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1.  Geographic Distribution of Staphylococcus aureus Causing Invasive Infections in Europe: A Molecular-Epidemiological Analysis 
PLoS Medicine  2010;7(1):e1000215.
Hajo Grundmann and colleagues describe the development of a new interactive mapping tool for analyzing the spatial distribution of invasive Staphylococcus aureus clones.
Staphylococcus aureus is one of the most important human pathogens and methicillin-resistant variants (MRSAs) are a major cause of hospital and community-acquired infection. We aimed to map the geographic distribution of the dominant clones that cause invasive infections in Europe.
Methods and Findings
In each country, staphylococcal reference laboratories secured the participation of a sufficient number of hospital laboratories to achieve national geo-demographic representation. Participating laboratories collected successive methicillin-susceptible (MSSA) and MRSA isolates from patients with invasive S. aureus infection using an agreed protocol. All isolates were sent to the respective national reference laboratories and characterised by quality-controlled sequence typing of the variable region of the staphylococcal spa gene (spa typing), and data were uploaded to a central database. Relevant genetic and phenotypic information was assembled for interactive interrogation by a purpose-built Web-based mapping application. Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 countries collected 2,890 MSSA and MRSA isolates from patients with invasive S. aureus infection. A wide geographical distribution of spa types was found with some prevalent in all European countries. MSSA were more diverse than MRSA. Genetic diversity of MRSA differed considerably between countries with dominant MRSA spa types forming distinctive geographical clusters. We provide evidence that a network approach consisting of decentralised typing and visualisation of aggregated data using an interactive mapping tool can provide important information on the dynamics of MRSA populations such as early signalling of emerging strains, cross border spread, and importation by travel.
In contrast to MSSA, MRSA spa types have a predominantly regional distribution in Europe. This finding is indicative of the selection and spread of a limited number of clones within health care networks, suggesting that control efforts aimed at interrupting the spread within and between health care institutions may not only be feasible but ultimately successful and should therefore be strongly encouraged.
Please see later in the article for the Editors' Summary
Editors' Summary
The bacterium Staphylococcus aureus lives on the skin and in the nose of about a third of healthy people. Although S. aureus usually coexists peacefully with its human carriers, it is also an important disease-causing organism or pathogen. If it enters the body through a cut or during a surgical procedure, S. aureus can cause minor infections such as pimples and boils or more serious, life-threatening infections such as blood poisoning and pneumonia. Minor S. aureus infections can be treated without antibiotics—by draining a boil, for example. Invasive infections are usually treated with antibiotics. Unfortunately, many of the S. aureus clones (groups of bacteria that are all genetically related and descended from a single, common ancestor) that are now circulating are resistant to methicillin and several other antibiotics. Invasive methicillin-resistant S. aureus (MRSA) infections are a particular problem in hospitals and other health care facilities (so-called hospital-acquired MRSA infections), but they can also occur in otherwise healthy people who have not been admitted to a hospital (community-acquired MRSA infections).
Why Was This Study Done?
The severity and outcome of an S. aureus infection in an individual depends in part on the ability of the bacterial clone with which the individual is infected to cause disease—the clone's “virulence.” Public-health officials and infectious disease experts would like to know the geographic distribution of the virulent S. aureus clones that cause invasive infections, because this information should help them understand how these pathogens spread and thus how to control them. Different clones of S. aureus can be distinguished by “molecular typing,” the determination of clone-specific sequences of nucleotides in variable regions of the bacterial genome (the bacterium's blueprint; genomes consist of DNA, long chains of nucleotides). In this study, the researchers use molecular typing to map the geographic distribution of MRSA and methicillin-sensitive S. aureus (MSSA) clones causing invasive infections in Europe; a MRSA clone emerges when an MSSA clone acquires antibiotic resistance from another type of bacteria so it is useful to understand the geographic distribution of both MRSA and MSSA.
What Did the Researchers Do and Find?
Between September 2006 and February 2007, 357 laboratories serving 450 hospitals in 26 European countries collected almost 3,000 MRSA and MSSA isolates from patients with invasive S. aureus infections. The isolates were sent to the relevant national staphylococcal reference laboratory (SRL) where they were characterized by quality-controlled sequence typing of the variable region of a staphylococcal gene called spa (spa typing). The spa typing data were entered into a central database and then analyzed by a public, purpose-built Web-based mapping tool (SRL-Maps), which provides interactive access and easy-to-understand illustrations of the geographical distribution of S. aureus clones. Using this mapping tool, the researchers found that there was a wide geographical distribution of spa types across Europe with some types being common in all European countries. MSSA isolates were more diverse than MRSA isolates and the genetic diversity (variability) of MRSA differed considerably between countries. Most importantly, major MRSA spa types occurred in distinct geographical clusters.
What Do These Findings Mean?
These findings provide the first representative snapshot of the genetic population structure of S. aureus across Europe. Because the researchers used spa typing, which analyzes only a small region of one gene, and characterized only 3,000 isolates, analysis of other parts of the S. aureus genome in more isolates is now needed to build a complete portrait of the geographical abundance of the S. aureus clones that cause invasive infections in Europe. However, the finding that MRSA spa types occur mainly in geographical clusters has important implications for the control of MRSA, because it indicates that a limited number of clones are spreading within health care networks, which means that MRSA is mainly spread by patients who are repeatedly admitted to different hospitals. Control efforts aimed at interrupting this spread within and between health care institutions may be feasible and ultimately successful, suggest the researchers, and should be strongly encouraged. In addition, this study shows how, by sharing typing results on a Web-based platform, an international surveillance network can provide clinicians and infection control teams with crucial information about the dynamics of pathogens such as S. aureus, including early warnings about emerging virulent clones.
Additional Information
Please access these Web sites via the online version of this summary at
This study is further discussed in a PLoS Medicine Perspective by Franklin D. Lowy
The UK Health Protection Agency provides information about Staphylococcus aureus
The UK National Health Service Choices Web site has pages on staphylococcal infections and on MRSA
The US National Institute of Allergy and Infectious Disease has information about MRSA
The US Centers for Disease Control and Infection provides information about MRSA for the public and professionals
MedlinePlus provides links to further resources on staphylococcal infections and on MRSA (in English and Spanish)
SRL-Maps can be freely accessed
PMCID: PMC2796391  PMID: 20084094
2.  Key Role for Clumping Factor B in Staphylococcus aureus Nasal Colonization of Humans 
PLoS Medicine  2008;5(1):e17.
Staphylococcus aureus permanently colonizes the vestibulum nasi of one-fifth of the human population, which is a risk factor for autoinfection. The precise mechanisms whereby S. aureus colonizes the nose are still unknown. The staphylococcal cell-wall protein clumping factor B (ClfB) promotes adhesion to squamous epithelial cells in vitro and might be a physiologically relevant colonization factor.
Methods and Findings
We define the role of the staphylococcal cytokeratin-binding protein ClfB in the colonization process by artificial inoculation of human volunteers with a wild-type strain and its single locus ClfB knock-out mutant. The wild-type strain adhered to immobilized recombinant human cytokeratin 10 (CK10) in a dose-dependent manner, whereas the ClfB− mutant did not. The wild-type strain, when grown to the stationary phase in a poor growth medium, adhered better to CK10, than when the same strain was grown in a nutrient-rich environment. Nasal cultures show that the mutant strain is eliminated from the nares significantly faster than the wild-type strain, with a median of 3 ± 1 d versus 7 ± 4 d (p = 0.006). Furthermore, the wild-type strain was still present in the nares of 3/16 volunteers at the end of follow-up, and the mutant strain was not.
The human colonization model, in combination with in vitro data, shows that the ClfB protein is a major determinant of nasal-persistent S. aureus carriage and is a candidate target molecule for decolonization strategies.
Heiman Wertheim and colleagues investigate the role ofStaphylococcus aureus clumping factor B, a cell wall protein, in bacterial adherence to epithelial cells and persistent colonization of human nostrils.
Editors' Summary
Staphylococcus aureus are common bacteria that normally live on the skin. They also colonize the nostrils of about one in five adults permanently and another one in three adults intermittently. Although these bacteria usually coexist peacefully with their human carriers, they can cause minor infections such as pimples and boils if they enter the skin through a cut or a sore. They can also cause potentially life-threatening infections such as blood poisoning and pneumonia. These serious, invasive infections are often “autoinfections.” That is, they are caused by strains of S. aureus that are present in the patient's nose before they become ill. Minor S. aureus infections can be treated without antibiotics—by draining a boil, for example. Invasive infections are usually treated with antibiotics such as flucloxacillin.
Why Was This Study Done?
There is no effective vaccine against S. aureus infections and these bacteria are becoming increasingly resistant to flucloxacillin, methicillin, and other antibiotics. Worryingly, although methicillin-resistant S. aureus (MRSA) infections occur most frequently among people in health-care facilities who have weakened immune systems, community-acquired MRSA infections among otherwise healthy people are increasingly common. Consequently, new ways to avoid S. aureus infections are urgently needed. Because persistent nasal carriers of S. aureus have an increased risk of infection, one strategy might be to prevent nasal colonization with S. aureus. How these bacteria colonize the nose is poorly understood, but is likely to involve interactions between molecules expressed on the surface of the bacteria and molecules expressed on the surface of the cells lining the nostrils. In this study, the researchers use a new human nasal colonization assay to investigate the involvement of a bacterial surface protein called clumping factor B (ClfB) in the survival of S. aureus in the human nose. ClfB binds to cytokeratin 10, a protein expressed by cells lining the human nose, and has been implicated in the colonization of mouse noses by S. aureus.
What Did the Researchers Do and Find?
The researchers introduced a strain of S. aureus that made ClfB and an otherwise identical, mutant strain that lacked ClfB into the nostrils of healthy human volunteers and measured how long the two strains survived. For safety reasons, the S. aureus strains used in this study have an additional defect that makes them less likely to colonize and persist in the human nose than the strains found in natural S. aureus carriers. Although both strains grew equally well in the laboratory, the mutant strain was eliminated from human noses much quicker than the strain that made ClfB. Mutant bacteria lacking ClfB were cleared from the nostrils of all the volunteers within two weeks, whereas the bacteria that made ClfB were still present in some of the volunteers four weeks after their introduction. When the researchers investigated how well the two strains stuck to a layer of human cytokeratin 10 in a plastic dish, they found that the bacteria that made ClfB stuck to the human protein but the mutant bacteria did not. Furthermore, the strain with ClfB stuck particularly well to cytokeratin 10 when the bacteria had been grown in conditions where nutrients were limiting, a situation that mimics bacterial growth in the human nose.
What Do These Findings Mean?
These findings show that ClfB is an important factor in the establishment of human nasal colonization by S. aureus and suggest that ClfB might be a target for S. aureus decolonization strategies. Furthermore, although ClfB is clearly important in human nasal colonization by S. aureus, it is likely that additional bacterial factors will also be involved in this process. The human nasal colonization model used in this study may be useful in the identification of these additional factors and also as a test bed for potential S. aureus decolonization strategies.
Additional Information.
Please access these Web sites via the online version of this summary at
The MedlinePlus encyclopedia has a page on Staphylococcus aureus and MRSA (in English and Spanish)
The US Centers for Disease Control and Prevention provides information on community-associated MRSA (in English and Spanish)
The UK National Health Service's health website (NHS Direct) provides information about staphylococcal infections and about MRSA
The UK Health Protection Agency provides information about Staphylococcus aureus
PMCID: PMC2194749  PMID: 18198942
3.  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
4.  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
5.  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
6.  Recurrent Challenges for Clinicians: Emergence of Methicillin-Resistant Staphylococcus aureus, Vancomycin Resistance, and Current Treatment Options 
Gram-positive pathogens mainly, Staphylococcus aureus, Enterococcus and coagulase-negative Staphylococcus, are developing increasing resistance to glycopeptides that pose a problem in treating infections caused by these pathogens. Vancomycin is the treatment of choice in treating methicillin-resistant S. aureus (MRSA). Community-acquired MRSA is associated with infections in patients without recent history of hospital admission and without the classical risk factors for MRSA carriage (including healthcare personnel). MRSA poses new threats and challenges beyond the hospital with the emergence of community-acquired MRSA. Indiscriminate use of vancomycin leads to the emergence and spread of vancomycin resistance in multidrug resistant strains is of growing concern in the recent years. Minimum Inhibitory concentration (MIC) remains an important determinant in choosing the right antibiotics. Infections caused by MRSA strains with vancomycin MIC > 4 μg/mL leads to the vancomycin treatment failure. The Clinical Laboratory Standards Institute had also lowered the cut-off susceptibility and resistance breakpoints for vancomycin. Despite the availability of newer antimicrobial agents (Linezolid, Daptomycin, Tigecycline) for drug-resistant Gram-positive pathogens, clinicians and patients still need options for treatment of MRSA infection. There is a need to reduce the global burden of infections caused by Gram-positive pathogens and its resistant strains (mainly MRSA). Continuous efforts should be made to prevent the spread and the emergence of glycopeptide resistance by early detection of the resistant strains and using the proper infection control measures in the hospital setting.
PMCID: PMC3968634  PMID: 24701097
Enterococcus; Gram-positive; minimum inhibitory concentration; methicillin resistant Staphylococcus aureas; resistance; Staphylococcus aureus; vancomycin; vancomycin-intermediate Staphylococcus aureus
7.  Staphylococcus aureus Bacteremia, Australia 
Emerging Infectious Diseases  2005;11(4):554-561.
S. aureus bacteremia in Australia is increasingly caused by MRSA, which is likely to affect empiric prescribing of antimicrobial drugs in suspected cases.
Staphylococcus aureus bacteremia (SAB) is common and increasing worldwide. A retrospective review was undertaken to quantify the number of cases, their place of acquisition, and the proportions caused by methicillin-resistant S. aureus (MRSA) in 17 hospitals in Australia. Of 3,192 episodes, 1,571 (49%) were community onset. MRSA caused 40% of hospital-onset episodes and 12% of community-onset episodes. The median rate of SAB was 1.48/1,000 admissions (range 0.61–3.24; median rate for hospital-onset SAB was 0.7/1,000 and for community onset 0.8/1,000 admissions). Using these rates, we estimate that ≈6,900 episodes of SAB occur annually in Australia (35/100,000 population). SAB is common, and a substantial proportion of cases may be preventable. The epidemiology is evolving, with >10% of community-onset SAB now caused by MRSA. This is an emerging infectious disease concern and is likely to impact on empiric antimicrobial drug prescribing in suspected cases of SAB.
PMCID: PMC3320328  PMID: 15829193
Staphylococcus aureus; bacteremia; hospital infections; methicillin resistance; mortality; fatal outcome; nosocomial infections; infection control; indwelling catheters
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
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
10.  Isolates with Low-Level Vancomycin Resistance Associated with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia 
Low-level vancomycin-resistant Staphylococcus aureus (vancomycin-intermediate S. aureus [VISA] and heterogenous VISA [hVISA]) is increasingly reported and leads to glycopeptide treatment failure. Various phenotypic features have been reported for these isolates, but the genetic changes leading to hVISA and VISA have yet to be clearly determined. We assessed phenotypic, antibiotic resistance, and genomic changes by using genomic DNA microarray comparison and sequencing of selected loci in five pairs of clinical hVISA/VISA strains and the initial methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained prior to vancomycin therapy. The isolates were from adult patients in Australia and New Zealand who had persistent MRSA bacteremia (>7 days) while receiving vancomycin therapy. In all cases, the initial isolates were found to be fully vancomycin-susceptible Staphylococcus aureus (VSSA). The hVISA/VISA phenotype was associated with increased cell wall thickness, reduced autolytic activity in four of five hVISA/VISA strains, and a striking reduction in biofilm formation compared to the parent strains in all pairs. All five pairs appeared to be isogenic, and genomic DNA microarray comparison suggested that major genetic changes are not required for the development of the resistant phenotype in these strains. No sequence differences were found in the agr locus or the tcaRA genes for any pair, but a marked reduction in RNAIII expression was found in four pairs. In summary, hVISA/VISA arises from fully VSSA during persistent infection that fails to respond to glycopeptide therapy and is associated with significant phenotypic changes, including a marked reduction in biofilm-forming ability. These clinically derived pairs of isolates will be a useful resource to elucidate the genetic mechanism of resistance in hVISA/VISA strains.
PMCID: PMC1563555  PMID: 16940100
11.  Clinical Outcomes in Patients with Heterogeneous Vancomycin-Intermediate Staphylococcus aureus Bloodstream Infection 
The prevalence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) infections varies in the literature, a problem complicated by the lack of routine screening procedures; however, limited data suggest that hVISA has been associated with persistent bloodstream infections (BSI) and vancomycin failure, yet these studies have been confounded by design issues. We conducted this study to compare the characteristics of patients with BSI caused by hVISA with those with vancomycin-susceptible Staphylococcus aureus (VSSA) treated with vancomycin. This retrospective, multicenter matched (1:1) cohort study compared the clinical characteristics and outcomes of hVISA and VSSA. Patients with hVISA methicillin-resistant Staphylococcus aureus (MRSA) BSI from 2004 to 2012 were matched to VSSA-MRSA BSI patients. The primary outcome was failure of vancomycin treatment, defined as a composite of persistent bacteremia (≥7 days), persistent signs and symptoms, change of MRSA antibiotic, recurrent BSI, or MRSA-related mortality. We identified 122 matched cases. The overall vancomycin failure rate was 57% (82% hVISA versus 33% VSSA; P < 0.001). The individual components of failure in hVISA versus VSSA were persistent bacteremia, 59% versus 21% (P < 0.001); change in MRSA therapy, 54% versus 25% (P = 0.001); MRSA-related mortality, 21% versus 10% (P = 0.081); and recurrence of BSI, 26% versus 2% (P < 0.001). Using logistic regression analysis and adjusting for covariates, hVISA (adjusted odds ratio [aOR], 11.1; 95% confidence interval [CI], 4.3 to 28.7) and intensive care unit (ICU) admission (aOR, 4.5; 95% CI, 1.8 to 11.6) were still independently associated with vancomycin failure. Relative to VSSA BSI, patients with hVISA were more likely to experience failure of vancomycin treatment, including persistent bacteremia and recurrence. Our results indicate that hVISA was responsible for considerable morbidity.
PMCID: PMC3754327  PMID: 23796929
12.  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
13.  Antimicrobial susceptibility patterns and characterization of clinical isolates of Staphylococcus aureus in KwaZulu-Natal province, South Africa 
Antimicrobial resistance of Staphylococcus aureus especially methicillin-resistant S. aureus (MRSA) continues to be a problem for clinicians worldwide. However, few data on the antibiotic susceptibility patterns of S. aureus isolates in South Africa have been reported and the prevalence of MRSA in the KwaZulu-Natal (KZN) province is unknown. In addition, information on the characterization of S. aureus in this province is unavailable. This study investigated the susceptibility pattern of 227 S. aureus isolates from the KZN province, South Africa. In addition, characterization of methicillin-sensitive S. aureus (MSSA) and MRSA are reported in this survey.
The in-vitro activities of 20 antibiotics against 227 consecutive non-duplicate S. aureus isolates from clinical samples in KZN province, South Africa were determined by the disk-diffusion technique. Isolates resistant to oxacillin and mupirocin were confirmed by PCR detection of the mecA and mup genes respectively. PCR-RFLP of the coagulase gene was employed in the characterization of MSSA and MRSA.
All the isolates were susceptible to vancomycin, teicoplanin and fusidic acid, and 26.9% of isolates studied were confirmed as MRSA. More than 80% of MRSA were resistant to at least four classes of antibiotics and isolates grouped in antibiotype 8 appears to be widespread in the province. The MSSA were also susceptible to streptomycin, neomycin and minocycline, while less than 1% was resistant to chloramphenicol, ciprofloxacin, rifampicin and mupirocin. The inducible MLSB phenotype was detected in 10.8% of MSSA and 82% of MRSA respectively, and one MSSA and one MRSA exhibited high-level resistance to mupirocin. There was good correlation between antibiotyping and PCR-RFLP of the coagulase gene in the characterization of MRSA in antibiotypes 1, 5 and 12.
In view of the high resistance rates of MRSA to gentamicin, erythromycin, clindamycin, rifampicin and trimethoprim, treatment of MRSA infections in this province with these antibacterial agents would be unreliable. There is an emerging trend of mupirocin resistance among S. aureus isolates in the province. PCR-RFLP of the coagulase gene was able to distinguish MSSA from MRSA and offers an attractive option to be considered in the rapid epidemiological analysis of S. aureus in South Africa. Continuous surveillance on resistance patterns and characterization of S. aureus in understanding new and emerging trends in South Africa is of utmost importance.
PMCID: PMC1564024  PMID: 16875502
14.  Predicting Risk for Death from MRSA Bacteremia1 
Emerging Infectious Diseases  2012;18(7):1072-1080.
Methicillin-resistant Staphylococcus aureus (MRSA) in the bloodstream is often fatal. Vancomycin is the most frequently prescribed drug for treatment of MRSA infections with demonstrated efficacy. Recently, however, some MRSA infections have not been responding to vancomycin, even those caused by strains considered susceptible. To provide optimal treatment and avoid vancomycin resistance, therapy should be tailored, especially for patients at highest risk for death. But who are these patients? A study that looked back at medical records and 699 frozen isolates found that risk for death from MRSA infection was highest among certain populations, including the elderly, nursing home residents, patients with severe sepsis, and patients with liver or kidney disease. Risk for death was not affected by the type of MRSA strain (vancomycin susceptible, heteroresistant, or intermediate resistant). Risk was lower among those who had consulted an infectious disease specialist. Thus, when choosing treatment for patients with MRSA infection, it is crucial to look at patient risk factors, not just MRSA strain type. For those at high risk, consultation with an infectious disease specialist is recommended.
Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is often fatal. To determine predictors of risk for death, we conducted a retrospective cohort study. We examined 699 episodes of MRSA bacteremia involving 603 patients admitted to an academic medical center in New York City during 2002–2007. Data came from chart reviews, hospital databases, and recultured frozen MRSA specimens. Among the 699 episodes, 55 were caused by vancomycin–intermediate resistant S. aureus strains, 55 by heteroresistant vancomycin-intermediate S. aureus strains, and 589 by non–vancomycin-resistant strains; 190 (31.5%) patients died. We used regression risk analysis to quantify the association between clinical correlates and death. We found that older age, residence in a nursing home, severe bacteremia, and organ impairment were independently associated with increased risk for death; consultation with an infectious disease specialist was associated with lower risk for death; and MRSA strain types were not associated with risk for death.
PMCID: PMC3376787  PMID: 22709685
MRSA; bacteremia; heteroresistant Staphylococcus aureus; hVISA; vancomycin intermediate Staphylococcus aureus; VISA; mortality; death; bacteria; antimicrobial resistance
15.  Reversible Antibiotic Tolerance Induced in Staphylococcus aureus by Concurrent Drug Exposure 
mBio  2015;6(1):e02268-14.
Resistance of Staphylococcus aureus to beta-lactam antibiotics has led to increasing use of the glycopeptide antibiotic vancomycin as a life-saving treatment for major S. aureus infections. Coinfection by an unrelated bacterial species may necessitate concurrent treatment with a second antibiotic that targets the coinfecting pathogen. While investigating factors that affect bacterial antibiotic sensitivity, we discovered that susceptibility of S. aureus to vancomycin is reduced by concurrent exposure to colistin, a cationic peptide antimicrobial employed to treat infections by Gram-negative pathogens. We show that colistin-induced vancomycin tolerance persists only as long as the inducer is present and is accompanied by gene expression changes similar to those resulting from mutations that produce stably inherited reduction of vancomycin sensitivity (vancomycin-intermediate S. aureus [VISA] strains). As colistin-induced vancomycin tolerance is reversible, it may not be detected by routine sensitivity testing and may be responsible for treatment failure at vancomycin doses expected to be clinically effective based on such routine testing.
Importance   Commonly, antibiotic resistance is associated with permanent genetic changes, such as point mutations or acquisition of resistance genes. We show that phenotypic resistance can arise where changes in gene expression result in tolerance to an antibiotic without any accompanying genetic changes. Specifically, methicillin-resistant Staphylococcus aureus (MRSA) behaves like vancomycin-intermediate S. aureus (VISA) upon exposure to colistin, which is currently used against infections by Gram-negative bacteria. Vancomycin is a last-resort drug for treatment of serious S. aureus infections, and VISA is associated with poor clinical prognosis. Phenotypic and reversible resistance will not be revealed by standard susceptibility testing and may underlie treatment failure.
Commonly, antibiotic resistance is associated with permanent genetic changes, such as point mutations or acquisition of resistance genes. We show that phenotypic resistance can arise where changes in gene expression result in tolerance to an antibiotic without any accompanying genetic changes. Specifically, methicillin-resistant Staphylococcus aureus (MRSA) behaves like vancomycin-intermediate S. aureus (VISA) upon exposure to colistin, which is currently used against infections by Gram-negative bacteria. Vancomycin is a last-resort drug for treatment of serious S. aureus infections, and VISA is associated with poor clinical prognosis. Phenotypic and reversible resistance will not be revealed by standard susceptibility testing and may underlie treatment failure.
PMCID: PMC4313918  PMID: 25587013
16.  Is methicillin-resistant Staphylococcus aureus an emerging community pathogen? A review of the literature 
To discuss the historical epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) and review the literature suggesting that MRSA has become a community pathogen.
A search of the MEDLINE database was performed, encompassing all English or French language citations from 1966 to 1999 and containing the subjects and/or text words: 'Staphylococcus aureus', 'methicillin resistance', 'endocarditis', 'cellulites', 'pneumonia' and 'community-acquired'. Articles published in other languages that provided English or French abstracts were included. All relevant references cited in articles obtained from the MEDLINE database and book chapters were also included.
All articles obtained from the above sources were examined and were included in the review if a laboratory or epidemiological study of community-acquired MRSA was presented.
MRSA has emerged over the past 30 years to become a worldwide nosocomial pathogen and has recently been reported as a cause of community-acquired infections. The changing epidemiology of MRSA is likely because of two mechanisms: the movement of nosocomial MRSA strains into the community and the de novo appearance of community strains resulting from the transfer of genetic material from methicillin-resistant Gram-positive organisms to sensitive S aureus strains. The emergence of MRSA as a community pathogen has occurred at a slower rate than it did for penicillin-resistant S aureus (PRSA) in the 1950s and 1960s, possibly because the mechanism of methicillin resistance does not exhibit the same ease of transferability as that of penicillin resistance. Four case reports, seven case series, 10 case-control studies and two cohort studies on community-acquired MRSA were analyzed. Determining whether these reports involve new community-acquired strains rather than previously acquired nosocomial strains can be problematic. It appears, however, that MRSA strains of both nosocomial and community origin are now endemic in certain communities in different parts of the world. Few surveillance studies of nonhospitalized patient populations have been performed to date; thus, the true prevalence of MRSA in the community at large is essentially unknown, although it appears to be low. At present, the empirical treatment of community-acquired S aureus infections with a beta-lactamase-stable beta-lactam antibiotic is appropriate for most populations. However, empirical vancomycin therapy for serious S aureus infections should be strongly considered for patients with significant risk factors for previously-acquired nosocomial MRSA or for patients belonging to outpatient populations with a proven high prevalence of MRSA. Increasing vancomycin use will likely have a significant impact on the development of resistance in Gram-positive organisms.
PMCID: PMC2094767  PMID: 18159291
Community-acquired disease; Drug resistance; Methicillin-resistant Staphyloccus aureus
17.  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
18.  Mortality and Hospital Stay Associated with Resistant Staphylococcus aureus and Escherichia coli Bacteremia: Estimating the Burden of Antibiotic Resistance in Europe 
PLoS Medicine  2011;8(10):e1001104.
The authors calculate excess mortality, excess hospital stay, and related hospital expenditure associated with antibiotic-resistant bacterial bloodstream infections (Staphylococcus aureus and Escherichia coli) in Europe.
The relative importance of human diseases is conventionally assessed by cause-specific mortality, morbidity, and economic impact. Current estimates for infections caused by antibiotic-resistant bacteria are not sufficiently supported by quantitative empirical data. This study determined the excess number of deaths, bed-days, and hospital costs associated with blood stream infections (BSIs) caused by methicillin-resistant Staphylococcus aureus (MRSA) and third-generation cephalosporin-resistant Escherichia coli (G3CREC) in 31 countries that participated in the European Antimicrobial Resistance Surveillance System (EARSS).
Methods and Findings
The number of BSIs caused by MRSA and G3CREC was extrapolated from EARSS prevalence data and national health care statistics. Prospective cohort studies, carried out in hospitals participating in EARSS in 2007, provided the parameters for estimating the excess 30-d mortality and hospital stay associated with BSIs caused by either MRSA or G3CREC. Hospital expenditure was derived from a publicly available cost model. Trends established by EARSS were used to determine the trajectories for MRSA and G3CREC prevalence until 2015. In 2007, 27,711 episodes of MRSA BSIs were associated with 5,503 excess deaths and 255,683 excess hospital days in the participating countries, whereas 15,183 episodes of G3CREC BSIs were associated with 2,712 excess deaths and 120,065 extra hospital days. The total costs attributable to excess hospital stays for MRSA and G3CREC BSIs were 44.0 and 18.1 million Euros (63.1 and 29.7 million international dollars), respectively. Based on prevailing trends, the number of BSIs caused by G3CREC is likely to rapidly increase, outnumbering the number of MRSA BSIs in the near future.
Excess mortality associated with BSIs caused by MRSA and G3CREC is significant, and the prolongation of hospital stay imposes a considerable burden on health care systems. A foreseeable shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections will exacerbate this situation and is reason for concern.
Please see later in the article for the Editors' Summary
Editors' Summary
Antimicrobial resistance—a consequence of the use and misuse of antimicrobial medicines—occurs when a microorganism becomes resistant (usually by mutation or acquiring a resistance gene) to an antimicrobial drug to which it was previously sensitive. Then standard treatments become ineffective, leading to persistent infections, which may spread to other people. With some notable exceptions such as TB, HIV, malaria, and gonorrhea, most of the disease burden attributable to antimicrobial resistance is caused by hospital-associated infections due to opportunistic bacterial pathogens. These bacteria often cause life-threatening or difficult-to-manage conditions such as deep tissue, wound, or bone infections, or infections of the lower respiratory tract, central nervous system, or blood stream. The two most frequent causes of blood stream infections encountered worldwide are Staphylococcus aureus and Escherichia coli.
Why Was This Study Done?
Although hospital-associated infections have gained much attention over the past decade, the overall effect of this growing phenomenon on human health and medical services has still to be adequately quantified. The researchers proposed to fill this information gap by estimating the impact—morbidity, mortality, and demands on health care services—of antibiotic resistance in Europe for two types of resistant organisms that are typically associated with resistance to multiple classes of antibiotics and can be regarded as surrogate markers for multi-drug resistance—methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli.
What Did the Researchers Do and Find?
Recently, the Burden of Resistance and Disease in European Nations project collected representative data on the clinical impact of antimicrobial resistance throughout Europe. Using and combining this information with 2007 prevalence data from the European Antibiotic Resistance Surveillance System, the researchers calculated the burden of disease associated with methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli blood stream infections. This burden of disease was expressed as excess number of deaths, excess number of days in hospital, and excess costs. Using statistical models, the researchers predicted trend-based resistance trajectories up to 2015 for the 31 participating countries in the European region.
The researchers included 1,293 hospitals from the 31 countries, typically covering 47% of all available acute care hospital beds in most countries, in their analysis. For S. aureus, the estimated number of blood stream infections totaled 108,434, of which 27,711 (25.6%) were methicillin-resistant. E. coli caused 163,476 blood stream infections, of which 15,183 (9.3%) were resistant to third-generation cephalosporins. An estimated 5,503 excess deaths were associated with blood stream infections caused by methicillin-resistant S. aureus (with the UK and France predicted to experience the highest excess mortality), and 2,712 excess deaths with blood stream infections caused by third-generation cephalosporin-resistant E. coli (predicted to be the highest in Turkey and the UK). The researchers also found that blood stream infections caused by both methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli contributed respective excesses of 255,683 and 120,065 extra bed-days, accounting for an estimated extra cost of 62.0 million Euros (92.8 million international dollars). In their trend analysis, the researchers found that 97,000 resistant blood stream infections and 17,000 associated deaths could be expected in 2015, along with increases in the lengths of hospital stays and costs. Importantly, the researchers estimated that in the near future, the burden of disease associated with third-generation cephalosporin-resistant E. coli is likely to surpass that associated with methicillin-resistant S. aureus.
What Do These Findings Mean?
These findings show that even though the blood stream infections studied represent only a fraction of the total burden of disease associated with antibiotic resistance, excess mortality associated with these infections caused by methicillin-resistant S. aureus and third-generation cephalosporin-resistant E. coli is high, and the associated prolonged length of stays in hospital imposes a considerable burden on health care systems in Europe. Importantly, a possible shift in the burden of antibiotic resistance from Gram-positive to Gram-negative infections is concerning. Such forecasts suggest that despite anticipated gains in the control of methicillin-resistant S. aureus, the increasing number of infections caused by third-generation cephalosporin-resistant Gram-negative pathogens, such as E. coli, is likely to outweigh this achievement soon. This increasing burden will have a big impact on already stretched health systems.
Additional Information
Please access these websites via the online version of this summary at
The World Health Organization has a fact sheet on general antimicrobial resistance
The US Centers for Disease Control and Prevention webpage on antibiotic/antimicrobial resistance includes information on educational campaigns and resources
The European Centre for Disease Control provides data about the prevalence of resistance in Europe through an interactive database
PMCID: PMC3191157  PMID: 22022233
19.  Outcome of Vancomycin Treatment in Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia▿  
Limited data on the clinical outcome of vancomycin treatment compared with that of beta-lactam treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia (MSSA-B) are available. We used different and complementary approaches: (i) a retrospective cohort study using a propensity score to adjust for confounding by treatment assignment and (ii) a matched case-control study. Of all patients with S. aureus bacteremia (SAB) in two university-affiliated hospitals over a 7-year period, 294 patients with MSSA-B were enrolled in the cohort study. The cases for the case-control study were defined as patients who received vancomycin treatment for MSSA-B; the controls, who were patients that received beta-lactam treatment for MSSA-B, were selected at a 1:2 (case:control) ratio according to the objective matching scoring system and the propensity score system. In the cohort study, SAB-related mortality in patients with vancomycin treatment (37%, 10/27) was significantly higher than that in those with beta-lactam treatment (18%, 47/267) (P = 0.02). In addition, multivariate analysis revealed that vancomycin treatment was associated with SAB-related mortality when independent predictors for SAB-related mortality and propensity score were considered (adjusted odds ratio of 3.3, 95% confidence interval of 1.2 to 9.5). In the case-control study using the objective matching scoring system and the propensity score system, SAB-related mortality in case patients was 37% (10/27) and in control patients 11% (6/54) (P < 0.01). Our data suggest that vancomycin is inferior to beta-lactam in the treatment of MSSA-B.
PMCID: PMC2223910  PMID: 17984229
20.  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
21.  A Report on The First Case of Vancomycin-Intermediate Staphylococcus aureus (VISA) in Hawai‘i 
Hawaii Medical Journal  2011;70(11):233-236.
The state of Hawai‘i has the highest prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection in the United States. Since vancomycin is the most frequently-prescribed antibiotic for healthcare-associated MRSA infection, there is concern for development of vancomycin resistance. We report on a 61 year-old woman with history of previous successful treatments of MRSA bacteremia with vancomycin. She was later hospitalized for catheter-related MRSA bacteremia that persisted despite vancomycin treatment. The vancomycin minimal inhibitory concentration (MIC) was initially 1–2 µg/ml, suggesting susceptibility, but changed to 4µg/ml. At this level, the organism was classified as a vancomycin-intermediate Staphylococcus aureus (VISA). Therapy was changed from vancomycin to daptomycin, and the patient's blood cultures were sterilized. High suspicion of VISA should be raised in MRSA-infected patients who fail or have a history of vancomycin therapy so that additional susceptibility testing and appropriate antibiotic therapy can be promptly commenced to reduce the morbidity associated with VISA infection.
PMCID: PMC3215986  PMID: 22162601
22.  MRSA (treatment) 
Clinical Evidence  2006;2006:0922.
Methicillin-resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin as well as to other beta lactam antibiotics including flucloxacillin, b-lactam/b-lactamase inhibitor combinations, cephalosporins, and carbapenems. MRSA can be part of the normal body flora (colonisation), especially in the nose, but can cause infection, especially in people with prolonged hospital admissions, with underlying disease, or after antibiotic use. About 40% of S aureus in blood cultures in the UK is resistant to methicillin.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment for MRSA infections at any body site? What are the effects of treatment for MRSA nasal or extra-nasal colonisation? We searched: Medline, Embase, The Cochrane Library and other important databases up to July 2005 (BMJ Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
We found 16 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
In this systematic review we present information relating to the effectiveness and safety of the following interventions: antiseptic body washes, chlorhexidine-neomycin nasal cream, clindamycin, daptomycin, fusidic acid, glycopeptides (teicoplanin, vancomycin), linezolid, macrolides (azithromycin, clarithromycin, erythromycin), mupirocin nasal ointment, quinolones (ciprofloxacin, levofloxacin, moxifloxacin), quinupristin-dalfopristin, rifampicin, systemic antimicrobials, tea tree preparations, tetracyclines (doxycycline, minocycline, oxytetracycline), trimethoprim, and trimethoprim-sulfamethoxazole.
Key Points
Methicillin resistant Staphylococcus aureus (MRSA) has a gene that makes it resistant to methicillin as well as other beta lactam antibiotics including flucloxacillin, cephalosporins and carbapenems. MRSA can be part of the normal body flora (colonisation), especially in the nose, but can cause infection, especially in people with prolonged hospital admissions, with underlying disease or after antibiotic use.About 40% of S aureus in blood cultures in the UK is resistant to methicillin.
Glycopeptides (teicoplanin, vancomycin) andlinezolidseem to have similar efficacy at curing MRSA infection. Trimethoprim-sulfamethoxazole may be as effective as vancomycin at curing MRSA infection in injecting drug users, with similar toxicity.
We don't know whether macrolides (azithromycin, clarithromycin, erythromycin), quinolones (ciprofloxacin, levofloxacin, moxifloxacin), tetracyclines (doxycycline, minocycline, oxytetracycline), clindamycin, daptomycin,fusidic acid, quinupristin-dalfopristin or rifampicin are effective at curing MRSA infection, as no adequate studies were found. Ciprofloxacin has been used in combination with rifampicin or fusidic acid for MRSA bone and joint infections. Fusidic acid or rifampicin should not be used as monotherapy as resistance rapidly develops.Clindamycin may be used in preference to macrolides in susceptible MRSA infections, as bioavailability may be better and resistance less likely.Oral tetracyclines are recommended for minor MRSA infections.
Mupirocin nasal ointment may improve eradication of colonised MRSA compared with placebo, and may be as effective as topical fusidic acid plus oral trimethoprim-sulfamethoxazole and more effective than tea tree oil, although studies have given conflicting results. We don't know whether antiseptic body washes, chlorhexidine-neomycin nasal cream or systemic antimicrobials are effective at clearing MRSA colonisation.
PMCID: PMC2907633
23.  Prior Vancomycin Use Is a Risk Factor for Reduced Vancomycin Susceptibility in Methicillin-Susceptible but Not Methicillin-Resistant Staphylococcus aureus Bacteremia 
Staphylococcus aureus is a cause of community- and healthcare-acquired infections and is associated with substantial morbidity, mortality, and costs. Vancomycin minimum inhibitory concentrations (MICs) among S. aureus have increased, and reduced vancomycin susceptibility (RVS) may be associated with treatment failure. We aimed to identify clinical risk factors for RVS in S. aureus bacteremia.
Academic tertiary care medical center and affiliated urban community hospital.
Cases were patients with RVS S. aureus isolates (defined as vancomycin E-test MIC >1.0 μg/mL). Controls were patients with non-RVS S. aureus isolates.
Of 392 subjects, 134 (34.2%) had RVS. Fifty-eight of 202 patients (28.7%) with methicillin-susceptible S. aureus (MSSA) isolates had RVS, and 76 of 190 patients (40.0%) with methicillin-resistant S. aureus (MRSA) isolates had RVS (P =.02). In unadjusted analyses, prior vancomycin use was associated with RVS (odds ratio [OR], 2.08; 95% confidence interval [CI], 1.00–4.32; P =.046). In stratified analyses, there was significant effect modification by methicillin susceptibility on the association between vancomycin use and RVS (P = .04). In multivariable analyses, after hospital of admission and prior levofloxacin use were controlled for, the association between vancomycin use and RVS was significant for patients with MSSA infection (adjusted OR, 4.02; 95% CI, 1.11–14.50) but not MRSA infection (adjusted OR, 0.87; 95% CI, 0.36–2.13).
A substantial proportion of patients with S. aureus bacteremia had RVS. The association between prior vancomycin use and RVS was significant for patients with MSSA infection but not MRSA infection, suggesting a complex relationship between the clinical and molecular epidemiology of RVS in S. aureus.
PMCID: PMC3983274  PMID: 22227985
24.  Mobile Genetic Element SCCmec-encoded psm-mec RNA Suppresses Translation of agrA and Attenuates MRSA Virulence 
PLoS Pathogens  2013;9(4):e1003269.
Community acquired-methicillin resistant Staphylococcus aureus (CA-MRSA) is a socially problematic pathogen that infects healthy individuals, causing severe disease. CA-MRSA is more virulent than hospital associated-MRSA (HA-MRSA). The underlying mechanism for the high virulence of CA-MRSA is not known. The transcription product of the psm-mec gene, located in the mobile genetic element SCCmec of HA-MRSA, but not CA-MRSA, suppresses the expression of phenol-soluble modulin α (PSMα), a cytolytic toxin of S. aureus. Here we report that psm-mec RNA inhibits translation of the agrA gene encoding a positive transcription factor for the PSMα gene via specific binding to agrA mRNA. Furthermore, 25% of 325 clinical MRSA isolates had a mutation in the psm-mec promoter that attenuated transcription, and 9% of the strains had no psm-mec. In most of these psm-mec-mutated or psm-mec-deleted HA-MRSAs, PSMα expression was increased compared with strains carrying intact psm-mec, and some mutated strains produced high amounts of PSMα comparable with that of CA-MRSA. Deletion of psm-mec from HA-MRSA strains carrying intact psm-mec increased the expression of AgrA protein and PSMα, and virulence in mice. Thus, psm-mec RNA suppresses MRSA virulence via inhibition of agrA translation and the absence of psm-mec function in CA-MRSA causes its high virulence property.
Author Summary
Methicillin-resistant Staphylococcus aureus (MRSA) is resistant to various antibiotics, including β-lactams, thus causing serious clinical problems. Hospital-associated (HA)-MRSA infects immunocompromised patients in hospitals. Community-acquired (CA)-MRSA causes serious diseases in healthy people who have not had contact with hospitals in the United States, Canada, or Europe. CA-MRSA produces higher amounts of extracellular toxins and has higher virulence than HA-MRSA, although the reason for this is unclear. SCCmec is a foreign DNA integrated into the MRSA chromosome that contains several genes including the mecA gene that confers resistance against methicillin. The SCCmec of CA-MRSA does not contain the psm-mec gene that exists in the HA-MRSA SCCmec. In the present study, we found that the transcription product of psm-mec inhibits translation of the agrA gene encoding a positive transcription factor for many extracellular toxins by direct binding to the agrA mRNA, resulting in decreased extracellular toxin production. Furthermore, some HA-MRSA strains carry mutated psm-mec or no psm-mec and produce higher amounts of extracellular toxins than HA-MRSA strains carrying intact psm-mec. These findings suggest that psm-mec RNA negatively regulates agrA and mutation or absence of psm-mec leads to a high virulence capacity of MRSA.
PMCID: PMC3617227  PMID: 23592990
25.  Methicillin-Resistant Staphylococcus Aureus: A Pervasive Pathogen Highlights the Need for New Antimicrobial Development 
Staphylococcus aureus (S. aureus) has entered the spotlight as a globally pervasive drug-resistant pathogen. While historically associated exclusively with hospital-acquired infections in immunocompromised hosts, the methicillin-resistant form of S. aureus has been spreading throughout communities since the 1990s. Indeed, it has now become a common household term: MRSA. S. aureus has developed numerous mechanisms of virulence and strategies to evade the human immune system, including a host of surface proteins, secreted enzymes, and toxins. In hospital intensive care units, the proportion of MRSA-related S. aureus infections has increased strikingly from just 2 percent in 1974 to 64 percent in 2004. Its presence in the community has been rising similarly, posing a significant public health burden. The growing incidence of MRSA unfortunately has been met with dwindling efforts to develop new, more effective antibiotics. The continued emergence of resistant strains of bacteria such as MRSA demands an urgent revival of the search for new antibiotics.
PMCID: PMC3002151  PMID: 21165342
Staphylococcus aureus; methicillin-resistant Staphylococcus aureus; penicillin; antibiotic resistance; virulence factors; penicillin-binding proteins; community-associated MRSA; antibiotic development; 10x‘20 initiative

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