"The time may come when penicillin can be bought by anyone in the shops. Then there is the danger that the ignorant man may easily underdose himself and by exposing his microbes to non-lethal quantities of the drug, make them resistant," said Alexander Fleming, speaking in his Nobel Prize acceptance speech in 1945.
As predicted almost 70 years ago by the man who discovered the first antibiotic, drug resistance is upon us.
A 2013 report from the Centers for Disease Control and Prevention (CDC) revealed that more than 2 million people in the US alone become ill every year as a result of antibiotic-resistant infections, and 23,000 die from such infections.
In April this year, the World Health Organization (WHO) published their first global report on the issue, looking at data from 114 countries.
Their findings were worrying. The report revealed that resistance to common bacteria has reached "alarming" levels in many parts of the world, with some areas already out of treatment options for common infections.
For example, they found resistance to carbapenem antibiotics used to tackle Klebsiella pneumoniae - the bacteria responsible for hospital-acquired infections such as pneumonia and infections in newborns - has spread to all parts of the globe.
Dr. Keiji Fukuda, WHO's assistant director-general for health security, said of the report's findings:
"Effective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine. Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating."
In this spotlight feature, we look at what has contributed to antibiotic resistance since the drugs were discovered almost a century ago, and what is being done on a global scale to avoid falling into what WHO describe as a "post-antibiotic era."
Overuse and incorrect use of antibiotics 'main drivers of resistance'
Antibiotics are drugs that slow down or destroy the growth of microorganisms, such as bacteria, fungi and parasites. Antibiotic resistance occurs when these microorganisms adapt to the drug that is attempting to attack it and continue to multiply in its presence.
Since the discovery of the first antibiotic - penicillin - in 1928, subsequent antibiotic discoveries moved at a rapid pace, particularly from the 1940s to 1980s. Some notable discoveries include cephalosporins - a class of antibiotics structurally related to penicillin - in 1948, carbapenems in 1976 and fluoroquinolones - antibiotics used to treat urinary tract infections - in 1980.
Dr. Steve Solomon, director of the CDC's Office of Antimicrobial Resistance, told Medical News Today that although antibiotics have transformed modern medicine and have saved millions of lives over the years, their overuse has been a main driver of antibiotic resistance.
"During the last 70 years, bacteria have shown the ability to become resistant to every antibiotic that has been developed. And the more antibiotics are used, the more quickly bacteria develop resistance," he said.
"The use of antibiotics at any time in any setting puts biological pressure on bacteria that promotes the development of resistance.
When antibiotics are needed to prevent or treat disease, they should always be used. But research has shown that as much as 50% of the time, antibiotics are prescribed when they are not needed or they are misused (for example, a patient is given the wrong dose). This inappropriate use of antibiotics unnecessarily promotes antibiotic resistance."
Dr. Charles Penn, coordinator of antimicrobial resistance at WHO, told Medical News Today that incorrect use of antibiotics is also a driver behind resistance.
"One of many reasons why antibiotic use is so high is that there is a poor understanding of the differences between bacteria, viruses and other pathogens, and of the proper use and value of antibiotics," he said.
"Antibiotics are very often prescribed for no useful purpose. Too many antibiotics are prescribed for viral infections such as colds, flu and diarrhea. Unfortunately, these public misconceptions are often perpetuated by media and others. For example, through the use of generic terms such as 'germs' and 'bugs.'"
He noted that dependence on antibiotics for modern medical benefits has contributed to drug resistance.
"Surgery (elective and from trauma), cancer treatment (surgery and immunosuppressive therapy), intensive care generally, transplant surgery, even simple wound management would all become much riskier, more difficult options if we could not use antibiotics to prevent infection, or treat infections if they occurred," he said.
"Similarly, we now take it for granted that many infections are treatable with antibiotics, such as tonsillitis, gonorrhea and bacterial pneumonia. But some of these are now becoming untreatable."
Excessive and incorrect use of antibiotics in food-producing animals has also been a key player in drug resistance, since resistant bacteria can be transmitted to humans through the food we eat.
Has Fleming's warning been ignored?
We are now at a point where antibiotic resistance has become a serious threat to global public health. In a report earlier this year, Prof. Dame Sally Davies, chief medical officer for England, commented:
"The soaring number of antibiotic-resistant infections poses such a great threat to society that in 20 years' time we could be taken back to a 19th century environment where everyday infections kill us as a result of routine operations."
But the threat of antibiotic resistance is not new. As stated previously, Fleming warned of the problem almost 70 years ago. According to Dr. Solomon, such warnings have been overlooked, particularly when the development of antibiotics was at its peak.
"Although many warnings about resistance were issued, prescribers became somewhat complacent about preserving the effectiveness of antibiotics - new drugs always seemed to be available," he told us. "However, the pipeline for discovery of new antibiotics has diminished in the past 30 years and has now run dry. As bacteria have evolved to resist our current drugs, doctors are now seeing patients with infections that are virtually untreatable."
He noted, however, that health care providers have now started to become more vigilant in prescribing antibiotics.
"Greater awareness of the urgency of the problem has given new impetus to careful stewardship of existing antibiotics. Prescribers are now heeding the warning that Fleming gave in his Nobel Prize acceptance speech - to use antibiotics judiciously or else lose them forever."
Dr. Penn disagrees that warnings of antibiotic resistance have been ignored, telling us that there has been a great deal of research and monitoring of the problem. "The issue has now become much more serious because the supply of new antibiotics is drying up," he added, "and despite the efforts of some, it is clear that antibiotic use globally is still rising fast."
The barriers halting development of new antibiotics
Looking back over the past 30 years, there has been astounding progression in the world of medicine. But despite this, there has been a significant decline in research and development of new antibiotics.
A 2004 report from the Infectious Diseases Society of America (IDSA), for example, found that between 1998 and 2002, approval from the Food and Drug Administration (FDA) for new antibiotics fell by 56%, compared with approval between 1983 and 1987. Furthermore, out of 89 new drugs approved by the FDA in 2002, none of them were antibiotics.
As a result, we have been relying on the same antibiotics for decades, giving bacteria a better chance to evolve and develop resistance to them. In addition, we have been presented with an array of new infections that are already resistant to currently available antibiotics, such as methicillin-resistant staphylococcus aureus (MRSA).
The problem is that developing new antibiotics has become a more complex, costly and lengthy process. In a newsletter published by the Alliance for the Prudent Use of Antibiotics (APUA), Dr. Brad Spellburg, assistant professor of medicine at the University of California-Los Angeles (UCLA) and an author of the IDSA report, claims the "low-hanging fruit have been plucked" when it comes to identifying new antibiotics.
"Drug screens for new antibiotics tend to rediscover the same lead compounds over and over again," he said. "There have been more than 100 antibacterial agents developed for use in humans in the US since sulfonamides. Each new generation that has come to us has raised the bar for what is necessary to discover and develop the next generation."
He claims that economic factors have interfered with the development of new antibiotics. "The most obvious is that antibiotics are short-course therapies, and companies know that they will make much more money selling a drug you have to take every day for the rest of your life," he said, adding:
"Also, there are many types of infections, and approval for one type gets a company only one slice of the overall market pie. When antihypertensive drugs are approved, they are not approved to treat hypertension of the lung, or hypertension of the kidney. They are approved to treat hypertension. When antifungals are approved, they are approved to treat 'invasive aspergillosis,' or 'invasive candidiasis.'"
Developing new antibiotics an ongoing process
Global leaders are in agreement that developing new antibiotics is one way to combat the problem of resistance. Earlier this year, UK Prime Minister David Cameron made a call for global action to tackle antibiotic resistance. Within this, he announced:
"I have asked the economist Jim O'Neill to work with a panel of experts and report back to me and other world leaders on how we can accelerate the discovery and development of a new generation of antibiotics."
Last year, the US Department of Health and Human Services (HHS) announced it has formed an alliance with drug company GlaxoSmithKline in order to develop new drugs to combat both antibiotic resistance and bioterrorism.
"Working as strategic partners with a portfolio approach offers a new way to move forward in developing a robust pipeline of novel antibiotics that address gaps in our nation's preparedness as well as the evolving threat of antibiotic resistance," said Robin Robinson, PhD, director of the HHS' Biomedical Advanced Research and Development Authority.
Dr. Solomon told Medical News Today, however, that developing new antibiotics needs to be a continuous process in order to keep resistance at bay:
"Because antibiotic resistance occurs as part of a natural process in which bacteria evolve, it can be slowed but not completely stopped. Therefore, new antibiotics always will be needed to keep up with resistant bacteria, as will new tests to track the development of resistance."
There has already been some progress in the creation of new antibiotics. We recently reported on a study by researchers from Japan who say a novel antibiotic - S-649266 - has the potential to treat Gram-negative pathogens that are resistant to currently available antibiotics.
Earlier this year, a study from the University of East Anglia in the UK revealed a technique that could stop bacteria from becoming drug resistant. Co-author of this study Prof. Changjiang Dong told us: "This research provides the platform for urgently needed new generation drugs."
What else can be done to combat antibiotic resistance?
But developing new antibiotics alone will not tackle resistance. There needs to be a drastic change in the way antibiotics are prescribed by doctors and used by patients, since this has been a key contributor to resistance.
WHO recommend that patients only use antibiotics when they are prescribed by a doctor. Furthermore, patients should take the full prescription, even if feeling better, and they should never share antibiotics with others or use leftover antibiotics.
When it comes to health care workers, WHO say they should only prescribe antibiotics when patients truly need them, and should ensure they are prescribing the correct antibiotic to treat the illness.
A key strategy to tackling antibiotic resistance lies in preventing infection in the first place. "Avoiding infections reduces the amount of antibiotics that have to be used and reduces the likelihood that resistance will develop," Dr. Solomon told us. "Drug-resistant infections can be prevented by immunization, infection prevention actions in health care settings, safe food preparation and handling and general handwashing."
The CDC have launched a series of campaigns (resource no longer available at www.cdc.gov) to help educate health care professionals and the general public on the best ways to prevent infections and use antibiotics.
In addition, the organization launched an initiative called Detect and Protect against Antibiotic Resistance (resource no longer available at www.cdc.gov), which sets out four core actions that need to be addressed:
- Detect and track patterns of antibiotic resistance
- Respond to outbreaks involving antibiotic-resistant bacteria
- Prevent occurrence of infections and the spread of drug-resistant bacteria
- Discover new antibiotics and new diagnostic tests for drug-resistant bacteria.
Dr. Penn told Medical News Today that this year, WHO have the objective of developing a global action plan to address antibiotic resistance.
"Building on the many recommendations, initiatives, and proposals over many years including from WHO, the Food and Agriculture Organization and the World Organisation for Animal Health, the aim of this global action plan is to bring these together so that a cohesive, multisectoral set of actions, can be implemented against an agreed set of measurable goals and targets.
A commitment to report progress against such goals and targets, by all countries, WHO and all other organizations and stakeholders is key to ensuring sustainable and effective action."
"We have been consulting widely on this plan," he continued, "including a web-based call for contributions which elicited more than 130 responses from national governments and their agencies, industry, consumer groups and other organizations including in animal health and agriculture. The draft global action plan will be submitted to WHO's Executive Board by the end of this year, and will be open for further consultation early next year before going to the World Health Assembly in May 2015."
Antibiotic resistance is a very real threat to public health and one that needs to be taken seriously. It seems global efforts to combat this threat are underway, but many health experts say such efforts need to produce results fast.
As Dr. Spellburg says:
"If resistance to treatment continues to spread, our interconnected, high-tech world may find itself back in the dark ages of medicine, before today's miracle drugs ever existed."