Antimicrobials are natural or synthetic substances that will kill or inhibit a micro-organism's growth. When a micro-organism gains the ability to withstand an antimicrobial's effects, either by mutational events or engineered by evolutionary stress on a population, antibiotic resistance occurs. In his 2008 annual report, on the state of public health, Sir Liam Donaldson, United Kingdom's Chief Medical Officer, states "there should be a ban on the use of certain types of antibiotics (quinolones and cephalosporins) in animals, in order to protect their activity in humans" (Donaldson, 2009). If this ban is to pass into legislation it would have a tremendous impact on veterinary medicine. Loss of the usage of these antimicrobial drug classes will reduce the efficacy of veterinary surgeons ability to treat animals. Currently, farm usage in production animals is the main area of concern as this seems to be the main route of transfer between strains of antibiotic resistance between animals to humans. This issue has been previously surveyed which led to the restriction of growth promoters and the ban of certain antimicrobials. However, the veterinary field is not the only profession responsible for antimicrobial resistance as inappropriate administration and poor patient compliance is a concern for the human medical field as well. A blanket ban on the two drug classes may not be the most beneficial solution as other more appropriate routes may be less detrimental to animal care but have similar effects as a ban.
Quinolones and Fluoroquinolones:
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Developed in the 1960's, the first quinolone, known as nalidixic acid, was synthetically derived from an anti-malarial drug that was shown to have some antimicrobial properties. Nalidixic acid was soon shown to have a narrow spectrum of activity, poor pharmacological properties, toxic actions, and developed resistance. In the 1980's, it was found that if the hydrogen atom on position six of the nalidixic acid compound was replaced with a fluorine molecule an increase in activity could be conferred. With a few other tweaks and modifications the first fluoroquinolone was marketed as Norfloxacin. Fluoroquinolones are the most modern group of antimicrobial agents used in veterinary medicine today. They are all synthetically made and are bactericidal. That is, they actually kill the bacterial agent in question, as opposed to bacteriostatic, in which bacterial growth is inhibited, but the host's immune system is needed to actually clear the infection. Additionally, they have a relatively wide spectrum of activity with low toxic effects. They act by entering a bacterial cell through porins in the bacterial cell wall and inhibit the functions of bacterial topoisomerase II and IV, thus impairing bacterial cell protein synthesis, which eventually results in the death of the bacterial cell itself.
Antimicrobial drugs used in veterinary medicine in the fluoroquinolone class include: Norfloxacin and exclusively for veterinary usage: Enrofloxacin (Baytril), Donofloxacin (Advocin, Advocid), Marbofloxacin (Marbocyl, Zenequin) Difloxacin (Dicural, Vetequinon), Orbifloxacin (Orbax, Victas), Sarafloxacin (Floxasol, Saraflox, Sarafin), and Ibafloxacin (Ibaflin) (NOAH Compendium Online).
Like the quinolones, the cephalosporins were also introduced in the 1960's. However, this group is a sub-group of the beta-lactams drug class, and thus contains a large group of antimicrobial drugs that have similar mechanisms of action and pharmacokinetic properties as the penicillin's, but are less susceptible to cleavage and thus deactivation by beta lactamases. They are bactericidal agents, have a relatively wide spectrum of activity, and are generally safe. They act by disrupting the synthesis of the peptidoglycan layer of bacterial cell walls. They do this by attaching to transpeptidases, known as penicillin binding proteins, and inhibit these enzymes from catalyzing the cross linkage of the glycopeptide polymer units. In addition, they inactivate an inhibitor of autolytic enzymes in the cell wall. The combination of these two mechanisms causes the bacterial cell wall to lyse and death of the bacterial cell ensues.
The cephalosporins are divided into four generations based on oral bioavailability and activity. Generally, the first generation drugs have the highest oral bioavailability, the greatest activity towards gram positive bacteria, and the least effect on gram negative bacteria. Oral bioavailability and activity on gram positive bacteria decreases with subsequent generations, whereas activity on gram negative bacteria increases. Therefore, the fourth generation drugs have the lowest oral bioavailability, the least effect on gram positive bacteria, but the greatest effect on gram negative bacteria. Antimicrobial drugs used in veterinary medicine in the cephalosporin class include: First generation: Cefadroxil, Cafazolin, Cephalexin, Cephalonium, Second generation: Cefuroxime, Third generation: Ceftiofur (Excenel), Cefotaxime, Cefovecin (Convenia), and Fourth generation: Cefquinome (NOAH Compendium Online).
Antimicrobial usage in food animals:
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Bacteria develop resistance to antimicrobial attack by acquiring new characteristics through genetic mutation or transfer. Several studies have shown that antimicrobial use in food animals contributes to the selection of antimicrobial resistance. Additionally, antimicrobial usage in food animals poses risks to humans because of transmission of resistant zoonotic bacteria via the food chain and indirect transfer of resistance genes from animals to man (Wegener et al., 1999 and Kruse 1999). Therefore, every time an antibiotic is used in an animal, it potentially becomes less effective in the animal and human population as a whole. According to Sir Donaldson's 2008 annual report, the total volume of antibiotics used in the United Kingdom alone for agricultural purposes in 2007 was three-hundred and eighty-seven tonnes! It is, therefore, recommended that antibiotics must be used in moderation in agricultural settings and only when necessary for animal welfare (Donaldson, 2008).
A significant step forward has already been made by the European Union-wide ban on the use of antibiotics as growth promoters in animals. In order to preserve the effectiveness of vancomycin in human medicine, the use of avoparcin as a growth promoter in animal production was banned in the European Union in 1997, because it was liable to induce resistance to vancomycin (Commission Directive 97/6/RC of 30 January 1997). Sir Donaldson deems it is only right to follow suit with a ban on cephalosporins and fluoroquinolones as well.
However, some authors have recently questioned the hazard to human health caused by the use of antimicrobials in food animals (Phillips et al., 2004). Resistant bacteria might be acquired by humans through alternative pathways such as person-to-person transmission, environmental exposure, and direct exposure to animals. Barber et al. (2003), states that the role of food animals in transmission of antimicrobial resistance has been overemphasized in the scientific literature, with a consequent underestimation of non-foodborne sources of transmission.
Antimicrobial usage in companion animals:
Companion animal numbers have substantially increased in modern society and attention is increasingly devoted to pet welfare. As a consequence of these changes, antimicrobial agents are now frequently used in small animal veterinary practice, particularly canine medicine. This includes antimicrobial preparations licensed for human use and compounds of primary importance in the treatment of human infections, with heavy use of broad-spectrum agents such as aminopenicillins plus clavulanic acid, cephalosporins, and fluoroquinolones (Guardabassi et al., 2004).
The most frequent causes of antimicrobial treatment in dogs and cats are skin and wound infections, otitis externa, respiratory infections, and urinary tract infections. Recurrent pyoderma caused by Staphylococcus intermedius is often treated with the cephalosporin Cefalexin, and sometimes with continuous low-dose or regular pulse therapy (Mason & Keitzmann 1999). Difficult cases are often treated with fluoroquinolones and can involve continuous therapy for periods up to seven months (Carlotti et al., 1999). Chronic otitis externa, which commonly involves multi-resistant Pseudomonas aeruginosa, is often treated topically and/or systemically with fluoroquinolones (Peterson et al., 2002).
The licensing of fluoroquinolones for use in small animals has been associated with increasing resistance to these antimicrobials amongst Pseudomonas isolates from otitis externa in dogs, Staphylococcus intermedius isolates from pyoderma in dogs, and Escherichia coli and alpha-haemolytic Streptococcus species from canine urinary tract infections (Cohn et al., 2003). A further increase in the prevalence of fluoroquinolone resistance is expected to occur in coming years as a consequence of the rising use of Enrofloxacin and other fluoroquinolones in small animal veterinary practice. In vitro studies indicate that prolonged or inappropriate use might favour development of resistant strains in vivo, particularly when long-term treatment is required (Ganiere et al., 2001).
Resistance from animals to humans:
One of the main problems with antibiotic resistance in many antimicrobial drug classes is that it promotes a complete cross resistance. This means that if a particular bacteria is resistant to one antimicrobial drug in a particular class, then that same bacteria will be resistant to all antimicrobial drugs in that class. For example, if Pasteurella species is resistant to the fluoroquinolone Marbofloxacin, then it will be resistant to all of the other fluoroquinolone drugs as well. The fact that virtually the same classes of antimicrobial agents are used in human medicine and in small and large animal practice poses a real disconcerting problem. If antimicrobial drug resistance of a bacterial pathogen develops in an animal and is then transferred to a human (or vice versa) then there might not be an adequate armoury of antimicrobial drugs available to treat the infection. This is why Sir Donaldson would like to save the cephalosporins and fluoroquinolones solely for human usage against severe antimicrobial infections.
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As stated above, resistance to various antimicrobial agents has emerged amongst companion animal isolates of Staphylococcus intermedius, Escherichia coli, and other bacteria. Additionally, resistance has emerged in bacteria with a potential for zoonotic transmission and resistance phenotypes of clinical importance in humans, such as methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant Enterococci, and multidrug-resistant Salmonella Typhimurium phage type DT104 (Guardabassi et al., 2004). The close contact between household pets and humans offers favourable conditions for the transmission of bacteria by direct contact (petting, licking, physical injuries, etc.) or through domestic environment (contamination of food, furnishings, etc.).
Young children are more susceptible than adults. Direct evidence of transmission of Campylobacter jejuni between human patients and pets living in the same households has been shown based on amplified-fragment length polymorphism (AFLP) and pulse-field gel electrophoresis (PGFE). In the PGFE study, a two-year-old girl and her dog were found to share the same fluoroquinolone-resistant strain. Neither of them had ever been treated with fluoroquinolones, indicating that the strain was not selected by previous exposure of any of the two individuals to quinolones but that it was acquired from an external source. Even though the dog was fed a commercial diet, acquisition from a common food source was possible, since the dog was occasionally given human food scraps (Damborg et al., 2004).
Who is responsible for propagating antimicrobial resistance? EVERYONE!
The Veterinarians and Doctors:
The tendency of veterinarians and medical doctors to prescribe broad-spectrum antimicrobials can be explained by the fear of possible treatment failure using first-line antimicrobials such as penicillins and sulphonamides. Treatment failure is detrimental to animal and human health, and discourages owners and clients who must pay for additional consultations and antimicrobials while questioning the effectiveness of further treatment (Guardabassi et al., 2004).
The Pharmaceutical Companies:
Pharmaceutical companies are only likely to bear the high cost of new drug development if they make a profit. Antibiotics give a lower return on investment than most other drugs, as they are usually used in short course treatments. As a result, new antibiotic drug discovery has fallen drastically. According Sir Donaldson's annual 2008 report, only three new classes of antibiotics have been licensed in the United Kingdom in the last five years. Additionally, in pursuit of profit, drug companies aggressively market new products to ensure that they are prescribed as often as possible. Along those same lines, pharmaceutical companies may also have some responsibility by exerting marketing pressures on veterinarians for the use of newer drugs in cases where older drugs are still effective (Prescott et al., 2002). This is probably also the case in the human medical field as well.
Recently the United Kingdom has made moves to make certain antibiotics available from pharmacists without a prescription. Azithromycin, an antibiotic used to treat Chlamydia, can now be purchased without a prescription, provided the patient can provide a positive test result for the disease. Although this is an innovative way to deal with the considerable public health implications of Chlamydia, further moves to widen access to antibiotics without prescription will need to be balanced carefully against the risks of promoting greater resistance (Donaldson, 2008).
The General Public:
Other countries have been successful in reducing the volume of antibiotics prescribed merely by educating the general public. For example, from 2000 until 2007, the Belgian Ministry of Health ran a seasonal (autumn and winter) advertisement campaign aimed to educate the public about the rational use of antibiotics. As a result, outpatient antibiotic prescriptions were reduced by thirty-six percent (Donaldson, 2008).
The United Kingdom's Chief Medical Officer Recommendations (Donaldson, 2008):
Existing public education campaigns about responsible use of antibiotics should be raised in profile.
Antibiotic packaging should carry a warning, reminding people of the need to take them responsibly and appropriately. Alert "flashes" should be added to packaging for antibiotics where resistance levels are rising rapidly.
No further antibiotic drug classes should be made available without prescription.
Consideration should be given to novel ways to stimulate research and development of new antibiotics, including public-private partnerships.
There should be a ban on the use of certain types of antibiotics (quinolones and cephalosporins) in animals, in order to protect their activity in humans.
My reaction to the recommendations:
For the most part I agree with everything that Sir Donaldson states and recommends in order to combat antimicrobial resistance. As a future veterinarian, I am, of course, opposed to the banning of fluoroquinolones and cephalosporins usage in animals, as this would seriously affect my ability to treat some very specific and serious infections in my patients. I do, however, understand the rationale behind the ban. In my opinion, veterinary surgeons are educated individuals with a moral and legal obligation to promote the good health and welfare of all animal species and so should have the responsibility to make decisions as they see fit. Hopefully, veterinarians will not abuse this power and in good conscience they will make the right decision when it comes to this dilemma by prescribing these drug classes where appropriate, at the correct dosage, and educating owners about proper compliance measures.
Other recommendations I would suggest:
There are few or no mechanisms to control the prudent used of antimicrobials in small animal medicine. Most national monitoring systems focus on food animals, but small animal medicine should be monitored as well.
Emphasis should be made for the need for bacterial culture with species identification and susceptibility testing of site-specific isolates in order to choose the appropriate antimicrobial therapy (Hoekstra & Paulton 2002).
Allow for smaller-volume bottles for injectibles. Multi-dose bottles force the quick usage of antimicrobials. Once the bottle is breached it must be used or it is lost to wastage, which promotes over-usage.
In order to ensure the success of antimicrobial therapy, veterinarians frequently tend to use newer and/or broad-spectrum drugs, such as fluoroquinolones or cephalosporins, as first-line antimicrobial defences in the treatment of certain infections in both companion and large animal medicine. As a consequence, resistance to these drugs has emerged in pathogenic bacteria as well as in commensal bacteria of pet animals. Although resistance to fluoroquinolones and cephalosporins appear to be infrequent, such antimicrobials should receive a "last choice status" and their use should be limited to those situations in which other antimicrobial agents can not be used (Guardabassi et al., 2004). This precautionary measure would preserve the efficacy of these very important drugs in human medicine as well as in veterinary medicine, when their use is required for the eradication of infections caused by multi-resistant strains.