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1.  Vancomycin In Vitro Bactericidal Activity and Its Relationship to Efficacy in Clearance of Methicillin-Resistant Staphylococcus aureus Bacteremia▿  
We examined the relationship between the time to clearance of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia while patients were receiving vancomycin therapy and the in vitro bactericidal activity of vancomycin. Vancomycin killing assays were performed with 34 MRSA bloodstream isolates (17 accessory gene regulator group II [agr-II] and 17 non-agr-II isolates) from 34 different patients with MRSA bacteremia for whom clinical and microbiological outcomes data were available. Vancomycin doses were prospectively adjusted to achieve peak plasma concentrations of 28 to 32 μg/ml and trough concentrations of 8 to 12 μg/ml. Bactericidal assays were performed over 24 h with ∼107 to 108 CFU/ml in broth containing 16 μg/ml vancomycin. The median time to clearance of bacteremia was 6.5 days for patients with MRSA isolates demonstrating ≥2.5 reductions in log10 CFU/ml at 24 h and >10.5 days for patients with MRSA isolates demonstrating <2.5 log10 CFU/ml by 24 h (P = 0.025). The median time to clearance was significantly longer with MRSA isolates with vancomycin MICs of 2.0 μg/ml compared to that with MRSA isolates with MICs of ≤1.0 μg/ml (P = 0.019). The bacteremia caused by MRSA isolates with absent or severely reduced delta-hemolysin expression was of a longer duration of bacteremia (10 days and 6.5 days, respectively; P = 0.27) and had a decreased probability of eradication (44% and 78%, respectively; P = 0.086). We conclude that strain-specific microbiological features of MRSA, such as increased vancomycin MICs and decreased killing by vancomycin, appear to be predictive of prolonged MRSA bacteremia while patients are receiving vancomycin therapy. Prolonged bacteremia and decreased delta-hemolysin expression may also be related. Evaluation of these properties may be useful in the consideration of antimicrobial therapies that can be used as alternatives to vancomycin for the treatment of MRSA bacteremia.
PMCID: PMC1913284  PMID: 17452488
2.  Factors Influencing Time to Vancomycin-Induced Clearance of Nonendocarditis Methicillin-Resistant Staphylococcus aureus Bacteremia: Role of Platelet Microbicidal Protein Killing and agr Genotypes 
Vancomycin susceptibility, the accessory gene global regulator (agr) genotype and function, staphylococcal cassette chromosome (SCC) mec type, and susceptibility to cationic thrombin-induced platelet microbicidal protein 1 (tPMP-1) have been individually predictive of duration of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia. This investigation evaluated the interrelationship of these factors with time to clearance of MRSA bacteremia during vancomycin therapy in patients without endocarditis.
Vancomycin minimum inhibitory concentration and in vitro killing, agr function (δ-hemolysin activity), agr group, SCCmec type, and survival in tPMP-1 killing assays were determined for 29 MRSA bacteremia isolates.
Increased resistance to tPMP-1 killing was observed with agr group III MRSA (P =.025) and MRSA with reduced or absent agr function (P =.023). The median time to clearance of MRSA bacteremia was earlier for agr group III (3 days) versus group I (10.5 days) or II (15 days) (P =.001). In multivariate analysis, agr group II, reduced tPMP-1 killing in vitro, and prior vancomycin exposure were significant independent predictors of longer MRSA bacteremia duration.
Specific genotypic, phenotypic, and clinical parameters appear to correlate with persistent MRSA bacteremia. The interrelationship of these and other factors probably contributes to vancomycin-mediated clearance of MRSA bacteremia.
PMCID: PMC2819315  PMID: 20001853
3.  Relationship of agr Expression and Function with Virulence and Vancomycin Treatment Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus ▿ 
Antimicrobial Agents and Chemotherapy  2011;55(12):5631-5639.
The accessory gene regulator (agr) locus has been shown to be important for virulence in several animal models of Staphylococcus aureus infection. However, the role of agr in human infections, and specifically in antibiotic treatment, is controversial. Interestingly, agr dysfunction has been associated with reduced vancomycin responses. To systematically investigate the role of agr in virulence and treatment outcome in the context of endovascular infection, 10 well-characterized vancomycin-susceptible methicillin-resistant S. aureus (MRSA) bloodstream isolates (5 agr-I [clonal complex 45, or CC45] and 5 agr-II [CC5]) were studied for (i) agr function, (ii) RNAIII transcriptional profiles, (iii) agr locus sequences, (iv) intrinsic virulence and responses to vancomycin therapy in an experimental infective endocarditis (IE) model, and (v) in vivo RNAIII expression. Significant differences in agr function (determined by delta-hemolysin activity) correlated with the time point of RNAIII transcription (earlier RNAIII onset equals increased agr function). Unexpectedly, four MRSA strains with strong delta-hemolysin activities exhibited significant resistance to vancomycin treatment in experimental IE. In contrast, five of six MRSA strains with weak or no delta-hemolysin activity were highly susceptible to vancomycin therapy in the IE model. agr sequence analyses showed no common single-nucleotide polymorphism predictive of agr functionality. In vivo RNAIII expression in cardiac vegetations did not correlate with virulence or vancomycin treatment outcomes in the IE model. Inactivation of agr in two strains with strong delta-hemolysin activity did not affect virulence or the in vivo efficacy of vancomycin. Our findings suggest that agr dysfunction does not correlate with vancomycin treatment failures in this experimental IE model in two distinct MRSA genetic backgrounds.
PMCID: PMC3232782  PMID: 21968365
4.  Relationship of MIC and Bactericidal Activity to Efficacy of Vancomycin for Treatment of Methicillin-Resistant Staphylococcus aureus Bacteremia 
Journal of Clinical Microbiology  2004;42(6):2398-2402.
We attempted to find a relationship between the microbiological properties of bloodstream isolates of methicillin-resistant Staphylococcus aureus (MRSA) and the efficacy of vancomycin in the treatment of bacteremia. Vancomycin susceptibility testing was performed, and bactericidal activity was determined for 30 isolates from 30 different patients with MRSA bacteremia for whom clinical and microbiological outcome data were available. The majority of these patients had been previously enrolled in multicenter prospective studies of MRSA bacteremia refractory to conventional vancomycin therapy. Logistic regression found a statistically significant relationship between treatment success with vancomycin and decreases in both vancomycin MICs (≤0.5 μg/ml versus 1.0 to 2.0 μg/ml; P = 0.02) and degree of killing (reduction in 1og10 CFU/milliliter) by vancomycin over 72 h of incubation in vitro (P = 0.03). For MRSA isolates with vancomycin MICs ≤ 0.5 μg/ml, vancomycin was 55.6% successful in the treatment of bacteremia whereas vancomycin was only 9.5% effective in cases in which vancomycin MICs for MRSA were 1 to 2 μg/ml. Patients with MRSA that was more effectively killed at 72 h by vancomycin in vitro had a higher clinical success rate with vancomycin therapy in the treatment of bacteremia (log10 < 4.71 [n = 9], 0%; log10 4.71 to 6.26 [n = 13], 23.1%; log10 > 6.27 [n = 8], 50%). We conclude that a significant risk for vancomycin treatment failure in MRSA bacteremia begins to emerge with increasing vancomycin MICs well within the susceptible range. Elucidating the mechanisms involved in intermediate-level glycopeptide resistance in S. aureus should begin by examining bacteria that begin to show changes in vancomycin susceptibility before the development of obvious resistance. Prognostic information for vancomycin treatment outcome in MRSA bacteremia may also be obtained by testing the in vitro bactericidal potency of vancomycin.
PMCID: PMC427878  PMID: 15184410
5.  Vancomycin Tolerance in Methicillin-Resistant Staphylococcus aureus: Influence of Vancomycin, Daptomycin, and Telavancin on Differential Resistance Gene Expression 
Methicillin-resistant Staphylococcus aureus (MRSA) isolates that are susceptible to vancomycin but are tolerant to its killing effect may present a potential challenge for effective treatment. This study compared the microbiologic characteristics of clinical vancomycin-tolerant (VT-MRSA) and vancomycin-susceptible (VS-MRSA) strains using phenotypic and gene regulation studies. MRSA isolates collected from vancomycin-treated patients with bacteremia over a 5-year period were analyzed for vancomycin, daptomycin, and telavancin susceptibility, as well as accessory gene regulator (agr) group and function. Vancomycin tolerance was defined by a minimum bactericidal concentration (MBC)/minimum inhibitor concentration (MIC) ratio of ≥32 mg/liter. VT-MRSA isolates were compared to VS-MRSA isolates for differences in antimicrobial susceptibility, time-kill activity, and gene expression of key cell envelope response genes vraSR, dltA, and mprF. All 115 isolates evaluated were susceptible to vancomycin, daptomycin, and telavancin. Seven isolates (6%) were VT-MRSA. agr group II was more prevalent in isolates with vancomycin MBC/MIC ratios of ≥8. In time-kill analyses, VT-MRSA had reduced vancomycin killing, but daptomycin and telavancin activities were maintained. Significantly greater gene expression was observed in VT-MRSA after 72 h of subinhibitory antibiotic exposures. Vancomycin most notably increased vraSR expression (P = 0.002 versus VS-MRSA strains). Daptomycin and telavancin increased expression of all genes studied, most significantly mprF expression (P < 0.001). Longer durations of antibiotic exposure (72 h versus 24 h) resulted in substantial increases in gene expression in VT-MRSA. Although the clinical impact of VT-MRSA is not fully recognized, these data suggest that VT-MRSA strains, while still susceptible, have altered gene regulation to adapt to the antimicrobial effects of glyco- and lipopeptides that may emerge during prolonged durations of exposure.
PMCID: PMC3421561  PMID: 22687502
6.  Genotypic and phenotypic relationships among methicillin-resistant Staphylococcus aureus from three multicentre bacteraemia studies 
At a time when the molecular epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) was changing, we sought to characterize several genotypic markers and glycopeptide susceptibility features of clinical isolates from patients with bacteraemia.
One hundred and sixty-eight MRSA bloodstream isolates obtained from three multicentre clinical trials were microbiologically and genotypically characterized.
All isolates were susceptible to vancomycin (MIC ≤ 2 mg/L); 38% belonged to accessory gene regulator (agr) group I, 52% belonged to group II and 10% belonged to group III. Typing of the staphylococcal cassette chromosome mec (SCCmec) showed that 67% were type II and 33% were type IV. The agr group II polymorphism was associated with SCCmec II (P < 0.001). Fifty-three percent of SCCmec II and 27% of SCCmec IV isolates had vancomycin MICs ≥1 mg/L (P = 0.001). One hundred percent of agr II strains were predicted to be members of clonal complex 5. SCCmec II was the genetic marker most predictive of vancomycin MICs of ≥1 mg/L. SCCmec IV isolates were more likely to have vancomycin MICs ≤0.5 mg/L.
Given that SCCmec IV is a marker for a community-based organism for which less prior vancomycin exposure is predicted, we conclude that prior antibiotic exposure in agr group II organisms may account for their increased vancomycin MICs.
PMCID: PMC2667134  PMID: 19261624
MRSA; SCCmec types; clonal types; Staphylococcus spp.
7.  Predicting High Vancomycin Minimum Inhibitory Concentration in Methicillin-Resistant Staphylococcus aureus Bloodstream Infections 
MSRA isolates with high vancomycin MIC have been associated with treatment failure. Predicting CIR090 the likelihood of high vancomycin MIC may be useful for clinical decision making. We present a simple tool to help predict vancomycin MIC in MRSA bacteremia.
Background. Increased mortality, treatment failure, and hospital length of stay have been reported in patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia when their isolates have a vancomycin minimum inhibitory concentration (MIC) > 1 μg/mL. Automated testing often fails to identify these isolates. We developed a simple clinical rule to predict vancomycin MIC of 2 μg/mL in patients with MRSA bacteremia.
Methods. This cohort study was conducted at a tertiary care hospital and an affiliated acute rehabilitation facility. Consecutive patients with MRSA bacteremia from 2001 through 2007 were prospectively identified. Patient characteristics were examined for their association with high vancomycin MIC and a predictive model was created.
Results. A total of 296 MRSA bacteremic episodes among 272 patients were identified; 19% of the episodes had isolates with a vancomycin MIC of 2 μg/mL. Variables associated with a vancomycin MIC of 2 μg/mL included older age (odds ratio [OR], 4.0; 95% confidence interval [CI], 1.5–10.4); prior vancomycin (OR, 3.8; 95% CI, 1.9–7.6) or daptomycin (OR, 7.9; 95% CI, 1.8–34.0) exposure; the presence of a nontunneled central venous catheter (OR, 1.9; 95% CI, 1.1–3.4) or prosthetic heart valve (OR, 3.6; 95% CI, 1.3–10.0); a history of MRSA bacteremia (OR, 3.0; 95% CI, 1.6–5.6); and the presence of sepsis (OR, 2.7; 95% CI, 1.4–5.1) or shock (OR, 2.2; 95% CI, 1.1–4.2) at the time of culture. The final predictive rule included age > 50 years (3 points), prior vancomycin exposure (2 points), history of MRSA bacteremia (2 points), history of chronic liver disease (2 points), and presence of a nontunneled central venous catheter (1 point). A score cutoff of ≥ 4 resulted in a sensitivity of 75% and specificity of 59% (negative predictive value, 91%; positive predictive value, 30%).
Conclusions. Several factors that predict high vancomycin MIC were identified, and a simple predictive tool was created to help clinicians determine which patients are likely to have MRSA isolates with high vancomycin MIC.
PMCID: PMC3070034  PMID: 21460313
8.  Predictors of agr Dysfunction in Methicillin-Resistant Staphylococcus aureus (MRSA) Isolates among Patients with MRSA Bloodstream Infections ▿ 
Antimicrobial Agents and Chemotherapy  2011;55(12):5433-5437.
Despite emerging evidence that dysfunction in the accessory gene regulator (agr) locus is associated with deleterious outcomes among patients treated with vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) infections, factors predictive of agr dysfunction have not been evaluated. This study describes the epidemiology of agr dysfunction, identifies predictors of agr dysfunction in MRSA isolates among those with MRSA bloodstream infections, and describes the relationship between agr dysfunction and other microbiologic phenotypes. A cross-sectional study of patients with MRSA bloodstream infections at two institutions in upstate New York was performed. Clinical data on demographics, comorbidities, disease severity, hospitalization history, and antibiotic history were collected. Microbiologic phenotypes, including agr dysfunction, MIC values by broth microdilution (BMD) and Etest, and vancomycin heteroresistance (hVISA) were tested. Multivariable analyses were performed to identify factors predictive of agr dysfunction. Among 200 patients with an MRSA bloodstream infection, the proportion of strains with agr dysfunction was 31.5%. The distribution of MICs determined by both BMD and Etest were equivalent across agr groups, and there was no association between agr dysfunction and the presence of hVISA. Severity of illness, comorbidities, and hospitalization history were comparable between agr groups. In the multivariate analysis, prior antibiotic exposure was the only factor of variables studied found to be predictive of agr dysfunction. This relationship was predominantly driven by prior beta-lactam and fluoroquinolone administration in the bivariate analysis. Identifying these institution-specific risk factors can be used to develop a process to assess the risk of agr dysfunction and guide empirical antibiotic therapy decisions.
PMCID: PMC3232784  PMID: 21930887
9.  Reduced vancomycin susceptibility and staphylococcal cassette chromosome mec (SCCmec) type distribution in methicillin-resistant Staphylococcus aureus bacteraemia 
Journal of Antimicrobial Chemotherapy  2012;67(10):2346-2349.
Recent epidemiological evidence suggests that genotypic and phenotypic characteristics that have typically distinguished community-associated methicillin-resistant Staphylococcus aureus (MRSA) and healthcare-associated MRSA strains may be evolving. The objective of this study was to examine the association between reduced vancomycin susceptibility (RVS) and staphylococcal cassette chromosome mec (SCCmec) type in MRSA bloodstream isolates.
A cohort study of patients who were hospitalized from 2007 to 2009 with S. aureus bacteraemia was conducted within a university health system. Bivariable analyses were conducted to determine the association between RVS and SCCmec type, as well as other microbiological characteristics including Panton–Valentine leucocidin, accessory gene regulator (agr) dysfunction and vancomycin heteroresistance.
A total of 188 patients with MRSA bacteraemia were identified: 116 (61.7%) and 72 (38.3%) patients had infections due to healthcare-associated MRSA and community-associated MRSA, respectively. As defined by a vancomycin Etest MIC > 1.0 mg/L, the prevalence of RVS was 40.4%. Isolates with RVS were significantly more likely to be associated with SCCmec II compared with isolates without RVS (74.7% and 47.3%, respectively, P < 0.001), but not with Panton–Valentine leucocidin (P = 0.10), agr dysfunction (P = 0.19) or healthcare-associated infection (P = 0.36).
The results of our study demonstrate important microbiological characteristics among MRSA isolates characterized by RVS, including a significant association between SCCmec II and elevated vancomycin MIC. It is clear that the clinical and molecular epidemiology of MRSA is evolving, and further understanding of factors determining virulence will be important for the elucidation of optimal treatment approaches for associated infections.
PMCID: PMC3444231  PMID: 22761330
MRSA; virulence factors; antimicrobial resistance; epidemiology
10.  The impact of serum vancomycin levels and minimum inhibitory concentrations of methicillin-resistant Staphylococcus aureus on mortality in patients with nosocomial pneumonia 
Vancomycin is the treatment of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections; however, treatment failure is not uncommon, even when the minimum inhibitory concentration (MIC) of the MRSA strain is within the susceptible range for vancomycin.
To describe the relationship between molecular markers such as the mecA and agrII genes, serum vancomycin levels and vancomycin MICs, and the 30-day mortality rate of patients with nosocomial MRSA pneumonia in an intensive care unit (ICU).
The present study was a prospective cohort study including all patients with MRSA hospital-acquired pneumonia or ventilator-associated pneumonia who were admitted to the ICU of a tertiary care hospital between June 2009 and December 2011. The MIC for vancomycin was determined using the E-test and broth microdilution methods. Variables analyzed included age, sex, comorbid conditions, serum vancomycin trough concentration, the Acute Physiology and Chronic Health Evaluation II (APACHE) score and the presence of the agrII gene. The primary outcome was mortality at 30 days.
Thirty-six (42.4%) patients died within 30 days of the index MRSA culture. A multiple regression analysis that included the variables of MIC (determined using the E-test or broth microdilution methods), APACHE II score, serum vancomycin level and the presence of agrII revealed that only the APACHE II score was related to the 30-day mortality rate (P=0.03). Seven patients (9.0%) with isolates exhibiting an MIC ≥1.5 μg/mL according to the E-test method died, and nine patients (11.6%) survived (P=0.76). Of the patients for whom MICs were determined using the broth microdilution method, 11 (14.1%) patients with MICs of 1.0 μg/mL died, and 16 (20.5%) survived (P=0.92). The median APACHE II score of survivors was 22.5, and the median score of nonsurvivors was 25.0 (P=0.03). The presence of the agrII gene was not related to the 30-day mortality rate.
Patients with severe hospital-acquired pneumonia presented with MRSA isolates with low to intermediate vancomycin MICs in the ICU setting. At the Hospital de Clínicas de Porto Alegre (Porto Alegre, Brazil), the 30-day mortality rate was high, and was similar among patients with severe hospital-acquired pneumonia infected with MRSA isolates that exhibited MICs of ≤1.5 μg/mL determined using the E-test method and ≤1.0 μg/mL determined using the broth microdilution method in those who achieved optimal serum vancomycin levels. The APACHE II scores which provides an overall estimate of ICU mortality were independently associated with mortality in the present study, regardless of the MICs determined. Molecular markers, such as the agrII gene, were not associated with higher mortality in the present study.
PMCID: PMC3852462  PMID: 24421835
Methicillin-resistant Staphylococcus aureus; Nosocomial pneumonia; Vancomycin
11.  The impact of vancomycin susceptibility on treatment outcomes among patients with methicillin resistant Staphylococcus aureus bacteremia 
BMC Infectious Diseases  2011;11:335.
Management of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia remains a challenge. The emergence of MRSA strains with reduced vancomycin susceptibility complicates treatment.
A prospective cohort study (2005-2007) of patients with MRSA bacteremia treated with vancomycin was performed at an academic hospital. Vancomycin minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were determined for stored MRSA isolates. Cox regression analysis was performed to predict 28-day all-cause mortality.
One hundred sixty-three patients with MRSA bacteremia were evaluated. One hundred twelve patients (68.7%) had bacteremia due to MRSA with a vancomycin MIC ≥ 2 ug/mL. Among strains with a vancomycin MIC ≥ 2 ug/mL, 10 isolates (8.9%) were vancomycin-intermediate S. aureus (VISA). Thirty-five patients (21.5%) died within 28 days after the diagnosis of MRSA bacteremia. Higher vancomycin MIC was not associated with mortality in this cohort [adjusted hazard ratio (aHR), 1.57; 95% confidence interval (CI), 0.73-3.37]. Vancomycin tolerance was observed in 4.3% (7/162) of isolates and was not associated with mortality (crude HR, 0.62; 95% CI, 0.08-4.50). Factors independently associated with mortality included higher age (aHR, 1.03; 95% CI 1.00-1.05), cirrhosis (aHR, 3.01; 95% CI, 1.24-7.30), and intensive care unit admission within 48 hours after the diagnosis of bacteremia (aHR, 5.99; 95% CI, 2.86-12.58).
Among patients with MRSA bacteremia treated with vancomycin, reduced vancomycin susceptibility and vancomycin tolerance were not associated with mortality after adjusting for patient factors. Patient factors including severity of illness and underlying co-morbidities were associated with the mortality.
PMCID: PMC3254119  PMID: 22142287
12.  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
13.  High Prevalence of Isolates with Reduced Glycopeptide Susceptibility in Persistent or Recurrent Bloodstream Infections Due to Methicillin-Resistant Staphylococcus aureus 
Reduced susceptibility to glycopeptides in methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates is considered a risk factor for failure of glycopeptide therapy. We compared the prevalences of MRSA isolates with reduced glycopeptide susceptibility in patients with versus without persistent or recurrent MRSA bloodstream infections. A retrospective cohort study at the University Hospital of Geneva identified 27 patients with persistent or recurrent clonally related MRSA bacteremic episodes over an 8-year period, which included 208 consecutive nosocomial MRSA bacteremic episodes. Vancomycin and teicoplanin MICs were determined by a modified macrodilution assay allowing improved detection of glycopeptide-intermediate MRSA isolates (GISA), characterized by elevated teicoplanin or/and vancomycin MICs (≥4 μg/ml). For 16 patients (59%), their pretherapy and/or posttherapy MRSA isolates showed elevated teicoplanin MICs, among which 10 (37%) concomitantly displayed elevated vancomycin MICs. In contrast, 11 other patients (41%) were persistently or recurrently infected with non-GISA isolates. In comparison, only 39 (22%) of 181 single isolates from patients with no microbiological evidence of persistent or recurrent infections showed elevated teicoplanin MICs, among which 14 (8%) concomitantly displayed elevated vancomycin MICs. Clinical, microbiological, and pharmacokinetic variables for patients persistently or recurrently infected with GISA or non-GISA isolates were similar. Bacteremic patients with a poor response to glycopeptide therapy had a 2.8-fold- and 4.8-fold-higher rates of MRSA isolates displaying elevated teicoplanin and vancomycin MICs, respectively, than patients with single isolates (P < 0.0001). Detection of elevated teicoplanin MICs may help to predict a poor response to glycopeptide therapy in MRSA bacteremic patients.
PMCID: PMC3294919  PMID: 22155824
14.  Characterization of heterogeneous vancomycin-intermediate resistance, MIC and accessory gene regulator (agr) dysfunction among clinical bloodstream isolates of staphyloccocus aureus 
BMC Infectious Diseases  2011;11:287.
The development of hVISA has been associated with vancomycin clinical failures and is commonly misidentified in clinical microbiology laboratories. Therefore, the objectives of this present study was to improve the reliability of methodologies and criteria for identifying hVISA, evaluate the prevalence of hVISA among clinical bloodstream isolates of S. aureus and determine if there exists a relationship between accessory gene regulator (agr) dysfunction and the hVISA phenotype.
The presence of hVISA in 220 clinical S. aureus isolates (121 MSSA, 99 MRSA) from bloodstream infections was examined by CLSI broth microdilution, Macro & Standard Etest. Isolates which were classified as hVISA by Macro Etest, were additionally evaluated using a modified PAP-AUC method using a modified starting inoculum of 1010 CFU/mL, and growth on brain heart infusion agar with 4 mg/L vancomycin (BHIV4) at 108 and 1010 CFU/mL, and agr function was assessed by delta-hemolysin production.
Broth microdilution MIC50/90 of S.aureus and hVISA was 1.0/2.0 and 1.5/2.0 mg/L (p= 0.02), respectively. Macro Etest identified 12 (5.5%) hVISA isolates; higher among MRSA (9.1%) versus MSSA (2.5%) (p = 0.03). The mean modified PAP-AUC ratios (> 0.8) of 7 MRSA strains and 3 MSSA strains were significantly different (p = 0.001). 58% of hVISA strains were found to be agr dysfunctional when 21% of MRSA strains were agr dysfunctional. hVISA was detected among S. aureus bloodstream isolates, which were classified as susceptible among clinical microbiology laboratories.
Evaluating the correlation between Etest MICs and modified PAP-AUC ratio values will add further improvement of discriminating hVISA, and agr dysfunction may be predictive of strains which display a greater predilection to display the hVISA phenotype.
PMCID: PMC3215976  PMID: 22026752
15.  Prospective Comparison of the Clinical Impacts of Heterogeneous Vancomycin-Intermediate Methicillin-Resistant Staphylococcus aureus (MRSA) and Vancomycin-Susceptible MRSA▿ †  
Although methicillin (meticillin)-resistant Staphylococcus aureus (MRSA) strains with reduced susceptibility to vancomycin (RVS-MRSA; including vancomycin-intermediate S. aureus [VISA] and heterogeneous VISA [hVISA]) have been linked with vancomycin treatment failure, it is unclear whether they are more pathogenic than vancomycin-susceptible MRSA (VS-MRSA). We prospectively assessed patients with clinical MRSA isolates during a 10-month period to determine clinical status (infection versus colonization) and therapeutic outcome before correlating these findings with the results of detailed in vitro assessment of vancomycin susceptibility, including population analysis profile (PAP) testing. hVISA and VISA were defined by standard PAP criteria (area-under-the-curve ratio compared to that of the reference hVISA strain Mu3 [≥0.9]) and routine CLSI criteria (vancomycin MIC, 4 to 8 μg/ml), respectively. Among the 117 patients assessed, 58 had RVS-MRSA isolates (56 hVISA and 2 VISA) and 59 had VS-MRSA isolates; the patient demographics and comorbidities were similar. RVS-MRSA was associated with a lower rate of infection than VS-MRSA (29/58 versus 46/59; P = 0.003), including a lower rate of bacteremia (3/58 versus 20/59, respectively; P < 0.001). The cure rates in RVS-MRSA and VS-MRSA groups were not statistically different (16/26 versus 31/42; P = 0.43), but the post hoc assessment of treatment regimes and study size made detailed conclusions difficult. The results of the macro method Etest correlated well with the PAP results (sensitivity, 98.3%, and specificity, 91.5%), but broth microdilution and our preliminary RVS-MRSA detection method correlated poorly. All isolates were susceptible to linezolid and daptomycin. These data suggest that detailed prospective laboratory identification of RVS-MRSA isolates may be of limited value and that, instead, such in vitro investigation should be reserved for isolates from patients who are failing appropriate anti-MRSA therapy.
PMCID: PMC2715624  PMID: 19506056
16.  Impact of Reduced Vancomycin MIC on Clinical Outcomes of Methicillin-Resistant Staphylococcus aureus Bacteremia 
Antimicrobial Agents and Chemotherapy  2013;57(11):5536-5542.
Vancomycin has been a key antibiotic agent for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. However, little is known about the relationship between vancomycin MIC values at the higher end of the susceptibility range and clinical outcomes. The aim of this study was to determine the impact of MRSA bacteremia on clinical outcomes in patients with a vancomycin MIC near the upper limit of the susceptible range. Patients with MRSA bacteremia were divided into a high-vancomycin-MIC group (2 μg/ml) and a low-vancomycin-MIC group (≤1.0 μg/ml). We examined the relationship between MIC, genotype, primary source of bacteremia, and mortality. Ninety-four patients with MRSA bacteremia, including 31 with a high vancomycin MIC and 63 with a low MIC were analyzed. There was no significant difference between the presence of agr dysfunction and SCCmec type between the two groups. A higher vancomycin MIC was not found to be associated with mortality. In contrast, high-risk bloodstream infection sources (hazard ratio [HR], 4.63; 95% confidence interval [CI] = 1.24 to 17.33) and bacterial eradication after treatment (HR, 0.06; 95% CI = 0.02 to 0.17), irrespective of vancomycin MIC, were predictors of all-cause 30-day mortality. Our study suggests that a high-risk source of bacteremia is likely to be associated with unfavorable clinical outcomes, but a high vancomycin MIC in a susceptible range, as well as genotype characteristics, are not associated with mortality.
PMCID: PMC3811271  PMID: 23979741
17.  Clinical Characteristics, Outcomes, and Microbiologic Features Associated with Methicillin-Resistant Staphylococcus aureus Bacteremia in Pediatric Patients Treated with Vancomycin ▿  
Journal of Clinical Microbiology  2010;48(3):894-899.
Vancomycin is the first-line therapy for methicillin-resistant Staphylococcus aureus (MRSA) bacteremia, but its efficacy in adult patients has been questioned. Less is known about the outcomes of MRSA bacteremia treated with vancomycin in pediatric patients. This study reviews the outcomes and clinical characteristics of MRSA bacteremia in children treated with vancomycin and characterizes the microbiologic and molecular features of the bloodstream isolates. A retrospective cohort study was conducted among pediatric patients with MRSA bacteremia treated with vancomycin for >5 days from 1 August 2005 to 31 May 2007 in a large tertiary care center. MRSA bloodstream isolates were characterized by antimicrobial susceptibility testing, PCR analysis of virulence genes, and Diversilab typing. Clinical records were reviewed for outcomes and comorbidities. A total of 22 pediatric patients with MRSA bacteremia were identified. Eleven cases (50.0%) were considered vancomycin treatment failures. Features significantly associated with vancomycin treatment failure were prematurity (P = 0.02) and isolates positive for Panton-Valentine leukocidin (PVL) (P = 0.008). Features typically associated with community-associated MRSA strains were identified in hospital-associated isolates. A dominant clone was not responsible for the high number of treatment failures. Further studies are needed to determine if vancomycin should be the first-line treatment for MRSA bacteremia in premature infants and for PVL-positive isolates.
PMCID: PMC2832419  PMID: 20089758
18.  Difference in agr Dysfunction and Reduced Vancomycin Susceptibility between MRSA Bacteremia Involving SCCmec Types IV/IVa and I–III 
PLoS ONE  2012;7(11):e49136.
Dysfunction of agr, with reduced susceptibility or hetero-resistance to vancomycin, is thought to be associated with a worse outcome of methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB). However, the difference in agr dysfunction according to the SCCmec type in MRSA infection is undetermined. We compared the prevalence of agr dysfunction, reduced vancomycin susceptibility and the outcomes of SCCmec IV/IVa and I–III MRSAB.
The study included 307 cases of MRSAB. SCCmec types were determined by multiplex PCR. The clinical and microbiological features and outcomes of 58 SCCmec IV/IVa MRSAB were compared with those of 249 SCCmec I–III MRSAB.
Compared with SCCmec I–III MRSAB, SCCmec IV/IVa MRSAB was associated with lower rates of agr dysfunction (3% vs. 43%), vancomycin minimum inhibitory concentration (MIC) = 2 µg/mL (3% vs. 15%), and hetero-resistance to vancomycin (0% vs. 8%) (all P<0.05). However, the 30-day and S. aureus-related mortality in patients with SCCmec IV/IVa MRSAB were not different from those in patients with SCCmec I–III MRSAB in multivariate analyses (HR 1.168, 95% CI 0.705–1.938; HR 1.025, 95% CI 0.556–1.889).
SCCmec IV/IVa MRSAB was associated with lower rates of agr dysfunction and hetero-resistance to vancomycin and a lower vancomycin MIC, compared with SCCmec I–III MRSAB. However, the outcomes of SCCmec IV/IVa MRSAB did not differ from those of SCCmec I–III MRSAB.
PMCID: PMC3495764  PMID: 23152862
19.  Evaluation of Vancomycin Population Susceptibility Analysis Profile as a Predictor of Outcomes for Patients with Infective Endocarditis Due to Methicillin-Resistant Staphylococcus aureus 
Infective endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA IE) is associated with high morbidity and mortality. Vancomycin continues to be the primary treatment for this disease. The emergence of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA), defined as a modified population analysis profile (PAP) of ≥0.9, may affect patient outcomes. The objective of this study was to evaluate the relationship of vancomycin subpopulation susceptibility and the clinical outcomes of MRSA IE. We conducted a retrospective cohort study of patients treated with vancomycin for MRSA IE from 2002 to 2013 at the Detroit Medical Center. A modified PAP was used to measure the vancomycin PAP MIC and the PAP-to-area under the curve (AUC) ratio. Treatment failure was defined as bacteremia for ≥7 days or death attributed to MRSA. Classification and regression tree (CART) analysis was used to select a failure breakpoint between the PAP-AUC ratios and the PAP MIC. A total of 202 patients were included in the study. Twenty-seven percent of the patients had left-sided IE, 19% of the strains were hVISA, and 70% of the strains were staphylococcal cassette chromosome mec element (SCCmec) type IV. Overall treatment failure was observed in 64%; 59% had persistent bacteremia, and the 30-day attributable mortality rate was 21%. The CART breakpoint between failure and success in terms of the PAP-AUC ratio was 0.9035. On logistic regression analysis, intensive care unit (ICU) admission (adjusted odds ratio [aOR], 2.8; 95% confidence interval [CI], 1.5 to 5.2) and a PAP MIC of ≥4 mg/liter (aOR, 3.2; 95% CI, 1.3 to 8.4) were associated with failure (P = 0.001 and 0.015, respectively). A PAP MIC of ≥4 mg/liter and ICU admission were significant for treatment failure for patients with MRSA IE. The PAP-AUC ratio of ≥0.9035 predicted failure consistent with the hVISA definition. The role of population MIC analysis in predicting outcome with MRSA infections warrants further investigation.
PMCID: PMC4136033  PMID: 24890596
20.  Isolation of Asian endemic and livestock associated clones of methicillin resistant Staphylococcus aureus from ocular samples in Northeastern Iran 
Iranian Journal of Microbiology  2013;5(3):227-232.
Background and Objectives
Methicillin Resistant Staphylococcus aureus (MRSA) strains are divided into Community Associated (CA-) and Hospital Associated (HA-) MRSA. These strains vary in antimicrobial resistance and pathogenicity. S. aureus is one of the most common microorganisms in ocular infections. This study was aimed to determine antimicrobial resistance patterns and genetic characteristics of MRSA strains isolated from ocular infections in Iran.
Material and Methods
Out of 171 S. aureus strains isolated from various clinical samples during September-December 2011 at Mashhad Emam Reza Hospital, 3 were cultured from eye discharge samples. Antimicrobial resistance tests were performed with MIC and disk diffusion methods and also genetic evaluation was done with Staphylococcal Cassette Chromosome mec (SCCmec), Accessory Gene Regulator (agr) and Staphylococcal Protein A (spa) typing, Multi Locus Sequence Typing (MLST) and determination of toxin gene profile.
All strains were MRSA and showed resistance to tetracycline, gentamicin and clindamycin too. Vancomycin, minocyclin and trimethoprim/sulfamethoxazole were effective on all ocular isolates. All isolates belonged to SCCmec IV type. MRSA1 belonged to ST239, CC8, Spa type t7688 and agrIII and had tst1 and hla toxin genes. MRSA2 belonged to ST239, CC8, Spa type t037 and agrI and had the hla toxin gene. Finally, MRSA3 belonged to ST291, CC398, Spa type t304, and agrI and had pvl and hla toxin genes.
Phenotypic and genotypic evaluation of the isolated MRSA strains revealed that these strains belong to endemic Asian and livestock related clones that could reach from other body sites or environment to the eye of patients and developed ocular infection.
PMCID: PMC3895559  PMID: 24475328
Staphylococcus aureus; MRSA; MLST; Spa typing; SCCmec type; agr; ocular infection
21.  Impact of accessory gene regulator (agr) dysfunction on vancomycin pharmacodynamics among Canadian community and health-care associated methicillin-resistant Staphylococcus aureus 
The accessory gene regulator (agr) is a quorum sensing cluster of genes which control colonization and virulence in Staphylococcus aureus. We evaluated agr function in community- (CA) and healthcare-associated (HA) MRSA, to compare the pharmacodynamics and bactericidal activity of vancomycin against agr functional and dysfunctional HA-MRSA and CA-MRSA.
40 clinical isolates of MRSA from the Canadian Nosocomial Infection Surveillance Program were evaluated for delta-haemolysin production, as a surrogate marker of agr function. Time kill experiments were performed for vancomycin at 0 to 64 times the MIC against an initial inoculum of 106 and 108 cfu/ml of agr functional and dysfunctional CA-MRSA and HA-MRSA and these data were fit to a hill-type pharmacodynamic model.
15% isolates were agr dysfunctional, which was higher among HA-MRSA (26.3%) versus CA-MRSA (4.76%). Against a low initial inoculum of 106 cfu/ml of CA-MRSA, vancomycin pharmacodynamics were similar among agr functional and dysfunctional strains. However, against a high initial inoculum of 108 cfu/ml, killing activity was notably attenuated against agr dysfunctional CA-MRSA (USA400) and HA-MRSA (USA100). CA-MRSA displayed a 20.0 fold decrease in the maximal reduction in bacterial counts (Emax) which was 3.71 log10 CFU/ml for agr functional vs. 2.41 log10 CFU/ml for agr dysfunctional MRSA (p = 0.0007).
Dysfunction in agr was less common among CA-MRSA vs. HA-MRSA. agr dysfunction demonstrated an impact on vancomycin bactericidal activity and pharmacodynamics against a high initial inoculum of CA-MRSA and HA-MRSA, which may have implications for optimal antimicrobial therapy against persistent, difficult to treat MRSA infections.
PMCID: PMC3120648  PMID: 21599878
22.  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
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.  Molecular features of heterogeneous vancomycin-intermediate Staphylococcus aureus strains isolated from bacteremic patients 
BMC Microbiology  2009;9:189.
Heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) bacteremia is an emerging infection. Our objective was to determine the molecular features of hVISA strains isolated from bacteremic patients and to compare them to methicillin resistant S. aureus (MRSA) and methicillin sensitive S. aureus (MSSA) blood isolates.
We assessed phenotypic and genomic changes of hVISA (n = 24), MRSA (n = 16) and MSSA (n = 17) isolates by PCR to determine staphylococcal chromosomal cassette (SCCmec) types, Panton-Valentine leukocidin (PVL) and the accessory gene regulator (agr) loci. Biofilm formation was quantified. Genetic relatedness was assessed by PFGE. PFGE analysis of isolates was diverse suggesting multiple sources of infection. 50% of hVISA isolates carried SCCmec type I, 21% type II; 25% type V; in 4% the SCCmec type could not be identified. Among MRSA isolates, 44% were SCCmec type I, 12.5% type II, 25% type V, 12.5% were non-typable, and 6% were SCCmec type IVd. Only one hVISA isolate and two MSSA isolates carried the PVL. Biofilm formation and agr patterns were diverse.
hVISA isolates were diverse in all parameters tested. A considerable number of hVISA and MRSA strains carried the SCCmec type V cassette, which was not related to community acquisition.
PMCID: PMC2749053  PMID: 19732456
25.  Reduced Vancomycin Susceptibility Found in Methicillin-Resistant and Methicillin-Sensitive Staphylococcus aureus Clinical Isolates in Northeast China 
PLoS ONE  2013;8(9):e73300.
Strains of Staphylococcus aureus with an intermediate level of resistance to vancomycin (vancomycin-intermediate S. aureus, or VISA) or which contain subpopulations of mixed susceptibility (heterogeneous VISA, or hVISA) have been reported worldwide. However, the prevalence of VISA and hVISA infections in Northeast China is unknown. From 2007 through 2010, we surveyed the vancomycin susceptibility of methicillin-resistant and methicillin-sensitive S. aureus (MRSA and MSSA, respectively) clinical isolates in Northeast China.
S. aureus clinical isolates (369 MRSA and 388 MSSA) were screened for hVISA and VISA on brain heart infusion agar containing 3 μg/mL vancomycin, and their identity confirmed using a modified population analysis profile-area under the curve method and broth microdilution. All hVISA and VISA isolates were characterized genotypically and phenotypically.
Ten percent and 0.5 percent of the isolates were hVISA and VISA, respectively. The proportion of hVISA among MSSA isolates for the entire study period was 4.1%, but increased significantly year-by-year, from 1.2% in 2007 to 7.2% in 2010. The predominant sources of hVISA and VISA isolates were sputum (56.3%), pus (18.8%), and blood (8.8%). Molecular typing of hVISA and VISA strains revealed that, taken together, 80% contained the accessory gene regulator (agr) group II, and of these, 85.7% of the MR-hVISA and MR-VISA strains were staphylococcal cassette chromosome mec (SCCmec) type II. The adherence ability of all hVISA and VISA strains was reduced compared with that of vancomycin-susceptible strains, shown by biofilm assay.
The percentage of hVISA strains was high and increased each year. The proportion of hVISA among MSSA specifically also increased significantly each year. In isolates collected from diverse infection sites, hVISA and VISA strains were found predominantly in sputum, pus, and blood, in descending order. Testing for vancomycin susceptibility should include both MRSA and MSSA isolates collected from different clinical sites.
PMCID: PMC3772004  PMID: 24069184

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