Antibiotics in the human food chain: Establishing no effect levels of tetracycline, neomycin, and erythromycin using a chemostat model of the human colonic microflora

Carman, Robert J.; Simon, Mary Alice; Petzold, H. Earl; Wimmer, Robert; Batra, Monica R.; Fernández, A.; Miller, Margaret A.; Bartholomew, Mary J.

doi:10.1016/j.yrtph.2005.06.005

Cited by 32 publications

(35 citation statements)

References 37 publications

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“…The procedures used for the bioassay followed those described by Carman et al (18). Briefly, lawns of 10 6 CFU/ml Streptococcus salivarius were plated on unsupplemented blood agar plates.…”

Section: Methodsmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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bClostridium difficile infection (CDI) is a gastrointestinal disease caused by C. difficile, a spore-forming bacterium that in its spore form is tolerant to standard antimicrobials. Ramoplanin is a glycolipodepsipeptide antibiotic that is active against C. difficile with MICs ranging from 0.25 to 0.50 g/ml. The activity of ramoplanin against the spores of C. difficile has not been well characterized; such activity, however, may hold promise, since posttreatment residual intraluminal spores are likely elements of disease relapse, which can impact more than 20% of patients who are successfully treated. C. difficile spores were found to be stable in deionized water for 6 days. In vitro spore counts were consistently below the level of detection for 28 days after even brief (30-min) exposure to ramoplanin at concentrations found in feces (300 g/ml). In contrast, suppression of spore counts was not observed for metronidazole or vancomycin at human fecal concentrations during treatment (10 g/ml and 500 g/ml, respectively). Removal of the C. difficile exosporium resulted in an increase in spore counts after exposure to 300 g/ml of ramoplanin. Therefore, we propose that rather than being directly sporicidal, ramoplanin adheres to the exosporium for a prolonged period, during which time it is available to attack germinating cells. This action, in conjunction with its already established bactericidal activity against vegetative C. difficile forms, supports further evaluation of ramoplanin for the prevention of relapse after C. difficile infection in patients. Clostridium difficile infection (CDI) remains a clinically important disease, with increasing incidence and mortality rates in the United States; it now surpasses methicillin-resistant Staphylococcus aureus as the most common health care-associated infection (HAI) and results in an annual cost burden to the health care system of $4.8 billion (1-3). A prolonged cure for treated patients remains elusive, as evidenced by the high rates of relapse (same ribotype within 30 days) and reinfection (different ribotype within 30 days). Recurrence rates have ranged from 15% to 40% (4-6) and are most commonly associated with the ribotype 027 epidemic strain (7). One contributing factor for high relapse rates is the presence of spores that persist within the intestinal lumen and evade elimination by standard anti-CDI treatments (8, 9). C. difficile spores are tolerant to standard antimicrobial therapy; hence, antimicrobial interventions targeting vegetative cells alone are unlikely to eradicate this disease reservoir (10).Ramoplanin is a glycolipodepsipeptide antibiotic produced from Actinoplanes, which inhibits peptidoglycan biosynthesis by limiting lipid II availability (11); it is bactericidal to many Grampositive aerobic and anaerobic bacteria, including C. difficile and vancomycin-resistant Enterococcus (11). Ramoplanin has known bactericidal activities against wild-type C. difficile and strains with reduced susceptibilities to vancomycin and has been studied in an open-labe...

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“…The procedures used for the bioassay followed those described by Carman et al (18). Briefly, lawns of 10 6 CFU/ml Streptococcus salivarius were plated on unsupplemented blood agar plates.…”

Section: Methodsmentioning

confidence: 99%

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Kraus

Lyerly

Carman

2015

Antimicrob Agents Chemother

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“…Using in vitro chemostat models of human intestinal microbiota, researchers reported that 4.3 g/ml ciprofloxacin caused reductions in the numbers of Bacteroides fragilis group bacteria and selected for resistant variants of these species (5). Other intestinal microbiota functions, such as short-chain fatty acid concentration profiles and microbial enzyme activities, were also measured in chemostat models to assess the effects of various tetracycline, neomycin, and erythromycin concentrations on the microbial population balance (6). The in vitro chemostat models were able to detect changes in the microbiota population balance, but this is not the same as detection of the effects of antimicrobial drugs on colonization resistance to pathogens by the microbiota.…”

mentioning

confidence: 99%

In Vitro Model of Colonization Resistance by the Enteric Microbiota: Effects of Antimicrobial Agents Used in Food-Producing Animals

Wagner

Johnson

Cerniglia

2008

Antimicrob Agents Chemother

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A bioassay was developed to measure the minimum concentration of an antimicrobial drug that disrupts the colonization resistance mediated by model human intestinal microbiota against Salmonella invasion of Caco-2 intestinal cells. The bioassay was used to measure the minimum disruptive concentrations (MDCs) of drugs used in animal agriculture. The MDCs varied from 0.125 g/ml for some broad-spectrum antimicrobial drugs (e.g., streptomycin) to 16 g/ml for drugs with limited spectra of antimicrobial activity (e.g., lincomycin). The acceptable daily intake (ADI) residue concentration calculated on the basis of the MDCs were higher for erythromycin, lincomycin, and tylosin than the ADI residue concentrations calculated on the basis of the MICs. The MDC-based ADI values for apramycin, bacitracin, neomycin, novobiocin, penicillin G, streptomycin, tetracycline, and vancomycin were lower than the reported MIC-based ADI values. The effects of antimicrobial drugs at their MDCs on the bacterial composition of the microbiota were observed by denaturing gradient gel electrophoresis of 16S rRNA sequences amplified by PCR. Changes in the population composition of the model colonization resistance microbiota occurred simultaneously with reduced colonization resistance. The results of this study suggest that direct assessment of the effects of antimicrobial drugs on colonization resistance in an in vitro model can be useful in determining ADI values.

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“…Risk mitigation to assure consumer exposure to residues is below the ADI A number of studies have examined the effects of low levels of antibiotics in human intestinal microbiota and regulatory authorities have derived mADIs based on these and non-published studies provided in sponsor dossiers and submissions preapproval. [31,32,[42][43][44][45][46][47][48] A recent literature search did not produce any publications describing antimicrobial residues in foodstuffs derived from antimicrobial drug-treated animals that have resulted in a public health concern for resistance emergence or colonization barrier disruption. This should not be surprising.…”

Section: Recent Research Applicable To the Guidelinementioning

confidence: 99%

An update discussion on the current assessment of the safety of veterinary antimicrobial drug residues in food with regard to their impact on the human intestinal microbiome

Cerniglia

Piñeiro

Kotarski

2016

Drug Testing and Analysis

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The human gastrointestinal tract ecosystem consists of complex and diverse microbial communities that have now been collectively termed the intestinal microbiome. Recent scientific breakthroughs and research endeavours have increased our understanding of the important role the intestinal microbiome plays in human health and disease. The use of antimicrobial new animal drugs in food‐producing animals may result in the presence of low levels of drug residues in edible foodstuffs. There is concern that antimicrobial new animal drugs in or on animal‐derived food products at residue‐level concentrations could disrupt the colonization barrier and/or modify the antimicrobial resistance profile of human intestinal bacteria. Therapeutic doses of antimicrobial drugs have been shown to promote shifts in the intestinal microbiome, and these disruptions promote the emergence of antimicrobial‐resistant bacteria. To assess the effects of antimicrobial new animal drug residues in food on human intestinal bacteria, many national regulatory agencies and international committees follow a harmonized process, VICH GL36(R), which was issued by a trilateral organization of the European Union, the USA, and Japan called the International Cooperation on Harmonization of Technical Requirements for Veterinary Medicinal Products (VICH). The guidance describes a general approach currently used by national regulatory agencies and international committees to assess the effects of antimicrobial new animal drug residues in animal‐derived food on human intestinal bacteria. The purpose of this review is to provide an overview of this current approach as part of the antimicrobial new animal drug approval process in participating countries, give insights on the microbiological endpoints used in this safety evaluation, and discuss the availability of new information. Copyright © 2016 John Wiley & Sons, Ltd.

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Antibiotics in the human food chain: Establishing no effect levels of tetracycline, neomycin, and erythromycin using a chemostat model of the human colonic microflora

Cited by 32 publications

References 37 publications

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

Ambush of Clostridium difficile Spores by Ramoplanin: Activity in an In Vitro Model

In Vitro Model of Colonization Resistance by the Enteric Microbiota: Effects of Antimicrobial Agents Used in Food-Producing Animals

An update discussion on the current assessment of the safety of veterinary antimicrobial drug residues in food with regard to their impact on the human intestinal microbiome

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