The test results from the hospital’s laboratory were worse than the doctors had even dared to fear. They signalled the end-days of a war that had raged for more than 60 years between antibiotics-arguably the most successful group of drugs ever developed, and which have made much of modern medicine possible-and the bugs.
Specialists at the hospital in London knew from the results they were getting that the bugs had finally won. “They were looking at a doomsday scenario of a world without antibiotics,” said Professor John Conly, a specialist in infectious diseases, months later. “We are essentially back to an era with no anti-biotics” (Bull World Health Organ, 2010; 88: 805-6).
The tests revealed that a gene-already known to doctors in India-had made its way to the West. NDM-1 (New Delhi metallo-beta-lactamase) is the ultimate superbug. It transforms any bug into a ‘superbug’ that is resistant to every antibiotic, including the last-resort carbapenems. In August of last year (2010), when the discovery was made, 50 patients in hospitals in London and Nottingham had been infected with NDM-1, most of whom were ‘health tourists’ who had gone to India for cosmetic surgery.
Since then, NDM has been discovered in New Delhi’s public water. Researchers have found 11 new species of bacteria carrying the NDM-1 gene, some of which can cause cholera and dysentery, in the city’s water supply. Professor Tim Walsh, the lead researcher from Cardiff University’s School of Medicine, fears that public water throughout India, Pakistan and Bangladesh could be contaminated with the super-bug. Westerners who had not been in Indian hospitals have already been infected, he added (Lancet Infect Dis, 2011; 11: 355-62).
Ironically, the NDM superbug may be the creation of the pharmaceutical industry. Researchers have discovered that India’s waterways are polluted by pharmaceuticals, including antibiotics. Many pharmaceuticals are processed in India, where manufacturers can take advantage of lax environmental controls to deposit their waste into the nearest river.
Researchers from the University of Gothenburg in Sweden, who made the discovery, fear that the manufacture of pharmaceuticals could paradoxically spark a global epidemic of infectious diseases (PLoS ONE, 2011; 6: e17038).
NDM is the inevitable end-point of an injudicious use of antibiotics that, since the mid-1940s, have been inappropriately prescribed, used on crops, fed to live-stock, and washed away into our water-ways and back into the public systems.
The phage is set
The discovery of anti-biotics was accidental. While he was studying influenza at London’s St Mary’s Hospital Medical School in 1928, biologist Alexander Fleming noticed on his return from a holiday that mould had grown on a set of culture dishes being used to develop the staphylococci germ. The mould had created a bacteria-free circle around itself. Fleming experimented further and named the active substance ‘penicillin’. However, it took another 17 years before penicillin went into mass production.
Despite its slow progress, Fleming’s accidental discovery halted research into an equally promising antibacterial approach that was happening at the same time. Phage therapy harnesses the natural power of a type of virus called ‘bacteriophages’ (which literally translates to ‘bacteria-eaters’) to kill bacteria.
Just as with Fleming and antibiotics, bacteriophages were discovered by accident. In fact, two men-each working independently-discovered them at around the same time. One of them, George Eliava, head of the Central Bacteriology Laboratory in the Georgian capital of Tbilisi, collected specimens of water from the city’s Mtkvari river to study cholera bacteria. He left the slide under a microscope for three days and, when he next looked, the bacteria had gone. There had been something else in the water that was cholera’s natural enemy, he surmised, and that something was bacterio-phages, as they had been dubbed earlier by French-Canadian scientist F’elix d’Herelle.
The two men collaborated and, from 1923, worked together at a new institute in Tbilisi, which was later renamed in Eliava’s honour. Within a few years, the scientists at the institute had created an armamentarium of more than a dozen phages that could treat a range of bacterial infections.
Bacteriophages became part of conventional medicine in the new USSR. In the US, drugs giant Eli Lilly took a
keen interest in the therapy, and started its commercial development. However, the early results were not convincing, and research and production stopped once the first antibiotics were produced.
However, in the USSR, phage therapy continued, and bacterio-phages were regularly used to treat the wounds of Russian soldiers fighting in the Second World War. The therapy success-fully countered dysentery and gangrene.
Even after the war, Russian scientists persisted with the therapy, although the restric-tions of the Cold War prevented any research findings from reaching the West.
Phage one
Bacteriophages have many advantages over antibiotics. They are in limitless supply, they attack only a specific bacterial species and do not have the same debilitating effects on the overall immune system that antibiotics can have.
The one major disadvantage of the therapy is that there is only one bacteriophage for each
bug, so there has to be one Escherichia coli bacteriophage to nullify the E. coli bug. This presents two problems for the doctor: he may not be able to treat the patient immediately, as he first has to be sure of what is causing the infection and, second, there is no such thing as a ‘broad-spectrum bacteriophage’-one that will kill a wide range of bugs-as there is in antibiotics.
However, the greatest advan-tage of bacteriophages is their natural ability to adapt as quickly as their prey-the bacteria-whereas an antibiotic represents a frozen moment of millions of years of evolution while the bacteria continue to adapt, eventually creating an antibiotic-resistant superbug. As a result, there is no such thing as a superbug that can beat its bacteriophage-or, at least, not for long-as the phage will adapt in order to continue having the upper hand.
The age of the superbug
Superbugs began to appear within a few years of the start of penicillin’s mass production. By 1947, four years after penicillin was launched, researchers discovered the existence of a form of Staphylococcus aureus that was resistant to methicillin, then the most popular antibiotic in use. Today, these bacteria are better known by the initials ‘MRSA’ (methicillin-resistant Staphylococcus aureus), and they join a host of other antibiotic-resistant superbugs that have become familiar names, including E. coli, Clostridium difficile and Salmonella.
Each year, antibiotic-resistant bugs, such as MRSA, kill around 100,000 patients in hospitals in America alone (Clin Infect Dis, 2011; 52 [suppl 5]; doi: 10.1093/cid/cirl154). MRAB (multidrug-resistant Acinetobacter baumannii) is another common cause of infection in hospitals. In one study of 164 infected patients, 37 died, and 72 per cent of the MRAB samples were resistant to multiple drugs (BMC Infect Dis, 2010; 10: 196).
In Sweden, the staphylococcal skin bacteria S. epidermidis are widespread in hospitals. They have the capacity to adapt to hospital environments, accord-ing to a doctoral research paper by Micael Widerstr”om at Umea University, Sweden (submitted in September, 2010).
Another superbug, known as ‘KPC’ (Klebsiella pneumoniae carbapenemase), has been making its way across the US since its discovery on the East Coast in 1999, and there have also been outbreaks in Israel. According to a report from the Rush University Medical Center in Chicago, IL, in October 2010, KPC causes pneumonia and urinary tract infections.
The rise of the superbug has been caused by the wide-spread misuse of antibiotics. Today, there are more than 150 different antimicrobial compounds, and most of them are being prescribed inappro-priately. One st
udy estimates that 80 per cent of antibiotic prescriptions are written for ailments that the drugs cannot treat, such as viral infections (J Antimicrob Chemother, 2007; 60 [suppl 1]: i3-i90).
Finland’s health authority was one of the first to act when, 20 years ago, it issued new guidelines to stop indiscriminate antibiotic use. It had discovered that group A streptococci, a virulent infection, was becoming resistant to erythromycin, which is used as an alternative for people who are allergic to penicillin. After the policy change, the level of strepto-coccal bugs fell from 16.5 per cent in 1992 to 8.6 per cent in 1996 (N Engl J Med, 1997; 337: 441-6). The UK’s National Institute for Health and Clinical Excellence (NICE) issued its own edict in 2008 in an attempt to reduce the 38 million prescriptions written for antibiotics every year in Great Britain.
Eating and drinking antibiotics
In fact, even when we aren’t taking antibiotic drugs, we’re absorbing them through the environment and the food we eat. Researchers have discovered that nearly half of the meat and poultry sold in stores is contaminated by antibiotic-resistant staph infections. The bugs, which can cause life-threatening diseases such as pneumonia and sepsis, are the result of intensive-farming methods. The research team bought 136 meat samples from 26 stores in five US cities; of these samples, 47 per cent were contaminated with S. aureus bacteria. Although the bacteria are usually killed in the cooking process, the researchers fear that some of the bugs may be left on kitchen surfaces during preparation (Clin Infect Dis, 2011;
52: 1227-30). This is not a new development. In 1996, researchers discovered that mincemeat sold in German shops was contaminated with vancomycin-resistant entero-cocci (Lancet, 1996; 347: 1047).
Our waterways have also become a breeding ground for superbugs, and they may already have entered our drinking water, one research team fears.
They took water samples from rivers, lakes and wells throughout North America, Europe and East Asia, and discovered significant traces of pharmaceutical drugs, including antibiotics. Industrial plants wash the waste from the manufacture of pharmaceuticals into waterways, and patients often flush prescription drugs down the toilet. They are also used on farms for crop-growing to control disease and these, too, can be washed into the nearest river. The researchers found three classes of antibiotics in the water they analyzed that can create superbugs. Once in the waterways, they can make their way into the public supply and the water we drink, wash and cook with, says lead researcher S’ebastien Sauv’e, from the University of Montreal (Environ Health Perspect, 2009; 117: 675-84).
Turning the phage
Despite the rise of the superbug, research into phage therapy began to dwindle in the USSR and, by the mid-1970s, the Eliava Institute had virtually closed its doors. Without electricity, even the phage samples being stored in the refrigerators would have been lost had the researchers
not taken them home. In 1993, the electricity was switched off for good, and the Institute was closed.
Today, phage therapy is active only in Georgia and, to a lesser extent, in Poland.
However, in the West, it was beginning to dawn on the researchers who were studying the rise of superbugs that antibiotics carry the signature
of their own eventual ineffectiveness. They started to take a fresh look at phage therapy. In 1994, researchers used phages to help improve
the success of skin grafts in laboratory mice by reducing the underlying Pseudomonas aeruginosa infection (Burns, 1994; 20: 209-11).
Phages for killing Listeria, the food-poisoning bacteria, have started to be used tentatively in the West (Lancet, 2000; 356: 1418). A clinical trial of phage therapy for otitis, a bacteria-caused middle-ear infection, has been underway at London’s Royal National Throat, Nose and Ear Hospital (Clin Otolaryngol, 2009; 34: 349-57), while a research team at the University of Minnesota in Minneapolis tested a cocktail of phages against various antibiotic-resistant bugs such as MRSA and E. coli in venous leg ulcers (J Wound Care, 2009; 18: 237-8, 240-3).
Animals first
Acceptance of phage therapy may be slow in the West, but it appears to be happening faster for agricultural and livestock purposes. In 2006, the European Union banned the use of antibiotics for non-medical purposes in animals and livestock, while several manufacturers have been phasing out growth-promoting antibiotics.
A number of companies are currently working on the commercial mass production of phages for livestock.
One, Intralytix, has been granted a US license to develop a phage to combat Listeria monocytogenes in poultry. The licence, granted in 2006, is for
a product called ListShield (www.intralytix.com/Intral_News_PR062308.htm).
Intralytix-which recruited several researchers from the old Eliava Institute-is hoping that the use of ListShield will demonstrate the safety of phage therapy and will eventually herald in a way of combatting killer bugs in the way that Nature intended.
The new age of the phage
Antibiotics have been medicine’s greatest success story, and have doubtlessly saved millions of lives. They have been the doctor’s most powerful ally, and have granted him miraculous healing powers-and, as a result, have been absurdly overprescribed over the years.
While the antibiotic has been a moment of millions of years of evolution frozen into a chemical formula, its prey-the bug-has continued to adapt in order to survive. The superbug is just that-a bug that has adapted in order to ‘outwit’ the antibiotic.
Understanding this, antibiotics should have been treated as a precious resource and used sparingly. Instead, we have killed the goose that laid the golden egg.
Fortunately, there is another goose that can come to our rescue-Mother Nature herself. Bacteriophages are Nature’s own answer to bugs, and there
is one bacteriophage for every bug. They are found in limitless supply-just put a bucket into any river and you will fish out trillions of them-and they adapt along with the bug.
What’s needed is just for the West to realize that the end-days of antibiotics are with us now, and to work with the Russians on the research they carried out right up until the 1970s, and begin funding the age of the bacteriophage.
Bryan Hubbard
Factfile: Alternatives to antibiotics
Phage therapy is not the only alternative to antibiotics. Many others have been used for centuries in traditional medicine, although proof of their efficacy often rests on anecdotal stories and case studies. Good research is limited because funding usually comes from drug companies, which have no commercial interest in discovering non-drug approaches.
u Echinacea. Up until the late 1930s and the advent of antibiotics, Echinacea, a North American herbaceous flowering plant of the daisy family, was a popular herbal remedy for treating infections. In recent years, its primary use has been side-tracked by interest in its supposed abilities to fight the common cold, although some researchers are still interested in Echinacea’s antibacterial qualities.
Using the commercially available product Echinaforce, researchers at the University of British Columbia in Vancouver discovered that it could combat upper respiratory infections, often the result of a viral complication. Echinacea purpurea also has an anti-inflammatory effect, they discovered (Phytomedicine, 2010;
17: 563-8).
Echinacea works in a similar way to antibiotics by attacking the bug’s cell wall, researchers at Carleton University in Ottawa have found (Med Mycol, 2010; 48: 949-58).
u Essential oils. Used as aromatherapy, essential oils have successfully combatted a host of bacteria, such as staphylococci, streptococci and Proteus species. Within three hours, 90 per cent of the bugs were killed in one test that used clove, lavender, lemon, marjoram, mint, niaouli, pine, rosemary and thyme oils (Ch
ir Dent Fr, 1976; 46: 53).
u Goldenseal. This herb is a broad-spectrum natural antibiotic that is especially effective when used together with Echinacea. On its own, it has proved to be a successful antidote against some of the more familiar bugs, such as Chlamydia, E. coli, Salmonella and Helicobactor pylori (Antibiotics, 1976; 3: 577-88; Phytother Res, 2003; 17: 217-21).
u Honey. Manuka honey can clean chronically infected wounds and might help to reverse bacterial resistance to antibiotics. Honey interferes with the growth of three types of bacteria: Pseudomonas aeruginosa, streptococci and MRSA, researchers from the University of Wales have discovered (Presented at the Society for General Microbiology Spring Conference, held in Harrogate, England, April 13, 2011).
u Garlic. Crushed garlic has been a recognized natural antibiotic for many centuries, and was recommended by Hippocrates as a disinfectant. Even garlic juice can slow the growth of up to 20 types of bacteria. Yet, despite its age-old use, good research to prove its effectiveness is virtually non-existent.
u Tea tree oil. This essential oil, made from the leaves of Melaleuca alternifolia, has been used topically on the skin to fight MRSA and other skin infections, such as acne, athlete’s foot, nail fungus, wounds and infections. In laboratory tests, the oil killed the deadly MRSA bacteria, although funds have never allowed a full clinical study to be undertaken (Am J Infect Control, 2004; 32: 402-8).
u Cranberry. These berries-taken as a juice, an extract, capsule or tablet-are most often used against urinary tract infections (UTIs). They have also been tested against H. pylori infection, which can cause peptic ulcers. Although they are a proven UTI preventative, the evidence that they can also fight the infection is still inconclusive (Cochrane Database Syst Rev, 2008; 1: CD001321).
u Others. Other natural antibiotics that have plenty of anecdotal evidence, but precious little scientific support, include St John’s wort, colostrum, selasih, liver herbs, wild oregano, grapefruit seed extract, colloidal silver and liquorice root.
Factfile: Antibiotics down on the farm
Even if we don’t take antibiotics, we are still exposed to them whenever we eat meat-especially poultry.
But there’s an alternative for poultry breeders that American scientists have been testing. A dietary yeast extract appears to be every bit as good as an antibiotic for decreasing pathogens in organic turkey production, say researchers working for the US Department of Agriculture’s Agricultural Research Service (ARS).
The yeast extract works by boosting the immune system and so providing a natural defence against the bacteria that cause illness in the birds (Poult Sci, 2010;
89: 447-56).
In a separate study, researchers from the University of Delaware say there is growing evidence for several alternatives to antibiotics that poultry breeders could use. These include bacteriocins-natural agents that
are lethal to bacteria-as well as antimicrobial peptides-a natural defence against some pathogens-and bacteriophages (see main story) (Poult Sci, 2003;
82: 640-7).
Factfile: Probiotics and the good bacteria
The human gut contains hundreds of different types of bacteria. Most of them are ‘good’ probiotics; they maintain the ecological balance that keeps us healthy and wards off the ‘bad’ bacteria. However, when the ‘bad’ bacteria gain the upper hand, we take a broad-spectrum antibiotic that kills the good along with the bad.
When that happens, the gut’s natural eco-system is disturbed, the defence system is impaired, and we are more likely to become a host for ‘bad’ bacteria and especially Clostridium difficile.
Probiotics are the best way to restore our natural barriers after a course of antibiotics, researchers at the University of Paris-Sud in France have found. In one study of 53 infants, 26 tested positive for C. difficile bacteria. Those who did not have the bug had high levels of Bifidobacterium longum, a species of the ‘good’ probiotic bacteria (J Clin Microbiol, 2010;
49: 858-65).
Factfile: Diseases caused by antibiotics
Antibiotics don’t only help to create the superbugs. They can also cause asthma, leave us open to serious bacterial attack, cause birth defects and send us to the hospital emergency room with hypotension (abnormally low blood pressure).
u Asthma. Babies who are given antibiotics are 50 per cent more likely to develop asthma when they are small children. In a study of around 1400 children with asthma, around one-third had been given antibiotics by the time they were six years old. The antibiotics interfere with the ‘good’ bacteria in the gut, which prevents the immune system from maturing, say researchers from the Norwegian University of Science and Technology (Am J Epidemiol, 2010; 173: 310-8).
u Birth defects. Antibiotics-and the sulphonamides and nitrofurantoins in particular-can cause birth defects if taken when a woman is pregnant. Although defects were also seen in women who had taken penicillin, the risk was less evident (Arch Pediatr Adolesc Med, 2009; 163: 978-85).
u Immunity. Our natural immunity can be impaired for up to two years after taking antibiotics, leaving us more open to serious infection. A study by the Swedish Institute for Infectious Disease Control revealed that the impact of antibiotics is far greater
than the common belief that impairment lasts for only a month or so (Microbiology,
2010; 156: 3216-23).
u Hypotension. Antibiotics can cause life-threatening shock and hypotension (too-low blood pressure) if they are taken with common blood-pressure medications. The macrolide antibiotics-which include erythromycin, clarithromycin and azithromycin-can increase the risk of sudden hypotension sixfold if taken with a calcium-channel blocker drug (CMAJ, 2011; doi: 10.1503/cmaj.100702).
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