Abstract
Non‐typhoidal Salmonella is the primary foodborne zoonotic agent of salmonellosis in many countries. Non‐typhoidal Salmonella infections are transmitted to humans primarily through consumption of contaminated foods from animal origin, whereas S. Typhi and Paratyphi infections are spread directly or indirectly by contact with an infected person. Quinolones exhibit potent antibacterial activity against Salmonella and are usually the first choice of treatment for life‐threatening salmonellosis due to multidrug‐resistant strains. However, by the early 1990s, quinolones have been approved for use in food‐producing animals. The increased use of this group of antimicrobials in animal has led to the concomitant emergence of quinolone‐resistant non‐typhoidal Salmonella strains. However, in some countries, there are no legal provisions, which apply to veterinary drugs. This situation provides favorable conditions for spread and persistence of quinolone‐resistant bacteria in food‐producing animals. The objective of this chapter is to review the current regulatory controls for the use of quinolones in food‐producing animals, its effect on development of quinolone resistance, and the potential impact on human and animal health. Moreover, this chapter reviews the current knowledge of quinolone resistance mechanisms and the future directions of research with particular attention to the strategies to control the emergence of quinolone‐resistant Salmonella.
Keywords
- non‐typhoidal Salmonella
- quinolones
- resistance
1. Introduction
Non‐typhoidal
Non‐typhoidal
Antimicrobial therapy can prolong the duration of excretion of non‐typhoidal
The emergence of quinolone‐resistant non‐typhoidal
2. Quinolone use in food‐producing animals
The first quinolone was generated in the early 1960s. The first member of the quinolones is nalidixic acid (NAL), a 1,8‐naphthyridine as shown in Figure 1, which had a good activity against Gram‐negative pathogens and was used to treat urinary tract infections. However, the use of NAL was decreased due to the increasing resistance of this drug and because of the synthesis of new, broad‐spectrum, and safer antimicrobials. The molecular modifications of the core quinolone structure significantly affect their antimicrobial activity, allowing the synthesis of various compounds of this drug class.
FQs (fluorinated derivatives of quinolones) were first developed since the 1980s. The presence of fluorine in position 6 of the core quinolone structure provides broad and potent antimicrobial activity against Gram‐positive and Gram‐negative bacteria because it significantly enhances the antibiotics’ penetration into the bacterial cell membrane. Norfloxacin (NOR), launched in 1980, is a first broad‐spectrum FQ which consisted of a piperazinyl ring that replaces the methyl group at position 7 (Figure 1) results in enhancing activity against Gram‐negative bacteria [13]. Ciprofloxacin (CIP) has similar structure to NOR except the ethyl group at N‐1 of CIP is replaced by a cyclopropyl group (Figure 1) that increasing the spectrum of action which not only active against Gram‐negative bacteria but also against Gram‐positive bacteria [14]. The structure of enrofloxacin (ENR) is similar to CIP but with an additional ethyl group on the piperazinyl ring (Figure 1).
All these structural modifications in the molecular molecule of quinolones improved a spectrum of drug activity, tissue penetration, long half‐life in the body, lower toxicity, and greater capacity to cross bacterial cell membranes and consequently better activity against Gram‐negative bacteria and Gram‐positive species. Their treatment indications developed from urinary infection to applications against many other systemic diseases. The last generations of quinolones provide the activity against anaerobic bacteria.
FQs have been licensed for use in food animals at the beginning of the 1990s, and subsequently, a new FQs extensively have been authorized, and a large number of different veterinary pharmaceutical products have been launched in the market [15]. ENR exhibits good activity against most Gram‐negative bacteria, including
Finland and Denmark ban all the uses of FQs in poultry; however, they are used in other species of farm livestock. Australia has never approved the use of FQs in poultry and any farm animals, and consequently, resistance to FQs in zoonotic bacteria such as
In September 2005, the U.S. Food and Drug Administration (FDA) banned the use of FQs for treating bacterial infections in U.S. poultry result from concerns about increasing in FQ resistance among
3. A contribution of veterinary usage of quinolones to resistance in human non‐typhoidal Salmonella isolates
Multidrug resistance in non‐typhoidal
Quinolones were introduced for veterinary use in various countries, and subsequent use has been followed by the development of quinolone resistance in bacteria of food‐producing animals and consequently transmits the resistant zoonotic bacteria to humans [29]. In many countries, FQs are drug of first choice for prescription in acute gastrointestinal symptoms caused by
The data indicate that it would be reasonable to assume that the veterinary usage of FQs will have made a remarkable contribution to FQ resistance in human
4. The potential impact on human health
FQ resistance in
5. The potential impact on animal health
FQs are highly potent antimicrobial agents rapidly absorbed after oral administration and have a long half‐life and widespread distribution to most body tissues, which made them suitable for using in herd treatment of food‐producing animals. FQs are effective for serious infections in food‐producing animals such as systematic gastroenteritis and severe respiratory diseases and are also used to treat urinary tract, skin, and soft‐tissue infections caused by Gram‐negative or some Gram‐positive aerobic bacteria. Moreover, they also have potential for treatment of infections caused by
However, the potential clinical disadvantage associated with FQ use was a rapid selection for resistance. Several pathogenic bacteria of food‐producing animals have been investigated the increasing of resistance to FQs following the introduction of ENR [46]. If FQ resistance emerges in animal pathogenic bacteria, this may result in treatment failure and increased mortality. This is a risk for poor animal welfare conditions and will result in economical losses. Consequently, for some animal infectious diseases, antimicrobial therapeutic use will be complicated if FQs lose their efficacy. As described in a previous study, multidrug‐resistant
6. The current state of knowledge of quinolone resistance mechanisms
FQs are strong inhibitors of bacterial enzymes, which are necessary enzymes associated in major biological processes including DNA replication [47–49]. In prokaryotes, DNA is known as a double helix because there are two strands that intertwine around each other. However, additional complexity comes from the further twisting (supercoiling) of the double‐strand structure to put the double helix under torsion stress [50]. This supercoiling process that enables the long strands of DNA is condensed into compact supercoils permitting large amounts of DNA to be packed into the cell [51].
Topoisomerase I and topoisomerase II enzymes are enzymes that regulate the overwinding or underwinding of DNA and control the level of twisting within DNA. Topoisomerase I removes the number of negative supercoils, in contrast to topoisomerase II, which introduces negative supercoils that facilitate the unwinding of the over‐twisted DNA and can further change the DNA topology into an under‐twisted DNA [50]. DNA gyrase and DNA topoisomerase IV are type II topoisomerase comprising 2 A subunits and 2 B subunits encoded by the
FQs are direct inhibitors of bacterial DNA synthesis by inhibiting two enzymes, DNA gyrase and topoisomerase IV, which have important roles in DNA replication. The quinolones bind to these enzymes with DNA to form drug‐enzyme‐DNA complexes (known as a ternary complex) subsequently induces double‐strand DNA breaks and blocks replication, therefore, results in damage to bacterial DNA and bacterial cell death [55–58]. However, the primary target enzyme, either DNA gyrase or topoisomerase IV, of FQs varies depending on the bacterial species. The preferential target of FQs in Gram‐negative bacteria is DNA gyrase, whereas in Gram‐positive microorganisms, topoisomerase IV is the primary target [58].
Resistance to quinolones occurs by different ways. The major mechanisms of bacterial resistance to FQs are altered target enzymes, expression of an active efflux, and altered membrane permeability.
6.1. Target‐site mutation
The main mechanism of FQ resistance is due to mutation in target genes (
In
These target‐site mutations show that different mutations of FQ‐resistant
6.2. Transmissible quinolone‐resistance mechanisms
Plasmid‐mediated quinolone resistance (PMQR) genes on mobile genetic elements are able to reduce susceptibility of quinolone or FQ antimicrobials. The PMQR gene,
Another plasmid‐encoded quinolone resistance determinant is a variant of an aminoglycoside acetyl transferase gene,
6.3. Membrane permeability
The membrane permeability and the ability of FQs to enter the bacterial cells are an important determinant of the potency of these drugs that have intracellular targets [79]. The outer‐membrane proteins (OMPs) of Gram‐negative bacteria consist of pore‐forming outer‐membrane proteins which serve as a particular barrier for the entry of hydrophilic molecules into the cell. It has been shown that CIP (hydrophilic quinolones) preferentially entry into the cells via porin pathway [80]. Down‐regulation of OMPs results in reduced FQ susceptibility in FQ‐resistant isolates of different species [81–84]. Very few researches have investigated on alterations of OMP expression or the role of lipopolysaccharide composition in quinolone‐resistant
6.4. Efflux
Chromosomal multidrug efflux pumps are capable of actively removing FQs and a broad range of antimicrobial agents from the bacterial cell and are mostly encoded by chromosomal genes. These efflux systems consist of different classes of transporters such as the resistance nodulation division (RND) family of tripartite transporters of Gram‐negative pathogens [91, 92]. These systems are mainly responsible for the intrinsic pattern of reduced susceptibility to FQs and other antimicrobial agents but are also responsible for increased resistance resulting from derepression of the transporter. Previous studies showed the evidence for the participation of active efflux in quinolone‐resistant
6.5. The fitness costs
Mechanisms associated with high‐level FQ resistance are multiple mutations in the type II topoisomerase‐encoding genes and the over‐expression of multidrug resistance efflux pumps. The presence of mutations in these structural or regulatory genes not only increases resistance to quinolones but also affects fitness costs such as reduced growth rates and virulence of the bacterial cell in a lack of antibiotic selective pressure [95–99]. However, maintenance of resistance can arise through the development of second‐site compensatory mutations that restore fitness and virulence without loss of resistance [100].
The fitness cost of the genes responsible for quinolone resistance traits has not been fully elucidated in high‐level FQ‐resistant
Quinolone resistance of non‐typhoidal
7. To decrease the emergence and spread of quinolone resistance
FQs are intensively used in animal production and have allowed better treatment of several animal infectious diseases. The risks of the overuse and misuse of FQs in food‐animal production can contribute to higher levels of resistance in human
Priority setting of agendas for research on minimizing the emergence of FQ resistance in
Furthermore, sufficient research funding for minimizing the FQ resistance of
Urgently address complex barriers that limit the quality of data on the use of FQs in food‐producing animals and human medicine. Currently, such data from human and veterinary medicine are provided on a voluntary basis, and the methods used to collect, analyze, and report are not standardized because of political, economic, and social barriers. Effective surveillance of FQ use in food‐producing animals and humans is a key first step toward for estimating the full scope of FQ resistance in
8. Conclusion
Infections in humans with quinolone‐resistant
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