Swan song for antibiotics? Can phage therapy and gene editing fill the gap?

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It’s time to face the music: the golden age of antibiotics is over.

Humans have been in an endless war against bacteria — indeed it can kill us — and for decades antibiotics have been our only real weapon against them. They revolutionized medicine in the 20th century, and have together with vaccination led to the near eradication of many diseases in the developed world.

But despite their amazing success, and they’ve had a miracle like run, drug resistant superbugs like MRSA, CRE and VRE are slowly winning. Every year more and more people die from drug resistant infections as we inch closer back to the pre-penicillin days. Their effectiveness and easy access led to overuse, especially in live-stock raising, prompting bacteria to develop resistance. This led the World Health Organization last year to classify antimicrobial resistance as a “serious threat [that] is no longer a prediction for the future, it is happening right now in every region of the world and has the potential to affect anyone, of any age, in any country”

There is a lot of blame to be shared for this reversal: doctors prescribing antimicrobials for the common cold, patients demanding the drugs for the flu, governments de-incentivizing the development of new antibiotics and pharmaceutical companies deeming unprofitable.

Regardless of who might be blamed, this current situation was bound to happen; our haphazard behavior simply hastened the arrival of this day. Whenever the goal is to kill a living organism resistance is inevitable. It’s how nature works: natural selection. In this case an antibiotic kills off all susceptible bacteria, but a hardy few resistant to the drug because of random mutations survive, and eventually thrive. On the verge of wiping out a problem, it roars back even worse than how it started.

This is how all life responds to stressors. We adapt. It shows up in the plant world as well. Look at the firestorm debate over herbicide resistant weeds in agriculture. Whether a farmer uses organic approved herbicides, conventionally bred ones (such as conventionally bred sunflower crops) or crops genetically engineered to resist glyphosate, mutant weeds survive and adapt and supersedes develop. It’s the law of nature. Yes, we can change up herbicides or create new ones, but the process then begins again. That’s true about antibiotics as well. So even if we create a new class of antibiotics, resistance will eventually follow, no matter how responsible we are with using it.

In this light, it’s clear that terms like “superbugs” and “superweeds” are misnomers because these organisms aren’t special in any way, they are simply doing exactly what nature intends them to do.

What compounds the challenge for antibiotics is that bacteria appear to be able to evolve resistance faster than any other type of organism. Conjugation (bacterial sex) allows bacteria to share resistance genes with not only members of their species, but across species and even across bacterial type (i.e. gram positive to gram negative). This is called horizontal gene transfer and allows advantageous traits to be spread among members of the current generation, instead of in future generations. Furthermore, some evidence suggests that bacteria can also sense when their back is against the wall and mutate their genome at faster rates in a last ditch effort for one of their descendants to mutate enough to develop resistance to the antibiotic.

But Darwin aside, it’s in our best interest to move beyond the era of antibiotics. Using antibiotics to treat an infection is like using a sledge hammer to pound in a nail. Sure the nail will get pounded in but there’s also going to be a large hole in your wall. Even the most narrow spectrum of antibiotics drastically affect our normal flora in ways that can have far reaching consequences on our physiology.

Phage therapy

What we need in our war against microbes are biocidal agents that are effective but also have more species specificity. One strategy in the works involves turning to the natural enemy of the bacteria, the virus for help. In other words the enemy of my enemy is my friend.

Viruses don’t just infect humans, in fact every species on the planet has numerous species of virus that can infect them. When a virus infects a bacteria, scientists have a special name for them: bacteriophage, or just phage. In bacteria, as they do in humans, viruses work by gaining access to the interior of a cell and manipulating the host’s cell machinery (i.e. enzymes, ribosomes etc) into making more copies of the virus. At a certain point, the number of copies of a virus induces the cell to burst releasing sometimes thousands of new copies of the virus, which can then go on to infect another cell and the process repeats.

Corrupting this process to fit human needs in the fight against antibiotics has actually been going on since the early days of the cold war. While the U.S. was investing in antibiotics, the Soviets were developing what is now called phage therapy. In fact in places like the country of Georgia, Russia and Poland phage therapy is still widely used today to treat infections.

One of the major benefits of phage therapy over traditional antibiotics is the specificity a phage has for its host. For the most part, a phage that infects an E. coli will not be able to infect another bacteria type, like a commensal Staphylococcus. There is even some evidence that phages are strain specific meaning we can develop phages that can differentially infect pathogenic strains of E. coli (i.e. E. coli O157:H7) while leaving the healthy commensal E.coli strains alone.

Another advantage of phage therapy is that it is self-repleting. A single phage infecting a cell will produce thousands of new copies of itself that can go on to kill more bacteria. However, some point to the mechanism in which viruses kill cell, by bursting it open, presents a drawback to the treatment as it will release bacterial toxins which can lead to sepsis, a potentially deadly condition in which the immune system overreacts to dieing bacteria.

But researchers are already working up a solution to this problem. At MIT, they have developed “phagemids”: engineered phages that carry plasmids instead of a whole genome. Plasmids are short piece of circular DNA that carry a couple of genes which often code for virulence factors and/or for antibiotic resistance factors. When bacteria undergo conjugation this is generally what they share to pass around resistance genes. In a phagemid, the plasmid is encoded with genes that kill the bacteria without the cell being lysed. No lysis means those internal toxins aren’t released into the body. These scientists have already had a high degree of success treating mice for peritonitis.

CRISPR-Cas9

Gene editing using CRISPR-Cas9 (clustered repeating interspaced short palindromic repeats) could be used to fighting bacteria. If bacteria successfully fights off infection from a phage, they save a short portion of the viruses genome in the genome. The bacteria expresses these sequences as short RNA sequences that are complementary to parts of the phage’s genome. If the bacteria becomes reinfected with the same phage, the RNA sequence binds complementary to that portion of the phages genome. Inside the cell, these RNA sequences are associated with a DNA cutting protein called Cas9, which cleave the phage genome, rendering it ineffective.

The trick with CRISPR-Cas9 is that RNA sequence can be made to be complementary to anything including bacterial resistance genes. For example, a group at Tel Aviv University has created a CRISPR-Cas9 system to target the Beta lactamase gene. This gene produces an enzyme that inactivates a wide variety of antibiotics including penicillins, cephamycins, and carbapenems. Other groups have seen excellent success targeting the genes that turn Staphylococcus aureus into MRSA.

The CRISPR sequence and the Cas9 protein will be delivered to bacteria via an engineered phage and the technique is successful at targeting both chromosomal genes and plasmid based ones. Currently, much of the research on this technique has been to re-sensitize bacteria to common antibiotics, but it is not out of the realm of possibility that CRISPR-Cas9 could be engineered to target essential bacterial genes, thus making the technique bactericidal.

The use of phages, phagemids and CRISPR-Cas9 present to us a more sophisticated and targeted way to treat infections from bacteria. However, in no way should this be thought of as a magic bullet; that’s the kind of thinking that got us into trouble with antibiotics. Resistance to these techniques will happen. It is inevitable that these organisms will adapt.

Resistance to CRISPR-Cas9 in phages has already been documented in some species, so it is possible bacteria could evolve resistance to them too. Bacteria will also develop CRISPR-Cas9 systems to create a memory of the engineered phages we will use in phage therapy. But these are not reasons to abandon this technology. These should serve as a blueprint for what we should be prepared for when the day comes that resistance to our initial phage therapy options is observed. In essence, we now have the enemy’s battle plans for how they will react to our newest defense. We need to use that information to have our counter attacks waiting in the wings.

One way though to maximize the time until resistance is observed is to develop multiple phages that are distinct genetically (i.e. create multiple phage strains with distinct targets) and then use a cocktail of phages in the treatment given to patients. The odds of a bacteria developing resistance to one phage are good but the odds of a bacteria developing simultaneous resistance to multiple phage strains during the course of one infection are infinitesimally small. And if this were to happen, then even I’d be ok with using the term “superbug”.

Nicholas Staropoli is the associate director of GLP and director of the Epigenetics Literacy Project. He has an M.A. in biology from DePaul University and a B.S. in biomedical sciences from Marist College. Follow him on twitter @NickfrmBoston.

  • ines trabelsia

    Are US vaccine rates going down because public trust and social ties are eroding?

    The state already controls vast swathes of what we can do with our lives: What professions we may enter, how and where we may conduct business, what substances we cannot ingest, how much of the money we earn we are allowed to keep… If you do not believe that individuals have the right to control what goes into their own bodies then I have to wonder what rights – if any – you do believe people still have.

    Read Full Article here:

    http://publictabs.com/tabs/are-us-vaccine-rates-going-down-because-public-trust-and-social-ties-are-eroding/

  • SameDarnLunch

    nice piece. however, seems to me that there are some important unanswered questions about phage therapy in particular. in the current pharmaceutical landscape, there are some non-trivial barriers for the development of phage therapy (http://www.ncbi.nlm.nih.gov/pubmed/24228220). Then, based on the public’s reaction to GM crops, I am skeptical that their response to CRISPR/Cas gene drives will be at all positive. not that phage therapy doesn’t deserve more research (it definitely does). I am just not quite willing to give up on antibiotics yet–people say that we have mined soil bacteria for all the effective antibiotics they produce, but the discovery of teixobactin a little while back (http://www.ncbi.nlm.nih.gov/pubmed/26089440) suggests that previously un-culturable soil bacteria (that can now be cultured using technology such as the iChip) may produce effective new antibiotics ripe for discovery. Resistance will develop to any new drug we throw out there, yes, but that doesn’t have to occur overnight. From when we started using Vancomycin, It took 30 years for resistance to Vancomycin to show up in human pathogens, after all (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC358160/). If we develop diagnostic technologies to inform proper use of antibiotics and make them widely available, antibiotics may remain effective much longer.

    • Nick Staropoli

      Remember, its not just about resistance with antibiotics. The elimination of the microflora is a keep step in the development infections such as C. diff. phages offer an opportunity, if they hold to their promise, to selectively kill just the bacterium causing the infection w/o harming normal flora. I certainly agree w your worries about how the public would react to all this. But we got the public to take botulism toxin shots to the face so maybe we can convince them to take a phage for their ear infection.

  • Bill Riedel

    Two points I would like to make:
    All of these technologies will be needed to fight antimicrobial resistance, and that includes antibiotics. And second, most papers on phage therapy forget to mention that phage therapy can be used in most countries right now after “approved” medicines fail as there are international and national compassionate use provisions – withholding phage therapy from patients when antimicrobial treatments fail seems like cruel and unusual punishment and it seems to me that every infection control specialist knows or ought to know about phage therapy as the science is over 100 years old…

  • Farmer with a Dell

    Hey, c’mon, let’s not be so hasty in our put-down of antibiotics here. They’re still an important tool in managing bacterial infections and no reason to proclaim the end to their usefulness. It’s also a little disingenuous, Nick, to throw antibiotics under the bus in order to hype phage therapy (that’s a tactic of organic food hucksters, trash talking a competitor to make their common schlock look special by comparison). I mean, phage therapy can easily stand and be promoted on it’s own merits and remarkable benefits. And phage therapy could also be complementary to antibiotic therapy; they’re not in competition. We’re all looking forward to actually seeing what phage therapy and CRISPR can do for us.

    And one other small nitpick — antibiotics are not and never have been “our only real weapon against [bacteria]”. Hygiene and disinfectants are our first line of defense. Always have been, always will be. This is too frequently overlooked (and actually prohibited in some cases with organic food production) and that’s how so many food recalls and outbreaks of food poisoning occur.

    Not dissing or calling you out, Nick. Just a couple of background points. Otherwise a great piece explaining an exciting new set of medical therapies.

    • Nicholas Staropoli

      Haha. Always love to hear criticisms and I don’t mean to throw antibiotics under the bus. They have been amazing for us no doubt!

      In terms of your second point, sanitation and hygiene are important but hygiene isn’t going to stop a MRSA infection thats already eating away at your skin. Antibiotics are our only weapon once an infection has already started is what I meant. But yes in preventing the spread from person to person and the initiation of an infection, hygiene and disinfectants are vital and have save probably millions of lives.

      To be honest I would love to see other methods be developed for treatment of infections in humans and have antibiotics be used exclusively in agriculture for animal growth enhancement or disease treatment.

      • Farmer with a Dell

        I hear ya. MRSA infections are serious business. In a hospital setting they’re difficult to keep from spreading and almost impossible to eradicate. Unfortunately it seems like even hospital staff have to live through an episode in order to take precautions seriously. Then there’s antibiotic resistant TB and STDs. I’d say we need to add public health measures to our short list of “superbug” management.

  • Peter Olins

    While it seems plausible that the widespread use of antibiotics in animal husbandry may have contributed to drug resistance in human infections, how strong is the evidence that this has actually been significant contributor?

    Good article, though, Nick.

    • Nicholas Staropoli

      It is certainly something that is highly debated. Heard intelligent arguments on both sides.

      • Roy Williams

        Nick, I’ve written some software for an ongoing research project (that is part of a loosely coupled international effort at many research institutions) to develop the capability to computationally determine protein activity. The “holy grail” (one of them, at least) is to be able to specify to a computer program protein (or maybe small molecule) to which you want a new, never-before-made protein to bind. The goal is to have the software reliably give you a DNA sequence that will generate the protein. As you noted in your essay, no matter what approach we take to kill bacteria (or weeds, or insects), resistance will appear. If we achieve the “holy grail” of protein design efforts, we in principle could stay ahead of the curve (so to speak), by being able to predict likely mutations, and design, in advance, proteins that counteract them. You can then dream up all sorts of ways to exploit that sort of capability; one might be creating proteins that “confuse” the bacteria by binding to specific surface receptors on the bacterium, causing it to behave while outside a host cell as through it were inside the host cell. For some pathogens, that would be a lethal mistake…lots of possibilities. Obviously computer-designed proteins would be a huge success for pesticides that could be delivered by a virus. Viruses are pretty simple, and they are usually happy even if you change their coat proteins – so conceivably you could re-design a virus “on demand” as the target plant/insect mutated.
        Right now, this all seems a little far into the future, but one significant breakthrough in deciphering the molecular mechanics behind why a protein (nearly) always folds up in exactly the same way every time would unleash a whole new era in agriculture and medicine.

    • Farmer with a Dell

      In livestock we have always been acutely aware of antibiotic resistance. We’ve learned to manage it fairly successfully.

      There are a lot of bacterial infections that can move from animal to man (zoonoses, they’re called) and it is rather astonishing, really, that there haven’t been more documented cases of antibiotic resistant “superbugs” leaping from animal to man – I think there is maybe one documented case in a hog farmer from his own hogs. That said, it isn’t implausible to culture antibiotic resistant bacteria from dairy foods or meats. Certainly some of these must have been typed and implicated in human infections, but documentation of these events is also remarkably scarce. So, not trying to beg off responsibility of agriculture here, but merely remarking the state of affairs is not and never has been anything approaching a crisis, not even credible threat of epidemic.

      Likewise, the odious activist fanfare surrounding antibiotics fed as growth promoters is overblown. Very little medically significant antibiotic is used in that fashion any more, although several antibiotics have traditionally been labeled for that application. We long ago learned to avoid lacing feed or water with antibiotics in order to manage resistance Only a novice or a quack would routinely resort to it. Some ionophores, which are not medically significant antibiotics, but which technically are classified and tallied as “antibiotics” are fed, primarily in some classes of poultry to control gastrointestinal parasites. With improved livestock environments even the use of ionophores has become more targeted and effective during the last decade, or so.

      That being said, if you want to contract a good hot infection with an antibiotic superbug, there are two likely venues. One significant “superbug” outbreak occurred a few years ago in India (sorry, I don’t have the ref right at my fingertips at the moment, can pull it later if you wish). There are also increasing reports of “superbug” variants of human TB and STDs. So travel, mingle and maybe you’ll get lucky. The other place to pick up a lively infection is in most any hospital. This is where virtually all of the documented “superbug” infections have been recorded and even TV documentaries have featured these (nosocomial infection is the technical terminology). By far the most common human bacterial “superbug” infections derive from human bugs that have been “supersized” by contact with popular antibiotics prescribed by your doctor, dentist or pediatrician. No need for these “superbugs” also to leap across species — born and bred in Homo sapiens. That’s the key reservoir.

      To be fair, this column about phage therapy is probably neither the place nor time to litigate the complex pharmacology and epidemiology of antibiotic resistance.

      • Peter Olins

        Excellent overview, FWAD. Your comments confirmed my overall impression that animal use of antibiotics is not a major issue for people concerned about human infections, and that hospitals are the primary source of drug-resistant infections in the U.S.

        I also note that “antibiotic-free” appears to be a common marketing feature of “natural” and “organic” meats.

        As you point out, this discussion is somewhat off-topic.

      • Bruce__H

        A good question from Peter Olins and a good response from you Farmer!

        I think I am hearing you say that the antibiotics used in agriculture tend to be different from those with medical uses. Did I get that right? If it is true, is it just by happenstance or is it a policy?

        • Farmer with a Dell

          A little bit of policy and a lot of practicality makes it so (“happenstance” unfortunately seems to be a popular stereotype of how farmers operate, and it is a myth). In fact, many of the same modern antibiotics are used in agriculture and in human medicine – several have recently been reserved exclusively for human applications. However, in practice most of those antibiotics used to treat disease in pets and livestock are not the same drugs most popularly prescribed by your doctor, dentist or pediatrician. In agriculture we require pharmacological properties (such as broad spectrum of action or rapid and complete clearance from organs and tissues) that do not correspond to human medical priorities and we are constrained in agriculture by cost-benefit considerations that are seemingly unimportant to practitioners in our modern health care and insurance system. So, we all end up selecting different styles of hammers to drive various types of nails. In the case of ionophores, which are most often blended into feed, those are pretty much unique to agriculture (largely targeting protozoa instead of bacteria), with not much potential to invoke multiple drug resistance to antibiotics used to treat bacterial infections. You see, there is complexity enough to provide cover for all nature of crusading zealots to cherrypick and distort reality…to suit any agenda. I just farm.

          In treating pets and livestock we most often are dealing with bacterial infections uniquely adapted to the species, even to the organ system. Few of these bacteria routinely jump across species to sponsor widespread infections. Bacteria do display remarkable ability to develop specific resistances to antibiotics and some of them are adept at passing that developed trait on to other bacteria. When taken out of context this property of bacteria seems terrifying, the stuff of science fiction movies (and ideal for scare mongering to advance a political agenda). Fact is, bacteria have always possessed these skills, it’s part of how they make their living. We’ve managed it pretty successfully in a practical sense. Yes, there is the fantastic possibility of some maniacal farmer systematically abusing antibiotics to successfully create an evil “superbug” in goats (or name your preferred species) which, in turn would coincidentally be enhanced by some unforeseen or rare set of amplifying anomalies, resulting in the monster bacteria that ate Los Angeles. Somewhat more likely is your pediatrician prescribing the same one-size-fits-all antibiotic therapy to 50 local kids with ear infections, most of whose mothers discontinue the dosage too soon because the damned kids get feeling well enough to cry and make a fuss over taking the medicine. Before long the pediatrician is seeing 250 kids with ear infections and none of ’em seem to get much relief from the same old boiler plate prescription (and now we have angry mommies and we desperately need a scapegoat). Most likely is the absolute indiscriminate use and haphazard disposal of antibiotics that prevails in places like India. God only knows what goes on over there, but they managed to cook up a true “superbug” with no difficulty at all. And that wasn’t just “happenstance” either, but probably a studied combination of chaos, ignorance, sloth, corruption and restrictive cost-benefit considerations that you and I cannot even begin to imagine.

          So, Brian, that’s my first-hand overview from out here in the field and I don’t intend to be drawn into nitpicking arguments about MRSA or R-plasmids or any of the rest of it with anti-agriculture zealots. I’m determined to leave it in the capable hands of credible pharmacologists, medical microbiologists and epidemiologists. All the rest, the poetry professors, the bus drivers, the kindergarten teachers, the travel agents, the retired car salespeople are all welcome to frighten themselves to their little hearts’ content with misinformation. I regret all that makes them distrust and fear me and my fellow farmers. I resent all that makes anti-agriculture activist cranks determined to destroy my livelihood as a successful modern farmer. Hate is contagious and I worry I may be catching it. Worse, I fear hate has a developed resistance to reason. There may be no cure.

          • Bruce__H

            I’m interested in the antibiotics that have recently been reserved for human use. Do you know where I can find out more about that? I am wondering what the justification is for this step, how they choose which antibiotics to restrict, and which authority actually establishes the regulations and enforces them.

            I expect that as a farmer what you do is act as you think best while staying inside the regulations. That seems rational to me. I am wondering, however, what the regulations should be. Creating a break between human and agricultural antibiotics seems like a good idea.

          • Farmer with a Dell

            I can only speak from experience here in the USA. Here our FDA determines which drugs are labeled for veterinary use, thus restricting which antibiotics are actually used and specifically how they are used to treat pets and farm animals, right down to formulation and routes of administration, permitted dosages and required withdrawal times. These laws are specific, they are clearly printed on the label of every vial of medication, they are enforced and very, very few livestock growers have any interest in circumventing them. There is and can be no confusion about any of this.

            The tendency of FDA is to intensify restricted use and to intensify requirements for professional oversight of use by veterinarians. For the most part these restrictions have been tolerable and some have even been helpful, I think, in legislating more responsible use of medications. FDA is, of course, more recently under intense pressure from politically motivated activist organizations to act and, so, FDA’s actions are increasingly more in the spirit of appeasing this pressure than in assuring the humane, safe and effective delivery of needed medications to livestock.

            Anyway, bottom line is if FDA doesn’t approve a narrowly specified usage, then pets & livestock will effectively be excluded, in effect “reserving” that for human medical use. Thus there are so-called “drugs of last resort” spoken of in the medical community; vancomycin, some cousins of the cephalosporins come to mind but I’m not aware of the full extent of my physician’s arsenal of antibiotic formulations and routes of administration. I’m familiar with livestock products we have available to us here, but to be honest we use very little medication (thankfully and credited to our skilled caretakers and to our heavy capital investment in modern livestock environments – buildings & equipment – that cater to animal safety, convenience and comfort). I honestly don’t know where you could find an accurate and concise side-by-side listing of antibiotic usages approved for medical use alongside the same for veterinary use, sorry, it’s not anything I’ve needed to concern myself with or it would be on a hard drive somewhere here in the farm office; it’s not.

            Good luck, Bruce. The immediate difficulty you will encounter in researching this area will be accessing accurate and timely information. I would guess 99.999% of what you’ll find published on the ol’ interwebs is biased. Probably 66.666% of that is complete rubbish. I am annoyed to have to report about 75% of what FDA, itself, publishes is redundant rambling sophomoric drivel from which no solid conclusions can be drawn. You will read a lot of speculative subjective and hypothetical opinions from people not remotely qualified to opine and you will be dazzled and attracted by the awe inspiring hyperbole, some of which is truly spectacular, a work of sheer propaganda genius. My heart goes out to the handful of credentialed medical microbiologists, pharmacologists and epidemiologists who are doing real science in this field. They are being drowned in the towering depth of politicized collateral horseshit, and that is scandalous in my opinion.

            As for “creating a break between human and agricultural antibiotics”, if you succeed in digging down to the complicated truth of the matter (and the pertinent pharmacology, medical microbiology and epidemiology of the thing is truly fascinating) you will understand how futile it is to try to attempt a practical sorting out of the type you suggest. The question inevitably distills to whether or not agriculture should be deprived of access to antibiotics altogether (and therein you find the brass ring sought by anti-ag hate groups). All I know, as a successful stockman of long standing, is although we actually use relatively few antibiotics in our more modern livestock operations, but just like having a bunch of kids mingling in school some of our livestock occasionally becomes ill. On those relatively rare occasions it is cruel and inhumane to deprive pets and farm animals of effective modern medical care. Anti-ag cranks simply love to slander us farmers, hatefully claiming we care nothing for our animals, charging that we abuse them, accusing us of creating dangerous and unhealthy surroundings for them so that they are constantly sick and dying without feeding them antibiotics — nothing could possibly be farther from the truth — but these same lying activist bastards who feign concern for animal welfare are, in fact, hellbent upon depriving your pets and my livestock from humane health care, preventive and therapeutic, when they occasionally require it. I would quit livestock farming before I will let that happen. In the meantime I can find no opening for rational informed debate on the topic of antibiotics in agriculture, and that is very sad indeed. With that, i wonder if we’ve derailed Nick’s post sufficiently with all this?

          • Bruce__H

            I had thought (no doubt naively) that the majority of agricultural antibiotic use was nontherapeutic. Is this so?

          • Farmer with a Dell

            OK, final run at this Bruce, if you don’t mind (or if you do). I just get this creeping feeling with your vague open-ended questions you’re paying out rope, hoping I will blunder and create an opening for a troll attack – please don’t take it personally, you just ought to understand how you’re coming across in this monologue, is all).

            No real hope of sorting all this so you can digest it in a few soundbites, sorry. That’s been the problem with populist angst over antibiotics — too many self styled woo experts repeating too much mythology and ginning up too much panic. The science is complex, even for PhDs in medicine and agriculture. Anyone else can only thrash away at oversimplified opinions and gross misinterpretations. For these people, on this issue, a little bit of factual knowledge is a dangerous thing – just like handing a loaded handgun to a chimpanzee. Appalling to watch, even from a safe distance. Activist chimps, of course, relish the opportunity to wreak havoc.

            Anyway, here goes: Tough to know for sure what you’re fishing for here, Bruce, but virtually all antibiotic used in agriculture serves a “therapeutic” purpose. We have no interest and no budget for maliciously dumping unnecessary antibiotics or anything else, for that matter, into our farm operations. Charges to the contrary are simply wrong and malicious. True, much of what are classified as “antibiotics” are administered proactively to maintain disease incidence at low levels, instead of waiting for full-blown epidemics to break out and reacting with too little too late at the expense of animal welfare. We prefer disease prevention and control supportive of humane animal husbandry. We contend that is the most responsible use of the technology.

            I’d say out here in the field “antibiotic” use breaks out something like this:

            Ionophores are mostly preventive these days. We see some production response by reducing intestinal parasite loads in all species and also by reducing methane production in ruminants. Ionophores are “antibiotics” by technical classification but are an entirely different biochemistry from any human antibiotics you and your physician might recognize. They are fed to livestock and dosage rates are substantial — because they have to be, they are not effective in an injectable form. They work in the gut against intestinal parasites. The ionophores probably get the most routine use and probably account for the greater portion of “antibiotics” used in American agriculture these days – just my observation, no relevant surveys to back it up, sorry. So anyway, we make use of ionophore “antibiotics” to optimize animal health and, coincidentally to reduce methane emissions and reduce our impact on global warming. So what happens? Well, you do something nice and assholes shit all over you for it. That’s modern agriculture.

            All the other drugs, those antibiotics you’d recognize corresponding to those used in humans, are used therapeutically against diagnosed disease, some preventive. Not much of any used (or “abused”) as the evil “growth promoters” every angry mommy blogger is hysterically prolapsing a rectum over. FDA is making that old fashioned labeling pretty much disappear anyway, and because we seldom see medically significant antibiotics used that way out here any more the FDA ruling is more a sop to public sentiment than any sort of sea change in the farming biz. It’s a big boring non-issue for us. Nobody in modern commercial agriculture who possesses two warm brain cells to rub together has fed old fashioned ‘growth promotion’ antibiotics in the past 10 years, maybe 20 or longer. But still people are bitching about it as if that’s all we ever do out here. That’s how far behind the 8 ball activists are (doubt that? – look up the EWG farm subsidy database and see how long ago most of those evil “farm subsidies” they continually still bitch about were last paid out and when most of that stopped happening). It’s much ado about ancient history, much like re-litigating slavery.

            But I digress…back to this “antibiotics” hysteria. Maybe a practical recent example will help:
            I’m sure Frank Perdue didn’t have to change much of anything to create his premium priced “antibiotic free” chicken. Like everyone else who intends to keep farming into the future (including hogs, beef & dairy) he has been building and remodeling livestock housing to keep pace with healthy productive state-of-the-art animal environments. These days the only “antibiotics” Frank used was likely one ionophore to manage subcliical coccidiosis (a common protozoal parasite of young birds), and probably only sporadically, at that. If he quit the ionophore in broiler production it’s not terribly inhumane; birds are a little less healthy with larger parasite loads, but few die and overall growth rate is reduced maybe only 1 – 3 % on average. Finished birds will now show a bit more variability in size and muscling detectable to the trained eye, but you and other consumers would never know the difference. So Frank eats, say, a 2% hit to production, he demands a 30 – 40% premium in pricing and is first to successfully exploit a new boutique market segment. He’s a hero to hypochondriacs and makes a real tidy score in the process. This no-brainer move by Perdue may truly be the biggest real time event to come out of the whole antibiotics screaming match and, in practical ag production terms, it’s a big yawn.

          • Bruce__H

            I am ignorant about much of this, so I ask questions. You seem like someone with a lot of practical experience so I am asking the questions of you.

            By nontherapeutic antibiotic use I essentially mean what you call preventative use. And certainly, one of the sources of anxiety about farming today is that large-scale use of antibiotics will eventually lead to antibiotic resistance in bacteria that can then be horizontally transferred to pathogenic organisms that infect humans. Just calling the doing preventative doesn’t change the situation from the bacteria’s point of view.

            I am cheered, on the other hand by 2 things you say. First, that improved techniques for maintaining animal health can reduce antibiotic use. I think I hear you are saying that the use of antibiotics in farming is seeing a downward trend.(is that correct?). Second, the main antibiotics you mention in use for preventative purposes seems to be ionophores. This is good news it seems to me because the mechanism of action is so different from antibiotics in wide use for humans that any resistance that does develop will have little significance for human health.

          • Farmer with a Dell

            I won’t get into a pissing match with you over terminology, Bruce. You may rest assured every use in livestock of medically familiar antibiotics is, indeed and in fact intended to manage populations of domestic animals to the relative disadvantage of adjacent populations of pathogens. We monitor and sometimes detect very low levels of subacute infection, and treat in order to “prevent” the situation progressing to a more deleterious stage, to the detriment of livestock – that is “therapeutic” and “preventive”, particularly if you are a dog or a cat or a chicken or a horse or a cow. The discouraged pathogens, I am certain, have a correspondingly accurate “point of view” of the situation, regardless of your opinion, Bruce.
            Many years ago (back around the 1950s) animal scientists noticed antibiotic feeding seemed to slightly increase growth rates in livestock. It was a phenomenon not well understood and in those days before anal retentive LGBT hypochondriacs ruled the world there was some “nontherapeutic’ feeding of antibiotics. It lasted a decade or two, until we noticed a couple of important things: 1) antibiotic resistance developed, as expected and 2) it wasn’t a very profitable use of these drugs anyway. Animal science evolved beyond the “nontherapeutic feeding of antibiotics for growth promotion”. Ancient history.
            What you ought to “think you hear me saying”, Bruce, is that yes, we continue to improve our animal environments (facilities, equipment, feed and caretakers are a priority in modern livestock agriculture). As a result our use of antibiotics is more targeted and more effective. It is more responsible than ever. Residues are fewer and fewer, truly approaching zero (the FDA issues only several warning letters to individual farmers each year across the entire industry). You should not be
            “hearing” we no longer need antibiotics or that we can humanely do without them any time in the foreseeable future.
            You might also want to research and quantify your surmise that after three quarters of a century of antibiotic therapy, not only to relieve the suffering of diseased animals, but especially to stem the progression of outbreaks of bacterial disease, that suddenly we must gin up a mob hysteria over the remote prospect of some unique horizontal transfer to an unspecified human bacteria featuring a never befere seen virulence and pathogenicity on a par with viruses such as ebola, for example.
            We need to continue with objective research and recommendations from qualified experts, not from activist chimps frolicking about with handguns loaded with soundbites of scary misinformation. This is truly one arena where, if you are not a credible part of the “solution”, you are an unwitting part of the overhyped “problem”. I can understand how novices and activists might resent this reality, just as they are probably annoyed because they cannot take a wrench to the Mars rover or muck about with the coding in the software of our nuclear plants. Some stuff is simply out of your league, champ. Trust the professionals to keep it real. We’re not evil, and not even sinister. We are, however, pretty damned capable at what we’re trained to do…if I do say so myself. We let our record speak for itself. Now, how ’bout you?

  • Bill Riedel

    ” While the U.S. was investing in antibiotics, the Soviets were developing what is now called phage therapy. In fact in places like the country of Georgia, Russia and Poland phage therapy is still widely used today to treat infections.” This gives a false immage of phage therapy – it is not a Russian technology as it was discovered in France and then used worldwide – the West stopped using phage therapy after penicillin was discovered I think the West was short sighted as phage therapy should have been used as complimentary to antibiotics and I think that it is cruel and unusual punishment to not offer phage therapy to patients now when antibiotics fail! And we are now equally short sighted if we keep reinventing phage therapy rather than ask Russia, Georgia and Poland to help us establish phage therapy centers – hubris and venal are the words that come to mind.

  • Bill Riedel

    ” And phage therapy could also be complementary to antibiotic therapy; they’re not in competition. We’re all looking forward to actually seeing what phage therapy and CRISPR can do for us”. You are absolutely right – phage therapy is not THE ANSWER. If used properly it can cure some patients. I think there are too many red herrings like, phages are live viruses – many vaccines are live viruses; we need results from double blind studies – I was reading that more than 50% of techniques used in medicine rely on observational studies; phage therapy is Russian technology and/or new – reality is it is French technology and is almost 100 years old and has been used in many countries in the past. I also like the one that tells us antibiotics are safe and effective and the next paper outlines that they are no longer effective and the once that are are more toxic – truly a worthwhile read to understand the contradictory rhetoric on phage therapy can come from reading Joe Bennett (2012) Double Happiness – How bullshit works. Let’ get real and be more careful what we say about phage therapy.

    • Sam Dolbel

      Hello Bill, I have some personal experience observations on the use of phages in a clinical setting, good in theory, bad in actual practice for me. Chance of getting touch with you to discuss? (nicois at gmail)