Methicillin-resistant Staphylococcus Aureus Endocarditis Research Articles

Gp05, a Prophage-Encoded Virulence Factor, Contributes to Persistent Methicillin-Resistant Staphylococcus aureus Endovascular Infection.

Persistent methicillin-resistant Staphylococcus aureus (MRSA) endovascular infections represent a serious public health threat. We recently demonstrated that the presence of a novel prophage ϕSA169 was associated with vancomycin (VAN) treatment failure in experimental MRSA endocarditis. In this study, we assessed the role of a ϕSA169 gene, ϕ80α_gp05 (gp05), in VAN-persistent outcome using gp05 isogenic MRSA strain sets. Of note, Gp05 significantly influences the intersection of MRSA virulence factors, host immune responses, and antibiotic treatment efficacy, including the following: (i) activity of the significant energy-yielding metabolic pathway (e.g., tricarboxylic acid cycle); (ii) carotenoid pigment production; (iii) (p)ppGpp (guanosine tetra- and pentaphosphate) production, which activates the stringent response and subsequent downstream functional factors (e.g., phenol-soluble modulins and polymorphonuclear neutrophil bactericidal activity); and (iv) persistence to VAN treatment in an experimental infective endocarditis model. These data suggest that Gp05 is a significant virulence factor which contributes to the persistent outcomes in MRSA endovascular infection by multiple pathways. IMPORTANCE Persistent endovascular infections are often caused by MRSA strains that are susceptible to anti-MRSA antibiotics in vitro by CLSI breakpoints. Thus, the persistent outcome represents a unique variant of traditional antibiotic resistance mechanisms and a significant therapeutic challenge. Prophage, a critical mobile genetic element carried by most MRSA isolates, provides their bacterial host with metabolic advantages and resistance mechanisms. However, how prophage-encoded virulence factors interact with the host defense system and antibiotics, driving the persistent outcome, is not well known. In the current study, we demonstrated that a novel prophage gene, gp05, significantly impacts tricarboxylic acid cycle activity, stringent response, and pigmentation, as well as vancomycin treatment outcome in an experimental endocarditis model using isogenic gp05 overexpression and chromosomal deletion mutant MRSA strain sets. The findings significantly advance our understanding of the role of Gp05 in persistent MRSA endovascular infection and provide a potential target for development of novel drugs against these life-threatening infections.

Adult-onset Mild Encephalitis/Encephalopathy with a Reversible Splenial Lesion Induced by MRSA Endocarditis.

BackgroundMild encephalitis/encephalopathy and a reversible splenial lesion (MERS) is a clinicoradiological syndrome with an unknown pathogenic mechanism, which usually involves children. Thus, adult-onset MERS is quite rare.Case presentationA 71-year-old man, undergoing haemodialysis due to diabetes-induced chronic kidney disease, manifested a persistent fever and disorientation. Blood culture detected methicillin-resistant Staphylococcus aureus (MRSA), while echocardiography revealed vegetation in the aortic and mitral valves. Magnetic resonance imaging of the head revealed a fluid-attenuated inversion recovery-high, diffusion-weighted image-high lesion in the splenium of the corpus callosum, with a number of emboli. Accordingly, the patient was diagnosed with MERS induced by MRSA endocarditis.DiscussionNeurological impairment by MERS can be reversible. However, the differential diagnosis of the disease includes ischaemic lesions, multiple sclerosis, malignant lymphoma, acute disseminated encephalomyelitis, and posterior reversible encephalopathy. Clinicians should consider these diseases when MERS is suspected.LEARNING POINTSAdult-onset mild encephalitis/encephalopathy and a reversible splenial lesion (MERS) is quite rare, and physicians should be aware of it as a differential diagnosis of a diffusion-weighted image-high lesion in the splenium of the corpus callosum.Methicillin-resistant Staphylococcus aureus (MRSA) has rarely been reported as a triggering factor for MERS.

Microbiology of infective endocarditis in Hong Kong from 2000 to 2019: a 20-year analysis

Abstract Background Infective endocarditis (IE) is associated with high mortality and complex microbiological profile. The antibiotic prophylaxis guidelines underwent a major revision in 2009 to reduce unnecessary antibiotic exposure. Substantial geographic variations in microbiological profiles exist, of which the understanding in an Asian population is lacking. Purpose We aim to describe the trends in the microbiology of IE in Hong Kong in the past 2 decades. Methods All patients aged 20 or above diagnosed with incident IE with blood culture results from 2000–2019 were included from a well-validated territory-wide database in Hong Kong, and were classified as 7 groups of causative organisms as shown in Figure 1. To evaluate the association between microbiology and 1-year all-cause death, a multivariable Cox proportional-hazards model was used, adjusted with demographics and comorbidities. Temporal trends in the proportion of each organism were characterised using Poisson regression. Interrupted time series analysis was used to evaluate the change in the organism-specific incidence after the revision of guidelines. Results In a total of 5,657 patients (age 59.9±18.3 years, 37.2% females), there were 2,185 (38.6%) patients with culture-negative endocarditis. Staphylococcus aureus (22.4%) and Streptococci (20.5%) were the most common organisms identified. Over time, there was a significant reduction in the proportion of culture-negative endocarditis (annual percentage change [APC] −2.3% [−2.8 to −1.7], P<0.001), and a significant increase in the proportion of endocarditis due to Staphylococcus aureus (APC 1.6% [0.7 to 2.4], P<0.001) and Streptococci (APC 2.3% [1.4 to 3.3], P<0.001) (Figure 1). After guidelines revision in 2009, there was no significant change in organism-specific incidence (all P-values for relative change>0.05). Compared to patients with culture-negative endocarditis, those infected with Staphylococcus aureus (hazard ratio [HR] 2.19 [1.94–2.47], P<0.001), other Staphylococci (HR 1.56 [1.20–2.01], P<0.001), Enterococci (HR 1.60 [1.25–2.05], P<0.001), other microorganisms (HR 1.30 [1.05–1.60], P=0.015), and mixed microorganisms (HR 2.40 [2.02–2.84], P<0.001) had a higher risk of 1-year all-cause death (Figure 2). There was a significant increase in the proportion of methicillin-resistant Staphylococcus aureus (MRSA) endocarditis (APC 4.1% [1.9 to 6.3], P<0.001), with no significant interval change after 2009. Patients infected with MRSA had a higher all-cause death (HR 2.00 [1.70–2.36], P<0.001). Conclusions Different causative organisms carry variable mortality signals in infective endocarditis. Over time, there were fewer cases of culture-negative endocarditis, and the revision of antibiotic prophylaxis guidelines did not result in a significant change in the microbiological profile. There was an increasing trend for MRSA endocarditis, which was associated with a higher risk of death. Funding Acknowledgement Type of funding sources: Public Institution(s). Main funding source(s): The Shenzhen Key Medical DisciplineThe Sanming Project of HKU-SZH Cardiology

697. 8 Years of Characteristics and Outcomes of Patients with MRSA Endocarditis Based on Vancomycin Minimum Inhibitory Concentration: Experience at a Tertiary Care Hospital

BackgroundVancomycin has been the mainstay of treatment for methicillin-resistant Staphylococcus aureus (MRSA) infective endocarditis (IE). MRSA reduced susceptibility to vancomycin is a growing threat. Data assessing the effect of vancomycin reduced susceptibility on outcomes is limited. Our study aimed to evaluate characteristics and outcomes of MRSA-related IE based on the minimum inhibitory concentration (MIC) to vancomycinCharacteristics and outcomes of 51 patients with MRSA-related endocarditis according to the minimal inhibitory concentration (MIC) to vancomycin MethodsIRB approval was obtained for a retrospective cohort study at a tertiary care center. Records of hospitalized adults diagnose with IE by ICD-9/ICD-10 CM codes were identified from 2011 to 2018. 51 patients had MRSA-related IE and were selected for the analysis. Demographic, microbiologic, Imaging and outcome variables were obtained. Characteristics and outcomes of patients with MRSA-related IE according to the MIC to vancomycin (≤ vs. > 1 mcg/mL) were comparedResults35.3% of patients had a MIC > 1 mcg/mL. 59% were men, mean age was 46±3 years old. 65% acquired the infection through injection drug use. Only 3.9% of patients had prosthetic valve IE. 35.3% had tricuspid valve vegetation, 25.5% mitral valve and 21.6% aortic valve vegetation. Two patients had IE possibly related to a PICC-line infection; both of these patients had a MIC to vancomycin >1 mcg/mL, suggestive of prolonged antibiotic therapy. All patients with MRSA-related IE were started empirically on vancomycin. Patients with a MIC > 1 mcg/mL were more likely to be switched to a combination of daptomycin and ceftaroline, compared to those with a MIC ≤ 1 mcg/mL (44.4% vs. 6.1%; P=0.001). 25.4% underwent valvular replacement within 6 months. 12% died within 90 days. MRSA-related IE with MIC > 1mcg/mL did not confer and an increase risk in in-hospital mortality (11.1% vs. 15.2%; P=0.67) or mortality at 90 days (11.1% vs. 12.5%; P=0.89).ConclusionIn this single-center experience, we found that in 8 years 35% of patients with MRSA-related IE had MIC >1 mcg/mL. This is an alarming finding. Although our study did not reach statistic significance we didn’t found difference in valvular surgery requirement or mortality among those with MIC > 1mcg/d as compared to those with a more sensitive MRSA strain. A study with more power or a metha-analysis will be require to better answer this question.Disclosures All Authors: No reported disclosures

A Randomized Controlled Clinical Trial on Therapeutic Effects of Teicoplanin and Vancomycin after Cardiac Surgery due to MRSA infective endocarditis in ICU Patients

Background: Infective endocarditis (IE) is a relatively rare disease but with significant rates of morbidity and mortality. The goal of IE treatment is to eradicate the foci of infection, including antimicrobial therapy with or without surgery. The decision on the selection of an empirical therapy regimen is diverse and based on patient characteristics. Vancomycin and teicoplanin are bacteriostatic glycopeptide antibiotics used for the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections, including MRSA-IE, and patients allergic to penicillin who are infected with methicillin-sensitive Staphylococcus aureus. Objective: The current study aimed to compare the efficacy and adverse effects of vancomycin and teicoplanin in the treatment of patients with MRSA-IE. Materials and Methods: This parallel, randomized, and controlled trial study was carried out on the efficacy and safety of teicoplanin versus vancomycin in the treatment of MRSA endocarditis within August 2012 and April 2017. The present study recruited adult patients with a definite or possible diagnosis of IE based on the Modified Duke Criteria. A central computer-generated random number list was used to allocate the patients (1:1) to the treatment with teicoplanin or vancomycin. Vancomycin was intravenously administered at a dose of 30 mg/kg/day in two doses. Teicoplanin was administered at a loading dose of 6-12 mg/kg every 12 h in four doses and then continued once a day. Results: Out of 86 patients screened with suspected IE, 66 patients were randomly assigned to the vancomycin (n=33) and teicoplanin (n=33) groups. The mean age values of the study subjects were 41±11.8 and 39±13.1 years in the vancomycin and teicoplanin groups, respectively. In addition, 27 patients (81.8%) in the vancomycin group met the criteria for microbiological cure, compared to 25 subjects (89.3%) in the teicoplanin group. In this regard, the observed difference was not statistically significant (P=0.41). Moreover, 26 (78.8%) and 23 (82.1%) patients in the vancomycin and teicoplanin groups achieved clinical cure, respectively (P=0.97). Overall, the patients in the vancomycin group experienced more adverse events in comparison to those of the teicoplanin group (P=0.04). The rate of acute kidney injury over time, especially in the first week of therapy, was higher in the vancomycin group than that reported for the teicoplanin group (P=0.05). Six and four patients in the vancomycin and teicoplanin groups required dialysis, respectively. The use of dialysis was not different between the two groups (P=0.88). Seven (21.3%) and five (17.9%) patients in the vancomycin and teicoplanin groups died, respectively, which was not statistically different between the two groups (P=0.74). Conclusions: It was concluded that the administration of vancomycin or teicoplanin does not significantly change the outcome of patients undergoing empirical treatment for MRSA-IE. This finding indicates the patients are similar in clinical outcomes and mortalities despite some adverse effects, such as skin rashes; therefore, teicoplanin can be considered a treatment choice for these diseases.

Combination of Vancomycin or Daptomycin and Beta‐lactam Antibiotics: A Meta‐analysis

Observational and randomized controlled trials of the combination of vancomycin or daptomycin with a beta-lactam (BL) in patients with methicillin-resistant Staphylococcus aureus (MRSA) bacteremia have shown conflicting results on patient outcomes. The primary purpose of this meta-analysis was to compare clinical failure with the combination of vancomycin or daptomycin with a BL versus vancomycin or daptomycin monotherapy in MRSA bacteremia or endocarditis. A systematic literature search of PubMed, Embase, CINAHL, and meeting proceedings was conducted from inception through February 11, 2020, to identify relevant studies. The primary outcome was clinical failure and secondary outcomes were mortality, nephrotoxicity, and bacteremia. The meta-analysis was performed using Comprehensive Meta Analysis (version 3.0) with a random effects model. Outcomes were reported as odds ratios (ORs) with corresponding 95% confidence intervals (CIs). Nine studies of 1636 patients receiving vancomycin or daptomycin monotherapy versus the combination of vancomycin or daptomycin plus BL for MRSA bacteremia were included. Results showed combination therapy was associated with significantly lower clinical failure rates (OR 0.56, 95% CI 0.39-0.79, I2 =26.22%, p=0.001). Improvement in clinical failure was driven by lower rates of bacteremia relapse and persistence. However, no difference was seen with mortality. Combination therapy with vancomycin or daptomycin plus BL for MRSA bacteremia showed lower clinical failure rates, however, no significant difference was seen in mortality.

Development of Phage Lysins as Novel Therapeutics: A Historical Perspective.

Bacteriophage lysins and related bacteriolytic enzymes are now considered among the top antibiotic alternatives for solving the mounting resistance problem. Over the past 17 years, lysins have been widely developed against Gram-positive and recently Gram-negative pathogens, and successfully tested in a variety of animal models to demonstrate their efficacy. A lysin (CF-301) directed to methicillin resistant Staphylococcus aureus (MRSA) has effectively completed phase 1 human clinical trials, showing safety in this novel therapeutic class. To validate efficacy, CF-301 is currently the first lysin to enter phase 2 human trials to treat hospitalized patients with MRSA bacteremia or endocarditis. If successful, it could be the defining moment leading to the acceptance of lysins as an alternative to small molecule antibiotics. This article is a detailed account of events leading to the first therapeutic use and ultimate development of phage-encoded lysins as novel anti-infectives.

Transmission of Methicillin-Resistant Staphylococcus aureus via Deceased Donor Liver Transplantation Confirmed by Whole Genome Sequencing

Donor-derived bacterial infection is a recognized complication of solid organ transplantation (SOT). The present report describes the clinical details and successful outcome in a liver transplant recipient despite transmission of methicillin-resistant Staphylococcus aureus (MRSA) from a deceased donor with MRSA endocarditis and bacteremia. We further describe whole genome sequencing (WGS) and complete de novo assembly of the donor and recipient MRSA isolate genomes, which confirms that both isolates are genetically 100% identical. We propose that similar application of WGS techniques to future investigations of donor bacterial transmission would strengthen the definition of proven bacterial transmission in SOT, particularly in the presence of highly clonal bacteria such as MRSA. WGS will further improve our understanding of the epidemiology of bacterial transmission in SOT and the risk of adverse patient outcomes when it occurs.

Transmission of Methicillin-Resistant Staphylococcus aureus Infection Through Solid Organ Transplantation: Confirmation Via Whole Genome Sequencing

We describe two cases of donor-derived methicillin-resistant Staphylococcus aureus (MRSA) bacteremia that developed after transplantation of organs from a common donor who died from acute MRSA endocarditis. Both recipients developed recurrent MRSA infection despite appropriate antibiotic therapy, and required prolonged hospitalization and hospital readmission. Comparison of S. aureus whole genome sequence of DNA extracted from fixed donor tissue and recipients' isolates confirmed donor-derived transmission. Current guidelines emphasize the risk posed by donors with bacteremia from multidrug-resistant organisms. This investigation suggests that, particularly in the setting of donor endocarditis, even a standard course of prophylactic antibiotics may not be sufficient to prevent donor-derived infection.

Ceftaroline-Fosamil efficacy against methicillin-resistant Staphylococcus aureus in a rabbit prosthetic joint infection model.

Ceftaroline (CPT), the active metabolite of the prodrug ceftaroline-fosamil (CPT-F), demonstrates in vitro bactericidal activity against methicillin-resistant Staphylococcus aureus (MRSA) and is effective in rabbit models of difficult-to-treat MRSA endocarditis and acute osteomyelitis. However, its in vivo efficacy in a prosthetic joint infection (PJI) model is unknown. Using a MRSA-infected knee PJI model in rabbits, the efficacies of CPT-F or vancomycin (VAN) alone and combined with rifampin (RIF) were compared. After each partial knee replacement with a silicone implant that fit into the tibial intramedullary canal was performed, 5 × 10(7) MRSA CFU (MICs of 0.38, 0.006, and 1 mg/liter for CPT, RIF, and VAN, respectively) was injected into the knee. Infected animals were randomly assigned to receive no treatment (controls) or CPT-F (60 mg/kg of body weight intramuscularly [i.m.]), VAN (60 mg/kg i.m.), CPT-F plus RIF (10 mg/kg i.m.), or VAN plus RIF starting 7 days postinoculation and lasting for 7 days. Surviving bacteria in crushed tibias were counted 3 days after ending treatment. Although the in vivo mean log10 CFU/g of CPT-treated (3.0 ± 0.9, n = 12) and VAN-treated (3.5 ± 1.1, n = 12) crushed bones was significantly lower than those of controls (5.6 ± 1.1, n = 14) (P < 0.001), neither treatment fully sterilized the bones (3/12 were sterile with each treatment). The mean log10 CFU/g values for the antibiotics in combination with RIF were 1.9 ± 0.5 (12/14 were sterile) for CPT-F and 1.9 ± 0.5 (12/14 were sterile) for VAN. In this MRSA PJI model, the efficacies of CPT-F and VAN did not differ; thus, CPT appears to be a promising antimicrobial agent for the treatment of MRSA PJIs.

Ceftaroline—An Anti-MRSA Cephalosporin and Its Implications for Singapore

Ceftaroline is a fifth-generation cephalosporin with activity against methicillin-resistant Staphylococcus aureus (MRSA) that was recently launched in Singapore. It received approval from the United States (US) Food Drug Administration (FDA) and European Commission for the treatment of adult patients with community-acquired pneumonia (CAP) and complicated skin and soft tissue infections (cSSTI). This study aimed to review current published data and determine its clinical role, particularly in the local setting. A literature review on published articles in English on ceftaroline, focusing in particular on clinical trials and other clinical reports. Susceptibility testing was also performed on a limited sample of local MRSA and Streptococcus pneumoniae isolates. Ceftaroline has an extensive spectrum of activity, including coverage of MRSA and multidrug-resistant S. pneumoniae. However, it has limited activity against non-fermenting Gram-negative bacteria and is susceptible to hydrolysis by extended spectrum beta-lactamases. It is only available for intravenous delivery, with a reconstituted stability of just 6 hours, rendering it unavailable for use for outpatient antibiotic therapy. Clinical trials demonstrate non-inferiority compared to first-line comparators in the treatment of CAP and cSSTI. Published case reports/series suggest a potential greater role in the treatment of MRSA bacteremia and endocarditis. No resistance was found among local archived MRSA and S. pneumoniae isolates. We believe ceftaroline will occupy primarily niche roles for culture-directed treatment of various infections--in particular those caused by MRSA--until further clinical trial data become available. A variety of factors render it less useful or appealing for empirical treatment of CAP or healthcare-associated infections.

Addition of Rifampin to Vancomycin for Methicillin-Resistant Staphylococcus aureus Infections: What Is the Evidence?

To evaluate evidence supporting efficacy and safety of the combination of vancomycin and rifampin for treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections. MEDLINE (1946-February 2013), EMBASE (1974-February 2013) and Cochrane Database of Systematic Reviews were searched. All human prospective trials and retrospective studies evaluating clinical outcomes of vancomycin-rifampin combinations were included. Case reports, case series, and in vitro or animal data were excluded. Full-text articles were included and abstracts excluded; 43 of 421 references were reviewed. Five articles met inclusion and were evaluated. A nonrandomized prospective trial reported complete clearance of MRSA bacteremia at 24 hours in all 14 burn patients receiving vancomycin-rifampin therapy. In a case-control study of 42 patients with MRSA endocarditis, adding rifampin prolonged bacteremia (5.2 vs 2.1 days, p < 0.001), decreased survival rates (79% vs 95%, p = 0.048), resulted in drug interactions (52% of cases), and increased hepatic transaminases (21% vs 2%, p = 0.014). In a retrospective analysis of 28 patients with persistent MRSA bacteremia requiring salvage therapy, switching from vancomycin-based to linezolid-based treatment was associated with better salvage success than adding rifampin (88% vs 0%, p < 0.001). In a randomized open-label trial of 42 patients with MRSA endocarditis, addition of rifampin to vancomycin did not affect cure rates (90% combination vs 82% monotherapy, p > 0.20), but increased duration of bacteremia (9 vs 7 days, p > 0.20) compared with vancomycin monotherapy. Another randomized open-label trial of combination versus monotherapy for MRSA pneumonia in 93 intensive care unit patients reported higher clinical successes (53.7% vs 31.0%, p = 0.047), similar 30-day mortality rates, and more adverse events with combination therapy (11 vs 6). Limited evidence exists to support the adjunctive use of rifampin to treat MRSA infections. The combination may increase drug interactions, adverse effects, and rifampin resistance. Further studies are needed to define the role of rifampin adjunct therapy.

Daptomycin Failure for Treatment of Pulmonary Septic Emboli in Native Tricuspid and Mitral Valve Methicillin-ResistantStaphylococcus aureusEndocarditis

Daptomycin has been used with success for the treatment of right-sided methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. However, its efficacy has not been completely assessed for the treatment of MRSA endocarditis when it is associated with pulmonary septic emboli. Hereby, we present a case of MRSA mitral and tricuspid native valve endocarditis with pulmonary septic emboli, which was treated with daptomycin as a sole agent, resulting in worsening pulmonary infiltrates and treatment failure.

Comparison of Six Generic Vancomycin Products for Treatment of Methicillin-Resistant Staphylococcus aureus Experimental Endocarditis in Rabbits

Concerns have recently emerged about the potency and the quality of generic vancomycin (VAN) products approved for use in humans, based on experiments in a neutropenic mouse thigh infection model. However, other animal models may be more appropriate to decipher the bactericidal activities of VAN generics in vivo and to predict their efficacy in humans. We aimed to compare the bactericidal activities of six generic VAN products currently used in France (Mylan and Sandoz), Spain (Hospira), Switzerland (Teva), and the United States (Akorn-Strides and American Pharmaceutical Products [APP]) in a rabbit model of aortic valve endocarditis induced by 8 × 10(7) CFU of methicillin-resistant Staphylococcus aureus (MRSA) strain COL (VAN MIC, 1.5 μg/ml). In vitro, there were no significant differences in the time-kill curve studies performed with the six generic VAN products. Ten rabbits in each group were treated with intravenous (i.v.) VAN, 60 mg/kg of body weight twice a day (b.i.d.) for 4 days. Mean peak serum VAN levels, measured 45 min after the last injection, ranged from 35.5 (APP) to 45.9 μg/ml (Teva). Mean trough serum VAN levels, measured 12 h after the last injection, ranged from 2.3 (Hospira) to 9.2 (APP) μg/ml. All generic VAN products were superior to controls (no treatment) in terms of residual organisms in vegetations (P < 0.02 for each comparison) and in the spleen (P < 0.005 for each comparison). Pairwise comparisons of generic VAN products found no significant differences. In conclusion, a stringent MRSA endocarditis model found no significant differences in the bactericidal activities of six generic VAN products currently used in Europe and America.

Methicillin-resistant Staphylococcus aureus bacteraemia and endocarditis treated with ceftaroline salvage therapy

One of the newest methicillin-resistant Staphylococcus aureus (MRSA) antibiotics to receive FDA approval is ceftaroline fosamil, a member of a new subclass of cephalosporins with unique activity against MRSA. However, ceftaroline is currently only FDA approved for complicated skin/soft tissue infections and community-acquired pneumonia; there are currently no clinical data regarding its use in MRSA bacteraemia and endocarditis. We report a series of six patients in which ceftaroline was utilized as salvage monotherapy in persistent MRSA bacteraemia or endocarditis. Using pharmacy records, 11 ceftaroline-treated patients were identified between January 2011 and November 2011 at University Health System and the South Texas Veterans Health Care System in San Antonio, TX, USA. All cases were reviewed and six patients received ceftaroline therapy for MRSA bacteraemia or endocarditis due to persistent or recurrent bacteraemia while on standard antibiotics (vancomycin or daptomycin). All six patients experienced rapid clearance of their bacteraemia after starting ceftaroline. In the case of endocarditis for which the patient subsequently developed heart failure and required valve replacement, there was no evidence of growth from cultures taken from the excised valve, suggesting sterilization within 13 days of starting ceftaroline. Ceftaroline exhibits potent anti-MRSA activity in both in vitro and animal studies, including rabbit endocarditis models; however, the lack of clinical data has limited its use in bacteraemia and endovascular infections in humans. We hope that this series serves as an initial stepping stone for further evaluation of this compound for more invasive infections due to MRSA.

Serious Infections Caused by Methicillin‐ResistantStaphylococcus aureus

Although first identified just >4 decades ago, methicillin-resistant Staphylococcus aureus (MRSA) has undergone rapid evolutionary changes and epidemiologic expansion to become a major cause of nosocomial and community-acquired infections worldwide. Increasing resistance to vancomycin among MRSA strains in conjunction with availability of new antibiotics, including daptomycin and linezolid, have increased treatment choices but made clinical treatment decisions more challenging. This article describes the clinical features and management issues of 2 challenging-to-treat manifestations of MRSA infection, bacteremia and/or endocarditis and osteomyelitis. It also presents a brief review of community-associated MRSA infections and preventive strategies directed against MRSA.

Clinical outcomes and nephrotoxicity associated with vancomycin trough concentrations during treatment of deep-seated infections

Objective: Higher vancomycin concentrations are thought necessary for treatment of deep-seated methicillin-resistant Staphylococcus aureus (MRSA) infection, yet this may result in greater risk of nephrotoxicity. We evaluated the relationship of serum vancomycin trough concentration with clinical outcomes and nephrotoxicity for patients with deep-seated MRSA infection.Methods: A retrospective cohort study evaluated adults with MRSA pneumonia, endocarditis or osteomyelitis who received vancomycin for ≥ 5 days from June 2005 to June 2007. Patients were stratified by mean vancomycin trough level [low (< 15 mg/l), high (≥ 15 mg/l)]. Outcomes were clinical response, mortality, length of stay (LOS) and nephrotoxicity. Three definitions of nephrotoxicity were used: i) rise in serum creatinine (SCr) ≥ 0.5 mg/dl; ii) 50% increase in SCr; and iii) 25% decrease in estimated creatinine clearance.Results: Fifty-five patients experiencing MRSA pneumonia (n = 28), endocarditis (n = 9), osteomyelitis (n = 20) and multiple infections (n = 2) were stratified into low (n = 39) and high (n = 16) groups. High group patients were more likely to be septic (p = 0.01) and have a higher APACHE II score (p = 0.01). After adjustment for APACHE II score, clinical response rates among survivors did not differ significantly. Risk of death was not significantly different between the high (19%) and low (5%) group patients (p = 0.1). LOS did not differ significantly between groups (p = 0.7). Nephrotoxicity occurred in the low and high groups, respectively, for 10 and 31% (p = 0.04) with definition 1, 10 and 31% (p = 0.04) with definition 2, and 13 and 25% (p = 0.1) with definition 3. After adjustment for APACHE II score, odds of nephrotoxicity based on definitions 1 or 2 were increased among the high versus low groups (OR = 3.27, 95% CI: 0.7 – 15.25, p = 0.1), although not statistically significant.Conclusions: Clinical outcomes did not differ significantly between high and low trough groups for deep-seated MRSA infections. Nephrotoxicity was consistently higher in the high trough group, regardless of the definition used.

Documento de consenso sobre el tratamiento de la bacteriemia y la endocarditis causada por Staphylococcus aureus resistente a la meticilina

Bacteremia and endocarditis due to methicillin-resistant Staphylococcus aureus (MRSA) are prevalent and clinically important. The rise in MRSA bacteremia and endocarditis is related with the increasing use of venous catheters and other vascular procedures. Glycopeptides have been the reference drugs for treating these infections. Unfortunately their activity is not completely satisfactory, particularly against MRSA strains with MICs > 1 microg/mL. The development of new antibiotics, such as linezolid and daptomycin, and the promise of future compounds (dalvabancin, ceftobiprole and telavancin) may change the expectatives in this field.The principal aim of this consensus document was to formulate several recommendations to improve the outcome of MRSA bacteremia and endocarditis, based on the latest reported scientific evidence. This document specifically analyzes the approach for three clinical situations: venous catheter-related bacteremia, persistent bacteremia, and infective endocarditis due to MRSA.

Methicillin Resistant Staphylococcus aureus Endocarditis in an Australian Tertiary Hospital: 1991–2006

Methicillin resistant Staphylococcus aureus (MRSA) endocarditis is increasing in frequency and has a high mortality. This condition has not been specifically described in an Australian population previously. To describe the characteristics, management and outcomes of patients with MRSA endocarditis in an Australian hospital and identify trends in this group over 16 years. Retrospective case series of MRSA endocarditis patients between 1991 and 2006. Between 1991 and 2006, 27 patients were managed for MRSA endocarditis. This group consisted of 18 males (67%). The median age was 64 years. Infection was related to a prosthetic valve or annular ring in 10 patients (37%). The most common comorbidities were diabetes mellitus 8 (30%) and malignancy 8 (30%). Nosocomial acquisition occurred in 16 (59%), non-nosocomial healthcare associated acquisition in 10 (37%) and community acquisition in 1 (4%). Management was with a single antimicrobial agent in 5 (19%) and combination antimicrobial therapy in 22 (81%). Surgery was undertaken in 16 patients (59%). The mortality was 66%. Over this time there was increased non-nosocomial acquisition and presentations to non-tertiary hospitals. There was no clear improvement in survival over the 16 years. In this Australian setting, MRSA endocarditis was mostly nosocomial or healthcare associated. Common characteristics were older patients with multiple co-morbidities. Despite high rates of combination antibiotic therapy and surgery, mortality was very high. There is a need for randomised comparative antibiotic studies.

Treatment of infective endocarditis caused by methicillin-resistant Staphylococcus aureus: Teicoplanin versus vancomycin in a retrospective study

Infective endocarditis caused by methicillin-resistant Staphylococcus aureus (MRSA) is increasing. Vancomycin and teicoplanin are 2 intravenous glycopeptides appropriate for its treatment. There is no human study comparing teicoplanin and vancomycin for the treatment of MRSA endocarditis. Between 1996 and 2006, 51 MRSA endocarditis patients were treated at the authors' hospital. There were 29 patients with nosocomial infection; 15 were treated with teicoplanin. Teicoplanin was used as the first therapeutic agent in 3 patients because of renal insufficiency. Vancomycin was used as the first therapeutic agent in 12 patients. Treatment was changed to teicoplanin because of adverse reactions in 10 and persistent bacteremia in 2 patients. Early operation was performed in 2 patients because of persistent MRSA bacteremia. Overall, 7 patients died in hospital. There was no statistically significant difference in hospital mortality rate (42% vs 47%) and bacteriologic failure rate (34% vs 40%) between 36 patients treated with vancomycin and 15 patients treated with teicoplanin. Teicoplanin can be an alternative therapy of MRSA infective endocarditis.