Guest post by Tim Fothergill, Ph.D.
In January of this year the British Chief Medical Officer urged her government to add threat posed by superbugs to the official list of "Apocalypses to Worry About" along with catastrophic terrorist attacks and massive flooding. With typical British understatement, its actual name is the National Risk Register of Civil Emergencies but a very stark picture was painted of a post-antibiotic world in which routine operations, such as hip replacements, could prove fatal. In September, The Centers for Disease Control in the US issued a similar statement which estimated that 23,000 people die every year in the US from antibiotic resistant infections. So what is it that has Dame Sally Davies and so many others so worried?
"Superbug" is a term used to describe bacteria which are resistant to many common antibiotics which are used to treat infection. Resistance to these drugs makes treatment more difficult and has increased mortality rates. As resistance to individual antibiotics becomes more prevalent the number of deaths is only set to increase, especially because there is a dearth of research into new antibiotics. Antibiotics are used medically in the short term, so don't offer the same kind of return on investment for the pharmaceutical companies as drugs for chronic diseases or long-term treatments, such as anti-depressants or hypertension medications. Even more worryingly of all is that strains of potentially deadly infectious bacteria, such tuberculosis have already been identified that are resistant to every potential drug.
Against this background the FDA's announcement of a plan to phase out the agricultural use of antibiotics is very welcome. Many animals raised for human production are fed antibiotics as a matter of course to boost growth rates. The animals are not suffering from infection, but the drugs can help them grow faster, resulting in a more efficient production of meat for the market. For most drugs, there is a mandatory withdrawal period during which the animals are fed no antibiotics so that they will clear out of the meat prior to slaughter. However, the antibiotics can impact the food supply and human health in other ways. Not only is there concern about meat contaminated with resistant bacteria but the standard agricultural practice of using animal waste as fertilizer only increases the risk of releasing resistant bacteria into the environment contributes to the spread of resistance. This is of particular concern if the land fertilized in this manner is subsequently used to grow food crops that are typically consumed raw. Previous recalls due to bacterial contamination have included spinach and cantaloupe melons. The potential for harm would only have been greater if these cases had involved superbugs, but this possibility is becoming more and more likely. Resistant bacteria that are spread onto crops via animal manure fertilizer have been demonstrated to not only persist in the soil but to also pass the genes for antibiotic resistance onto other species. As we have no control over this genetic transfer it is quite possible that they spread to even more pathogenic species.
The FDA's proposal to limit antibiotics in cattle feed would seem like good news then. However, the most significant caveat with this plan is that it is voluntary and as such is dependent on the cooperation of the drug producers and farmers. Two of the largest antibiotic producers, Zoetis and Elanco, have indicated that they will no longer labelling their products as suitable for growth promotion. Any subsequent use of these antibiotics for growth promotion would be "off-label" and something that the FDA can and does regulate. However, as with all regulation the devil will be in the details. We do not know yet what the change in labelling will actually say. If their new label can be interpreted in such a way that cattle are still regularly fed antibiotics then nothing will have been achieved.
For example, in Denmark they found that after introducing a ban on antibiotic use for growth promotion in cattle that the quantities of antibiotics actually increased. Animals no longer fed a sub-therapeutic level of antibiotic became more susceptible to infection and thus need therapeutic treatment more often. At first glance this might seem as if little has changed but antibiotics taken at therapeutic levels for the prescribed duration will result in fewer occurrences of resistance to the antibiotic in question. Anybody who has been told by their doctor to ensure that they take the full course for an infection will know this. By reserving antibiotic use for therapeutic use only, where it is needed in greater quantities to fight infections, not only will there be fewer superbugs released into the environment, but the drug companies will stand to increase their sales. This might explain their willingness to cooperate with these proposals. Their other option would be to switch production to antibiotics which are not regarded as being important for human health (such as the ionophores) as these are not covered by these new proposals. However, this is something that would presumably involve some cost to them.
It is also worth comparing the timescale for voluntary phase-out (three years) with the length of time it would take the FDA (presumably in collaboration with the USDA) to implement a strategy for an obligatory regulatory framework, which might have more teeth in terms of enforcement, but which is not yet on the table. The FDA has many admirable qualities but turning on a dime is not one of them. This process would take at least that long if not longer. What we do not know at this point is whether there are plans for the FDA to pursue such mandatory regulation if this voluntary arrangement is found not to be working. Such efforts would presumably require specific budgeting and it seems unlikely that this will happen any time soon given the current state of Congressional deliberations on budget matters. Another possible mandatory option would be Louise Slaughter's PAMTA bill which is currently with the Health Subcommittee.
If our goal is to reduce the spread of antibiotic resistant bacteria from agriculture then the FDA plan may in fact be the best option, and it is certainly better than doing nothing. Mandatory regulation seems unlikely at this point. However, accountability is still vital to the success of this voluntary agreement. What form could this accountability take? The FDA must be prepared to state publicly if insufficient progress is being made. Also, it is to be hoped that increased demand from major chains like Chipotle, McDonalds and KFC will help. If they were to make this demand then cattle production would change at a much faster pace than that proposed currently. This means that consumers are in a position to contribute by choosing to support suppliers of meat produced in a way consistent with these new guidelines.
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It didn't take three years to strengthen airport security after 9.11.
If there was an overt terrorist threat in the mix here, you can be sure the gov would crack down on agricultural antibiotics and start insisting on proper agricultural sanitation again.
Meanwhile I'm just about to finish a course of metronizadole for a nasty C.Diff infection; hopefully this will clear it, but the possibility that it may not is cause for serious worry.
"We're living in the times we warned you about years ago."
There certainly does seem to be something of a problem in terms of communicating just how serious this is. I suspect part of the problem is that there are very few people that still remember a time before antibiotics.
There are just so many issues that need to be addressed that I could write a huge number of blog posts. Perhaps I need to start up my own on just this subject.
It is not correct to state that antibiotic use overall went up in Denmark after the ban. The 2009 Danmap report does not include information on the amounts of antimicrobials used for growth promotion before the ban. Danmap does not include this information in any report after 2006. If you add in the amount of antibiotics used before the ban 105,000 kg in 1996 the last year reported before ban started in 1998 you find a significant drop even though there was an increase in therapeutic use. Also over half of the growth use was macrolides a critically important drug.
You're absolutely correct that 2009 report does not include numbers for growth promotion consumption (you can find them all here: http://www.danmap.org/Downloads/Reports.aspx). It certainly doesn't make sense to keep recording something after you've banned it and ascertained it isn't happening any more. However, there are previous records of growth promotion use though. These are all very nicely summarised in this figure (as a caveat I should say this is from an article by the Animal Health Institute who's conclusions I do not support but I believe the numbers used in the figure to be accurately copied from the reports):
If you look at the numbers for the last year of growth promotion use (1999), the total amount of antibiotics has indeed gone up quite significantly. The same could be said for 1998. Compared to previous years the total has not gone up so I suppose it depends what you want to use as your starting point. I think it's accurate to say that since the ban the totals have increased.
Also, I do think the figure amply shows the increase in therapeutic use though since the ban. This trend in the increase of antibiotic use has been consistent since the ban and I'm sure is one of the primary considerations of the major drug companies in this country when agreeing to these new FDA guidelines.
Apologies if my referencing wasn't extensive enough and that I didn't fully explore in the text the origin of all of this data. My aim was to inform rather than debate the sources.
Very nice article Tim. One concern is the statement "At first glance this might seem as if little has changed but antibiotics taken at therapeutic levels for the prescribed duration will result in fewer occurrences of resistance to the antibiotic in question." Are we absolutely sure about this? I have struggled to find good literature that convincingly demonstrates that this is true, particularly for the "superbugs" in question that spread their genes via plasmid transfer. If you have any relevant papers to support this please share!!
Very good question indeed. When I wrote that I was thinking of the standard medical advice about finishing a course of antibiotics, eg:
I'm not at all sure of the mechanism for preventing the occurrence of resistance though. Perhaps the antibiotics knock the population down to a size that your own immune system can handle, so you need to keep taking them until you've done so. If your immune system destroys bacteria carrying such plasmids and the drugs take care of the rest then I could see it working. That does of course presume that the proportion of the population already carrying these resistance genes is relatively small at the point of taking the antibiotics. If the majority of a bacterial population causing an infection are already resistant then that can only lead to trouble, as we're seeing.
I'm now going to be spending some considerable time searching pubmed, etc. for the basis of that medical advice. Thanks ;)
Thanks for this informative balanced approach. And thanks everyone else for the insightful comments. We're just putting the final touches on a new film that by all accounts does 'communicate just how serious this problem is'. not only in veterinary and agricultural practice, but in human medicine as well. We filmed all over the US, in Denmark and Canada. We even filmed some with this blog's very own Tara Smith. You can see a teaser and find out more about the film at resistancethefilm.com It would be great to connect at some point about getting you involved in a screening at some point.