London in 1941 was under Hitler’s siege. Nightly bombing raids delivered terror, destruction and disease. Fifty-five miles to London’s northwest, Alan Turing and his mathematical geniuses were working around the clock in hushed Bletchley to break the Germans’ enigma radio signal encryption device, hoping to stop the U-boat carnage in the North Atlantic. Meanwhile, 30 miles to their south, in Oxford, another expert team was diligently working to explore new approaches to combat the war’s most lethal killer, bacterial infections.
Twelve years earlier, Professor Alexander Fleming had (re)discovered a compound he called penicillin. Following Fleming’s discovery, Howard Florey and Ernst Chain assembled a biochemical team at Oxford to extract and purify sufficient material to begin the first clinical testing. On February 12 of the same year, Albert Alexander, a 43-year-old local policeman, became the first patient dosed after having developed advanced bacterial septicemia from which he had already lost one of his eyes. Albert saw dramatic improvement when treated with the limited supply of penicillin available, but died when drug supply ran out. The new biological arms race was on.
Seventy-fours years since Albert’s treatment, the human population has more than tripled from ~2.25B to ~7B. For humans, the average generation span is 25 years, meaning that three generations have passed since Albert’s treatment. In the microbial world, generations pass in 12 – 60 minutes, meaning that ~1.3M generations have passed since Albert’s treatment, with each generation providing the opportunity for selection pressure-driven evolution. Advantage: microbes.
The struggle between humans and disease-causing microorganisms is timeless. The earliest evidence of human antibiotic use dates back to ~300 AD and the bones of Sudanese Nubian populations living near the Dakhleh Oasis in Egypt during the Roman Period. Other antimicrobial drugs may have been used even before then, but it is the uniquely strong chelation properties of tetracycline that allow it to be detected in hydroxyapatite in teeth and bones of these Egyptians. Many of the traditional medicines that have been used over the millennia have since been shown to rely on the presence of antibiotics as their active ingredient. Artemisinin, for example, remains our only currently effective drug to treat malaria. It was extracted from the Artemisia plant after having been long used in Traditional Chinese Medicine.
Beyond Fleming and Florey et al., the beneficial widespread use of antibiotics in modern times can be credited to Paul Ehrlich, who had the vision to see that compounds could be made and found that had specific activity on bacteria, while being sufficiently non-toxic to the patient. Ehrlich focused his energies on syphilis, then an incurable and highly prevalent and debilitating sexually transmitted bacterial infection. Given the tools of the day it is nothing short of remarkable that Ehrlich did in fact make and test an active compound (~1910), subsequently marketed by Hoechst as Salvarsan, and used as the standard of care in syphilis for many years. One hundred years later, we still do not know its mechanism of action.
However, despite extraordinary strides in modern antibiotic development, we find ourselves at a near standstill. This week “The End of Antibiotics” was front and center at the World Economic Forum (WEF) in Davos. Jeff Drazen (editor of the New England Journal of Medicine) led the discussion among Nobel laureates and other experts on how the world must more effectively wrangle with the tremendous threat posed by rapid dissemination of multi-drug resistant super bugs. In economic parlance, the overuse of antibiotics is a so-called “tragedy of the commons” in which self-interested behavior of one person or group has broad implications for society writ large. The misguided use of antibiotics to treat infections like influenza (as a virus, it is not susceptible to antibiotics); widespread and ineffective use of antibiotics without prescriptions in the developing world; and release of antibiotics into ecosystems from large-scale industrial agricultural and human waste have synergized to drive multi-drug resistance throughout the globe. The economics of finding ways to limit the use of antibiotics in ways analogous to reducing greenhouse gas emissions was on center stage at WEF 2015.
Aside from limiting widespread use, the creation of new antibiotics remains technically very difficult, despite huge advances in genomic tools and microbiome research. Since the Infectious Disease Society of America (IDSA) established its 10 x ’20 initiative in 2010, only seven new antibiotics targeting multi-drug resistant Gram-negative bacilli have reached Phase 2 clinical trials or beyond. Given the attrition rate among drugs, the global pipeline is tragically sparse.
Combined with more effective discovery must be new sensibilities (and controls) concerning the global use of antibiotics. Globally sufficient incentives are lacking as well. As of September 2014 a list of 21 pathogens are now eligible for special incentives under the 2012 Generating Antibiotics Incentives Now (GAIN) provisions of the Food and Drug Administration Safety and Innovation Act (FDASIA) that provides five additional years of U.S. market exclusivity for new antibiotics. Only time will tell if this truly tips the balance and spurs investment but based on the early evidence, the level of new investment into antibiotic development by industry, it is clear that while helpful, incentives derived from GAIN are too often insufficient. A voucher system that provides for expedited regulatory review has been used to incent development of drugs for the developing world. Something similar for antibiotics has been discussed and if approved might provide the tipping point.
Resistance and the incidence of MDR pathogens is ever-increasing; contributing to at least 2M illnesses this year in the U.S. alone. Despite the attempts of antibacterial stewardship and stringent efforts of infection-control in hospitals, these super bugs have escaped and are joining the ranks of the community pathogens. The ubiquitous use of broad-spectrum antibiotics has resulted in large-scale, major extinctions in the microbial world, much of which has escaped detection but has had major impacts on the human microbiome, associated with increased prevalence of obesity, inflammatory bowel disease and asthma among other diseases.
New discoveries about the interplay among microbes within us and other animals are proving startling. Immunity to normal commensal bacteria has been shown to prime innate immune responses against pathogenic gut viruses, and the list of previously unrecognized organisms interacting with each other continues to rapidly climb. Only last year scientists discovered a bacteriophage (virus that infects bacteria) which is present in up to 90 percent of people worldwide but was previously unknown — another element of microbial “dark matter” that is only now coming into focus.
Rightly credited with saving millions of lives, antibiotics are wonder drugs in the setting of pathogenic infections. The tightwire act on which we must not stumble is understanding that as we build new arsenals to treat microbes, these bugs can and surely will develop genetic workarounds and rapidly share them. It is only through highly controlled use and monitoring of how we treat them can we strike the right balance. Moving toward rapid precision diagnostics coupled with highly specific antibiotics, as opposed to our history of broad spectrum approaches, will help pave the way. Long road, but one on which we must travel.