Methicillin-Resistant Staphylococcus aureus Prosthetic Valve Endocarditis: Pathophysiology, Epidemiology, Clinical Presentation, Diagnosis, and Management.

Staphylococcus aureus prosthetic valve endocarditis (PVE) remains among the most morbid bacterial infections, with mortality estimates ranging from 40% to 80%. The proportion of PVE cases due to methicillin-resistant Staphylococcus aureus (MRSA) has grown in recent decades, to account for more than 15% of cases of S. aureus PVE and 6% of all cases of PVE. Because no large studies or clinical trials for PVE have been published, most guidelines on the diagnosis and management of MRSA PVE rely upon expert opinion and data from animal models or related conditions (e.g., coagulase-negative Staphylococcus infection). We performed a review of the literature on MRSA PVE to summarize data on pathogenic mechanisms and updates in epidemiology and therapeutic management and to inform diagnostic strategies and priority areas where additional clinical and laboratory data will be particularly useful to guide therapy. Major updates discussed in this review include novel diagnostics, indications for surgical management, the utility of aminoglycosides in medical therapy, and a review of newer antistaphylococcal agents used for the management of MRSA PVE.

Reevaluation of the impact of methicillin-resistance on outcomes in patients with Staphylococcus aureus bacteremia and endocarditis.

BACKGROUND/AIMS: Methicillin-resistant Staphylococcus aureus (MRSA) is highly prevalent in hospitals, and has recently emerged in the community. The impact of methicillin-resistance on mortality and medical costs for patients with S. aureus bacteremia (SAB) requires reevaluation. METHODS: We searched studies with SAB or endocarditis using electronic databases including Ovid-Medline, Embase-Medline, and Cochrane Library, as well as five local databases for published studies during the period January 2000 to September 2011. RESULTS: A total of 2,841 studies were identified, 62 of which involved 17,563 adult subjects and were selected as eligible. A significant increase in overall mortality associated with MRSA, compared to that with methicillin-susceptible S. aureus (MSSA), was evidenced by an odds ratio (OR) of 1.95 (95% confidence interval [CI], 1.73 to 2.21; p < 0.01). In 13 endocarditis studies, MRSA increased the risk of mortality, with an OR of 2.65 (95% CI, 1.46 to 4.80). When three studies, which compared mortality rates between CA-MRSA and CA-MSSA, were combined, the risk of methicillin-resistance increased 3.23-fold compared to MSSA (95% CI, 1.25 to 8.34). The length of hospital stay in the MRSA group was 10 days longer than that in the MSSA group (95% CI, 3.36 to 16.70). Of six studies that reported medical costs, two were included in the analysis, which estimated medical costs to be $9,954.58 (95% CI, 8,951.99 to 10,957.17). CONCLUSION: MRSA is still associated with increased mortality, longer hospital stays and medical costs, compared with MSSA in SAB in studies published since the year 2000.

Risk assessment for infected endocarditis in Staphylococcus aureus bacteremia patients: When is transesophageal echocardiography needed?

AIMS: Echocardiography is the main technique for the diagnosis of endocarditis in patients with Staphylococcus aureus bacteremia (SAB), but a consensus about performing transthoracic echocardiography or transesophageal echocardiography (TEE) as first-line tests is currently lacking. Recently, a new scoring system has been proposed by Palraj et al. to guide the use of TEE in this population. Our aim was to validate this scoring system or modify it, if necessary. METHODS AND RESULTS: Data from SAB patients admitted from 2012 to 2014 were collected. We tested the Palraj scores to stratify patients' risk for endocarditis. Moreover, we analyzed our population to identify any other possible clinical predictors of endocarditis not included in the score. Endocarditis was diagnosed in 38 of 205 patients (18.5%). Palraj's score was effective in the detection of patients at high risk of endocarditis. In addition, we identified the presence of cardiac devices, prolonged bacteremia and intravenous drug abuse (IVDA) as elements strongly correlated with endocarditis. Two scoring systems (Day-1 and Day-5) were derived including IVDA as a variable. Using a Day-1 cut-off value ≥5 and a Day-5 cut-off value ≥2, the 'modified Palraj's score' showed sensitivities of 42.1% and 97.0% and specificities of 88.6% and 32.0% for Day-1 and Day-5 scores, respectively. CONCLUSION: We modify and expand upon an effective scoring system to identify SAB patients at high risk for endocarditis in order to guide use of TEE. The inclusion of IVDA in the criteria for the calculation of the scores improves its effectiveness.

Assessment of the Dual Role of Clumping Factor A in S. Aureus Adhesion to Endothelium in Absence and Presence of Plasma.

Adhesion of Staphylococcus aureus to endothelial cells (ECs) is paramount in infective endocarditis. Bacterial proteins such as clumping factor A (ClfA) and fibronectin binding protein A (FnbpA) mediate adhesion to EC surface molecules and (sub)endothelial matrix proteins including fibrinogen (Fg), fibrin, fibronectin (Fn) and von Willebrand factor (vWF). We studied the influence of shear flow and plasma on the binding of ClfA and FnbpA (including its sub-domains A, A16+, ABC, CD) to coverslip-coated vWF, Fg/fibrin, Fn or confluent ECs, making use of Lactococcus lactis, expressing these adhesins heterologously. Global adherence profiles were similar in static and flow conditions. In the absence of plasma, L. lactis-clfA binding to Fg increased with shear forces, whereas binding to fibrin did not. The degree of adhesion of L. lactis-fnbpA to EC-bound Fn and of L. lactis-clfA to EC-bound Fg, furthermore, was similar to that of L. lactis-clfA to coated vWF domain A1, in the presence of vWF-binding protein (vWbp). Yet, in plasma, L. lactis-clfA adherence to activated EC-vWF/vWbp dropped over 10 minutes by 80% due to vWF-hydrolysis by a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13 and that of L. lactis-fnbpA likewise by > 70% compared to the adhesion in absence of plasma. In contrast, plasma Fg supported high L. lactis-clfA binding to resting and activated ECs. Or, in plasma S. aureus adhesion to active endothelium occurs mainly via two complementary pathways: a rapid but short-lived vWF/vWbp pathway and a stable integrin-coupled Fg-pathway. Hence, the pharmacological inhibition of ClfA-Fg interactions may constitute a valuable additive treatment in infective endocarditis.

Assessment of periodontitis and its role in viridans streptococcal bacteremia and infective endocarditis.

OBJECTIVES: To evaluate the role of periodontitis in viridans group streptococci (VGS) bacteremia and infective endocarditis (IE). METHODS: A total of 200 subjects including two groups. Group A- 34 subjects undergoing tooth extraction with periodontitis, 46 subjects undergoing tooth extraction without periodontitis and 40 healthy controls. Group B: 40 confirmed cases of IE (17 with and 23 without periodontitis) and 40 healthy controls. Subgingival plaque and blood samples were obtained and processed by standard procedures. RESULTS: A total of 53 blood samples (66.25%) yielded positive cultures after tooth extraction. The relationship between the presence of periodontitis and a positive blood culture was significantly higher (p=0.05) for tooth extraction cases with periodontitis (79.40%) than tooth extraction cases without periodontitis (56.50%). Periodontitis was observed in 42.5% of IE cases. Out of the 40 patients of IE, the blood samples yielded 40 different isolates, majority were viridans streptococci 15 (37.5%) and staphylococci nine (22.5%). No statistically significant difference was observed between the subgingival plaque and blood isolates of periodontitis in both the groups, indicating similarity of biotypes of viridans streptococci isolated from the blood and the subgingival plaque. Similarity was also observed between the antibiogram profiles of viridans streptococci from both the groups. CONCLUSIONS: Periodontitis enhances viridans streptococcal bacteremia and may be a potential risk factor for IE.

Risk assessment of legionellosis in cardiology units.

Infective Endocarditis (IE) is a disease with high morbidity and mortality. Nowadays, in addition to classic pathogens were isolated exigent Gram negative bacteria as A. baumannii, A. lwoffii, C. burnetii, Bartonella, Chlamydia and Legionella. We present our experience of Legionella isolations in environmental sample (water and air) collected from the Cardiology units belonging to two hospitals in Messina (Italy). A total of 80 samples were carried out, 30 and 50, respectively in the first and in the second structure: 55 of water and 25 of aerosol. The positivity of 30% of the water samples analyzed and 15% of those aerosol strengthens the conviction of the need for greater environmental monitoring, especially in the wards at high risk.

Evaluation of Daptomycin Exposure and Efficacy and Safety Endpoints To Support Risk-versus-Benefit Considerations.

The choice of an antimicrobial agent must balance optimization of efficacy endpoints with the minimization of safety events. The risk versus benefit of daptomycin for patients with Staphylococcus aureus bacteremia with or without infective endocarditis receiving daptomycin at 6, 8, and 10 mg/kg of body weight/day was assessed. The relationships between the area under the concentration-time curve over 24 h (AUC)/MIC ratio and both clinical response and time to decreased susceptibility were evaluated using data from patients with such infections who received daptomycin at 6 mg/kg/day. Using these relationships, plus the previously identified relationship between the minimum concentration and an elevation in the creatine phosphokinase (CPK) concentration (CPK elevation) (S. M. Bhavnani, C. M. Rubino, P. G. Ambrose, and G. L. Drusano, Clin Infect Dis 50:1568-1574, 2010) and Monte Carlo simulation, the probability of each outcome by MIC for daptomycin at 6, 8, and 10 mg/kg/day was calculated. The function for exposure-response relationships for clinical response (P = 0.06) and time to decreased susceptibility (P = 0.01) resembled U and inverted U shapes, respectively. Multivariable analyses demonstrated AUC/MIC ratio, creatinine clearance, albumin concentration, and disease category to be predictors of clinical response. The results of simulations failed to demonstrate large improvements in the probabilities of clinical success among cohorts of simulated patients defined by the above-described predictive factors or the probability of decreased susceptibility at 30 days when the daptomycin dose was increased from 6 to 10 mg/kg/day. The probability of CPK elevation increased from 0.073 to 0.156 over this dose range. These data can be used to inform risk-versus-benefit decisions for daptomycin dose selection in patients with S. aureus bacteremia with or without infective endocarditis. The risk of CPK elevation, which is reversible, should be weighed in the context of the mortality and severe morbidity associated with these types of serious staphylococcal infections.

Daptomycin pharmacokinetics and pharmacodynamics in a pooled sample of patients receiving thrice-weekly hemodialysis.

While the pharmacokinetic (PK) properties of daptomycin in hemodialysis (HD) patients have been evaluated previously by three groups, resultant dosing recommendations have varied. To address this clinical conundrum, this study combined concentration-time data from these PK evaluations and derived uniform dosing recommendations among patients on HD receiving daptomycin. A two-compartment model with separate HD and non-HD clearance terms was fit to the PK data from these studies by using BigNPAG. Embedded with PK parameters from the population PK analysis, 5,000-subject Monte Carlo simulations (MCS) were performed to identify HD dosing schemes that provided efficacy (cumulative and daily area under the concentration-time curve [AUC] values) and toxicity (trough concentrations of ≥ 24.3 mg/liter) profiles comparable to those from simulations employing the daptomycin PK model derived from the Staphylococcus aureus bacteremia-infective endocarditis (SAB-IE) study. Separate HD dosing schemes were sought for the two weekly interdialytic periods (48 and 72 h). For the 48-h interdialytic period, intra- and post-HD dosing provided the most isometric cumulative and daily AUCs. For the 72-h interdialytic period, all HD dosing schemes provided noncumulative AUC values from 48 to 72 h (AUC(48-72)) that were <50% of the SAB-IE AUC(48-72) values. Increasing the parent dose by 50% intra- or post-HD provided comparable AUC(48-72) values, while maintaining acceptable trough concentration (C(min)) values. When efficacy and toxicity profiles were evaluated for each individual study, higher probabilities for C(min) reaching ≥ 24.3 mg/liter were observed in one of the three studies. Given the high probability of C(min) being ≥ 24.3 mg/liter in one of the three studies, more intensive creatine phosphokinase (CPK) monitoring may be warranted in HD patients receiving daptomycin.

[Pharmacoeconomic analysis of the treatment of methicillin-resistant Staphylococcus aureus with daptomycin or vancomycin]. / Análisis farmacoeconómico del tratamiento de la bacteriemia por Staphylococcus aureus resistente a meticilina con daptomicina y vancomicina.

INTRODUCTION: The increased morbidity, mortality and high costs associated with bacteremia caused by methicillin-resistant Staphylococcus aureus (MRSA) is a major public health problem. Pharmacoeconomic analysis was performed to compare the efficiency of daptomycin (DAP) against vancomycin (VAN) in the treatment of this infection. METHODS: Retrospective, deterministic and probabilistic cost-effectiveness analysis. The effectiveness of the treatments was estimated from the results of a randomized clinical trial, which compared DAP (6 mg / kg IV daily) and VAN (1 g IV every 12 hours), both with or without gentamicin (1 mg / kg IV every 8 hours). Resource utilization was estimated from the clinical trial of the drug datasheets and Spanish sources, the unit costs were obtained also from Spanish sources. Monte Carlo probabilistic analysis and deterministic analysis were performed. RESULTS: The clinical trial cure rates were higher with DAP (44.4%, 95% CI 43.5 to 45.4%) than with VAN (31.8%, 95% CI 30.9 to 32.7%) not statistically significant (p = 0.2203) but with economic impact. With DAP would occur less costs due to treatment failure (rescue antibiotics, additional tests, prolonged hospital stay and adverse reactions) than with VAN. In the base case the average cost of disease per patient was € 12,329 to € 12,696 with DAP and VAN (difference of 367 €). DAP treatment was dominant (more effective, with lower costs than VAN) both in the deterministic and probabilistic analysis. In the Monte Carlo simulation, DAP was the most cost-effective treatment in 100% of the 10,000 simulations, for a willingness to pay € 12,000 per additional cure (approximate cost of MRSA bacteraemia episode). CONCLUSIONS: According to this model, daptomycin is more cost-effective than vancomycin in treating MRSA bacteremia. The higher cost of acquisition of daptomycin does not imply a higher cost of treating this infection.

Assessment of interindividual variability of plasma concentrations after administrazion of high doses of intravenous amoxicillin or cloxacillin in critically ill patients.

The aim of the present retrospective observational clinical study was to assess the interindividual pharmacokinetic variability of plasma concentrations of amoxicillin or cloxacillin administered in high doses intravenously in critically ill patients, related to renal function or administration method.Four hundred and two plasma concentrations were measured at steady-state with a high performance liquid chromatography technique in 162 patients treated with 100 - 300 mg/kg/day of intravenous amoxicillin or cloxacillin.For both drugs and administration methods, plasma concentrations were significantly higher for patients with creatinine clearance below 60 ml/min, even though doses were adapted for renal impairment. the correlations calculated between plasma concentrations and creatinine level, creatinine clearance or doses were all low. There were fewer outlying drug concentrations in patients receiving continuous rather than intermittent regimens.Our results are in favor of adapting dosages of these beta-lactam antibiotics based on plasma concentrations, especially in cases of renal impairment.

Outcomes and costs associated with a history of vancomycin exposure in patients with MRSA-related complicated bacteremia and infective endocarditis.

BACKGROUND: Methicillin-resistant Staphylococcus aureus (MRSA) is the primary cause of complicated bacteremia (CB) and infective endocarditis (IE). Studies have compared the costs of treatment with vancomycin to those of other agents, as well as the efficacy and tolerability of these treatments. However, a literature search found no published studies of the effects of vancomycin exposure on outcomes and hospital costs in patients with CB or IE due to MRSA. OBJECTIVE: The aim of this study was to determine whether there is a quantitative relationship between the duration of vancomycin treatment or cumulative vancomycin exposure and outcomes or costs in patient with CB or IE due to MRSA. METHODS: Electronic medical records of confirmed cases of MRSA-related CB or IE from July 1, 2006, to June 30, 2008, were retrospectively reviewed to identify patients with a history of vancomycin exposure or no vancomycin exposure. Those who received vancomycin were stratified by the amount of drug administered or the duration of treatment to determine the relationship between treatment and outcomes. Data collected included demographic information, treatment information, attributable mortality, MIC data, and hospital costs. Classification and regression tree analysis (CART) was used to determine whether a history of vancomycin exposure was associated with treatment failure, attributable mortality, or both. The Mann-Whitney U test and the Fisher exact test were used for univariate analyses, and logistic regression was used for multivariate modeling. RESULTS: Data from 50 patients were evaluated (CB, 32; IE, 18). Overall rates of failure and attributable mortality were 32% and 16%, respectively. No significant differences were observed between the variables and costs. The CART break points for failure were ≥18.75 g and ≥14 days of vancomycin treatment in the previous 3 years; for attributable mortality, the CART break points were ≥45 g and ≥31 days. In the final multivariate model for failure, ≥18.75 g and ≥14 days of vancomycin treatment in the previous 3 years were predictors of failure (both, P = 0.002). Acute Physiology and Chronic Health Evaluation (APACHE) II score (P = 0.04), ≥45 g (P = 0.002), and ≥31 days of treatment (P = 0.002) in the previous 3 years were predictors of attributable mortality after adjustment for all covariates. CONCLUSIONS: Using the present model, cumulative vancomycin amount and duration were associated with attributable mortality and clinical failure but not with costs.

Ceftriaxone plus gentamicin or ceftriaxone alone for streptococcal endocarditis in Japanese patients as alternative first-line therapies.

This study included 31 patients who had definite or possible infectious endocarditis as defined by the modified Duke's criteria Of these patients, 27 were treated with ceftriaxone plus gentamycin combination therapy and four with ceftriaxone monotherapy. Of these 31 cases, 29 had infections with Streptococcus species, and showed good responses to penicillin G and cefotaxime. Excluding one patient who died because of the underlying disease, all patients achieved clinical cure after treatment with either of the two regimens, showing no recurrence during a follow-up period of 6 months after completion of drug treatment. Although valve replacement was performed in 10 patients during the follow-up period, there were no recurrences in any of these patients 6 months postoperatively. Ceftriaxone allows a simple regimen of once-daily administration. Although indications are limited, ceftriaxone therapy is feasible on an outpatient basis, offering favorable medical economics. Consistent with previous reports, the therapeutic effect of ceftriaxone was equivalent to that of penicillin G in this study, showing this agent to be an alternative first-line drug for infectious endocarditis.

Staphylococcus aureus, the major pathogen in orthopaedic and cardiac surgical site infections: a literature review.

Due to the increasing number of orthopaedic and cardiac procedures, these units are considered as high-risk areas because of the potentially serious consequences of surgical site infections (SSI), primarily caused by Staphylococcus aureus. The goal of this review was to evaluate the impact of S. aureus on the incidence of SSI in these high risk wards. Studies were identified by a search on the MEDLINE literature using the following mesh terms: S. aureus, cardiac, orthopaedic, surgery, SSI. Beside, data from different surveillance systems were also included. Overall, biological investigation was performed only on a small proportion of identified SSIs. Of those identified, S. aureus represented the most common pathogen accounting for approximately 20% of all SSIs. Of the 59,274 hip prostheses reported from the HELICS surveillance network, S. aureus formed 48.6% of the pathogens (416 bacteria isolated). Similarly, it represented 43.7% of pathogens after coronary artery bypass grafting. Although S. aureus turned out to be the major pathogen, this work identifies the relative lack of knowledge on the overall incidence of S. aureus infections and on the impact of this pathogenic agent when taking into consideration the degree of wound contamination and category of SSI. There is a need for more detailed information on the role of S. aureus in the burden of surgical site infections and consequently how to establish multiple approach prevention programs.

In vitro and in vivo assessment of linezolid combined with ertapenem: a highly synergistic combination against methicillin-resistant Staphylococcus aureus.

Linezolid in combination with ertapenem showed in vitro synergy against methicillin-resistant Staphylococcus aureus strains. We confirmed this interaction in vivo by using a rabbit endocarditis experimental model and simulation of the human pharmacokinetics in animals for both antibiotics. Linezolid plus ertapenem exhibited highly synergistic activity in vivo after 4 days of treatment.

Preliminary assessment of genome differences between the reference Nine Mile isolate and two human endocarditis isolates of Coxiella burnetii.

This study investigates the complete genome sequences of the Nine Mile, K, and G isolates to improve our understanding of the unique virulence properties of C. burnetii and to provide important insight into the genome architecture and genetic diversity of this pathogen.