Abstract

Keywords

antibiotic resistance, superbugs, livestock production, public health, growth promoters, food animals

Introduction

Antibiotic-resistant bacteria, difficult to treat, are becoming increasingly common and are causing a global health problem. The phenomenon of antibiotic resistance is not new. Discoverer of penicillin Nobel laureate Alexander Fleming in his speech in 1928 had warned of resistance against antibiotic penicillin. Much before the antibiotics came into human use, bacteria had harbored resistance genes (9). This suggests antibiotic resistance arises from an evolutional process and therefore it cannot be stopped. However, efforts may keep it under control.

The widespread and indiscriminate use of antibiotics throughout the world has resulted in emergence of antibiotic resistant pathogens. Many of them are multidrug resistant (MDR) and pose a serious threat to human and animal health. Today, antibiotic resistance is viewed by the experts as one of the greatest threats to global public health. The international agencies World Health Organization (WHO), World Organization for Animal Health (OIE), and Food and Agriculture Organization (FAO) have called for united global efforts in curtailing indiscriminate and irresponsible use of antimicrobials in livestock, poultry, fishery, agriculture, and human medicine.

Antibiotic Resistance

Antibiotic resistance is the ability of microbes, such as bacteria, to grow in the presence of an antibiotic that would normally kill them, or limit their growth. This occurs when an antibiotic has lost its ability to effectively control or kill bacterial growth. The bacteria then become “resistant” and continue to multiply in the presence of an antibiotic.

Repeated and improper use of antibiotics, both in humans and animals, induces drug resistance and has made some forms of bacteria virtually indestructible to modern medicines (7). More than 70% of the bacteria that cause hospital-acquired infections are resistant to at least one antibiotic, and antimicrobial resistance is a serious threat to public health (6).

Antibiotic resistance continues to expand for a number of reasons, but mainly from the use of antibiotics in animals as growth promoters by the food industry. If animals carry resistant bacteria, then food produced from them may be colonized with these microorganisms. After ingesting these foods people may carry these resistant bacteria and even develop infections. In poultry, antibiotics are used for three main purposes: therapeutic use to treat sick birds; prophylactic use to prevent infections, and as growth promoters to improve feed utilization and production.

Mechanisms of Antibiotic Resistance

When bacteria are first exposed to an antibiotic, those most susceptible die, leaving surviving bacteria to pass on their resistant features to the succeeding generations (11). Antibiotics cause a selective pressure by killing susceptible bacteria, allowing antibiotic resistant bacteria to survive and multiply (4). Selective pressure is the influence exerted by the antibiotics to promote one group of organisms over another. In this process natural selection follows the rule of survival of the fittest (11). The indiscriminate use of antibiotics in animals and humans has accelerated the pace of resistance against both pathogenic and non-pathogenic bacteria.

Bacteria develop resistance in two ways: (i) by genetic mutations (vertical evolution), and (ii) by acquiring resistance genes from other bacteria (horizontal gene transfer).

(i) Through Genetic Mutations (Vertical Gene Transfer or Vertical Evolution) Susceptible bacteria can become resistant through mutations in their genes. Mutations are spontaneous changes in the genetic material (DNA). They are thought to occur in about one in one million to one in ten million cells (4). Through mutations bacteria acquire defense mechanisms against antibiotics. Different genetic mutations result in different types of resistance. For example, some bacteria have developed biochemical “pumps” that can remove an antibiotic before it reaches its target, while others have evolved to produce enzymes to inactivate the antibiotic (11).

Bacteria reproduce rapidly, sometimes in as little as 20 minutes. Therefore, it does not take long for the antibiotic resistant bacteria to comprise a large proportion of a bacterial population (11).

Once the resistance genes have developed, they are transferred to all the bacterial progeny during DNA replication. The phenomenon is known as “vertical gene transfer” or “vertical evolution”.

(ii) Acquiring Resistance from Other Bacteria (Horizontal Gene Transfer) Susceptible bacteria can become resistant also by acquiring antibiotic resistance genes from resistant bacteria. Development of resistance occurs by the exchange of small pieces of DNA called plasmids. Plasmids are extra-chromosomal circular molecules of DNA that replicate independently of the bacterial chromosome. Plasmids carry antibiotic resistance genes and have the ability to transfer themselves to other bacteria. They are called “resistance (R) plasmids” and act as vectors to transfer resistance genes.

Bacteria readily exchange plasmids among both related and unrelated species. This way the antibiotic resistance genes from one type of bacteria are incorporated into other bacteria. Non-resistant bacteria acquire resistance genes in three ways: (a) conjugation, (b) transduction, and (c) transformation.

a. Conjugation Conjugation is the mechanism by which genetic material is transferred through plasmids between two bacterial cells. It requires cell-to-cell contact. A bacterial cell, containing an R plasmid, forms a mating pair with a bacterial cell that does not contain an R-plasmid. They undergo a mating process called “conjugation”. By a complex mechanism, plasmid containing resistant genes is transferred from the plasmid-containing bacterial cell (the donor) to the recipient. This enables the antibiotic susceptible bacteria express resistance as coded by the newly acquired resistance genes. Most antibiotic resistance in Gram-negative bacteria is acquired through horizontal gene transfer. Genes, encoding antibiotic resistance, are transferred between bacteria via plasmids. Plasmids are often capable of self-movement (conjugation) from one bacterium to another. They are also highly stable once established in a bacterium. Among E. coli and Salmonella enterica alone, there are more than 30 plasmid types identified and this number continues to grow. Plasmids associated with multidrug resistance are primarily a concern among E. coli, S. enterica, and Klebsiella pneumoniae, although numerous other Gramnegative bacteria have been shown to possess multi-drug resistance-encoding plasmids (5).

b. Transduction Transduction involves transfer of DNA from one bacterial cell (donor) to another (recipient) by bacteria-specific viruses (bacteriophages). It occurs between two closely related bacteria.

c. Transformation Transformation occurs from the uptake of short fragments of free DNA from the surrounding medium by non-resistant bacteria. The free DNA is normally present in the surrounding medium from the death and lysis of other bacteria. Bacteria like Streptococcus are capable of natural transformation.

Obstacles in the Way

No new effective antibiotic has been developed in the past more than 20 years. Perhaps pharmaceutical companies are not investing required financial resources for antibiotic drug discovery, because the profit margins have declined. Apparently the antibiotics are becoming ineffective at faster rate due to the emergence of antibiotic resistance, largely from abuse of these drugs. It takes almost 15-20 years to bring a new antibiotic in the market, and the return on investment is uncertain due to the development of new resistance.

Antibiotic Resistance in Livestock

Numerous studies have demonstrated that routine use of antibiotics on the farm promotes drug-resistant superbugs. This is because there are always some bacteria the drug can’t kill, and these survive and proliferate (3, 9).

A simple way to overcome the health problems caused by antibiotic resistance is to stop adding antibiotics to animal feed. It was found that when poultry and beef are produced without antibiotics, bacterial resistance quickly declines. Feeding antibiotics to livestock creates an ever-increasing number of antibiotic-resistant bacteria, including many that cause disease in humans.

The US Food and Drug Administration (FDA) say that 80% of all antibiotics sold in the US are fed to food animals. Meat animals are fed antibiotics because doing so increases their weight gain, prevents disease, and makes meat production cheaper.

Many countries have already acted to curb antibiotic feeding to livestock. Most notably, the European Union banned feeding of all medically important antibiotics to livestock in 1998.This was followed with a total ban on all antibiotics in 2006.

Threat to public health from the overuse of antibiotics in food animals is real and growing. Humans are at risk both due to potential presence of superbugs in meat and poultry and to their migration into the environment, where they can transmit their genetic immunity against antibiotics to other bacteria, including those that make people sick.

Prevention and Control of Antibiotic Resistance

A simple way to overcome the emergence of antibiotic resistance in bacteria is to stop adding antibiotics to animal feed. Ban on the use of antibiotics for growth promotion in some countries has indicated that they could be avoided without any significant impact in livestock production. The experiences from different countries suggest that major reductions can be achieved without significant negative effects on animal health or productivity, and for the long-term benefit of public, environmental, and animal health (10).

However, the veterinarians should still be allowed to use antibiotics to treat animals in case of diseases, but only drugs which are not used for humans; and all treatments should be documented to allow retrospective analysis of field data.

Alternatives to antibiotics to treat or control infections are other important areas that need attention. This may include acidifiers, enzymes, prebiotics and probiotics, boosting host’s immune system, and certain other approaches to control infectious agents.

The feed industry, in the meantime, must offer other options to keep animals as healthy as possible.

Improving hygiene and sanitation counter infectious diseases, and is crucial to reducing the rise in drug resistance. The less people get infected, the less they need to use medicines such as antibiotics, and the less drug resistance arises (9). Improving the general hygiene in all stages of production and thereby reducing the microbial load on food products will also reduce the antimicrobial resistance load (10). Sensitivity tests should be done to make sure the right antibiotic is prescribed. Also, antibiotics should be administered exactly as prescribed by the veterinarian. Doses should not be skipped and the prescribed course of treatment be completed even when the flocks start feeling better.

Certain essential oils can prevent the transmission of some drug resistance strains of pathogens, especially Staphylococcus, Streptococcus, and also Candida. Essential oils are extracted from different parts of plants such as eucalyptus, clove, tea tree, and lavender.

Herbal medicines have been and should be further explored as alternatives to antibiotics.

Discussion

Antimicrobial resistance in humans is interlinked with antimicrobial resistance in other populations, especially farm animals, and in the wider environment (12). Resistance can pass between these different populations, and homologous resistance genes have been found in pathogens (12). Farm animals are an important component of this complex system. Despite attempts at reduction, they are exposed to enormous quantities of antibiotics and act as another reservoir of resistance genes. Whole genome sequencing is beginning to quantify the two-way traffic of antimicrobial resistance between the farm and the clinic. Surveillance of bacterial disease, drug usage and resistance in livestock is still relatively poor, though improving, but achieving better antimicrobial control on the farm is challenging (12). There are multiple links between the human, animal, and environmental compartments that allow not only movement of the bacteria but also of mobile genetic elements (MGEs) and the drugs themselves. The challenge of antimicrobial resistance has even been viewed as somewhat similar to climate change (12).

There is a risk resistant bacteria could pass into the food chain (2). The food borne route is the major transmission pathway for resistant bacteria and resistance genes from food animals to humans (10). Recently a number of antimicrobial resistant pathogens have emerged in the foodproduction chain, which can transmit to, and cause infections in, humans (10). Farmers need to drastically cut the amount of antibiotics used in agriculture, because of the threat to human health. The use of antibiotic in agriculture is driving up levels of antibiotic resistance, leading to new “superbugs” (2, 3). A ban on the use of growth promoters was implemented throughout the EU in 2006. However, this has not led to any consistent decrease in antibiotic consumption (12). In Europe, the volume of agricultural usage of antibiotics continues to rival that of medical usage and in the USA agricultural usage exceeds medical usage (12). Reducing the levels of antimicrobial consumption in farm animals has not proved straightforward, as the experience of the EU-wide ban on growth promoters has shown (12). Industrial agriculture relies heavily on the widespread use of antimicrobials to improve animal health, welfare and productivity. A complete ban on the use of antimicrobials in farm animals would inevitably have serious repercussions for animal health, welfare and productivity. Growth promotion has become a particularly controversial issue (12).

However, the big question is if we were to ban the use of an antimicrobial drug in farm animals what would be the impact on levels of resistance in human clinical cases, and to what degree antimicrobial resistance poses a threat to human health. We still are a long way from being able to give clear answers to that kind of question (12). There are surprisingly few published studies which directly address this question (12). The evidence suggests the amount of antimicrobials used in food production internationally is almost the same as that in humans, and in some places is higher. For example, in the US more than 70% of antibiotics that are medically important for humans are used in animals (2, 9). It is estimated that the volumes of antimicrobials used in food animals exceeds the use in humans worldwide, and nearly all the classes of antimicrobials that are used for humans are also being used in food animals, including the newest classes of drugs (10). The majority of scientists see this as a threat to human health (9).

More recently, a long-dreaded superbug has been found in human and animal in US (1, 8). A 49-year-old woman showed the presence of a rare kind of E. coli in a urinary tract infection, the first known case of its kind in the United States. It was resistant to many antibiotics, even colistin, which doctors use as a last resort when other antibiotics fail (1). That turned out to be because the organism carried 15 different genes conferring antibiotic resistance. One element included the new, dreaded gene mcr-1 (8). There was no indication of how the bacteria got into the woman’s system. She had not travelled outside the United States within the past five months. The discovery heralds the emergence of truly pan-drug resistant bacteria (8). In his exhaustive review on antimicrobial resistance, O’Neill (2016) describes this discovery of transferable colistin resistance highly disturbing (9).

The US Department of Agriculture believes this to be the first identification of the antibiotic resistance factor MCR in the United States in an animal. It was found in a stored sample of pig intestine (8). The existence of MCR was reported for the first time by British and Chinese researchers who said they had found the gene in people, animals, and meat in several areas of China. Subsequently it has been found in people, animals, or meat in at least 20 countries across the world (8). MCR is so troublesome because it confers protection against colistin. Being a toxic drug, colistin is seldom prescribed in humans (1, 8, 9). As it was used so infrequently bacteria had not adopted to it. But because it is effective, agriculture adopted it instead, using it widely for prevention of diseases in food animals. By the time the medical community discovered that it needed the drug back, resistance to colistin was already moving from agriculture into the human world. However, MCR has not as yet combined with other resistance genes into becoming a completely untreatable organism (8). Some last-resort antibiotics for humans are being used extensively in animals, and there are no replacements currently on the way (2, 9).

Recently, in a literature review, only 5% of the 139 academic papers identified argued there was not a link between antibiotic consumption in animals and resistance in humans, while 72% found evidence of a link (2, 9). The authors concluded these results provide enough justification to reduce the global use of antibiotics in food production to a more appropriate level.

O’Neill (2016), in his report and recommendations on tackling drug-resistant infections globally, states antimicrobial resistance is inevitable. This is because as people keep finding ways to kill the microbes that infect us, those microbes, through evolutionary processes, will mutate to counteract them (9). If not tackled, antimicrobial resistance could have a devastating impact. The seriousness and magnitude of the problem cannot be over-emphasized.