In my last post, I summarized a few of the, to put it politely, bad outcomes of industrial animal agriculture ("factory farms"). This style of very intense animal husbandry is mainly feasible because of antibiotics1. But the current attempts to regulate antibiotic use have little to do with abuse of animals and everything to do with fears of disease in humans. In the previous post, I mentioned that there were "surprisingly few documented cases" of antibiotic-resistant bacteria being bred in livestock and then transferring to humans. I based this on my fairly limited memory of cases mentioned in Superbug by Maryn McKenna. I'd remembered being surprised when I read that book how few cases she gave.
I should have dug into this more. The reality is that there is much more evidence for it that I'd imagined, but that the evidence is complicated.
Why is it hard to answer?
The cases I'd remembered from Superbug were the (seemingly) straightforward cases where a human infection was found to be from a antibiotic-resistant bacteria and there was a simple causal link back to a farm where antibiotics were used and the animals carried the same strain. It's not actually simple or easy to prove these. The steps seem simple enough:
- Human is sick with an antibiotic-resistant bacterial infection.
- Human recently interacted with a source for the infection, such as eating contaminated meat or working on a farm.
- Animals on the farm are carrying the same strain as the human.
- The animals were treated with a related antibiotic.
But all of these steps are remarkably hard to prove in practical terms. All kinds of problems can crop up:
- How do you prove that the resistant bacteria X causing an infection didn't gain the resistance factors from normally harmless bacteria Y that the patient already had?
- You can't identify the source of the human infection clearly. This is especially difficult if you don't have full data. What if the infection is Salmonella but the patient hasn't eaten any obvious source (chicken)? The possible sources include every food item that might have been cross-contaminated. The FDA has become really good at this for food products not expected to have contamination (candy, vegetables, etc) but generally no one bothers to trace infectious agent origins unless a lot of people are affected.
- The source (such as meat) has to be traced back to the originated farm. This can be really hard. If you buy conventional ground beef in a grocery store, it could contain meat (and bacteria) from any of hundreds or thousands of animals from multiple farms, slaughtered at different times, etc.
- By the time you find the farm, maybe none of the animals living there were part of the population from which your source was taken, so the expected strain may not exist in the population any more.
These are cases where someone has traced a specific infection back to a zoonotic source.
- A major outbreak of Salmonella in 1985 was traced from human consumption of hamburgers, thru the meat-processing plants and eventually all the way back to dairy farms where the cattle were raised25 (dairy cows are often made into hamburger at end of productive life).
- A specific case of ceftriaxone-resistant Salmonella occurred in a child in Nebraska that was eventually traced back to cattle treated with antibiotics on his father's farm. Notably the strain was actually found to be resistant to a large number of antibiotics (not all used to treat Salmonella infections in humans, of course): "ampicillin, chloramphenicol, tetracycline, sulfisoxazole, kanamycin, and streptomycin as well as to broad-spectrum cephalosporins (e.g., cephalothin) and expanded-spectrum cephalosporins (e.g., ceftriaxone, which is used in humans, and ceftiofur, which is used in animals), aztreonam, cefoxitin, gentamicin, and tobramycin."6
- A comparison study7 was done with poultry workers at both battery and free-range style farms. The battery farms were fed antibiotics (as is typical). The workers were tested before and after for Escherichia coli, specifically looking for resistant varieties. The results showed that workers caring for birds being fed antibiotics quickly began to harbor resistant varities of E. coli in their stool, similar to the poultry.
These are some of the major direct cases that I've found (no doubt I've missed some!) The indirect evidence for particular organisms is much more substantial, indicating that zoonotic-origin antibiotic-resistant infections are probably relatively common, but proving it for particular cases is much harder.
Several Campylobacter spp. cause a significant proportion of gastroenteritis cases in the United States (otherwise known as "food poisoning"). It is not usually treated with antibiotics because for most individuals it doesn't greatly improve recovery speed. Chickens are treated with quinolone antibiotics to prevent infections and quinolone-resistant strains of Campylobacter have been found in chickens, chicken products, and human beings289. Significantly, a Danish study10 demonstrated that domestically acquired infections were significantly less likely to be quinolone-resistant strains: quinolones are rarely used on chickens in Denmark.
Salmonella of the food-poisoning variety is usually acquired from food: undercooked meat or eggs or food that has been cross-contaminated (though you can also catch it from wild and pet reptiles such as turtles!) There are numerous strains of it and they are frequently the subject of recalls due to major outbreaks. There have been several cases where a particular strain is more prevalent in animals and human infections are linked to animal reservoirs11. Antibiotic-resistant Salmonella has been found in ground meat12.
A US federal government program (NARMS) monitors Salmonella cases and tests for resistance on a proportion, allowing us to know over time which strains exist and which are resistant. Swartz2 summarizes this confusing data. The results are mixed: some strains look to be gaining resistance and affecting humans, other perhaps not. Resistant strains of Salmonella may even be associated with more frequent bloodstream infections and hospitalizations13.
Vancomycin-Resistant Enterococcus (VRE) are often acquired in the hospital and are nearly untreatable. There is some evidence that a similar antibiotic (avoparcin) used in animals creates a reservoir for continued VRE infections in humans, at least in Europe which decreased when avoparcin use decreased (summarized in Swartz2 and Smith14). The evidence here is fairly confusing to me, but certainly worrisome.
Convincing? Should we worry?
Considering I'm a dilettante just poking around PubMed and other sources, this is not exactly a complete review of the literature. Previous to looking into this a bit more, I had a vague notion that treating animals with antibiotics (subtherapeutically in most cases) definitely led to resistant infections in humans. After looking the literature, I'm well convinced that it does indeed happen. But like all things in science, it's more complicated. For example, for Salmonella it may only be happening for some strains and not others. Why is that? Is it a risk for humans? Moreover, transfer of resistance genes between bacteria is really hard to demonstrate in practice, which is one of the major fears I've read about.
Still, what would happen if we greatly decreased (or even banned) subtherapeutic — prophylactic and growth-enhancing — uses of antibiotics on animals? The main outcome seems that we would be able to raise fewer animals, but in better conditions generally, and meat and dairy would become a bit more expensive. Lipsitch3 and Smith15 argue that perhaps there would be little medical impact from restricting antibiotics in animals in cases where there are already resistant-bacteria in humans — the horse has left the barn. In any case, the research supports reducing many uses of antibiotics in animals to mitigate demonstrable effects in human beings.
A follow-on post to this one may cover some links to some random studies I found interesting or curious when looking into this issue. Spelunking through science articles is fun though sometimes disturbing.
- Tellingly, though, it's possible to create inhumane conditions for animals even without antibiotics. Some "organic", "free range" chicken eggs are from hens raised in batteries just like "conventional" operations. But due to the conditions and the fact that antibiotics can't be given, the facility must be kept nearly sterile. ↩
- Swartz, M. 2002. Human diseases caused by foodborne pathogens of animal origin. Clin. Infect. Dis. 34:S111-S122. ↩
- Lipsitch M, Singer RS, and Levin BR. 2002. Antibiotics in agriculture: when is it time to close the barn door? Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):5752-4. ↩
- ML Cohen and RV Tauxe. 1986. Drug-resistant Salmonella in the United States: an epidemiologic perspective. Science 21 November 1986: Vol. 234 no. 4779 pp. 964-969. ↩
- Spika JS, et. al. 1987. Chloramphenicol-resistant Salmonella newport traced through hamburger to dairy farms. N Engl J Med 1987; 316:565-570. I sadly wasn't able to actually go read this article as it's not accessible to me, so I'm going off the references to it in other literature and the abstract. ↩
- Fey PD, Safranek TJ, et. al. 2000. Ceftriaxone-resistant salmonella infection acquired by a child from cattle. N Engl J Med. 2000 Apr 27;342(17):1242-9. ↩
- Ojeniyi AA. 1989. Direct transmission of Escherichia coli from poultry to humans. Epidemiol Infect. 1989 Dec;103(3):513-22. ↩
- Smith KE, et. al. 1999. Quinolone-resistant Campylobacter jejuni infections in Minnesota, 1992-1998. N Engl J Med. 1999 May 20;340(20):1581-2. ↩
- Zhao S, et. al. 2010. Antimicrobial resistance of Campylobacter isolates from retail meat in the United States between 2002 and 2007. Appl Environ Microbiol. 2010 Dec;76(24):7949-56. ↩
- Engberg J, et. al. 2004. Quinolone-resistant Campylobacter Infections in Denmark: Risk Factors and Clinical Consequences. Emerg Infect Dis. 2004 Jun;10(6):1056-63. ↩
- Akkina JE, et al. 1999. Epidemiologic aspects, control, and importance of multiple-drug resistant Salmonella Typhimurium DT104 in the United States. J Am Vet Med Assoc 1999; 214:790–8. ↩
- White DG, et. al. 2001. The isolation of antibiotic-resistant salmonella from retail ground meats. N Engl J Med. 2001 Oct 18;345(16):1147-54. ↩
- Varma JK, et. al. 2005. Antimicrobial-resistant nontyphoidal Salmonella is associated with excess bloodstream infections and hospitalizations. J Infect Dis. 2005 Feb 15;191(4):554-61. ↩
- Smith DL, Dushoff J, and Morris JG. 2005. Agricultural antibiotics and human health. PLoS Med. 2005 Aug;2(8):e232. ↩
- Smith DL, et. al. 2002. Animal antibiotic use has an early but important impact on the emergence of antibiotic resistance in human commensal bacteria. Proc Natl Acad Sci U S A. 2002 Apr 30;99(9):6434-9. ↩