Clostridium difficile vaccine - development on track that may produce a useable vaccine in at least 3 years time.

Jab to beat superbugs: British vaccine could save thousands of lives a year is the Evening Standard screaming headline today. (and stablemate Daily Mail)

Well up to a point Lord Copper.

On the 18th December Acambis (LSE: ACM), a vaccine development company, who are developing the first (and only) vaccine against Clostridium difficile-associated disease (CDAD) announced that "a number of vaccine formulations that show improved stability profiles compared with material used in previous Phase 1 trials." ...in outside the lab speak that means they were getting better at producing a potential vaccine.


Furthermore they said they would start (initiate) a proof-of-concept trial of its vaccine towards the end of 2008, which will provide data within 12-18 months of commencing the study.

Dr Michael Watson, Acambis' Executive Vice President, Research & Development, said in their press release of that date ;

'C. difficile-associated disease is a major public health problem and Acambis has the only vaccine in development. We have previously shown that this vaccine can achieve seroconversion rates of up to 100% and, with our formulation work now completed, we are focused on getting our vaccine to proof-of-concept as quickly as possible.'

Acambis say that there are at least 360,000 cases of CDAD in the US alone, with estimated annual costs to the US and European healthcare systems totalling more than $5bn

No need to get excited about jabs crushing superbugs, hygienic handwashing, more controls on antiobiotic use, isolation of patients meanwhile might help.

Clostridium difficile in hospitals - a present and growing danger

Lord Patel has always maintained an unhealthy interest in the communicable diseases that patients enjoy during their hospital visits, since the National Audit report in 2002. It is evident that Clostridium difficile (especially amngst the elderly) is a a growing and very unpleasant problem.

Updates on Clostridium difficile in NI Hospitals

The Irish Times reports that Stormont (NI) Health Minister Michael McGimpsey has allocated an additional expenditure ( well he called it an "investment") £9 million would be invested over the next 3 years in a bid to improve patient safety and reduce the spread of infections like MRSA and Clostridium difficile

Single rooms are to be introduced in Northern Ireland hospitals and a new e hospital being built in Co Fermanagh will be the first to have single rooms for all appropriate patients. new measuress have also been introduced , including restrictions on visitors, a rolling programme of unannounced hygiene inspections to all hospitals and a new dress code for all health care staff.

An official outbreak of Clostridium difficile ( of a highly virulent ribotype 027 ) has been declared at Antrim Hospital (which Members of Stormont's health committee visited yesterday) where a specialist ward has been set up to treat patients after the number of cases in a month nearly trebled.

Updates on Clostridium difficile in Scotland

C. difficile Working Group, 1st report in December 2007 on the (now mandatory) surveillance of Clostridium difficile associated disease (CDAD) in Scotland (which only has data for cases in hospital patients > 65 years) states that there were 6035 cases for the whole of Scotland. The annual rate for Scotland per 1000 acute occupied bed days in persons ≥ 65 years old was 2.03 which they say is "comparable to rates generated in England".

The report is a model of it's kind and it is good to see that "approximately 65 % of the laboratory data are received by HPS via the electronic reporting system ECOSS (Electronic Communication of Surveillance in Scotland)". Analysis of samples includes ribotyping which is best presented int his graph - only two cases of ribotype o27 were found with 1 isolate in October.

In a sombre conclusion they say

"In conclusion this first year of data collection under the mandatory surveillance programme for Scotland has shown that healthcare associated Clostridium difficile associated disease is a significant problem throughout the healthcare system in Scotland. CDAD is today considered the leading cause of healthcare associated diarrhoea in the industrialised countries."

It is interesting to note that on Monday, 29 October 2007 Lord Darzi of Denham Parliamentary Under-Secretary, Department of Health in answer to a question from Lord Morris was only able to give such figures up to 2005. But they were alarming

	1999	2001	2002	2003	2004	2005
Mentions of C.diff	918	1,150	1,338	1,702	2,155	3,697
Number of these where underlying cause of death is C. diff	499	661	709	912	1,187	2,008

Figures from ONS for deaths involving CDI for primary care trusts cannot be provided "without disproportionate costs".

The number of deaths in hospital in Fife involving Clostridium difficile were 23 in 2005, and 41 in 2006 , where it was the main cause have gone down, from 13 in 2005, to 11 in 2006 which means that thenumber of deaths where the bug was considered to be a contributing cause trebled in one year.

NHS Highland said there had been 120 cases of Clostridium difficile last year, up from 50 in 2005, C. difficile was also an "underlying or contributing cause of death" for 5 patients in the area last year.

Clostridium difficile Ribotype 027 - Global incidence

Since 2003, the emergence and distribution of a hypervirulent strain of Clostridium difficile PCR ribotype 027 has been described in North America, Japan, England and Wales, Ireland, the Netherlands, Belgium, Luxembourg, and France, and has also been detected in Austria, Scotland, Switzerland, Poland and Denmark and has ben present in Sweden for several years.This new epidemic strain (PFGE type BI/NAP1 in the USA , also called ribotype 027) appears to be more virulent, with the ability to produce greater quantities of toxins A and B due to a mutant toxin controlling gene.

C. difficile is difficult to culture and none of the commercially available toxin tests differentiate between the various strains of C. difficile - it also appears to be it is resistant to newer fluoroquinolones. Both factors which may have aided it's rapid spread.

Alyson Smith Thames Valley Health Protection Unit, Bucks,UK reported the first evident UK cases in June 2005.

In the Netherlands, St. Jansdal Hospital in Harderwijk, the incidence of C. difficile-associated diarrhoea (CDAD) increased from 4 per 10 000 patient admissions in 2004 to 83 per 10 000 in the months April to July 2005 -this was characterised as C. difficile ribotype 027. (see also In total 17 Dutch institutions have detected patients with ribotype 027 so far, 15 hospitals
and 2 nursing homes )

In December 2007, C. difficile PCR ribotype 027 was found in two cases of C. difficile-associated disease treated in a hospital in Oslo, Norway.

Evidently treatment of severe or recurrent C. difficile -associated diarrhea is an evolving science and recent literature from outbreaks of severe disease in Canada and the U.S. suggest that mortality is associated with advanced age (≥ 75 years), immunosuppression, shock requiring vasopressors, very high WBC (> 50,000 cells/mm), and elevated lactate levels ( ≥ 5 mmol/L).

Advice from the Dutch Working Party on Infection Prevention is that in all patients who develop diarrhoea in hospital, especially during or after treatment with antibiotics or chemotherapeutic agents, an infection with C. difficile ribotype 027 should be suspected... and treated accordingly.


Hospitals on alert as superbug C difficile becomes resistant to key drug - news report in the Scotsman Sunday January 28th states that a new report by public health officials at the Health Protection Agency Centre for Infections has a report that taken from patients in the Leeds area of England showed that a C difficile ribotype 001 , the 2nd most common in the UK had "reduced susceptibility" to metronidazole - the antibiotic of choice in treating infections.That leaves only vancomycin as the last line of defence for antibiotic treatment.

Out of 88 tests 21 showed "reduced susceptibility".

Examination of the HPA website could find no evidence of the quoted report

There is however a useful article by Jon Brazier, Consultant Clinical Scientist and Head of the
Anaerobe Reference Laboratory, part of the National Public Health Service for Wales Microbiology Cardiff laboratory situated in the University Hospital of Wales. This can be found here. Clostridium difficile disease: a case of greater virulence and new risk factors page 20 HPA magazine Volume 5 Suimmer 2006. This has valuable information on the increasing numbers and spread of different ribotypes of C. difficile within the UK.

See also the Leeds Health Trust Annual report November 26th 2007 - The total number of C difficile laboratory reports for LTHT (indicative of cases of antibiotic-associated diarrhoea) across the Trust: 860(≥65; 648) in 2006/7, 645(≥65;490) in 2005/6, 692 in 2004/5, 743 in 2003/4, and 883 in 2002/3. The C. difficile rate for patients equal to or greater than 65 years in LTHT for 2004 was 2.0/1000 bed days, for 2005 1.86/1000 bed days, and for 2006 1.53/1000 bed days. Nationally there has been an increase of 5.5% in the number of C difficile reports for patients equal to or greater than (≥) 65 years.

Leeds have introduced routine intensive prospective molecular and clinical surveillance of hospital and community CD cases to determine the relative prevalence of epidemic strains, and the spread of CD 027. It is the only such service in the UK. We have examined ~500 cases in detail. C. difficile 027 was identified in both hospital and GP patients (4% of all cases), mainly causing mild/mod disease, and with only minimal evidence of spread or clustering. Intensive surveillance will continue to improve our understanding of C. difficile infection epidemiology and to detect emergent strains.

The Health Protection Agency asked Leeds to establish and lead a Clostridium difficile Ribotyping Network for England (CDRNE). The CDRNE consists of six regional microbiology laboratories in England: Leeds (Reference Laboratory, Leeds General Infirmary), Birmingham (Heartlands Hospital), London (University College Hospital), Manchester (Manchester Royal Infirmary), Newcastle (Newcastle General Hospital) and Southampton (Southampton General Hospital). The CDRNE service is now operational, and is to be used by hospitals/infection control teams in England to investigate increased frequency or severity of cases of C. difficile infection, increased mortality, or increased recurrence rate.


PS : Minister humiliated over Rose Gibb NHS payout Rose Gibb resigned 1 day ahead of a damning Healthcare Commission report into two outbreaks of Clostridium difficile, which led to the deaths of at least 90 patients, at Maidstone and Tunbridge Wells NHS Trust . She will receive a £75,000 pay-off despite the Health Secretary Alan Johnson’s pledge at the time that it would be witheld.

Clostridium epidemics and the overprescription and use of antibiotics - some history notes

Lancelot Hogben in his entertaining "unauthorised autobiography" explained how when he was Head of Medical Statistics at the War Office his team unearthed the localised resistance of Neisseria gonorrhoeae in the region of Naples at the end of the war.

This resistance of up to 40% of the strains tested, was a direct result of the German military medical authorities in providing free supplies of sulphonamides as a prophylactic measure to prostitutes who might entertain the bored German soldiery.

This is the first recorded instance of micro-organisms developing resistance to chemical treatments. A remarkable and little known success of medical science.

Hgben was to remark in his autobiography ( page 186) that even 15 years later "surgeons were dismayed by the incidence of post-operative sepsis due to resistant strains of microorganisms which had developed following indiscriminate prescribing of sulphonamides and antiobiotics."

The continuing widespread use of vancomycin and other "wide spectrum" antibiotics in UK medicine which has contributed (with many other factors) to the epidemics of Staphylococcal and Clostridium is a lesson still to be learnt over 60 years later.

History of Sulfonamides

Bayer AG (who had synthesised apirin) first synthesised the drug as part of their work on dye chemicals, they eventually marketed as Prontasil in 1932. This was undertaken by Josef Klarer and was tested in animals by Gerhard Domagk.

For this Klarer was awarded the 1939 Nobel prize, but in 1937, Hitler had issued a decree that forbade Germans from accepting Nobel Prizes. He considered pacifist journalist Carl von Ossiettzky's 1935 peace prize a slap in the face. ( He was a German pacifist, editor of the antimilitarist weekly Weltbühne from 1927, imprisoned in 1932 for articles exposing secret rearmament in Germany. After election in 1933 Hitler had him put in a concentration camp. Suffering from tuberculosis, he was removed to a prison hospital shortly before the announcement that he had been awarded the 1935 Nobel Peace Prize. Brandt a Swedish MP nominated Hitler for the Peace prize in 1938 !)

Publication of the results of the antiobiotic effects of the sulphonamides was delayed until 1935 and it was patented at the same time by Klarer and his research partner Fritz Mietzsch.

Later the Pasteur Insitute discovered that the action of the drug was a result of being metabolized into 2 parts - one of which interrupted the folate synthesis system which was critical to the production of nucleic acids... an important step in unravelling the structure and function of DNA. (See pic of Linus Pauling with model of sulfanilimide structure)

This wasn't helpful to Bayer because sulfanilimide's dye patent had expired and its manufacture readily undertaken , the drug was therefore widely available.

The drug was widely used throughout WWII on the surface of open battle wounds, shaken on by a sort of pepper pot, by all the forces in the conflict.

In war time and post war Britain the drug M&B 693 , (boxed in 25's) synthesised by May & Baker in Dagenham from Sulphapyridine provided the cure for the hitherto killer-disease, bacterial pneumonia. Their prescription by the doctor signified to the family the measure of concern for the patient - no doubt they were a huge expemnse in pre NHS Britain.

A variant was branded and sold as "Gonazole".

The pale pink tablets stamped with the initials M&B were probably one of the first widely counterfeited pharmacuetical products.

M&B 760 was Sulphathiazole and introduced later ,then came Sulphanilamide then Sulphadiazine, etc each a little better and less dangerous than the previous one. Sulphacetamide is still in use - one of the best eye drops for conjunctivitis.

Hospital Acquired Infections - A Bad News Day

Rosa Kleb, one of the more evil masterminds of Flemings curious and sinister world is not responsible for Klebsiella pneumoniae. This talented microbe was named after the famous German pathologist (one of many in the last century) Edwin Klebs (1834–1913) who worked with Rudolf Virchow at the Pathological Institute in Berlin from 1861 until 1866. His main claim to fame is his identification of the bacterium Corynebacterium diphtheriae as the aetiological cause of diphtheria. The bacterial genus Klebsiella is named in to honour him.

Klebsiella pneumoniae (KP) is a bacterium normally found in the mouth, skin and intestines. Strains resistant to antibiotics are being found with increasing frequency in hospitals. KP causes bacterial pneumonia, it is commonly involved in hospital-acquired wound and urinary-tract infections, particularly in patients with weak immune systems, especially the elderly - the same group who are susceptible to other HAI's such as Staphylococcus aureus.

Faeces are the most significant source of infection, followed by contact with contaminated instruments, catheters, speculums, colonoscopes. Therefore strict regimes of hand washing are required by anyone who handles patients.

Early in March there were reports on Israeli TV that apparently KP killed more than 100 very sick patients in a number of hospitals around the country and sensational charges of a cover up against the Health Ministry were made.

It soon became apparent that the problem was more serious than was at first reported.

Responding belatedly the Ministry of Health appointed Prof. Yehuda Carmeli, a leading epidemiologist at Tel Aviv's Sourasky Medical Center, to head a team, to deal with an outbreak whose scale had been previously not made public.

“Between 400 to 500 people have been infected by the bug, and 30 to 40 percent of them have already died,”

said Yehuda Carmeli, the head of the epidemiology unit at the Sourasky Medical Center in Tel Aviv.

“However, it is important to note that most of them were in a serious condition, and some were suffering from prior medical conditions.”

The Ministry said later that most of those infected have been hospitalized for over 25 days, and their average age was about 75. It appears that the organism is resistant to third generation cephalosporins and the latest aminoglycosides of the Streptomycin family. It appears that KP has a neat trick of producing a mutant that produces an enzyme known as "extended-spectrum beta lactamases," or ESBLs which allows them to hydrolyze cephalosporins. 2 New York hospitals report 25% of infections with this refined biochemistry. The Sourasky Medical Center laboratory has expertise in molecular typing of bacterial pathogens, genetic analysis of mechanisms of antibiotic resistance, including beta-lactamases and collaborate with several international groups on the study of antibiotic resistance. ( Carmeli has identified Acinetobacter baumanii as a newer and possibly more dangerous antiobiotic resistant organism - Israel hospital report- see Footnote)

Although Health Ministry Director-General Professor Avi Yisraeli told reporters only very ill patients in hospitals are at risk, the public reacted to the news reports of the infections by avoiding hospitals altogether. Emergency rooms in Israeli hospitals emptied,leading doctors and the Health Ministry to warn of the dangers of avoiding treatment when necessary.

Riding on the back of this, Avi Yisraeli seized the opportunity to tackle Prime Minister Olmert to ask for 2.5 million shekels (US$600,000) of emergency funding to control the infection, and to invest in three new hospitals by 2015. At the time, Ben-Yizri told the Prime Minister that hospitals are in immediate need of an additional 3,000 beds - there are no reports about how successful he was.

It appears that Israel is the only country outside the US to have reported widespread antibiotic-resistant strain of Klebsiella although very isolated cases have been reported as widely as Thailand. the Czech republic and Hangzou in China. The emergence of multi-drug resistant Klebsiella will become a global concern just as MRSA's have ,and increasingly Multiple Drug Resistant TB's (MDRTB) have been invading the EU from eastern Europe and Russia whose prisons are a huge and potent resevoir of HIV / TB - the peristent habit of health autorities to conceal the problem from the public only hinders the resolution of the problem.... unless of course the policy is to kill off the old and save on their pension benefits.

For an example go to these 2 rports today at BBC Online (Outbreak details Costs of clean up) about the Clostridium difficile outbreak in the James Paget Hospital in Gorleston, Norfolk which occurred between December and March and resulted in 17 deaths. This has just been disclosed and will involve costs of £400,000 to sterilise this one hospital. There were 2 previous outbreaks of the same organism at Stoke Mandeville between October 2003 and June 2005, and overall 334 patients were infected and at least 33 died in this period. An enquiry ordered by Patricia Hewitt that reported last June said that ther may have been up to 65 fatalities.

Cases of C. difficile infection in patients aged 65 years and above increased by 17.2% in England over the last year, from 44,107 in 2004 to 51,690 in 2005, (Source Health Protection Agency.)
The Healthcare Commission's inquiry (June 2006) into the Stoke Mandeville outbreak identified failings by the senior managers at the hospital, which forms part of the Buckinghamshire Hospitals NHS Trust.

It said they failed to follow advice on stopping the spread of infection, even at the height of the outbreak, from infection control staff, clinicians, nurses, and the Health Protection Agency and failed to learn lessons after the 1st outbreak.

The report said they were too busy focusing on other areas, such as meeting government targets and finance control.

In other words they were more concerned about controlling cash than disease... which we find throughout the world results in perfect cash control ... and rampaging lethal, and often fatal infections.

FOOTNOTE

Acineobacter baumannii has it's own website somewhat sensational it does appear that this is a major problem with soldiers returning from medical treatment in Gwermany after wounding in Iraq and Afghanistan ....

Early this year an outbreak of MDR Acinetobacter baumannii swept over Arizona, 236 cases in just 2 months. It was reported by the state disease monitoring systems, but ignored on the national level.This outbreak that is spreading nation wide is largely due to the war in Iraq, and because of a legal technicality in reporting, the military and CDC will not disss it publicly. More people come forward, bit by bit, telling stories of how the hospital played down their infection. The one person who could have done something about it, "Rep. Dennis Moore" has walked away from the issue deciding it wasn't worth getting into even after what he had seen on a visit to Walter Reed.Acinetobacter baumannii infections among patients at military medical facilities treating injured U.S. service members, 2002-2004.

Analysis of antibiotic resistance genes in multidrug-resistant Acinetobacter sp. isolates from military and civilian patients treated at the Walter Reed Army Medical Center.

The CDC reported reported an increasing number of A. baumannii bloodstream infections in patients at military medical facilities in which service members injured in theoperations in Iraq and Afghanistan in 2004. A. baumannii survives even on dry surfaces for up to 20 days, and so constitutes a high risk of spread and contamination in hospitals, putting immune-compromised and other patients at risk for drug resistant infections that are often fatal and generally expensive to treat. (there is increasing evidence that smokers with COPD are especially prone to infection).

See this for news of "adverse events" in UK hospitals...if you can find it , also read Ivan Illych LIMITS TO MEDICINE. Medical Nemesis: The Expropriation of Health. London. Calder and Boyars. Ideas in Progress 1976. The first sentence of which is "'The medical establishment has become a major threat to health'. he also identified the habit of the medical / pharma nexus to "medicalise" problems which has led to the more modern blight of "Disease Mongering".Got a pain in your foot ... well you may have "painful foot syndrome." .. You think this is a joke , 3 million Australians are said by one Oz medical luminary to suffer from "restless leg syndrome".. and will prescribe you a pharmaceutical treatment.