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Background: Daptomycin is a high‐use intravenous antimicrobial agent affording the convenience of once‐daily dosing. Prior studies suggest an opportunity to use a more operationally convenient fixed rather than weight‐based dosing but this approach has not been studied prospectively. Methods: This study quantified the probability of toxicity and efficacy end points by prospectively testing a fixed dose regimen of daptomycin (750 mg) in obese and non‐obese adults. At least, three daptomycin concentrations were measured at steady‐state for each patient. A population pharmacokinetic model was constructed to evaluate concentration‐time profiles and investigate covariates of daptomycin clearance. Simulations were performed to evaluate the probability of achieving efficacy (24‐h area under the curve (AUC0‐24) ≥ 666 mg∙h/L) and toxicity (minimum concentration (Cmin) ≥24.3 mg/L) targets for fixed (500–1000 mg) and weight‐based (6–12 mg/kg) daptomycin doses. Results: Thirty‐one patients (16 females, 15 males) with median (interquartile range (IQR)) age of 50 (30, 62) years and weight of 74 (54, 156) kg were included in the final analysis. Fixed dose daptomycin (750 mg) resulted in similar exposure across weights with a median (IQR) AUC0‐24 of 819 (499, 1501) mg∙h/L and 749 (606, 1265) mg∙h/L in patients weighing ≤74 kg and >74 kg, respectively. Overall, male sex and increased kidney function necessitate higher fixed and weight‐based doses to achieve efficacy. Creatine phosphokinase elevation was observed in two patients (6.5%) and predicted to be lower with fixed versus weight‐based regimens. Conclusions: Fixed daptomycin dosing adjusted for sex and kidney function is expected to improve the efficacy‐to‐toxicity ratio, transitions of care, and costs compared to weight‐based doses. However, no empiric dosing approach is predicted to achieve ≥90% efficacy while minimizing the risk of toxicity, so therapeutic drug monitoring should be considered on a patient‐specific basis. [ABSTRACT FROM AUTHOR]

Study Objective: The preferred antibiotic salvage regimen for persistent methicillin‐resistant Staphylococcus aureus bacteremia (MRSAB) is unclear. We sought to evaluate the effectiveness and safety of vancomycin plus ceftaroline for persistent MRSAB. The primary outcome was time to MRSAB clearance post‐ceftaroline initiation. Secondary outcomes included microbiological cure, hospital length of stay, 90‐day readmission for MRSAB, 90‐day all‐cause mortality, MRSAB‐related mortality, and incidence of antibiotic‐associated adverse effects. Design: Single‐center, retrospective cohort study between January 1, 2016, and December 31, 2021. Setting: State University of New York Upstate University Hospital, a 748‐bed tertiary care, academic medical center in Syracuse, NY. Patients Adult patients were included if they had blood cultures positive for MRSA ≥72 h, received vancomycin monotherapy initially, and received vancomycin plus ceftaroline for ≥24 h. Patients were excluded if they received other anti‐MRSA antibiotics, were pregnant, or were incarcerated. Of the 178 patients identified, 30 unique patients were evaluated. Measurements and Main Results: Patients were medically complex with a median Pitt bacteremia score of 3, 63.3% (19/30) were admitted to the intensive care unit, and 66.7% (20/30) had infective endocarditis. Vancomycin‐associated acute kidney injury was observed in 10% (3/30) of patients, which resulted in dose adjustments. No patients experienced ceftaroline‐associated neutropenia or Clostridioides difficile infection, but 6.7% (2/30) developed a rash attributed to ceftaroline. Median time to MRSAB clearance post‐ceftaroline initiation was 2.6 days. Microbiologic cure occurred in nearly all patients 96.7% (29/30). Median hospital length of stay was 19.5 days, and 6.7% (2/30) of patients had 90‐day readmission for MRSAB. 90‐day all‐cause mortality and MRSAB‐related mortality occurred in 26.7% (8/30) and 13.3% (4/30) of patients, respectively. Conclusions: Vancomycin plus ceftaroline may represent an effective and well‐tolerated salvage regimen option for persistent MRSAB. [ABSTRACT FROM AUTHOR]

Introduction : 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. Objectives : 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. Methods : 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). Results : 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. Conclusions : Combination therapy with vancomycin or daptomycin plus BL for MRSA bacteremia showed lower clinical failure rates, however, no significant difference was seen in mortality. [ABSTRACT FROM AUTHOR]

Objectives: To compare daptomycin exposures and predicted safety outcomes with a simulated weight‐based and fixed dose in morbidly obese and nonobese subjects. Methods: We performed a nonparametric population pharmacokinetic analysis of daptomycin concentration‐time data from a prior obese and nonobese kidney function–matched cohort of healthy adult volunteers. Monte Carlo simulations were performed to compare the maximum concentrations (Cmax), minimum concentrations (Cmin), and area under the curve (AUC) with the standard daptomycin 6 mg/kg/day dose or a 500‐mg daily fixed dose in obese and nonobese subjects. The probability of exceeding a daptomycin Cmin target (24.3 mg/L or higher) associated with creatine phosphokinase (CPK) elevations was computed with the two regimens. Results: No significant differences were observed in clearance, volume of distribution at steady state, or terminal half‐life between the morbidly obese and nonobese PK models. Daptomycin 6 mg/kg/day resulted in AUC, Cmax, and Cmin values that were ~2‐fold higher in morbidly obese subjects relative to nonobese individuals. In contrast, fixed dosing (500 mg/day) resulted in relatively isometric exposures. The fraction of simulated morbidly obese subjects with a Cmin target associated with CPK elevations was 10.8% with 6 mg/kg/day and 2.0% at the 500 mg/day dosage. Conclusions: Weight‐based maintenance dosing of daptomycin is less likely to yield bioequivalent exposures in morbidly obese subjects and provides credence for the evaluation of fixed maintenance doses across adult body size to improve safety. [ABSTRACT FROM AUTHOR]

Study Objective: Current guidelines recommend higher daptomycin doses than the daptomycin label dose of 6 mg/kg for methicillin‐resistant Staphylococcus aureus (MRSA) bacteremia; however, the evidence supporting this recommendation is from in vitro and case series studies. This study evaluated the comparative effectiveness of the daptomycin label dose versus higher daptomycin doses in patients with MRSA bacteremia. Design: Retrospective national cohort study. Setting: Veterans Affairs medical centers. Patients: A total of 371 adults with MRSA bacteremia who were admitted between 2002 and 2015 and treated initially with vancomycin within 24 hours of initial culture collection and then switched to daptomycin therapy within 7 days; 138 patients (37.2%) received daptomycin doses higher than the daptomycin label dose (7 mg/kg or greater), and 233 (62.8%) received the daptomycin label dose (6 mg/kg). Measurements and Main Results: Clinical outcomes were compared among those who received the daptomycin label dose and those who received the higher dose using propensity score–matched Cox proportional hazards regression models. To identify dose partitioning associated with optimal survival, classification and regression tree (CART) analysis was used among patients, controlling for confounding with a 30‐day mortality disease risk score. Propensity score–matched 30‐day mortality was 8.6% (6/70 patients) among the higher dose group versus 18.6% (13/70 patients) among the label dose group (hazard ratio 0.31, 95% confidence interval 0.10–0.94). No significant differences were observed in inpatient mortality, length of stay, 30‐day readmission, or 30‐day S. aureus reinfection between groups. CART analysis resulted in doses of 7 mg/kg or greater providing benefit only among patients with higher (more than 51%) predicted probabilities of 30‐day mortality (p<0.001). Conclusion: To our knowledge, this is the first comparative effectiveness study of daptomycin doses in patients with MRSA bacteremia. Survival benefits were observed with doses higher than the daptomycin label dose (7 mg/kg or greater) for the treatment of MRSA bacteremia. These data suggest that higher doses than the daptomycin label dose may be preferred over the label dose for improving clinical outcomes in patients with MRSA bacteremia. [ABSTRACT FROM AUTHOR]

Enterococcus species are the second most common cause of nosocomial infections in the United States and are particularly concerning in critically ill patients with preexisting comorbid conditions. Rising resistance to antimicrobials that were historically used as front-line agents for treatment of enterococcal infections, such as ampicillin, vancomycin, and aminoglycosides, further complicates the treatment of these infections. Of particular concern are Enterococcus faecium strains that are associated with the highest rate of vancomycin resistance. The introduction of antimicrobial agents with specific activity against vancomycin-resistant Enterococcus ( VRE) faecium including daptomycin, linezolid, quinupristin-dalfopristin, and tigecycline did not completely resolve this clinical dilemma. In this review, the mechanisms of action and resistance to currently available anti- VRE antimicrobial agents including newer agents such as oritavancin and dalbavancin will be presented. In addition, novel combination therapies including β-lactams and fosfomycin, and the promising results from in vitro , animal studies, and clinical experience in the treatment of VRE faecium will be discussed. [ABSTRACT FROM AUTHOR]

Limited data exist for appropriate drug dosing in obese children. This comprehensive review summarizes pharmacokinetic (PK) alterations that occur with age and obesity, and these effects on antimicrobial dosing. A thorough comparison of different measures of body weight and specific antimicrobial agents including cefazolin, cefepime, ceftazidime, daptomycin, doripenem, gentamicin, linezolid, meropenem, piperacillin-tazobactam, tobramycin, vancomycin, and voriconazole is presented. PubMed (1966-July 2015) and Cochrane Library searches were performed using these key terms: children, pharmacokinetic, obesity, overweight, body mass index, ideal body weight, lean body weight, body composition, and specific antimicrobial drugs. PK studies in obese children and, if necessary, data from adult studies were summarized. Knowledge of PK alterations stemming from physiologic changes that occur with age from the neonate to adolescent, as well as those that result from increased body fat, become an essential first step toward optimizing drug dosing in obese children. Excessive amounts of adipose tissue contribute significantly to body size, total body water content, and organ size and function that may modify drug distribution and clearance. PK studies that evaluated antimicrobial dosing primarily used total (or actual) body weight ( TBW) for loading doses and TBW or adjusted body weight for maintenance doses, depending on the drugs' properties and dosing units. PK studies in obese children are imperative to elucidate drug distribution, clearance, and, consequently, the dose required for effective therapy in these children. Future studies should evaluate the effects of both age and obesity on drug dosing because the incidence of obesity is increasing in pediatric patients. [ABSTRACT FROM AUTHOR]

Introduction The management of gram-positive infections has been complicated in recent years by the emergence of antimicrobial resistance, leaving fewer options for therapy. Daptomycin is a lipopeptide antibiotic used for the systemic treatment of gram-positive infections. It has a distinct mechanism of action and a favorable side effect profile, and it requires once/day dosing. Unfortunately, there is a paucity of safety, efficacy, and pharmacokinetic data in neonatal and pediatric patients. The objective of this study was to review our experience with daptomycin use for the treatment of gram-positive infections in these patient populations. Methods We conducted a retrospective analysis of electronic medical records of hospitalized children who received daptomycin between October 2008 and June 2014 for the treatment of proven gram-positive infections. Results Of the 146 patients who received at least 3 days of daptomycin therapy, 109 patients had a proven gram-positive infection and were included for further analysis. Of the 109 patients, 71 were males (65%) and the median age was 12 years (range: 2.5 mo to 24 yrs). The median duration of therapy was 12 days (range: 3-121 days; mean = 16 days). Catheter-related bloodstream infections were the most common type of infections (n=81 patients) in those receiving daptomycin treatment. One hundred seven patients (98%) had documented improvement and resolution at the time of hospital discharge. One hundred four patients (95%) had a baseline creatine phosphokinase ( CPK) level obtained. Of these 104 patients, 48 (46%) had at least one follow-up CPK level after the start of therapy. Three patients' charts showed laboratory evidence of elevated CPK values. Conclusions The majority of patients demonstrated clinical improvement after receiving daptomycin as primary therapy for proven gram-positive infections. Larger randomized controlled trials focusing on safety and efficacy are necessary to assess these outcomes with daptomycin use in the pediatric population. [ABSTRACT FROM AUTHOR]

Objectives Enterococcus species are the fourth leading cause of bacteremia. Resistance rates are rising and delays in appropriate initial antimicrobial therapy have been associated with increased mortality. Empiric treatment of patients with suspected enterococcal bacteremia varies and significant cost differences exist between alternatives. The objective of this study was to determine the cost-effectiveness of various empiric treatments for patients with suspected enterococcal bacteremia. Methods A decision-analytic model was constructed from the hospital perspective to assess the cost-effectiveness of alternative empiric treatment options for enterococcal bacteremia, including antimicrobials active against vancomycin-resistant enterococcus ( VRE). The model was populated from available literature sources and included resistance patterns, associated mortality with early versus delayed effective treatment, and the cost of treatment. Univariate sensitivity analyses tested the robustness of the model to determine the degree to which model uncertainties influenced outcomes. We also undertook a probabilistic sensitivity analysis varying parameters in 10,000 Monte Carlo simulations. Main Results The incremental cost-effectiveness ratio was $791 and $749/quality-adjusted-life-year utilizing empiric daptomycin and linezolid, respectively. The model also predicted an incremental cost/life saved of $11,703 by utilizing empiric daptomycin and $11,084 with linezolid utilization. Ampicillin was dominated (i.e., less effective and associated with increased costs) by both VRE-active agents and vancomycin. A probabilistic Monte Carlo sensitivity analysis showed that an agent with VRE activity had a 100% chance of being cost-effective at traditionally used willingness-to-pay thresholds. The decision-analytic model was sensitive to variations in E. faecium mortality and short-term postdischarge survival rates. Conclusion Results of our model showed that empiric utilization of an antimicrobial with activity against VRE may be a cost-effective option for the treatment of suspected enterococcal bacteremia when compared with vancomycin or β-lactam therapy. [ABSTRACT FROM AUTHOR]

Study Objective Daptomycin is a therapeutic option for patients with underlying renal insufficiency who are vulnerable to nephrotoxicity from vancomycin. We evaluated the efficacy and safety of daptomycin in patients with renal impairment. Design Multicenter, retrospective, observational, case series analysis. Setting Two academic medical centers. Patients One hundred and sixty adults with creatinine clearance (Clcr) of 50 ml/minute or less who received daptomycin for at least 72 hours for complicated Gram-positive infections from 2008-2011. Measurements and Main Methods Clinical and microbiologic outcomes were assessed at the end of daptomycin therapy. Safety evaluations were documented for all patients, and when available, creatine phosphokinase ( CPK) levels were recorded. Thirty-eight (23.8%) patients were on hemodialysis, and 122 (76.3%) had a decreased baseline renal clearance not requiring hemodialysis with a median interquartile range ( IQR) Clcr of 32.4 ml/minute (24.2-40.4 ml/min). The median ( IQR) daptomycin dose was 6.0 mg/kg (5.8-7.8 mg/kg) administered every 24 hours in 68 patients (42.5%) and every 48 hours in 92 patients (57.5%). Daptomycin success, including cure or improvement, (Cure: signs and symptoms resolved and no additional antibiotic therapy required, or infection cleared with negative cultures reported at the end of daptomycin therapy; Improvement: partial resolution of signs and symptoms and additional antibiotic therapy necessary at the end of daptomycin therapy) was achieved in 128 of 160 (80.0%) patients at the end of therapy. Methicillin-resistant Staphylococcus aureus ( MRSA) was the most common pathogen (45%) isolated. The most frequent reason for using daptomycin was due to vancomycin-associated nephrotoxicity (20%). Daptomycin therapy was discontinued in six patients (3.8%) because of elevated CPK (median time to onset, 11.5 days). Loss of daptomycin susceptibility occurred in two patients with complex endovascular infections who were on hemodialysis. Conclusions Daptomycin demonstrated clinical and microbiologic success rates comparable with prior studies. Discontinuation of therapy because of elevated CPK levels may have been avoided in some patients with adjustment to every 48-hour dosing for Clcr less than 30 ml/minute. The relatively early time to onset suggests the need for CPK monitoring more frequently than once/week in renally impaired patients receiving daptomycin. The treatment of bacteremia in patients with renal insufficiency warrants further study. [ABSTRACT FROM AUTHOR]

Study Objective Data are limited for antimicrobial outcomes in obese patients. This study investigated the safety and clinical outcomes of daptomycin therapy in a hospitalized obese population in the southeastern United States. Design Multicenter retrospective cohort study. Setting Thirteen hospitals in the southeastern United States. Patients A total of 126 hospitalized adult obese patients (body mass index [ BMI] more than 30 kg/m2) admitted from January 2005 through May 2010 who received daptomycin dosed on actual body weight for any indication for a minimum of 7 days. Measurements and Main Results Primary safety outcomes included incidence of creatine phosphokinase ( CPK) elevations more than 1000 units/L, more than 500 units/L, myalgias, and discontinuation of therapy due to adverse drug events ( ADEs). Patients were stratified by BMI class ( I, II, or III) for analyses. The average weight was 121 kg, and 39% of patients were considered morbidly obese. Factors associated with an increased risk of primary safety outcomes were assessed through regression analysis. Clinical effectiveness was evaluated as a secondary outcome. CPK elevations more than 1000 units/L occurred in 8.4% of evaluable patients and specifically in 1 (3.6%), 3 (10.3%), and 4 (10.5%) patients in BMI class I, II, and III, respectively (p=0.554). CPK elevations more than 500 units/L occurred in 13.7% of patients with no statistically significant difference noted across BMI classes. Discontinuation due to ADEs occurred in 8 patients (6.3%). One patient developed rhabdomyolysis on day 9 of therapy. Clinical effectiveness was documented in 71% of patients and was consistent across BMI classes. Conclusion Although elevations in CPK increased in high-risk obese patients on daptomycin, discontinuation rates due to ADEs remained low. Further evaluation in a prospective trial is warranted. [ABSTRACT FROM AUTHOR]

Study Objective To evaluate a clinical pathway using daptomycin in patients with bacteremia caused by methicillin-resistant Staphylococcus aureus ( MRSA) isolates exhibiting vancomycin minimum inhibitory concentrations (MICs) greater than 1 mg/L. Design Two-phase quasi-experimental study. Setting Level I trauma center in Detroit, Michigan. Patients The study population consisted of a total of 170 patients with MRSA bacteremia susceptible to vancomycin: 70 patients who had initial blood MRSA isolates exhibiting a vancomycin MIC > 1 mg/L and were treated with vancomycin were included in phase I (retrospective baseline period [2005-2007]) and 100 patients who were switched to daptomycin after initial vancomycin therapy according to the institutional MRSA bacteremia treatment pathway were included in phase II (the period after implementation of the treatment pathway [2008-2010]). Intervention The MRSA bacteremia treatment pathway was as follows: vancomycin therapy was initiated, optimizing target trough concentrations to 15-20 mg/L; for isolates demonstrating vancomycin MICs greater than 1 mg/L, therapy was switched to daptomycin, initiated at dosages of 6 mg/kg/day or higher. Measurements and Main Results Infection characteristics, patient outcomes, and costs were evaluated. Patient characteristics were similar between the phase I and phase II groups. Phase II patients were more likely to achieve clinical success than were phase I patients (75.0% vs 41.4%, p<0.001). Phase II patients demonstrated a shorter total hospital length of stay and shorter durations of inpatient therapy, fever, and bacteremia. Treatment during phase I was independently associated with failure. Nine patients during phase I experienced nephrotoxicity, and two patients during phase II experienced increases in creatine kinase level. Costs were similar between phases I and II ($18,385 vs $19,755, p>0.05), although the hospital readmission rate was higher in phase I (33% vs 21%, p=0.08). Conclusion Among the patients with bacteremia who had MRSA isolates that exhibited elevated vancomycin MICs, the switch to daptomycin improved clinical success without increasing treatment cost. [ABSTRACT FROM AUTHOR]

Study Objective. To determine the safety of daptomycin administered using a variety of doses and dosing frequencies in patients receiving intermittent hemodialysis who had probable or confirmed gram-positive infections. Design. Analysis of data from the Cubicin Outcomes Registry and Experience (CORE), a multicenter, retrospective, observational registry. Setting. Fifty-four study sites, mostly (46%) large teaching hospitals. Patients. Three hundred ninety-three adults in the CORE registry who received intermittent hemodialysis between 2005 and 2008. Measurements and Main Results. The CORE registry is noninterventional and collects standard-of-care data on daptomycin treatment from health care institutions. Of the 393 patients, 370 (94%) could be categorized by daptomycin dosing frequency: every 48 hours (251 patients [64%]), 3 times/week (87 [22%]), and every 24 hours (32 [8%]); the remaining 23 (6%) had unreported dosing frequencies or received a single dose of daptomycin. Three hundred eighty-four patients (98%) received part of their daptomycin therapy as an inpatient and 129 patients (33%) received part of their daptomycin therapy in an intensive care setting. The primary infection type was bacteremia (224 patients [57%]), and the most common pathogen was Staphylococcus aureus (155 patients [39%]). Thirty-eight adverse events possibly related to daptomycin occurred in 28 patients (7%); increased blood creatine kinase level (7 patients [1.8%]) was the most common adverse event. Adverse-event rates were similar across all dosing regimens. Conclusion. In these patients undergoing hemodialysis, daptomycin was a well-tolerated treatment for gram-positive infections across several doses and dosing frequencies. Further study in prospective trials is warranted. [ABSTRACT FROM AUTHOR]

Study Objective. To determine whether daptomycin has the potential to be an effective alternative treatment to vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) endogenous endophthalmitis by measuring daptomycin penetration into the vitreous humor. Design. Laboratory analysis of serum and intravitreal fluids to quantify the ratio between vitreous humor and serum daptomycin concentrations. Setting. Critical care unit in a university-affiliated tertiary care medical center. Patient. A 53-year-old woman treated with intravenous daptomycin for MRSA bacteremia, endophthalmitis, and pericarditis. Measurements and Main Results. After the first dose of intravenous daptomycin 10 mg/kg was administered to the patient, serum and intravitreal fluids were analyzed by using high-performance liquid chromatography to determine daptomycin concentrations; pericardial fluid was also analyzed to determine whether adequate levels were present in actively infected tissue. A vitreous concentration of approximately 28% of the serum concentration was achieved. Although therapeutic efficacy could not be assessed in the absence of intraocular cultures, the presence of adequate drug concentrations in the vitreous humor is promising. Ophthalmic infections caused by resistant isolates continue to increase, and effective alternatives to vancomycin, the standard of care, are needed. For endogenous endophthalmitis, these alternative therapies will need to reach therapeutic concentrations in the vitreous humor and adequately penetrate the terminal source of infection. In this analysis, the intravitreal concentration of daptomycin was comparable to concentrations previously reported with vancomycin; thus daptomcyin may be an attractive option when vancomycin therapy fails or is contraindicated. To our knowledge, this is the first report of intravitreal daptomycin concentrations measured in a patient receiving intravenous daptomycin. Conclusion. Adequate concentrations of daptomycm were achieved in the vitreous fluid after a single systemic dose of the drug. Daptomycin may be an effective alternative to vancomycin in patients with ophthalmic infections. Future clinical studies comparing daptomycin with vancomycin in this clinical setting are warranted. [ABSTRACT FROM AUTHOR]

Enterococci are a common cause of urinary tract infections (UTIs) among hospitalized patients. The rising prevalence of vancomycin-resistant enterococci (VRE) is of particular concern within many institutions because of its association with increased mortality and health care costs, as well as limited treatment options. Clinicians need to differentiate between VRE-associated urinary colonization, asymptomatic bacteriuria, and UTIs in order to determine the need for treatment, optimal therapeutic options, and length of therapy. Unnecessary use of antibiotics in patients simply colonized and not infected with VRE in the urine has become a large problem in both hospitals and long-term care facilities. A PubMed-MEDLINE search was conducted to identify all English-language literature published between January 1975 and March 2010 in order to summarize diagnostic criteria and treatment options for VRE UTIs. Several antimicrobials are discussed, with the specific focus on those with the potential to treat VRE UTIs and susceptibility patterns of VRE from urinary sources: ampicillin, amoxicillin, daptomycin, doxycycline, fosfomycin, imipenem-cilastatin, linezolid, nitrofurantoin, penicillin, piperacillin, quinupristin-dalfopristin, tetracycline, and tigecycline. Recommendations for empiric treatment of enterococcal UTIs and definitive treatment of VRE UTIs, including an evidence-based treatment algorithm, are proposed. Ampicillin generally is considered the drug of choice for ampicillin-susceptible enterococcal UTIs, including VRE. Nitrofurantoin, fosfomycin, and doxycycline have intrinsic activity against enterococci, including VRE, and are possible oral options for VRE cystitis. Linezolid and daptomycin should be reserved for confirmed or suspected upper and/or bacteremic VRE UTIs among ampicillin-resistant strains. Use of other antimicrobials, such as quinupristin-dalfopristin and tigecycline, should be evaluated on a case-by-case basis due to concerns of toxicity resistance, and insufficient supportive data. Additional clinical data are needed to determine the optimal management and duration of therapy for VRE UTIs. [ABSTRACT FROM AUTHOR]

Study Objective. To determine clinical and microbiologic outcomes of daptomycin for the treatment of bacteremia caused by vancomycin-resistant enterococci (VRE). Design. Retrospective medical record review. Setting. Academic tertiary care hospital. Patients. Thirty patients (median age 59 yrs, range 19-79 yrs, 50% male) who received daptomycin for the treatment of VRE bacteremia between January 2004 and July 2007. Measurements and Main Results. Patients were included if they received daptomycin and had a blood culture positive for VRE at the time daptomycin was started. The primary end point was microbiologic cure, defined as negative blood cultures for VRE at the end of therapy. Secondary outcomes were clinical outcomes, adverse events, and occurrence of elevated creatine kinase levels. Clinical outcomes were judged as positive, negative, or indeterminate. The median Acute Physiology and Chronic Health Evaluation (APACHE) II score was 17 (range 7-34), and 20 patients (67%) were in the intensive care unit. Patients received daptomycin for a median of 13 days (range 1-42 days), and the median dose administered was 6 mg/kg (range 3.7-8 mg/kg). Microbiologic cure was achieved in 24 patients (80%), and clinical success occurred in 17 patients (59% [one patient had an indeterminate clinical outcome and was excluded from this analysis]). All patients with a positive clinical outcome had microbiologic cure, six patients who died had microbiologic cure, and all patients with microbiologic failure died. On multivariable logistic regression, higher APACHE II score was associated with a lower chance of microbiologic success (adjusted odds ratio [AOR] 0.73, 95% confidence interval [CI] 0.56-0.95). Lower APACHE II score (AOR 0.86, 95% CI 0.74-1.0) and daptomycin dose of 6 mg/kg or more (AOR 7.29, 95% CI 1.02-52.0) were associated with clinical success. Adverse drug events possibly attributable to daptomycin were uncommon. Three patients had fever possibly related to daptomycin, and two patients had mild elevations of creatine kinase level. Conclusion. Our experience suggests that daptomycin may be an acceptable option for VRE bacteremia; however, larger studies should be performed before this antimicrobial is routinely used for this indication. [ABSTRACT FROM AUTHOR]

Antibiotic treatment for pelvic inflammatory discase (PID) is often broad spectrum and targets a diverse range of vaginal flora. Treatment of PID in nursing mothers presents a particular clinical challenge because use of antimicrobials during breastfeeding poses several potential risks to infants. Excretion of drugs into breast milk can occur through different mechanisms and depends on the characteristics of both the drug and the mother. Whether daptomycin is excreted into breast milk is unknown, as is its subsequent exposure to breastfeeding infants and the associated risks. We describe a case of PID caused by methicillin-resistant Staphylococcus aureus, an uncommon pathogen in PID, in a breastfeeding mother who was successfully treated with daptomycin. Daptomycin concentrations in her breast milk were measured to determine potential exposure to her infant. These concentrations were extremely low, with an estimated milk:plasma ratio of 0.001.2. Although additional confirmatory studies are needed, daptomycin may be a reasonable option in the treatment of PID caused by gram-positive organisms that are resistant to other antibiotics. [ABSTRACT FROM AUTHOR]

Study Objective. To assess the effect of daptomycin compared with vancomycin on the clinical and economic outcomes in patients with complicated skin and skin structure infections. Design. Prospective, open-label study. Setting. Level 1 trauma center in Detroit, Michigan. Patients. Fifty-three adult patients with complicated skin and skin structure infections at risk for methicillin-resistant Staphylococcus aureus (MRSA) infection who were treated with daptomycin and a matched cohort of 212 patients treated with vancomycin. Intervention. Patients in the prospective arm received intravenous daptomycin 4 mg/kg every 24 hours for at least 3 days but not more than 14 days. Historical controls received at least 3 days of vancomycin dosed to achieve trough concentrations of 5-20 µg/ml. Measurements and Main Results. Outcomes evaluated included blinded assessments of clinical resolution, duration of therapy, and costs. The most common diagnoses were cellulitis (31%), abscess (22%), and both cellulitis with abscess (37%). Microbiology differed significantly between groups, with S. aureus found in 27 patients (51%) in the daptomycin group and 167 patients (79%) in the vancomycin group and MRSA in 22 (42%) and 159 (75%), respectively (p<0.001). The proportions of patients with clinical improvement or resolution of their infections on days 3 and 5 were 90% versus 70% and 98% versus 81% in the daptomycin versus vancomycin groups, respectively (p<0.01 for both comparisons), and 100% at the end of therapy in both groups. Among patients with complete resolution of their infections (41 patients [77%] with daptomycin vs 89 patients [42%] with vancomycin, p<0.05), median duration of intravenous therapy was 4 and 7 days, respectively, (p<0.001), and hospital costs were $5027 and $7552 (p<0.001). Conclusions. Patients receiving daptomycin achieved more rapid resolution of symptoms and clinical cure and had a decreased duration of inpatient therapy compared with those receiving vancomycin. This study suggests that daptomycin is a cost-effective alternative to vancomycin for complicated skin and skin structure infections. [ABSTRACT FROM AUTHOR]

Infections caused by methicillin-resistant Staphylococcus aureus (MRSA) are a major public concern. Hospital-acquired MRSA rates have steadily increased over the past 25 years, and the bacterial strain is making inroads to the community. The morbidity and mortality burden of MRSA infection is compounded by delayed or inappropriate antibiotic treatment, taking a toll on health care resources that are already stretched thin. Vancomycin has historically been the drug of choice for this pathogen because its broad spectrum can address the multidrug resistance of most MRSA infections. Despite its sustained in vitro microbiologic inhibitory activity, researchers are beginning to question the continued utility of vancomycin for MRSA infections. Evidence against vancomycin is most notable with regard to nosocomial pneumonia and skin and soft tissue infections. In addition, because vancomycin must be administered intravenously, patients typically require prolonged hospitalization, which further increases the cost of MRSA treatment and exposes patients to additional nosocomial infections. Recent studies have shown that antibiotics with good bioavailability, such as linezolid, can be given orally to facilitate early hospital discharge, thus alleviating the economic burden of MRSA infections. Several agents have been developed over the past decade that have excellent in vitro activity against MRSA. Further studies are needed to determine if these drugs can better eradicate MRSA than vancomycin and remedy the adverse outcomes frequently observed with this organism. [ABSTRACT FROM AUTHOR]

Gram-positive pathogens are increasingly implicated in today's changing epidemiology of hospital-acquired infections. Staphylococci, streptococci, and enterococci are among the most frequently identified causes of surgical site, complicated skin-structure, and bloodstream infections. In accordance, the use of antimicrobial agents with gram-positive activity, especially those with activity against resistant organisms, has also increased. We describe a septic, neutropenic patient with bacteremia due to Enterococcus gallinarum. Therapeutic options were restricted due to resistance factors of the organism, limited guidance in the medical literature, and the patient's history and underlying condition. Despite these challenges, the patient was successfully treated with a combination of daptomycin and gentamicin and replacement of her indwelling central line. As antimicrobial stewards and diagnosticians, we must bear in mind. that selective pressures exerted by the increasing use of agents with gram-positive activity may result in an increased prevalence of organisms such as E. gallinarum. [ABSTRACT FROM AUTHOR]

Limited established treatment options exist for the treatment of serious, invasive infections caused by multidrug-resistant Staphylococcus aureus, most notably nosocomially acquired methicillin-resistant S. aureus (MRSA). Although vancomycin represents the gold standard for therapy of such invasive infections, reports of increasing in vitro resistance to vancomycin, combined with reports of clinical failures (with this and other anti-staphylococcal agents), underscore the need for alternative therapies. Older agents with favorable in vitro activity available in both oral and intravenous close forms include trimethoprim-sulfamelhoxazole and clindamycin. Limited clinical data exist to support their routine use as initial therapy in the treatment of invasive disease. However, these and other options (e.g., tetracyclines) are being reexplored in the setting of increasing concern over MRSA acquired in the community setting. Newer treatment options for MRSA include linezolid, quinupristin-dalfopristin, daptomycin, and tigecycline. With the exception of linezolid, these newer agents require intravenous administration. Combination therapy may be considered in select invasive diseases refractory to standard monotherapies. These diseases include infections such as endocarditis, meningilis, and prosthetic device infections. Additional alternatives to vancomycin are under clinical investigation. Those in later stages of development include oritavancin, dalbavancin, telavancin, and ceftobiprole. [ABSTRACT FROM AUTHOR]

Study Objective. To differentiate the characteristics of community-associated methicillin-resistant Staphylococcus aureus (MRSA) and hospital-associated MRSA isolates on the basis of their susceptibility profiles, induction of clindamycm resistance, and staphylococcal chromosomal cassette (SCC) mec types. Design. In vitro molecular and susceptibility study of isolates obtained from December 2004-January 2006 as part of a large, ongoing clinical study. Setting. Level I trauma center in Detroit, Michigan. Bacterial Strains. Three hundred eight MRSA isolates randomly collected from patients; 130 were classified as community-associated, and 178 were classified hospital-associated by using definitions from the Centers for Disease Control and Prevention (CDC). Intervention. Minimum inhibitory concentrations were tested on the basis of current guidelines from the Clinical and Laboratory Standards Institute. Measurements and Main Results. All tested MRSA isolates were susceptible to daptomycin, linezolid, and vancomycin. In addition, community-associated MRSA isolates were significantly (all p≤0.05) more susceptible to trimethoprim-sulfamethoxazole (99%), clindamycin (96%), and a fluoroquinolone (76%) than hospital-associated MRSA isolates. Inducible resistance to clindamycin was demonstrated in 8.4% of community-associated MRSA isolates versus 50% of hospital-associated MRSA isolates (p≤0.001). Of interest, 35% of the MRSA isolates collected from hospitalized patients (> 48 hrs alter admission and according to the CDC definition) possessed SCCmec type IV. Conclusion. Overall, inducible clindamycin resistance occurred at significantly higher rates in the hospital-associated MRSA isolates, susceptibility differed significantly between community- and hospital-associated MRSA, and most of the hospital isolates contained SCCmec type IV. [ABSTRACT FROM AUTHOR]

Daptomycin is a lipopeptide antibiotic active against multidrug-resistant gram-positive organisms. Our search of the literature found no published pediatric pharmacokinetic data. We report the use and pharmacokinetic analysis of daptomycin in a 13-year-old boy with vancomycin-resistant Enterococcusfaecium endocarditis. Pharmacokinetic parameters were found to be significantly different from published adult parameters, such as a faster elimination rate, shorter half-life, and increased clearance. These age-related differences in the pharmacokinetic profile of daptomycin have significant dosing implications. As the use of this drug for off-label indications and in pediatric populations increases, it is important for clinicians to better understand the drug's pharmacokinetic profile in these patient populations. [ABSTRACT FROM AUTHOR]

Study Objective. To evaluate the outcomes in patients with bacteremia and/or infective endocarditis who were treated with daptomycin. Design. Retrospective chart review. Setting. A university-affiliated medical center in Chicago, Illinois, and a regional hospital in Fountain Valley, California. Patients. Thirty-one inpatients treated with daptomycin for bacteremia and/or infective endocarditis. Measurements and Main Results. Patients were given daptomycin 4-6 mg/kg intravenously every 24-48 hours based on the practitioner's discretion and depending on the patient's clinical condition and presence of comorbidities. Primary end points were resolution of signs and symptoms of infection and discharge from the hospital. Methicillin-resistant Staphylococcus aureus ([MRSA] 11 patients) and vancomycin-resistant entercocci ([VRE] 11 patients) were the most common pathogens, whereas 7 patients had methicillin-sensitive S. aureus infection and 1 patient had coagulase-negative Staphylococcus infection. One patient with endocarditis had a negative culture result. Overall, 24 (77%) of the 31 patients achieved clinical resolution and were discharged, including all patients infected with MRSA; 7 patients died, 6 of whom had VRE infection. Duration of treatment for infective endocarditis lasted longer (typically 22-43 days) than that for bacteremia only (≤ 14 days), and no patients discontinued daptomycin because of adverse events. Conclusion. In these patients, daptomycin was safe and well tolerated even for extended durations of treatment. Daptomycin may provide an effective option for treating drug-resistant gram-positive bloodstream infections and endocarditis. [ABSTRACT FROM AUTHOR]

Methicillin-resistant Staphylococcus aureus (MRSA) is a common bacterial pathogen responsible for a variety of infections in both children and adults. Treatment of infections caused by this organism is problematic due to its resistance to many drugs. Recent reports of community-associated MRSA (CA-MRSA) infections in patients with no known risk factors have serious public health implications. Therapeutic options for these infections are untested; therefore, the potential exists for high morbidity and mortality. Recently, clinical definitions have been established, and new molecular approaches have allowed investigators to distinguish CA-MRSA more easily from traditional nosocomial-derived MRSA strains. Identifying potential risk factors for CA-MRSA acquisition and fully characterizing the epidemiologic, clinical, and molecular properties of these strains are necessary to provide effective therapeutic guidelines. [ABSTRACT FROM AUTHOR]

Daptomycin, the first in a class of agents known as lipopeptides, is a novel antimicrobial agent used For the treatment of gram-positive infections. The compound has a distinctive mechanism of action that exerts its bactericidal activity by disrupting plasma membrane function without penetrating into the cytoplasm. The agent has received much interest because of its activity against multidrug-resistant, gram-positive bacteria such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci, and glycopeptide-intermediate and resistant S. aurcus. Daptomycin demonstrates concentration-dependent killing and is eliminated primarily by glomerular filtration. It was approved in September 2003 far the treatment of complicated skin and soft tissue infections. It has a safety profile similar to other agents commonly administered to treat gram-positive infections, Daptomycin is a welcome addition to the antimicrobial armamentarium for the treatment of bacterial infections. Further clinical experience with this compound will help define its role in the treatment of resistant gram-positive organisms. [ABSTRACT FROM AUTHOR]

Glycopeptide antibiotics in the form of vancomycin have been available for almost 30 years. In the past, vancomycin usually was reserved as an alternative agent to treat staphylococcal and streptococcal infection in patients with a penicillin allergy or hemodialysis shunt infection. With the increasing frequency of both methicillin-resistant Staphylococcus aureus and Staphylococcus epidermidis, now it is often used as a first-line agent. Over a 10-year period, vancomycin sales have increased by almost $1 hundred million. Several new glycopeptide and lipopeptide antibiotics are in various stages of evaluation. While vancomycin resistance to date is a rare phenomenon, these drugs represent a potentially more potent and safer antibiotic alternative to vancomycin. Teicoplanin and daptomycin are two of these investigational agents.