The Microbiota and Antibiotics
The microbiota plays an important role in the hosts ability to resist disease through preventing colonisation of the gastrointestinal tract by harmful bacteria.[1] This is called colonisation resistance and is brought about through multiple mechanisms. Firstly, the microbiota can activate the innate immune system including mucosal immune cells within gut-associated lymphoid tissue (GALT) and produce defensive metabolites, such as antimicrobial peptides and short-chain fatty acids. The microbiota also directly competes with pathogenic bacteria for nutrients and mucosal binding sites as well as producing bacteriocins, a type of antimicrobial peptide secreted from commensal bacteria that can kill or inhibit other bacteria without harming themselves.[2]
During dysbiosis, this protective function is compromised and the host can experience negative health effects. Antibiotics are a common cause of dysbiosis due to their non-selective bacteriostatic or bactericidal nature, meaning they will indiscriminately kill beneficial bacterial species of the microbiota (e.g. Bifidobacteria spp and Lactobacilli). This reduces the host’s colonisation resistance and creates an opportunity for harmful species to proliferate and fill the void.
Simultaneously, antibiotic administration can exert a selection pressure, promoting the development of antibiotic resistant genes (ARGs) in both pathogenic and commensal bacteria of the microbiota. This collection of ARGs is termed the intestinal resistome. Reduced colonisation resistance and increased intestinal resistome could increase the risk of ARG transfer between commensals and potential pathogens, making the microbiota a potential reservoir for antibiotic resistant bacteria.[1][3]
Interestingly, it appears that the resistome is established during the first few months of life and is either maternally acquired or attained through contact with the external environment, shown by the presence of ARGs in infants without prior exposure to antibiotics. [4] Whilst neonates that were exposed to antibiotics showed reduced bacterial diversity and increased risk of antibiotic resistance development, in particular to extended spectrum beta-lactamase (ESBL) -producing gram-negative bacteria[5] ( ESBL is an enzyme which allows bacteria to become resistant to extended-spectrum penicillin, cephalosporins, and many monobactams).[6]
Since their domestication, ARGs have appeared within the gut microbiota of domestic dogs and appear to be different to those found in the wolf population. In one study, cephalosporin-resistant Enterobacteriaceae were isolated in 22/151 (14.6%) of dogs, of which 21 produced ESBL.[7]Interestingly, antibiotic resistance in the dog microbiome appears to be more common against clinical antibiotics, in contrast to wolves where resistance was most prevalent to antibiotics used in livestock (e.g. tetracyclines).[7][8]This finding has also been reported in other wild species such as the red fox and Iberian lynx.[9][10]Tetracycline antibiotics are frequently utilised to improve feed growth efficiency in livestock, therefore could enter the food chain through predation or from exposure to antibiotics in the environment, such as in contaminated faecal material.[8][11]
The microbiota of domestic pets can act as a potential reservoir for ARGs which could transfer to humans and could have potential repercussions for the effectiveness of antimicrobials in humans medicine.[12]A clinically relevant example is the appearance of colistin resistant isolates in faecal samples of companion animals.[13][14]Colistin (polymyxin E) is a ‘last resort’ critically important antimicrobial in human medicine and is in the same class as Polymyxin B, an antibiotic commonly found in topical aural treatments for otitis externa in dogs and cats and the systemic treatment of endotoxemia associated with colic or gastrointestinal disease in horses.[15]Although topical use of polymyxin B would not directly select for colistin resistance within the gut microbiota,[13]the possibility of ingestion and cross resistance could contribute to the development of resistant isolates which have the potential to transfer between pets and their owners.[16][17]
When looking at interspecies ARG transfer more generally a greater amount of evidence exists; one study demonstrated that pig farm workers carried higher levels of ARGs compared to non-exposed controls [18]and ARGs to antibiotics only documented to have been used in animals have been found in both animal and human commensal gut bacteria, suggesting transfer has occurred through some mechanism. [19]A recent study (2019) performed in three UK veterinary hospitals revealed that the prevalence of faecal carriage of ESBL-producing E.coli in participants was around 6%, however almost 26% of longitudinal participants tested positive for this bacteria during the six-week study period.[20] Not only do these findings have implications for the personal health of veterinary professionals, but could also impact the wellbeing of direct family members and the wider community.
In summary, the use antibiotics by any route of administration should be carefully considered due to the direct effect exerted upon the animals own microbiota, the selection pressure placed on the intestinal resistome and the potential impact that these clinical decisions can have an impact upon global health and the development of antimicrobial resistance. Due to close animal contact, individuals working in a veterinary setting may be a high risk population for carriage of these resistant bacteria and raising awareness is important in order to protect themselves and the wider public.
Author: Pippa Coupe BVSc, MRCVS Veterinary Product Manager at Protexin Veterinary. Protexin Veterinary is a brand of ADM Protexin Ltd
References
- ↑ 1.0 1.1 Casals-Pascual C, Vergara A, Vila J. Intestinal microbiota and antibiotic resistance: perspectives and solutions. Hum. Microbiome J 2018; 9: 11-5
- ↑ Yang SC, Lin CH, Sung CT, Fang JY. Antibacterial activities of bacteriocins: application in foods and pharmaceuticals. Front Microbiol 2014;5:241
- ↑ Sommer MO, Church GM, Dantas G. The human microbiome harbors a diverse reservoir of antibiotic resistance genes. Virulence 2010 ;1(4):299-303
- ↑ Moore AM, Patel S, Forsberg KJ, et al. Pediatric fecal microbiota harbor diverse and novel antibiotic resistance genes. PLoS One 2013;8(11):e78822
- ↑ Fjalstad JW, Esaiassen E, Juvet LK, van den Anker JN, Klingenberg C. Antibiotic therapy in neonates and impact on gut microbiota and antibiotic resistance development: a systematic review. J Antimicrob Chemother 2018;73(3):569-580
- ↑ Teklu DS, Negeri AA, Legese MH, Bedada TL, Woldemariam HK, Tullu KD. Extended-spectrum beta-lactamase production and multi-drug resistance among Enterobacteriaceae isolated in Addis Ababa, Ethiopia.Antimicrob Resist Infect Control 2019;8:39
- ↑ 7.0 7.1 Liu Y, Liu B, Liu C, et al. Differences in the gut microbiomes of dogs and wolves: roles of antibiotics and starch. BMC Vet Res 2021; 17:112
- ↑ 8.0 8.1 Gonçalves A, Igrejas G, Radhouani H, et al. Antimicrobial resistance in faecal enterococci and Escherichia coli isolates recovered from Iberian wolf. Lett Appl Microbiol 2013; 56(4):268-74
- ↑ Radhouani H, Igrejas G, Gonçalves A, et al. Antimicrobial resistance and virulence genes in Escherichia coli and enterococci from red foxes (Vulpes vulpes). Anaerobe 2013; 23:82-6
- ↑ Gonçalves A, Igrejas G, Radhouani H, et al. Detection of antibiotic resistant enterococci and Escherichia coli in free range Iberian Lynx (Lynx pardinus). Sci Total Environ 2013;456-457:115-9
- ↑ Granados-Chinchilla F, Rodríguez C. Tetracyclines in Food and Feeding stuffs: From Regulation to Analytical Methods, Bacterial Resistance, and Environmental and Health Implications. J Anal Methods Chem 2017; 2017:1315497
- ↑ Lloyd DH. Reservoirs of antimicrobial resistance in pet animals.Clin Infect Dis2007;45 (2):S148-52
- ↑ 13.0 13.1 Joosten P, Ceccarelli D, Odent E, et al. Antimicrobial Usage and Resistance in Companion Animals: A Cross-Sectional Study in Three European Countries. Antibiotics (Basel) 2020;9(2):87
- ↑ Ortega-Paredes D, Haro M, Leoro-Garzón P, et al. Multidrug-resistant Escherichia coli isolated from canine faeces in a public park in Quito, Ecuador. J Glob Antimicrob Resist 2019;18:263-268
- ↑ Scott A, Pottenger S, Timofte D, et al. Reservoirs of resistance: polymyxin resistance in veterinary‐associated companion animal isolates of Pseudomonas aeruginosa. Vet.Rec 2019; 185(7):206
- ↑ Zhang XF, Doi Y, Huang X, et al. Possible transmission of mcr-1–harboring Escherichia coli between companion animals and human. Emerg. Infect. Dis 2016; 22 (9):1679
- ↑ Lei L, Wang Y, He J, et al. Prevalence and risk analysis of mobile colistin resistance and extended-spectrum β-lactamase genes carriage in pet dogs and their owners: a population based cross-sectional study. Emerg. microbes & infect 2021;10(1) :242-51
- ↑ Van Gompel L, Luiken RE, Hansen RB, et al. Description and determinants of the faecal resistome and microbiome of farmers and slaughterhouse workers: A metagenome-wide cross-sectional study. Environ Int 2020; 143:105939
- ↑ Van den Bogaard AE, Stobberingh EE. Epidemiology of resistance to antibiotics. Links between animals and humans. Int J Antimicrob Agents 2000; 14 (4):327-35
- ↑ Royden A, Ormandy E, Pinchbeck G, et al. Prevalence of faecal carriage of extended-spectrum β-lactamase (ESBL)-producing Escherichia coli in veterinary hospital staff and students. Vet Rec Open 2019;6 (1):e000307