Friday, December 23, 2016 Written by Ellen Jo Baron, Ph.D., D(ABMM), Prof. Emerita, Stanford University Director of Medical Affairs, Cepheid

Clostridium difficile Ribotype 027: Why Should We Care?

The first hint that something new was happening with regard to Clostridum difficile infections (CDI) was a study presented at the 2004 annual meeting of the Infectious Diseases Society of America by epidemiologists from the Centers for Disease Control and Prevention (CDC) and other investigators describing an emerging epidemic strain that was typically resistant to fluoroquinolones.1

In 2005, a Lancet paper described an emerging strain associated with outbreaks of severe disease in North America and Europe.2 Authors from a hospital in Quebec noticed that patients with CDI were dying within 30 days of diagnosis at a rate in 2003 that was twice that observed in earlier periods. After testing 124 strains of C. difficile and finding 58 hospital-acquired and 14 community-acquired strains of toxinotype III (a previously uncommon toxinotype), they realized that a new strain was emerging. Along with CDC and experts from the United Kingdom, they fully characterized 15 of the new toxinotype III isolates, comparing them with historical strains of the previous prevailing toxinotype 0.3

Several reports were published in the medical literature describing more severe disease, more rapid and more common relapses, and higher mortality rates associated with isolates of the new strain.4 Scientists studying this strain, now being called "hypervirulent" and "epidemic," found some interesting characteristics. The most striking finding, thought to contribute to its enhanced virulence, was a missing base at nucleotide 117 of the pathogenicity locus (PaLoc) regulatory gene tcdC. This regulator gene controls the expression of both the toxin A gene (tcdA) and toxin B gene (tcdB) located in the pathogenicity locus. A landmark paper by Lyras and colleagues from Australia showed in animal models that C. difficile organisms lacking toxin B were not pathogenic, even if they produced toxin A, but toxin B-only strains were fully pathogenic.5 New studies have shown the importance of both toxins in the hamster model.6 Toxin B, the cytotoxin, results in the destruction of the colonic mucosal cells that leads directly to production of the necrotic and eroded mucosal lining known as pseudomembranous colitis. The single nucleotide deletion found in strains of the emerging toxinotype III, also referred to by PCR ribotyping as type 027, by restriction endonuclease analysis (REA) as BI, and by pulsed-field gel electrophoresis (PFGE) as NAP1, down-regulated the toxin-limiting action of the tcdC gene, allowing these strains to produce considerably higher amounts of both toxins A and B than wild type toxinotype 0 strains.7 In fact, these strains produced 20 times more toxins A and B than most previously circulating strains.8 The 027 strain also had an 18-base pair deletion within tcdC, although the effect of that deletion, which keeps the protein in frame, was unknown. Finally, the epidemic strain produced a third toxin, called binary toxin, which is not exclusive to this ribotype but may contribute to increased capacity to cause disease. Independent studies have shown binary toxin to have ADP-ribosyltransferase activity.9

Ribotype 027 isolates had another characteristic that no doubt contributed to their ability to spread quickly in a healthcare environment, they produced very high levels of spores compared to other C. difficile strains.7,8 Some infection preventionists even fumigated patient rooms with aerosolized hydrogen peroxide, the same sporicidal compound used to clear the Hart Senate Office Building after the anthrax scare in 2001,10 in an effort to control spread of the disease. Higher levels of spores in the environment may lead to more efficient spread from patient to patient, but may also lead to higher loading doses per patient who is exposed. Most models of infection show that there is a relationship between the size of the inoculating dose and the severity of disease… another potential explanation for poor patient outcomes in the hospital outbreak setting.

Some clinicians have expressed the opinion that the 027 strain deserves more aggressive treatment measures, such as using vancomycin instead of metronidazole, even for the initial episode, but the current prevailing view is that treatment should be based on disease severity and not on strain type, since there are reports of mild disease in sporadic (as opposed to epidemic) cases of 027 infection.11 This observation could be consistent with the "spore loading dose" hypothesis; in a hospital outbreak setting, environmental spore counts are likely to be higher, especially so for an organism like the 027 strain that produces more than its fair share of spores. Sporadic or community exposure levels are not as likely to be concentrated.

Hospital outbreaks of C. difficile strain 027 seem to represent a special challenge; only extensive bundles of interventions seemed to work in eradicating the organism from a patient care unit once it gained a foothold, as noted by Muto and colleagues.12 Many authorities have agreed that knowing that 027 was present in their hospital would prompt them to scale up their infection control activities earlier and impose more controls, including limitations of fluoroquinolone use, as quickly as possible.13 Knowing that the patient is infected with the 027 may also be useful for predicting the likelihood of relapse after therapy, either as an inpatient or after discharge. The clearest evidence for a strain-associated difference in relapse rate was presented as part of a recent study of the newest antimicrobial agent for CDI, i.e., fidaxomicin. The study, published in the New England Journal of Medicine, showed that in a cohort of patients being treated with vancomycin and/or fidaxomicin, a greater number of recurrences of disease occurred in patients who harbored the 027 strain compared with those who carried a variety of other C. difficile strains.14

So let's ask the question again: of what value is the rapid identification of patients infected with ribotype 027 strains versus other strain types? First, the identification of multiple patients in a healthcare setting with ribotype 027 strains (especially from the same ward) indicates a possible outbreak much more rapidly than epidemiologic data would alert infection preventionists to a problem. This could be an indication that the infection control bundles described by Muto et al12 should be considered; including switching from alcohol-based hand gels to soap and water for hand disinfection, longer isolation of patients, possible pharmacy controls including general restriction of fluoroquinolones at an institution, and more aggressive tracking of cases. This is also an indication that the individual patient should be monitored closely for possible relapse. Indication of infection caused by ribotype 027 should not be used to guide therapy, since therapy should be based on severity of disease (treat the patient, not the microbe).15 Ribotype 027 strains have now spread worldwide and will likely continue to cause both epidemic and sporadic disease. They will likely be a challenge for years to come.

REFERENCES

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