular Infection Caused by Staphylococcus aureus Bacteremia 
Staphylococcus aureus bacteremia (SAB) often leads to ocular infections, including endophthalmitis and chorioretinitis. However, the incidence, risk factors, and outcomes of ocular infections complicated by SAB are largely unknown. We retrospectively analyzed the incidence and risk factors of ocular involvement in a prospective cohort of patients with SAB at a tertiary-care hospital. Ophthalmologists reviewed the fundoscopic findings and classified the ocular infections as endophthalmitis or chorioretinitis. During the 5-year study period, 1,109 patients had SAB, and data for 612 (55%) who underwent ophthalmic examinations within 14 days after SAB onset were analyzed. Of those 612 patients, 56 (9% [95% confidence interval [CI], 7 to 12%]) had ocular involvement, including 15 (2.5%) with endophthalmitis and 41 (6.7%) with chorioretinitis. In a multivariate analysis, infective endocarditis (adjusted odds ratio [aOR], 5.74 [95% CI, 2.25 to 14.64]) and metastatic infection (aOR, 2.38 [95% CI, 1.29 to 4.39]) were independent risk factors for ocular involvement. Of the 47 patients with ocular involvement who could communicate, only 17 (36%) had visual disturbances. Two-thirds of the patients with endophthalmitis (10/15 patients) were treated with intravitreal antibiotics combined with parenteral antibiotics, whereas all of the patients with chorioretinitis were treated only with systemic antibiotics. No patients became blind. Among 42 patients for whom follow-up assessments were available, the ocular lesions improved in 29 (69%) but remained the same in the others. Ocular involvement was independently associated with death within 30 days after SAB onset. Ocular involvement is not uncommon among patients with SAB. Routine ophthalmic examinations should be considered for patients with infective endocarditis or metastatic infections caused by SAB.
PMCID: PMC4808144  PMID: 26824952
21.  Outcome of Community-Acquired Staphylococcus aureus Bacteraemia in Patients with Diabetes: A Historical Population-Based Cohort Study 
PLoS ONE  2016;11(4):e0153766.
Patients with diabetes (DM) experience increased risk of Staphylococcus aureus bacteraemia (SAB), but the prognostic impact of diabetes in patients with SAB remain unclear. Therefore, we investigated 30-day all-cause mortality in patients with and without DM.
Population-based medical databases were used to conduct a cohort study of all adult patients with community-acquired SAB in Northern Denmark, 2000–2011. Using Cox proportional hazards regression, we computed hazard ratios as estimates of 30-day mortality rate ratios (MRRs) among patients with and without DM. We further investigated whether the prognostic impact of DM differed among patients with and without recent preadmission healthcare contacts (within 30 days of the current hospitalization) and by age, sex, marital status, level of comorbidity, and DM-related characteristics (e.g., duration of DM and presence of DM complications).
Among 2638 SAB patients, 713 (27.0%) had DM. Thirty-day cumulative mortality was 25.8% in patients with DM and 24.3% in patients without DM, for an adjusted MRR (aMRR) of 1.01 (95% confidence interval (CI), 0.84–1.20). In analyses with and without recent healthcare contacts, the corresponding aMRRs were 0.84 (95% CI, 0.62–1.14) and 1.13 (95% CI, 0.91–1.41), respectively. Compared to patients without DM, the aMRR was 0.94 (95% CI, 0.74–1.20) for male patients with DM and 1.13 (95% CI, 0.87–1.47) for female patients with DM. The prognostic influence of DM on mortality did not differ notably with age, level of comorbidity, or characteristics of patients with DM.
Patients with DM and community-acquired SAB did not experience higher 30-day mortality than patients without DM.
PMCID: PMC4833306  PMID: 27082873
22.  Increased Age-Dependent Risk of Death Associated With lukF-PV-Positive Staphylococcus aureus Bacteremia 
Open Forum Infectious Diseases  2016;3(4):ofw220.
Panton-Valentine leucocidin is a Staphylococcus aureus virulence factor encoded by lukF-PV and lukS-PV that is infrequent in S aureus bacteremia (SAB), and, therefore, little is known about risk factors and outcome of lukF-PV/lukS-PV-positive SAB.
This report is a register-based nationwide observational cohort study. lukF-PV was detected by polymerase chain reaction. Factors associated with the presence of lukF-PV were assessed by logistic regression analysis. Adjusted 30-day hazard ratios of mortality associated with lukF-PV status were computed by Cox proportional hazards regression analysis.
Of 9490 SAB cases, 129 were lukF-PV-positive (1.4%), representing 14 different clonal complexes. lukF-PV was associated with younger age, absence of comorbidity, and methicillin-resistant S aureus. In unadjusted analysis, mortality associated with lukF-PV-positive SAB was comparable to SAB. However, lukF-PV-positive SAB nonsurvivors were significantly older and had more comorbidity. Consequently, by adjusted analysis, the risk of 30-day mortality was increased by 70% for lukF-PV-positive SAB compared with SAB (hazard ratio, 1.70; 95% confidence interval, 1.20–2.42; P = .003).
lukF-PV-positive SAB is rare in Denmark but associated with a significantly increased risk of mortality. Although the risk of lukF-PV-positive SAB was highest in the younger age groups, >80% of deaths associated with lukF-PV-positive SAB occurred in individuals older than 55 years.
PMCID: PMC5146761  PMID: 27957504
bacteremia; lukF/S-PV; mortality; Panton-Valentine leucocidin; Staphylococcus aureus.
23.  Early oral switch therapy in low-risk Staphylococcus aureus bloodstream infection (SABATO): study protocol for a randomized controlled trial 
Trials  2015;16:450.
Current guidelines recommend that patients with Staphylococcus aureus bloodstream infection (SAB) are treated with long courses of intravenous antimicrobial therapy. This serves to avoid SAB-related complications such as relapses, local extension and distant metastatic foci. However, in certain clinical scenarios, the incidence of SAB-related complications is low. Patients with a low-risk for complications may thus benefit from an early switch to oral medication through earlier discharge and fewer complications of intravenous therapy.
The major objective for the SABATO trial is to demonstrate that in patients with low-risk SAB a switch from intravenous to oral antimicrobial therapy (oral switch therapy, OST) is non-inferior to a conventional course of intravenous therapy (intravenous standard therapy, IST).
The trial is designed as randomized, parallel-group, observer-blinded, clinical non-inferiority trial. The primary endpoint is the occurrence of a SAB-related complication (relapsing SAB, deep-seated infection, and attributable mortality) within 90 days. Secondary endpoints are the length of hospital stay; 14-day, 30-day, and 90-day mortality; and complications of intravenous therapy. Patients with SAB who have received 5 to 7 full days of adequate intravenous antimicrobial therapy are eligible. Main exclusion criteria are polymicrobial bloodstream infection, signs and symptoms of complicated SAB (deep-seated infection, hematogenous dissemination, septic shock, and prolonged bacteremia), the presence of a non-removable foreign body, and severe comorbidity. Patients will receive either OST or IST with a protocol-approved antimicrobial and are followed up for 90 days. Four hundred thirty patients will be randomized 1:1 in two study arms. Efficacy regarding incidence of SAB-related complications is tested sequentially with a non-inferiority margin of 10 and 5 percentage points.
The SABATO trial assesses whether early oral switch therapy is safe and effective for patients with low-risk SAB. Regardless of the result, this pragmatic trial will strongly influence the standard of care in SAB.
Trial registration NCT01792804 registered 13 February 2013; German Clinical trials register DRKS00004741 registered 4 October 2013, EudraCT 2013-000577-77. First patient randomized on 20 December 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0973-x) contains supplementary material, which is available to authorized users.
PMCID: PMC4600306  PMID: 26452342
Oral switch therapy; Intravenous; Antimicrobial; Bloodstream infection; Bacteremia; Staphylococcus aureus; Randomized controlled trial; Pragmatic trial
24.  Stable incidence and continued improvement in short term mortality of Staphylococcus aureus bacteraemia between 1995 and 2008 
BMC Infectious Diseases  2012;12:260.
The objective of this study was to assess temporal changes in incidence and short term mortality of Staphylococcus aureus bacteraemia (SAB) from 1995 through 2008.
The study was conducted as a nation-wide observational cohort study with matched population controls. The setting was hospitalized patients in Denmark 1995-2008. Uni- and multivariate analyses were used to analyze the hazard of death within 30 days from SAB.
A total of 16 330 cases of SAB were identified: 57% were hospital-associated (HA), 31% were community-acquired (CA) and 13% were of undetermined acquisition. The overall adjusted incidence rate remained stable at 23 per 100 000 population but the proportion of SAB cases older than 75 years increased significantly. Comorbidity in the cohort as measured by Charlson comorbidity index (CCI) score and alcohol-related diagnoses increased over the study period. In contrast, among the population controls the CCI remained stable and alcohol-related diagnoses increased slightly. For HA SAB crude 30-day mortality decreased from 27.8% to 21.8% (22% reduction) whereas the change for CA SAB was small (26.5% to 25.8%). By multivariate Cox regression, age, female sex, time period, CCI score and alcohol-related diagnoses were associated with increased mortality regardless of mode of acquisition.
Throughout a 14-year period the overall incidence of SAB remained stable while the overall short term prognosis continued to improve despite increased age and accumulation of comorbidity in the cohort. However, age and comorbidity were strong prognostic indicators for short term mortality.
PMCID: PMC3507819  PMID: 23075215
Bacteraemia; Epidemiology; Incidence; Mortality; Comorbidity; Alcoholism; Staphylococcus aureus; Charlson comorbidity index
25.  A genome-wide association study of variants associated with acquisition of Staphylococcus aureus bacteremia in a healthcare setting 
Humans vary in their susceptibility to acquiring Staphylococcus aureus infection, and research suggests that there is a genetic basis for this variability. Several recent genome-wide association studies (GWAS) have identified variants that may affect susceptibility to infectious diseases, demonstrating the potential value of GWAS in this arena.
We conducted a GWAS to identify common variants associated with acquisition of S. aureus bacteremia (SAB) resulting from healthcare contact. We performed a logistic regression analysis to compare patients with healthcare contact who developed SAB (361 cases) to patients with healthcare contact in the same hospital who did not develop SAB (699 controls), testing 542,410 SNPs and adjusting for age (by decade), sex, and 6 significant principal components from our EIGENSTRAT analysis. Additionally, we evaluated the joint effect of the host and pathogen genomes in association with severity of SAB infection via logistic regression, including an interaction of host SNP with bacterial genotype, and adjusting for age (by decade), sex, the 6 significant principal components, and dialysis status. Bonferroni corrections were applied in both analyses to control for multiple comparisons.
Ours is the first study that has attempted to evaluate the entire human genome for variants potentially involved in the acquisition or severity of SAB. Although this study identified no common variant of large effect size to have genome-wide significance for association with either the risk of acquiring SAB or severity of SAB, the variant (rs2043436) most significantly associated with severity of infection is located in a biologically plausible candidate gene (CDON, a member of the immunoglobulin family) and may warrant further study.
The genetic architecture underlying SAB is likely to be complex. Future investigations using larger samples, narrowed phenotypes, and advances in both genotyping and analytical methodologies will be important tools for identifying causative variants for this common and serious cause of healthcare-associated infection.
PMCID: PMC3928605  PMID: 24524581
Genomics; Genome-wide association study; Case–control study; Staphylococcus aureus; Bacteremia; Gram-positive bacterial infections; Polymorphism, single-nucleotide; Infections; Nosocomial; Cross infection

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