In January 2016, the Lancet confirmed what the medical world has been dreading: a bacterial organism with essentially unfettered protection against all the antibiotics available to control it has been discovered in a human patient in Germany. The Lancet has been spoon-feeding us with worrying developments regarding the emergence of a bacterial gene, mcr-1, in an ever-growing tally of countries. This gene confers protection for its bacterial ‘host’ against the antibiotic of last resort to kill it, colistin. Bacteria with this gene were discovered in China in November 2015, and at the time of writing, eighteen more nations have isolated them as well, but until this discovery, not yet residing in humans.
Bacterial Adaptation
Unlike humans who pass on their genetic material solely via their nuclear membrane-bound chromosomes to their offspring, bacteria can reproduce themselves by replicating their single, circular chromosome as well as ‘share’ genes that exist as smaller segments outside of their ‘nucleoid’ region; this is how survival adaptations, such as mutations conferring antibiotic resistance, have emerged among bacteria of the same species or unrelated varieties.
Enteric bacteria (organisms that live in the intestines of animals), which include various E. coli and Klebsiella species, have already developed resistance to a class of antibiotics, the carbapenems. This class has been used as a back-up for other antibiotics that have been rendered ineffective, such as penicillin and cephalosporins. Colistin, which belongs to a different class of antibiotics, the polymyxins, was developed in 1949, but has not been used in humans for decades for two reasons: it can be toxic to nervous tissue and the kidneys, and medical authorities designated it to be preserved against the development of resistance. In a notably unfortunate case of mismanagement, instead of leaving the polymyxin class of drugs on the shelf, medical authorities released them for application in livestock around the world for the prevention of disease. Their intention was to use them in place of drugs such as penicillin, the tetracyclines and vancomycin to preserve their antimicrobial effectiveness. Of these, vancomycin was the last to hold out against bacterial resistance, succumbing in 1988.
Dark Ages of Medicine Revisited
Today the world confronts a “scenario where antibiotics no longer work and we are cast back into the dark ages of medicine where treatable infections and injuries will kill once again,” as British Prime Minister David Cameron predicted in July 2014. Some progress has been made in turning the tide against bacterial pathogens. The CDC reports reductions at the national level in 2013 for nearly all healthcare-associated infections, including an 8% reduction in bacteremia caused by MRSA (methicillin-resistant S. aureus), which along with Klebsiella pneumoniae are two of seven major organisms that are getting far harder to treat. Progress came about largely from improved hygiene practices; even then, the US fell short of goals set in 2009. That is about the extent of the good news.
In 2013, the CDC noted that 70% of common hospital infections were resistant to at least one antibiotic. Around 2 million people are infected with antibiotic-resistant bacteria in the US annually; of these cases, 23,000 die. Rates of death in the US related to infectious diseases declined steadily from 1900 by a factor of 20 until 1980. The rates over the succeeding twenty years nearly doubled from what they had been in 1980, mostly because of HIV, but the rise of resistant and multiple-drug-resistant bacteria made significant contributions.
Today, Staphylococcus aureus organisms cause 20% of all surgical site infections in the US, and MRSA kills more people in the US than does AIDS. Treatment for MRSA costs the US around $10 billion annually, averaging about $60,000 per patient.
How Did We Get Here?
Some drugs become less effective the more they are used in a patient: this is the concept of tolerance. Tolerance can be managed by applying greater concentrations of a drug to a patient within a range between ineffectiveness and toxicity. Antibiotics present a different problem: the more they are applied, the less effective they become against their target organism across a population of patients. The effect of selective pressure is hardly better illustrated than with the quid pro quo battle of adaptation between antibiotics and the organisms they attenuate or kill.
Antibiotic Overuse in Humans
It is not as if we have not seen this day coming. Yet, instead of reserving antibiotic drugs to which organisms have remained highly susceptible, we have recklessly squandered our advantage. Over the past four years, antibiotic use has increased by 6.5% in England. In the US, estimates are that two-thirds of all antibiotic prescriptions are unnecessary: 27 million courses of antibiotics are wasted each year. A high proportion of the total prescribed is for sore throats, ear infections, coughs that can self-resolve and for viral infections against which antibiotics are pointless.
In the developed world, demand from patients and reliance on empirical judgments cause physicians to overprescribe antibiotics; in the developing world, there are few barriers to self-prescription at retail outlets. A recent study found that the gold standard used since the 1960s to test bacteria for susceptibility to drugs is highly inaccurate: not only has this led to ineffective drugs being applied (according to the CDC, inappropriate prescriptions of antibiotics in outpatient settings causes $3 billion in waste each year in the US), but breakthrough candidate medications in the research pipeline have likely been overlooked. Worldwide, patients fail to complete full courses of treatment because they stop taking their antimicrobial drugs when their symptoms resolve; this enhances the selective pressure for resistant bacteria to emerge.
Antibiotic Overuse in Animals
Around 70% of all antibiotics manufactured in the US are applied to livestock for growth promotion and disease prevention. Introducing low dosages of antibiotics into the guts of healthy animals increases meat production, but also serves as an ideal method to produce resistance in microorganisms. At least this reckless dispersal will be curtailed in December of 2016, as the use of antibiotics in animal feed solely for growth promotion will be banned. However, the EU took this step in 2006, and the quantities of antibiotics used in livestock in Europe remained the same until recently. On top of this, the natural world trumps mankind’s wanton abuse of antimicrobial drugs, because it is reasoned that bacteria living in soil contribute the majority of genes that confer resistance to antibiotics.
The Drive for New Antibiotics
We are tantalized by the ‘golden age’ of antibiotics when new drugs were continuously discovered. Many today think we can stay this course against bacterial infection with the development of new antibiotics. For this to work, we need new classes of drugs and not merely novel variations within existing classes against which bacteria are already primed to quickly develop immunity. The battle against tuberculosis (another of the seven major organisms getting harder to treat) has demonstrated that one new breakthrough drug won’t be enough: prevention of rapid development of resistance requires prescribing more than one novel drug class simultaneously to a patient in order to pile on their neutralizing effects against ‘naïve’ bacterial targets. Since the ‘80s, only two new classes of antibiotics have been rolled out that are effective against one classification of bacteria (the Gram-positives); for a second major classification of bacteria, which also includes many drug-resistant and dangerously pathogenic organisms (the Gram-negatives), we have developed none.
Pipeline Is Set to Deliver Hardly a Trickle
The search for new antimicrobial drugs is difficult, and pharmaceutical manufacturers have had little incentive to discover and develop them. Antibiotics account for about a 5% share of the total pharmaceutical market with an average growth rate in the single digits, compared to around 16% annual growth for antivirals and vaccines. The projected earnings of antibiotics are far lower than those for essentially all other categories of medications. Antibiotics command little appeal with drug manufacturers: they treat acute, transient infections instead of chronic life-long diseases, resistance limits their lifespan, and novel breakthrough antibiotics will have to be prescribed sparingly to preserve their effectiveness. There are calls for ‘delinkage’ of antibiotic innovation from profits by offering incentives from governments to drug manufacturers and reducing regulatory obstacles.
Slowing the Inevitable
The Center for Disease Dynamics, Economics and Policy (CDDEP) has produced a report that proposes that the answer to extreme antibiotic resistance across the world is not “filling the so-called ‘empty pipeline’ of new drugs,” but more careful management and conservation of all antibiotics. However, this proposal is dependent on universal political cooperation and commitment; it may be overly optimistic to expect governments uniformly to recognize the urgency or possess the capacity to radically stem their nations’ autochthonous overuse of antibiotics. Even with the strictest stewardship of antibiotics, perhaps we are only slowing bacteria’s inexorable evolution to resistance. Time is not on our side: Ramanan Laxminarayan, CDDEP’s founder admits “things are going to get a lot worse before they get better.”
There are encouraging developments with virally (bacteriophage) delivered enzymes (CRISPR-Cas nucleases) that can penetrate bacteria and neutralize their resistance genes. A family of chemicals harvested from soil-based bacteria, one of which is teixobactin, have been found to kill bacteria without selecting for resistance or harming mammalian cells. However, new drugs incorporating these breakthrough agents will not reach the market for many years.
A New Paradigm Is Upon Us
Vaccines make up only about 2% of the total pharmaceutical market in the world, but their share is growing. From 1980 through 2006, at least 22 new vaccines were brought to market; most of these were prophylactics against viruses. Today there are over 300 vaccines in development to prevent cancers, allergies, neurological disorders, genetic diseases, chronic diseases and infectious diseases. Of these over 30 vaccines against new or next generation bacterial targets are in one of three phases of clinical trials, including candidates that could prevent five of the seven major organisms that are getting harder to treat due to antibiotic resistance.
Protection from a vaccine does not only protect the person receiving it; that person is less likely to pass on an infection to others. Antibiotics act against a patient’s microbiota wantonly, killing pathogens along with beneficial bacterial flora. Once a course of antimicrobial drugs is complete, pathogens can outpace other species in repopulating a patient’s body, which often leads to runaway proliferation and serious disease. Vaccines induce one’s immune system to focus on a single pathogen, leaving the rest of a patient’s microbiota unscathed.
Certainly, vaccines are not free of temporary unwanted side-effects: swelling at the injection site, mild fever, headache, irritability, loss of appetite and joint pain. Very rarely, vaccinations cause fever-related seizures and transient allergic reactions. However, antibiotics have also been found, in rare cases, to cause these more severe reactions, as well as a higher risk of disrupted immune development, lifelong allergies, obesity, and development of celiac disease in children.
Vaccine Manufacturers Face Similar Financial Disincentives as Antibiotic Suppliers
Economies of scale are required to produce vaccines, as the cost to develop each new vaccine is around $1 billion (about the same to bring any new molecule to market). Most of the expense for manufacturers of vaccines is comprised of fixed costs in research and the construction and maintenance of new production facilities designed around the components and processes unique to each vaccine. Projected earnings for vaccines are relatively low versus other classes of drugs, simply because they are applied to each patient as a one-time treatment (several, if boosters are required).
Time to Redirect Our Efforts
It is interesting to note that first of six main points in the CDDEP’s proposal calls for the reduction in the need for antibiotics through improved water, sanitation and immunization. Should we stop waiting for the late-night bus (new classes of antibiotics) that is not going to arrive in time to serve us? The funds at our disposal to address the scenario of an incipient dark age of infectious disease are finite; can we not expect to reverse the encroaching contagion if we redirect those funds at the many promising vaccines already in the pipeline to market? Vaccines cannot address all of the issues associated with drug-resistant bacterial pathogens, but they can buy us time against their spread. Elimination has never been achieved through antimicrobials, but it is tantalizingly possible with vaccines.
Steven Smith, M.Sc. is a Infectious diseases epidemiologist
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