29


THE ADVENT OF NAP1


evaluated, taking into consideration that EIA assays which fail to detect as many as 52% of C. difficile-infected patients were used to generate 94.4% of the results, it is clear that the actual magnitude of the CDI problem was greatly underestimated.


SPEED COUNTS


The two-step algorithm lacks sensitivity, and as the data cited above show, the delay in results may have disastrous consequences to patients.


Dr Nancy Cornish, Director of Microbiology at Methodist and Childrens’ Hospitals, Omaha, Nebraska has articulated her concern about the state of C. difficile testing. Dr Cornish is a strong voice for pathologists, publishing often on microbiology- related issues in CAP Today - the monthly publication of the College of American Pathologists.


Dr Cornish said: “When I realised that our physicians were not waiting for our laboratory results when we used the two-day cytotoxicity tissue culture assay test to confirm positive GDH results, but were resorting to performing colonoscopy procedures to confirm the diagnosis of C. difficile colitis, then the decision to change testing methods to include PCR was easy. The cost-benefit ratio of having a rapid result that delivers the best possible sensitivity and specificity is very attractive to our clinicians.


“They are interested in having this test as it will allow a rapid diagnosis resulting in faster treatment and implementation of Infection Control measures in addition to reducing the use of unnecessary testing such as colonoscopy. A rapid negative result allows the clinician to pursue testing for other causes, saves the patient from having to take unnecessary antibiotics and saves the hospital the costs of isolation.”


ACTION ITEMS FOR HOSPITALS


What should healthcare institutions be doing to control CDI? Dr Cliff McDonald from the Centers for Disease Control and Prevention has outlined surveillance strategies for infection control monitoring [9]. If invasive techniques such as endoscopic evaluation are not used, a positive laboratory test is necessary for the diagnosis of CDI.


In addition to healthcare-associated disease, Dr McDonald advocates for surveillance for community-acquired disease. In a 2008 study, Kutty and coworkers found that 23% of 780 CDI included in their study had community onset and approximately half of those patients had no healthcare exposure [10]. Clearly, the algorithm for testing patients with diarrhea is changing rapidly. Laboratories that previously only tested inpatients after the third day of their admission should be modifying their practices.


BENEFITS OF FAST, RELIABLE IDENTIFICATION


What activities does a rapid and reliable test result for the presence of C. difficile in a patient’s stool generate in the healthcare institution? First, the offending antibiotic should be discontinued if possible. Second, treatment with metronidazole or vancomycin should be started. Vancomycin has been advocated for more severe disease [11].


Both medications have been associated with relapses. If retreatment fails, other treatment options are sometimes tried, such as probiotics, immunotherapy, or ‘fecal transplant’. Aslam and Musher reviewed treatment approaches in 2006 [12]. Some experimental agents such as nitazoxanide and oritavancin are still under investigation.


The rise in rates and severity of CDI in the last several years has been paralleled by an increase in the detection of a recently recognised strain of C. difficile, called variously North American Pulsed Field Gel type 1 (NAP1), ribotype 027, or BI (based on restriction enzyme analysis) [13]. This strain may cause more severe disease than other strains because of its increased production of toxin B, the major virulence factor of C. difficile. The NAP1 strain also produces more spores, purported to give it an environmental advantage. Importantly, this strain is quinolone resistant, and antibiotic usage can contribute to its persistence. Does knowing that NAP1 is present in your hospital translate into any changes in practice?


Dr Dale Gerding, in a 2007 editorial, suggested that knowledge of whether the infecting strain were the hypervirulent NAP1, 027 strain could be important, at least epidemiologically [14]. Patients are immediately placed on contact precautions, as the spores persist in the environment and spread the pathogenic strain from patient to patient. Healthcare personnel must forego alcohol gel hand disinfection and go back to soap and water, the only effective handwashing method when spores are in the environment.


More institutional systemic activities include terminal disinfection of any room in which a CDI patient was housed. The anthrax attacks of 2001 created the need to disinfect entire buildings containing spores. Some of the techniques developed then are being evaluated for patient room disinfection in cases of CDI.


Boyce and colleagues have reported that hydrogen peroxide vapor decontamination, although more difficult to administer than cleaning with bleach, was successful in eliminating spore recovery in vapour-treated rooms and that the incidence of C. difficile infection dropped significantly during the intervention period [15]. This is even more remarkable when one considers that the outbreak in Boyce’s institution was caused by the NAP1 increased spore-producing strain. Knowing that this strain was present in a healthcare environment could trigger the more effective but more difficult to administer peroxide vapour disinfection.


Antibiotic restriction has also been effective in reducing CDI incidence in facilities with epidemic situations [16]. The outbreak strain in the case reported by Kallen and colleagues at the CDC was also NAP1 [16]. In addition to fluoroquinolone restriction, which significantly reduced cases of CDI at the community hospital studied, the hospital also changed its environmental services provider, ostensibly resulting in more effective cleaning strategies.


For each false-negative laboratory test, patients are denied appropriate therapy and infection control practices are delayed. [14] At the time of his 2007 editorial, Dr. Gerding was correct that only toxigenic culture methods were able to detect pathogenic C. difficile with sufficient sensitivity to be reliable, and that culture was the only test that would yield the epidemiologic and treatment information of presence of the NAP1 hypervirulent strain. However, the results were only available days after the initial patients present with symptoms, thus of primarily epidemiologic interest. The situation has improved and rapid, reliable molecular tests are now available.


In summary, the way we diagnose C. difficile infection is about to change. Factors contributing to this paradigm shift include:


* Advent of a hypervirulent new strain;


* Realisation that CDI is more rampant than previously imagined;


* Recognition that current widespread testing methods are


Interested in publishing a Technical Article?


Contact Gwyneth Astles on +44 (0)1727 855574 or email: gwyneth@intlabmate.com


Spotlight


inaccurate or too slow to benefit patients and modify infection control practices; and


* Availability of rapid and specific molecular tests, placing the ability to obtain the correct answer in less than an hour in the hands of every laboratorian.


Once clinicians and infection preventionists know what they are dealing with, they can quickly move to intervene.


1. Jarvis WR, Schlosser J, Jarvis AA, Chinn RY. National point prevalence of Clostridium difficile in US health care facility inpatients, 2008. American Journal of Infection Control. 2009; 37(4):263–70.


2. Kenneally C et al. Analysis of 30-day mortality for Clostridium difficile-associated disease in the ICU setting. Chest. 2007; 132:418–24.


3. Stamper PD et al. Comparison of a Commercial Real-Time PCR Assay for tcdB Detection to a Cell Culture Cytotoxicity Assay and Toxigenic Culture for Direct Detection of Toxin-Producing Clostridium difficile in Clinical Samples. Journal of Clinical Microbiology. 2009; 47(2):373–8.


4. Ticehurst JR et al. Effective Detection of Toxigenic Clostridium difficile by a Two-Step Algorithm Including Tests for Antigen and Cytotoxin. Journal of Clinical Microbiology. 2006; 44(3):1145–9.


5. Gilligan PH. Is a two-step glutamate dehyrogenase antigen- cytotoxicity neutralisation assay algorithm superior to the premier toxin A and B enzyme immunoassay for laboratory detection of Clostridium difficile? Journal of Clinical Microbiology. 2008; 46(4):1523–5.


6. George WL, Sutter VL, Citron D, Finegold SM. Selective and differential medium for isolation of Clostridium difficile. Journal of Clinical Microbiology. 1979; 9(2):214–9.


7. She et al. Evaluation of enzyme immunoassays to detect Clostridium difficile toxin from anaerobic stool culture. American Journal of Clinical Pathology. 2009; 131(1):81–4.


8. Sloan LM et al. Comparison of Real-Time PCR for Detection of the tcdC Gene with Four Toxin Immunoassays and Culture in Diagnosis of Clostridium difficile Infection. Journal of Clinical Microbiology. 2008; 46(6):1996–2001.


9. McDonald LC et al. Ad Hoc Clostridium difficile Surveillance Working Group. Recommendations for surveillance of Clostridium difficile-associated disease. Infection Control and Hospital Epidemiology. 2007; 28(2) Epub:140–5.


10. Kutty PK et al. Assessment of Clostridium difficile–Associated Disease Surveillance Definitions, North Carolina, 2005. Infection Control and Hospital Epidemiology. 2007; 29:197–202.


11. Pepin J. Vancomycin for the treatment of Clostridium difficile Infection: for whom is this expensive bullet really magic? Clinical Infectious Diseases. 2008; 46(10):1493–8.


12. Aslam S, Musher DM. An update on diagnosis, treatment, and prevention of Clostridium difficile-associated disease. Gastroenterology Clinics of North America. 2006; 35(2):315–35.


13. O’Conner JR, Johnson S, Gerding DN. Clostridium difficile Infection Caused by the Epidemic BI/NAP1/027 Strain. Gastroenterology. 2009; 136:1913–1924.


14. Gerding, DN. New Definitions Will Help, but Cultures are Critical for Resolving Unanswered Questions About Clostridium difficile. Infection Control and Hospital Epidemiology. 2007; 28(2):113–5.


15. Boyce JM et al. Impact of Hydrogen Peroxide Vapor Room Decontamination on Clostridium difficile Environmental Contamination and Transmission in a Healthcare Setting. Infection Control and Hospital Epidemiology. 2008; 29:723–9.


16. Kallen AJ et al. Complete restriction of fluoroquinolone use to control an outbreak of Clostridium difficile infection at a community hospital. Infection Control and Hospital Epidemiology. 2009; 30(3):264–72.


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