While having nothing to do with my previous rants on the topic, the FDA has issued warning letters to the manufacturers of Angels' Eyes and similar products that are vaguely disguised antibiotics sold for purely cosmetic reasons, and without a veterinary prescription. These products have been widely available to decrease tear staining (hardly a life-threatening problem) in dogs, fully at odds with any concepts of prudent antibiotic use.
Here’s some of the FDA letter text:
“We have determined that your tear stain remover products containing tylosin tartrate are intended for use in the mitigation, treatment, or prevention of disease in animals, and/or to affect the structure or function of the body of animals, which makes them drugs under section 201(g)(1) of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) [21 U.S.C. § 321(g)(1)]. Statements on your labeling, including your website and product labels, that establish these intended uses of your products include, but are not limited to, the following:
• "The active ingredient in Angels' Eyes®, Tylosin as Tartrate, will prevent your dog from contracting Ptyrosporin (Red Yeast) and bacterial infections which causes excess tearing and staining."
• "May help keep tear stains away by reducing oxidation released through tear ducts."
• "Angels' Eyes® is the first product specifically developed for BOTH DOGS & CATS to help eliminate unsightly tear stains from the inside out!"
• "Only ANGELS' EYES® helps give your pets tear stain free eyes and bright coats."
In addition, your tear stain remover products containing tylosin tartrate are new animal drugs, as defined by section 201(v) of the FD&C Act, [21 U.S.C. § 321(v)], because they are not generally recognized among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling. You are using Tylovet Soluble (tylosin tartrate) as an ingredient in the formulation of your product. Although Tylovet Soluble is an approved drug, your use of Tylovet Soluble in your product is not a use covered by its approved application, and your products are not the subject of an approved new animal drug application, conditionally approved new animal drug application, or index listing under sections 512, 571, and 572 of the FD&C Act [21 U.S.C. §§ 360b, 360ccc, and 360ccc-1]. Therefore, the products are unsafe within the meaning of section 512(a) of the FD&C Act, [21 U.S.C. § 360b(a)], and adulterated under section 501(a)(5) of the FD&C Act [21 U.S.C. § 351(a)(5)]. Introduction of an adulterated drug into interstate commerce is prohibited under section 301(a) of the FD&C Act [21 U.S.C. § 331(a)].
We acknowledge the receipt of three written responses submitted after the inspection in December 2013. These responses discuss your facility's compliance with the Current Good Manufacturing Practices for Finished Pharmaceuticals (Title 21 Code of Federal Regulations Part 211 ). However, your responses do not adequately address our concerns regarding the approval status of your products and your use of tylosin tartrate in those products, as discussed above.
Failure to promptly correct the violations specified above may result in enforcement action without further notice. Enforcement action may include seizure of violative products and/or injunction against the manufacturers and distributors of violative products. “
Interestingly, there’s no mention of anything on the Angels' Eyes website. It will be interesting to see what happens, but it’s great to see some attention paid to this completely illogical use of antibiotics. Hopefully the FDA follows through with this and doesn’t leave it at the warning letter stage.
The US Food and Drug Administration has released the 2011 NARMS (National Antimicrobial Resistances Monitoring System) executive report. It's a good-news/bad-news outcome, which may be as good as can be expected, but at least there's some good news.
- Eighty-five percent of non-typhoidal Salmonella collected from humans had no resistance to any of the antibiotics tested.
- In people, the five-drug resistance pattern “ACSSuT” (resistance to ampicillin, chloramphenicol, streptomycin, sulfonamide, and tetracycline) in Salmonella Typhimurium has declined to 19.5% in 2011, from its peak in 1997 at 35.1%.
- During its 16-year history, NARMS has found Salmonella resistance to ciprofloxacin, one of the most common antibiotics to treat Salmonella infections in humans, to be very low (less than 0.5% in humans, less than 3% in retail meat, and less than 1% in animals at slaughter).
- Multi-drug resistance in Salmonella from humans, slaughtered chickens and slaughtered swine was the lowest since NARMS testing began. However, multi-drug resistance in Salmonella from retail poultry meats generally increased, with slight fluctuations.
- Erythromycin resistance in Campylobacter jejuni (C. jejuni) has remained at less than 4% in isolates obtained from humans, retail chicken and slaughtered chicken since testing began. The antibiotic erythromycin is the drug of choice for treating Campylobacter infections, more than 90% of which are caused by C. jejuni.
- Campylobacter resistance to ciprofloxacin has increased slightly in isolates from humans since 2005. Ciprofloxacin is not approved for use in poultry, and the FDA withdrew approval for the use of enrofloxacin in poultry in 2005. Ciprofloxacin and enrofloxacin are both in the same class of drugs (fluoroquinolones).
- Resistance to third-generation cephalosporins, another important drug class for the treatment of Salmonella infections, rose among isolates from retail ground turkey between 2008 and 2011, and among certain Salmonella serotypes in cattle between 2009 and 2011. In April 2012, FDA prohibited certain uses of cephalosporin drugs in cattle, swine, chickens, and turkeys. NARMS will continue to monitor these trends over time.
Clinical guidelines are fairly new (and limited) in veterinary medicine, although they’re widespread in human medicine. Following up on recent guidelines for diagnosis of treatment of urinary tract infections in dogs and cats, a working group from the International Society for Companion Animal Infectious Diseases (ISCAID) has completed guidelines for the treatment of a common type of skin infection in dogs, superficial folliculitis (pyoderma).
Antibiotic resistance is a big deal. Lots of people and animals die because of it every year. It costs the healthcare systems (human and veterinary) tremendous amounts of money and it’s not getting better.
It’s been clear for years that we have to do a better job of using antibiotics responsibly, in both animals and humans. It’s a complex area, and people often spend too much time complaining about the "other" side (human vs veterinary) rather than trying to address their own problems. However, there are issues with certain practices that seem so straightforward I’m amazed they're allowed to continue and that they haven't already been addressed.
One such issue is the ability to buy certain antibiotics in large volumes over the counter at feed stores in some countries (like Canada), with no veterinary involvement.
Another is the plethora of fish antibiotics you can buy all too easily in pet stores (and which often end up being used on dogs and cats).
And today’s rant is about a group of products that's ongoing use boggles my mind: tear stain prevention products like Angels' Eyes. These are over-the-counter products marketed to reduce tear staining, mostly in small, white dogs. Yes, tear staining - an entirely cosmetic problem that has absolutely no impact on health. The scary part is that products like Angels' Eyes contain tylosin, an antibiotic of the macrolide family. (How much it contains is a bit of a mystery since that information isn't even included on the label.)
Does it make any sense to treat animals for a purely cosmetic problem for long periods of time (or lifelong) with a (presumably) low dose of any antibiotic, let alone one in a drug class that includes many antibiotics that are important for treating infections in people and animals?
In some countries, irrational antibiotic use like this is banned. More countries need to follow suit.
Last week, I mentioned the antibiotic use plenary session at the ASM-ESCMID conference on methicillin-resistant staphylococci in animals. The session was designed to discuss the use of "critically important antibiotics" in companion animals - drugs like carbapenems (imipenem, meropenem) and vancomycin, which are used for treating serious multidrug-resistant infections in people as well. After the (very lively) session, I was asked when I was going to write a follow-up post, so here it is.
The session went well and I’ll hit on some highlights.
I was on a panel with good colleagues Ulrika Gronlund-Andersson (Sweden) and Engeline van Duijkeren (Netherlands). Both are extremely well versed in the field and come from countries with different, but in general restrictive, policies pertaining to antibiotic use in animals. They also (not completely coincidentally) come from countries with less antibiotic resistance in companion animals, which means they don’t see the same degree of resistant bugs in patients that I do.
I was there as the guy from North America where we have absolutely no control over antibiotic use. It was strange being the one supporting more liberal use of antibiotics, since I’m often seen as being on the other extreme when I speak in North America. As I wrote earlier, I think (at least in my patient population) that we need to use some "big gun" drugs at times, but we also need to use them right.
It was a tough crowd. There were some nice differences in opinion, partly reflected in individuals’ backgrounds (clinical vs non-clinical, northern Europe vs other regions), but there were some great points too.
At one end, there was the opinion that banning the use of these drugs in animals altogether is acceptable. (A comment along the lines of "there are lots of dogs and cats available in animal shelters as a replacement if a pet gets a multidrug-resistant infection" was made, to varying degrees of agreement and outrage). I was at the other end of the spectrum, which really wasn’t at the other end of the whole spectrum, meaning I think we need to use these drugs at times, but we certainly don’t want unrestricted, imprudent use. We need to use them right, and very sparingly. I emphasized the point that every culture result is attached to a patient AND there’s a moral obligation to make sure that patient doesn’t suffer AND every patient is attached to an owner AND that attachment might be profound, with definite emotional and even health effects for the person associated with the animal's presence and condition.
An interesting set of comments came from a clinical colleague in southern Europe who said something along the lines of “I see vets in my country misusing these drugs so badly that I think we need to ban them. People won’t do it right so they shouldn’t do it." That’s hard to argue, and shows how we need to improve antibiotic use in veterinary practice. If it's clear they're being used poorly, we should lose access to them.
Another comment was along the lines of “I’m not concerned about OVC, where they have awareness, some restrictions and someone [me] as both a monitor and resource. But, that’s not the way most of the world works.” Again (taking the compliment and not trying to sound arrogant here), it’s hard to argue that point. However, it again comes back to figuring out how to improve antibiotic use and do things right. I think we’ve done at good job at our institution reining in use of important drugs, through education, peer pressure, surveillance and a bit of internal restriction.
There were a couple of comments like "If you only use them very sparingly, there can’t be any realistic risk, particularly compared to massive use in humans" and “Our hospital only uses them a couple of times a month,” supporting the general notion that internal restriction can be effective, and that makes sense, at least to me.
At the end, the moderator (another good colleague and expert in his own right, Luca Guardabassi from Denmark) polled the audience: Should these drugs be banned completely from animals or allowed with restrictions?
It was a pretty even split, but I think banning them came out ahead (with the disclaimer that the audience was biased towards people from countries with fewer resistance issues and more restrictions, and fewer clinical people). (A few people also came up to me after and said “I agree with you, but I was too chicken to say anything.”)
It was a great discussion, and I think it made both sides rethink their positions somewhat. I still think we need to have access to these drugs, since otherwise we’ll be saying "Sorry, your dog has a multidrug-resistant infection but I can’t use the antibiotic that would treat it, so we need to euthanize him now." At the same time, the status quo can’t continue. Misuse and overuse of critically important drugs is a problem in North America and beyond, and we have to figure out how to deal with it. Ultimately, restriction might be required, but it’s much better for the veterinary profession to deal with it internally, by improving practices on their own and internally restricting or regulating how they are used.
One question I posed to the audience was, rank these actions in terms of what you think their impact would be on antibiotic resistance in people and animals:
- 1% reduction in fluoroquinolone use in humans
- 5% reduction in amoxicillin/clavulanic acid use in humans
- 5% reduction in ceftiofur use in food animals
- 1% reduction in fluoroquinolone use in companion animals
- 5% reduction in amoxicillin/clavulanic acid use in companion animals
- 75% reduction in carbapenem use in animals
- Ban on vancomycin use in animals
More food for thought (and maybe for a future post).
Yes, Ulrika, Engeline, Luca and I are still on speaking terms. A little wine and a (4 hour) Italian dinner heal all wounds.
I'm getting ready for next week's ASM/ESCMID conference on methicillin-resistant staphylococci in animals, for which I'm involved in a plenary session about critically important antibiotics in companion animals. The whole area of antibiotics and animals in complex and controversial (and made worse by political agendas, lack of evidence and confusion about different issues).
Anyway, one thing that often gets overlooked is the difference between companion animals and food animals in how antibiotics are used, what regulations are in place, and what differences should be present between species. Just discussing antibiotics "in animals" isn't adequate, because a pet dog is very different from a feedlot steer in many respects, and many of the issues around antimicrobial use are different as well.
One question that's going to be up for debate is "should antibiotics that are used in serious resistant infections in people be used in animals?"
My answer to this important question has evolved a bit over the years. It's "yes, but..."
The but is the important part.
- As a veterinary clinician, I see the need to treat my patients (or the patients I'm providing advice on).
- As someone who works in the field of antimicrobial resistance, I see the issues with drug use and resistance.
- As a parent, I don't want my kids to develop a serious infection that I may have played a role in fostering.
- As a pet owner, I understand the desire to try to save the life of a pet.
That doesn't even cover all the issues, but it shows the variety of standpoints that need to be considered.
Back to the question at hand. As I said, my answer is yes, but with disclaimers:
- We need to use antimicrobials only when required.
- We need to use antimicrobials properly.
- We need to take measures to reduce infections overall (so that less antimicrobial use is required).
At our veterinary teaching hospital, we have a restriction policy for vancomycin, an important human drug. For it to be used in an animal, the following criteria must be met:
- The offending bacterium must be susceptible to vancomycin (duh!).
- There must be no other reasonable antibiotic options that are likely to work.
- There must be a reasonable chance of survival with treatment.
- Systemic treatment of the infection is needed (i.e. it can't just be treated with local therapy).
- The clinician must get approval from infection control (i.e. me).
That has happened twice in the past 12 years. Both cases were dogs with life-threatening abdominal infections; they were each treated with a short course of vancomycin and survived.
That's probably 10-14 days of vancomycin use per ~200 000 patients. I don't know what the comparable numbers would be for people in Guelph General Hospital down the road, but their use would be staggering compared to ours. Also, the risk of resistance with each use is presumably much higher for each human patient since they are in an environment where vancomycin resistant bugs are present (and therefore can be selected for with treatment). Vancomycin resistance is exceedingly rare in our hospital population, further decreasing the risk.
Is there some risk? Certainly. Use inevitably carries some risk.
Does our 2 / 200 000 use constitute a reasonable human health risk? I can't see how it does.
So, is antibiotic use in animals something we can just ignore? Absolutely not. It's a big problem, just like antibiotic use in people. However, just as all animal species issues aren't the same, all types of antibiotic use aren't the same.
Are there other things we can focus on to reduce resistance? Absolutely.
- A 1% improvement (i.e. decrease) in use of fluoroquinolones in animals would probably have a dramatically greater effect on resistance in human and animal pathogens than a complete ban on vancomycin. Fluoroquuinolones are a commonly used drug class in animals that is also important in people, and one in which resistance is certainly an issue.
- A 1% improvement (i.e. decrease) in use of of fluoroquinolones in humans would probably have an even greater effect.
- Better infection control, preventive medicine and other practices could potentially have an even greater impact by reducing infections and therefore the need for any drug therapy, and delaying the treat-resistance-more treatment-more resistance cascade.
Some people would say that any drug that's of any relevance in humans should not be used in animals. Some veterinarians would say no one should control their prescribing practices. Like most things, I think there's a happy (and more effective and practical) middle ground. It's not the status quo, though. We need to have discussions about how to control antimicrobial use in all species, including humans, and not just pointing fingers at the other side. We also need to discuss how to improve infection control to reduce the need for antimicrobials, and how to improve the way we use antimicrobials when they are required. In order to have good discussions, we also need proper data (something that's still lacking).
Different opinion? Feel free to comment (or show up in Copenhagen next week).
Antibiotic use in animals, and the impact on humans is a controversial area. At a conference a few years ago, one of the organizers posed the question, "What percentage of resistance in human pathogens is attributable to antibiotic use in animals?" They had people write their answers on cards, and later in the day they gave a synopsis of the results. Basically, the responses ranged from 0-96% (or something like that). That's not surprising really, as there are a lot of opinions but there's been a lack of good data. Clearly, use of certain antibiotics in animals in certain situations can lead to increased resistance in some human pathogens. Sorting out the "certains" and "somes" is the problem. It's also clear that there's massive overuse (and abuse) of antibiotics in human medicine that leads to lots of resistance.
The biggest problem is our current lack of data. It's not for lack of trying, but it's an extremely complex area. A study in the upcoming issue of Emerging Infectious Diseases (Collignon et al. 2013) starts to put some more solid numbers behind the concerns. The study took data from a variety of sources and attempted to figure out the number of human deaths from resistant E. coli (just one of the bugs we're concerned about, but a big one) that is attributable to antibiotic use in animals. Their conclusion was that infections with E. coli resistant to 3rd generation cephalosporins (an antibiotic group which is used in some animals and is also important in humans), in which resistance was attributable to antibiotic use in poultry, accounted for 21 deaths and 908 hospital bed-days in the Netherlands in 2007. If this is extrapolated to Europe (which can only be done loosely because of differences in antibiotic use and infection trends between the vastly different EU countries), it would mean 1518 deaths and 67 236 hospital admissions. That's a very small percentage of people in Europe overall, and a small percentage of all the people in Europe who die of resistant infections, but it's still a lot and it's therefor still a concern.
What does this mean more broadly for other countries, other bugs, other drugs? It's hard to say. To quote the authors, "To more accurately estimate the associated increased deaths among persons resulting from third-generation cephalosporin use in poultry, detailed data from more countries is essential." I'd substitute "third-generation cephalosporin use" with "antibiotic use," since we also need to know about other drugs. It's always amazed me how hard it is to get even a basic idea of how much antibiotic use occurs in people and animals, with profoundly different estimates by different groups (often driven by different agendas).
Antibiotic use is a necessity in some situations. We have a moral obligation to keep animals healthy, and healthy animals help make healthy food. However, at the same time, we need to think about standard practices and make sure antibiotics are truly being used wisely in both people and animals. Stopping all antibiotic use isn't practical at this time, nor will it eliminate resistance. Knee-jerk reactions like simply banning antibiotics might actually make some things worse, if they result in other practices that also drive resistance (e.g. adding heavy metals like zinc to animal feed to help prevent diarrhea, resulting in the same pressure for antibiotic resistance, or replacing prophylactic treatment using drugs that are of limited concern in people with later use of therapeutic drugs that are important in humans). However, the use of antibiotics as a replacement for good management practices needs to end, and more thought needs to be given to how to use antibiotics wisely, effectively and sparingly - in all cases (animals and people).
A call to arms from guest blogger and University of Guelph professor, Dr. John Prescott:
Watching the global emergence and spread of multi-drug resistant bacteria is like seeing a train wreck in slow motion. There’s a sense of both inexorability and powerlessness. In the March 2013 issue of the Equine Veterinary Journal, Mark Bowen of the School of Veterinary Medicine and Science, University of Nottingham, writes that there is clear evidence of the need for change in our relationship with antimicrobials. Change is what many bacteria do for a living; of course the problem is not that bacteria change to resistance, but also that people are so resistant to change.
The excellent editorial (“Antimicrobial stewardship: Time for change”) describes the sensible steps taken by the British Equine Veterinary Association (BEVA) in 2012 to promote the stewardship of antimicrobial drugs in horses. These steps are summarized on the BEVA website: http://www.beva.org.uk/useful-info/Vets/Guidance/AMR. They provide an excellent approach to stewardship of antimicrobials in horses. BEVA has developed neat and simple promotional material to help equine veterinarians using these drugs do their part to help preserve them.
The BEVA project is summarized by the acronym PROTECT ME, which encompasses 9 steps to promote stewardship. PROTECT comes from for Practice policy; Reduce prophylaxis; Other options; Types of drugs and bacteria; Culture and sensitivity; Treat effectively, and ME come from Monitor and Educate. The brilliance and perhaps even contrariness of the BEVA approach is that it believes that policies should be created at the local level, and should be both dynamic and follow simple key concepts, rather than be national guidelines developed by people working in ivory towers.
The BEVA website provides the templates and forms for equine practitioners everywhere to develop simple and local policies that commit to stewardship. An important element in the PROTECT ME documents is to try to protect the drugs classified by the World Health Organization as the “Critically Important Antimicrobials” (3rd and 4th generation cephalosporins, fluoroquinolones). These drugs are categorized as “protected”. Drugs such as vancomycin and imipenem are categorized as “avoided”. The PROTECT ME approach promotes the use of “first line” antimicrobials as first choice for treatment of common conditions as part of the practice policy, and link this to the British “cascade” approach to antimicrobial drug choice. The BEVA approach is refreshing because it takes an intelligent, long-term approach that embraces the responsibility that users share to preserve the miracle while our scientists work feverishly to develop the next generation of antimicrobials. These are however going to be extremely expensive and perhaps also unavailable for animal use, except perhaps through the black market.
The antimicrobial “miracle drugs” revolutionized medicine and came into widespread use long before there was any science behind their optimal use. We’re still discovering how best to use them but we need to continue to develop strategies and approaches that optimize their use and minimize resistance and other side effects. The easily followed BEVA approach encourages user engagement with and responsibility for stewardship. Change is painful, but we have no choice. Let’s embrace it.
Methicillin-resistant Staphylococcus aureus (MRSA) and other antibiotic-resistant bacteria are big problems. They account for millions of illnesses, thousands of deaths and billions of dollars in costs every year internationally. Antibiotic-resistance is a complex issue, but some people try to over-simplify (and under-analyse) the problem.
A recent article on Examiner.com is an example. Entitled "MRSA cases double in five years while natural solution is overlooked", the article - while providing very little real information - claims that essential oils are "unmatched tools in the fight against MRSA."
- It talks about the bacterial killing power of essential oils. That's certainly true. Many essential oils are potent antibacterial substances.
- It also claims that essential oils are "free of the side-effects common to antibiotics." That's not so true. In fact, essential oils can be quite toxic. Tea tree oil, one of the more popular essential oils, can cause a range of adverse effects, and I'm aware of a couple of dogs that have died from suspected tea tree oil toxicity. A study presented at the North American Dermatology Forum last fall (Valentine et al.) showed that while some essential oils were effective against resistant staphylococci, they also had damaging effects on canine skin cells. One oil had essentially no antibacterial effect but did a lot of damage to skin cells.
The antibacterial effects of essential oils might be useful, but only if they do no damage to the animal (or person) at the same time. The problem is these products are not technically sold as drugs, despite the fact that they are really marketed as drugs, so they bypass the requirement to demonstrate safety and effectiveness. If a product showed good antibacterial activity and no toxicity, it would be a potential option for the treatment of superficial infections, but in the absence of proper testing demonstrating safety, I wouldn't use an essential oil, as it may do more harm than good.
The Examiner.com article doesn't contain much useful information and is more of an infomercial than anything else. It highlights on particular company called Young Living Essential Oils. The author of the article also seems to be that company's "Product Training Program Manager," according to articles he's also written on the website. No conflict of interest there, obviously!
A complex problem like antimicrobial resistance requires complex solutions. Non-antimicrobial options are one part of this, which is why my lab has done work in this area. However, all-natural doesn't necessarily mean safe or effective, and we need to demand proper testing of such products. Too many companies take the cheap and easy way out and don't do any testing. While they may make money, their customers (and their pets) are the ones who can end up paying the price.
Sometimes, I get a little concerned when research papers get picked up by the press. It's not necessarily because the research is weak, it's just that results sometimes get overstated or misinterpreted when they work their way outside of scientific forums.
A paper published in the latest edition of the American Journal of Veterinary Research is one of those. The paper (Tsuchiya et al. 2012) describes a study that looked at the impact of interferon-alpha (used to stimulate the immune system) and enrofloxacin (an antibiotic) on body temperature and lung fluid white blood cell counts in 32 horses that were shipped for approximately 26 hours in commercial vans. Horses either received just interferon or interferon and enrofloxacin before being shipped.
- After shipping, 3 antibiotic-treated and 9 untreated horses developed fevers. That's actually not statistically significant, by my calculations, and it's quite strange that the authors didn't do that analysis (and that the reviewers didn't pick that up).
- Two antibiotic-treated and 7 untreated horses were treated with antibiotics after arrival because of concerns about infections. Again, that's not statistically significant and it's surprising (and concerning) no one pointed that out.
- Overall, the average temperature of horses in the treatment group was significantly lower after arrival, but the clinical relevance of that is questionable since it was only a 0.4 C difference. Further, it's hard to say what a temperature immediately after arrival really means, since that's pretty early for a bacterial infection to have developed.
- There were significant differences in tracheobroncial fluid (fluid collected from the airways) between the groups, with lower white blood cell counts in the treated group. That's an interesting finding and is consistent with less inflammation. What that means in terms of disease prevention is harder to say, but it's something worth investigating further.
- There does not appear to have been any difference between the two groups in the ultimate health status of the horses.
This study provides some interesting information to help us think about how, when and why infections and inflammation develop after shipping. Results suggest that antibiotics might be useful in certain situations, but many questions remain. Any antibiotic use runs some risk of complications such as antibiotic-associated diarrhea. It also increases the risk of antibiotic resistance (and ultimately more problems trying to treat disease). We have to remember these issues when considering these results. Further, while it is typically much better to prevent disease than treat it, in situations like this, it's hard to say whether mass prophylactic treatment is actually preferable to early treatment, since horses can be observed closely after arrival and treated when early signs of disease develop. Ultimately, it's still not even clear from these data whether pre-treatment with antibiotics actually does have a positive clinical effect.
It's important to remember what this study tells us, and what it doesn't. Despite what some lay articles that have picked up the story say, it doesn't mean that antibiotics are broadly useful for keeping shipped horses healthy. The authors address this by stating "The use of enrofloxacin raises concerns regarding the emergence of antimicrobial-resistant bacteria, and it is important that antimicrobials such as enrofloxacin are not used inappropriately. The guidelines for enrofloxacin use in the Japan Racing Association’s medical office require that it is only administered as prophylaxis against transportation-associated fever when the duration of transportation is expected to be ≥ 20 hours and the horse has had clinical signs of transportation-associated fever before or is considered to be at risk for developing transportation-associated fever (eg, if the horse has undergone laryngoplasty or has a history of pneumonia)."
Regarding the big picture, however, this should make us think again about how we manage horses. Antibiotics should never be used as a crutch in place of good management. In a situation like this, where 19% of horses treated with interferon and enrofloxacin and 56% of horses treated with interferon alone get sick, something's wrong. Antibiotics may be an easy way to try to reduce the likelihood of disease in some situations, but that doesn't mean it's a good idea. Considering the number of horses that get sick (and die) every year from shipping-associated illness, maybe we need to rethink how they are transported. Is lack of antibiotics the problem, or is it how (and how long) horses are shipped? Maybe long, interrupted trips aren't a good idea, antibiotics or not.
At a time when there’s much concern about antibiotic use and resistance, and when there’s talk about restricting antibiotic use in animals, it amazes me that some huge, illogical and easy-to-correct loopholes remain in the current system.
The approach to access to antibiotics for animals varies greatly in different countries:
- In some, access to antibiotics for use in animals is tightly controlled, and these drugs are only available from veterinarians.
- In some, pretty much anything is available over the counter.
- In others (yes, including Canada and the US), most antibiotic use must be supervised by a veterinarian (via prescription), but people can still buy certain drugs over the counter and use them however they want - quite an illogical system.
One of the loopholes that allows individuals to use these drugs without veterinary supervision is the ready availability of a range of antibiotics at farm supply stores, feed stores and similar places. I’ve seen lots of completely illogical, ineffective (and ultimately irresponsible) antibiotic use in large animals from drugs obtained this way, with less common (but not uncommon) misuse in pets.
Another small but still relevant loophole is "fish antibiotics." Various antibiotics can be purchased over the counter in pet stores that are marketed for treatment of fish, but are the same as the antibiotics used in other pets (and people). Unfortunately the internet also abounds with descriptions of how to treat your dog (or you) with fish drugs.
Why do these loopholes remain?
- I have no idea. It’s just dumb. They probably just remain because governments haven’t bothered to do anything about it. It might be partly because it’s perceived as a minor contributor to antibiotic misuse (which fish drugs presumably are), but you can’t talk about the importance of such an issue and simultaneously ignore some parts of the problem.
What are the problems with this kind of free access to antibiotics?
- One of the biggest issues is use of antibiotics when they are not needed, which is a common problem. When I was in mixed animal practice, it was far from rare to be called to treat animals that the owner had already treated (unsuccessfully) with his/her own antibiotics. Often the treatment was ineffective because of underdosing or inadequate frequency of administration (both of which will lead to treatment failure and an increased risk of antibiotic resistance). Not uncommonly, though, the antibiotics didn't work because the animal didn't actually have an infectious disease (a steer with a broken leg that was treated for a week with low dose penicillin jumps to mind), meaning antibiotic use just led to unnecessary delays, expense and the potential for resistance, not to mention animal suffering.
Is there any real benefit to having these drugs available over the counter?
- Not that I can see. Sure, people save some money by bypassing veterinary involvement, but how often are treatable diseases improperly treated, resulting in unnecessary animal illness or death, and a loss of more money than a call to the veterinarian would have cost in the first place? Animal welfare aspects need to be considered too.
Some people would put up a fight if these loopholes were closed, including some farmers who like to treat their animals without veterinary assistance (sometimes effectively, sometimes not), stores that sell the drugs and a small subset of people who think they can treat their animals with whatever drug they can track down.
Antibiotics are incredibly important drugs, for both humans and animals. Use of antibiotics in animals can lead to resistance in humans, and vice versa - despite the head-in-the-sand approach of the American Veterinary Medical Association and their infamous position “There is little to no evidence that restricting or eliminating the use of antimicrobials in food-producing animals would improve human health or reduce the risk of antimicrobial resistance to humans.”
Concerns about overuse and misuse of antibiotics lead to calls to restrict antibiotic use in animals. Overuse and misuse are common, in both veterinary and human medicine, and they need to be addressed by both groups. However, antibiotics are needed in veterinary medicine to ensure proper patient care, limit pain and suffering and facilitate production of safe food. What we don’t need is excessive use, inappropriate use or use of antibiotics to make up for bad management practices, which are all things that are more likely in the absence of veterinary oversight.
While it shouldn't come as a surprise considering other studies, a recent study in PLoS One (O'Brien et al 2012) has caused a bit of a stir in the US. This study, headed up by Dr. Tara Smith's research group in Iowa, looked for methicillin-resistant Staphylococcus aureus (MRSA) in retail pork. They bought pork from different stores in Iowa, Minnesota and New Jersey, and tested it for the presence of MRSA. They focused on pork because MRSA can be found widely in pigs internationally, including in the US.
Not surprisingly, they found MRSA. Overall, they tested 395 pork samples from 36 stores, including both "conventional" pork (300 samples) and "alternative" pork (95 samples). The latter consisted of samples labelled "raised without antibiotics" or "raised without antibiotic growth promotants." MRSA was found in 6.6% of samples; 6.3% of conventional pork samples and 7.4% of alternative pork samples.
When they looked at the MRSA types that were present, 27% were the ST398 "livestock-associated" MRSA that's most commonly found in pigs. However, like our earlier Canadian studies, they found common "human-associated" MRSA strains more often. These strains can also be found in pigs, albeit less commonly than ST398, and it's unclear whether meat contamination with these strains comes from pigs or from people who handle the meat throughout the processing chain.
The fact that there was no difference between conventional and antibiotic-free pork isn't surprising to me, although it catches some people off-guard because of some basic over-assumptions about the relationship between antibiotics and MRSA in food animals. We can find MRSA quite commonly on both regular and antibiotic-free farms. While it's reasonable to assume that antibiotics were a key factor in driving the emergence of MRSA in pigs, there's not much evidence showing that ongoing antibiotic use is an important factor in determining whether MRSA is present on specific farms or in specific pigs. One potential explanation is that in order to control infections, farms that stop using antibiotics start using other substances such as zinc in feed to help control overgrowth of certain intestinal bacteria, and these compounds may be just as effective at selecting for certain resistant bugs as classical antibiotics. That's just one possible explanation, but it shows how complex the issue of antibiotic-resistance is, and it shows that simply saying "stop using antibiotics," without really looking at the overall problem, won't necessarily reduce MRSA.
What does the presence of MRSA in food mean? Who knows? MRSA is a pretty high profile bug, and with good reason, because it's a very important cause of infection in people. A key aspect of MRSA in food is that cooking food will kill the bacteria (as well as many of the other harmful bacteria that often contaminate raw meat). So proper attention to food safety, including thorough cooking, cleaning of surfaces, prevention of cross-contamination and hand hygiene, should greatly reduce any risk (the problem is a lot of these things aren't usually done very well).
A two-part study (Maddox et al. 2011) was recently published online in the Equine Veterinary Journal looking at antimicrobial resistant "superbugs" in horses in the UK. The first part of the study had the simple objective of estimating the prevalence of both MRSA nasal colonization and fecal shedding of antimicrobial resistant E. coli in the UK horse population. The reason they were looking at E. coli is because this bacterium is part of the normal intestinal flora of most animals (including horses), so it's easy to find, and it is frequently exposed to antimicrobials whenever a horse is treated systemically (i.e. with either oral or injectable antibiotics), so researchers use it as an "indicator" for resistance that may develop in other bacteria as well. E. coli doesn't typically cause gastrointestinal disease in horses like it can in people, nonetheless E. coli is a common cause of uterine, urinary and wound infections in horses, as well as septicemia in foals, and antimicrobial resistant infections in these situations can certainly be a big problem.
Out of 678 nasal swabs (taken from horses on over 500 premises), only 4 (0.6%) were positive for MRSA. That's good to see, as it's very easy for MRSA to spread in a horse population "under the radar," because colonized horses do not have any outward signs that they are carrying the pathogen. The overall low prevalence in the community setting is similar to previous community studies in the UK and other areas. Out of 650 fecal samples, 452 (72.2%) were positive for an E. coli that was resistant to at least one antimicrobial. That's not too surprising. The bigger concern is that 233 (37.6% - over one third of all horses tested) samples contained multidrug-resistant E.coli (defined in this study as resistance to more than three antimicrobial classes) and 42 (6.3%) samples contained an E. coli that produced an extended-spectrum beta-lactamase (ESBL). ESBLs are particularly problematic because they can be relatively easily transferred between bacteria, they confer resistance to a large number of commonly used antimicrobials in the beta-lactam class (which includes penicillins and cephalosporins), and are frequently associated with genes that confer resistance to other antimicrobial classes as well. Bacteria that produce ESBLs are a significant problem in human medicine and have been reported to cause infection in horses as well.
The second part of the study used information collected from questionnaires filled out by the horse owners to try to determine risk factors that affected the odds of a particular horse shedding antimicrobial-resistant E. coli. They used some pretty heavy-duty statistical analysis because they were looking at so many factors and different outcomes, and any time that happens you have to take the final numbers with a grain of salt. Nonetheless, the results can help point the way for future studies to help determine which factors may have the biggest impact on the risk. The authors found recent hospitalization and veterinary treatment for various conditions over the last six months were associated with higher odds of shedding multidrug-resistant strains of E. coli, and the type of farm/facility also affected the odds. In addition, having a recently hospitalized horse on the premises (among other things) increased the odds of a horse shedding ESBL E.coli.
What does all this mean for the average horse owner? The results really aren't new or startling. We already know that antimicrobial resistance is a growing problem in equine medicine, as it is in veterinary and human medicine in general, and this is one more set of studies that provides evidence to that effect. I have no doubt that if a similar study was performed in North America the same kinds of resistant bacteria would be detected, although the numbers may vary somewhat one way or another. The second part of the study also re-emphasize the role that antimicrobial use plays in promoting development of and selection for resistant bacteria, and the potential for the treatment of certain horses to affect the microbes being carried and shed by the animals around them. In the end, it comes down to being responsible about how we use antimicrobials in order to curb the development of resistance, so that these important drugs remain effective for treating serious infections in the future. This applies equally to their use in people and animals of all kinds.
Urinary tract disease is a common reason for use (and misuse) of antibiotics. In veterinary medicine, one thing that we lack is clear clinical guidelines (particularly regarding antimicrobial use) to help manage specific types of diseases. In human medicine, there are some excellent guidelines of this kind (e.g. the Infectious Disease Society of America guidelines) available for a range of diseases, and these can greatly assist with proper management of cases.
Because of the lack of veterinary guidelines, the International Society for Companion Animal Infectious Diseases has started a guideline development program. Using a committee of international experts in the fields of infectious diseases, internal medicine, microbiology and pharmacology, from both human and veterinary medicine, and extensive discussion, debate and revision, specific treatment guidelines are being developed for different types of infectious diseases. The first set, Antimicrobial Use Guidelines for Treatment of Urinary Tract Disease in Dogs and Cats, has now passed peer-review and the guidelines have been published in Veterinary Medicine International, an open-access journal available to all veterinarians.
To download the guidelines, you can also click here.
The Swedish Veterinary Association has released an English version of their 2009 "Guidelines for the clinical use of antibiotics in the treatment of dogs and cats". It's a very comprehensive document that goes through various medical conditions and discusses antibiotic use recommendations. As concerns about antibiotic use and misuse increase, more organizations are putting the significant effort that is required into developing such guidelines, and they can be a tremendous asset. While there are still significant limitations in the available research needed to produce evidence-based guidelines, a combination of careful review of existing information and expert opinion can provide good guidance for treatment of infections in companion animals.
There are always a few disclaimers that need to be given when presenting antibiotic use guidelines:
- They are guidelines, not standards. They provide a general overview of the issues and how to manage most patients, but some patients don't read the book and need to be treated differently.
- Disease and drug resistance patterns vary between regions. These patterns need to be considered, particularly when considering guidelines produced in another area or country.
- Things change over time. As guidelines age, some parts of them may become less relevant.
- There are differences in antibiotic access and licensing between regions.
Regardless, sound guidelines like these are needed and will hopefully help improve both patient care and control of the scourge of antibiotic resistance.
A large percentage of advice calls that I get about methicillin-resistant staph infections in dogs are regarding skin infections. Skin infections (pyoderma) are a common problem, a leading cause of antibiotic use in dogs, and an often frustrating problem for vets and pet owners alike. One problem is that, unlike many other types of infections, skin infections are often recurrent. This frequently leads to an ongoing cycle of infection-treatment-resolution-infection-treatment-resolution... The net result is some dogs get treated very regularly and for long periods of time with antibiotics, and it's not particularly surprising that highly drug-resistant bacteria like MRSA or MRSP eventually become involved.
Normal, healthy, intact skin is an excellent barrier to bacterial infection. Various bacteria normally live on the skin but do not usually cause infection. Skin infections typically (if not always) develop in response to some underlying skin disease, such as flea allergy dermatitis, food allergy, atopy, Cushing's disease or hypothyroidism. Identifying and treating a skin infection is one thing. Identifying and treating the reason for the infection is another, and that is arguably the most critical component. Ignoring the underlying cause may not be the end of the world for a single infection, because proper treatment and a susceptible bacterium can result in a successful outcome, but ultimately ignoring the real problem can lead to a difficult-to-treat, resistant infections.
Any diagnosis of pyoderma should be accompanied by consideration of the underlying cause. If a cause is apparent, this should be treated (if possible). If a cause is not readily apparent, it should be investigated. By investigated, I mean a real search for the problem, not a cursory examination, half-hearted feeding trial and little more. There is almost certainly an underlying cause and, at the end of the day, time, effort and money are better spent on trying to identify the root issue rather than just throwing round after round of antibiotics at the dog. In some cases, the cause (while it's probably there) can't be identified, but it's definitely worth trying anyway.
If your dog has been diagnosed with a skin infection, ask why it happened. If there is not a clear answer, talk to your veterinarian about the best plan to identify the cause. If at all possible, follow through with the plan. It may include certain diagnostic tests (which cost money) or dietary restriction (which takes effort), but it should be thought of as an investment in your pet's health, as well as a potential way to keep multidrug-resistant bacteria (some of which can infect people) out of the house, to save future treatment costs, and to keep your pet much more comfortable.
On the way home from an MRSA symposium in the US the other day, I was (perhaps fittingly) listening to a podcast about new antibiotic development. The podcast, by The Lancet Infectious Diseases, discussed the small number of new antibiotics that are in the pipeline (about 15), particularly in contrast to the number of new anti-cancer drugs (about 800). There are many reasons for this, and development of new anti-cancer drugs is certainly important. However, we have definitely not "won the war" against bacteria, and resistance continues to be a serious threat to human and animal health.
The small number of potential new drugs (since many drugs in development will not ever make it past drug trials) is a concern if resistance continues to increase. The disparity in development between antibiotics and anti-cancer drugs is also concerning when you consider that good antibiotics are very important for cancer therapy - people with cancer often get infections, and often their infections are caused by multidrug-resistant bugs. As we develop more and better anti-cancer drugs, there will be more people who are susceptible to these potentially severe infections, and ways to treat them are needed.
Why are there so few antibiotics in development compared to other drug types?
- $$$ - Money. The potential return on investment for pharmaceutical companies is much greater for many other drug types. Huge amounts of money must be invested to develop, test and license drugs. Logically, companies are going to focus on the higher yield drugs, leaving some important areas with less research and development than would be desired.
What do we do?
Well, unless you own a pharmaceutical company or have millions of dollars to spend, you're probably not going to have an impact on drug development. Since we can't control what will be available to us in the future, we need to make sure that we delay, as much as possible, the emergence and dissemination of highly resistant bacteria.
Common sense practices such as only using antibiotics when necessary, using them properly (e.g. proper dose and route, giving the entire treatment course), good preventive medicine to reduce the risk of bacterial infections and good infection control measures are critical and often underused. While not as fancy as high-tech drug develop, these are the ways that we can have a positive impact in both human and animal health, and reduce our need for new drugs.
Antibiotic resistant bacteria are a huge problem in human medicine, and they're an increasing problem in veterinary medicine. In pets, we are seeing dramatic increases in multidrug-resistant bacteria, some as a result of transmission from humans and some that are developing in animals. Regardless of the source, infections caused by resistant bacteria are a major problem. As resistance increases and we have fewer and fewer treatment options for some infections, the potential need to use certain antibiotics that are important for serious infections in humans ("big-gun" antibiotics) increases. This is a very contentious issue because concerns have been raised over the use of these drugs in animals and the potential impact on humans.
There are two extremes to the argument:
- These are critically important drugs in human medicine and they should never be used in animals.
- These drugs are used thousands of times a day in people and very rarely in animals, so the impact of periodic use in animals should be minimal, and failure to use them would result in animal deaths from potentially treatable infections.
I take the middle ground here. I am very concerned about antibiotic resistance (in pets and people) and I want to make sure that what I do does not have a negative impact on public health. I also realize that very rare and appropriate use of these drugs will realistically be unlikely to have any negative impact on public health, and that withholding treatment could cause animal suffering, death and prolonged infections that could be transmitted to their owners. The key, to me, is ensuring that use of these drugs is truly very rare and appropriate. At the Ontario Veterinary College, we have strict guidelines for use of "big-gun" antibiotics to try to ensure that there are used rarely and properly. For example, vancomycin can be used, but only when:
- An infection is present and it is known that the bacterium is resistant to all other options and susceptible to vancomycin.
- Local antibiotic administration or other types of alternative treatment are not options.
- It's a serious infection that needs to be treated but it is treatable (i.e. no throwing a big gun drug at a patient that clearly has a terminal disease and does not have a realistic chance of surviving).
- Approval is obtained from the Chief of Infection Control (i.e. me).
With this approach, we've only had 1 case where vancomycin was used, and that was in 2001. That's a pretty good record for a busy referral centre with a tertiary care caseload that sees "the worst of the worst." There have been a few instances when vancomycin was requested but with discussion and review of the case, better alternatives were identified. I'm certain that these guidelines have reduced the use of vancomycin and increased awareness of the problem, but have had no negative impact on patient care.
Antimicrobial resistance isn't going away. We can control it but not eradicate it. Scrutiny of antibiotic use in veterinary medicine is also not going to go away, and in some ways, that's a good thing. It should provide impetus to make sure that we improve how we use drugs, from the big guns down to our day-to-day drugs. Realistically, it's the regular use (appropriate use, overuse and misuse) of less exotic antibiotics that is having a bigger impact on antimicrobial resistance, and we need to pay attention to that as much as to the high-profile drugs.
I recently attended a meeting to develop antibiotic use guidelines for dogs and cats. One recurring theme during the discussions was our paucity of scientific evidence about how to use antibiotics in certain situations. It's really interesting when you compare antibiotic treatment regimens that are used in humans and standard practices for dogs and cats. Almost invariably, we treat dogs and cats for much longer periods of time than people, even when very similar diseases are compared. Why is this?
One reason is a lack of people doing research and the difficulty performing (and funding) the large clinical trials that are needed to evaluate different treatment protocols. For example, we tend to treat urinary tract infections in dogs for 7-10 days, while in people, just 3 days of treatment is much more common. However, longer treatment courses were used in humans until various research studies showed that shorter treatment was as effective and had fewer side effects. It's likely that we could treat urinary tract infections in dogs for shorter periods of time but we don't have the data to support it at this point.
It's possible that longer treatments for certain conditions are indeed needed in dogs and cats compared to humans. An argument to this effect is that disease in pets can often be more advanced (and therefore potentially harder to treat) when first detected than similar disease in people. For example, if someone has a urinary tract infection, they are probably going to get to their physician quickly. Many owners may not notice the signs of an infection in their pets as early. More established infections may take longer to treat. Does that really happen? We don't know, but it's something we need to know to determine proper treatment durations.
"If it ain't broke, don't fix it". This isn't a very good philosophy when it comes to medicine but it's understandable. If a certain treatment plan usually works, people are hesitant to look at alternatives. The problems with longer term therapy, such as adverse effects of drugs and development of antibiotic resistance, are not necessarily considered (but they need to be).
Bottom line: We need good research to determine optimal treatment protocols for pets. It's very likely that we can greatly decrease the amount of antibiotics that we use while improving patient care, but without good evidence, it's hard to know what to do and where to start. Being too aggressive and dropping treatment times in the absence of evidence may not be a wise decision - too short a treatment period could result in treatment failures and ultimately more sick animals and overall more antibiotic use.
A recent study just published in the journal Emerging Infectious Diseases evaluated risk factors for dogs having an infection with methicillin-resistant Staphylococcus aureus (MRSA) versus methicillin-susceptible S. aureus (MSSA). This study, headed by Dr. Meredith Faires, compared dogs with MRSA versus MSSA infections from three different veterinary referral hospitals in Canada and the US. Among the more important findings were the following:
- Staying in a veterinary hospital was not a risk factor for MRSA infection, reinforcing the notion that this is predominantly a community-associated disease in dogs (meaning it typically develops in dogs in the general population).
- Most infections, in both the MRSA and MSSA groups, were skin infections. While serious deeper infections can and do occur, skin and ear infections are very common.
- Prior treatment with antibiotics was associated with development of MRSA versus MSSA infections. Dogs that received any antibiotic within 90 days were approximately 3.8 times as likely to have MRSA versus MSSA infection. Dogs treated with drugs from the fluoroquinolone class of antibiotics were 4.6 times as likely to have MRSA versus MSSA infection.
The association between prior antibiotic use and development of a resistant (i.e. MRSA) infection is not surprising, but it is important to document these events and to be aware of them. Antibiotics are critically important drugs in veterinary and human medicine. They save countless lives, but are also overused and misused frequently, and resistance is a critical problem. Studies such as this demonstrate the need for prudent antibiotic use - use them when needed, but use them properly. Don't use them when a bacterial infection is not present or unlikely to occur.
Image source: http://animalphotos.info/a/
European Antibiotic Awareness Day is an initiative of the European Centre for Disease Prevention and Control. This year it falls on November 18. The aim of the Day is to provide an annual opportunity for raising awareness about the threat to public health of antibiotic resistance and how to use antibiotics responsibly.
Responsible use of antibiotics can help stop resistant bacteria from developing and help keep antibiotics effective for the use of future generations. Successful national public awareness campaigns are already resulting in more rational use of antibiotics and a reduction in levels of antibiotic resistance in Europe.
Responsible use of antibiotics includes use in people and in animals. Here are some of the things you can do to help with regard to antibiotic use in your pets:
- Only give your pet antibiotics if directed to do so by your veterinarian.
- Make sure your pet gets the full dose of medication at the correct time(s) of day. If you are having problems getting your pet to swallow pills or take medication, contact your veterinarian as soon as possible. Your veterinarian may be able to give you advice on some "tricks" for getting your pet to take the medication, or sometimes the medication can be provided in a different form (e.g. a liquid instead of a pill).
- Always ensure your pet finishes the entire prescription. There should be no leftover pills or medication. Do not stop giving your pet the antibiotics just because it looks/acts like its feeling better. This is a common mistake that can have disasterous consequences! You should NEVER "save a few pills for the next time."
- Never give your pet antibiotics that were prescribed for you or any other person, whether they are expired or not.
Clostridium difficile is a high-profile bacterium, being an important cause of illness and death in people. It can also be found in various animal species, including dogs and cats. In a study we published earlier this year (Lefebvre et al, Journal of the American Veterinary Medical Association, 2009), factors associated with acquisition of Clostridium difficile by dogs involved in hospital and non-hospital therapy programs were assessed. Things that were significantly associated with a dog acquiring C. difficile were:
- Contact with human hospitals: Not too surprising since it's clear that hospitals can be highly contaminated with C. difficile and the hands of some patients petting the dogs are probably also contaminated.
- Contact with children: Most parents know that kids are biohazardous (we've getting over a round of illness in our house brought home by the kids - not an unusual event). Whether the increased risk for dogs is because kids have higher rates of C. difficile carriage, or because they have closer contact with dogs (with little hygiene) or some other factor isn't clear.
- Recent use of antibiotics: No surprise here. Antibiotic use is a well-recognized risk factor for C. difficile, since antibiotics can disrupt the normal protective bacterial population of the intestinal tract and allow C. difficile to grow.
- Recent use of antibiotics by a person in the house: I think this is a fascinating result and a great example of the close inter-relatedness of people and pets microbiologically. What presumably happens is that when someone is treated with antibiotics, they are more likely to acquire C. difficile and pass it in their feces. By doing so, there is a greater chance that their dog will be exposed to C. difficile, perhaps from the person's hands or the household environment. (The toilet would be a great source if the dog's a toilet-drinker). The implications of this, for both dogs and people, are unclear. It could be primarily an academic risk (i.e. of little practical significance), or it could be that interspecies transmission of C. difficile plays a role in disease in both species. We simply don't know at this point.
This is also a good example of why educational efforts regarding prudent antibiotic use need to be directed at both animal and human healthcare.
More information about Clostridium difficile can be found on the Worms & Germs Resources page.
Image source: www.sciencedaily.com/releases/2009/05/090507101820.htm
A reader's question to InsideToronto.com highlights numerous issues with antibiotic misuse is pets (and people). Here's the situation, with my comments.
The reader has a cocker spaniel that's had a urinary tract infection for a year. She took it to her vet and a urine culture was recommended but she declined it. Antibiotics were prescribed but she stopped giving them after 48 hours because the dog looked better. She has not mentioned it to the vet since then.
- This dog has had a treatable, painful infection for a year. I have major ethical problems with this. Instead of turning to InsideToronto.com, she needs to see her vet. Fortunately, she got some good advice from the columnist and hopefully was convinced to take her dog to a vet.
- Simple urinary tract infections that go untreated can lead to other, sometimes serious or life-threatening problems. Infection can ascend from the bladder to the kidneys. More commonly, bladder stones can develop. One type of bladder stone is associated with urinary tract infections and it's quite possible that, in addition to a severe (and potentially difficult-to-treat by now) urinary tract infection, the dog also has bladder stones that will need a prescription diet or surgery to eliminate.
- She stopped treating an infection before the recommended treatment course was finished. That's too common and a recipe for treatment failure and antibiotic resistance.
When signs of the infection returned, she gave the dog "a few antibiotics" and stopped again when the dog looked better.
- See above. Perfect recipe for treatment failure and resistance.
When she ran out of the originally prescribed drugs, she used a different antibiotic from an "open prescription" from her MD that she had for her own medical problems.
- Where do I start? Many drugs used in dogs are used in people, but not all. Some human drugs can be harmful in dogs. Dosing may be different. This is completely irresponsible (but unfortunately, probably not uncommon).
- I wonder who paid for the drugs? If her insurance company paid for it, that's insurance fraud.
- This is also a good reason why "open prescriptions" from MDs are a problem. Who knows how often these drugs are used by the patient for the wrong reason or given to other people or pets?
Antibiotic misuse is a huge problem. It goes on in human medicine and veterinary medicine. We need to clean up what we do from both sides to address the critical problem of antibiotic resistance. Cases like this highlight the need for better controls and better education.
Methicillin-resistant Staphylococcus aureus (MRSA) infections are an emerging problem in dogs and cats. They're a huge problem in human medicine, and the emergence of MRSA in pets can be directly traced to the spread of MRSA in people.
A big problem with MRSA infections is that they can be difficult to treat because they can be resistant to many antibiotics (not just methicillin). This complicates treatment, but it's important to remember that most MRSA infections are treatable.
An important concern with MRSA is that it may lead to unnecessary veterinary use of drugs that are critically important for treatment of life-threatening infection in humans. Vancomycin is an antibiotic that is occasionally used to treat MRSA infections in dogs, although I've never had to use it. I stumbled across a supposed "veterinary information website" today that stated vancomycin is the main treatment for MRSA in dogs. It quickly became clear the authors had no clue about the topic, because they kept calling MRSA a virus (always scrutinize the source of information, especially on the internet). Information like this doesn't help with prudent use of drugs like vancomycin. It's important for pet owners and veterinarians alike to realize that these "big-gun" antibiotics (such as vancomycin) are rarely needed for MRSA infections in dogs and cats. There are almost always other, and usually better, options.
Vancomycin is also sometimes inappropriately used in animals, which can lead to worsening of infection. For example, if vancomycin is mistakenly given orally, the drug is not absorbed from the intestinal tract and therefore has no chance of fighting infection elsewhere on the body.
In general, MRSA infections are quite treatable. Survival rates tend to be high and, with proper treatment, should be no lower for MRSA infections versus infections caused by susceptible strains of S. aureus. A comparison of MRSA versus susceptible S. aureus infections presented last year reported no difference in survival rates, with an overall survival rate of >80%. The key is diagnosing the infection early and getting started on the right treatment. That means getting cultures done earlier, rather than later.
While increasing antibiotic resistance may lead to more need for "big-gun" antibiotics in some cases, we need to act prudently and restrict their use to situations in which they are absolutely required. Use in animals needs to be very prudent to avoid contributing to antibiotic resistance in people. Inappropriate use in animals could lead to more calls to restrict veterinary access to various drugs, which could threaten treatment of other animals with other types of infections.
Don't confuse "big-gun" antibiotics with the best treatment.
More information about MRSA can be found on the Worms & Germs Resources page.
A recent post that discussed, among other things, expired antibiotics generated a lot of comments. Some accused me of various things and stated their belief that expired drugs are fine and that requiring antibiotics to be prescribed is a global conspiracy. I'll leave the conspiracy theory alone and just address the issue of expired drugs.
Expiry dates must be provided by manufacturers. They are essentially a guarantee that the stated level of active ingredient will be present at least until the expiry date. Drugs don't instantly vanish the day after, but once you have passed the expiry date, you no longer can be certain about what is present. It's possible the full amount is present, but it's also possible that less is present, and it's impossible to predict. If you don't know how much is present, you can't be certain that you are giving the proper dose. Giving inadequate doses is associated with treatment failure and increased likelihood of antibiotic resistance developing. Therefore, unless you have a pharmacology lab in your house (or readily accessible) to test expired drugs, you shouldn't use them.
It's not just my opinion. Here's what some other groups say on the subject:
Centers for Disease Control and Prevention (CDC): "...make sure you properly dispose of leftover and expired antibiotics."
University of Michigan University Health Service: "Do not take expired antibiotics."
The Alliance for Prudent Use of Antibiotics quotes Dr. Alfred DeMaria, an Assistant Commissioner at the Massachusetts Department of Public Health (MDPH) suggests that "stockpiling of antibiotics is strongly discouraged because it could lead to inappropriate patient decisions to self medicate, incomplete courses of antibiotics that might select for resistant organisms, the eventual use of expired medications, and the depletion of national supplies for medically-indicated uses. Antibiotics should be selected according to the specific infection of concern."
The advice from these respected groups, who have no financial stake in the sale of drugs, sounds pretty clear to me. Trying to save a little money by re-using expired antibiotics is a bad idea. The infection might get better, but it might not. If it doesn't then the animal (or person) will be sick longer and may require more intensive (and expensive) treatment. If antibiotic resistance increases because of the use of inadequate doses, then more expensive drugs may be required and infections may be harder to treat. None of these are worth the potential cost savings. This is a different situation than using expired drugs like painkillers for your headache. If those drugs are no longer effective, the worst thing that will probably happen is you won't get better, which you would know in short order and be able to address. With antibiotics it's harder to tell whether they are working early on during treatment (the critical time), and treatment failure could have much more serious consequences, both for the pet and for drug resistance.
When antibiotics expire, get rid of them. Always complete prescriptions as directed and you won't have leftovers to worry about.
People are justifiably concerned about overuse of antibiotics, in both veterinary and human medicine. There's ample talk about restrictions on use of antibiotics in animals (especially livestock), which is an area that needs good, objective research and discussion. Some politicians have made grand statements about restricting antibiotic use and have proposed strict legislation. (In North America, there's a lot more talk than action). However, I continue to be amazed that amongst all the hand-wringing about antibiotic use in animals, governments haven't taken the very simple initial step of making all antibiotics only available by a veterinarian's prescription. This seems to be a very logical first step, but it's one that almost never gets discussed.
A good example of why this type of regulation is needed comes from a website about Terriers, which says:
"Almost all human antibiotics can be used on dogs and almost everyone either has old antibiotics in their medicine cabinet or knows people that do. Look around, and you will probably find what you need."
- What??!! Just what we need... recommendations that people sift through old drug supplies for a dose or two of who-knows-what, which may or may not be expired and may or may not be potentially useful for whatever problem is present, and may even be harmful. Determining whether or not an antibiotic should be used, and determining the drug and dose is not something that should be up to a pet owner. It should be up to a veterinarian.
"Drugs past the expiration date are going to be fine as long as they are no older than a year or so past the expiration date (even then they may be fine)."
- Dumb. Drugs don't instantly go bad at their expiration date, but you don't know what you have left at that point. If you actually need an antibiotic, you need one that works like it's supposed to.
"If you prefer to order your medications outright, you can order cephelaxin (Fish-Flex) from most dog catalogues and it will cure 99% of your flesh wounds as well as most urinary tract and ear infections. Cephalexin or cefalexin is sold as a fish antibiotic in dog catalogues with full-knowledge it is being used for off-label treatment in dogs. It should cost about $30 for 100 250 mg. capsules, which is a perfect dose for a terrier."
- Ugh!! A good example of why loopholes like easy access to antibiotics for fish use need to be closed. Many dog internet sites sell fish drugs. I wonder what percentage of "fish" drugs actually make it into fish?
"You probably have some old amoxicillin around the house from the last time you got sick. This is fine to use even if "expired" more than a year ago. Expiration dates on non-liquid antibiotics are a marketing tool (i.e. they encourage people to throw good drugs down the drain) and have no scientific basis -- a fact demonstrated by the U.S. military."
- Can't say I've seen that study. Expiry dates aren't a marketing ploy. You should use all the antibiotics prescribed, and if for some reason you have any left, you should throw the rest out. It has to do with health and proper use of antibiotics, not marketing.
Take home messages:
- It's time for politicians to actually do something about antibiotic use and ban all over-the-counter access.
- Beware of internet advice. Scrutinize sources of information carefully.
A recent press release from All Pet Naturals proclaims "First All Natural Organic Antibiotic for Pets Now Available."
I know that "organic" and "all natural" are big catch-words for some people, and may be mistakenly perceived as indicators of safety or quality. There are very good reasons why we used manufactured and tested pharmaceuticals. If I wanted an organic, all natural approach to antibiotic therapy, I could eat some moldy bread and hope that an antibiotic-producing yeast was present, hope that it was producing adequate levels of antibiotic to fight my infection, hope that the antibiotic would survive the acid environment of my stomach and be absorbed into my bloodstream, and hope that it would kill the bacterium that's making me sick. Doesn't sound like a good idea to me. Personally, if I need any antibiotic, I'd rather use one that has been shown to be effective, is produced using good manufacturing practices, can be taken at a known concentration and has good dosing recommendations, among other things. Playing around with unknowns in the face of a bacterial infection is not a good idea.
Back to the supposed "all natural organic antibiotic" product in question. It is a grape seed and grapefruit seed extract product. Those compounds have some biocidal activities, meaning they can have effects on some bacteria and viruses in laboratory tests. Evidence for its use for treatment of disease is less convincing, but some topical biocides may be useful adjunctive treatments for skin infections. The manufacturers claim that this product can be used to:
- Treat skin problems caused by bacteria, even basic cuts and wounds.
- Fight tooth decay and gum disease, prevent free-radical damage to the lens and retina of the eye, and even treat glaucoma by protecting collagen structures in the eye.
- Help relieve asthma and emphysema.
- Help to support brain function with daily use.
I have a general line when it comes to products like these: the more a product claims to cure, the less likely it's going to do anything. There's simply little to no evidence for these claims. (Making health claims like this for a nutraceutical is also illegal.) I hate seeing animals that have suffered because people used products like these instead of recommended antibiotic therapy.
Products like this are typically harmless (unless they are used instead of proper treatment and medications) but, if you need an antibiotic, use a real antibiotic. If there's no clear evidence of need, don't use anything. Any compound with activity against bacteria, whether it's a traditional pharmaceutical antibiotic, an organic alternative or a disinfectant, can exert pressure for development of further resistance. So, we only want to risk that if it's really necessary. It's another example of the need to think, read, critically assess and ask questions about potential treatments before jumping on "all natural organic" bandwagon.
In an interview with the San Francisco Chronicle, veterinary dermatologist Dr. George Doering makes a pretty obvious but very important comment that is worth repeating:
"The biggest problem we have in almost all the fields of veterinary medicine is compliance. You say to a client, "This dog needs to take this antibiotic twice a day." Well, the reality is we might be lucky if they get it once a day. ...They don't want to accept the seriousness of the problem."
This very true and very important. Compliance with recommended antibiotic therapy is probably a major factor in treatment failure, recurrent infection and antibiotic resistance. Antibiotic dosing regimens are specifically designed to ensure that the right concentration of drug is present in the body for the appropriate time. Missing doses, skipping days, not making sure the animal actually ingests the drug, and other problems that result in the pet not getting what is was supposed to get are very important.
It's easy to understand why this happens, because administering antibiotics (particularly to some difficult-to-pill dogs and cats who can smell the medication when it comes in the house!) can be a hassle. Because of this (and the very natural human tendency to take the easy way out), it's really important for people to understand the concerns about inadequate antibiotic administration and what they need to do.
- Follow the entire treatment course. You should have no antibiotic left at the end of the recommended treatment time.
- Make sure your pet actually swallows the antibiotic. If you add pills to food, make sure you check to see that the pill isn't left behind. It's amazing how animals can eat a big bowl of food and leave behind a little pill. The picture shows how my dog Meg can, in the process of inhaling her food at an incredible rate, leave behind a tiny ephedrine pill.
- If your pet will not eat the drug voluntarily, talk to your vet about other ways to administer it, such as compounded in chewable treats. Depending on you and your pet, opening your pet's mouth and placing the pill at the back of the tongue may be an option. Talk to your vet about this first and make sure you wash your hands after. If you think there is a risk you might be bitten, if you are at high-risk for infection because you are immunocompromised, elderly or pregnant, don't try to "pill" an animal in this manner.
- If you still can't get the drug into your pet, talk to your vet right away. If you wait a couple of days or a week or more to tell your vet, your pet may be even sicker by then. There may be other options to oral drugs such as injectable antibiotics. This might end up being more expensive or difficult (e.g. you may have to take your pet to the vet every day for its medication), but it will be better for your pet and may even save you money in the long run by ensuring the infection is properly and completely treated the first time.
- Never stop treatment because your pet looks better. Often, signs of infection get better before the bacterium is completely eliminated. Stopping too soon allows the bacterium to regrow, potentially as a more resistant form.
- If you are supposed to take your pet to the vet for a recheck at the end of treatment, then do so. Sometimes longer courses of antibiotics may be needed, and it's much better to continue the current treatment course than to have to start again a couple weeks down the road when the infection has returned (sometimes with a vengeance).
- If in doubt about anything, call your veterinarian. He or she is there to help, and wants your pet to get the best treatment possible.
Antibiotic resistance is a major problem. Anyone that denies that is delusional. Anyone who thinks that antibiotic use in veterinary AND human medicine don't contribute to resistance are similarly clueless.
Most people do understand these basic facts. However, what people feel should be done about the problem is quite variable, ranging from doing nothing to proposing strict bans on antibiotic use. More legislators are proposing strong restrictions on antibiotic use in agriculture, but little gets mentioned about use in companion animals and humans. A broad approach looking at all sectors, involving all available evidence, and looking at the potential impact of restrictions is needed. Restrictions that have so may loopholes that they don't curtail overall use are not helpful, nor are restrictions that are so severe that they result in increased illness in animals (which could then require more antibiotics and/or public health risks because of more zoonotic infections). I certainly don't have the answers. A concerted, broad-based effort is needed.
In an era where we have major concerns about antibiotic resistant bacteria and scrutiny of antibiotic use in veterinary and human medicine, it's completely ludicrous that you can walk into a farm supply store or pet shop in Canada and buy huge quantities of antibiotics, or order pretty much any antibiotic you want over the internet. Politicians like to talk about antibiotic overuse and restricting drug use in animals, but fail to take the simple step of making NO antibiotics available without a prescription from a physician or veterinarian. That wouldn't solve all our problems, but would be a great start! One case from my time in private practice stands out - it was a steer (a castrated male cow) with a broken leg. The farmer noticed that the animal wasn't using the leg and tried treating it with penicillin for a few days, which didn't fix anything (surprise, surprise). This certainly isn't an uncommon event. Many people treat their animals (farm animals and pets) with antibiotics without any guidance, often for problems that are not bacterial infections, and sometimes using inadequate dosing regimens (which further increase the risk of microbial resistance).
Taking the simple step of removing free access to antibiotics is easy and needs to be done. Controlling internet purchases is more difficult. One veterinary pharmacy website proudly states "We also have a wide variety of human grade antibiotics, none of which require a prescription!" This site has a wide selection of antibiotics for sale. Most are labeled for fish tank use, but the site mentions the human product names, and it's very clear these products are not really being sold for fish. These pharmacies are harder to control, but many are clearly located in countries like Canada and the US, and are blatantly breaking existing regulations. Take a look at the picture above... this human pharmacy is offering free Viagra, a prescription drug, with every order of levofloxacin, another prescription drug... all without a prescription from a physician. This isn't a matter of needing rules. It's a matter of simply enforcing them.
Antibiotic resistance is a complicated problem and simple measures aren't going to fix everything. However, if we don't even take simple steps, how are we ever going to take the bigger steps required to address this issue?
As we see more and more infections caused by antibiotic-resistant bacteria, we have to re-think our approach towards antibiotic therapy. This often involves using new drugs, but sometimes it also involves considering the use of older drugs that we haven't used very much for a long time.
One such drug is chloramphenicol. Years ago, this antibiotic was widely used, and is still used in people and animals in some situations. In some respects, it is a very good antibiotic - it is often effect against many bacteria including those that are resistant to many other drugs, such as MRSA and MRSI/MRSP. Chloramphenicol can also be given orally, and it's relatively cheap. Unfortunately this drug can also be very toxic, both to the animals being treated with it and to people that come in contact with with it in the process. In some animals, chloramphenicol can cause suppression of the bone marrow, where red and white blood cells are produced. This is more of a concern with long term use, but if the bone marrow does become suppressed, stopping treatment with the chloramphenicol typically resolves the problem. Unfortunately, this bone marrow suppression is much more of a concern in people - the supression is very severe, and can occur with exposure to even a very low dose (or probably single dose) of chloramphenicol. This results in a condition known as aplastic anemia, which it typically fatal. Fortunately this reaction is very rare in people, but there is no way to predict who might develop this condition, and since it is usually fatal, we obviously need to be cautious about using this drug. In some countries, chloramphenicol use in banned in all animals. In many others, it cannot be used in food animals, but can be used in pets.
- Chloramphenicol should only be used as a drug of last resort. There are situations where it is useful and may be life-saving, but the human health risks cannot be overlooked.
- If chloramphenicol is being considered, it is critical that people who would need to handle the drug understand the risk and how to safely handle the drug to avoid exposure.
- Chloramphenicol tablets should not be crushed or otherwise processed at home because of the potential for breathing in the drug when it is in powder form.
Direct contact with pills or liquids should be avoided by use of gloves or other safe handling practices.
- If a liquid form is used and is squirted onto food, the food bowl should be handled as if it is contaminated.
- If pills are being used, the animal should be observed to ensure that the pill is ingested and not spit up and left on the floor.
- Contact with the mouth and face and animals that are being treated with chloramphenicol should be avoided in case drug residues are present.
If people are unable or unwilling to follow safe handling recommendations, they should not use this drug.
Methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant S. pseudintermedius (MRSP) are important causes of infection in pets, and are resistant to many different antibiotics. It's therefore very important that these bacteria are cultured and tested in a lab to determine what antibiotics may be effective. Even then, choosing an effective medication can be difficult due to the limited number of potentially effective drugs.
Treatment selection is further complicated by problems that can occur when methicillin-resistant staphylococci are tested against certain drugs in the lab - problems that are not readily apparent unless extra testing is done. One "problem" drug is the antibiotic clindamycin. Clindamycin can be an effective treatment for MRSA or MRSP infections, but some MRSA strains may be resistant to it despite appearing to be susceptible based on normal laboratory testing. This is because the bacteria can have "inducible resistance". Inducible resistance can be detected by a special test called a D-test (see picture), but this test is not widely performed in veterinary laboratories.
In recent study presented by Dr. Meredith Faires (University of Guelph) at a conference last week, 55% of MRSA from dogs and cats that were reported to be resistant to erythromycin and susceptible to clindamycin were actually inducibly resistant to clindamycin. But no MRSA that were susceptible to erythromycin were inducibly resistant to clindamycin. In contrast, inducible resistance to clindamycin was not identified in any MRSP. Therefore, in the absence of specific testing for inducible resistance (i.e. a D-test), it is wise to consider all erythromycin resistant MRSA to be clindamycin resistant as well, regardless of the results of traditional antibiotic susceptibilty testing.
Even though MRSA in pets probably originated from people, now that it is in the pet population, pets can spread it to other animals and back to people. It is unclear how frequently this occurs - most people are still more likely to encounter MRSA from another person than from an animal.
The emergence and spread of MRSA in humans was largely driven by extensive antibiotic use in people. Once MRSA crossed over to pets, antibiotic use in these animals almost certainly played a role in helping MRSA spread in the pet population. Antibiotic treatment has been identified as a risk factor for development of MRSA infection in dogs, and for MRSA carriage in horses.
Prudent antibiotic use is likely the most important factor in reducing the risk of MRSA in individual pets. Using antibiotics prudently means doing things like:
- Only using antibiotics when they're really necessary
- Using the most basic antibiotic possible (instead of the fanciest or most powerful antibiotic)
- Finishing every prescription completely and as directed)
- Do not encourage your vet to prescribe antibiotics when they are not necessary. Vets (and physicians) often feel pressure to prescribe 'something', even though they have no clear evidence of a bacterial infection. Antibiotics do not work for viral infections.
- Never give antibiotics to your pet without the direction of your vet.
- Always give the full antibiotic course, as prescribed. Do not stop early. Your pet may look better but the infection could still be there.
- Never save antibiotics for 'future use'. If your pet develops another infection, you need to have your pet evaluated by a vet to determine if antibiotics are needed, and what antibiotic would be best.