From obscurity to ‘superbug’ – The rise of Clostridium difficile

Abstract

The anaerobic bacterium Clostridium difficile is a major nosocomial pathogen, the most commonly diagnosed cause of infectious hospital diarrhoea. C. difficile infection has a wide clinical spectrum, ranging from asymptomatic carriage, to mild-self limiting diarrhoea, and more severe pseudomembranous colitis (PMC). Antimicrobial exposure is the most significant risk factor for acquiring C. difficile and, of course, being exposed to the organism. Prior to the advent of antibiotics, PMC was a relatively rare disease, largely associated with colonic, pelvic or gastric surgery. As the use of antimicrobial agents becamemore common, PMCemerged as an important complication. Although C. difficile was first described in 1935, it was not identified as the aetiological agent of PMC and cases of antibiotic-associated diarrhoea (AAD) until the late 1970s. The observations that the toxic activity of faecal filtrates of patients with PMC could be neutralised by C. sordellii antisera (due to cross-reactivity with C. difficile toxins), together with the failure to isolate C. sordellii from patients, eventually led to C. difficile being incriminated. Toxigenic isolates ofC.difficileusually produce two toxins, toxin A and toxin B, and these are thought of as the major virulence factors. Some strains of C. difficile produce an additional toxin, binary toxin (actin-specific ADP-ribosyltransferase, CDT), first reported in 1988 but not considered important until now. Over the last 25 years, most patients with C. difficile infection have not progressed to PMC, due to increased awareness and better laboratory diagnosis. The term C. difficile-associated diarrhoea (CDAD) was initially a popular way of describing the disease; however, this has largely been replaced by the term ‘C. difficile infection’ (CDI). Inhospitals,C.difficilehasbeenviewedbymany asmoreof an annoyance rather than a serious hospital-acquired infection. This has changed as a recent epidemic in North America, associated with high mortality and morbidity, has been due to the emergence of a new strain of C. difficile. The new strain is resistant to fluoroquinolone antimicrobials and fluoroquinolone use in humans appears to be driving the epidemic. The strain of C. difficile responsible for the epidemic in Canada (NAP1/BI in North America and PCR ribotype 027 in Europe) has now been linked to outbreaks in multiple countries, including Great Britain, the USA, France, BelgiumandTheNetherlands, and poses a significant threat to public health in the Australasian region. Even non-epidemic CDI represents a major burden to the healthcare system. One study from ~15 years ago showed that C. difficile cost a 700-bed teaching hospital in Australia about AU$1.25million annually, either as a real or opportunity cost. Current conservative estimates suggest that the cost of CDI in the USA now exceeds US$3 billion annually. The attributable mortality and morbidity between 2002 and 2003 in the Canadian epidemic has been calculated. On average, each case resulted in an additional 10.7 days in hospital and, compared with controls, patients with CDI had a significantly higher mortality of >10% in those aged 70 years or more. There has also been an apparent increase in communityacquired CDI overseas in the absence of classic risk factors, such as antibiotic exposure. Despite assertions that community-acquired CDI is a new disease, it is not new, just under-diagnosed. Therefore, it is difficult to tell whether this is a true increase or better case ascertainment. Unfortunately many laboratories servicing general practitioners often do not examine faecal samples forC. difficile unless asked because of the continuing misconception that CDI is a hospital problem only. Because of the increase in community-acquired CDI there has been speculation thatC. difficilemay be part of a zoonosis and that transmission of infection via spores is food-borne. C. difficile is known to colonise many animals. Indeed, as with humans, the gastrointestinal tracts of most infant animals are probably colonised by C. difficile until weaning. Most animal isolates of C. difficile produce binary toxin, and both pigs and cattle in Europe harbour PCR ribotype 078 a strain that, like ribotype 027, also produces more toxins A and B. In The Netherlands, since 2005, there has been an increase in prevalence of human CDI with ribotype 078 strains. These infections were in a younger population and more frequently community-acquired. In the eastern part of The Netherlands where >90% of the country’s pig farms are located, 22.4% of human isolates were ribotype 078, and human and pig strains ofC.difficilewerehighlygenetically related.Ofgreat concern is the fact that ribotype 078 is now the third most common ribotype of C. difficile isolated from human infections across Europe.