SummaryBackgroundStaphylococcus aureus bacteraemia is a common cause of severe community-acquired and hospital-acquired infection worldwide. We tested the hypothesis that adjunctive rifampicin would reduce bacteriologically confirmed treatment failure or disease recurrence, or death, by enhancing early S aureus killing, sterilising infected foci and blood faster, and reducing risks of dissemination and metastatic infection.MethodsIn this multicentre, randomised, double-blind, placebo-controlled trial, adults (≥18 years) with S aureus bacteraemia who had received ≤96 h of active antibiotic therapy were recruited from 29 UK hospitals. Patients were randomly assigned (1:1) via a computer-generated sequential randomisation list to receive 2 weeks of adjunctive rifampicin (600 mg or 900 mg per day according to weight, oral or intravenous) versus identical placebo, together with standard antibiotic therapy. Randomisation was stratified by centre. Patients, investigators, and those caring for the patients were masked to group allocation. The primary outcome was time to bacteriologically confirmed treatment failure or disease recurrence, or death (all-cause), from randomisation to 12 weeks, adjudicated by an independent review committee masked to the treatment. Analysis was intention to treat. This trial was registered, number ISRCTN37666216, and is closed to new participants.FindingsBetween Dec 10, 2012, and Oct 25, 2016, 758 eligible participants were randomly assigned: 370 to rifampicin and 388 to placebo. 485 (64%) participants had community-acquired S aureus infections, and 132 (17%) had nosocomial S aureus infections. 47 (6%) had meticillin-resistant infections. 301 (40%) participants had an initial deep infection focus. Standard antibiotics were given for 29 (IQR 18–45) days; 619 (82%) participants received flucloxacillin. By week 12, 62 (17%) of participants who received rifampicin versus 71 (18%) who received placebo experienced treatment failure or disease recurrence, or died (absolute risk difference −1·4%, 95% CI −7·0 to 4·3; hazard ratio 0·96, 0·68–1·35, p=0·81). From randomisation to 12 weeks, no evidence of differences in serious (p=0·17) or grade 3–4 (p=0·36) adverse events were observed; however, 63 (17%) participants in the rifampicin group versus 39 (10%) in the placebo group had antibiotic or trial drug-modifying adverse events (p=0·004), and 24 (6%) versus six (2%) had drug interactions (p=0·0005).InterpretationAdjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia.FundingUK National Institute for Health Research Health Technology Assessment.

ObjectivesTo describe the patient populations and infections being treated with daptomycin, as well as the efficacy and safety outcomes.Patients and methodsData from the European Cubicin Outcomes Registry and Experience (EU-CORESM), retrospectively collected at 118 institutions between January 2006 and August 2008, were analysed.ResultsDaptomycin treatment was documented in 1127 patients with diverse infections, including complicated skin and soft tissue infections (33%), bacteraemia (22%), endocarditis (12%) and osteomyelitis (6%). It was used empirically, before microbiological results became available, in 53% of patients. Staphylococcus aureus was the most common pathogen (34%), with 52% of isolates resistant to methicillin; coagulase-negative staphylococci and enterococci were also frequent, with 22% of Enterococcus faecium isolates resistant to vancomycin. Daptomycin was used as first-line therapy in 302 (27%) patients. When used second line, the most common reasons for discontinuation of previous antibiotic were treatment failure and toxicity or intolerance. The use of concomitant antibiotics was reported in 65% of patients. Most frequent doses were 6 mg/kg (47%) and 4 mg/kg (32%). The median duration of daptomycin therapy was 10 days (range 1–246 days) in the inpatient setting and 13 days (range 2–189 days) in the outpatient setting. The overall clinical success rate was 79%, with a clinical failure rate of <10% for all infection types. Low failure rates were observed in first- and second-line therapy (6% and 8%, respectively). Daptomycin demonstrated a favourable safety and tolerability profile regardless of treatment duration.ConclusionsDaptomycin has a relevant role in the treatment of Gram-positive infections.

Aims-To assess the reliability of the detection of erythrophagocytic amoebic trophozoites in stool samples in the diagnosis of dysentery associated with invasive Entamoeba histolytica. Methods--Amoebic culture was carried out on single stool samples collected from patients from Mexico, Colombia, and Bangladesh. The stools had been examined by light microscopy. Amoebic dysentery was diagnosed when erythrophagocytic E histolytica trophozoites were observed in a case of bloody diarrhoea. E histolytica isolates were characterised by isoenzyme electrophoresis and results correlated with microscopical findings in stools. Statistical analysis was performed using the x2 test. Results-Where erythrophagocytic amoebae had been observed in dysenteric stool specimens the E histolytica phenotype was invariably invasive (p < 0*0001). Observation of erythrophagocytic amoebae in dysentery is 100% specific and predictive of infection with invasive E histolytica. When amoebic culturepositive cases only are considered it is 96% sensitive. In this study E histolytica of zymodeme XIV was more commonly associated with amoebic dysentery than zymodeme II. There was no significant difference between the carriage rate of invasive and non-invasive E histolytica in non-dysenteric diarrhoea. Asymptomatic subjects carried non-invasive E histolytica more frequently than invasive E histolytica. Patients with non-amoebic dysentery, when shown to be infected with E histolytica, carried non-invasive strains (12%

BackgroundPooled data from two large registries, Cubicin® Outcomes Registry and Experience (CORE; USA) and European Cubicin® Outcomes Registry and Experience (EU-CORE; Europe, Latin America, and Asia), were analyzed to determine the characteristics and clinical outcomes of daptomycin therapy in patients with Gram-positive infections across wide geographical regions.MethodsPatients receiving at least one dose of daptomycin between 2004 and 2012 for the treatment of Gram-positive infections were included. Clinical success was defined as an outcome of ‘cured’ or ‘improved’. Post-treatment follow-up data were collected for a subset of patients (CORE: osteomyelitis and orthopedic foreign body device infection; EU-CORE: endocarditis, intracardiac/intravascular device infection, osteomyelitis, and orthopedic device infection). Safety was assessed for up to 30 days after daptomycin treatment.ResultsIn 11,557 patients (CORE, 5482; EU-CORE, 6075) treated with daptomycin (median age, 62 [range, 1–103] years), the most frequent underlying conditions were cardiovascular disease (54.7 %) and diabetes mellitus (28.0 %). The most commonly treated primary infections were complicated skin and soft tissue infection (cSSTI; 31.2 %) and bacteremia (21.8 %). The overall clinical success rate was 77.2 % (uncomplicated SSTI, 88.3 %; cSSTI, 81.0 %; osteomyelitis, 77.7 %; foreign body/prosthetic infection (FBPI), 75.9 %; endocarditis, 75.4 %; and bacteremia, 69.5 %). The clinical success rate was 79.1 % in patients with Staphylococcus aureus infections (MRSA, 78.1 %). An increasing trend of high-dose daptomycin (>6 mg/kg/day) prescribing pattern was observed over time. Clinical success rates were higher with high-dose daptomycin treatment for endocarditis and FBPI. Adverse events (AEs) and serious AEs possibly related to daptomycin therapy were reported in 628 (5.4 %) and 133 (1.2 %) patients, respectively.ConclusionsThe real-world data showed that daptomycin was effective and safe in the treatment of various Gram-positive infections, including those caused by resistant pathogens, across wide geographical regions.

Infections caused by Gram-positive pathogens remain a major public health burden and are associated with high morbidity and mortality. Increasing rates of infection with Gram-positive bacteria and the emergence of resistance to commonly used antibiotics have led to the need for novel antibiotics. Daptomycin, a cyclic lipopeptide with rapid bactericidal activity against a wide range of Gram-positive bacteria including methicillin-resistant Staphylococcus aureus, has been shown to be effective and has a good safety profile for the approved indications of complicated skin and soft tissue infections (4 mg/kg/day), right-sided infective endocarditis caused by S. aureus, and bacteremia associated with complicated skin and soft tissue infections or right-sided infective endocarditis (6 mg/kg/day). Based on its pharmacokinetic profile and concentration-dependent bactericidal activity, high-dose (>6 mg/kg/day) daptomycin is considered an important treatment option in the management of various difficult-to-treat Gram-positive infections. Although daptomycin resistance has been documented, it remains uncommon despite the increasing use of daptomycin. To enhance activity and to minimize resistance, daptomycin in combination with other antibiotics has also been explored and found to be beneficial in certain severe infections. The availability of daptomycin via a 2-minute intravenous bolus facilitates its outpatient administration, providing an opportunity to reduce risk of health care-associated infections, improve patient satisfaction, and minimize health care costs. Daptomycin, not currently approved for use in the pediatric population, has been shown to be widely used for treating Gram-positive infections in children.

IntroductionThe aim of this study was to evaluate the clinical outcomes and safety of daptomycin therapy in patients with serious Gram-positive infections.MethodsPatients were enrolled in the European Cubicin® Outcomes Registry and Experience (EU-CORESM), a non-interventional, multicenter, observational registry. The real-world data were collected across 18 countries (Europe, Latin America, and Asia) for patients who had received at least one dose of daptomycin between January 2006 and April 2012. Two-year follow-up data were collected until 2014 for patients with endocarditis, intracardiac/intravascular device infection, osteomyelitis, or orthopedic device infection.ResultsA total of 6075 patients were enrolled. The most common primary infections were complicated skin and soft tissue infection (31.7%) and bacteremia (20.7%). Staphylococcus aureus was the most frequently reported pathogen (42.9%; methicillin-resistant S. aureus [MRSA], 23.2%), followed by Staphylococcus epidermidis and other coagulase-negative staphylococci (CoNS, 28.5%). The most commonly prescribed dose of daptomycin was 6 mg/kg/day (43.6%), and the median duration of therapy was 11 (range 1–300) days. Overall clinical success rate was 80.5%, and was similar whether daptomycin was used as first-line (82.9%) or second-line (79.2%) therapy. Clinical success rates were high in patients with S.aureus (83.9%; MRSA 83.0%) and CoNS (including S. epidermidis, 82.5%) infections. The majority of patients with endocarditis or intracardiac/intravascular device infection (86.7%) or osteomyelitis/orthopedic device infection (85.9%) had a sustained response during the 2-year follow-up period. There were no new or unexpected safety findings.ConclusionResults from real-world clinical experience showed that daptomycin is a valuable therapeutic option in the management of various difficult-to-treat Gram-positive infections.FundingThis study was funded by Novartis Pharma AG.Electronic supplementary materialThe online version of this article (doi:10.1007/s12325-015-0220-6) contains supplementary material, which is available to authorized users.

A retrospective analysis of data from patients receiving daptomycin as outpatient parenteral antimicrobial therapy (OPAT) within the European Cubicin Outcomes Registry and Experience (EU-CORE(SM)) was performed. Of 4592 enrolled patients in 15 countries, 550 (12%) received daptomycin OPAT. Of these, 149 (27%) received daptomycin without hospital admission, 84% had significant underlying diseases and 44% were ≥65 years of age. Most frequently treated infections were complicated skin and soft-tissue infections (28%), osteomyelitis (17%), foreign body/prosthetic infections (15%) and endocarditis (14%). In patients with culture results available, Staphylococcus aureus and coagulase-negative staphylococci were the most commonly isolated primary pathogens [n = 218 (46%) and n = 102 (21%), respectively]. Daptomycin was typically used at doses of 6 mg/kg (n = 210; 38%) and 4 mg/kg (n = 160; 29%), with concomitant antibiotics used in 41%. The median treatment duration was 22 days (range 1-300 days), with a median of 13 OPAT days (range 1-290 days). Overall clinical success was observed in 89%, with high success rates across the wide range of infections, including those caused by meticillin-resistant and meticillin-susceptible S. aureus (88% and 90%, respectively). Daptomycin exhibited a favourable safety profile; 3.1% of patients discontinued treatment owing to an adverse event. These data demonstrate that daptomycin is effective and well tolerated in the treatment of a wide range of Gram-positive infections in the outpatient setting. Ease of administration of daptomycin, via a daily 2-min injection, and its efficacy and safety combine to make it an attractive treatment option for OPAT.

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