Phages – the antedote to MRSA and other ‘superbugs’ ?

Robert  Whiston  Sept 15th 2012

“Phage” – no, it’s not a misprint, there really is such a word. But how many of the general public know that this misspelt-looking word might one day and certainly within a generation save their life ? Above: Phages attacking a bacterial cell – illustrative depiction only.

Phages are viruses that attack and kill bacteria. Phages are by far the most diverse predator organism on earth. Phages, which are viruses, identify, attack and then kill bacteria. They inject themselves into the bacteria multiply inside and ‘explode’ the bacteria cell.

BBC Horizon gave phages some long overdue publicity in their programme “Defeating the Superbugs” aired on 10 Sept 2012.

Left: Phages alight onto a bacteria cell

When I wrote my first article on phages in April 2005, none of the ‘quality newspapers’ or health care journals wanted to know or were just ignorant of phages and to be fair very little was published in the public domain  (see https://motoristmatters.wordpress.com/2012/09/11/33/).   [1]  The health care journals, in particular, wanted peer reviewed material but since there was none how could it be provided ? This was akin to asking pioneers like Faraday, Bell, Marconi and Heaviside to find other experts.

Everyone is by now familiar with the term ‘superbugs’ – those infectious bacteria that stalk our hospitals unseen and kill patients who appear to be well on their way to recovery. But how many of us know that the range of anti-biotic every GP and hospital depends upon are losing their effectiveness ?

In a few years time there will be no antibiotic available to counter the simplest of infections.

The reason is probably linked to over-prescribing, failing to keep to the designated number of pills per day and the routine introduction of low levels of antibiotics in animal feed, e.g. pigs, beef herds, which we then consume. If GM seed can infect non-GM crops in a neighbouring field, humans may be infected with ‘background levels’ of antibiotics that will make us vulnerable in the near future.

Acute problem

Planning ahead in matters of public health is a task we expect others to perform and we rely on that assumption. But the truth is that the only effective antibiotics in our health arsenal may soon have such severe side-effects, e.g. toxicity causing renal failure, that they can only be used in extremis.

The problem lies not with antibiotics as a concept but in their inability to mutate as fast as superbugs can mutate (the various ‘strains’).

The reason why superbugs are so successful a pathogen is due to in-built immuno-evasive strategies. ‘Staphylococcus aureus’ (S. aureus) is carried long-term by 20% of the human population and treatment is commonly by the application of a penicillin based product, i.e. Methicillin. When it is resistant to standard antibiotics we know it as MRSA (Methicillin-resistant Staphylococcus aureus)

Another of the many superbugs is Clostridium difficile (or C. difficile), which is associated with diarrhoea with frequency and severity of C. difficile of the colitis remaining high and appears to be associated with increased death rates (also E. coli).

The rate of Clostridium difficile acquisition is estimated to be 13% in patients with hospital stays of up to two weeks and 50% for those with hospital stays longer than four weeks (see Appendic A and the estimated cost to the NHS in 2005).

The reasons why these otherwise dormant infectious bacteria are simultaneously ‘triggered’ at a given moments we will come onto later.

Why phages ?

The answer to that is simple. Unlike antibiotics – which have been around for 60 years – phages are capable of self-mutation. Bacteria have evolved to fend off antibiotics and thus neutralise therapy. But any bacteria hoping to escape annihilation by phages are in for a surprise – phage mutate with the bacteria. In effect it is an arms race with every twist and turn made by the bacteria mimicked by the phage.

Over and above that, the world is full of at least a billion (some say 100 billion) different types of phages – far more than antibiotics – and they don’t have to be ‘engineered’, they already exist. All science has to do is isolate the ones that combat a particular infection and specific bacteria and find a pre-made phage for it.

How Phages attack

Phages offer the perfect prospect of a mechanism that automatically targets its prey. Having recognised and identified the bacteria in question it automatically attacks. Phages attached themselves to bacteria and inject them with their own DNA. This results in the bacterial cell “exploding”.

The perfect tool ?

If all this seems too good to be true and very science fictiony just recall that phages were first discovered 100 years ago in 1915 and then ignored – overshadowed by the money thrown at antibiotics. The old Soviet Union got left behind on the antibiotic front during the ‘cold war’ both before and after World War II, and relied on phages to achieve the same end results as the West using antibiotics.

As I found in my 2005 article, most learned papers on phages were of Soviet or eastern block in origin, and whether for political reasons, ignorance, fear of the new, or bone fide objections, the rigour of these findings were always questioned. The scientific rapprochement since that date may well result in a favourable reassessment.

Right: Dr David Harper

In the ‘Horizon’ programme, Dr David Harper of Amphliphi Biosciences outlined the benefits of phages but conceded that:

  • “One of the most telling things against bacteria phages, as a drug, is that no one has yet developed one.”

Dr Harper and his team are currently working to correct that situation with a counter lung infections such as Cystic Fibrosis (CF). Among other symptoms cystic fibrosis affects the internal organs, especially the lungs and digestive system, by clogging them with thick sticky mucus. This makes it hard to breathe and digest food.

Phages are naturally occurring in the fecal waters of sewage plants and polluted rivers like the Ganges in India or those in China. Harnessing the power of phages that break down the sticky fecal, and similar products, makes them ideal for CF.

The down side is that phages are living organisms and that is why producing them as a pill is so challenging. It may well be that, like polio, rubella, measles, mumps, small-pox, etc injections of a live culture via immunisation will be needed.[2]

Phages in action

Prior to a short spell in Soviet Tbilisi, the Canadian d’Herelle had gone to India, in 1927, to demonstrate the efficacy of anti-cholera phage by reducing the mortality rate in Punjab from 63% in the untreated group to 8% for the phage-treated group. [3]

  • “Whereas 300 to 500 people died during the cholera epidemics in 1925 – 1928, following the use of phage in 1929, the death rates fell to less than ten per year in the period 1930 – 1935, the duration of the study.”

NB. In my 2005 article I reported that an effective phage treatment for cholera was said to be unlikely, however this newly found citation from the Royal Society of Tropical Medicine & Hygiene (Volume 28, pp 563 -570, 1935), appears to disprove that report.

Soviet experience

In 2005 there were only fleeting references available regarding Prof. George Eliava and his work with phages in the Soviet sphere of influence.

Prof. Eliava was, in fact, quite unaware of bacteriophages until he met Felix d’Herelle during a visit to the Pasteur Institute in Paris (1919 – 1921).

D’Herelle later went to work with Prof. Eliava in Tbilisi, Georgia, with the personal blessing of Stalin. Unfortunately, Stalin in yet another of his paranoid moments ordered the execution (in 1937), of the Georgian phage expert, Prof. Eliava, on the usual trumped up charge of being an “enemy of the people.” [4]

Nevertheless, Georgia managed to benefit from the input of the French-Canadian Felix d’Herelle’s expertise, during the 18 months worked there (1933 – 34).

Testing phages

One of the most, if not the most, extensive studies evaluating the utility of therapeutic phages for prophylaxis of infectious diseases was conducted in Tbilisi, Georgia, during 1963 and 1964. It involved phages against bacterial dysentery. This is a summary:

  • A total of 30,769 children were included in the study and were aged between 6 months to 7 years old.
  • Of these, children on one side of the streets (17,044 children) were given Shigella phages orally (once every 7 days), and the children on the other side of the streets (13,725) did not receive phages.
  • The children in both groups were visited on a once-a-week basis to administer phages and monitor their overall status.

Based on clinical diagnosis, the incidence of dysentery was 3.8-fold higher in the placebo group than in the phage-treated group (6.7 and 1.76 per 1,000 children, respectively) during the 109-day study period; based on the culture-confirmed cases, the incidence of dysentery was 2.6-fold higher in the placebo group than in the phage-treated group (1.82 and 0.7, respectively). [5]

Again, I can do no better than quote from “Bacteriophage Therapy”:

  • “ . . .  Many similar clinical studies, albeit conducted on a smaller scale, have yielded similar results (see Table ​(Table1)1). To give but a few examples, phages have been reported to be effective in treating staphylococcal lung infections, P. aeruginosa infections in cystic fibrosis patients (50), eye infections (43), neo-natal sepsis (38), urinary tract infections (40), and surgical wound infections (39, 41).

However, as with the Polish studies, controls were not included in the majority of these trials or controls were used but information needed for rigorous evaluation of the authors’ conclusions was not provided.

For example, a study which was meant to be a double-blind trial evaluating the efficacy of bacteriophages for prophylaxis and/or treatment of bacterial dysentery was conducted in 1982-1983 and included soldiers of the Red Army stationed in four distinct geographic regions of the former Soviet Union. . . . “.

It would therefore appear that Dr Harper is on the right track in that some previous research has been done into cystic fibrosis and phages particularly when cystic fibrosis are especially susceptible to Pseudomonas aeruginosa (P. aeruginosa) infections.

Some of the major human phage therapy studies performed in Poland and the former Soviet Union. The Table below gives an idea of the type of infection and the phage treatment used  (Click to enlarge).

The obstacles

Earlier phages were described as possibly being a perfect tool to fight infection; however, they do have severe limitations.

If cigarettes are simply a ‘delivery system’ for the addictive drug ‘nicotine’ then we have some way to go before a universally simple ‘delivery system’ is devised for phages.

The other major limitation is funding. Antibiotics have attracted huge amounts of investments and reputations have been made on the back of them for over 60 years. They represent a near-monopoly in the health care system and have been made very profitable by the half dozen world players. Their ‘resistance to change’ will be substantial. The US company Pfizer, for example, employs 81,800 and has revenues of US$ 48,296 million per annum.[6]

Phages are viruses and companies have had their fingers burnt with the AIDS ‘retro virus.’  Where a virus usually consists of a protein capsule with a nucleic acid inside which can be either DNA or RNA. If the virus uses DNA, it can directly insert into the host genome and start producing clones of its self.

However, retroviruses use RNA which can not work in a host cell without being first translated into DNA then inserted into the host genome. The sequence is as follows: RNA → DNA → RNA → protein, whereas the sequence for a plain virus is: DNA → RNA → protein.

The transforming by the virus from the DNA state to the RNA state is none too stable resulting in errors which speeds up evolution. The rapid evolution induced causes the “offspring” of many millions of retroviruses to be vastly different than the original.

Both AIDS and HIV were once thought to be separate retrovirus and evolved faster than science can work out ways inhibit or treat them using antibiotics. The same problem is faced by ‘flu vaccine’ makers and results in it not working most of the time.

It may well be that anti-biotics will have to step aside so that a phage solution can be found to all of the above. Garry Hamilton, a science writer based in Seattle, Washington, summed up the situation when he wrote:

  • “Viruses are often thought of as simple creatures. But their staggering diversity and genetic promiscuity could make them the most creative force in evolution.”

Before moving on to possible trigger mechanisms, a review of the characteristics, again taken from Bacteriophage Therapy,of bacterio-phages versus anti-biotics. Of note taking the first comparator is that although bacterio-phages are very specific anti-biotics target both pathogenic microorganisms.

Correct identification of the disease-causing bacterium is more essential if phage therapy is to be used successfully compared with anti-biotics where identification of the pathogen (the etiologic agent or germ) is not clear.  

 

However as the last entry shows “selecting new phages” (e.g., against phage-resistant bacteria) is a relatively rapid process compared with the time necessary to develop a new antibiotic.

Trigger mechanism

If every normal healthy individual walks around with millions of bacteria (germs) inside them and yet more millions of phages in their system, why aren’t we ill all of the time ?

What is the event that tells every single bacterium to act in unison and attack a particular part of the body ?

Professor Bonnie Bassler of Princeton University, New Jersey thinks she may have the answer. A type of small squid is able to light up its underside and project light so as not to cast a shadow on the ocean flour – which would otherwise make it identifiable to its predators.

This light is created by bacteria (not phages) and Prof. Bassler work has shown that a signalling molecule is at work which is able to trigger all the light emitting bacteria at the same time.

The title for this relatively newly found phenomenon is ‘quorum sensing.’

Left: Prof. Bonnie Bassler.

This view, however, has been challenged. An alternative and complementary model to quorum sensing is the concept of diffusion sensing. She also takes a tangential approach to curbing the destructive powers of bacteria. She believes in ‘behavioural modification.’ Rather then seeking to destroy the bacteria entirely she is looking at ways for them to co-exist harmlessly in our bodies.

Recent research into quorum sensing systems has produced compounds that can disrupt the bacteria’s ability to communicate, thereby disabling or diminishing the bacteria’s ability to become pathogenic (toxic to the body). Prof. Bassler is working on the molecular switch mechanism. If this can be short circuited no message will get through to the harmful bacteria and their presence in the human body will remain benign.

The added advantage of finding such a trigger would be that the body’s integrity and immune system would not be compromised by cell damage, inflammation, toxicity, or other effects associated with bacterial attacks. This would give the body time to eradicate the bacteria naturally through normal immune system functions.

Another advantage of the anti-quorum sensing approach to controlling infection is that there are not many evolutionary forces in the body that select for resistance. The consequence is that there is little in the body’s defence processes that would create resistant strains to mutating bacteria – a rare instance where ‘natural selection’ fails to come into play.

The Third World

Since 1999, if not earlier, Africa has been on the Agenda at the G8 summits. Publicly the world’s leaders promised money, food aid, and medicines, though one suspects little was ever delivered.

The West stands on the brink of a catastrophe that will originate in the Third World. Firstly, the over- prescribing in the West is as nothing compared to the abuse of antibiotics in SE Asia. In that region antibiotic are totally unregulated and individual antibiotic pills can be bought at every corner shop. Indonesia and Pakistan are typical cases.

Ignorance of how to use antibiotics leads to the taking of too few which allows the bacteria to mutate and build up its defences against antibiotics that we in the West depend upon.

More recently we have all learnt of the alacrity and gravity of flu epidemics: SARS (2002) and bird flu (H5N1), swine influenza virus (SIV) H1N1, H1N2, H3N1, H3N2, and H2N3 (2009).

A mere six infectious diseases account for 50% of deaths among children or young adults around the around the world. [7] This handful of diseases are:

  1. AIDS (mainly in Africa)
  2. tuberculosis (TB)
  3. measles
  4. malaria
  5. diarrhoeal diseases such as dysentery and cholera
  6. acute respiratory infections such as pneumonia

Together they wereresponsible for 90% of all deaths due to infectious diseases in 1998. HIV and AIDS were thought by some at first to be retroviruses and both compromise the immune system so a short diversion is called for.

  • HIV versus AIDS – For years the academic world has, behind the scenes, divided into two camps; one that believes HIV is a precursor to AIDS and the second camp that believes HIV is quite distinct from AIDS (their argument being that one is lethal and the other isn’t).
  • According to one school of thought it is HIV that is the virus and AIDS is simply the definition of the illness. According to the second school of thought if that were true HIV would lead to AIDS, and AIDS deaths would be in their millions – as widely predicted in 1986 – but as statistics from the UK and the US alone show, relatively few people with AIDS die every years and very much fewer, if any, die of HIV.
  • Human Immuno-deficiency Virus (known as HIV) is from a family of retrovirus which causes immune system deficiency which can lead to the progressive failure of organs in human beings. Technically, it is termed an ‘acquired syndrome’ and was first clinically observed in 1981 in the United States and France.
  • The initial cases (of AIDS / HIV) were concentrated drug addicts using injection and gay men. Although there is said to be no known cause of impaired immunity symptoms among gay men, their over-use of antibiotics to treat infections singular to their life style may well have compromised their immune systems (see Third World above). Drug addicts, of course also have compromised immune systems. The modern consensus is that the phrase A’IDS’ means the acquiring of a collapsed immune system as a result of HIV.
  • However, there are ‘deniers’ principally the “Duesberg hypothesis” headed by Prof. Peter Duesberg of University of California, Berkeley.  He and Neville Hodgkinson say that HIV does not exist (see Ivor Catt).
  • This brings us neatly to Arica. Thinking that the origins of AIDS were somewhere in Africa large sums of money were offered to African government to set up medical a schemes to stem the epidemic.
  • Incentives were paid for finding, testing and treating AIDS sufferers. The only problem with the concept was that it was flawed. Tropical diseases, as anyone who has contracted even 2 or 3 of them can attest, leave patients quite debilitated i.e. their immune system is weakened or ‘compromised.’
  • A healthy person usually has a white blood cells count (CD4), of between 600 and 1,200. When the CD4 count drops below 200, a person’s immune system can be said to be severely weakened, and that person is then diagnosed with AIDS, “even if the person has not become ill from other infections” which grammatically is a little confusing.
  • Pneumocystis carinii pneumonia (PCP), is commonly found in the lungs of healthy people, but, being a source of opportunistic infection, it can cause a lung infection in people with a weak immune system. Pneumocystis pneumonia is especially seen in people with cancer, HIV/AIDS and the use of medications that affect the immune system (i.e. drug treatments to combat HIV and AIDS).
  • Pneumocystis (PCP), is rare but an ‘opportunistic’ pathogen that was first known to occur in the very compromised immune systems of gay men and can now commonly be found in:  premature babies, severely malnourished children, and the elderly.
  • Kaposi’s sarcoma (KS) is another ‘opportunistic’ pathogen which causes tumors. It became more widely known, though erroneously, as the “AIDS rash” (Human herpesvirus 8, or HHV8). It was one of the AIDS defining symptoms in the 1980s but by 1994 the separate viral cause for this skin cancer was discovered.

Air travel

If the Black Death took years to travel across Europe (1328 to 1351), modern diseases are not so reticent – they can be here within 24 hours. However, what modern superbugs and the Black Death do have in common is that they follow trade routes.

Globalisation is not limited to passenger aircraft but commercial shipping, e.g. supertankers, huge container ship etc, that use enormous quantities of water, as ballast, to stabilise the vessel at sea. Biologists in the US have discovered that in dumping more than 79 million tonnes every year into the seas near the US alone millions of germs and potentially dangerous micro-organisms are discharged.

Scientists say this can harm both humans and ocean wildlife – which may account for why whales, sharks, dolphins and seals etc are falling prey to illnesses or displaying a variety of behavioural symptoms.

CONCLUSIONS

Bacteriophage represent a missed opportunity. Their neglect since their discovery in 1915 will be hard to make good.

The poverty and plight of Africa which was uppermost in Tony Blair’s mind at the G8 Summit of 2005 when he was PM, could have been eased by combining with the experience to be found in Russia. But Putin and Russia were largely ignored.

This is not to say that phage treatments have never been available in the United States or the West. Small commercial sales of phages occurred in the 1940s but were overshadowed by the antibiotics industry which has government sponsor ship to cut down on gunshot wounds and tropical diseases in the jungles of Malaya, Burma and New Guinea.

The fact remains that phages are highly specific and very effective at targeting bacteria. Their use in India and extensive clinical use in Eastern Europe and the former Soviet Union underscores their safety. But the clincher is that phages are infinitely adoptable and rapidly modifiable to combat the emergence of any newly emerged bacterial threat.

E N D

Appendix A

‘C.difficile’ superbug is killing twice as many people as MRSA

 By Jeremy Laurance, Health Editor, The Independent, 16 June 2005

http://news.independent.co.uk/uk/health_medical/story.jsp?story=647198

 The hospital bug Clostridium difficile, which is sweeping through NHS hospitals, is killing twice as many people as MRSA.

Figures from the Office for National Statistics show there were 1,748 deaths recorded in 2003 in which C.difficile was mentioned on the death certificate. In 934 of those deaths, C.difficile was given as the underlying cause.

In the same year, Methicillin Resistant Staphylococcus Aureus (MRSA) was mentioned on the death certificates of 955 patients, in 321 of which it was given as the underlying cause.

The new figures for C.difficile were obtained in response to a parliamentary question by David Lidington, the Conservative MP for Aylesbury.

A spokesman for the staistics office said: “We occasionally carry out searches for any mention of a cause of death on death certificates because it gives a fuller picture.

C.difficile causes severe diarrhoea, and cases have doubled since 2001 to more than 43,000 in 2004. Some of the increase is due to better reporting. Deaths due to the bug, which occur mostly in the over 65s, rose 38% between 2001 and 2003.

Patricia Hewitt, the Health Secretary, announced this week that she would order an inquiry into an outbreak of a virulent new strain of the bug at Stoke Mandeville Hospital, which has claimed 12 lives and infected 300 people since the end of 2003.

The official toll of 12 deaths was challenged yesterday by the family of a man who died at the hospital in Aylesbury, Buckinghamshire, after contracting the infection, but was not listed among the 12. Ernest Bruver died, aged 80, on 8 May 2004 after being admitted to hospital five weeks earlier with severe gastroenteritis.

The cause of death on his death certificate was given as (1) broncho-pneumonia and respiratory failure, and (2) C.difficile. But when his family contacted the hospital last week, managers denied that he had died from the infection. Mr Bruver’s son, Nigel, 50, said:

  • It took them 48 hours to come back to me and they said my father was not one of the 12. Yet there it was on his death certificate. I couldn’t make head or tail of it.”

Ernest Bruver was admitted to intensive care at Stoke Mandeville on 2 April 2004. Nigel Bruver said: “He succumbed to an infection and got diarrhoea, but we weren’t told what it was. The death certificate said he died of pneumonia. But he got pneumonia because he was lying flat on his back for five weeks with diarrhoea caused by C.difficile.”

  • “If he hadn’t got C.difficile, he wouldn’t have ended up with pneumonia. I think we were kept in the dark.”

A spokesman for Stoke Mandeville said:

  • “C.difficile infection is very common, and it is not uncommon to have it listed on death certificates. The 12 deaths we have referred to are cases where the death was directly attributed to C.difficile as the primary or probable cause.”

END

Reference:

See also: “Lethal bug is costing NHS £160m a year – and is spreading at a phenomenal rate”, June 2005. http://news.independent.co.uk/uk/health_medical/story.jsp?story=645088

“Phages – a belated vindication” https://motoristmatters.wordpress.com/2012/09/11/33/

PS. one also has to question the virtue and value of cleaners “mopping” hospital corridors and wards when analysis of the process reveals a dirty mop being plunged into dirty water and then spread from one area to another.

Footnotes:

[1] Phages were discovered during World War I by British bacteriologist Frederick Twort and independently two years later by the French-Canadian Felix D’Herelle. See also http://biology.science.oregonstate.edu/courses/genomics-lab/phage.html

[2] Routine childhood immunisation first began in the 1940s for: diphtheria, pertussis, BCG, polio, tetanus, meningitis C, pneumococcus, human papillomavirus (HPV), etc

[3] Morison, Director of the King Edward VII Pasteur Institute in Assam (Transactions of the Royal Society of Tropical Medicine & Hygiene, Volume 28, pp 563 -570, 1935). ‘Are phages useful in treating cholera ?’ http://www.gangagen.com/faqs.asp#7

[4] Contemporaneously see also  Dr. Alexander Sulakvelidze, based in Florida USA. Eliava Institute of Bacteriophage, Microbiology, and Virology, Georgian Academy of Sciences, Tbilisi, Georgia http://www.evergreen.edu/phage/eliava/eliava.htm   and http://aac.asm.org/cgi/content/full/45/3/649

[5] “Bacteriophage Therapy” by Alexander Sulakvelidze, Zemphira Alavidze and J. Glenn Morris. Jr. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC90351/

[6] Others include Hoffmann–La Roche, GlaxoSmithKline, Sanofi-Aventis, Merck & Co., Novartis, Johnson & Johnson, AstraZeneca, and together they form a world oligarchy.

[7] World Health Organisation (WHO) report circa 1998. See also Smithsonian magazine, Oct 2000. http://www.smithsonianmag.com/science-nature/phenom_oct00.html#ixzz26e9kY0hQ

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