As its genesis so potently illustrates, the rise of antimicrobial resistance (AMR) will not be defused by an antibiotics arms race against the superbug.
Yes, new antibiotics form part of the answer, but work is needed in other areas and sectors to ensure the effectiveness of existing and novel drugs is maintained.
With resistant bacteria emerging in humans, animals and the environment – and spreading from one compartment to another – there is no geographical frontier or human/animal barrier.
That means responding to AMR requires a comprehensive and concerted plan of action. Some of the main issues, and how they complement moves to promote discovery and development of new antimicrobials, are considered here.
Given the straight line that can be drawn between exposure and resistance, one of the biggest issues to be dealt with in addressing AMR is inappropriate use of antibiotics in farm animals.
The potential harm caused by AMR that is generated through misuse of antibiotics in agriculture is compounded by the fact that 60 percent of human pathogens originate in animals. The prospect is that infections can neither be controlled in animals or humans.
As the final report of the recently concluded U.K. Review of AMR highlighted, "the quantity of antibiotics used in agriculture is vast." In the U.S., of the antibiotics defined by FDA as medically important for humans, more than 70 percent by weight are sold for use in animals.
That is likely to be paralleled in many other countries, but they do not collect the data.
The World Organization for Animal Health has the responsibility for establishing a global database on the use of antibiotics in animal husbandry, based on information provided by its 180 member countries.
However, the difficulties in compiling the data are underlined by a survey of members, which found that in 110 of 130 countries questioned there is a lack of legislation relating to use of antimicrobials. "Consequently, these products are often freely sold and their use is unsupervised," the organization said in May when it set out its strategy for combating AMR.
The lack of data makes it impossible to model the economic costs of adopting alternative products or production systems to cut the use of antibiotics in farming.
However, there are examples of their use being limited to treating animals with infections, and not as a preventative measure or growth promoter, with little impact on productivity.
A November 2015 paper, "The economics of antibiotics use in U.S. livestock production," published by the U.S. Department of Agriculture, concluded that restricting use to the treatment of sick animals would have minimal economic impact, reducing the value of meat production by less than 1 percent.
According to the United Nations Food and Agriculture Organization, the most economically developed countries of the G20 account for 80 percent of world meat production. In view of the limited impact using antibiotics solely in case of infections would have on production levels, a large part of controlling antibiotic use in agriculture could start from here.
Food processors and retailers also have a role to play, by setting antibiotic reduction targets, agreeing standards for responsible use and labelling food to drive consumer choice.
In addition to prompting AMR in farm animals, the blanket use of antibiotics in agriculture and aquaculture results in discharges into water and soil, fueling development of AMR in the wild. Between 75 percent and 90 percent of antibiotics administered to animals are excreted un-metabolized.
Antibiotics also reach the environment through sewage systems, and again, the majority of antibiotics consumed by humans are not metabolized.
While the industry can have little influence over these sources, it can take measures to reduce or prevent release of antibiotics in the effluent from manufacturing plants.
Most active pharmaceutical ingredients (APIs) for antimicrobial drugs are manufactured in China and India. A 2007 study by Swedish researchers analyzed discharges from a wastewater treatment plant in India that received effluent from 90 API manufacturers, finding high levels of APIs were being released into the environment.
The concentration of the antibiotic ciprofloxacin in the receiving river exceeded by 1,000-fold the level that is toxic to some bacteria. Similar results have been found in studies in Asia and Europe.
As a 2015 study, "Environmental Risk Assessment of Human Pharmaceuticals," published in the journal Environmental Science noted, there are currently very few standards for API discharges and limited monitoring.
While the formulation and adoption of new international regulations will take time, the industry itself could drive change by requiring higher standards from suppliers. Individual API productions facilities could have on-site dedicated wastewater treatment systems, for example.
Based on data from an unnamed major manufacturer, the AMR Review estimates it would cost $180 million per year, or 50 cents per kilogram of APIs produced, to prevent 30,000 to 70,000 tons of waste from antibiotics manufacturing reaching the environment.
Though this is a fraction of the antibiotics excreted by humans and animals, it is far more amenable to control measures, being released by around 200 sites. The high concentration of antibiotics in these discharges also makes these production facilities hotspots for breeding resistance.
Reducing inappropriate use in humans
The U.S. Centers for Disease Control and Prevention estimates that up to half of all human use of antibiotics is unnecessary or inappropriate. Much of this is down to the fact that doctors are required to treat first and diagnose second, due to the time taken to identify the precise cause of an infection.
The U.K. AMR Review called on governments in the richest countries to counter this by mandating that by 2020 all antibiotic prescriptions are informed by a rapid diagnostic test. That would provide a market stimulus and open the door to investment and innovation, the review said.
Human consumption also could be cut through awareness campaigns to convince people not to demand antibiotics from their physicians, or to buy them over the counter or via the internet, without genuine need.
One study in Belgium showed that campaigns to reduce antibiotic use during the winter flu season resulted in a cumulative 36 percent reduction in prescriptions over 16 years. In the U.K., the introduction of financial incentives in April 2015 led to a 7.6 percent drop, or two million fewer prescriptions for antibiotics, from April to December compared to the same period of 2014.
Global monitoring of AMR
To inform the various aspects of preserving the effectiveness of antibiotics by restricting their use, there is a requirement for systematic global monitoring of AMR.
Surveillance has long been the foundation of infectious disease management, providing information for clinical decision-making at a local level, informing national and international policies and providing early warning signs of emerging threats.
Alongside monitoring the use of antibiotics, there is a requirement for data on resistance rates to various drugs and where it is emerging. The information must be open and accessible anywhere in the world.
Genomics is a powerful tool here, as was demonstrated in December 2015, after the first report – from China – of a gene conferring bacterial resistance to colistin, the antibiotic of last resort for treating gram-negative infections in humans.
Following identification and sequencing of the gene, mcr-1, isolated from hospital patients and pigs in China, researchers in Denmark checked to see if it was present in their country's national database of bacterial DNA profiles.
They found mcr-1 in samples from a patient who had a blood infection in 2012 and in five samples of food imported from 2012-2014. Mcr-1 subsequently was reported in the U.S. too. As yet it is not clear where the gene originated.
Finally, quarantine and better hygiene that were the only means of combating infections in the pre-antibiotic era have gone out of fashion. Fewer infections mean less need for antibiotics and it is time for a revival of these measures.
Some of the wider aspects of tackling AMR, such as controlling discharges from antibiotic manufacturing plants, providing advice to avoid inappropriate use, and working with devices companies to develop point-of-care rapid diagnostics, fall under the biopharmaceutical industry's influence.
Other issues such as indiscriminate use of antibiotics in agriculture, prescribing policies, and monitoring the emergence of resistance, are outside its sphere. However, the industry has knowledge and expertise to contribute to the formulation of responses to these aspects of the brewing AMR crisis, alongside its role in the discovery and development of new antimicrobials.