Use of dalbavancin in infective endocarditis: a case series.

BACKGROUND: Infective endocarditis, typically caused by Gram-positive organisms such as viridans group streptococci and Staphylococcus aureus, is associated with high mortality and morbidity and requires aggressive, prolonged antimicrobial treatment and sometimes surgery. Dalbavancin, a lipoglycopeptide active against Gram-positive pathogens, has a long half-life, which allows IV treatment as one dose or two doses with a prolonged interval, offering personalized treatment for complex psychosocial situations or facilitating early discharge. In the absence of randomized controlled trials in infective endocarditis, current evidence derives from real-world case series involving off-licence use. The Austrian Society for Infectious Disease and Tropical Medicine includes dalbavancin as an option for infective endocarditis. OBJECTIVES: This retrospective case series reports use of dalbavancin in a small cohort of patients with infective endocarditis treated at Lancashire Cardiac Centre, Blackpool Teaching Hospitals Foundation Trust, UK. RESULTS: The pharmacy database included 11 patients in whom dalbavancin was used to address either complex psychosocial circumstances or the need for early discharge. The endocarditis multidisciplinary team selected dalbavancin from available treatment options. Structures affected by infective endocarditis included aortic, mitral and tricuspid valves; aortic composite grafts; implantable cardioverter defibrillator leads; and prosthetic aortic valves. Eight patients underwent surgery; three were managed conservatively with antibiotics. Dalbavancin was curative in all but one patient, whose signs and symptoms of infection improved. No patients developed adverse reactions. CONCLUSIONS: Dalbavancin is an alternative treatment option at hospital discharge when conventional antibiotics may not be suitable due to complex psychosocial issues or early discharge is required.

Adjunctive rifampicin to reduce early mortality from Staphylococcus aureus bacteraemia: the ARREST RCT.

BACKGROUND: Staphylococcus aureus bacteraemia is a common and frequently fatal infection. Adjunctive rifampicin may enhance early S. aureus killing, sterilise infected foci and blood faster, and thereby reduce the risk of dissemination, metastatic infection and death. OBJECTIVES: To determine whether or not adjunctive rifampicin reduces bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. Secondary objectives included evaluating the impact of rifampicin on all-cause mortality, clinically defined failure/recurrence or death, toxicity, resistance emergence, and duration of bacteraemia; and assessing the cost-effectiveness of rifampicin. DESIGN: Parallel-group, randomised (1 : 1), blinded, placebo-controlled multicentre trial. SETTING: UK NHS trust hospitals. PARTICIPANTS: Adult inpatients (≥ 18 years) with meticillin-resistant or susceptible S. aureus grown from one or more blood cultures, who had received < 96 hours of antibiotic therapy for the current infection, and without contraindications to rifampicin. INTERVENTIONS: Adjunctive rifampicin (600-900 mg/day, oral or intravenous) or placebo for 14 days in addition to standard antibiotic therapy. Investigators and patients were blinded to trial treatment. Follow-up was for 12 weeks (assessments at 3, 7, 10 and 14 days, weekly until discharge and final assessment at 12 weeks post randomisation). MAIN OUTCOME MEASURES: The primary outcome was all-cause bacteriological (microbiologically confirmed) failure/recurrence or death through 12 weeks from randomisation. RESULTS: Between December 2012 and October 2016, 758 eligible participants from 29 UK hospitals were randomised: 370 to rifampicin and 388 to placebo. The median age was 65 years [interquartile range (IQR) 50-76 years]. A total of 485 (64.0%) infections were community acquired and 132 (17.4%) were nosocomial; 47 (6.2%) were caused by meticillin-resistant S. aureus. A total of 301 (39.7%) participants had an initial deep infection focus. Standard antibiotics were given for a median of 29 days (IQR 18-45 days) and 619 (81.7%) participants received flucloxacillin. By 12 weeks, 62 out of 370 (16.8%) patients taking rifampicin versus 71 out of 388 (18.3%) participants taking the placebo experienced bacteriological (microbiologically confirmed) failure/recurrence or died [absolute risk difference -1.4%, 95% confidence interval (CI) -7.0% to 4.3%; hazard ratio 0.96, 95% CI 0.68 to 1.35; p = 0.81]. There were 4 (1.1%) and 5 (1.3%) bacteriological failures (p = 0.82) in the rifampicin and placebo groups, respectively. There were 3 (0.8%) versus 16 (4.1%) bacteriological recurrences (p = 0.01), and 55 (14.9%) versus 50 (12.9%) deaths without bacteriological failure/recurrence (p = 0.30) in the rifampicin and placebo groups, respectively. Over 12 weeks, there was no evidence of differences in clinically defined failure/recurrence/death (p = 0.84), all-cause mortality (p = 0.60), serious (p = 0.17) or grade 3/4 (p = 0.36) adverse events (AEs). However, 63 (17.0%) participants in the rifampicin group versus 39 (10.1%) participants in the placebo group experienced antibiotic or trial drug-modifying AEs (p = 0.004), and 24 (6.5%) participants in the rifampicin group versus 6 (1.5%) participants in the placebo group experienced drug-interactions (p = 0.0005). Evaluation of the costs and health-related quality-of-life impacts revealed that an episode of S. aureus bacteraemia costs an average of £12,197 over 12 weeks. Rifampicin was estimated to save 10% of episode costs (p = 0.14). After adjustment, the effect of rifampicin on total quality-adjusted life-years (QALYs) was positive (0.004 QALYs), but not statistically significant (standard error 0.004 QALYs). CONCLUSIONS: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S. aureus bacteraemia. FUTURE WORK: Given the substantial mortality, other antibiotic combinations or improved source management should be investigated. TRIAL REGISTRATIONS: Current Controlled Trials ISRCTN37666216, EudraCT 2012-000344-10 and Clinical Trials Authorisation 00316/0243/001. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 22, No. 59. See the NIHR Journals Library website for further project information.

Adjunctive rifampicin for Staphylococcus aureus bacteraemia (ARREST): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Staphylococcus 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. METHODS: In 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. FINDINGS: Between 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). INTERPRETATION: Adjunctive rifampicin provided no overall benefit over standard antibiotic therapy in adults with S aureus bacteraemia. FUNDING: UK National Institute for Health Research Health Technology Assessment.

Effectiveness and safety of daptomycin in patients with infective endocarditis undergoing heart valve replacement: a subgroup analysis from real-world data.

BACKGROUND: European Cubicin® Outcomes Registry and Experience (EU-CORE) was a retrospective, non-interventional, multicenter registry that collected real-world clinical outcomes following daptomycin use for the treatment of Gram-positive infections. EU-CORE data from patients with infective endocarditis (IE) who underwent heart valve replacement were analysed. METHODS: Clinical outcomes were assessed as success (cured or improved), failure, or non-evaluable. Adverse events (AEs) were recorded for up to 30 days after daptomycin treatment. RESULTS: Of 610 patients with IE, 198 [32.5%; left-sided IE (LIE), 166 (83.8%); right-sided IE (RIE), 21 (10.6%); both LIE and RIE, 11 (5.6%)] underwent heart valve replacement. Other than cardiovascular disease, renal disease (18.2%), sepsis (16.2%), and diabetes mellitus (15.2%) were the most significant underlying diseases. Major pathogens in patients with positive culture results (68.0%) were Staphylococcus aureus [36.8%; methicillin-resistant S. aureus (MRSA), 12.8%] and coagulase-negative staphylococci (CoNS; 31.6%). Daptomycin treatment [median duration (range), 21 days (1-112)] resulted in high clinical success in patients with S. aureus (88.4%; MRSA, 80.0%) and CoNS (81.1%) infections, with an overall success rate of 83.3%. Clinical success rate was high (90.0%) in patients who received daptomycin dose >6 mg/kg/day. Overall clinical success rate in patients followed for up to 2 years was 90.7%. AEs and serious AEs possibly related to daptomycin were reported in 6 (3.0%) and 4 (2.0%) patients, respectively. CONCLUSIONS: Daptomycin treatment was effective and well tolerated with a sustained response in patients with IE who underwent heart valve surgery. A trend towards better clinical outcomes was observed with higher daptomycin doses.

Daptomycin for the treatment of infective endocarditis: results from a European registry.

OBJECTIVES: Infective endocarditis (IE) is a complex infection associated with high mortality. Daptomycin, a cyclic lipopeptide antibiotic highly active against Gram-positive bacteria, has recently been incorporated into IE treatment guidelines. This retrospective analysis provides insights into the use of daptomycin in IE in the European Cubicin(®) Outcomes Registry Experience (EU-CORE(SM)) between 2006 and 2010. PATIENTS AND METHODS: Three hundred and seventy-eight (10%) of 3621 enrolled patients received daptomycin for treatment of IE. Two hundred and fifty-nine (69%) had left-sided IE (LIE) and 182 patients (48%) underwent concomitant surgery. RESULTS: Staphylococcus aureus was the most frequently identified pathogen (n=92; methicillin susceptible, n=50) and daptomycin was used empirically in 134 patients. Among cases of second-line therapy (n=312), the most common reason for switching to daptomycin was failure of the previous regimen (including glycopeptides and penicillins). Daptomycin was administered at 6 mg/kg in 224 patients and at ≥ 8 mg/kg in 72 patients. Clinical success rates were 80% overall, 91% for right-sided IE (RIE) and 76% for LIE, with similar rates seen for infections caused by methicillin-susceptible S. aureus (84%) and methicillin-resistant S. aureus (81%). The clinical success rate in patients treated with ≥ 8 mg/kg daptomycin was 90% [n=72 (RIE, 91%; LIE, 89%)]. No new safety signals were observed. CONCLUSIONS: In patients with IE registered in EU-CORE, daptomycin was most frequently used as second-line treatment after treatment failure. The majority of patients had LIE and most commonly received daptomycin for the treatment of staphylococcal infections. Clinical success was high in this difficult-to-treat population. The role of doses ≥ 8 mg/kg per day in the empirical treatment of IE deserves further investigation.

Salvage therapy with topical antifungal for Aspergillus fumigatus empyema complicating extrapleural pneumonectomy.

We describe an unusual case of Aspergillus fumigatus empyema and bronchopleural fistulae after extrapleural pneumonectomy (EPP) and chemoradiotherapy (CRT), which was treated successfully under salvage conditions with debridement, an innovative topical antifungal application and supplemented systemic antifungal therapy and which went on for a definitive surgical procedure. Combinations of CRT and EPP have been recommended in a select group of patients with malignant mesothelioma. Irrespective of the combination, EPP is associated with mortality in the range of 4-15% and a complication rate as high as 62%.

Anaphylaxis to chlorhexidine-coated central venous catheters: a case series and review of the literature.

BACKGROUND: Anaphylactic reactions to chlorhexidine are rare but are being reported increasingly in association with a variety of products. METHODS: We report three cases of anaphylaxis to chlorhexidine in patients presenting for cardiac surgery. RESULTS: In each case, anaphylaxis was precipitated by the insertion of a central venous catheter impregnated with chlorhexidine acetate. Subsequent investigations confirmed chlorhexidine as the causal agent. CONCLUSION: Extensive use of chlorhexidine to reduce hospital-acquired infections has the potential to sensitize a small proportion of patients, leading to life-threatening anaphylaxis on subsequent exposure.