Donald P. Levine

Clinical Practice Guidelines by the Infectious Diseases Society of America for the Treatment of Methicillin-Resistant Staphylococcus aureus Infections in Adults and Children

Evidence-based guidelines for the management of patients with methicillin-resistant Staphylococcus aureus (MRSA) infections were prepared by an Expert Panel of the Infectious Diseases Society of America (IDSA). The guidelines are intended for use by health care providers who care for adult and pediatric patients with MRSA infections. The guidelines discuss the management of a variety of clinical syndromes associated with MRSA disease, including skin and soft tissue infections (SSTI), bacteremia and endocarditis, pneumonia, bone and joint infections, and central nervous system (CNS) infections. Recommendations are provided regarding vancomycin dosing and monitoring, management of infections due to MRSA strains with reduced susceptibility to vancomycin, and vancomycin treatment failures.

Slow response to vancomycin or vancomycin plus rifampin in methicillin-resistant Staphylococcus aureus endocarditis

OBJECTIVE To determine the median response time to therapy with vancomycin alone or with vancomycin plus rifampin in patients with methicillin-resistant Staphylococcus aureus (MRSA) endocarditis. DESIGN Cohort analysis of a randomized study. SETTING University medical center. PATIENTS Forty-two consecutive patients with MRSA endocarditis were randomly assigned to receive either vancomycin (group I) or vancomycin plus rifampin (group II) for 28 days. MEASUREMENTS Clinical signs and symptoms were recorded, and blood cultures were obtained daily to determine the duration of bacteremia. MAIN RESULTS The median duration of bacteremia was 9 days (7 days for group I and 9 days for group II). The median duration of fever for all patients and for each treatment group was 7 days. Six patients failed therapy, including three patients who died 5, 6, and 9 days after therapy was started, respectively. The other three patients who failed therapy required valve surgery on days 2, 22, and 27, respectively. Although patients had sustained bacteremia, no unusual complications were seen in either treatment group, and most patients responded to continued antibiotic therapy. CONCLUSIONS Slow clinical response is common among patients with MRSA endocarditis who are treated with vancomycin or vancomycin plus rifampin. Nevertheless, few complications appear to be related solely to this sustained bacteremia.

Vancomycin: A History

Vancomycin became available for clinical use >50 years ago but was soon discarded in favor of other antibiotics that were deemed to be more efficacious and less toxic. The advent of pseudomembranous enterocolitis, coupled with the spread of methicillin-resistant Staphylococcus aureus, led to a resurgence in the use of vancomycin. Almost immediately, concerns arose with regard to its therapeutic utility. In addition, resistance to vancomycin developed, first in enterococci and later in staphylococci. Several types of resistance have now been identified, each with a unique effect on infections treated with vancomycin. Recent studies have rekindled interest in the best way to administer the antibiotic. The findings of future studies may result in a return to measuring levels of vancomycin in serum, to assure a successful therapeutic outcome.

Impact of Vancomycin Exposure on Outcomes in Patients With Methicillin-Resistant Staphylococcus aureus Bacteremia: Support for Consensus Guidelines Suggested Targets

BACKGROUND High rates of vancomycin failure in methicillin-resistant Staphylococcus aureus (MRSA) infections have been increasingly reported over time. The primary objective of our study was to determine the impact of vancomycin exposure and outcomes in patients with MRSA bacteremia initially treated with vancomycin. METHODS This was a single-center retrospective analysis of 320 patients with documented MRSA bacteremia initially treated with vancomycin from January 2005 through April 2010. Two methods of susceptibility, Etest and broth microdilution, were performed for all isolates to determine the correlation of susceptibility testing to patient outcomes. RESULTS Among a cohort of 320 patients, more than half (52.5%) experienced vancomycin failure. Independent predictors of vancomycin failure in logistic regression included infective endocarditis (adjusted odds ratio [AOR], 4.55; 95% confidence interval [CI], 2.26-9.15), nosocomial-acquired infection (AOR, 2.19; 95% CI, 1.21-3.97), initial vancomycin trough <15 mg/L (AOR, 2.00; 95% CI, 1.25-3.22), and vancomycin minimum inhibitory concentration (MIC) >1 mg/L by Etest (AOR, 1.52; 95% CI, 1.09-2.49). With use of Classification and Regression Tree (CART) analysis, patients with vancomycin area under the curve at 24 h (AUC(24h)) to MIC ratios <421 were found to have significantly higher rates of failure, compared with patients with AUC(24h) to MIC ratios >421 (61.2% vs 48.6%; P = .038). CONCLUSIONS In light of the high failure rates associated with this antimicrobial, optimizing the pharmacokinetic/pharmacodynamic properties of vancomycin by targeting higher trough values of 15-20 mg/L and AUC(24h)/MIC ratios ≥400 in selected patients should be considered.

Initial Low-Dose Gentamicin for Staphylococcus aureus Bacteremia and Endocarditis Is Nephrotoxic

BACKGROUND The safety of adding initial low-dose gentamicin to antistaphylococcal penicillins or vancomycin for treatment of suspected Staphylococcus aureus native valve endocarditis is unknown. This study evaluated the association between this practice and nephrotoxicity. METHODS We performed a prospective cohort study of safety data from a randomized, controlled trial of therapy for S. aureus bacteremia and native valve infective endocarditis involving 236 patients from 44 hospitals in 4 countries. Patients either received standard therapy (antistaphylococcal penicillin or vancomycin) plus initial low-dose gentamicin (n=116) or received daptomycin monotherapy (n = 120). We measured renal adverse events and clinically significant decreased creatinine clearance in patients (1) in the original randomized study arms and (2) who received any initial low-dose gentamicin either, as a study medication or <or= days before enrollment. RESULTS Renal adverse events occurred in 8 (7%) of 120 daptomycin recipients, 10 (19%) of 53 vancomycin recipients, and 11 (17%) of 63 antistaphylococcal penicillin recipients. Decreased creatinine clearance occurred in 9 (8%) of 113 of evaluable daptomycin recipients, 10 (22%) of 46 vancomycin recipients, and 16 (25%) of 63 antistaphylococcal penicillin recipients. An additional 21 patients received initial low-dose gentamicin <or=2 days before study enrollment. A total of 22% of patients who received initial low-dose gentamicin versus 8% of patients who did not receive initial low-dose gentamicin experienced decreased creatinine clearance (P = 005 ). Independent predictors of a clinically significant decrease in creatinine clearance were age >or=65 years and receipt of any initial low-dose gentamicin. CONCLUSIONS Initial low-dose gentamicin as part of therapy for S. aureus bacteremia and native valve infective endocarditis is nephrotoxic and should not be used routinely, given the minimal existing data supporting its benefit.

Community-acquired methicillin-resistant Staphylococcus aureus endocarditis in the Detroit Medical Center.

Between June 1980 and September 1981 we evaluated 24 cases of endocarditis from methicillin-resistant Staphylococcus aureus. All of the cases occurred in drug addicts and all were community-acquired. The patients ranged in age from 21 to 59 years and represented an older population than that generally reported for bacterial endocarditis in addicts. Men and women were equally represented (one man presented twice). This unusually high proportion of women may reflect a difference in the rate and location of carriage of methicillin-resistant S. aureus compared with that of methicillin-sensitive staphylococci. Three patients died, one of whom had signed out of the hospital on the 14th day and returned moribund 27 days later. Vancomycin treatment for 28 days was adequate therapy for most patients.

Candida infective endocarditis

Candida infective endocarditis (IE) is uncommon but often fatal. Most epidemiologic data are derived from small case series or case reports. This study was conducted to explore the epidemiology, treatment patterns, and outcomes of patients with Candida IE. We compared 33 Candida IE cases to 2,716 patients with non-fungal IE in the International Collaboration on Endocarditis—Prospective Cohort Study (ICE-PCS). Patients were enrolled and the data collected from June 2000 until August 2005. We noted that patients with Candida IE were more likely to have prosthetic valves (p < 0.001), short-term indwelling catheters (p < 0.0001), and have healthcare-associated infections (p < 0.001). The reasons for surgery differed between the two groups: myocardial abscess (46.7% vs. 22.2%, p = 0.026) and persistent positive blood cultures (33.3% vs. 9.9%, p = 0.003) were more common among those with Candida IE. Mortality at discharge was higher in patients with Candida IE (30.3%) when compared to non-fungal cases (17%, p = 0.046). Among Candida patients, mortality was similar in patients who received combination surgical and antifungal therapy versus antifungal therapy alone (33.3% vs. 27.8%, p = 0.26). New antifungal drugs, particularly echinocandins, were used frequently. These multi-center data suggest distinct epidemiologic features of Candida IE when compared to non-fungal cases. Indications for surgical intervention are different and mortality is increased. Newer antifungal treatment options are increasingly used. Large, multi-center studies are needed to help better define Candida IE.

High-dose daptomycin for treatment of complicated gram-positive infections: A large, multicenter, retrospective study

Study Objective. To evaluate the clinical response and safety of high‐dose daptomycin for treatment of complicated gram‐positive infections.

Emergence of Coagulase-Negative Staphylococci as a Cause of Native Valve Endocarditis

BACKGROUND Coagulase-negative staphylococci (CoNS) are an infrequent cause of native valve endocarditis (NVE), and our understanding of NVE caused by CoNS is incomplete. METHOD The International Collaboration on Endocarditis-Prospective Cohort Study includes patients with endocarditis from 61 centers in 28 countries. Patients with definite cases of NVE caused by CoNS who were enrolled during the period June 2000-August 2006 were compared with patients with definite cases of NVE caused by Staphylococcus aureus and patients with NVE caused by viridans group streptococci. Multivariable logistic regression was used to determine factors associated with death in patients with NVE caused by CoNS. RESULTS Of 1635 patients with definite NVE and no history of injection drug use, 128 (7.8%) had NVE due to CoNS. Health care-associated infection occurred in 63 patients (49%) with NVE caused by CoNS. Comorbidities, long-term intravascular catheter use, and history of recent invasive procedures were similar among patients with NVE caused by CoNS and among patients with NVE caused by S. aureus. Surgical treatment for endocarditis occurred more frequently in patients with NVE due to CoNS (76 patients [60%]) than in patients with NVE due to S. aureus (150 [33%]; P=.01) or in patients with NVE due to viridans group streptococci (149 [44%]; P=.01). Despite the high rate of surgical procedures among patients with NVE due to CoNS, the mortality rates among patients with NVE due to CoNS and among patients with NVE due to S. aureus were similar (32 patients [25%] and 124 patients [27%], respectively; P=.44); the mortality rate among patients with NVE due to CoNS was higher than that among patients with NVE due to viridans group streptococci (24 [7.0%]; P=.01). Persistent bacteremia (odds ratio, 2.65; 95% confidence interval, 1.08-6.51), congestive heart failure (odds ratio, 3.35; 95% confidence interval, 1.57-7.12), and chronic illness (odds ratio, 2.86; 95% confidence interval, 1.34-6.06) were independently associated with death in patients with NVE due to CoNS (c index, 0.73). CONCLUSIONS CoNS have emerged as an important cause of NVE in both community and health care settings. Despite high rates of surgical therapy, NVE caused by CoNS is associated with poor outcomes.

Non-HACEK Gram-Negative Bacillus Endocarditis

Context Infective endocarditis due to non-HACEK organisms has been considered to be associated with injection drug use. Contribution Analysis of 2761 cases of patients with infective endocarditis from an international collaborative of 61 hospitals found that non-HACEK organisms account for fewer than 2% of the cases, and that most patients with non-HACEK endocarditis had infections associated with health care. Of patients with non-HACEK infections, 59% had implanted endovascular devices or prosthetic valves, but only 4% had injection drug use. More than one half of patients with non-HACEK infections required cardiac surgery and 24% died. Implication Infective endocarditis due to non-HACEK organisms is a rare but frequently fatal condition. It is much more frequently associated with implanted endovascular devices than with injection drug use. The Editors Infective endocarditis caused by non-HACEK (species other than Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kingella species) gram-negative bacilli is a rare and poorly characterized disease. The literature describing non-HACEK gram-negative bacillus endocarditis primarily consists of several small case series from the 1970s and 1980s of outbreaks in injection drug users in large urban areas, such as Detroit (1, 2), Cleveland (3), and San Francisco (4, 5). As a result, endocarditis due to non-HACEK gram-negative bacilli has been considered to be almost exclusively associated with injection drug use (6, 7). In contrast to this reporting bias, however, non-HACEK gram-negative bacillus endocarditis has been occasionally reported to be a nosocomial problem, particularly in patients with early endocarditis after cardiac surgery (811). The International Collaboration on Endocarditis Prospective Cohort Study (ICE-PCS) database was created in 1999. From 1 January 2000 to 31 August 2005, 2761 patients with definite endocarditis from 61 centers in 28 countries were prospectively enrolled. This resource offers a unique opportunity to evaluate the epidemiology, characteristics, and outcome of endocarditis due to non-HACEK gram-negative bacilli in a large, contemporary, and international cohort of well-characterized patients with endocarditis. Methods The International Collaboration on Endocarditis Prospective Cohort Study Hospitalized patients with endocarditis (12) were identified prospectively by using site-specific procedures to ensure consecutive enrollment. Informed consent (oral or written) was obtained from all patients according to local institutional review board or ethics committee instructions. A standard case report form containing 275 variables was completed for each patient on enrollment at the participating site. The ICE-PCS database is maintained at the Duke Clinical Research Institute, Durham, North Carolina, which serves as the coordinating center for the ICE studies, with approval from the institutional review board. We included all patients with endocarditis from sites that met performance criteria for participation. These site criteria included 1) minimum enrollment of 12 cases per year in a center with access to cardiac surgery, 2) the presence of patient identification procedures to ensure consecutive enrollment and to minimize ascertainment bias (as described elsewhere) (13, 14), 3) high-quality data with query resolution, and 4) institutional review board or ethics committee approval or waiver based on local standards. All patients from sites that did not meet these criteria (totaling 494 case-patients from 14 sites) were excluded. Sample We included patients who had both definite endocarditis according to the modified Duke criteria (12) and isolation of a pure culture of an aerobic gram-negative bacillus from the bloodstream or valve. To ensure that the diagnosis of gram-negative endocarditis was accurate, the following additional criteria were applied when interpreting the blood culture results: 1) the patients bacteremia had to meet the definition for persistently positive blood cultures when applying the modified Duke criteria; 2) a single blood culture positive for a gram-negative organism was not considered to constitute a minor microbiological criterion when applying the modified Duke criteria; and 3) patients with endocarditis due to anaerobes, Brucella species, HACEK organisms, or other fastidious gram-negative pathogens (for example, Pasteurella species) or polymicrobial infections were excluded. Definitions We used published definitions of health carerelated variables (15, 16). Nonnosocomial health careassociated infection was defined as a health careassociated infection that was not acquired as a hospital inpatient (for example, hemodialysis, outpatient cancer chemotherapy, or receipt of intravenous antibiotics at home) (16). A nosocomial infection was defined as a health careassociated infection that was acquired after at least 48 hours as a hospital inpatient. Prosthetic endocarditis was defined as endocarditis involving a prosthetic heart valve or implanted endovascular device, such as a permanent cardiac pacemaker, cardioverter defibrillator, or aortic stent. Statistical Analysis Patients with definite non-HACEK gram-negative bacillus endocarditis were compared with all other patients with definite endocarditis in the ICE-PCS database. Continuous variables are presented as medians and 25th and 75th percentiles. Categorical variables are presented as frequencies and percentages of the specified group. Univariable comparisons were made by using the Wilcoxon rank-sum test or the chi-square test as appropriate. For all tests, a P value of 0.05 or less was considered statistically significant. Missing data for each variable were excluded from the denominator as indicated in Table 1. All statistical analyses were performed by using SAS software (version 8.2, SAS Institute, Cary, North Carolina). Table 1. Frequency of Individual Duke Criteria among 49 Patients with Non-HACEK Gram-Negative Bacillus Endocarditis* Role of the Funding Source The study did not receive funding. Results Of the 2761 patients with definite endocarditis, 49 (1.8%) had endocarditis due to non-HACEK gram-negative bacilli. Twenty-six of these patients (53%) were enrolled from Europe; 11 (22%) from North America; and the remainder from South America, New Zealand, Australia, the Middle East, and Asia. Patient enrollment was constant throughout the study period. Characteristics of Non-HACEK Gram-Negative Bacillus Endocarditis Patients with non-HACEK gram-negative bacillus endocarditis were more likely to have had symptoms for more than 1 month than were patients infected with other pathogens (90% [95% CI, 82% to 98%] vs. 77% [CI, 75% to 79%], respectively; P= 0.035) (Table 2). Injection drug use was uncommon in patients with non-HACEK gram-negative bacillus endocarditis and in patients with endocarditis due to other organisms (4% [CI, 0% to 9%] vs. 10% [CI, 9% to 11%]; P= 0.20). In contrast, health care contact was a statistically significant risk factor for non-HACEK gram-negative bacillus endocarditis (57% [CI, 43% to 71%] vs. 30% [CI, 28% to 32%]; P< 0.001), largely because the proportion of nosocomial infections was higher in the non-HACEK gram-negative bacillus endocarditis group (39% [CI, 25% to 53%] vs. 14% [CI, 13% to 15%]; P< 0.001). The Figure shows the routes of acquisition of non-HACEK gram-negative bacillus endocarditis compared with Staphylococcus aureus endocarditis (15) and all other causes of endocarditis in the ICE-PCS database. Table 2. Characteristics of Patients with Non-HACEK Gram-Negative Bacillus Infective Endocarditis and Those with Other Causes of Endocarditis* Figure. Routes of acquisition among patients with definite endocarditis due to non-HACEK gram-negative bacilli, Staphylococcus aureus , and other pathogens. HACEK = Haemophilus species, Actinobacillus actinomycetemcomitans, Cardiobacterium hominis, Eikenella corrodens, or Kingella species. Implanted endovascular devices were more common in patients with non-HACEK gram-negative bacillus endocarditis than in patients with other pathogens (29% [CI, 16% to 42%] vs. 11% [CI, 10% to 12%]; P< 0.001). Patients with non-HACEK gram-negative bacillus endocarditis were also statistically significantly more likely than patients with other causes of endocarditis to have a presumed source of infection involving the genitourinary or nonoral gastrointestinal tract (35% [CI, 22% to 48%] vs. 12% [CI, 11% to 13%]; P< 0.001). A nondental invasive procedure within 60 days before symptom onset was more likely in patients with non-HACEK gram-negative bacillus endocarditis than in patients with other causes of endocarditis (38% [CI, 24% to 52%] vs. 19% [CI, 18% to 20%]; P= 0.002). Intracardiac abscesses were statistically significantly more common in patients with non-HACEK gram-negative bacillus endocarditis than in patients with endocarditis due to other organisms (25% [CI, 13% to 37%] vs. 14% [CI, 13% to 15%]; P= 0.034). The in-hospital mortality rate was 24% (CI, 12% to 36%) for patients with non-HACEK gram-negative bacillus endocarditis and 17% (CI, 16% to 18%) for patients with other causes of endocarditis (P= 0.190). Of the 49 patients with non-HACEK gram-negative bacillus endocarditis, 20 (41%) had native-valve endocarditis and 29 (59%) had prosthetic endocarditis. All 49 cases were confirmed as definite endocarditis by the modified Duke criteria: 22 (45%) were histopathologically (16 patients [33%]) or macroscopically (at surgery in 6 patients [12%]) confirmed (Table 1). Of the 16 patients with pathologic confirmation, 8 had valve cultures, 2 had device cultures, and 1 had an aortic aneurysm culture. Microbiology of Non-HACEK Gram-Negative Bacillus Endocarditis The most common pathogens in patients with non-HACEK gram-negative bacillus endocarditis were Escherichia coli (14 patients [29%]) and Pseudomonas aeruginosa (11 patients [22%]). Othe