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1.  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
2.  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
HIV medicine  2008;9(10):858-862.
To define the incidence and risk factors for methicillin resistant Staphylococcus aureus (MRSA) bacteremia in an urban HIV-infected population.
A retrospective cohort study and nested, case-control analyses set in an urban HIV outpatient clinic in Baltimore.
Over a four-year period (2000–2004) the incidence of Staphylococcus aureus bacteremia (SAB) was determined from an electronic database of blood culture results. Risk factors for MRSA bacteremia were assessed over a five-year period (2000–2005) using methicillin sensitive Staphylococcus aureus (MSSA) bacteremia and bacteremia-free controls.
Of 4,607 patients followed for a total of 11,020 person-years (PY) of follow-up, 216 episodes of SAB occurred (incidence: 19.6 cases per 1000 PY.) Of these, 94 cases (43.5%) were methicillin-resistant (MRSA bacteremia incidence: 8.5 per 1000 PY.) The incidence of MRSA bacteremia increased from 5.3 per 1000 PY in 2000–01 to 11.9 per 1000 PY in 2003–04 (p = 0.001). Significant risk factors for MRSA bacteremia included injection drug use (IDU) [Adjusted Odds Ratio (AOR) = 4.61 (95% CI: 2.32–20.72)], end-stage renal disease (ESRD) [7.78 (2.92–20.72)], and CD4 count <200 cells/mm3 at the event. Patients with MRSA were more likely to have ESRD [AOR = 2.89 (1.12–7.49)] and greater immunosuppression than those with MSSA bacteremia.
The incidence of MRSA bacteremia increased from 2000 to 2004 in our HIV-infected cohort. Our data suggest that initial therapy for S. aureus bacteremia in HIV-infected patients, particularly in those with MRSA bacteremia risk factors, may require antimicrobial agents active against MRSA.
PMCID: PMC2581476  PMID: 18754806
HIV; MRSA; Staphylococcus aureus; Bacteremia
4.  Impact of Methicillin-Resistance on Mortality in Children and Neonates with Staphylococcus aureus Bacteremia: A Meta-analysis 
Infection & Chemotherapy  2013;45(2):202-210.
Staphylococcus aureus bacteremia (SAB) is the Staphylococcal infections in blood, one of the most common and fatal bacterial infectious diseases worldwide in adults as well as children or neonates. Recently, some studies have yielded inconsistent findings about the association between methicillin-resistance and mortality in patients with SAB. We performed a meta-analysis to assess the impact of methicillin-resistance on mortality in children or neonates with S. aureus bacteremia.
Materials and Methods
We searched using electronic databases such as Ovid-Medline, EMBASE-Medline, and Cochrane Library, as well as five local databases for published studies during the period of 1 January 2000 to 15 September 2011. Two reviewers independently selected articles in accordance with predetermined criteria and extracted prespecified data based on standardized forms. All cohort studies, which compared in-hospital mortality or SAB-related mortality in children and neonates with methicillin-resistant S. aureus (MRSA) infection to those with methicillin-susceptible S. aureus (MSSA), were included. We conducted meta-analysis using the fixed-effect model to obtain pooled estimates of effect.
Of 2,841 screened studies, seven cohort studies were finally selected for analysis. In children or neonates, MRSA bacteremia was associated with a higher mortality compared with MSSA bacteremia (pooled odds ratio [OR] 2.33, P = 0.0008, 95% confidence interval [CI] 1.42 to 3.82, I2 = 0%). Four studies reported SAB-related mortality, the pooled OR of these studies was 2.03 (P = 0.29, 95% CI 0.55 to 7.53, I2 = 0%). A significant increase in mortality associated with methicillin resistance was found in the subgroup analyses of the studies with only neonates (OR: 2.66, 95% CI: 1.46 to 4.85, P = 0.001), prospectively design ones (OR: 3.20, 95% CI: 1.66 to 6.15, P = 0.0005,), the larger studies (OR: 2.89, 95% CI: 1.62 to 5.16, P = 0.0003) and the higher quality studies (OR: 2.76, 95% CI: 1.50 to 5.06, P = 0.001).
MRSA bacteremia is associated with increased mortality compared with MSSA bacteremia in children or neonates. Due to limited studies for mortality in children or neonates with SAB, further research is needed to evaluate the impact of methicillin resistance on mortality in those populations.
PMCID: PMC3780954  PMID: 24265968
Staphylococcus aureus; Bacteremia; Methicillin Resistance; Mortality; Meta-analysis
5.  The Value of Infectious Diseases Consultation in Staphylococcus aureus Bacteremia 
The American journal of medicine  2010;123(7):631-637.
Staphylococcus aureus bacteremia results in substantial mortality. Infectious diseases specialist consultation can improve adherence to evidence-based management of S. aureus bacteremia, but its effect on mortality is unclear.
We performed a 2-year prospective cohort study of patients with S. aureus bacteremia at a large, tertiary care hospital. Patients who died within 2 days of diagnosis were excluded. Independent risk factors for 28-day mortality were determined.
Among 341 patients with S. aureus bacteremia, 189 (55%) were male; 196 (58%) were Caucasian; 185 (54%) had methicillin-resistant S. aureus; 108 (32%) had nosocomial bacteremia; and 231 (68%) had a central venous catheter at the time of diagnosis. The median age was 56 years (range 22-95). One hundred eleven (33%) patients had an infectious diseases consultation. Fifty-four (16%) patients died with 28 days after diagnosis. Factors associated with mortality were intensive care unit admission ≤ 48 hours after the first positive blood culture [adjusted hazard ratio (aHR), 4.65; 95% confidence interval (CI), 2.65-8.18], cirrhosis (aHR, 4.44; 95% CI, 2.40-8.20), and advanced age (aHR, 1.27 per every 10 years of age; 95% CI, 1.08-1.50). Infectious diseases consultation was associated with a 56% reduction in 28-day mortality (aHR, 0.44; 95% CI, 0.22-0.89).
Only one-third of patients with S. aureus bacteremia in this cohort had an infectious diseases specialist consultation. Infectious diseases consultation was independently associated with a reduction in 28-day mortality. Routine infectious diseases consultation should be considered for patients with S. aureus bacteremia, especially those with higher severity of illness or multiple co-morbidities.
PMCID: PMC3606273  PMID: 20493464
Staphylococcus aureus bacteremia; Mortality; Infectious diseases consultation
6.  Combination therapy with an aminoglycoside for Staphylococcus aureus endocarditis and/or persistent bacteremia is associated with a decreased rate of recurrent bacteremia: a cohort study 
Infection  2011;39(6):549-554.
Although limited data exist on the efficacy and potential risk of synergistic aminoglycoside therapy for persistent Staphylococcus aureus bacteremia and endocarditis, aminoglycosides are frequently used in clinical practice.
As our study population, we included subjects fulfilling the modified Duke criteria for S. aureus endocarditis and/or having greater than 72 h of S. aureus bacteremia. Among these subjects, we compared patients who did and did not receive aminoglycoside therapy for their S. aureus bloodstream infection. These groups were comared for the primary outcome of recurrent bacteremia, as well as for the duration of bacteremia, mortality, complication rate, and incident renal failure.
Eighty-seven subjects fulfilled the inclusion criteria. Of these, 49 received aminoglycoside therapy, whereas 38 did not. There were no significant differences in the baseline characteristics when comparing groups who did or did not receive aminoglycoside therapy. Four (8.2%) subjects treated with aminoglycoside therapy experienced recurrent bacteremia versus nine (23.7%) who did not receive aminoglycoside therapy [relative risk and 95% confidence interval [RR (95%CI)] = 0.51 (0.22–1.17), p = 0.04]. In multivariable analyses, aminoglycoside use remained significantly associated with a decrease in recurrent bacteremia [adjusted odds ratio (OR) (95%CI) = 0.26 (0.07–0.98), p = 0.046]. No significant differences were seen between groups treated with and without an aminoglycoside in terms of the 6-month all-cause mortality (51.0 vs. 42.1%, p = 0.41), complication rate (71.4 vs. 73.7%, p = 0.82), or incident renal failure (54.5 vs. 46.9%, p = 0.54).
The use of combination therapy with an aminoglycoside in persistent S. aureus bacteremia and/or endocarditis may be associated with a lower rate of recurrent bacteremia without significant differences in the incident renal failure.
PMCID: PMC3501533  PMID: 21898120
7.  Bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus: the potential role of daptomycin 
Staphylococcus aureus bacteremia is a common disease with a high risk of mortality and complications. An increasing proportion of cases are methicillin-resistant S.aureus (MRSA), and methicillin-resistance is being observed from both community-acquired bacteremias and in healthcare-associated infections. The duration of bacteremia and transesophageal echocardiographic findings are useful in predicting the likelihood of complications including endocarditis. Therapy with vancomycin has been the mainstay in the treatment of MRSA bacteremias, but is associated with a long duration of bacteremia on therapy and relapses. Loss of susceptibility to vancomycin, due to thickened cell walls and through the acquisition of the vanA gene, has been described. Daptomycin is newly approved lipopeptide that is highly bactericidal against most strains of MRSA. In a randomized trial, daptomycin was demonstrated to be effective in the treatment of S. aureus bacteremia and right-sided endocarditis. However treatment failures associated with isolates with daptomycin non-susceptibility are reported, and there is a correlation between isolates with reduced vancomycin susceptibility and reduced daptomycin susceptibility. Daptomycin is a useful alternative to vancomycin in the therapy of MRSA bacteremia and endocarditis. However the appropriate role of daptomycin in optimizing therapy with MRSA bacteremia and endocarditis remains to be elucidated.
PMCID: PMC2374935  PMID: 18472990
methicillin-resistant Staphylococcus aureus; bacteremia; endocarditis; daptomycin
8.  Temporal Trends in Incidence of Staphylococcus aureus Bacteremia in Olmsted County, Minnesota, 1998 to 2005: A Population-Based Study 
There is a paucity of population-based studies on Staphylococcus aureus bacteremia (SAB) in the United States. We determined the incidence and trends of SAB in Olmsted County, Minnesota, over an 8-year period.
A retrospective, population-based, cohort study was done to evaluate the initial episodes of SAB occurring in adult residents of Olmsted County, Minnesota, from January 1, 1998 through December 31, 2005 using the microbiology databases at Mayo Clinic and Olmsted Medical Center.
Among 247 evaluable adult patients with SAB, who were included in the incidence calculation, 57.9% were males and the median age was 72.1 years (range 19.5 - 98.5). Bacteremic episodes were classified according to acquisition site: 23.5% were nosocomial (NA-SAB); 58.7% were healthcare-associated (HCA-SAB); and 23.8% were community-acquired (CA-SAB). MRSA constituted 31.6% of the cases. No community-acquired MRSA bacteremia was noted. The age-adjusted incidence rate of SAB was 28.3/100,000 person-years for females, and 53.5/100,000 person-years for males, with an age- and gender-adjusted rate of 38.2/100,000 person-years. The age- and gender-adjusted incidence of NA-SAB, HCA-SAB, and CA-SAB was 9.0, 22.6 and 6.6/100,000 person-years, respectively. The age- and gender-adjusted incidence of MSSA was 25.4/100,000 and of MRSA was 12.4/100,000 person-years. Overall, the incidence rate increased with age, but not over calendar year. The exception was MRSA-B, which increased at a rate of 19.8% (± 5.5%) per year during the study period.
The incidence of SAB in adults remained stable in Olmsted County, Minnesota, from 1998 to 2005, but the proportion due to MRSA has significantly increased over the 8-year period.
PMCID: PMC3050712  PMID: 19916797
Incidence; Staphylococcus aureus; bacteremia; population-based; Olmsted County
9.  Quantifying Cost-Effectiveness of Controlling Nosocomial Spread of Antibiotic-Resistant Bacteria: The Case of MRSA 
PLoS ONE  2010;5(7):e11562.
The costs and benefits of controlling nosocomial spread of antibiotic-resistant bacteria are unknown.
We developed a mathematical algorithm to determine cost-effectiveness of infection control programs and explored the dynamical interactions between different epidemiological variables and cost-effectiveness. The algorithm includes occurrence of nosocomial infections, attributable mortality, costs and efficacy of infection control and how antibiotic-resistant bacteria affect total number of infections: do infections with antibiotic-resistant bacteria replace infections caused by susceptible bacteria (replacement scenario) or occur in addition to them (addition scenario). Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was used for illustration using observational data on S. aureus bacteremia (SAB) in our hospital (n = 189 between 2001–2004, all being methicillin-susceptible S. aureus [MSSA]).
In the replacement scenario, the costs per life year gained range from € 45,912 to € 6590 for attributable mortality rates ranging from 10% to 50%. Using € 20,000 per life year gained as a threshold, completely preventing MRSA would be cost-effective in the replacement scenario if attributable mortality of MRSA is ≥21%. In the addition scenario, infection control would be cost saving along the entire range of estimates for attributable mortality.
Cost-effectiveness of controlling antibiotic-resistant bacteria is highly sensitive to the interaction between infections caused by resistant and susceptible bacteria (addition or replacement) and attributable mortality. In our setting, controlling MRSA would be cost saving for the addition scenario but would not be cost-effective in the replacement scenario if attributable mortality would be <21%.
PMCID: PMC2905392  PMID: 20661278
10.  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
11.  Staphylococcus aureus cholecystitis: a report of three cases with review of the literature. 
Infection of the hepatobiliary system is most commonly due to enteric bacteria. We report three unusual cases of acute cholecystitis in which Staphylococcus aureus was the primary pathogen. Infection of the gallbladder with this organism has been rarely described and may be associated with gallstones and obstructive disease as well as acalculous cholecystitis in the setting of staphylococcal bacteremia and endocarditis. Two of our patients had multiple chronic medical conditions and were infected with oxacillin-resistant S. aureus (ORSA) suggesting nosocomial acquisition. Including our cases with a review of the literature, three of nine reports of S. aureus cholecystitis were associated with infectious endocarditis. Thus, the finding of S. aureus cholecystitis with bacteremia is rare and should prompt an investigation for a possible endovascular focus of infection.
PMCID: PMC2588812  PMID: 14580109
12.  Multicenter Evaluation of the Clinical Outcomes of Daptomycin with and without Concomitant β-Lactams in Patients with Staphylococcus aureus Bacteremia and Mild to Moderate Renal Impairment 
Patients with underlying renal disease may be vulnerable to vancomycin-mediated nephrotoxicity and Staphylococcus aureus bacteremia treatment failure. In light of recent data demonstrating the successful use of β-lactam plus daptomycin in very difficult cases of S. aureus bacteremia, we examined safety and clinical outcomes for patients who received daptomycin with or without concomitant β-lactams. We identified 106 patients who received daptomycin for S. aureus bacteremia, had mild or moderate renal insufficiency according to FDA criteria, and enrolled in the Cubicin Outcomes Registry and Experience (CORE), a multicenter registry, from 2005 to 2009. Daptomycin treatment success was 81%. Overall treatment efficacy was slightly enhanced with the addition of a β-lactam (87% versus 78%; P = 0.336), but this trend was most pronounced for bacteremia associated with endocarditis or bone/joint infection or bacteremia from an unknown source (90% versus 57%; P = 0.061). Factors associated with reduced daptomycin efficacy (by logistic regression) were an unknown source of bacteremia (odds ratio [OR] = 7.59; 95% confidence interval [CI] = 1.55 to 37.2), moderate renal impairment (OR = 9.11; 95% CI = 1.46 to 56.8), and prior vancomycin failure (OR = 11.2; 95% CI = 1.95 to 64.5). Two patients experienced an increase in creatine phosphokinase (CPK) that resolved after stopping daptomycin. No patients developed worsening renal insufficiency related to daptomycin. In conclusion, daptomycin appeared to be effective and well tolerated in patients with S. aureus bacteremia and mild to moderate renal insufficiency. Daptomycin treatment efficacy might be enhanced with β-lactam combination therapy in primary endovascular and bone/joint infections. Additional studies will be necessary to confirm these findings.
PMCID: PMC3591880  PMID: 23254428
13.  USA300 Methicillin-Resistant Staphylococcus aureus Bacteremia and the Risk of Severe Sepsis: Is USA300 MRSA Associated with More Severe Infections? 
USA300 methicillin-resistant Staphylococcus aureus (MRSA) is increasing as a cause of severe community-associated bacteremic infections. We assessed severe sepsis in response to infection in patients with USA300 MRSA compared to non-USA300 MRSA bacteremia.
A cohort study was conducted from 1997–2008 comparing sepsis in response to infection in 271 patients with MRSA bacteremia from four VA hospitals.
Sixty-seven (25%) patients with MRSA bacteremia were USA300 MRSA; 204 (75%) were non-USA300 MRSA. The proportion of MRSA bacteremia caused by USA300 MRSA increased over time (χ2 p<0.0001). Adjusting for age and nosocomial infection, patients with USA300 MRSA bacteremia were more likely to have severe sepsis or septic shock in response to infection than patients with non-USA300 MRSA bacteremia (adjusted Relative Risk=1.82; 95% CI: 1.16–2.87; p=0.01).
This suggests that patients with USA300 MRSA are more likely to develop severe sepsis in response to their infection, which could be due to host or bacterial differences.
PMCID: PMC3118841  PMID: 21558047
14.  Analysis of Methicillin Resistance among Staphylococcus aureus Blood Isolates in an Emergency Department 
Journal of Korean Medical Science  2007;22(4):682-686.
The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has become of great concern in both hospital and community settings. To evaluate the prevalence and risk factors for methicillin resistance among Staphylococcus aureus, blood isolates in our Emergency Department (ED) were collected. All patients with S. aureus bacteremia (SAB) who presented to the ED from January 2000 to August 2005 were included, and a retrospective study was performed. A total of 231 patients with SAB were enrolled (median age, 59 yr; M:F, 125:106). Among these patients, methicillin-resistant strains accounted for 27.3% (63 patients). Catheter-related infection was the most frequent primary site of SAB (39.0%), followed by skin and soft tissue infection (16.5%). In multivariate analysis, recent surgery (OR, 3.41; 95% CI, 1.48-7.85), recent hospitalization (2.17; 1.06-4.62), and older age (≥61 yr) (2.39; 1.25-4.57) were independently associated with the acquisition of methicillin-resistant strains. When antimicrobial therapy is considered for the treatment of a patient with suspected SAB, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage for patients with risk factors: older age, recent hospitalization, and recent surgery.
PMCID: PMC2693820  PMID: 17728510
Staphylococcus aureus; Community-acquired Infections; Methicillin Resistance; Risk Factors
15.  Nosocomial infection update. 
Emerging Infectious Diseases  1998;4(3):416-420.
Historically, staphylococci, pseudomonads, and Escherichia coli have been the nosocomial infection troika; nosocomial pneumonia, surgical wound infections, and vascular access-related bacteremia have caused the most illness and death in hospitalized patients; and intensive care units have been the epicenters of antibiotic resistance. Acquired antimicrobial resistance is the major problem, and vancomycin-resistant Staphylococcus aureus is the pathogen of greatest concern. The shift to outpatient care is leaving the most vulnerable patients in hospitals. Aging of our population and increasingly aggressive medical and surgical interventions, including implanted foreign bodies, organ transplantations, and xenotransplantation, create a cohort of particularly susceptible persons. Renovation of aging hospitals increases risk of airborne fungal and other infections. To prevent and control these emerging nosocomial infections, we need to increase national surveillance, "risk adjust" infection rates so that interhospital comparisons are valid, develop more noninvasive infection-resistant devices, and work with health-care workers on better implementation of existing control measures such as hand washing.
PMCID: PMC2640303  PMID: 9716961
16.  Corynebacterium endocarditis species-specific risk factors and outcomes 
Corynebacterium species are recognized as uncommon agents of endocarditis, but little is known regarding species-specific risk factors and outcomes in Corynebacterium endocarditis.
Case report and Medline search of English language journals for cases of Corynebacterium endocarditis. Inclusion criteria required that cases be identified as endocarditis, having persistent Corynebacterium bacteremia, murmurs described by the authors as identifying the affected valve, or vegetations found by echocardiography or in surgical or autopsy specimens. Cases also required patient-specific information on risk factors and outcomes (age, gender, prior prosthetic valve, other prior nosocomial risk factors (infected valve, involvement of native versus prosthetic valve, need for valve replacement, and death) to be included in the analysis. Publications of Corynebacterium endocarditis which reported aggregate data were excluded. Univariate analysis was conducted with chi-square and t-tests, as appropriate, with p = 0.05 considered significant.
129 cases of Corynebacterium endocarditis involving nine species met inclusion criteria. Corynebacterium endocarditis typically infects the left heart of adult males and nearly one third of patients have underlying valvular disease. One quarter of patients required valve replacement and one half of patients died. Toxigenic C. diphtheriae is associated with pediatric infections (p < 0.001). Only C. amycolatum has a predilection for women (p = 0.024), while C. pseudodiphtheriticum infections are most frequent in men (p = 0.023). C. striatum, C. jeikeium and C. hemolyticum are associated with nosocomial risk factors (p < 0.001, 0.028, and 0.024, respectively). No species was found to have a predilection for any particular heart valve. C. pseudodiphtheriticum is associated with a previous prosthetic valve replacement (p = 0.004). C. jeikeium infections are more likely to require valve replacement (p = 0.026). Infections involving toxigenic C. diphtheriae and C. pseudodiphtheriticum are associated with decreased survival (p = 0.001 and 0.032, respectively).
We report the first analysis of species-specific risk factors and outcomes in Corynebacterium endocarditis. In addition to species-specific associations with age, gender, prior valvular diseases, and other nosocomial risk factors, we found differences in rates of need for valve replacement and death. This review highlights the seriousness of these infections, as up to 28% of patients required valve replacement and 43.5% died.
PMCID: PMC1804271  PMID: 17284316
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.  Addition of Rifampin to Standard Therapy for Treatment of Native Valve Infective Endocarditis Caused by Staphylococcus aureus▿  
Staphylococcus aureus is a common cause of native valve infective endocarditis (IE). Rifampin is often added to traditional therapy for the management of serious S. aureus infections. There are no large, prospective studies documenting the safety and efficacy of adjunctive therapy with rifampin for treatment of native valve S. aureus IE. We reviewed all cases of definite native valve S. aureus IE confirmed by modified Duke criteria in a large urban hospital between 1 January 2004 and 31 December 2005. A retrospective cohort analysis was used to assess the impact of the addition of rifampin to standard therapy. There were 42 cases of S. aureus IE treated with the addition of rifampin and 42 controls. Cases received a median of 20 days of rifampin (range, 14 to 48 days). Rifampin-resistant S. aureus isolates developed in nine cases who received rifampin before clearance of bacteremia (56%), while significant hepatic transaminase elevations also occurred in nine cases, all of whom had hepatitis C infection. Unrecognized significant drug-drug interactions with rifampin occurred frequently (52%). Cases were more likely to have a longer duration of bacteremia (5.2 versus 2.1 days; P < 0.001) and were less likely to survive (79% versus 95%; P = 0.048) than controls. Our results suggest that the potential for hepatotoxicity, drug-drug interactions, and the emergence of resistant S. aureus isolates warrants a careful risk-benefit assessment before adding rifampin to standard antibiotic treatment of native valve S. aureus IE until further clinical studies are performed.
PMCID: PMC2443910  PMID: 18474578
19.  Microbiological Characteristics of Community-Associated Staphylococcus aureus Causing Uncomplicated Bacteremia and Infective Endocarditis▿ †  
Journal of Clinical Microbiology  2009;48(1):292-294.
Staphylococcus aureus is an important cause of community-associated bacteremia (SAB) and infective endocarditis (IE). No significant differences in distribution or frequency of genes encoding virulence factors, including genes encoding adhesins, were found between isolates from the IE and SAB groups (12 IE and 10 SAB patients).
PMCID: PMC2812277  PMID: 19846649
20.  Increased Mortality with Accessory Gene Regulator (agr) Dysfunction in Staphylococcus aureus among Bacteremic Patients ▿ †  
Accessory gene regulator (agr) dysfunction in Staphylococcus aureus has been associated with a longer duration of bacteremia. We aimed to assess the independent association between agr dysfunction in S. aureus bacteremia and 30-day in-hospital mortality. This retrospective cohort study included all adult inpatients with S. aureus bacteremia admitted between 1 January 2003 and 30 June 2007. Severity of illness prior to culture collection was measured using the modified acute physiology score (APS). agr dysfunction in S. aureus was identified semiquantitatively by using a δ-hemolysin production assay. Cox proportional hazard models were used to measure the association between agr dysfunction and 30-day in-hospital mortality, statistically adjusting for patient and pathogen characteristics. Among 814 patient admissions complicated by S. aureus bacteremia, 181 (22%) patients were infected with S. aureus isolates with agr dysfunction. Overall, 18% of patients with agr dysfunction in S. aureus died, compared to 12% of those with functional agr in S. aureus (P = 0.03). There was a trend toward higher mortality among patients with S. aureus with agr dysfunction (adjusted hazard ratio [HR], 1.34; 95% confidence interval [CI], 0.87 to 2.06). Among patients with the highest APS (scores of >28), agr dysfunction in S. aureus was significantly associated with mortality (adjusted HR, 1.82; 95% CI, 1.03 to 3.21). This is the first study to demonstrate an independent association between agr dysfunction and mortality among severely ill patients. The δ-hemolysin assay examining agr function may be a simple and inexpensive approach to predicting patient outcomes and potentially optimizing antibiotic therapy.
PMCID: PMC3067101  PMID: 21173172
21.  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
22.  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
23.  Staphylococcus aureus bloodstream infections in children: A population-based assessment 
Paediatrics & Child Health  2011;16(5):276-280.
Although Staphylococcus aureus is a major cause of bloodstream infections, population-based data on these infections in children are limited.
To describe the epidemiology of S aureus bacteremia in children.
Population-based surveillance for all incident S aureus bacteremias was conducted among children (18 years of age or younger) living in the Calgary Health Region (Alberta) from 2000 to 2006.
During the seven-year study, 120 S aureus bloodstream infections occurred among 119 patients; 27% were nosocomial, 18% health care associated and 56% community acquired. The annual incidence was 6.5/100,000 population and 0.094/1000 live births. A total of 52% had a significant underlying condition, and this was higher for nosocomial cases. Bone and joint (40%), bacteremia without a focus (33%), and skin and soft tissue infections (15%) were the most common clinical syndromes. Infections due to methicillin-resistant S aureus were uncommon (occurring in one infection) and three patients (2.5%) died.
S aureus bacteremia is an important cause of morbidity in the paediatric age group. Underlying medical conditions and implanted devices are important risk factors. Methicillin-resistant S aureus and mortality rates are low.
PMCID: PMC3114991  PMID: 22547946
Bloodstream infection; Clinical syndromes; Staphylococcus aureus
24.  Prevalence of infective endocarditis in patients with Staphylococcus aureus bacteraemia: the value of screening with echocardiography 
Staphylococcus aureus infective endocarditis (IE) is a critical medical condition associated with a high morbidity and mortality. In the present study, we prospectively evaluated the importance of screening with echocardiography in an unselected S. aureus bacteraemia (SAB) population.
Methods and results
From 1 January 2009 to 31 August 2010, a total of 244 patients with SAB at six Danish hospitals underwent screening echocardiography. The inclusion rate was 73% of all eligible patients (n= 336), and 53 of the 244 included patients (22%; 95% CI: 17–27%) were diagnosed with definite IE. In patients with native heart valves the prevalence was 19% (95% CI: 14–25%) compared with 38% (95% CI: 20–55%) in patients with prosthetic heart valves and/or cardiac rhythm management devices (P= 0.02). No difference was found between Main Regional Hospitals and Tertiary Cardiac Hospitals, 20 vs. 23%, respectively (NS). The prevalence of IE in high-risk patients with one or more predisposing condition or clinical evidence of IE were significantly higher compared with low-risk patients with no additional risk factors (38 vs. 5%; P < 0.001). IE was associated with a higher 6 months mortality, 14(26%) vs. 28(15%) in SAB patients without IE, respectively (P < 0.05).
SAB patients carry a high risk for development of IE, which is associated with a worse prognosis compared with uncomplicated SAB. The presenting symptoms and clinical findings associated with IE are often non-specific and echocardiography should always be considered as part of the initial evaluation of SAB patients.
PMCID: PMC3117467  PMID: 21685200
Infective endocarditis; Echocardiography; Staphylococcus aureus; Screening
25.  Community-associated Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis among HIV Patients: A cohort study 
BMC Infectious Diseases  2011;11:298.
HIV patients are at increased risk of development of infections and infection-associated poor health outcomes. We aimed to 1) assess the prevalence of USA300 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) among HIV-infected patients with S. aureus bloodstream infections and. 2) determine risk factors for infective endocarditis and in-hospital mortality among patients in this population.
All adult HIV-infected patients with documented S. aureus bacteremia admitted to the University of Maryland Medical Center between January 1, 2003 and December 31, 2005 were included. CA-MRSA was defined as a USA300 MRSA isolate with the MBQBLO spa-type motif and positive for both the arginine catabolic mobile element and Panton-Valentin Leukocidin. Risk factors for S. aureus-associated infective endocarditis and mortality were determined using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Potential risk factors included demographic variables, comorbid illnesses, and intravenous drug use.
Among 131 episodes of S. aureus bacteremia, 85 (66%) were MRSA of which 47 (54%) were CA-MRSA. Sixty-three patients (48%) developed endocarditis and 10 patients (8%) died in the hospital on the index admission Patients with CA-MRSA were significantly more likely to develop endocarditis (OR = 2.73, 95% CI = 1.30, 5.71). No other variables including comorbid conditions, current receipt of antiretroviral therapy, pre-culture severity of illness, or CD4 count were significantly associated with endocarditis and none were associated with in-hospital mortality.
CA-MRSA was significantly associated with an increased incidence of endocarditis in this cohort of HIV patients with MRSA bacteremia. In populations such as these, in which the prevalence of intravenous drug use and probability of endocarditis are both high, efforts must be made for early detection, which may improve treatment outcomes.
PMCID: PMC3214174  PMID: 22040268

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