Dataset Information

CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: study protocol for a randomised controlled trial.

ABSTRACT:

Background

Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking.

Methods

An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in methicillin-susceptible S. aureus; and vancomycin/daptomycin in methicillin-resistant S. aureus) and standard treatment plus an additional clindamycin given for 7?days. We will include a minimum of 60 participants (both adult and children) in the pilot study. Participants will be enrolled within 72?h of an index culture. Severe infections will include septic shock, necrotising pneumonia, or multifocal and non-contiguous skin and soft tissue/osteoarticular infections. Individuals who are immunosuppressed, moribund, with current severe diarrhoea or Clostridiodes difficile infection, pregnant, and those with anaphylaxis to ?-lactams or lincosamides will be excluded. The primary outcomes measure is the number of days alive and free (1 or 0) of systemic inflammatory response syndrome (SIRS) within the first 14?days post randomisation. The secondary outcomes measure will include all-cause mortality at 14, 42, and 90?days, time to resolution of SIRS, proportion with microbiological treatment failure, and rate of change of C-reactive protein over time. Impacts of inducible clindamycin resistance, strain types, methicillin susceptibility, and presence of various exotoxins will also be analysed.

Discussion

This study will assess the effect of adjunctive clindamycin on patient-centred outcomes in severe, toxin-mediated S. aureus infections. The pilot study will provide feasibility for a much larger RCT.

Trial registration

Australian New Zealand Clinical Trials Registry, ACTRN12617001416381p . Registered on 6 October 2017.

SUBMITTER: Dotel R

PROVIDER: S-EPMC6567404 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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Publications

CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: study protocol for a randomised controlled trial.

Dotel Ravindra R Tong Steven Y C SYC Bowen Asha A Nelson Jane N JN O'Sullivan Matthew V N MVN Campbell Anita J AJ McMullan Brendan J BJ Britton Philip N PN Francis Joshua R JR Eisen Damon P DP Robinson Owen O Manning Laurens L Davis Joshua S JS

Trials 20190613 1

<h4>Background</h4>Exotoxins are important virulence factors in Staphylococcus aureus. Clindamycin, a protein synthesis inhibitor antibiotic, is thought to limit exotoxin production and improve outcomes in severe S. aureus infections. However, randomised prospective data to support this are lacking.<h4>Methods</h4>An open-label, multicentre, randomised controlled trial (RCT) will compare outcome differences in severe S. aureus infection between standard treatment (flucloxacillin/cefazolin in met ...[more]

PMID: 31196132

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Project description:BackgroundStaphylococcus 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.

Project description:ObjectiveTo show non-inferiority of trimethoprim-sulfamethoxazole compared with vancomycin for the treatment of severe infections due to meticillin resistant Staphylococcus aureus (MRSA).DesignParallel, open label, randomised controlled trial.SettingFour acute care hospitals in Israel.ParticipantsAdults with severe infections caused by MRSA susceptible to trimethoprim-sulfamethoxazole and vancomycin. Patients with left sided endocarditis, meningitis, chronic haemodialysis, and prolonged neutropenia were excluded.InterventionsTrimethoprim-sulfamethoxazole 320 mg/1600 mg twice daily versus vancomycin 1 g twice daily for a minimum of seven days and then by indication.Main outcome measuresThe primary efficacy outcome was treatment failure assessed at day 7, consisting of death, persistence of haemodynamic instability or fever, stable or worsening Sequential Organ Failure Assessment score, and persistence of bacteraemia. The primary safety outcome was all cause mortality at day 30. Non-inferiority was defined by a difference of less than 15% for treatment failure.Results252 patients were included in the trial, of whom 91 (36%) had bacteraemia. No significant difference in treatment failure was seen for trimethoprim-sulfamethoxazole (51/135, 38%) versus vancomycin (32/117, 27%)-risk ratio 1.38 (95% confidence interval 0.96 to 1.99). However, trimethoprim-sulfamethoxazole did not meet the non-inferiority criterion-absolute difference 10.4% (95% confidence interval -1.2% to 21.5%). For patients with bacteraemia, the risk ratio was 1.40 (0.91 to 2.16). In a multivariable logistic regression analysis, trimethoprim-sulfamethoxazole was significantly associated with treatment failure (adjusted odds ratio 2.00, 1.09 to 3.65). The 30 day mortality rate was 32/252 (13%), with no significant difference between arms. Among patients with bacteraemia, 14/41 (34%) treated with trimethoprim-sulfamethoxazole and 9/50 (18%) with vancomycin died (risk ratio 1.90, 0.92 to 3.93).ConclusionsHigh dose trimethoprim-sulfamethoxazole did not achieve non-inferiority to vancomycin in the treatment of severe MRSA infections. The difference was particularly marked for patients with bacteraemia. Trial registration Clinical trials NCT00427076.

Project description:BackgroundMethicillin-resistant Staphylococcus aureus (MRSA) bacteraemia is a serious infection resulting in 20-50 % 90-day mortality. The limitations of vancomycin, the current standard therapy for MRSA, make treatment difficult. The only other approved drug for treatment of MRSA bacteraemia, daptomycin, has not been shown to be superior to vancomycin. Surprisingly, there has been consistent in-vitro and in-vivo laboratory data demonstrating synergy between vancomycin or daptomycin and an anti-staphylococcal β-lactam antibiotic. There is also growing clinical data to support such combinations, including a recent pilot randomised controlled trial (RCT) that demonstrated a trend towards a reduction in the duration of bacteraemia in patients treated with vancomycin plus flucloxacillin compared to vancomycin alone. Our aim is to determine whether the addition of an anti-staphylococcal penicillin to standard therapy results in improved clinical outcomes in MRSA bacteraemia.Methods/designWe will perform an open-label, parallel-group, randomised (1:1) controlled trial at 29 sites in Australia, New Zealand, Singapore, and Israel. Adults (aged 18 years or older) with MRSA grown from at least one blood culture and able to be randomised within 72 hours of the index blood culture collection will be eligible for inclusion. Participants will be randomised to vancomycin or daptomycin (standard therapy) given intravenously or to standard therapy plus 7 days of an anti-staphylococcal β-lactam (flucloxacillin, cloxacillin, or cefazolin). The primary endpoint will be a composite outcome at 90 days of (1) all-cause mortality, (2) persistent bacteraemia at day 5 or beyond, (3) microbiological relapse, or (4) microbiological treatment failure. The recruitment target of 440 patients is based on an expected failure rate for the primary outcome of 30 % in the control arm and the ability to detect a clinically meaningful absolute decrease of 12.5 %, with a two-sided alpha of 0.05, a power of 80 %, and assuming 10 % of patients will not be evaluable for the primary endpoint.DiscussionKey potential advantages of adding anti-staphylococcal β-lactams to standard therapy for MRSA bacteraemia include their safety profile, low cost, and wide availability.Trial registrationClinicalTrials.gov Identifier: NCT02365493 . Registered 24 February 2015.

Project description:Staphylococcus aureus, an important nosocomial pathogen, is frequently associated with infections in human. The management of the infections by it especially methicillin resistant ones is often difficult because methicillin resistant S. aureus is usually resistant to multiple antibiotics. Macrolide-lincosamide streptogramin B family of antibiotics is commonly used to treat such infections as an alternative to vancomycin.This study was conducted over the period of one and half year from November 2013-April 2015 in Microbiology laboratory of Nepal Medical College and Teaching Hospital, Kathmandu, Nepal to find the incidence of different phenotypes of MLSB resistance among S. aureus from clinical samples and their association with methicillin resistance. Two hundred seventy isolates of S. aureus were included in the study. Methicillin resistance was detected by cefoxitin disc diffusion method and inducible clindamycin resistance by erythromycin and clindamycin disc approximation test (D-test).Of the 270 clinical isolates of S. aureus, 25.1% (68/270) were MRSA. Erythromycin and clindamycin resistance was seen in 54.4% (147/270) and 41.8% (113/270) isolates respectively. Resistance to erythromycin and clindamycin were higher in MRSA as compared to MSSA (erythromycin-resistance: 88.2% Vs 39.1% and clindamycin-resistance: 79.4% Vs 41.8%). The overall prevalence of iMLSB and cMLSB phenotype was 11.48% (31/270) and 29.25% (79/270) respectively. Both iMLSB and cMLSB phenotypes predominated in MRSA strains.Detection rate of MRSA in our study shows the necessity to improve in healthcare practices and to formulate new policy for the control of MRSA infections. Clindamycin resistance in the form of iMLSB and cMLSB especially among MRSA emphasizes the need of D-test to be performed routinely in our set up while using clindamycin as an alternative choice to anti-staphylococcal antibiotics like vancomycin and linezolid in the treatment of staphylococcal infections.

Project description:BackgroundA third of patients diagnosed with major depressive disorder (MDD) experience treatment-resistant depression (TRD). Relatively few pharmacological agents have established efficacy for TRD. Therefore, the evaluation of novel treatments for TRD is a pressing priority. Statins are pleiotropic agents and preclinical studies as well as preliminary clinical trials have suggested that these drugs may have antidepressant properties.AimsTo report on a protocol for a 12-week, randomised, double-blind, placebo-controlled trial of add-on treatment with simvastatin for patients meeting DSM-5 criteria for MDD who have failed to respond to at least two adequate trials with approved antidepressants. The trial has been registered with Clinicaltrials.gov in (ClinicalTrials.gov identifier: NCT03435744).MethodAfter screening and randomisation to the two parallel arms of the trial, 75 patients will receive simvastatin and 75 patients will receive placebo as adjuncts to treatment as usual. The primary outcome is change in Montgomery-Åsberg Depression Rating Scale scores from baseline to week 12 and secondary outcomes include changes in scores on the 24-item Hamilton Rating Scale for Depression, the Clinical Global Impression scale, the 7-item Generalized Anxiety Disorder scale and change in body mass index from baseline to week 12. Assessments will take place at screening, baseline, and weeks 2, 4, 8 and 12. Checklists for adverse effects will be undertaken at each visit. Simvastatin (20 mg) will be given once daily. Other secondary outcomes include C-reactive protein and plasma lipids measured at baseline and week 12.ResultsThis trial will assess simvastatin's efficacy and tolerability as an add-on treatment option for patients with TRD and provide insights into its putative mechanisms of action.ConclusionsAs the first trial investigating the use of simvastatin as an augmentation strategy in patients with TRD, if the results indicate that adjuvant simvastatin is efficacious in reducing depressive symptoms, it will deliver immediate clinical benefit.Declaration of interestI.B.C. and N.H. have given lectures and advice to Eli Lilly, Bristol Myers Squibb, Lundbeck, Astra Zeneca and Janssen pharmaceuticals for which they or their employing institution have been reimbursed. R.R. and M.M.H. have received educational grants and support for academic meetings from Pfizer, Roche, Novartis and Nabiqasim. A.H.Y. has been commissioned to provide lectures and advice to all major pharmaceutical companies with drugs used in affective and related disorders. A.H.Y. has undertaken investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. None of the companies have a financial interest in this research.

Project description:INTRODUCTION:Methicillin-susceptible Staphylococcus aureus (MSSA) bacteraemia is a common and severe disease responsible for approximately 65?000 deaths every year in Europe. Intravenous antistaphylococcal penicillins (ASP) such as cloxacillin are the current recommended antibiotics. However, increasing reports of toxicity and recurrent stock-outs of ASP prompted healthcare providers to seek for alternative antibiotic treatment. Based on retrospective studies, cefazolin, a first-generation cephalosporin, is recommended in patients at risk of severe ASP-associated toxicity.We hypothesised that cefazolin has a non-inferior efficacy in comparison to cloxacillin, with a better safety profile for the treatment of MSSA bacteraemia. METHODS AND ANALYSIS:The CloCeBa trial is an open-label, randomised, controlled, non-inferiority trial conducted in academic centres throughout France. Eligible patients are adults with MSSA bacteraemia without intravascular device or suspicion of central nervous system infection. Patients will be randomised (1:1) to receive either cloxacillin or cefazolin by the intravenous route, for the first 14 days of therapy. The evaluation criteria is a composite criteria of negative blood cultures at day 5, survival, absence of relapse and clinical success at day 90 after randomisation. Secondary evaluation criteria include both efficacy and safety assessments. Three ancillary studies are planned to describe the epidemiology of ?-lactamase encoding genes, the ecological impact and pharmacokinetic/pharmacodynamic parameters of cefazolin and cloxacillin. Including 300 patients will provide 80% power to demonstrate the non-inferiority of cefazolin over cloxacillin, assuming 85% success rate with cloxacillin and taking into account loss-to-follow-up, with a 0.12 non-inferiority margin and a one-sided type I error of 0.025. ETHICS AND DISSEMINATION:This protocol received authorisation from the ethics committee Sud-Est I on 13 November 2017 (2017-87-PP)and French National Agency for Medicines and Health Products (170661A-43). Results will be disseminated to the scientific community through congresses and publication in peer-reviewed journals. TRIAL REGISTRATION NUMBER:NCT03248063 and 2017-003967-36.

Dataset Information

CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: study protocol for a randomised controlled trial.

Background

Methods

Discussion

Trial registration

Publications

CASSETTE-clindamycin adjunctive therapy for severe Staphylococcus aureus treatment evaluation: study protocol for a randomised controlled trial.

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