In recent years there has been a lot of news about the impending antibiotics crisis, brought to a head by renewed awareness that we are running out of drugs to treat evolving superbugs, and with the startling revelation following the NDM-1 discovery, that microorganisms are also capable of sharing bits of themselves with each other to thwart even our most powerful last-line antibiotics.

Is this the beginning of the end of antibiotics, as some scientists are predicting, are we about to return to a pre-penicillin world where a common bacterial infection could be a death sentence? Or are we just at the cusp of a new wave of inventions that will spur a new generation of drugs that will keep us ahead of the evolutionary race against harmful microorganisms?

This article does not answer these questions, but attempts to present a digest of key facts and recent developments to illuminate the issues around them.

It starts with a summary of what we mean by antibiotics and what they can and cannot treat. It then goes on to explain how antibiotic resistance arises, including the problem of multiple drug resistance, and why many experts say widespread and misguided use is to blame for the accelerated rate at which resistance has become a global problem, as has the dearth in new drug developments. It then describes some of the things researchers and organizations say we can do to to slow down the development of superbugs, and ends with a round up of some surprising new directions that could offer alternative solutions. Antibiotics and Microorganisms Antibiotics are drugs that kill microorganisms like bacteria, fungi and parasites. They do not work against viruses because viruses are not microorganisms. When the press and media talk about antibiotics they generally mean drugs that kill bacteria, because most of the stories that have been hitting the headlines in recent years are about antibiotic-resistant bacteria or "superbugs" like the Methicillin-resistant Staphylococcus aureus (MRSA).

Bacteria are very small creatures of usually only one cell, comprising internal cell structures but no distinct nucleus, surrounded by a cell wall. They can make their own proteins and reproduce themselves as long as they have a source of food.

As far as humans are concerned, some bacteria are friendly and essential to wellbeing, they do helpful things like break down food in our gut, while others are dangerous because they attack our tissue and cells to make their food, or they produce toxins that poison and kill.

Some bacteria cause no harm while they live in one part of the body, but then become potentially deadly once they enter the bloodstream. A good example is Escherichia coli (E. coli), which lives in the human gut and helps break down food, but if it enters the bloodstream (eg through a perforation in the intestines), it can cause severe cramping, diarrhea, and even death from peritonitis if not treated promptly.

Another example is Staphylococcus, which lives harmlessly on human skin or even in our nostrils, but if it enters the bloodstream, it can lead to potentially fatal conditions like toxic shock syndrome.

Our immune system has special cells that recognize bacteria as foreign agents and mobilize existing counter-agents or antibodies, or trigger the production of new antibodies, to attack and destroy the bacteria before they get a chance to seize a foothold and start replicating inside us. However, sometimes we lose the fight and succumb to infection, and in some cases, without treatment, the consequences can be very severe and even deadly.

Antibiotics have made a big difference to mankind's fight against infectious microorganisms and have vastly improved the conditions and chances of success in many fields of medicine all over the world.

They work because they block a life-sustaining function in the unwelcome microorganism. Some stop the microorganism from being able to make or maintain a cell wall, while others target a particular protein that is vital for survival or replication.

An example of the former is penicillin, the first commercially available antibiotic that Alexander Flemming discovered in 1929. Penicillin stops bacteria like Strep (Streptococcus, a bacterium that is commonly found on skin or in the throat) from making strong cell walls. Before the introduction of penicillin in World War II, soldiers were more likely to die of bacterial infections than from their wounds.

Viruses are not microorganisms, and although capable of self-replicating, do not appear to be "alive" at all: they are particles consisting of DNA or RNA, some long molecules, and a protein coat. They are much smaller than bacteria, have none of their internal cell machinery, and no cell wall. To replicate they have to get inside host cells and hijack their resources.

And here lies a clue as to why we have a global problem with antibiotics and antibiotic resistance: too many doctors and healthcare professionals, often encouraged by patient demand, have been prescribing antibiotics to treat viral infections. This leads to imprudent use of antibiotics and greater opportunity for bacteria to mutate into resistant forms.
How Antibiotic Resistance Arises Microorganisms are always evolving. By chance, every now and again, a generation gives rise to offspring with slightly different genes to their forebears, and the ones whose variations confer a survival advantage, eg to make better use of a resource or withstand an environmental stress, get to produce more offspring.

Now add to that scenario the efforts of mankind: the production of antibiotics that are designed to kill off bacteria. From the perspective of microorganisms, this is just another environmental stress, or "selective pressure" that ensures those with the survival advantage get to produce proportionally more offspring next time around.

This survival advantage perchance could be to evolve a slightly different protein or cellular mechanism to the one targeted by the antibiotic. Now you have a recipe for breeding resistant mutants, while killing off the ones with no resistance. Eventually, the dominant strain becomes the resistant one, as long as there is enough exposure to the antibiotic.

In fact, several mechanisms have evolved in bacteria to make them antibiotic resistant. Some chemically modify the antibiotic rendering it inactive, some physically expel it from the bacterial cell, and others change the target site so the antibiotic can't find it or latch onto it.

This evolutionary process is further boosted by the fact that bacteria also "swap" bits of genetic material, thus increasing the opportunity for bits that confer survival advantage to spread "horizontally" among species and not just "vertically" down generations of the same species. This is known as "horizontal gene transfer", or HGT.

An example of HGT that hit the headlines in 2010 is the transfer of a piece of genetic material that codes for the enzyme NDM-1 (New-Delhi metallo beta-lactamase), an enzyme that destroys antibiotics, even (and this is why NDM-1 is cause for alarm) the super-strong carbapenems, which are generally reserved for use in emergencies and the treatment of infections caused by multiple-drug-resistant bacteria.

NDM-1 is most often seen in Klebsiella pneumoniae and Eli.

Many of the antibiotics in use today are chemically synthesized cousins of naturally occurring molecules that evolved in microorganisms over millions of years, as they fought for dominance over limited resources. They themselves powered the means to produce and overcome, different antibiotic molecules.

But the problem we are seeing now, of rising antibiotic resistance, has not taken millions of years, but only decades to come about, so what might explain that?

When we began to use antibiotic molecules to treat bacterial infections, we exposed far more bacteria to much higher levels of antibiotics than they would come across in the natural world, producing an effect that the British Society for Immunology describes as "evolution in real time".

In fact, resistance to antibiotics is not a new thing, and the early signs started quite soon after their introduction. For instance, resistance to streptomycin, chloramphenicol and tetracycline and the sulfonamides, was noted in the 1953 Shigella dysentery outbreak in Japan, only a decade after those drugs were introduced. Widespread and Misguided Use Is to Blame Many experts believe that it is our widespread, and often misguided use of antibiotics to treat humans and animals that is responsible for the vastly accelerated speed at which antibiotic-resistant microorganisms have evolved.

However, while numerous studies have shown there is a dynamic relationship between the prescribing of antibiotics, and the levels of antibiotic resistance in populations, too many doctors still prescribe antibiotics to patients to treat viral infections like coughs and colds.

Some suggest this habit persists because doctors and patients fail to recognize that a course of antibiotics can result in resistance in a single person: they assume it is a population effect. Others may also not realize the full extent of the risks to health of inappropriate prescribing.

In a study published last year in Infection Control and Hospital Epidemiology, US researchers found that giving patients antibiotics for viral infections not only did not benefit them, but may even have harmed them. For instance, a significant number of the patients they studied developed Clostridium difficile diarrhea, a bacterial condition linked with antibiotic use.

The problem of medical over-use not just confined to the US. For instance, in most European countries, antibiotics are the second most widely used drugs after simple analgesics.

Also, prescription drugs are not the only source of antibiotics in the environment to put "selective pressure" on bacteria.

Antibiotics are in food and water. In the US, for example, giving antibiotics to animals is routine on large, concentrated farms that breed beef cattle, pigs and poultry for human consumption. The drugs are given not just to cure infection in sick animals, but also to prevent infection and promote faster growth in healthy animals. The antibiotics then find their way via effluent from houses and feedlots into the water systems and contaminate streams and groundwater.

Such routine use of antibiotics affects not only the animals and the people who eat them, but also all those who consume the contaminated water.

In his comprehensive and highly readable online "Textbook of Bacteriology", Dr Kenneth Todar, an emeritus lecturer in Microbiology at the University of Wisconsin-Madison, calls this a "double hit", because "...we get antibiotics in our food and drinking water, and we meanwhile promote bacterial resistance".

For this reason, the European Union and other industrialized nations, have banned feeding antibiotics to animals, and recently, the US Food and Drug Administration (FDA) started urging farmers to limit their use of antibiotics. In fact, after decades of deliberation, it appears the FDA may be poised to issue its tightest guidelines yet on use of antibiotics in animals, with the intention of bringing to an end the use of the drugs simply to make animals grow faster.

Todar says that the "non-therapeutic use of antibiotics in livestock production makes up at least 60 per cent of the total antimicrobial production in the United States", so this is not a small thing.

Another industry that is starting to be a cause for concern is genetically modified crops, because some have antibiotic-resistant genes inserted as "markers". The marker genes are introduced into the crop plant during the early stages of development for scientific reasons (eg to help detect herbicide-resistant genes), but then serve no further purpose, and are left in the final product.

Some people have criticized this approach because they say it could be a way for microorganisms in the environment to acquire the antibiotic-resistant genes. Todar says that in some cases, these "marker genes confer resistance to front-line antibiotics such as the beta-lactams and aminoglycosides". Multiple Drug Resistance (MDR) As the bacteria have evolved and acquired resistance to antibiotics, we have tried to stay one step ahead by developing new drugs, and adopting a protocol of first, second and last-line treatment. Last-line treatment drugs are reserved for patients whose bacterial infection is resistant to first and second-line treatments.

But we are now seeing more and more multiple-drug-resistant (MDR) bacteria, that are able to resist even last-line treatments.

In December 2010, the journal Infection Control and Hospital Epidemiology, published a study that reported a three-fold increase in cases involving drug-resistant strains of Acinetobacter in US hospitals from 1999 and 2006. This dangerous bacteria strikes patients in Intensive Care Units (ICUs) often causing severe pneumonia or bloodstream infection, some of which are now resistant to imipenem, a last-line treatment antibiotic.

The researchers said that a lot of attention was being paid to MRSA, but we should also be worried about other bacteria like Acinetobacter because there are even fewer drugs in the development pipeline and we are running out of treatment options.

As well as affecting ICU and other patients, Acinetobacter infections are arising in soldiers returning from the war in Iraq.

It would appear that a contributing factor to the surge in MDR bacteria, or "superbugs", is that they spread from patient to patient in hospitals and long term care facilities like nursing homes.

A study published in the journal Clinical Infectious Diseases in June 2005, found that living in a long-term care facility, being 65 or older, or taking antibiotics for two or more weeks, were all factors that increased patients' likelihood of carrying MDR bacteria upon admission to a hospital.

Also, more recent research suggests that the problem of MDR may be more than just genetic. In a study published online in January 2011 in the Journal of Medical Microbiology, researchers proposed that a non-genetic mechanism called "persistence" makes bacteria temporarily hyper-resistant to all antibiotics at once. They found "persister" bacterial cells of Pseudomonas aeruginosa, an opportunistic human pathogen and a significant cause of hospital-acquired infections, were able to survive normally lethal levels of antibiotics without being genetically resistant to the drug. Fewer Drugs in the Pipeline One of the reasons that despite being around for decades, it is only now that the threat of antibiotic resistance is being taken so seriously, is there has been a massive decline in the development of new antibiotics.

Since the discovery of two classes of antibiotic over 70 years ago, penicillin in 1929 and the first sulfonamide, prontosil, in 1932, the ensuing decades have given rise to a total of 13 classes of antibiotic, some now in their fifth generation. At the peak of development, new drugs were coming out at a rate of 15 to 20 every ten years, but in the last ten years, we have seen only 6 new drugs, and, according to another article in the May 2010 issue of BMJ, titled "Stoking the Antibiotic Pipeline", only two new drugs are under development, and both are in the early stages when failure rates are high.

In that article, authors Chantal Morel and Elias Mossialos of the London School of Economics and Political Science, cite that in 2004, only 1.6 per cent of drugs in the pipeline of the world's 15 largest drug companies were antibiotics, and give a number of reasons why the companies have reduced investment in antibiotics research. Among these (ironically) is the fact doctors are being encouraged to restrict use of antibiotics for the more serious cases, and antibiotics are not as profitable as drugs that mitigate symptoms. Plus of course, the spectre of antibiotic resistance means the lifespan of a new drug is likely to be curtailed, which means smaller returns on investment.

This bleak scenario prompted Professor Tim Walsh of UK's Cardiff University, and colleagues, who in the September 2010 Lancet Infectious Diseases told us about NDM-1 and its threat to public health worldwide, to ask the question, "Is this the end of antibiotics?"

In an interview with the Guardian newspaper, Walsh said there are no antibiotics in the pipeline that are effective against bacteria that produce NDM-1 enzymes:

"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," said Walsh.

"In many ways, this is it," he said, "this is potentially the end."

The British Society for Immunology agrees: the idea that all you have to do to keep on fighting the bacteria successfully is every year come up with "something new" no longer works when the pipeline for new drugs runs dry, they say. "Push and Pull" Incentives for Drug Research Against this prospect of a bleak future for our fight against harmful bacteria,with many experts saying it will take decades to reverse the dearth in research and development of antibacterial treatments, governments appear to be converging on a two-pronged approach: accelerate the development of new drugs and be very prudent with how we use our current and future arsenal of antibiotics so as to minimize exposure and slow down the evolution of drug-resistant strains of infectious bacteria.

With the first of these strategies in mind, the European Council and the US have recently set up task forces and committees to spur the research and development of new antibacterial drugs, with the goal of developing 10 new drugs by 2020. To do this will take a huge concerted effort, plus significant changes in funding and legislation.

In their BMJ paper, Morel and Mossialos suggest a range of mechanisms to encourage drug companies to develop new antibiotics. These include "push" mechanisms to subsidize early research, "pull" mechanisms to reward results, some significant changes to laws and regulations, and others that use a combination of methods.

For instance, under "push" mechanisms they suggest tax incentives tied to early research activities, plus greater funding of public-private partnerships and schemes that train new and experienced researchers, promote multidisciplinary collaboration and create open access resources such as molecule libraries.

And under "pull" mechanisms they suggest introducing schemes to purchase drugs at pre-agreed prices and volumes, plus prizes and lump sum rewards, including the option of allowing developers to choose between keeping ownership of the patent for a new drug, or being bought out of it with a financial lump sum.

To accelerate the timescale of drug development, Morel and Mossialos also suggest ways to speed up assessment, and that some or even a large proportion of phase III trials should be allowed to take place after the drug is already on the market.

They also suggest relaxing anti-trust laws to encourage developers of products with similar resistance-related characteristics to work together, eg so as to reduce the risk of drug resistance arising from different products for the same condition.

Another idea is to give antibiotic drugs "orphan-like" status, a scheme currently used in Europe to incentivize drug companies to make drugs for rare diseases, such as getting help with protocols, tax incentives, fee reductions before and after authorization, and 10-year market exclusivity.

Morel and Mossialos point out, none of this will work, if we don't at the same dismantle the current "incentive structures that lead to overuse of antibiotics, which is currently fueling the spread of resistant bacteria".

However, despite this rather pessimistic backdrop, there appears to be a faint glimmer of optimism among some scientists who believe that the tide is already starting to turn.

In a paper published in the July 2010 issue of the International Journal of Antimicrobial Agents, Dr Ursula Theuretzbacher, founder and principal of the Center for Anti-Infective Agents in Vienna, Austria, wrote that innovation in antibiotic drugs "proceeds in waves", and that "interest in antibiotics, particularly in drugs effective against MDR Gram-negative bacteria, is back".

She said we appear to be at the start of a new wave that will hopefully yield new antibiotic drugs in about 10 to 15 years time; but, she agrees with many others who say that in the meantime we must continue to address the problem with "a multifaceted set of solutions based on currently available tools".

A November 2010 article in the New York Times also hints of a new wave, suggesting signs that the drug industry is picking up on its own. This is supported by figures from the FDA that show the number of antibiotics in clinical trials has gone up in the last three years, which the New York Times says is mostly due to the efforts of small drug companies, who can be satisfied with lower sales volumes. Meanwhile, Make Prudent Use of Antibiotics Whether "push and pull", or any other incentives can help stoke the research and development pipeline, it still makes sense to make prudent use of antibiotics, because unnecessary exposure just gives bacteria another opportunity to develop resistance.

The consensus appears to be that a multifaceted strategy is needed, which includes ongoing education of prescribers and users of antibiotics, evidence-based guidelines and policies for hospitals and healthcare settings (including improving hospital hygiene), and improved prescribing practices.

For example, as part of a set of key messages for hospital prescribers the European Centre for Disease Prevention and Control (ECDC), suggests: Monitoring of hospital antibiotic resistance and antibiotic use.
Optimizing timing and duration of antibiotics for surgery to lower surgical site infections and reduce emergence of resistant bacteria.
In some cases, shorter rather than longer treatments can be given without affecting patient outcomes and lowers the frequency of antibiotic resistance.
Taking samples before therapy, monitoring culture results, and streamlining use of antibiotics based on these results can lead to reductions in unnecessary use of antibiotics. The "European Antibiotic Awareness Day" is run in November every year by the ECDC. The latest campaign stresses a number of messages for primary care prescribers, pointing out that primary care accounts for 80-90% of all antibiotic prescriptions, and that:

"If we continue to consume antibiotics at the current rate, Europe may face a return to the pre-antibiotic era where a common bacterial infection could be a death sentence." The ECDC urges doctors to: Note that antibiotic exposure is linked to the emergence of antibiotic resistance.
Take responsibility for promoting appropriate use of antibiotics in order to keep antibiotics effective.
Only prescribe antibiotics when necessary.
Base antibiotic prescriptions on a symptomatic diagnosis and not on patient pressure.
Use their status as an authoritative source of information to advise patients on the risks of inappropriate antibiotic use. Across the Atlantic, the US Centers for Disease Control and Development (CDC) "Get Smart: Know When Antibiotics Work" campaign repeatedly emphasizes that:

"Antibiotics cure bacterial infections, not viral infections such as colds or flu, most coughs and bronchitis, sore throats not caused by strep, or runny noses".

Get Smart includes a comprehensive set of education materials for doctors and patients, and also urges doctors not to give way to patient pressure and to educate their patients about appropriate use of antibiotics.

The message appears to be getting through, because National Ambulatory Medical Care Survey (NAMCS) data shows that the Get Smart Campaign contributed to a 25% reduction in antimicrobial use per outpatient office visit for presumed viral infection, and has reduced antibiotic prescriptions for children under 5 in ambulatory ear infection visits: in 2007, there were 47.5 antibiotic prescriptions per 100 visits, down from 61 in 2006 and 69 in 1997. Some Interesting Directions for the Future A number of new studies published recently suggest that our fight against harmful microorganisms might proceed in some rather interesting new directions: Cold plasma therapy: A team of Russian and German scientists found that a ten-minute treatment with low temperature plasma (high energy ionized gas) killed drug-resistant bacteria causing wound infections in rats and increased the rate of wound healing by damaging microbial DNA and surface structures. Their study appears in the January 2010 issue of the Journal of Medical Microbiology.
Fungus-farming ants: Researchers at the University of East Anglia in the UK found that ants, who tend farms of fungi that they grow to feed their larvae and queen, use antibiotics to inhibit the growth of unwanted microorganisms. The antibiotics are made by actinomycete bacteria that live on the ants in a mutual symbiosis. The researchers said they not only found a new antibiotic, but they also learned important clues that can teach us how to slow drug-resistant bacteria. The study appeared in the journal BMC Biology in August 2010.
Natural enzymes in body fluids: A US team from Georgia Institute of Technology and University of Maryland has developed a pioneering method of identifying naturally occurring "lytic enzymes" found in body fluids like tears and saliva that are capable of attacking harmful bacteria, including antibiotic-resistant ones like MRSA, while leaving friendly bacteria alone. The study appeared in the journal Physical Biology in October 2010.
Good Samaritan bacteria: Dr James Collins, a biologist at Boston University and his team were astonished to find an example of Good Samaritan behavior among bacteria, whereby resistant mutants were secreting a molecule called "indole" that thwarts their own growth but helps other bacteria survive by triggering drug-expelling pumps on their cell membranes. The team hope their research on "bacterial charity", which appeared in a September 2010 issue of Nature, will spur the development of more powerful antibiotics. Also, the current crisis in antibiotic therapy, may also mean that we turn our attention to other, long forgotten ways of overcoming microorganisms. One of these is Phage Therapy, which has been practised in the Soviet Union since the days of Stalin.

Phages are natural viruses that specifically infect and kill target bacteria, in a similar way to the lytic enzymes discovered by the US team reported in the Physical Biology study.

The discovery of antibiotics is thought to have turned Western countries away from phage therapy, but there are reports that soldiers with dysentry in World War I were successfully treated with phages, as were cholera victims in India in the 1920s.

The Eliava Institute of Bacteriophage, Microbiology, and Virology (EIBMV) in Tbilisi, Georgia receives patients from all over the world for treatment with phage therapy. They have successfully treated patients with chronic conditions like sinusitis, urinary tract infections, prostatitis, methicillin-resistant Staph infections, and non-healing wounds, according to an article that appeared in Genetic Engineering and Biotechnology News in October 2008.

EIBMV have a large phage collection and have recently partnered with a California-based company to bring their expertise to a wider international market.

Sources: blog Archives; MedicineNet; ExplorePAHistory; "The Future of Antibiotics", British Society for Immunology, May 2010; So, Gupta and Cars, "Tackling antibiotic resistance", BMJ BMJ 2010, 340:c2071; "Antibiotic resistance" European Research in Action Leaflet, European Commission, Aug 2003; Shiley, Lautenbach, and Lee, "The Use of Antimicrobial Agents after the Diagnosis of Viral Respiratory Tract Infections in Hospitalized Adults: Antibiotics or Anxiolytics?" Infection Control and Hospital Epidemiology Nov 2010, 31:11; Pop-Vicas and D'Agata, "The Rising Influx of Multidrug-Resistant Gram-Negative Bacilli into a Tertiary Care Hospital", Clinical Infectious Diseases, Jun 2005, 40:12; De Groote et al "Pseudomonas aeruginosa fosfomycin resistance mechanisms affect non-inherited fluoroquinolone tolerance", Journal of Medical Microbiology 2011; Morel and Mossialos, "Stoking the antibiotic pipeline", BMJ 2010, 340:c2115; Kumarasamy, Toleman, Walsh et al, "Emergence of a new antibiotic resistance mechanism in India, Pakistan, and the UK: a molecular, biological, and epidemiological study", Lancet Infectious Diseases, 10 (9), Sep 2010; Sarah Boseley, "Are you ready for a world without antibiotics?" Guardian, 12 Aug 2010; Theuretzbacher, "Future antibiotics scenarios: is the tide starting to turn?", International Journal of Antimicrobial Agents, 34 (1), Jul 2009; Andrew Pollack, "Antibiotics Research Subsidies Weighed by US", New York Times, 5 Nov 2010; "Questions and answers about NDM-1 and carbapenem resistance", Health Protection Agency, 2010; Erik Eckholm, "US Meat Farmers Brace for Limits on Antibiotics", New York Times, 14 Sep 2010; Todar's Online Textbook of Bacteriology; "Bacteriophage-Based Antibiotic Therapy", Genetic Engineering and Biotechnology News, Oct 2008.

: Catharine Paddock, PhD