Resistance to antimicrobials in humans and animals

Overusing antibiotics is not the only cause and reducing use is not the only solution

Warning signs of antimicrobial resistance, chinks in the antimicrobial armour, began to appear in the middle of the last century, and by the 1990s various reports had signalled the dangers of excessive or inappropriate use of antibiotics in clinical medicine and of the use of antibiotics in animal feed as growth promoters.1^–3 Overuse of antimicrobials emerged as the main culprit, and reducing their use was seen as the answer. But it may not be that simple.

The idea that reducing antibiotic use would redress the problem formed part of a positive response on the part of the United Kingdom government to the House of Lords report,1 including a public information campaign, surveillance of resistance along the food chain, targets with respect to hospital acquired infections, and setting up of an overarching advisory body on all aspects of antibiotic use. However, the concept of overuse has proved too simplistic, for, although the evidence of overprescribing as the main driver of resistance is overwhelming,4 reductions in antibiotic use have not necessarily resulted in lowered levels of resistance: some pathogens' resistance has remained stable, and with others it may even have increased. For example, although penicillin resistance in Streptococcus pneumoniae has been declining,5 macrolide resistance in S pneumoniae has remained stable,6 and other species such as Haemophilus influenzae have shown no evidence of a fall in resistance.7

Resistance to fluoroquinolones in Escherichia coli has increased sharply despite a reduction in prescribing.8 Such resistant strains arethought to originate from patients' gut flora.4 The advent of extended spectrum β lactamases in E coli isolates resistant to cephalosporins through CTX-M enzymes now pose problems with urinary tract infections being resistant to the fluoroquinolones. The relation of E coli with extended spectrum β lactamases in animals to human infection is not yet clear. Such E coli can cause severediarrhoea and death in calves, but it also has the ability to confer resistance to a wide range of β lactam compounds such as penicillin and cephalosporins.

Reports of hospital infections with methicillin resistant Staphylococcus aureus (MRSA) have epitomised antibiotic resistance in the public eye and galvanised hospital authorities to improve ward cleanliness and hygiene. MRSA infection is most prevalent in surgical wards and in long term care facilities, where indwelling devices are used, and has recently been recognised as a community problem in the United States.9 The organism is commensal on humans under ordinary conditions, and varying percentages of nursing staff have been found to carry the organism.10 It is also found on the coats of animals, and in animal surgery has accounted for the same problems in dogs, horses, and a cat as it has in human surgery. Transfer of resistant organisms between companion animalsand human patients has been detected,11 and it is generally acknowledged that MRSA in animals is most likely derived from humans. MRSA has not been reported from food animals.

The use of antibiotics in animals has raised controversy, particularly with respect to their use as feed additives to promote growth of livestock. There can be little doubt that the clinical therapeutic use of antibiotics in animals is justified, and, with large collections of animals, individual treatment is not feasible—hence drug delivery in water or feed is necessary and justified. However, the difference between mass prophylaxis and growth promotion is poorly defined. For example, the fluoroquinolone enrofloxacin is used to treat respiratory infections in turkeys and chickens and is sometimes given to an entire flock in water. The concern is that the use ofenrofloxacin leads to drug resistant Campylobacter—a common cause of food poisoning in humans—and the prevalence of fluoroquinolone resistant Campylobacter in humans is increasing.12 As a result, the US Food and Drug Administration has recently banned enrofloxacin's use in poultry (July 2005).

Certain growth promoters have also been banned in the European Union, but controversy continues as to the potential health risk of transfer of antibiotic resistance from animals to man when set against the increased production costs and food prices—a trade off between public healthand economic benefits. The British veterinary profession and livestock community have responded well to the challenge of potential antibiotic resistance in animals. RUMA (Responsible use of Medicines in Agriculture Alliance), a consortium of 18 organisations, has addressed the use of antibiotics in the main species of farm animal and has recently launched guidelines on the “responsibleuse of antimicrobials” in these species, with the comment that human health must be the overriding consideration. This is a unique initiative involving organisations representing every stage of the process from “farm to fork” and promoting the highest standards of food safety and animal health and welfare.

The magic bullets have lost some of their magic. One solution may be to find alternatives to antibiotics when resistance appears, but there is also an urgent need for new antibiotics to be developed. Few pharmaceutical companies are now involved in antibiotic development, however. The high cost of development, the prolonged safety evaluation, and the probable short duration of fielduse and the present tendencyfor any new compound to induce resistance all militate against major investment in new compounds.