The end of modern medicine?

By Marie Shields

For more than 60 years, we have depended on antibiotics not only for the treatment of routine viral infections, but also during difficult procedures such as transplant surgery – where the necessary suppression of patients’ immune systems to prevent organ rejection leaves them susceptible to infection – or in the case of immuno-suppressant cancer drugs.

We've come to take them for granted, but if recent reports in the press are to be believed, our happy relationship with antibiotics may be coming to an end. The emergence of a new enzyme has brought the topic of antibiotic resistance back into the public consciousness. In a paper published in the journal Lancet Infectious Diseases in September, Professor Tim Walsh and colleagues published details of the discovery of NDM-1, which passes easily between types of bacteria called enterobacteriaceae such as E. coli and Klebsiella pneumoniae and makes them resistant to almost all of the most powerful group of antibiotics, the carbapenems.

At the time of the paper's publication, Professor Walsh, who is based at Cardiff University in the UK, appeared confident that the discovery of NDM-1 spelled the end of antibiotics as we know them. "In many ways, this is it," he told the Guardian newspaper. "This is potentially the end. There are no antibiotics in the pipeline that have activity against NDM 1-producing enterobacteriaceae. We have a bleak window of maybe 10 years, where we are going to have to use the antibiotics we have very wisely, but also grapple with the reality that we have nothing to treat these infections with."

The reality of a life without effective antibiotics could be bleak, with many common medical interventions becoming difficult or even impossible. Transplant surgery, for example: without antibiotics, organ recipients would not be able to fight off life-threatening infections they are subject to thanks to the need for immune-suppressing drugs to prevent rejection of the new organs. Or the removal of a burst appendix: without antibiotics bacteria can get into the patient's bloodstream via an infected incision, resulting in septicaemia. Pneumonia could once again become a leading killer of the elderly, gonorrhea could become difficult to treat and TB could become virtually incurable.

According to the World Health Organization, "The bacterial infections that contribute most to human disease are also those in which emerging and microbial resistance is most evident: diarrhoeal diseases, respiratory tract infections, meningitis, sexually transmitted infections, and hospital-acquired infections."

Some important examples include penicillin-resistant Streptococcus pneumoniae, vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, multi-resistant salmonellae, and multi-resistant Mycobacterium tuberculosis. The WHO says the development of resistance to drugs commonly used to treat malaria is of particular concern, as is the emerging resistance to anti-HIV drugs.

The circumstances that have led us to this point are well known. Antibiotics can be prescribed when they're not needed, often in response to patient demand. Or patients complete only part of a course, which kills the more vulnerable bacteria while allowing the stronger ones to flourish. The widespread use of antibiotics in intensive livestock farming has also contributed to the problem.

According to the WHO, "Bacteria are particularly efficient at enhancing the effects of resistance, not only because of their ability to multiply very rapidly but also because they can transfer their resistance genes, which are passed on when the bacteria replicate.

"In the medical setting, such resistant microbes will not be killed by an antimicrobial agent during a standard course of treatment. Resistant bacteria can also pass on their resistance genes to other related bacteria through 'conjugation', whereby plasmids carrying the genes jump from one organism to another."

Resistance to a single drug can thus spread rapidly through a bacterial population. When anti-microbials are used incorrectly - for too short a time, at too low a dose, at inadequate potency; or for the wrong disease - he likelihood that bacteria and other microbes will adapt and replicate rather than be killed is greatly enhanced.

Difficult battle

So far, so bad. But humankind has an illustrious history of conquering the most difficult medical challenges. What makes this situation particularly tricky is that bacteria are everywhere - there are 10 times as many bacterial cells in the human body than 'human' cells - and they are incredibly adaptable. The more we try to wipe them out, the stronger they get. If we beat them on one attack, that often only means they will regroup, change, and launch a second wave.

This is why, in the world before antibiotics, death from infection was common; and why the idea that our most successful weapon against them may be rendered useless engenders such panic.

Yet this is not the first time experts have sounded the death knell for antibiotics. As far back as 1994, Newsweek ran an article by Sharon Begley titled 'The End of Antibiotics', which covered in detail the alarming situation modern medicine found itself in, with bacteria capable of beating back any drugs thrown at them. Here we are, 16 years later, and the worst hasn't happened. Are we really facing bacterial Armageddon, or is a case of the media leaping on a scare story and running with it?

Jean Patel, Deputy Director of the CDC Office of Antimicrobial Resistance, believes that while there is reason to worry, there is no need for all-out panic. "The emergence of NDM-1 is concerning, but we have been seeing isolates that are resistant to carbapenems in the United States for a while, as well as in other parts of the world," she points out. "For example, there is another mechanism of resistance called the KPC enzyme that has a similar resistance profile as isolates that harbor the NDM-1 enzyme.

"These are enzymes that are occurring in bacteria called Enterobacteriaceae, and they are resistant to nearly all antibiotic agents. But usually there are one or two active agents that can be considered for therapy."

However, Patel does stress that: "We are facing a situation where there are going to be very limited treatment choices, and we have seen reports of cases where there are no active antimicrobial agents. This is happening primarily in patients who are already hospitalized with a serious illness.

"In that scenario, we would expect to see increased mortality and morbidity because of antimicrobial resistance. But the alarm has been set, and we have ways to address the problem."

While Patel is not unduly concerned about the short term, she does emphasize that it will take more than pharmaceuticals to solve the problem: "There's nothing new happening that would make us alarmed that anything more serious is going to happen 24 months down the line. However, longer term we're facing bacteria that are resistant to nearly all antibiotics. And the way we need to address that is with prevention and control efforts and with attempts to increase the number of antibiotics that are being developed. There has to be a multi-prong approach to this antimicrobial resistance problem. There's not going to be one answer."

Patel stresses that she does appreciate and share Tim Walsh's concerns, although she prefers not to use quite such alarmist language. "We need to be careful how we use antibiotics." she says. "We need to use them wisely. And our need to use them wisely is going to expand beyond this 10-year period [mentioned by Dr. Walker]."

Varied approach

Regardless of how many new drugs are coming to market, we are beyond the point of taking antibiotics for granted. This is where the multi-pronged approach comes in, including better hygiene and infection control practices, and better control of antibiotic use in both hospitals and in the community.

"Anywhere that antibiotics are used, they contribute to antimicrobial resistance," says Patel. "That includes antibiotic use in the healthcare setting, in the community, and also on the farm. Antibiotics can be used appropriately and inappropriately in all three of these settings.

"One of the important strategies to combating antimicrobial resistance will be to improve antibiotic use and make sure they are used appropriately in all of the settings in which they're considered. An important way of doing this is through educational campaigns and teaching prescribers how to use antibiotics correctly."

There are those who accuse the pharmaceutical industry of not doing enough to develop new antibiotics, given that there are fewer financial incentives to working in this area than in other areas of lifelong illness, such as cancer and heart disease.

Patel, however, believes that the possibilities for drug discovery are great. "This is an important topic of research and we have great minds thinking about new ways of fighting bacteria. So I think we're going to see new drugs becoming available, it's just going to take some time.

"There has been a dip in the pipeline, so we need to come out from under that dip and see more drugs that are being developed. But that will not be the only answer, and we have to stop transmission and improve use of the antibiotics that we currently have."

As part of its frontline work on this problem, CDC is a co-Chair of the Interagency Task Force on Antimicrobial Resistance, which includes federal agencies within the health and human services group, including the NIH and the FDA, as well as outside agencies such as the Department of Defense, the EPA and the USDA.

The taskforce coordinates and communicates antimicrobial resistance work between these federal agencies, providing a forum for them to discover how their work might either complement or avoid duplication of work happening elsewhere.

In 2001, the Interagency Task Force developed a Public Health Action Plan to Combat Antimicrobial Resistance as a blueprint for specific, coordinated federal actions to address the emerging threat of antimicrobial resistance.

Patel calls the action plan "comprehensive," pointing out that it addresses antimicrobial resistance, not just in bacteria, but in all microorganisms, and is broken down into different areas. One of these is surveillance to measure antimicrobial resistance, determining what is occurring and where.

"Prevention and control of antimicrobial resistance, product development and research are the other areas covered," says Patel. "And within all of those, there are specific action items at the federal level to combat the problem."

The Task Force is currently working on a revised action plan which should be completed by the end of this year. One of the aims for this revision is to make the plan a more useful document, as Patel explains. "We're developing a new vision for how the action plan will work. In the past, it was a document that was created and used as a template for prioritizing research. So, for example, in my prior life, I worked in an antimicrobial resistance laboratory here at CDC, and I would look to the action plan for what kind of work was important for fighting antimicrobial resistance, and design our work around that.

"In the future, though, we want to make our action items more specific, and to provide timelines for when we think this work will be done. That's an ongoing process. We expect to revise the action plan every two years and to provide regular reports of progress toward implementation."

The CDC is not the only agency urging action on this front. In 2001, the WHO launched a global strategy for combating the serious problems caused by the emergence and spread of antimicrobial resistance. Known as the WHO Global Strategy for Containment of Antimicrobial Resistance, the strategy recognizes that antimicrobial resistance is a global problem that must be addressed in all countries.

"No single nation, however effective it is at containing resistance within its borders, can protect itself from the importation of resistant pathogens through travel and trade," say the strategy documents. "Poor prescribing practices in any country now threaten to undermine the potency of vital antimicrobials everywhere."

The strategy recommends interventions that can be used to slow the emergence and re duce the spread of resistance in a diverse range of settings. The interventions are organized according to groups of people whose practices and behaviors contribute to resistance and where changes are judged likely to have a significant impact at both national and international levels. These include consumers, prescribers and dispensers, veterinarians, and managers of hospitals and diagnostic laboratories as well as national governments, the pharmaceutical industry, professional societies, and international agencies.

According to the WHO, much of the responsibility for containing resistance rests with national governments, which is why the strategy gives particular attention to interventions involving the introduction of legislation and policies governing the development, licensing, distribution and sale of antimicrobial agents. 

Task forces and action plans and multi-pronged approaches - much more sensible and a lot less attractive to the media than mass panic and despair. If this common sense, methodical approach prevails, then we still have a fighting chance of beating our old bacterial enemies at their own game. Patel believes the trick is not to depend on antibiotics quite so much.

"Antibiotics will always be critical," she says, "And we will definitely still be using antibiotics in the future because they're such a critical piece in treating an infectious disease. But we will no longer be counting on them as a sole tool for combating antimicrobial resistance and for controlling infections. Instead, we'll see a much greater emphasis on infection control to prevent transmission of resistant bacteria,and a continued effort on improving and making sure that antimicrobial use is appropriate."

Discovery of penicillin

Like many cornerstones of modern life, penicillin - one of the earliest and most well-known antibiotics - was discovered by accident. In 1928, Scottish bacteriologist Alexander Fleming observed that no bacteria grew around the mold of the genus Penicillium notatum, which had accidentally fallen into a bacterial culture in his laboratory.

It was more than 10 years, however, before penicillin was successfully purified and tested, then finally extracted, and then finally produced on a large scale in 1945. That year, Fleming, along with fellow British scientists Howard Florey and Ernst Chain, received the Nobel prize in medicine, signaling the beginning of the golden age of antibiotics.

Antibiotics through the ages

Ancient times

The ancient Egyptians, the Chinese, and Indians of central America all used molds to treat infected wounds.

Late 1800s

With the growing acceptance of the germ theory of disease, the search for antibiotics began in the late 1800s.

1871

Surgeon Joseph Lister began researching the phenomenon that urine contaminated with mold would not allow the successful growth of bacteria.

1890s

Rudolf Emmerich and Oscar Low were the first to make an effective medication from microbes. It didn't always work, however.

1928

Sir Alexander Fleming observed that colonies of the bacterium Staphylococcus aureus could be destroyed by the mold Penicillium notatum.

1942

Howard Florey and Ernst Chain invented the manufacturing process for Penicillin G Procaine, allowing penicillin to be sold as a drug.

1955

Lloyd Conover patented Tetracycline, which went on to become the most prescribed broad spectrum antibiotic in the United States.

1981

SmithKline Beecham patented the semisynthetic antibiotic, Amoxicillin, still commonly prescribed today for minor bacterial infections.

Growing resistance

Global trends that have encouraged antimicrobial resistance include:

• urbanization with its associated overcrowding and poor sanitation, which greatly facilitate the spread of such diseases as typhoid, tuberculosis, respiratory infections and pneumonia

• pollution, environmental degradation and changing weather patterns, which can affect the incidence and distribution of infectious diseases, especially those, such as malaria, that are spread by insects and other vectors

• demographic changes, which have resulted in a growing proportion of elderly people needing hospital-based interventions and thus at risk of exposure to highly resistant pathogens found in hospital settings

• the AIDS epidemic, which has greatly enlarged the population of immunocompromised patients at risk of numerous infections, many of which were previously rare

• the resurgence of old diseases, such as malaria and tuberculosis, which are now responsible for many millions of infections every year

• the growth of global trade and travel which have increased the speed and facility with which both infectious diseases and resistant microorganisms can spread between continents