Human Health Risk Assessment (HHRA) for environmental development and transfer of antibiotic resistanc

This is the final version of the article. Available from NIEHS via the DOI in this record.Open access journalBACKGROUND: Only recently has the environment been clearly implicated in the risk of antibiotic resistance to clinical outcome, but to date there have been few documented approaches to formally assess these risks. OBJECTIVE: We examined possible approaches and sought to identify research needs to enable human health risk assessments (HHRA) that focus on the role of the environment in the failure of antibiotic treatment caused by antibiotic-resistant pathogens. METHODS: The authors participated in a workshop held 4-8 March 2012 in Québec, Canada, to define the scope and objectives of an environmental assessment of antibiotic-resistance risks to human health. We focused on key elements of environmental-resistance-development "hot spots," exposure assessment (unrelated to food), and dose response to characterize risks that may improve antibiotic-resistance management options. DISCUSSION: Various novel aspects to traditional risk assessments were identified to enable an assessment of environmental antibiotic resistance. These include a) accounting for an added selective pressure on the environmental resistome that, over time, allows for development of antibiotic-resistant bacteria (ARB); b) identifying and describing rates of horizontal gene transfer (HGT) in the relevant environmental "hot spot" compartments; and c) modifying traditional dose-response approaches to address doses of ARB for various health outcomes and pathways. CONCLUSIONS: We propose that environmental aspects of antibiotic-resistance development be included in the processes of any HHRA addressing ARB. Because of limited available data, a multicriteria decision analysis approach would be a useful way to undertake an HHRA of environmental antibiotic resistance that informs risk managers.This manuscript was conceived at a workshop (Antimicrobial Resistance in the Environment: Assessing and Managing Effects of Anthropogenic Activities) held 4–8 March 2012 in Montebello, Québec, Canada. The workshop was sponsored by the Canadian Society of Microbiologists, with financial support from AstraZeneca Ltd.; Pfizer Animal Health; F. Hoffman-La Roche Ltd.; GlaxoSmithKline; Unilever; Huvepharma; the American Cleaning Institute; the Canadian Animal Health Institute; the German Federal Ministry for the Environment, Nature Conservation and Nuclear Safety; Health Canada; and the Public Health Agency of Canada

Enterobactin-Mediated Delivery of β-Lactam Antibiotics Enhances Antibacterial Activity against Pathogenic Escherichia coli

The design, synthesis, and characterization of enterobactin–antibiotic conjugates, hereafter Ent-Amp/Amx, where the β-lactam antibiotics ampicillin (Amp) and amoxicillin (Amx) are linked to a monofunctionalized enterobactin scaffold via a stable poly(ethylene glycol) linker are reported. Under conditions of iron limitation, these siderophore-modified antibiotics provide enhanced antibacterial activity against Escherichia coli strains, including uropathogenic E. coli CFT073 and UTI89, enterohemorrhagic E. coli O157:H7, and enterotoxigenic E. coli O78:H11, compared to the parent β-lactams. Studies with E. coli K-12 derivatives defective in ferric enterobactin transport reveal that the enhanced antibacterial activity observed for this strain requires the outer membrane ferric enterobactin transporter FepA. A remarkable 1000-fold decrease in minimum inhibitory concentration (MIC) value is observed for uropathogenic E. coli CFT073 relative to Amp/Amx, and time-kill kinetic studies demonstrate that Ent-Amp/Amx kill this strain more rapidly at 10-fold lower concentrations than the parent antibiotics. Moreover, Ent-Amp and Ent-Amx selectively kill E. coli CFT073 co-cultured with other bacterial species such as Staphylococcus aureus, and Ent-Amp exhibits low cytotoxicity against human T84 intestinal cells in both the apo and iron-bound forms. These studies demonstrate that the native enterobactin platform provides a means to effectively deliver antibacterial cargo across the outer membrane permeability barrier of Gram-negative pathogens utilizing enterobactin for iron acquisition.Pacific Southwest Regional Center of Excellence for Biodefense and Emerging Infectious DiseaseKinship Foundation. Searle Scholars ProgramMassachusetts Institute of Technology. Department of Chemistr

Studies on the metabolism of the rumen bacteria Streptoccus Bovis and Selenomonas Ruminantium

SIGLEAvailable from British Library Document Supply Centre- DSC:D44412/83 / BLDSC - British Library Document Supply CentreGBUnited Kingdo