Raphael Saginur

Multiple Combination Bactericidal Testing of Staphylococcal Biofilms from Implant-Associated Infections

ABSTRACT Standardized susceptibility testing fails to predict in vivo resistance of device-related infections to antimicrobials. We assessed agents and combinations of antimicrobials against clinical isolates of Staphylococcus epidermidis and S. aureus (methicillin-resistant S. aureus and methicillin-sensitive S. aureus) retrieved from device-associated infections. Isolates were grown planktonically and as biofilms. Biofilm cultures of the organisms were found to be much more resistant to inhibitory and bactericidal effects of single and combination antibiotics than planktonic cultures (P < 0.001). Rifampin was the most common constituent of antibiotic combinations active against staphylococcal biofilms. Other frequently effective antimicrobials were vancomycin and fusidic acid. Susceptibility testing involving biofilm-associated bacteria suggests new options for combination antibiotic therapy.

Severe Group A Streptococcal Soft-Tissue Infections in Ontario: 1992–1996

A prospective, population-based, surveillance study of invasive soft-tissue infections due to group A streptococci was conducted in Ontario, Canada, from 1992 through 1996. Demographic and clinical information was obtained by patient interview and chart review. Isolates were characterized by M protein and T agglutination typing. The incidence of necrotizing fasciitis (NF) increased from 0.08 cases per 100,000 population in 1992 to 0.49 cases per 100,000 population in 1995. The case-fatality rate was 13% (68 of 520 patients died). Hypotension and multiorgan dysfunction complicated 64 cases (12%), and NF complicated 119 cases (23%). Underlying diabetes, alcohol abuse, cancer, and cardiac and pulmonary disease increased the risk of disease. Prior use of nonsteroidal anti-inflammatory agents did not influence disease severity. All 197 patients without NF, underlying illness, and hypotension at presentation survived, as did 95 (99%) of 96 normotensive patients who were <65 years old but who had underlying chronic illness. Previously healthy patients without hypotension or NF may be considered for outpatient treatment.

Single and Combination Antibiotic Susceptibilities of Planktonic, Adherent, and Biofilm-Grown Pseudomonas aeruginosa Isolates Cultured from Sputa of Adults with Cystic Fibrosis

ABSTRACT Evidence suggests that Pseudomonas aeruginosa bacteria form biofilms within the airways of adults with cystic fibrosis (CF). The objective of this study was to determine whether clinical isolates of P. aeruginosa recovered from adults with CF have similar susceptibilities to individual antibiotics and to antibiotic combinations when grown as adherent monolayers or as biofilms compared to when they are grown using planktonic methods. Twelve multiresistant P. aeruginosa isolates, one mucoid and one nonmucoid from each of six CF patients, were grown conventionally under planktonic conditions, as adherent bacterial monolayers, and as biofilms. Each bacterial isolate remained genotypically identical despite being cultured under planktonic, adherent, or biofilm growth conditions. Isolates grown as adherent monolayers and as biofilms were less susceptible to bactericidal killing by individual antibiotics compared to those grown planktonically. More importantly, biofilm-grown bacteria, but not adherent monolayer-grown bacteria, were significantly less susceptible to two- and three-drug combinations of antibiotics than were planktonically grown bacteria (P = 0.005). We conclude that biofilm-grown bacteria derived from patients with CF show decreased susceptibility to the bactericidal effects of antibiotic combinations than do adherent and planktonically grown bacteria.

When is informed consent required in cluster randomized trials in health research

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the cluster trial is to be set on a firm ethical foundation. This paper addresses the second of the questions posed, namely, from whom, when, and how must informed consent be obtained in CRTs in health research? The ethical principle of respect for persons implies that researchers are generally obligated to obtain the informed consent of research subjects. Aspects of CRT design, including cluster randomization, cluster level interventions, and cluster size, present challenges to obtaining informed consent. Here we address five questions related to consent and CRTs: How can a study proceed if informed consent is not possible? Is consent to randomization always required? What information must be disclosed to potential subjects if their cluster has already been randomized? Is passive consent a valid substitute for informed consent? Do health professionals have a moral obligation to participate as subjects in CRTs designed to improve professional practice?We set out a framework based on the moral foundations of informed consent and international regulatory provisions to address each of these questions. First, when informed consent is not possible, a study may proceed if a research ethics committee is satisfied that conditions for a waiver of consent are satisfied. Second, informed consent to randomization may not be required if it is not possible to approach subjects at the time of randomization. Third, when potential subjects are approached after cluster randomization, they must be provided with a detailed description of the interventions in the trial arm to which their cluster has been randomized; detailed information on interventions in other trial arms need not be provided. Fourth, while passive consent may serve a variety of practical ends, it is not a substitute for valid informed consent. Fifth, while health professionals may have a moral obligation to participate as subjects in research, this does not diminish the necessity of informed consent to study participation.

Ethical and policy issues in cluster randomized trials: rationale and design of a mixed methods research study

BackgroundCluster randomized trials are an increasingly important methodological tool in health research. In cluster randomized trials, intact social units or groups of individuals, such as medical practices, schools, or entire communities – rather than individual themselves – are randomly allocated to intervention or control conditions, while outcomes are then observed on individual cluster members. The substantial methodological differences between cluster randomized trials and conventional randomized trials pose serious challenges to the current conceptual framework for research ethics. The ethical implications of randomizing groups rather than individuals are not addressed in current research ethics guidelines, nor have they even been thoroughly explored. The main objectives of this research are to: (1) identify ethical issues arising in cluster trials and learn how they are currently being addressed; (2) understand how ethics reviews of cluster trials are carried out in different countries (Canada, the USA and the UK); (3) elicit the views and experiences of trial participants and cluster representatives; (4) develop well-grounded guidelines for the ethical conduct and review of cluster trials by conducting an extensive ethical analysis and organizing a consensus process; (5) disseminate the guidelines to researchers, research ethics boards (REBs), journal editors, and research funders.MethodsWe will use a mixed-methods (qualitative and quantitative) approach incorporating both empirical and conceptual work. Empirical work will include a systematic review of a random sample of published trials, a survey and in-depth interviews with trialists, a survey of REBs, and in-depth interviews and focus group discussions with trial participants and gatekeepers. The empirical work will inform the concurrent ethical analysis which will lead to a guidance document laying out principles, policy options, and rationale for proposed guidelines. An Expert Panel of researchers, ethicists, health lawyers, consumer advocates, REB members, and representatives from low-middle income countries will be appointed. A consensus conference will be convened and draft guidelines will be generated by the Panel; an e-consultation phase will then be launched to invite comments from the broader community of researchers, policy-makers, and the public before a final set of guidelines is generated by the Panel and widely disseminated by the research team.

A retrospective analysis of biofilm antibiotic susceptibility testing: a better predictor of clinical response in cystic fibrosis exacerbations.

BACKGROUNDnBacteria grow as biofilms within CF airways. However, antibiotic susceptibility testing is routinely performed on planktonically-growing bacteria. This study assessed whether CF patients infected with multiresistant organisms had improved clinical outcomes if given antibiotics that inhibited their biofilm-grown bacteria.nnnMETHODSn110 patients with pulmonary exacerbations were treated with intravenous antibiotics based on susceptibility testing of planktonically-growing bacteria. A retrospective analysis was done using bacterial isolates grown from their sputum at exacerbation. Each isolate was grown as a biofilm and combination antibiotic susceptibility testing was performed. Clinical outcomes in patients treated with biofilm-susceptible antibiotics were compared to those that were not.nnnRESULTSn66 of 110 patients (60%) were treated with antibiotic combinations that inhibited all of their planktonically-grown bacterial isolates, however, when the same isolates were grown as biofilms, only 24 patients (22%) had all of their biofilm-grown isolates remaining susceptible to the antibiotics (P=<0.001 ). When patients with at least one biofilm-grown susceptible isolate (n=61) were compared to those with none (n=49), there was a significant decrease in sputum bacterial density (P=0.02) and length of stay (P=0.04) and a non-significant decrease in treatment failure. Survival analyses of time to next exacerbation showed non-significant trends favoring patients treated with biofilm-effective antibiotics.nnnCONCLUSIONSnMost patients with CF exacerbations do not receive antibiotics that inhibit all biofilm-grown bacteria from their sputum at exacerbation. Patients treated with biofilm-effective therapy seemed to have improved clinical outcomes.

Inadequate Reporting of Research Ethics Review and Informed Consent in Cluster Randomised Trials: Review of Random Sample of Published Trials

Objectives To investigate the extent to which authors of cluster randomised trials adhered to two basic requirements of the World Medical Association’s Declaration of Helsinki and the International Committee of Medical Journal Editors’ uniform requirements for manuscripts (namely, reporting of research ethics review and informed consent), to determine whether the adequacy of reporting has improved over time, and to identify characteristics of cluster randomised trials associated with reporting of ethics practices. Design Review of a random sample of published cluster randomised trials from an electronic search in Medline. Setting Cluster randomised trials in health research published in English language journals from 2000 to 2008. Study sample 300 cluster randomised trials published in 150 journals. Results 77 (26%, 95% confidence interval 21% to 31%) trials failed to report ethics review. The proportion reporting ethics review increased significantly over time (P<0.001). Trials with data collection interventions at the individual level were more likely to report ethics review than were trials that used routine data sources only (79% (n=151) v 55% (23); P=0.008). Trials that accounted for clustering in the design and analysis were more likely to report ethics review. The median impact factor of the journal of publication was higher for trials that reported ethics review (3.4 v 2.3; P<0.001). 93 (31%, 26% to 36%) trials failed to report consent. Reporting of consent increased significantly over time (P<0.001). Trials with interventions targeting participants at the individual level were more likely to report consent than were trials with interventions targeting the cluster level (87% (90) v 48% (41); P<0.001). Trials with data collection interventions at the individual level were more likely to report consent than were those that used routine data sources only (78% (146) v 29% (11); P<0.001). Conclusions Reporting of research ethics protections in cluster randomised trials is inadequate. In addition to research ethics approval, authors should report whether informed consent was sought, from whom consent was sought, and what consent was for.

Research Recruitment Practices and Critically Ill Patients. A Multicenter, Cross-Sectional Study (The Consent Study)

RATIONALEnLimited cross-sectional data exist to characterize the challenges of enrolling critically ill patients into research studies.nnnOBJECTIVESnWe aimed to describe recruitment practices, document factors that impact recruitment, and identify factors that may enhance future research feasibility.nnnMETHODSnWe conducted a prospective, observational study of all critically ill adults eligible to participate in research studies at 23 Canadian intensive care units. We characterized eligibility events into one of five consent outcomes, identified reasons why opportunities to recruit were missed or infeasible, and documented decision makers rationale for providing or declining consent.nnnMEASUREMENTS AND MAIN RESULTSnPatients made decisions for themselves in 8.9% of encounters. In 452 eligibility events, consent was not required in 14 (3.1%), missed in 130 (28.8%), infeasible due to operational reasons in 129 (28.5%), obtained in 140 (31.0%), and declined in 39 (8.6%). More than half (57.3%) of all opportunities to recruit patients were missed or infeasible, largely because of research team workload, limited availability, narrow time windows for inclusion, difficulties in contacting families, nonexistent substitute decision makers (SDMs), physician refusals, and protocols prohibiting coenrollment. The rationale for providing consent differed between patients and SDMs. Greater research coordinator experience and site research volume and broader time windows for inclusion were significant predictors of fewer declined consents.nnnCONCLUSIONSnA large gap exists between eligibility and the frequency with which consent encounters occur in intensive care unit research. Recruitment is susceptible to design and procedural inefficiencies that hinder recruitment and to personnel availability, given the need to interact with SDMs. Current enrollment practices may underrepresent potential study populations.

Who is the research subject in cluster randomized trials in health research

This article is part of a series of papers examining ethical issues in cluster randomized trials (CRTs) in health research. In the introductory paper in this series, we set out six areas of inquiry that must be addressed if the CRT is to be set on a firm ethical foundation. This paper addresses the first of the questions posed, namely, who is the research subject in a CRT in health research? The identification of human research subjects is logically prior to the application of protections as set out in research ethics and regulation. Aspects of CRT design, including the fact that in a single study the units of randomization, experimentation, and observation may differ, complicate the identification of human research subjects. But the proper identification of human research subjects is important if they are to be protected from harm and exploitation, and if research ethics committees are to review CRTs efficiently.We examine the research ethics literature and international regulations to identify the core features of human research subjects, and then unify these features under a single, comprehensive definition of human research subject. We define a human research subject as any person whose interests may be compromised as a result of interventions in a research study. Individuals are only human research subjects in CRTs if: (1) they are directly intervened upon by investigators; (2) they interact with investigators; (3) they are deliberately intervened upon via a manipulation of their environment that may compromise their interests; or (4) their identifiable private information is used to generate data. Individuals who are indirectly affected by CRT study interventions, including patients of healthcare providers participating in knowledge translation CRTs, are not human research subjects unless at least one of these conditions is met.

Sputum versus bronchoscopy for diagnosis of Pseudomonas aeruginosa biofilms in cystic fibrosis

The present authors hypothesised that bronchoscopy with protected specimen brush may sample biofilm-forming bacteria adherent to the airway wall, whereas traditional sputum collection may not. Pseudomonas aeruginosa obtained from sputum, bronchoalveolar lavage and protected brush, taken from the right upper lung bronchus of 12 adult patients with cystic fibrosis, were compared. Retrieved bacteria were genotyped, and grown in planktonic cultures and as biofilms, and susceptibilities to individual antibiotics and to antibiotic combinations were determined. Bacterial cultures obtained using bronchoscopy did not yield any new strains of bacteria that were not also found in sputum. A total of 10 patients (83%) had a single strain of P. aeruginosa found using sputum, bronchoalveolar lavage and protected brush techniques, and two patients (17%) had two strains recovered in sputum, but only one strain was recovered using bronchoscopic techniques. Susceptibility to single antibiotics and to antibiotic combinations were not different between planktonically or biofilm-grown bacteria derived from sputum, as compared to those obtained by bronchoalveolar lavage and protected brush. In conclusion, sputum collection provides as much information as bronchoscopy for characterising the genotype and antibiotic susceptibility of chronic Pseudomonas aeruginosa infection in patients with stable cystic fibrosis.