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1.  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
2.  Activity of Telavancin against Staphylococcus aureus Strains with Various Vancomycin Susceptibilities in an In Vitro Pharmacokinetic/Pharmacodynamic Model with Simulated Endocardial Vegetations ▿  
We investigated the activity of telavancin, a novel lipoglycopeptide, alone and combined with gentamicin or rifampin (rifampicin) against strains of Staphylococcus aureus with various vancomycin susceptibilities. Strains tested included methicillin (meticillin)-resistant S. aureus (MRSA) 494, methicillin-sensitive S. aureus (MSSA) 1199, heteroresistant glycopeptide-intermediate S. aureus (hGISA) 1629, which was confirmed by a population analysis profile, and glycopeptide-intermediate S. aureus (GISA) NJ 992. Regimens of 10 mg/kg telavancin daily and 1 g vancomycin every 12 h were investigated alone and combined with 5 mg/kg gentamicin daily or 300 mg rifampin every 8 h in an in vitro model with simulated endocardial vegetations over 96 h. Telavancin demonstrated significantly greater killing than did vancomycin (P < 0.01) for all isolates except MRSA 494 (P = 0.07). Telavancin absolute reductions, in log10 CFU/g, at 96 h were 2.8 ± 0.5 for MRSA 494, 2.8 ± 0.3 for MSSA 1199, 4.2 ± 0.2 for hGISA 1629, and 4.1 ± 0.3 for GISA NJ 992. Combinations of telavancin with gentamicin significantly enhanced killing compared to telavancin alone against all isolates (P < 0.001) except MRSA 494 (P = 0.176). This enhancement was most evident against hGISA 1629, where killing to the level of detection (2 log10 CFU/g) was achieved at 48 h (P < 0.001). The addition of rifampin to telavancin resulted in significant (P < 0.001) enhancement of killing against only MSSA 1199. No changes in telavancin susceptibilities were observed. These results suggest that telavancin may have therapeutic potential, especially against strains with reduced susceptibility to vancomycin. Combination therapy, particularly with gentamicin, may improve bacterial killing against certain strains.
PMCID: PMC2704675  PMID: 19414568
3.  Community-associated Methicillin-resistant Staphylococcus aureus Bacteremia and Endocarditis among HIV Patients: A cohort study 
BMC Infectious Diseases  2011;11:298.
HIV patients are at increased risk of development of infections and infection-associated poor health outcomes. We aimed to 1) assess the prevalence of USA300 community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) among HIV-infected patients with S. aureus bloodstream infections and. 2) determine risk factors for infective endocarditis and in-hospital mortality among patients in this population.
All adult HIV-infected patients with documented S. aureus bacteremia admitted to the University of Maryland Medical Center between January 1, 2003 and December 31, 2005 were included. CA-MRSA was defined as a USA300 MRSA isolate with the MBQBLO spa-type motif and positive for both the arginine catabolic mobile element and Panton-Valentin Leukocidin. Risk factors for S. aureus-associated infective endocarditis and mortality were determined using logistic regression to calculate odds ratios (OR) and 95% confidence intervals (CI). Potential risk factors included demographic variables, comorbid illnesses, and intravenous drug use.
Among 131 episodes of S. aureus bacteremia, 85 (66%) were MRSA of which 47 (54%) were CA-MRSA. Sixty-three patients (48%) developed endocarditis and 10 patients (8%) died in the hospital on the index admission Patients with CA-MRSA were significantly more likely to develop endocarditis (OR = 2.73, 95% CI = 1.30, 5.71). No other variables including comorbid conditions, current receipt of antiretroviral therapy, pre-culture severity of illness, or CD4 count were significantly associated with endocarditis and none were associated with in-hospital mortality.
CA-MRSA was significantly associated with an increased incidence of endocarditis in this cohort of HIV patients with MRSA bacteremia. In populations such as these, in which the prevalence of intravenous drug use and probability of endocarditis are both high, efforts must be made for early detection, which may improve treatment outcomes.
PMCID: PMC3214174  PMID: 22040268
4.  Investigation of Reduced Susceptibility to Glycopeptides among Methicillin-Resistant Staphylococcus aureus Isolates from Patients in Ireland and Evaluation of Agar Screening Methods for Detection of Heterogeneously Glycopeptide-Intermediate S. aureus▿  
Journal of Clinical Microbiology  2007;45(10):3263-3269.
Methicillin-resistant Staphylococcus aureus (MRSA) isolates (n = 3,189) from 2,990 patients were investigated by agar screening and by the Etest macromethod for reduced susceptibility to glycopeptide. No vancomycin-resistant S. aureus or glycopeptide-intermediate S. aureus (GISA) isolates were detected, but 178 isolates were confirmed as hetero-GISA (hGISA) by vancomycin population analysis profile (vPAP)-area under the curve (AUC) ratio determination and/or teicoplanin PAP (tPAP) methods. Of 139 isolates detected using the recommended Etest macromethod cutoff values of ≥8 mg/liter for both vancomycin and teicoplanin or ≥12 mg/liter for teicoplanin alone, 73 were confirmed as hGISA by vPAP-AUC, 95 were confirmed as hGISA by tPAP, and 108 were confirmed as hGISA by both methods. An Etest macromethod cutoff value of 8 mg/liter for teicoplanin alone detected a further 70 hGISA (17 were confirmed by vPAP-AUC and 70 were confirmed by tPAP). Agar screening utilizing brain heart infusion (BHI) agar containing 6 mg of vancomycin/liter (BHIV6) and Mueller-Hinton (MH) agar containing 8 mg of teicoplanin/liter (MHT8) failed to detect hGISA. MH agar containing 5 mg of teicoplanin/liter (MHT5) and BHI containing 5 mg of teicoplanin/liter (BHIT5) were evaluated using 10-μl volumes of three inoculum concentrations (with densities equivalent to 0.5 and 2.0 McFarland turbidity standards and stationary-phase BHI broth subcultures [MHT50.5, MHT52.0, MHT5S, BHIT50.5, BHIT52.0, and BHIT5S]). The sensitivity of all methods except MHT50.5 and MHT52.0 was 100%. The specificity ranged from 4 to 82%. BHIT50.5 yielded the best performance, with a specificity of 84% for detecting isolates with teicoplanin Etest macromethod values of ≥8 mg/liter. Screening on BHIT50.5 is useful where screen-positive isolates are investigated with the Etest macromethod and confirmed by vPAP-AUC and tPAP. The prevalence of hGISA among patients with blood culture isolates recovered in Irish hospitals between 1999 and 2003 was 2.6%, whereas the prevalence among patients with isolates from all specimen sites collected during a 2-week survey in 1999 was 12%. The prevalence in one hospital decreased from 5.3% in 2003 to 1.5% in 2004.
PMCID: PMC2045355  PMID: 17687008
5.  USA300 Methicillin-Resistant Staphylococcus aureus Bacteremia and the Risk of Severe Sepsis: Is USA300 MRSA Associated with More Severe Infections? 
USA300 methicillin-resistant Staphylococcus aureus (MRSA) is increasing as a cause of severe community-associated bacteremic infections. We assessed severe sepsis in response to infection in patients with USA300 MRSA compared to non-USA300 MRSA bacteremia.
A cohort study was conducted from 1997–2008 comparing sepsis in response to infection in 271 patients with MRSA bacteremia from four VA hospitals.
Sixty-seven (25%) patients with MRSA bacteremia were USA300 MRSA; 204 (75%) were non-USA300 MRSA. The proportion of MRSA bacteremia caused by USA300 MRSA increased over time (χ2 p<0.0001). Adjusting for age and nosocomial infection, patients with USA300 MRSA bacteremia were more likely to have severe sepsis or septic shock in response to infection than patients with non-USA300 MRSA bacteremia (adjusted Relative Risk=1.82; 95% CI: 1.16–2.87; p=0.01).
This suggests that patients with USA300 MRSA are more likely to develop severe sepsis in response to their infection, which could be due to host or bacterial differences.
PMCID: PMC3118841  PMID: 21558047
6.  Prevalence, Molecular Epidemiology, and Clinical Significance of Heterogeneous Glycopeptide-Intermediate Staphylococcus aureus in Liver Transplant Recipients 
Journal of Clinical Microbiology  2003;41(11):5147-5152.
We investigated the prevalence, molecular epidemiology, and clinical significance of heterogeneous glycopeptide-intermediate Staphylococcus aureus (hGISA) isolates in 48 liver transplant recipients infected or colonized with methicillin-resistant S. aureus over a 5-year period. Strains were screened for hGISA on Mueller-Hinton agar containing 5 mg of teicoplanin per liter. Heterogeneous glycopeptide resistance was confirmed by the E-test method with a dense inoculum and a simplified method of population analysis. hGISA strains were found in 13 (27%) of the 48 patients studied. Eleven of the 13 strains shared a common multiresistant phenotype with homogeneous methicillin resistance and gentamicin resistance, and they were closely related according to the results of pulsed-field gel electrophoresis. Only 2 of the 13 patients infected or colonized with hGISA strains had previously received glycopeptide therapy. Most patients were successfully treated with vancomycin, but one patient who failed to respond to vancomycin subsequently died. These results suggest that the high prevalence of hGISA among our patients was due to the clonal spread of a multiresistant strain.
PMCID: PMC262463  PMID: 14605151
7.  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
8.  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
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.  Methicillin-resistant Staphylococcus aureus endocarditis and de novo development of daptomycin resistance during therapy 
Daptomycin resistance in Staphylococcus aureus has been previously reported, but the development of resistance while on therapy with subsequent clinical failure for endocarditis has been infrequently reported. A case of persistent methicillin-resistant S aureus (MRSA) bacteremia in the setting of right-sided endocarditis in a 38-year-old man with a history of intravenous drug use is presented. He developed de novo resistance to daptomycin during therapy after several courses of antibiotics, with subsequent clinical failure. Isolates were identified by molecular characterization to be community-acquired MRSA 10 (USA300). To the authors’ knowledge, the present case was the first in Canada to involve the de novo development of daptomycin resistance with clinical failure due to MRSA during therapy for endocarditis. Clinicians and microbiologists must be aware of this phenomenon given the implications for treatment and transmission of the strain. It also raises questions regarding the use of daptomycin in settings of heavily pretreated patients with persistent MRSA bacteremia.
PMCID: PMC2912106  PMID: 21629617
Daptomycin; Endocarditis; MRSA; Resistance
11.  Methicillin-Susceptible Staphylococcus aureus as a Predominantly Healthcare-Associated Pathogen: A Possible Reversal of Roles? 
PLoS ONE  2011;6(4):e18217.
Methicillin-resistant Staphylococcus aureus (MRSA) strains have become common causes of skin and soft tissue infections (SSTI) among previously healthy people, a role of methicillin-susceptible (MSSA) isolates before the mid-1990s. We hypothesized that, as MRSA infections became more common among S. aureus infections in the community, perhaps MSSA infections had become more important as a cause of healthcare-associated infection.
We compared patients, including children and adults, with MRSA and MSSA infections at the University of Chicago Medical Center (UCMC) from all clinical units from July 1, 2004-June 30, 2005; we also compared the genotypes of the MRSA and MSSA infecting bacterial strains.
Compared with MRSA patients, MSSA patients were more likely on bivariate analysis to have bacteremia, endocarditis, or sepsis (p = 0.03), to be an adult (p = 0.005), to be in the intensive care unit (21.9% vs. 15.6%) or another inpatient unit (45.6% vs. 40.7%) at the time of culture. MRSA (346/545) and MSSA (76/114) patients did not differ significantly in the proportion classified as HA-S. aureus by the CDC CA-MRSA definition (p = 0.5). The genetic backgrounds of MRSA and MSSA multilocus sequence type (ST) 1, ST5, ST8, ST30, and ST59 comprised in combination 94.5% of MRSA isolates and 50.9% of MSSA isolates. By logistic regression, being cared for in the Emergency Department (OR 4.6, CI 1.5-14.0, p = 0.008) was associated with MRSA infection.
Patients with MSSA at UCMC have characteristics consistent with a health-care-associated infection more often than do patients with MRSA; a possible role reversal has occurred for MSSA and MRSA strains. Clinical MSSA and MRSA strains shared genotype backgrounds.
PMCID: PMC3076382  PMID: 21533238
12.  High Percentage of Methicillin-Resistant Staphylococcus aureus Isolates with Reduced Susceptibility to Glycopeptides in The Netherlands 
Journal of Clinical Microbiology  2003;41(6):2487-2491.
While testing the in vitro activities of 14 antimicrobial agents against 107 methicillin-susceptible Staphylococcus aureus (MSSA) and 250 methicillin-resistant S. aureus (MRSA) isolates collected in The Netherlands, we found to our surprise that 19 (7.6%) MRSA isolates were suspected of having reduced susceptibilities to the glycopeptides when the Etest system (AB Biodisk, Solna, Sweden) was used with a large inoculum (no. 2 McFarland standard) and an extended incubation time (48 h) on brain heart infusion agar for MIC testing. Eventually, 15 of these isolates were classified as heterogeneously resistant to glycopeptides (heterogeneously glycopeptide-intermediate S. aureus [hGISA] isolates) according to the population analysis profile-area under the curve analysis. The MICs at which 50 and 90% of isolates are inhibited obtained with the Etest system with the large inoculum were as follows: for MSSA isolates, 3.0 and 4.0 μg/ml, respectively, for both teicoplanin and vancomycin; for MRSA isolates, 3.0 and 8.0 μg/ml, respectively, for teicoplanin, and 3.0 and 4.0 μg/ml, respectively, for vancomycin. This is the first report of hGISA isolates in The Netherlands.
PMCID: PMC156556  PMID: 12791870
13.  Clinical Significance of Varying Degrees of Vancomycin Susceptilibity in Methicillin-Resistant Staphylococcus aureus Bacteremia1 
Emerging Infectious Diseases  2003;9(6):657-664.
We conducted a retrospective study of the clinical aspects of bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) with heterogeneously reduced susceptibility to vancomycin. Bloodstream MRSA isolates were screened for reduced susceptibility by using brain-heart infusion agar, including 4 mg/L vancomycin with and without 4% NaCl. Patients whose isolates exhibited growth (case-patients) were compared with those whose isolates did not (controls) for demographics, coexisting chronic conditions, hospital events, antibiotic exposures, and outcomes. Sixty-one (41%) of 149 isolates exhibited growth. Subclones from 46 (75%) of these had a higher MIC of vancomycin than did their parent isolates. No isolates met criteria for vancomycin heteroresistance. No differences in potential predictors or in outcomes were found between case-patients and controls. These data show that patients with vancomycin-susceptible MRSA bacteremia have similar baseline clinical features and outcomes whether or not their bacterial isolates exhibit growth on screening media containing vancomycin.
PMCID: PMC3000153  PMID: 12781004
Staphylococcus aureus; methicillin resistance; vancomycin resistance; drug resistance; bacterial; bacteremia; bacterial infections; research
14.  Staphylococcus aureus Colonization Among Household Contacts of Patients With Skin Infections: Risk Factors, Strain Discordance, and Complex Ecology 
Among 350 households of patients with Staphylococcus aureus skin infections, extra-nasal S. aureus colonization was common. USA300 MRSA appeared more transmissible among household members than other S. aureus strain types. Multiple S. aureus genetic backgrounds were present in many households.
Background. The USA300 methicillin resistant Staphylococcus aureus (MRSA) genetic background has rapidly emerged as the predominant cause of community-associated S. aureus infections in the U.S. However, epidemiologic characteristics of S. aureus household transmission are poorly understood.
Methods. We performed a cross-sectional study of adults and children with S. aureus skin infections and their household contacts in Los Angeles and Chicago. Subjects were surveyed for S. aureus colonization of the nares, oropharynx, and inguinal region and risk factors for S. aureus disease. All isolates underwent genetic typing.
Results. We enrolled 1162 persons (350 index patients and 812 household members). The most common infection isolate characteristic was ST8/SCCmec IV, PVL+ MRSA (USA300) (53%). S. aureus colonized 40% (137/350) of index patients and 50% (405/812) of household contacts. A nares-only survey would have missed 48% of S. aureus and 51% of MRSA colonized persons. Sixty-five percent of households had >1 S. aureus genetic background identified and 26% of MRSA isolates in household contacts were discordant with the index patients' infecting MRSA strain type. Factors independently associated (P < .05) with the index strain type colonizing household contacts were recent skin infection, recent cephalexin use, and USA300 genetic background.
Conclusions. In our study population, USA300 MRSA appeared more transmissible among household members compared with other S. aureus genetic backgrounds. Strain distribution was complex; >1 S. aureus genetic background was present in many households. S. aureus decolonization strategies may need to address extra-nasal colonization and the consequences of eradicating S. aureus genetic backgrounds infrequently associated with infection.
PMCID: PMC3348950  PMID: 22474221
15.  Methicillin-Resistant Staphylococcus aureus, Samoa, 2007–2008 
Emerging Infectious Diseases  2011;17(6):1023-1029.
TOC Summary: A wide range of MRSA genotypes cause wound infections.
Little is known about the epidemiology of methicillin-resistant Staphylococcus aureus (MRSA) in most Pacific Island nations. Relatively high rates of MRSA have been reported in Polynesian people living outside the Pacific Islands. To determine the prevalence and characteristics of MRSA, we assessed wound swabs from 399 persons with skin and soft tissue infection living in Samoa. MRSA was isolated from 9% of study participants; 34 of the 196 S. aureus isolates were MRSA. Five MRSA genotypes were identified; the 3 most common were USA300, the Queensland clone, and a sequence type 1 MRSA strain that shares <85% homology with the sequence type 1 MRSA strain common in the region (WA MRSA-1). The Southwest Pacific MRSA clone was identified but accounted for only 12% of MRSA isolates. The high prevalence of MRSA in Samoa provides impetus for initiatives to improve antimicrobial drug resistance surveillance, infection control, and antimicrobial drug use in Pacific Island nations.
PMCID: PMC3358195  PMID: 21749763
Staphylococcus aureus; methicillin-resistant Staphylococcus aureus; wound infection; soft tissue infection; drug resistance; bacteria; Samoa; research
16.  Predictors and clinical outcomes of persistent methicillin-resistant Staphylococcus aureus bacteremia: a prospective observational study 
The high mortality attributable to persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia in spite of glycopeptide treatment has heightened the need for early detection and intervention with alternative agents. The purpose of this study was to determine the clinical characteristics of and risk factors for persistent MRSA bacteremia.
All first episodes of significant MRSA bacteremia at a 710-bed academic medical center from November 2009 through August 2010 were recorded. Blood cultures were conducted at 3 days and every 2 to 3 days thereafter until clearance. Clinical characteristics and outcomes were compared between persistent MRSA bacteremia (≥ 7 days) and nonpersistent MRSA bacteremia (≤ 3 days).
Of 79 patients with MRSA bacteremia during the study period, 31 (39.2%) had persistent MRSA bacteremia. The persistent MRSA bacteremia group had significantly higher 30-day mortality than the nonpersistent MRSA bacteremia group (58.1% vs. 16.7%, p < 0.001). Multivariate analysis indicated that metastatic infection at presentation (odds ratio [OR], 14.57; 95% confidence interval [CI], 3.52 to 60.34; p < 0.001) and delayed catheter removal in catheter-related infection (OR, 3.80; 95% CI, 1.04 to 13.88; p = 0.004) were independent predictors of persistent MRSA bacteremia. Patients with a time to blood culture positivity (TTP) of < 11.8 hours were at increased risk of persistent MRSA bacteremia (29.0% vs. 8.3%, p = 0.029).
High mortality in patients with persistent MRSA bacteremia was noted. Early detection of metastatic infection and early removal of infected intravascular catheters should be considered to reduce the risk of persistent MRSA bacteremia. Further studies are needed to evaluate the role of TTP for predicting persistent MRSA bacteremia.
PMCID: PMC3846993  PMID: 24307843
Methicillin-resistant Staphylococcus aureus; Mortality; Persistent
17.  In Vitro Activity of Daptomycin against Methicillin-Resistant Staphylococcus aureus, Including Heterogeneously Glycopeptide-Resistant Strains 
The purpose of the present study was to assess the in vitro activity of daptomycin against a well-defined collection of methicillin-resistant Staphylococcus aureus (MRSA) isolates (n = 98), including heterogeneously glycopeptide-resistant MRSA (hGISA) strains. Susceptibility testing was performed by using the Etest system. Daptomycin was potent against both glycopeptide-susceptible and hGISA strains.
PMCID: PMC1563506  PMID: 16940127
18.  Reduced Susceptibility of Staphylococcus aureus to Vancomycin and Platelet Microbicidal Protein Correlates with Defective Autolysis and Loss of Accessory Gene Regulator (agr) Function 
Loss of agr function, vancomycin exposure, and abnormal autolysis have been linked with both development of the GISA phenotype and low-level resistance in vitro to thrombin-induced platelet microbicidal proteins (tPMPs). We examined the potential in vitro interrelationships among these parameters in well-characterized, isogenic laboratory-derived and clinical Staphylococcus aureus isolates. The laboratory-derived S. aureus strains included RN6607 (agrII-positive parent) and RN6607V (vancomycin-passaged variant; hetero-GISA), RN9120 (RN6607 agr::tetM; agr II knockout parent), RN9120V (vancomycin-passaged variant), and RN9120-GISA (vancomycin passaged, GISA). Two serial isolates from a vancomycin-treated patient with recalcitrant, methicillin-resistant S. aureus (MRSA) endocarditis were also studied: A5937 (agrII-positive initial isolate) and A5940 (agrII-defective/hetero-GISA isolate obtained after prolonged vancomycin administration). In vitro tPMP susceptibility phenotypes were assessed after exposure of strains to either 1 or 2 μg/ml. Triton X-100- and vancomycin-induced lysis profiles were determined spectrophotometrically. For agrII-intact strain RN6607, vancomycin exposure in vitro was associated with modest increases in vancomycin MICs and reduced killing by tPMP, but no change in lysis profiles. In contrast, vancomycin exposure of agrII-negative RN9120 yielded a hetero-GISA phenotype and was associated with defects in lysis and reduced in vitro killing by tPMP. In the clinical isolates, loss of agrII function during prolonged vancomycin therapy was accompanied by emergence of the hetero-GISA phenotype and reduced tPMP killing, with no significant change in lysis profiles. An association was identified between loss of agrII function and the emergence of hetero-GISA phenotype during either in vitro or in vivo vancomycin exposure. In vitro, these events were associated with defective lysis and reduced susceptibility to tPMP. The precise mechanism(s) underlying these findings is the subject of current investigations.
PMCID: PMC1168700  PMID: 15980337
19.  Concurrent Epidemics of Skin and Soft Tissue Infection and Bloodstream Infection Due to Community-Associated Methicillin-Resistant Staphylococcus aureus 
The USA300 clone of methicillin-resistant Staphylococcus aureus causes concurrent epidemics of skin and soft tissue infections (SSTIs) and bloodstream infections (BSIs). Because USA300 SSTIs serve as a source for BSIs, strategies to control the USA300 SSTI epidemic may lessen the severity of the USA300 BSI epidemic.
Background. Since its emergence in 2000, epidemic spread of the methicillin-resistant Staphylococcus aureus (MRSA) clone USA300 has led to a high burden of skin and soft tissue infections (SSTIs) in the United States, yet its impact on MRSA bloodstream infections (BSIs) is poorly characterized.
Methods. To assess clonality of the MRSA isolates causing SSTI and BSI during the epidemic period, a stratified, random sample of 1350 unique infection isolates (from a total of 7252) recovered at the Community Health Network of San Francisco from 2000 to 2008 were selected for genotyping. Risk factors and outcomes for 549 BSI cases caused by the USA300 epidemic clone and non-USA300 MRSA clones were assessed by retrospective review of patient medical records.
Results. From 2000 to 2008, secular trends of USA300 SSTI and USA300 BSI were strongly correlated (Pearson r = 0.953). USA300 accounted for 55% (304/549) of BSIs as it was the predominant MRSA clone that caused community-associated (115/160), healthcare-associated community-onset (125/207), and hospital-onset (64/182) BSIs. Length of hospitalization after BSI diagnosis and mortality rates for USA300 and non-USA300 were similar. Two independent risk factors for USA300 BSI were identified: concurrent SSTI (adjusted relative risk, 1.4 [95% confidence interval {CI}, 1.2–1.6]) and anti-MRSA antimicrobial use in the preceding 30 days (0.7 [95% CI, .6–.8]). Isolates from concurrent SSTI were indistinguishable genotypically from the USA300 isolates that caused BSI.
Conclusions. USA300 SSTIs serve as a source for BSI. Strategies to control the USA300 SSTI epidemic may lessen the severity of the concurrent USA300 BSI epidemic.
PMCID: PMC3657511  PMID: 22670044
20.  Heterogeneous Vancomycin-Intermediate Susceptibility Phenotype in Bloodstream Methicillin-Resistant Staphylococcus aureus Isolates from an International Cohort of Patients with Infective Endocarditis: Prevalence, Genotype, and Clinical Significance 
The Journal of infectious diseases  2009;200(9):1355-1366.
The significance of heterogeneous vancomycin-intermediate Staphylococcus aureus (hVISA) is unknown. Using a multinational collection of isolates from methicillin-resistant S. aureus (MRSA) infective endocarditis (IE), we characterized IE patients with and without hVISA, and genotyped the infecting strains.
MRSA bloodstream isolates from 65 patients with definite IE from 8 countries underwent PCR for 31 virulence genes, pulsed-field gel electrophoresis, and multilocus sequence typing. hVISA was defined using population analysis profiling (PAP).
Nineteen (29.2%) of 65 MRSA IE isolates exhibited hVISA by PAP. Isolates from Oceania and Europe were more likely to exhibit hVISA than isolates from the United States (77.8% vs. 35.0% vs. 13.9%; P < .001). The prevalence of hVISA was higher among isolates with a vancomycin minimum inhibitory concentration of 2 mg/L (P = .026). hVISA-infected patients were more likely to have persistent bacteremia (68.4% vs. 37.0%; P = .029) and heart failure (47.4% vs. 19.6%; P = .033). Mortality of hVISA- and non-hVISA-infected patients did not differ (42.1% vs. 34.8%, P = .586). hVISA and non-hVISA isolates were genotypically similar.
In these analyses, hVISA occurred in over one-quarter of MRSA IE isolates, was associated with certain IE complications, and varied in frequency by geographic region.
PMCID: PMC3600359  PMID: 19811099
hVISA; Methicillin-resistant Staphylococcus aureus; endocarditis; genotype
21.  Changing Italian nosocomial-community trends and heteroresistance in Staphylococcus aureus from bacteremia and endocarditis 
Bloodstream infections due to Staphylococcus aureus (BSI) are serious infections both in hospitals and in the community, possibly leading to infective endocarditis (IE). The use of glycopeptides has been recently challenged by various forms of low-level resistance. This study evaluated the distribution of MSSA and MRSA isolates from BSI and IE in 4 Italian hospitals, their antibiotic susceptibility—focusing on the emergence of hVISA—and genotypic relationships. Our results demonstrate that the epidemiology of MRSA is changing versus different STs possessing features between community-acquired (CA)- and hospital-acquired (HA)-MRSA groups; furthermore, different MSSA isolated from BSI and IE were found, with the same backgrounds of the Italian CA-MRSA. The hVISA phenotype was very frequent (19.5%) and occurred more frequently in isolates from IE and in both the MSSA and MRSA strains. As expected, hVISA were detected in MRSA with vancomycin minimum inhibitory concentrations (MICs) of 1–2 mg/l, frequently associated with the major SCCmec I and II nosocomial clones; this phenotype was also detected in some MSSA strains. The few cases of MR-hVISA infections evaluated in our study demonstrated that 5 out of 9 patients (55%) receiving a glycopeptide, died. Future studies are required to validate these findings in terms of clinical impact.
PMCID: PMC3319882  PMID: 21822974
22.  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
23.  Accessory Gene Regulator (agr) Dysfunction in Staphylococcus aureus Bloodstream Isolates from South Korean Patients 
We describe the genetic and microbiological characteristics of methicillin-resistant Staphylococcus aureus (MRSA) bloodstream isolates with agr dysfunction from a tertiary-care hospital in Korea. Of these, ST5-SCCmec type II-agr group II MRSA isolates, which are known to be prevalent in hospital-acquired infections in Korea, were the most abundant, because of the clonal spread of a specific agr-defective lineage. This finding suggests that the loss of agr function may confer a potential advantage in a hospital setting. Clonal spread of a specific defective-agr strain was not observed among community-associated MRSA or methicillin-susceptible S. aureus clones, regardless of community or hospital acquisition of infection. agr-defective clones, including ST5 and ST239 MRSA, were enriched for heteroresistant vancomycin-intermediate S. aureus.
PMCID: PMC3591919  PMID: 23254438
24.  Vancomycin Heteroresistance Is Associated with Reduced Mortality in ST239 Methicillin-Resistant Staphylococcus aureus Blood Stream Infections 
PLoS ONE  2011;6(6):e21217.
Despite hVISA infections being associated with vancomycin treatment failure, no previous study has been able to detect a mortality difference between heteroresistant vancomycin intermediate Staphylococcus aureus (hVISA) and vancomycin susceptible Staphylococcus aureus (VSSA) bloodstream infections (BSI).
Consecutive methicillin-resistant S. aureus (MRSA) BSI episodes between 1996 and 2008 were reviewed. Patient demographics, clinical presentation, treatment and overall mortality at 30 days were extracted from the medical records. All isolates underwent vancomycin minimum inhibitory concentration (VMIC) testing by broth microdilution and Etest. hVISA was confirmed by population analysis profiling using the area under the curve method (PAP-AUC).
Principal Findings
401 evaluable MRSA BSI episodes were identified over the 12 years. Of these, 46 (11.5%) and 2 (0.5%) were confirmed as hVISA and VISA by PAP-AUC respectively. hVISA predominantly occurred in ST239-like MRSA isolates with high VMIC (2 mg/L). Compared to VSSA, hVISA was associated with chronic renal failure (p<0.001), device related infections (haemodialysis access) (p<0.001) and previous vancomycin usage (p = 0.004). On multivariate analysis, independent predictors of mortality included age, presence of multiple co-morbidities, principal diagnosis, transit to ICU and severity of illness while infection related surgery and hVISA phenotype were associated with increased survival.
The presence of hVISA is dependent on the appropriate interplay between host and pathogen factors. hVISA in ST239 MRSA is an independent predictor of survival. Whether these findings would be replicated across all MRSA clones is unknown and warrants further study.
PMCID: PMC3119693  PMID: 21713004
25.  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

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