Perhaps the most pressing crisis facing humanity is the development of antibiotic-resistant bacteria. It is estimated that by 2050, 10 million people will die every year from resistant bacterial infections. Bacteria have been developing antimicrobial resistance for over 2 billion years, we have known of the problem of resistant bacteria since the 1980s, yet it is only now that we are taking concerted action to address the problem. The question is: are we too late?

Toward a post-antibiotic era?

"A post-antibiotic era means, in effect, an end to modern medicine as we know it." - Margaret Chan, Director General, World Health Organization

The 'post-antibiotic era' is defined as that time when the majority of bacteria have developed resistance to all known antibiotics in our medicinal arsenal, and so something as simple as a childhood graze could once more carry the risk of death, and routine and safe surgical interventions likewise become routinely life-threatening. According to the US Centers for Disease Control (CDC), antibiotic-resistant bacterial infections affect at least 2 million people annually in the US, resulting in at least 23,000 deaths. These are conservative estimates, based on 2011 data. Globally, it is estimated that 700,000 people die each year from antimicrobial resistant bacterial infections, and modelling commissioned by the UK government in 2016 estimates 10 million deaths annually and a cumulative cost to society of 100 trillion US dollars by the year 2050.

Inappropriate or excessive use of antibiotics is a key driver not only of the development of antimicrobial resistance (AMR), but also of the increase in serious Clostridium difficile (C diff) infections as a result of antibiotic induced gut dysbiosis. In an initial look at 2011 data, 250,000 people at least were affected by C diff infections that year in the US, and at least 14,000 of those died. Alarmingly, C diff antimicrobial resistance is on the rise worldwide, which prompted the CDC to reanalyse the 2011 data, resulting in an increased estimate of 453,000 cases, and 29,000 deaths, and these figures are probably well below 2016 values. Research published by Katherine Fleming-Dutra (and co-contributors) published in the May 2016 issue of the Journal of the American Medical Association indicates that out of the 506 prescriptions for antibiotics given per 1000 people undergoing ambulatory (outpatient) care in the US, only 353 were deemed likely appropriate. Given that we are talking about somewhere in the order of 260 million outpatient antibiotic prescriptions every year, that means that roughly 79 million inappropriate antibiotic prescriptions are written annually in the US alone outside of hospitals. Globally, estimates of inappropriate antibiotic prescription range from 30 - 60%, dependent on country, and this may well be higher in countries where antibiotics can be obtained without a prescription.

The precautionary principle

"The first rule of antibiotics is try not to use them." - Dr Paul Merino

In a recent World Health Organization survey of 10,000 people across 12 countries, 64% of respondents were aware of the dangers of antibiotic resistance, but 64% also believed that antibiotics could be used to treat viral infections such as colds or flu. Overworked doctors often find it easiest to prescribe antibiotics to insistent patients with a viral infection, reasoning that prevention of a secondary bacterial infection may not be a bad thing. This precautionary principle is also generally used whenever a young child presents with a simple ear or upper respiratory tract infection, because even though serious complications with these infections are rare, no doctor wants to be responsible for what may have been a preventable death. The elderly, especially those in aged care facilities are another group that are routinely over over-prescribed antibiotics, with asymptomatic individuals of good relative health often being medicated as a management strategy or prophylactic. Now this would all be very good if antibiotics had no 'dark side', but here we run into a much older precautionary principle: first, do no harm (actually "…to help, or at least do no harm", the advice of Hippocrates in Epidemics). Dr Paul Merino provides a modern maxim for antibiotic use in his ICU Book, the standard reference worldwide for hospital intensive care units: "The first rule of antibiotics is try not to use them."

Antibiotics in agriculture

"There will come a time when bad things happen to good animals. We have a moral and ethical duty to treat sick animals." - Christine Daugherty, Vice President of Sustainable Food Production, Tyson Foods (Springdale, Arkansas)

The use of antibiotics in agriculture may contribute more to the development of AMR than inappropriate human clinical use. Estimated agricultural applications of antibiotics account for 70 - 80% of total antibiotic use worldwide. The practice of using low dose antibiotics as growth promoters ceased in the European Union in 2006, and both the US and Australia are now actively involved in phasing out the practice. Antibiotics are still used however to treat disease, and this application often becomes largely prophylactic, meaning that if two animals in an intensive facility are identified as housing a bacterial pathogen, the rest of the animals may be treated as a preventative measure, with growth promotion seen as an advantageous secondary outcome. Globally, in accord with the notion of antimicrobial stewardship (defined as: the systematic effort to educate and persuade prescribers of antimicrobials to follow evidence-based prescribing, in order to stem antibiotic overuse, and thus antimicrobial resistance), the use of antibiotics in food production is beginning to be monitored. The aim is that growth promotion ceases, and all medical usage be authorised by a veterinarian.

Meanwhile, in the real world, a veterinarian serving an area of concentrated intensive animal production can easily be swayed to prescribe what may be excessive or unnecessary antibiotics because failure to do so means that a more compliant professional might be employed. Systems for monitoring medical use of agricultural antibiotics are not yet sufficient to prevent this abuse, though steps are being taken to remedy this situation. Part of the solution, one which has not overly engaged any governmental agency to date concerns the "moral and ethical duty" alluded to in the above quote - surely producers of animal foods should be ethically bound to raise animals in conditions which are not conducive to the acquisition and spread of bacterial pathogens? In allowing corporate 'factory food' production where animals are kept in overcrowded and unhygienic conditions we cannot avoid massive antibiotic usage, and so we have another key driver of AMR to date left largely unchecked.

"There is a glaring reason that the necessary total ban on nontherapeutic use of antibiotics hasn't happened: The factory farm industry, allied with the pharmaceutical industry, has more power than public-health professionals." - Jonathan Safran Foer

The nuts and bolts of AMR

Generational turnover times for bacteria are very rapid indeed. In many species under ideal conditions the population may double in 20 minutes, or less than 10 minutes for some species. Reproduction is asexual, and by division - the organism grows until maximum size is reached, it divides, and two identical daughter cells are produced, unless there is some mutation during the process. High population sizes and rapid generational turnover means that the chance for mutation is high, and it is through natural selection driven by mutation that AMR to specific antibiotics develops and spreads. Genes coding for the development of both antimicrobial production and resistance developed in bacteria billions of years ago, so we are talking about processes that were refined and genetically set before complex life even evolved on earth. Complicating things from a human medical perspective is the fact that genes conferring AMR can be shared not only among bacteria of the same species, but between bacteria of different species as well. The genes are most usually carried on a plasmid, a small packet of DNA that can replicate independently of the chromosomes, and which can be passed between not only other bacteria, but other unicellular life forms too, such as archaea. Think of plasmids as being similar to those small packets of code you download to update a program on your computer - they are not the whole program, merely extra information that confers better functionality. This kind of efficient gene acquisition is called horizontal (or lateral) gene transfer, and is the secret of the success of bacteria as a life form.

The irresponsible way we use antibiotics could not be more suited to the development of AMR in bacteria. Whenever we use an antibiotic, we provide the opportunity for the development of resistance to it, and that resistance can be easily and rapidly passed to related and non-related bacteria alike. Antibiotics reduce the population of susceptible bacteria, so opening up a niche within which resistant bacteria may proliferate and then dominate. Once dominant, these are the bacteria which will be passed onto other hosts, and to other hosts, and so we are required to find new antibiotics which will work on the newly resistant strain. Irresponsible use of 'last resort' antibiotics eventually leads to the development of resistance to them as well, and as many fear, eventually we will have no last resort. It is universally agreed that antibiotics are over-prescribed, and every time a patient fails to complete a course of antibiotics, bacteria can be weakened but not killed, providing an opportunity for the development of resistance strategies within the organism.

Antibiotics are used recklessly in agriculture, both those considered important for human medicine, and those that are not. We use them in animals therapeutically to treat disease, as a prophylactic to prevent disease, and as a growth promoter. Antibiotics are also frequently included in crop and fruit tree sprays, and though these target different bacteria, resistance trends are easily passed from crop bacteria, to soil bacteria, to animal bacteria, and then to human bacteria. Because antibiotics belong to a particular class (related to their chemical structure), resistance of one species to an antibiotic in any class can lead to the development of a class-wide resistance, yet agrichemical companies claim they are acting responsibly by providing an antibiotic that is not humanly important, even though it is chemically similar to one that is. Factory farming, where hundreds or thousands of animals are kept in cramped, airless, unhygienic conditions with little or no access to sunlight is an ideal environment for the development and rapid spread of pathogenic bacterial infections. As mentioned earlier, massive applications of a wide range of antibiotics are required to prop up the factory farm house of cards, and while this may benefit a corporate 'bottom line', it comes at great cost to humanity as a whole.

The pharmaceutical industry, until recently, would not even contemplate the development of new classes of antibiotics. After a 40 year lull in research and development during which no new antibiotic classes were discovered, there was a minor flurry of activity in the first decade of the current century as the full implications of the AMR crisis became apparent. New antibiotic classes that deal with AMR are seen as a last resort, and used sparingly, which means research and development costs cannot be recouped. We should all understand that the pharmaceutical industry is comprised of a string of individual businesses, not philanthropic organisations - if there is no money it, there will be no research on it. Academics and governmental advisors now realise that we will have to offer financial incentives for the development of urgently needed new antibiotic classes, or at the very least penalties for companies which aren't actively researching new antibiotics in the form of a tax that is waived if active research in this area is being undertaken.

What can we do to combat AMR?

Stop overuse: social education is urgently needed to inform the global population about how and when to use antibiotics. At the very least, don't ask your doctor for antibiotics for the flu or a minor infection. Don't use an antibiotic prescription just because a doctor or hospital gives you one (unless the condition truly calls for it), and complete every course of antibiotics you do take.

Consumer power: agricultural use of antibiotics is a potent driver of AMR development. Organic, biodynamic , chemical free, ethically raised, and true free range livestock or produce are just some of the things we can buy to help end the intensive farming practices that use the bulk of agricultural antibiotics.

, chemical free, ethically raised, and true free range livestock or produce are just some of the things we can buy to help end the intensive farming practices that use the bulk of agricultural antibiotics. Stop or reduce meat consumption: animal production is generally antibiotic reliant, the less we eat, the more we help.

Lobby for the cessation of factory farming: without an end to factory farming, it will be virtually impossible to win the war against AMR.

Cultivate health: the best defence against bacteria is a healthy body and sound, balanced inner ecosystem of probiotic organisms. All drugs, even antibiotics, have side effects, something a functional immune system does not. Eat lots of raw vegetables, eat a high fibre diet, cut out all processed foods from the diet, reduce or eliminate sugar, heal your gut, and keep it populated with beneficial organisms by eating a diversity of fermented foods in small but regular doses.

End the war against germs: most bacteria are good for us, or neutral, and many pathogens only become pathogens when they achieve unnatural dominance in the body. Good bacteria (e.g. Lactobacillus sp.) produce bacteriocins, which are natural antibiotics free from side effects that prevent pathogen dominance. In killing all 'germs', we kill our first line of defence against pathogens.

Rediscover natural antibiotics: lab-created antibiotics generally kill good bacteria more easily than bad bacteria, but natural antibiotics from whole foods appear (and have been scientifically proven in some cases) to have the opposite effect. Natural antibiotics tend to have a very strong action against pathogens and a very weak action against probiotic (especially lactic acid) bacteria. As the pathogens die off, the effect against probiotic bacteria is not strong enough to prevent them expanding to fill the niche vacated by the dead pathogens. Garlic (which I recently used to cure a very severe combined abscess and ear infection without taking conventional antibiotics), oregano, lemon myrtle leaf, tea tree oil, and golden seal oil are some of the best natural antibiotics, but there are many to choose from. There is no recorded case I am aware of where bacteria have developed resistance to a natural antibiotic, and researchers in the field suggest the numerous complex natural compounds in natural antibiotics work synergistically together, and unlike human-created antibiotics, they work on multiple levels which exponentially reduces the likelihood of resistance developing.

For evidence-based research on antibiotic-resistant infections, visit the GreenMedInfo.com Research Dashboard.

References

Aminov RI (2010) A brief history of the antibiotic era: lessons learned and challenges for the future. Frontiers in Microbiology 1(134):1-7.

Bartlett JG, Gilbert DN, Spellberg B (2013) Seven ways to preserve the miracle of antibiotics.

Clinical Infectious diseases 56(10):1445-1450.

Centers for Disease Control and Prevention (2013) Antibiotic Resistance Threats in the United States, 2013. Accessed December 28 2016 from: https://www.cdc.gov/drugresistance/threat-report-2013/

Fleming-Dutra KE, Hersh AL, Shapiro DJ et al. (2016) Prevalence of inappropriate antibiotic prescriptions among US ambulatory care visits, 2010-2011. Journal of the American Medical Association 315(17):1864-73.

Luyt CE, Brechot N, Trouillet JL, Chastre J (2014) Antibiotic stewardship in the intensive care unit. Critical Care 18(5):480-491.

Marino PL (2007) "Antimicrobial Therapy". The ICU book (p. 817). Lippincott Williams & Wilkins, Hagerstown MD.

O'Neill J (2016) Tackling Drug Resistant Infections Globally: Final Report and Recommendations. The review on AMR, commissioned by the UK Government. Accessed January 4 from: https://amr-review.org/sites/default/files/160525_Final%20paper_with%20cover.pdf

Sengupta S, Chattopadhyay MK, Grossart HP (2013) The multifaceted roles of antibiotics and antibiotic resistance in nature. Frontiers in Microbiology 4(47):1-13.

Spellberg B (2014) The future of antibiotics. Critical Care 18:228.

US Food and Drug Administration (2015) Summary Report on Antimicrobials Sold or Distributed for Use in Food-Producing Animals. Accessed January 3 2017 from: https://www.fda.gov/downloads/ForIndustry/UserFees/AnimalDrugUserFeeActADUFA/UCM476258.pdf

Ventola CE (2015) The antibiotic resistance crisis. Part 1: causes and threats. Pharmacy and Therapeutics 40(4):277-83.

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