Cl Difficile: Worrying Life Cycle
Written by Dr Rob McEvoy
Friday, 29 September 2017
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We know that travellers can bring antibiotic resistant bugs to Australia from overseas, such as 29092017-Riley-Thomas-Prof-Sept17Prof Tom Riley MAppEpid, PhD, FASM, FAAM, FRCPath, FFSc(RCPA)resistant commensal gut E coli, and injudicious use of antibiotics in the parent country, or here, might make things worse. But what if the bug has characteristics that allow some human behaviours to select it out to cause illness?

That’s where Murdoch University Professor of Public Health Tom Riley and Clostridium difficile come in. Although Tom’s first paper was in 1980, this bacteria has been around for a lot longer as an opportunist that inhabits humans. The Cl difficile spores are a unique problem because they are transmitted easily in the community and are hard to kill.

When those weakened by something such as inflammatory bowel disease become infected the results can be catastrophic. It can bring hospitals to a standstill while everything is cleaned thoroughly, mainly to get rid of spores. If it happens to be a more resistant strain, such as ribotype 027 in North America, there is even more concern about spread.

Community full of spores

“The bug is different, so the story is different. We are talking about the spread of one bug and yet we have big piles of pig, horse and cow manure, full of Cl difficile, which we are spreading on vegetables and lawns,” he said.

This story is different in one main respect – how Clostridium spores are spread. Everyone is familiar with the wide use of broad spectrum antibiotics, creating selective pressure that encourages the transfer of genes from one bug to another, mainly in the human gut. In that way we get more resistant E coli, Klebsiella, Campylobacter, Staph aureus, Shigella etc. People can become carriers, get sick and are hospitalised where they prove a problem, and we read about how hospital doctors struggle to find the right antibiotic to fix them or their contacts.

“About 40 years ago we discovered that Cl difficile caused problems in hospitals. But the community prevalence of Cl difficile infection has increased dramatically, not primarily because antibiotics are more used in the community but because there is more Cl difficile multiplying in food-production animals,” Tom said.

“Wherever their manure goes, the potential to spread Cl difficile increases. Calves and piglets all get colonised because farmers use ceftiofur. We published a paper this year – most of the lawn in Perth is full of Cl difficile because much of the turf is grown on pig manure.”

“We have to stop putting antibiotics into production animals. Cl difficile is intrinsically resistant to cephalosporins so why approve it in production animals. It’s stupid.”

Some explanations

Ceftiofur is a third generation cepaholosporin approved only for veterinary medicine. Cl difficile is not normally a gut commensal except in young babies, whether human, piglet or calf, and is eliminated by the time babies are weaned, which in production animals (if the mother’s milk does not contain broad spectrum antibiotic), is at about three weeks. We arbitrarily say human babies are weaned by the age of two.

Some strains of Cl difficile are associated with explosive diarrhoea and conditions such as pseudomembranous colitis in humans, and colitis X in horses, perhaps because these Cl difficile bugs produce an enterotoxin and their presence is favoured by the use of broad spectrum antibiotics.

“I wrote in the MJA in 2006 about the ribotype 027 strain in hospitals. I said then, ‘be warned it is coming to kill us all’ but it didn’t. We didn’t get the nasty 027 strain that was the scourge of Europe and North America because we don’t use fluoroquinolones [e.g. levofloxacin and moxifloxacin] as much as they do in North America. The 027 strain’s resistance to fluoroquinolones was driving its spread there and it didn’t establish here because there wasn’t that selective pressure.”

In the US, fluoroquinolone use extended to acute bacterial sinusitis, acute on chronic bronchitis and uncomplicated urinary tract infections.

Those antibiotics again29092017-Pigs-sow-piglets-feeding

“Having said that, if you look at the mechanisms that allowed that strain to establish, we have all those features in Australia with our macrolide use. It’s because we are in love with macrolides [e.g. azithromycin] in the community and Cl difficile does mutate to macrolide resistance fairly easily.”

Antibiotic resistance of Cl difficile is one thing. The prevalence of Cl difficile in the community is another. Some of Tom’s observations have come from new technology (mainly the more specific identification of strains through genome sequencing), and the benefit of some recent hindsight.

“Typing of Cl difficile allows us to distinguish strains of bacteria with far greater accuracy. So we are sequencing more Cl difficile and inadvertently finding cases where there is contamination from contact with the most common source, food.”

“The reason the numbers of Cl difficile in Australia didn’t increase as expected was because, worldwide, Cl difficile in humans had been driven by the US use of cephalosporins [ceftiofur] in production animals.” This happened some 10 years before Australia.

“Australia only started using cephalosporins as a veterinary medicine from about 2000 and today most use occurs off label. A farmer might think that one of his piglets – one of 3000 in a farrowing shed – has an enteropathic Ecoli causing diarrhoea, and that all the piglets might die, even though they have been vaccinated, so he gives every mother pig in the shed a jab of ceftiofur.”

Colonised at first gulp

“Left alone, piglets get colonised by Cl difficile, depending on their birthing order which dictates the piglet that gets the biggest gulp of colostrum from the mother. Colonisation is highest by Day 7 and usually gone by Day 14, with other bowel flora replacing it. That’s what happens with human babies too but weaning is not regimented as in pig farming.”

Although Tom says Australian hospitals are better with their infection control and cleaning than US hospitals, he is worried that the spread of Cl difficile in our community will lead to its greater introduction into hospitals.

He says part of the problem in bringing what is happening to people’s attention is that we do not attribute cases to community infection as we should. He puts community infection rates at about 50%, and says many infections are in fact reinfections rather relapses after treatment.

“We don’t count hospital-identified cases very well e.g. ED presentations are classified as hospital [and other examples are below]. In WA, infections are coming from lawns, a little from eating contaminated vegetables, and contaminated households. In a pilot study we found that 10% of kitchens in Perth were affected.”

He has problems getting those that hold the purse strings interested in preventive measures. He thinks interest in his ideas is stronger in the UK, where they have about half the rate of Cl difficile infection, due to part of their funding requirements.

“There is a financial penalty if they get more than their allotted cases,” Tom said.

Anecdotal evidence overwhelming

For example, when they studied the of Cl difficile in the community in 2011-2013 they found two October-December seasonal peaks.

“That was due to imported onions. We were in an El Nino weather pattern in the summer of 2011-12, and the Australian onion crop in the eastern states failed because of drought, so we imported onions from California that were contaminated with Cl difficile. The epidemiological evidence was irrefutable. The situation is in reverse now, so the problem has gone away.”

“We only import about 4% of our food in Australia, so we have a good handle on where it comes from. That’s why it was relatively easy to investigate,” he explained.

“If you look at patients with IBS, their rates of Cl difficile infection have skyrocketed over the past 5-10 years. These people are coming into contact with Cl difficile more often in the community, and they have an abnormal gut flora so they are more likely to get Cl difficile, which doubles the chances of dying on top of your ulcerative colitis.”

“The other problem group is the haematology or oncology groups being treated at home. They are more susceptible because they are often on antibiotics and have a poor immune system. The problem with those patients is if they get Cl difficile it is called ‘hospital acquired’ because they are in and out of hospital all the time but most present to ED with diarrhoea and an animal bug.”

“There are case reports of two patients, a child and an elderly man, both infected with Cl difficile that came from an identical animal source. Because the patients lived in different locations the only way that could have happened was from a common source, I suspect salami or a poor quality meat where food preparation had not killed the spores.”

“Most of the Cl difficile infections are coming from the community. We need to educate GPs more about this and I don’t think there is enough testing of diarrhoea patients. However, the guidelines say don’t test unless there is blood in the stool and they have had diarrhoea for three weeks. Generally, Cl difficile infections in the community are not as bad because people are inherently more healthy.”