New research suggests that antibiotic treatment could be asymptomatically inducing the transmission of the healthcare-acquired infection, C. difficile, contributing to the outbreaks that have recently been widely reported in hospitals and other settings. A team of scientists have successfully mirrored the infection cycle of C. difficile by generating a 'mouse hospital' with conditions mimicking the human environment in which C. difficile is transmitted.
The results have implications for infection control measures in the healthcare environment and open the door for the development of treatments and improved diagnosis of C. difficile.
At present, healthcare professionals manage the threat of C. difficile by observing stringent hygiene and isolation practices primarily by dealing with patients who exhibit the symptoms of infection - including diarrhoea and fever. But today's publication suggests that widening the targets of infection control in hospitals, to include all patients receiving antibiotic treatment - although logistically complex - is worth investigating.
"C. difficile is a highly resistant and highly infectious pathogen and resistant to many front line antibiotics," explains Dr Trevor Lawley, Wellcome Trust Sanger Institute researcher and lead author on the study. "Until now, animal studies have focussed on the observable, acute symptoms of C. difficile. But, to understand how this highly infectious pathogen spreads, investigating the entire cycle of transmission is absolutely vital. We looked at mice carrying C. difficile and observed that they shed low levels of spores and, crucially, they did not infect other mice."
"But when we treated mice with antibiotics, we saw a dramatic rise in the levels of spores shed - leading to what we have described as a 'supershedder state' and transmission of C. difficile among mice. Importantly, transmission occurs even in the absence of clinical symptoms."
C. difficile transmission relies on the shedding of highly resistant spores in the faeces of humans. These bacterial spores are essentially dormant cells with protective outer layers making them well-adapted for survival and dispersal in a wide range of environmental conditions. When humans shed spores in their faeces, those spores are capable of surviving dormant in the environment for long periods of time, under harsh conditions and in temperatures up to 70ºC, before reintroduction and infection in a new human host.
"We treated mice with short and longer courses of antibiotics," says Professor Gordon Dougan, Head of Pathogen Genetics at the Sanger Institute and senior author on the study. "After a short course most mice had dropped back to normal spore shedding levels around two weeks after cessation of the treatment. But after long term exposure to antibiotics some of the mice remained in their 'supershedder' state for weeks or even longer after treatment was stopped. We should consider that patients still pose a considerable transmission threat some weeks after treatment is terminated even if they have not exhibited signs of C. difficile disease."
The team also found that there was a considerable threat from environmental contamination. Even short-term housing of 'supershedder' mice in transfer vessels could contaminate the area, leading to infection in naïve - or uninfected - mice, and suggesting that even the briefest environmental contamination is a potential infection threat.
The administration of antibiotics has been a known risk factor in the development of C. difficile infection for some time. The bacterium can live inside the gut of healthy human beings, existing as part of a natural, diverse and potentially beneficial ecosystem of bacteria and microorganisms -the microbiota - that we are all are host to.
When the team treated mice with antibiotics, the balance of the microbial ecosystem was disrupted. Because C. difficile is resistant to many antibiotics, the bacterium was able to exploit the opportunity and proliferate where other gut bacteria had succumbed to the antibiotics. This allowed the C. difficile to flourish and dominate the microbiota of the mouse.
Although the majority of mice exhibited no visible symptoms of C. difficile, the team found that one particular group of knockout mice with mutations associated with impaired immune defence began to lose weight and became moribund. The similarity with the human manifestation of the disease, where older or immune impaired patients tend to exhibit the symptoms of acute C. difficile infection, is clear and strengthens utility the mouse model as a valuable tool for investigation into the transmission of C. difficile.
Today's results are published soon after a previous publication, where the team demonstrated that C. difficile spores could be isolated and highly purified - essentially washed - in a way that maintains their natural characteristics and resistance to an array environmental conditions. This ability to purify spores, while preserving their characteristics, allows researchers to use them in experimental settings and to establish their structure.