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1.  Recurrent Challenges for Clinicians: Emergence of Methicillin-Resistant Staphylococcus aureus, Vancomycin Resistance, and Current Treatment Options 
Gram-positive pathogens mainly, Staphylococcus aureus, Enterococcus and coagulase-negative Staphylococcus, are developing increasing resistance to glycopeptides that pose a problem in treating infections caused by these pathogens. Vancomycin is the treatment of choice in treating methicillin-resistant S. aureus (MRSA). Community-acquired MRSA is associated with infections in patients without recent history of hospital admission and without the classical risk factors for MRSA carriage (including healthcare personnel). MRSA poses new threats and challenges beyond the hospital with the emergence of community-acquired MRSA. Indiscriminate use of vancomycin leads to the emergence and spread of vancomycin resistance in multidrug resistant strains is of growing concern in the recent years. Minimum Inhibitory concentration (MIC) remains an important determinant in choosing the right antibiotics. Infections caused by MRSA strains with vancomycin MIC > 4 μg/mL leads to the vancomycin treatment failure. The Clinical Laboratory Standards Institute had also lowered the cut-off susceptibility and resistance breakpoints for vancomycin. Despite the availability of newer antimicrobial agents (Linezolid, Daptomycin, Tigecycline) for drug-resistant Gram-positive pathogens, clinicians and patients still need options for treatment of MRSA infection. There is a need to reduce the global burden of infections caused by Gram-positive pathogens and its resistant strains (mainly MRSA). Continuous efforts should be made to prevent the spread and the emergence of glycopeptide resistance by early detection of the resistant strains and using the proper infection control measures in the hospital setting.
PMCID: PMC3968634  PMID: 24701097
Enterococcus; Gram-positive; minimum inhibitory concentration; methicillin resistant Staphylococcus aureas; resistance; Staphylococcus aureus; vancomycin; vancomycin-intermediate Staphylococcus aureus
2.  A Report on The First Case of Vancomycin-Intermediate Staphylococcus aureus (VISA) in Hawai‘i 
Hawaii Medical Journal  2011;70(11):233-236.
The state of Hawai‘i has the highest prevalence of methicillin-resistant Staphylococcus aureus (MRSA) infection in the United States. Since vancomycin is the most frequently-prescribed antibiotic for healthcare-associated MRSA infection, there is concern for development of vancomycin resistance. We report on a 61 year-old woman with history of previous successful treatments of MRSA bacteremia with vancomycin. She was later hospitalized for catheter-related MRSA bacteremia that persisted despite vancomycin treatment. The vancomycin minimal inhibitory concentration (MIC) was initially 1–2 µg/ml, suggesting susceptibility, but changed to 4µg/ml. At this level, the organism was classified as a vancomycin-intermediate Staphylococcus aureus (VISA). Therapy was changed from vancomycin to daptomycin, and the patient's blood cultures were sterilized. High suspicion of VISA should be raised in MRSA-infected patients who fail or have a history of vancomycin therapy so that additional susceptibility testing and appropriate antibiotic therapy can be promptly commenced to reduce the morbidity associated with VISA infection.
PMCID: PMC3215986  PMID: 22162601
3.  Staphylococcus aureus Bacteremia, Australia 
Emerging Infectious Diseases  2005;11(4):554-561.
S. aureus bacteremia in Australia is increasingly caused by MRSA, which is likely to affect empiric prescribing of antimicrobial drugs in suspected cases.
Staphylococcus aureus bacteremia (SAB) is common and increasing worldwide. A retrospective review was undertaken to quantify the number of cases, their place of acquisition, and the proportions caused by methicillin-resistant S. aureus (MRSA) in 17 hospitals in Australia. Of 3,192 episodes, 1,571 (49%) were community onset. MRSA caused 40% of hospital-onset episodes and 12% of community-onset episodes. The median rate of SAB was 1.48/1,000 admissions (range 0.61–3.24; median rate for hospital-onset SAB was 0.7/1,000 and for community onset 0.8/1,000 admissions). Using these rates, we estimate that ≈6,900 episodes of SAB occur annually in Australia (35/100,000 population). SAB is common, and a substantial proportion of cases may be preventable. The epidemiology is evolving, with >10% of community-onset SAB now caused by MRSA. This is an emerging infectious disease concern and is likely to impact on empiric antimicrobial drug prescribing in suspected cases of SAB.
PMCID: PMC3320328  PMID: 15829193
Staphylococcus aureus; bacteremia; hospital infections; methicillin resistance; mortality; fatal outcome; nosocomial infections; infection control; indwelling catheters
4.  Isolates with Low-Level Vancomycin Resistance Associated with Persistent Methicillin-Resistant Staphylococcus aureus Bacteremia 
Low-level vancomycin-resistant Staphylococcus aureus (vancomycin-intermediate S. aureus [VISA] and heterogenous VISA [hVISA]) is increasingly reported and leads to glycopeptide treatment failure. Various phenotypic features have been reported for these isolates, but the genetic changes leading to hVISA and VISA have yet to be clearly determined. We assessed phenotypic, antibiotic resistance, and genomic changes by using genomic DNA microarray comparison and sequencing of selected loci in five pairs of clinical hVISA/VISA strains and the initial methicillin-resistant Staphylococcus aureus (MRSA) isolates obtained prior to vancomycin therapy. The isolates were from adult patients in Australia and New Zealand who had persistent MRSA bacteremia (>7 days) while receiving vancomycin therapy. In all cases, the initial isolates were found to be fully vancomycin-susceptible Staphylococcus aureus (VSSA). The hVISA/VISA phenotype was associated with increased cell wall thickness, reduced autolytic activity in four of five hVISA/VISA strains, and a striking reduction in biofilm formation compared to the parent strains in all pairs. All five pairs appeared to be isogenic, and genomic DNA microarray comparison suggested that major genetic changes are not required for the development of the resistant phenotype in these strains. No sequence differences were found in the agr locus or the tcaRA genes for any pair, but a marked reduction in RNAIII expression was found in four pairs. In summary, hVISA/VISA arises from fully VSSA during persistent infection that fails to respond to glycopeptide therapy and is associated with significant phenotypic changes, including a marked reduction in biofilm-forming ability. These clinically derived pairs of isolates will be a useful resource to elucidate the genetic mechanism of resistance in hVISA/VISA strains.
PMCID: PMC1563555  PMID: 16940100
5.  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
6.  Threat of drug resistant Staphylococcus aureus to health in Nepal 
BMC Infectious Diseases  2014;14:157.
Staphylococcus aureus is the most commonly isolated organism from the different clinical samples in hospital. The emergence and dissemination of methicillin resistant Staphylococcus aureus (MRSA) and growing resistance to non-beta-lactam antibiotics is making treatment of infections due to this organism increasingly difficult.
This study was conducted to determine the frequency of Staphylococcus aureus isolated from different clinical samples, rates of MRSA and full antibiotic susceptibility profiles. Clinical samples were cultured and Staphylococcus aureus was identified using standard microbiological methods recommended by the American Society for Microbiology (ASM). Methicillin resistance was confirmed using cefoxitin and oxacillin disks. Inducible clindamycin resistance was identified using D-zone test.
From the processed samples, 306 isolates of Staphylococcus aureus were recovered. All the isolates were susceptible to vancomycin and teicoplanin. Methicillin resistance was observed in 43.1% of isolates while inducible clindamycin resistance in 12.4% of the isolates.
The results of our study reveals that rates of resistance to commonly prescribed antibiotics in Staphylococcus aureus clinical isolates is high. In particular, rate of methicillin resistance is alarming, prompting concern on the rational use of antibiotics and vigilant laboratory-based surveillance of resistance rates in Nepal.
PMCID: PMC3994362  PMID: 24655316
Staphylococcus aureus; MRSA; Inducible clindamycin resistance; Nepal
HIV medicine  2008;9(10):858-862.
To define the incidence and risk factors for methicillin resistant Staphylococcus aureus (MRSA) bacteremia in an urban HIV-infected population.
A retrospective cohort study and nested, case-control analyses set in an urban HIV outpatient clinic in Baltimore.
Over a four-year period (2000–2004) the incidence of Staphylococcus aureus bacteremia (SAB) was determined from an electronic database of blood culture results. Risk factors for MRSA bacteremia were assessed over a five-year period (2000–2005) using methicillin sensitive Staphylococcus aureus (MSSA) bacteremia and bacteremia-free controls.
Of 4,607 patients followed for a total of 11,020 person-years (PY) of follow-up, 216 episodes of SAB occurred (incidence: 19.6 cases per 1000 PY.) Of these, 94 cases (43.5%) were methicillin-resistant (MRSA bacteremia incidence: 8.5 per 1000 PY.) The incidence of MRSA bacteremia increased from 5.3 per 1000 PY in 2000–01 to 11.9 per 1000 PY in 2003–04 (p = 0.001). Significant risk factors for MRSA bacteremia included injection drug use (IDU) [Adjusted Odds Ratio (AOR) = 4.61 (95% CI: 2.32–20.72)], end-stage renal disease (ESRD) [7.78 (2.92–20.72)], and CD4 count <200 cells/mm3 at the event. Patients with MRSA were more likely to have ESRD [AOR = 2.89 (1.12–7.49)] and greater immunosuppression than those with MSSA bacteremia.
The incidence of MRSA bacteremia increased from 2000 to 2004 in our HIV-infected cohort. Our data suggest that initial therapy for S. aureus bacteremia in HIV-infected patients, particularly in those with MRSA bacteremia risk factors, may require antimicrobial agents active against MRSA.
PMCID: PMC2581476  PMID: 18754806
HIV; MRSA; Staphylococcus aureus; Bacteremia
8.  Marinopyrrole Derivatives as Potential Antibiotic Agents against Methicillin-Resistant Staphylococcus aureus (II) 
Marine Drugs  2013;11(8):2927-2948.
Methicillin-resistant Staphylococcus aureus (MRSA) continues to be a major problem, causing severe and intractable infections worldwide. MRSA is resistant to all beta-lactam antibiotics, and alternative treatments are limited. A very limited number of new antibiotics have been discovered over the last half-century, novel agents for the treatment of MRSA infections are urgently needed. Marinopyrrole A was reported to show antibiotic activity against MRSA in 2008. After we reported the first total synthesis of (±)-marinopyrrole A, we designed and synthesized a series of marinopyrrole derivatives. Our structure activity relationship (SAR) studies of these novel derivatives against a panel of Gram-positive pathogens in antibacterial assays have revealed that a para-trifluoromethyl analog (33) of marinopyrrole A is ≥63-, 8-, and 4-fold more potent than vancomycin against methicillin-resistant Staphylococcus epidermidis (MRSE), methicillin-susceptible Staphylococcus aureus (MSSA) and MRSA, respectively. The results provide valuable information in the search for new-generation antibiotics.
PMCID: PMC3766874  PMID: 23955285
antibiotics; marinopyrroles; MRSA; MRSE; MSSA; SAR
9.  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
10.  Nosocomial methicillin-resistant staphylococcus aureus (MRSA) pneumonia: linezolid or vancomycin? - Comparison of pharmacology and clinical efficacy 
The incidence of nosocomial pneumonia involving methicillin-resistant Staphylococcus aureus strains (MRSA) is on the rise worldwide. For years, vancomycin has been used as the drug of choice in the treatment of MRSA infections and was recommended as such by clinical guidelines. There is growing evidence that vancomycin, despite low resistance rates is a suboptimal therapeutic option in critically ill patients, particularly in patients with pneumonia. Disadvantages of vancomycin are i) slow bactericide action, ii) poor penetration into pulmonary tissue, iii) the globally slowly increasing vancomycin MICs ("creep") that result in increased clinical failure despite being susceptible according to defined break points and iv) nephrotoxicity. In contrast to other novel antibiotics with MRSA activity, Linezolid is currently approved for the treatment of nosocomial pneumonia in the USA and Europe. Several studies have compared vancomycin with linezolid for nosocomial pneumonia with conflicting results. This review compares both substances regarding pharmacodynamics, resistance, safety and clinical efficacy and discusses preliminary data of the ZEPHyR study. This study compared linezolid versus vancomycin in patients with proven MRSA pneumonia and was the largest trial ever conducted in this population.
PMCID: PMC3352099  PMID: 21163725
11.  Phase II, Randomized, Double-Blind, Multicenter Study Comparing the Safety and Pharmacokinetics of Tefibazumab to Placebo for Treatment of Staphylococcus aureus Bacteremia 
Tefibazumab (Aurexis), a humanized monoclonal antibody that binds to the surface-expressed adhesion protein clumping factor A, is under development as adjunctive therapy for serious Staphylococcus aureus infections. Sixty patients with documented S. aureus bacteremia (SAB) were randomized and received either tefibazumab at 20 mg/kg of body weight as a single infusion or a placebo in addition to an antibiotic(s). The primary objective of the study was determining safety and pharmacokinetics. An additional objective was to assess activity by a composite clinical end point (CCE). Baseline characteristics were evenly matched between groups. Seventy percent of infections were healthcare associated, and 57% had an SAB-related complication at baseline. There were no differences between the treatment groups in overall adverse clinical events or alterations in laboratory values. Two patients developed serious adverse events that were at least possibly related to tefibazumab; one hypersensitivity reaction was considered definitely related. The tefibazumab plasma half-life was 18 days. Mean plasma levels were <100 μg/ml by day 14. A CCE occurred in six patients (four placebo and two tefibazumab patients) and included five deaths (four placebo and one tefibazumab patient). Progression in the severity of sepsis occurred in four placebo and no tefibazumab patients. Tefibazumab was well tolerated, with a safety profile similar to those of other monoclonal antibodies. Additional trials are warranted to address the dosing range and efficacy of tefibazumab.
PMCID: PMC1538656  PMID: 16870768
12.  Synergism between a Novel Chimeric Lysin and Oxacillin Protects against Infection by Methicillin-Resistant Staphylococcus aureus▿ †¶  
Staphylococcus aureus is the causative agent of several serious infectious diseases. The emergence of antibiotic-resistant S. aureus strains has resulted in significant treatment difficulties, intensifying the need for new antimicrobial agents. Toward this end, we have developed a novel chimeric bacteriophage (phage) lysin that is active against staphylococci, including methicillin-resistant S. aureus (MRSA). The chimeric lysin (called ClyS) was obtained by fusing the N-terminal catalytic domain of the S. aureus Twort phage lysin with the C-terminal cell wall-targeting domain from another S. aureus phage lysin (phiNM3), which displayed Staphylococcus-specific binding. ClyS was expressed in Escherichia coli, and the purified protein lysed MRSA, vancomycin-intermediate strains of S. aureus (VISA), and methicillin-sensitive (MSSA) strains of S. aureus in vitro. In a mouse nasal decolonization model, a 2-log reduction in the viability of MRSA cells was seen 1 h following a single treatment with ClyS. One intraperitoneal dose of ClyS also protected against death by MRSA in a mouse septicemia model. ClyS showed a typical pattern of synergistic interactions with both vancomycin and oxacillin in vitro. More importantly, ClyS and oxacillin at doses that were not protective individually protected synergistically against MRSA septic death in a mouse model. These results strongly support the development of ClyS as an attractive addition to the current treatment options of multidrug-resistant S. aureus infections and would allow for the reinstatement of antibiotics shelved because of mounting resistance.
PMCID: PMC2849374  PMID: 20086153
13.  In Vitro Activity of Sodium New Houttuyfonate Alone and in Combination with Oxacillin or Netilmicin against Methicillin-Resistant Staphylococcus aureus 
PLoS ONE  2013;8(7):e68053.
Staphylococcus aureus can cause severe infections, including bacteremia and sepsis. The spread of methicillin-resistant Staphylococcus aureus (MRSA) highlights the need for novel treatment options. Sodium new houttuyfonate (SNH) is an analogue of houttuynin, the main antibacterial ingredient of Houttuynia cordata Thunb. The aim of this study was to evaluate in vitro activity of SNH and its potential for synergy with antibiotics against hospital-associated MRSA.
A total of 103 MRSA clinical isolates recovered in two hospitals in Beijing were evaluated for susceptibility to SNH, oxacillin, cephalothin, meropenem, vancomycin, levofloxacin, minocycline, netilmicin, and trimethoprim/sulfamethoxazole by broth microdilution. Ten isolates were evaluated for potential for synergy between SNH and the antibiotics above by checkerboard assay. Time-kill analysis was performed in three isolates to characterize the kill kinetics of SNH alone and in combination with the antibiotics that engendered synergy in checkerboard assays. Besides, two reference strains were included in all assays.
Principal Findings
SNH inhibited all test strains with minimum inhibitory concentrations (MICs) ranging from 16 to 64 µg/mL in susceptibility tests, and displayed inhibition to bacterial growth in concentration-dependent manner in time-kill analysis. In synergy studies, the combinations of SNH-oxacillin, SNH-cephalothin, SNH-meropenem and SNH-netilmicin showed synergistic effects against 12 MRSA strains with median fractional inhibitory concentration (FIC) indices of 0.38, 0.38, 0.25 and 0.38 in checkerboard assays. In time-kill analysis, SNH at 1/2 MIC in combination with oxacillin at 1/128 to 1/64 MIC or netilmicin at 1/8 to 1/2 MIC decreased the viable colonies by ≥2log10 CFU/mL.
SNH demonstrated in vitro antibacterial activity against 103 hospital-associated MRSA isolates. Combinations of sub-MIC levels of SNH and oxacillin or netilmicin significantly improved the in vitro antibacterial activity against MRSA compared with either drug alone. The SNH-based combinations showed promise in combating MRSA.
PMCID: PMC3699466  PMID: 23844154
14.  Analysis of Methicillin Resistance among Staphylococcus aureus Blood Isolates in an Emergency Department 
Journal of Korean Medical Science  2007;22(4):682-686.
The increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) has become of great concern in both hospital and community settings. To evaluate the prevalence and risk factors for methicillin resistance among Staphylococcus aureus, blood isolates in our Emergency Department (ED) were collected. All patients with S. aureus bacteremia (SAB) who presented to the ED from January 2000 to August 2005 were included, and a retrospective study was performed. A total of 231 patients with SAB were enrolled (median age, 59 yr; M:F, 125:106). Among these patients, methicillin-resistant strains accounted for 27.3% (63 patients). Catheter-related infection was the most frequent primary site of SAB (39.0%), followed by skin and soft tissue infection (16.5%). In multivariate analysis, recent surgery (OR, 3.41; 95% CI, 1.48-7.85), recent hospitalization (2.17; 1.06-4.62), and older age (≥61 yr) (2.39; 1.25-4.57) were independently associated with the acquisition of methicillin-resistant strains. When antimicrobial therapy is considered for the treatment of a patient with suspected SAB, clinicians should consider obtaining cultures and modifying empirical therapy to provide MRSA coverage for patients with risk factors: older age, recent hospitalization, and recent surgery.
PMCID: PMC2693820  PMID: 17728510
Staphylococcus aureus; Community-acquired Infections; Methicillin Resistance; Risk Factors
15.  Quantifying Cost-Effectiveness of Controlling Nosocomial Spread of Antibiotic-Resistant Bacteria: The Case of MRSA 
PLoS ONE  2010;5(7):e11562.
The costs and benefits of controlling nosocomial spread of antibiotic-resistant bacteria are unknown.
We developed a mathematical algorithm to determine cost-effectiveness of infection control programs and explored the dynamical interactions between different epidemiological variables and cost-effectiveness. The algorithm includes occurrence of nosocomial infections, attributable mortality, costs and efficacy of infection control and how antibiotic-resistant bacteria affect total number of infections: do infections with antibiotic-resistant bacteria replace infections caused by susceptible bacteria (replacement scenario) or occur in addition to them (addition scenario). Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia was used for illustration using observational data on S. aureus bacteremia (SAB) in our hospital (n = 189 between 2001–2004, all being methicillin-susceptible S. aureus [MSSA]).
In the replacement scenario, the costs per life year gained range from € 45,912 to € 6590 for attributable mortality rates ranging from 10% to 50%. Using € 20,000 per life year gained as a threshold, completely preventing MRSA would be cost-effective in the replacement scenario if attributable mortality of MRSA is ≥21%. In the addition scenario, infection control would be cost saving along the entire range of estimates for attributable mortality.
Cost-effectiveness of controlling antibiotic-resistant bacteria is highly sensitive to the interaction between infections caused by resistant and susceptible bacteria (addition or replacement) and attributable mortality. In our setting, controlling MRSA would be cost saving for the addition scenario but would not be cost-effective in the replacement scenario if attributable mortality would be <21%.
PMCID: PMC2905392  PMID: 20661278
16.  Impact of Methicillin-Resistance on Mortality in Children and Neonates with Staphylococcus aureus Bacteremia: A Meta-analysis 
Infection & Chemotherapy  2013;45(2):202-210.
Staphylococcus aureus bacteremia (SAB) is the Staphylococcal infections in blood, one of the most common and fatal bacterial infectious diseases worldwide in adults as well as children or neonates. Recently, some studies have yielded inconsistent findings about the association between methicillin-resistance and mortality in patients with SAB. We performed a meta-analysis to assess the impact of methicillin-resistance on mortality in children or neonates with S. aureus bacteremia.
Materials and Methods
We searched using electronic databases such as Ovid-Medline, EMBASE-Medline, and Cochrane Library, as well as five local databases for published studies during the period of 1 January 2000 to 15 September 2011. Two reviewers independently selected articles in accordance with predetermined criteria and extracted prespecified data based on standardized forms. All cohort studies, which compared in-hospital mortality or SAB-related mortality in children and neonates with methicillin-resistant S. aureus (MRSA) infection to those with methicillin-susceptible S. aureus (MSSA), were included. We conducted meta-analysis using the fixed-effect model to obtain pooled estimates of effect.
Of 2,841 screened studies, seven cohort studies were finally selected for analysis. In children or neonates, MRSA bacteremia was associated with a higher mortality compared with MSSA bacteremia (pooled odds ratio [OR] 2.33, P = 0.0008, 95% confidence interval [CI] 1.42 to 3.82, I2 = 0%). Four studies reported SAB-related mortality, the pooled OR of these studies was 2.03 (P = 0.29, 95% CI 0.55 to 7.53, I2 = 0%). A significant increase in mortality associated with methicillin resistance was found in the subgroup analyses of the studies with only neonates (OR: 2.66, 95% CI: 1.46 to 4.85, P = 0.001), prospectively design ones (OR: 3.20, 95% CI: 1.66 to 6.15, P = 0.0005,), the larger studies (OR: 2.89, 95% CI: 1.62 to 5.16, P = 0.0003) and the higher quality studies (OR: 2.76, 95% CI: 1.50 to 5.06, P = 0.001).
MRSA bacteremia is associated with increased mortality compared with MSSA bacteremia in children or neonates. Due to limited studies for mortality in children or neonates with SAB, further research is needed to evaluate the impact of methicillin resistance on mortality in those populations.
PMCID: PMC3780954  PMID: 24265968
Staphylococcus aureus; Bacteremia; Methicillin Resistance; Mortality; Meta-analysis
17.  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
18.  Reduced Vancomycin Susceptibility in an In Vitro Catheter-Related Biofilm Model Correlates with Poor Therapeutic Outcomes in Experimental Endocarditis Due to Methicillin-Resistant Staphylococcus aureus 
Staphylococcus aureus is the most common cause of endovascular infections, including catheter sepsis and infective endocarditis (IE). Vancomycin (VAN) is the primary choice for treatment of methicillin-resistant S. aureus (MRSA) infections. However, high rates of VAN treatment failure in MRSA infections caused by VAN-susceptible strains have been increasingly reported. Biofilm-associated MRSA infections are especially prone to clinical antibiotic failure. The present studies examined potential relationships between MRSA susceptibility to VAN in biofilms in vitro and nonsusceptibility to VAN in endovascular infection in vivo. Using 10 “VAN-susceptible” MRSA bloodstream isolates previously investigated for VAN responsiveness in experimental IE, we studied the mechanism(s) of such in vivo VAN resistance, including: (i) VAN binding to MRSA organisms; (ii) the impact of VAN on biofilm formation and biofilm composition; (iii) VAN efficacy in an in vitro catheter-related biofilm model; (iv) effects on cell wall thickness. As a group, the five strains previously categorized as VAN nonresponders (non-Rsp) in the experimental IE model differed from the five responders (Rsp) in terms of lower VAN binding, increased biofilm formation, higher survival in the presence of VAN within biofilms in the presence or absence of catheters, and greater biofilm reduction upon proteinase K treatment. Interestingly, sub-MICs of VAN significantly promoted biofilm formation only in the non-Rsp isolates. Cell wall thickness was similar among all MRSA strains. These results suggest that sublethal VAN levels that induce biofilm formation and reduce efficacy of VAN in the in vitro catheter-associated biofilms may contribute to suboptimal treatment outcomes for endovascular infections caused by “VAN-susceptible” MRSA strains.
PMCID: PMC3591927  PMID: 23295925
19.  Is It Time to Replace Vancomycin in the Treatment of Methicillin-Resistant Staphylococcus aureus Infections? 
The role of vancomycin has been challenged by the availability of alternative antibiotics, increased reports of vancomycin failure, and uncertainties in dosing. This manuscript considers the optimal treatment of methicillin-resistant Staphylococcus aureus infections.
For more than 4 decades, vancomycin has been the antibiotic of choice for methicillin-resistant Staphylococcus aureus (MRSA) infections. Recently, infections due to isolates with high but susceptible vancomycin minimum inhibitory concentrations have been associated with additional treatment failures and patient mortality. These poorer outcomes may in part be explained by the inability of attaining appropriate vancomycin levels in these patients. However, assumptions that these poor outcomes are solely due to failure to achieve optimal serum levels of vancomycin are premature. The availability of effective alternatives further erodes the position of vancomycin as first-line therapy. The emergence of resistance and cost considerations, however, favor a more measured approach when using alternative antimicrobials. Collectively, the current available data suggest that the optimal therapy for MRSA infections remains unclear. In the absence of further data, the Infectious Diseases Society of America guidelines remain relevant and inform clinicians of best practice for treating patients with MRSA infections.
PMCID: PMC3658366  PMID: 23511300
Staphylococcus aureus; MRSA, hVISA, VISA; vancomycin; AUC/MIC targets; minimum inhibitory concentration (MIC)
20.  Bench-to-bedside review: Understanding the impact of resistance and virulence factors on methicillin-resistant Staphylococcus aureus infections in the intensive care unit 
Critical Care  2009;13(5):222.
Methicillin-resistant Staphylococcus aureus (MRSA) displays a remarkable array of resistance and virulence factors, which have contributed to its prominent role in infections of the critically ill. We are beginning to understand the function and regulation of some of these factors and efforts are ongoing to better characterize the complex interplay between the microorganism and host response. It is important that clinicians recognize the changing resistance patterns and epidemiology of Staphylococcus spp., as these factors may impact patient outcomes. Community-associated MRSA clones have emerged as an increasingly important subset of Staphyloccocus aureus and MRSA can no longer be considered as solely a nosocomial pathogen. When initiating empiric antibiotics, it is of vital importance that this therapy be timely and appropriate, as delays in treatment are associated with adverse outcomes. Although vancomycin has long been considered a first-line therapy for serious MRSA infections, multiple concerns with this agent have opened the door for existing and investigational agents demonstrating efficacy in this role.
PMCID: PMC2784352  PMID: 19889197
21.  Experimental Endocarditis Model of Methicillin Resistant Staphylococcus aureus (MRSA) in Rat 
Endovascular infections, including endocarditis, are life-threatening infectious syndromes1–3. Staphylococcus aureus is the most common world-wide cause of such syndromes with unacceptably high morbidity and mortality even with appropriate antimicrobial agent treatments4–6. The increase in infections due to methicillin-resistant S. aureus (MRSA), the high rates of vancomycin clinical treatment failures and growing problems of linezolid and daptomycin resistance have all further complicated the management of patients with such infections, and led to high healthcare costs7, 8. In addition, it should be emphasized that most recent studies with antibiotic treatment outcomes have been based in clinical settings, and thus might well be influenced by host factors varying from patient-to-patient. Therefore, a relevant animal model of endovascular infection in which host factors are similar from animal-to-animal is more crucial to investigate microbial pathogenesis, as well as the efficacy of novel antimicrobial agents. Endocarditis in rat is a well-established experimental animal model that closely approximates human native valve endocarditis. This model has been used to examine the role of particular staphylococcal virulence factors and the efficacy of antibiotic treatment regimens for staphylococcal endocarditis. In this report, we describe the experimental endocarditis model due to MRSA that could be used to investigate bacterial pathogenesis and response to antibiotic treatment.
PMCID: PMC3471301  PMID: 22711072
Infection; Issue 64; Immunology; Staphylococcus aureus; endocarditis; animal model; methicillin resistance; MRSA; rat
22.  Comparative effectiveness of nafcillin or cefazolin versus vancomycin in methicillin-susceptible Staphylococcus aureus bacteremia 
BMC Infectious Diseases  2011;11:279.
The high prevalence of methicillin-resistant S. aureus (MRSA) has led clinicians to select antibiotics that have coverage against MRSA, usually vancomycin, for empiric therapy for suspected staphylococcal infections. Clinicians often continue vancomycin started empirically even when methicillin-susceptible S. aureus (MSSA) strains are identified by culture. However, vancomycin has been associated with poor outcomes such as nephrotoxicity, persistent bacteremia and treatment failure. The objective of this study was to compare the effectiveness of vancomycin versus the beta-lactam antibiotics nafcillin and cefazolin among patients with MSSA bacteremia. The outcome of interest for this study was 30-day in-hospital mortality.
This retrospective cohort study included all adult in-patients admitted to a tertiary-care facility between January 1, 2003 and June 30, 2007 who had a positive blood culture for MSSA and received nafcillin, cefazolin or vancomycin. Cox proportional hazard models were used to assess independent mortality hazards comparing nafcillin or cefazolin versus vancomycin. Similar methods were used to estimate the survival benefits of switching from vancomycin to nafcillin or cefazolin versus leaving patients on vancomycin. Each model included statistical adjustment using propensity scores which contained variables associated with an increased propensity to receive vancomycin.
267 patients were included; 14% (38/267) received nafcillin or cefazolin, 51% (135/267) received both vancomycin and either nafcillin or cefazolin, and 35% (94/267) received vancomycin. Thirty (11%) died within 30 days. Those receiving nafcillin or cefazolin had 79% lower mortality hazards compared with those who received vancomycin alone (adjusted hazard ratio (HR): 0.21; 95% confidence interval (CI): 0.09, 0.47). Among the 122 patients who initially received vancomycin empirically, those who were switched to nafcillin or cefazolin (66/122) had 69% lower mortality hazards (adjusted HR: 0.31; 95% CI: 0.10, 0.95) compared to those who remained on vancomycin.
Receipt of nafcillin or cefazolin was protective against mortality compared to vancomycin even when therapy was altered after culture results identified MSSA. Convenience of vancomycin dosing may not outweigh the potential benefits of nafcillin or cefazolin in the treatment of MSSA bacteremia.
PMCID: PMC3206863  PMID: 22011388
23.  Relationship between Vancomycin MIC and Failure among Patients with Methicillin-Resistant Staphylococcus aureus Bacteremia Treated with Vancomycin▿  
There is growing concern that vancomycin has diminished activity for methicillin-resistant Staphylococcus aureus (MRSA) infections, with vancomycin MICs at the high end of the CLSI susceptibility range. Despite this growing concern, there are limited clinical data to support this notion. To better elucidate this, a retrospective cohort study was conducted among patients with MRSA bloodstream infections who were treated with vancomycin between January 2005 and May 2007. The inclusion criteria were as follows: at least 18 years old, nonneutropenic, with an MRSA culture that met the CDC criteria for bloodstream infection, had received vancomycin therapy within 48 h of the index blood culture, and survived >24 h after vancomycin administration. Failure was defined as 30-day mortality, bacteremia ≥10 days on vancomycin therapy, or a recurrence of MRSA bacteremia within 60 days of vancomycin discontinuation. Classification and regression tree (CART) analysis identified the vancomycin MIC breakpoint associated with an increased probability of failure. During the study period, 92 patients met the inclusion criteria. The vancomycin MIC breakpoint derived by CART analysis was ≥1.5 mg/liter. The 66 patients with vancomycin MICs of ≥1.5 mg/liter had a 2.4-fold increase in failure compared to patients with MICs of ≤1.0 mg/liter (36.4% and 15.4%, respectively; P = 0.049). In the Poisson regression, a vancomycin MIC of ≥1.5 mg/liter was independently associated with failure (adjusted risk ratio, 2.6; 95% confidence interval, 1.3 to 5.4; P = 0.01). These data strongly suggest that patients with MRSA bloodstream infections with vancomycin MICs of ≥1.5 mg/liter respond poorly to vancomycin. Alternative anti-MRSA therapies should be considered for these patients.
PMCID: PMC2533486  PMID: 18591266
24.  Heterogeneous vancomycin-intermediate susceptibility in a community-associated methicillin-resistant Staphylococcus aureus epidemic clone, in a case of Infective Endocarditis in Argentina 
Community-Associated Methicillin Resistant Staphylococcus aureus (CA-MRSA) has traditionally been related to skin and soft tissue infections in healthy young patients. However, it has now emerged as responsible for severe infections worldwide, for which vancomycin is one of the mainstays of treatment. Infective endocarditis (IE) due to CA-MRSA with heterogeneous vancomycin-intermediate susceptibility-(h-VISA) has been recently reported, associated to an epidemic USA 300 CA-MRSA clone.
Case Presentation
We describe the occurrence of h-VISA phenotype in a case of IE caused by a strain belonging to an epidemic CA-MRSA clone, distinct from USA300, for the first time in Argentina. The isolate h-VISA (SaB2) was recovered from a patient with persistent bacteraemia after a 7-day therapy with vancomycin, which evolved to fatal case of IE complicated with brain abscesses. The initial isolate-(SaB1) was fully vancomycin susceptible (VSSA). Although MRSA SaB2 was vancomycin susceptible (≤2 μg/ml) by MIC (agar and broth dilution, E-test and VITEK 2), a slight increase of MIC values between SaB1 and SaB2 isolates was detected by the four MIC methods, particularly for teicoplanin. Moreover, Sab2 was classified as h-VISA by three different screening methods [MHA5T-screening agar, Macromethod-E-test-(MET) and by GRD E-test] and confirmed by population analysis profile-(PAP). In addition, a significant increase in cell-wall thickness was revealed for SaB2 by electron microscopy. Molecular typing showed that both strains, SaB1 and SaB2, belonged to ST5 lineage, carried SCCmecIV, lacked Panton-Valentine leukocidin-(PVL) genes and had indistinguishable PFGE patterns (subtype I2), thereby confirming their isogenic nature. In addition, they were clonally related to the epidemic CA-MRSA clone (pulsotype I) detected in our country.
This report demonstrates the ability of this epidemic CA-MRSA clone, disseminated in some regions of Argentina, to produce severe and rapidly fatal infections such as IE, in addition to its ability to acquire low-level vancomycin resistance; for these reasons, it constitutes a new challenge for the Healthcare System of this country.
PMCID: PMC3111347  PMID: 21527033
25.  Outcome of Vancomycin Treatment in Patients with Methicillin-Susceptible Staphylococcus aureus Bacteremia▿  
Limited data on the clinical outcome of vancomycin treatment compared with that of beta-lactam treatment in patients with methicillin-susceptible Staphylococcus aureus bacteremia (MSSA-B) are available. We used different and complementary approaches: (i) a retrospective cohort study using a propensity score to adjust for confounding by treatment assignment and (ii) a matched case-control study. Of all patients with S. aureus bacteremia (SAB) in two university-affiliated hospitals over a 7-year period, 294 patients with MSSA-B were enrolled in the cohort study. The cases for the case-control study were defined as patients who received vancomycin treatment for MSSA-B; the controls, who were patients that received beta-lactam treatment for MSSA-B, were selected at a 1:2 (case:control) ratio according to the objective matching scoring system and the propensity score system. In the cohort study, SAB-related mortality in patients with vancomycin treatment (37%, 10/27) was significantly higher than that in those with beta-lactam treatment (18%, 47/267) (P = 0.02). In addition, multivariate analysis revealed that vancomycin treatment was associated with SAB-related mortality when independent predictors for SAB-related mortality and propensity score were considered (adjusted odds ratio of 3.3, 95% confidence interval of 1.2 to 9.5). In the case-control study using the objective matching scoring system and the propensity score system, SAB-related mortality in case patients was 37% (10/27) and in control patients 11% (6/54) (P < 0.01). Our data suggest that vancomycin is inferior to beta-lactam in the treatment of MSSA-B.
PMCID: PMC2223910  PMID: 17984229

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