antibiotics Review Antimicrobials and Food-Related Stresses as Selective Factors for Antibiotic Resistance along the Farm to Fork Continuum Federica Giacometti 1 , Hesamaddin Shirzad-Aski 2 and Susana Ferreira 3,* 1 Department of Veterinary Medical Sciences, University of Bologna, Ozzano Emilia, 40064 Bologna, Italy; [email protected] 2 Infectious Diseases Research Center, Golestan University of Medical Sciences, Gorgan 49178-67439, Iran; [email protected] 3 CICS-UBI-Centro de Investigação em Ciências da Saúde, Universidade da Beira Interior, 6200-506 Covilhã, Portugal * Correspondence: [email protected] Abstract: Antimicrobial resistance (AMR) is a global problem and there has been growing concern associated with its widespread along the animal–human–environment interface. The farm-to-fork continuum was highlighted as a possible reservoir of AMR, and a hotspot for the emergence and spread of AMR. However, the extent of the role of non-antibiotic antimicrobials and other food- related stresses as selective factors is still in need of clarification. This review addresses the use of non-antibiotic stressors, such as antimicrobials, food-processing treatments, or even novel approaches to ensure food safety, as potential drivers for resistance to clinically relevant antibiotics. The co- selection and cross-adaptation events are covered, which may induce a decreased susceptibility of foodborne bacteria to antibiotics. Although the available studies address the complexity involved Citation: Giacometti, F.; in these phenomena, further studies are needed to help better understand the real risk of using Shirzad-Aski, H.; Ferreira, S. food-chain-related stressors, and possibly to allow the establishment of early warnings of potential Antimicrobials and Food-Related Stresses as Selective Factors for resistance mechanisms. Antibiotic Resistance along the Farm to Fork Continuum. Antibiotics 2021, Keywords: antimicrobial resistance; food chain; stressors; cross-resistance; adaptive response 10, 671. https://doi.org/10.3390/ antibiotics10060671 Academic Editor David 1. Introduction Rodríguez-Lázaro In recent years, there has been an effort to reduce foodborne diseases, by the implemen- tation of food safety measures from farm to fork. Nonetheless, a high burden of foodborne Received: 5 May 2021 diseases still exists, with the World Health Organization estimating that each year world- Accepted: 1 June 2021 wide, the consumption of unsafe food causes about 600 million cases of foodborne diseases Published: 4 June 2021 and 420,000 deaths [1]. Further, amongst the cases of foodborne diseases, the ones caused by antibiotic-resistant bacteria are increasing and are a major health problem, with the food Publisher’s Note: MDPI stays neutral chain being pointed to as a relevant vehicle of antibiotic resistance to humans [2]. with regard to jurisdictional claims in The use and misuse of antimicrobial compounds have been related to an increase in published maps and institutional affil- the emergence of antimicrobial resistance (AMR) amongst foodborne microorganisms. The iations. identification of resistant microorganisms at every stage of the food chain, from farm to fork, highlights the major concern that is AMR [2,3]. The cross-adaptation and selective pressure exercised by antibiotics and biocides are considered as a key motive power for the emergence and spread of antibiotic resistance along the food chain [4]. However, other Copyright: © 2021 by the authors. factors, such as different antimicrobial approaches, or even agricultural or food-processing Licensee MDPI, Basel, Switzerland. procedures, may have a role in the emergence and spread of antibiotic resistance along the This article is an open access article food chain. distributed under the terms and During food production and processing, different types of antimicrobials are used conditions of the Creative Commons throughout the several stages of the food chain, namely, antibiotics, agricides and biocides, Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ among others (e.g., agrochemicals, feed and food preservatives, decontaminants, or dis- 4.0/). infectants). These products are applied to ensure food quality and safety, as well as to Antibiotics 2021, 10, 671. https://doi.org/10.3390/antibiotics10060671 https://www.mdpi.com/journal/antibiotics Antibiotics 2021, 10, x FOR PEER REVIEW 2 of 29 Antibiotics 2021, 10, 671 2 of 29 disinfectants). These products are applied to ensure food quality and safety, as well as to assureassure the the efficiency efficiency of of the the system. system. Antibiotics Antibiotics may may be be used used not not only only for for the the treatment treatment of of animalsanimals with with a a manifest manifest clinical clinical disease, disease, but but also also for for metaphylaxis, metaphylaxis, prophylaxis, prophylaxis, growth growth promotion,promotion, or or even even in plantin plant agriculture. agriculture. Antimicrobials Antimicrobials may may also bealso added be added to feed to and feed food and asfood preservatives as preservatives to control to control foodborne foodborne bacteria, ba inhibitcteria, spoilageinhibit spoilage microorganisms, microorganisms, and extend and theextend shelf the life shelf of the life final of products.the final products. Decontaminants Decontaminants can be used can tobe inactivate,used to inactivate, or inhibit, or theinhibit, growth the of growth pathogenic of pathogenic and spoilage and spoilage microorganisms microorganisms in fresh food,in fresh while food, disinfectants while disin- arefectants mostly are used mostly to reduce used theto reduce level of the microorganisms level of microorganisms in abioticsurfaces, in abiotic equipment, surfaces, equip- and othersment, [4and,5]. others [4,5]. Overall,Overall, foodborne foodborne bacteria bacteria are are subject subject to to several several stresses stresses during during their their lifecycle, lifecycle, and and throughoutthroughout all all the the processes processes associated associated with with food food production, production, processing processing and and storage. storage. TheseThese stresses stresses can can be be physical, physical, chemical, chemical, or or biological, biological, and and ultimately ultimately may may lead lead to to a a stress stress adaptationadaptation (Figure (Figure1). 1). The The adaptative adaptative or protectiveor protective response response may, may, in turn, in turn, confer confer protection protec- totion the to same the stresssame orstress against or ag aainst different a different type of type stress, of knownstress, known as stress as cross-adaptation stress cross-adapta- [6]. Usually,tion [6]. this Usually, adaptation this adaptation occurs as a occurs cellular as response a cellular of response the bacterium of the to bacterium the stressor, to bythe regulatingstressor, by molecular regulating mechanisms molecular mechanisms that, ultimately, that, mayultimately, result inmay the result cellular in the repair cellular or damagerepair or tolerance, damage tolerance, in the maintenance in the maintenance of cell homeostasis, of cell homeostasis, or even inor theeven removal in the removal of the stressorof the stressor [6,7]. In [6,7]. turn, In this turn, cross-adaptation this cross-adap maytation select may variants select withvariants increased with increased tolerance ortol- resistance, including decreased susceptibility to several antibiotics, namely, some antibiotics erance or resistance, including decreased susceptibility to several antibiotics, namely, relevant to clinical practice. some antibiotics relevant to clinical practice. FigureFigure 1. 1.Schematic Schematic overview overview of of factors factors contributing contributing to to bacterial bacteria adaptativel adaptative responses. responses. AMR: AMR: antimicrobial antimicrobial resistance. resistance. TakingTaking this this into into consideration, consideration, this this review review focused focused on on the the cross-adaptation cross-adaptation due due to to the the non-antibiotic,non-antibiotic, food-chain-related food-chain-related stresses, stresses, associated associated with with a a diminished diminished susceptibility susceptibility to to antibioticsantibiotics and and facilitation facilitation of of antimicrobial antimicrobial emergence, emergence, and, and, thus, thus, the the spread spread of of antibiotic antibiotic resistanceresistance along along the the food food chain, chain, while while also also acting acting as as an an AMR AMR reservoir. reservoir. Antibiotics 2021, 10, 671 3 of 29 2. Interaction of the Use of Non-Antibiotic Antimicrobials with A Potential Antibiotic Decreased Susceptibility A further driver of resistance is the non-antibiotic antibacterial, such as agrochemicals, biocides, heavy metals, or food preservatives, for which bacteria could acquire antibiotic resistance by co- or cross-resistance mechanisms. 2.1. Agrochemicals Agricultural practices can be vastly affected by plant diseases, which may be managed by using agrochemicals to ensure a sustainable and prolific agricultural system. However, the intensive use of these chemicals contributes to its persistence and dispersion in the en- vironment, adversely affecting humans and the ecosystem [8,9]. Furthermore, the presence of a diversity of drugs, commonly used in humans and animals, as well as on agricultural procedures, in surface and wastewaters, even in trace amounts, may enter the food chain and potentiate