Phages – a belated vindication

Robert Whiston Sept 2012

It was in April of 2005 that I wrote an article on the obscure topic of “phages” which I predicted might be able to supplement or replace our diminishing arsenal of effective antibotic medicines.

None of the health care journals wanted to know, the daily qualities, and neither did any of the weighty Sunday papers. But BBC’s “Horizon” programme this week, Sept 10th 2012, not only re-emphasised the rapdly increasing impotency of antibiotics but the possibility of more phage research. The article below was sent to mainstram media outlets in 2005.

 

MRSA – the Bacteriophage cure

By  Robert Whiston   FRSA  – May 19th 2005

MRSA poses an acute problem in Britain. Known to everyone as one of the “superbugs”, MRSA has become resistant to most, if not all, antibiotics.

All the medical advances that we take for granted, from transplants to chemotherapy, are threatened and may become impossible as bacteria increasingly develop resistance to antibiotics.

The long term prospects for the effectiveness of anti-biotics generally is not hopeful. Their use, some would say over-use, has rendered them increasingly impotent in the fight against infections (see Appendix A). Some commentators have predicted a zero effectiveness in 10 years time.

The World Health Organization (WHO) reports that some 14,000 people die each year just from drug-resistant infections picked up in U.S. hospitals. Worldwide, up to 60% of hospital-acquired infections turn out to be drug-resistant. [1]

And according to a recent WHO report, nearly all gonorrhoea strains are unchecked by the antibiotic ‘penicillin’, in South East Asia. In India, typhoid species have developed resistance to three drugs commonly used against them. Drug-resistant tuberculosis has invaded one in ten TB patients in Estonia, Latvia, and parts of Russia and China. In Thailand, the top three anti-malarial drugs have been rendered useless.

The advent of antibiotics, such as penicillin, and their subsequent manufacture on an industrialised scale during World War 2 left other avenues unexplored. This is not surprising given that in the Pacific theatre, e.g. the Kokoda Trail, malaria accounted for three times as many Allied casualties as Japanese bullets.  Alternatives that showed promise were neglected, forgotten or under-funded. Today, we are paying the price for that neglect.

Infection and deaths in hospital is causing grave concern among politicians, a crisis in confidence among the general public, alarm in medical circles, and its defeat has become a Gov’t spending priority [not to mention the huge costs involved – see Appendix A].

One of the neglected areas is the realm and role of the bacteriophage. These are naturally occurring organisms that eat up “superbugs”.

Human phage therapy (bacteriophage) is not new. Before the discovery of penicillin, some doctors around the world investigated the use of phages as healers.

Phage viruses are ‘stalkers’ and destroyers of bacteria and were discovered during World War I by British bacteriologist Frederick Twort Frederick Twort FRS  [2]  and independently two years later by the French-Canadian Felix D’Herelle, at the Pasteur Institute in Paris. Phages can be administered by potion or injection.

Both scientists observed mysterious activity that produced clear areas in agar plates that should have been cloudy with thriving bacteria. D’Herelle identified the microscopic marvel as a new type of parasite – an invisible microbe – a virus parasite that lived on bacteria He named it bacteriophage, derived from two Greek words meaning “bacteria devouring.”

But it was Stalinist Russia and the Eastern Bloc countries that refined the use of human phage therapy (bacteriophage). Production was on a massive scale. The implications, both of their offensive and defensive military use, should not be overlooked.

Alexander Sulakvelidze, of the Eliava Institute, is reported as saying that in Tbilisi, phages never fell out of fashion. They have been used on humans for over  70 years with claims of miraculous results.

Phages offer other advantages over antibiotics. To begin with, they don’t harm benevolent bacteria living in symbiosis with human hosts. Sulakvelidze, the former Georgian lab director who worked extensively with the Eliava Institute describes the process as “a biological arms race.” [3]

However, there are two downsides to this inexpensive form of treatment. Firstly, over time, bacteria will naturally develop resistance to phages – in the same way they do to antibiotic drugs. In the case of the latter, antibiotic, drug resistance has been accelerated by global misuse of them. This does not apply to phages. By contrast phages automatically adapt to keep up with the bacteria, matching their prey’s every mutation. They, in effect, alter their own DNA with the MRSA or whichever superbug they are attacking.

Secondly, even with such positive traits, phages do have their downside. For instance, rather than kill bacteria, some phages make them even more lethal. This happens, for example, with the bacterium that causes cholera. [Addendun – this claim has now be en shown to be untrue – Sept 2012]

Unless a radically new approach is embraced the portents across the world for fighting superbugs are not good. Richard Honour, the CEO of a newly formed company, Phage Therapeutics International, in Bothell, Washington said:

  • “More American lives are lost each year to antibiotic-resistant bacterial infections than were claimed by the entire Vietnam War. The phenomenon isn’t just happening in developing nations,”

When the caring and medical professionals are more comfortable with the concept and use of bacteriophage then their extension into  areas other than antibiotics can be contemplated. One area could be Malaria. Malaria is caused not by the mosquito’s injection, per se, but by the infectious parasites carried within the mosquito.

END

Appendix A

[ only one month after my original 2005 article ]

 Lethal bug is costing NHS £160m a year – and is spreading at a phenomenal rate 

By Maxine Frith,  Social Affairs Correspondent, The Independent, 

8th June 2005

http://news.independent.co.uk/uk/health_medical/story.jsp?story=645088 

Hundreds of hospital wards are being closed and the NHS is losing £160 million a year because of the lethal bug Clostridium difficile (C )difficile), is affecting thousands of patients.

The Government is facing growing criticism from experts over its failure to tackle soaring rates of the C.difficile infection, which is linked to dirty wards and overuse of antibiotics.

The Independent revealed on Monday that the world-famous Stoke Mandeville Hospital in Buckinghamshire has been hit by a virulent new strain of the bug.

Twelve patients at the hospital have died and more than 300 have been infected by C.difficile, which causes severe diarrhoea and spreads quickly from person to person. But a leading microbiologist said the bug was “endemic” throughout the whole of the NHS.

Research by Professor Mark Wilcox at the University of Leeds has found that each case of C.difficile costs the NHS £4,000 in extended stays in hospital.

People over 65, who make up the majority of hospital patients, are particularly vulnerable to the bug. Infection with the bug can increase an elderly patient’s stay by more than three weeks and close a ward for up to eight days.

With 43,000 cases in 2004, an annual increase of 23 per cent, the infection is costing the health service more than £160m a year.

A study by Professor Wilcox, a member of the Hospital Infection Society, also found that one in six hospitals had been forced to close wards because of C.difficile infections. He said: “It is endemic in hospitals. The irony is that everyone has focused on MRSA [the drug-resistant superbug] and dirty hospitals, when in fact there is much more evidence about the link between the environment and C.difficile.”

  • “C.difficile has probably been relegated further back by an undue focus on MRSA, which is unfortunate. Experts in the field have known for years that this has been a rising problem, but the Government only started collecting data 18 months ago and it hasn’t even been published yet, which tells you something.”

He said better cleaning and concerted action to reduce antibiotic use could lead to a significant reduction in C.difficile infections. Overuse of antibiotics has led to bacteria developing resistance to drugs. People treated with antibiotics are also more vulnerable to bugs such as C.difficile, because the drugs destroy their body’s defences against other infections.

Hospitals nationwide have reported rises in cases of the infection in the past year leading to ward closures. Salford Royal Hospitals NHS Trust had to close six wards last year due to outbreaks of C.difficile. The Central Manchester and Manchester Children’s University Hospitals NHS Trust, reported that ward closures due to infections had increased from just one in 1991 to 19 in 2002. Cases of C.difficile at the trust rose from 73 in 1999 to 242 in 2003.

Paul Burstow, the Liberal Democrat spokesman on health, said: “This infection is lethal, and yet there has been very little Government action on it. The Department of Health has chased headlines about MRSA and set a target on that infection, which means managers will go out to hit that target at the expense of other bugs like this one.”

  • “What we need is an approach that looks at all hospital infections, rather than just MRSA.”

The National Audit Office estimates that hospital infections kill 5,000 people a year and cost the NHS £1bn.

In 2000, the NAO made a series of recommendations for the NHS to reduce hospital infections, but a progress report last year was critical about the lack of work to tackle the problem. Hospitals had still not implemented infection control plans and a lack of data, meant there was still no clear indication of the true extent of the problem.

Sir John Bourn, head of the NAO, said: “I am concerned that, four years on from my original report, the NHS still does not have a proper grasp of the extent and cost of hospital-acquired infections in trusts.”

A spokesman for the Department of Health said concerns about overuse of antibiotics were being addressed by the chief medical officer. He said:

  • “NHS hospital pharmacists received £12m from the Department in 2003 to monitor and control more carefully the use of antibiotics. More careful use of antibiotics is a vital part of preventing the development of future resistant bacteria.”

Last night, Stoke Mandeville Hospital said it was getting to grips with the outbreak. Infection rates peaked in February, a spokesman said, although there were still 17 people in the hospital with C.difficile.

Dr Graz Luzzi, associate medical director, said:

  • “Everyone – the infection control team, nurses, doctors and cleaners, have worked extremely hard to implement all the control measures agreed with the Health Protection Agency. “While we are pleased with the progress we are making, we are certainly not complacent and we continue to work hard.”

The hospital has set up a ward for patients hit by the bug, as well as decontaminating all the areas where the infection has been found.

Experts say that a major problem in containing the outbreak is the high bed-occupancy rate in hospitals, coupled with tough targets on waiting times.

Sue Wiseman, infection control adviser to the Royal College of Nursing, said:

  • “We have hospitals that are operating at maximum occupancy all year round now. Then you have targets like the four-hour maximum wait in accident and emergency adding to the problem. Patients get moved out of A & E so hospitals can hit that target, but a bed may not be available on the right ward, so they are moved round the hospital and that just adds to the spread of infection.”

Trusts have also warned that rising budget deficits will make it hard for them to recruit more infection control specialists in the current year. The National Audit Office has recommended that there should be one infection control nurse for every 250 beds, but some hospitals have less than a quarter of that number because of the shortage of trained staff.

Clostridium difficile : the facts

  • * Clostridium difficile earned its name because of the difficulty scientists encountered trying to grow the bacterium in laboratories when it was first identified in the 1930s.
  • * It is a spore forming bacterium, which is part of the ‘normal’ bacteria in up to two-thirds of children under two, but found in only 3 per cent of healthy adults, where the bacterium is kept under control by other bacteria. People over 65 are more susceptible to infection.
  • * C. difficile causes illness when certain antibiotics disturb the balance of ‘normal’ bacteria in the gut, which can lead to severe diarrhoea and, in some cases, death.
  • * Other symptoms can include fever, loss of appetite, nausea and abdominal pain. Its effects can range from extremely slight to diarrhoea of varying severity.
  • * The infection is highly contagious. The spores are hardy and can survive in the environment and be passed by healthcare professionals who have had contact with infected patients, or with surfaces contaminated by it.
  • * It is difficult to diagnose C. difficile infection on the basis of its symptoms alone, therefore the infection is normally diagnosed by carrying out laboratory testing which shows the presence of the toxins in the patient’s faeces.
  • * C. difficile can be treated with specific antibiotics, although there is a risk of relapse in 20-30 per cent of patients. Most sufferers of C. difficile diarrhoea make a full recovery.
  • * Overuse of antibiotics is linked to the infection’s rise. C. difficile is not resistant to treatment, but some cases can be difficult to treat.
  • * Patients who have had gastrointestinal surgery, had a long stay in hospitals, or suffer from weak immune systems are more susceptible to infection.
  • * The strain seen at Stoke MandevilleHospital is thought to be related to a strain which has emerged in the US and Canada.
 
[2] Frederick William Twort FRS (1877–1950) was an English bacteriologist and was the original discoverer in 1915 of bacteriophages (viruses that infect bacteria). He studied medicine atSt Thomas’s Hospital, London.

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

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