Clinical and Infection Control Implications of Clostridium difficile Infection With Negative Enzyme Immunoassay for Toxin

Guerrero, Dubert M.; Chou, Christina; Jury, Lucy A.; Nerandzic, Michelle M.; Cadnum, Jennifer C.; Donskey, Curtis J.

doi:10.1093/cid/cir361

Cited by 62 publications

(61 citation statements)

References 11 publications

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“…However, the data are conflicting. Although some studies suggest that patients with positive toxin assays have a worse prognosis than those with a positive NAAT only (1, 2), many other carefully conducted studies involving more than 2,000 patients have not found toxin assays to be predictive of symptoms, disease severity, mortality, transmissibility, or recurrence (11,15,16,38,42,43). In any case, whether the detection of toxin is indicative of a worse prognosis is beside the point.…”

Section: Why Do Studies Of Symptoms and Clinical Outcomes In Patientsmentioning

confidence: 99%

“…(iii) Anecdotal experiences with cases of severe CDI missed by toxin tests have promoted a desire for absolute sensitivity, regardless of specificity, and an erroneous belief that all patients with toxigenic C. difficile and diarrhea have CDI as the cause of their symptoms (9)(10)(11)(12)(13)(14). Widespread misclassification of non-CDI diarrhea in patients with C. difficile colonization as "CDI" has reinforced the belief that toxin tests are insensitive for CDI without systematic investigation to verify the true frequency of disease (2,9,11,(15)(16)(17).…”

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confidence: 99%

“…Widespread misclassification of non-CDI diarrhea in patients with C. difficile colonization as "CDI" has reinforced the belief that toxin tests are insensitive for CDI without systematic investigation to verify the true frequency of disease (2,9,11,(15)(16)(17).…”

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confidence: 99%

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Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

2017

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INTRODUCTION In 2010, we published an initial Point-Counterpoint on the laboratory diagnosis of Clostridium difficile infection (CDI). At that time, nucleic acid amplification tests (NAATs) were just becoming commercially available, and the idea of algorithmic approaches to CDI was being explored. Now, there are numerous NAATs in the marketplace, and based on recent proficiency test surveys, they have become the predominant method used for CDI diagnosis in the United States. At the same time, there is a body of literature that suggests that NAATs lack clinical specificity and thus inflate CDI rates. Hospital administrators are taking note of institutional CDI rates because they are publicly reported. They have become an important metric impacting hospital safety ratings and value-based purchasing; hospitals may have millions of dollars of reimbursement at risk. In this Point-Counterpoint using a frequently asked question approach, Ferric Fang of the University of Washington, who has been a consistent advocate for a NAAT-only approach for CDI diagnosis, will discuss the value of a NAAT-only approach, while Christopher Polage of the University of California Davis and Mark Wilcox of Leeds University, Leeds, United Kingdom, each of whom has recently written important articles on the value of toxin detection in the diagnosis, will discuss the impact of toxin detection in CDI diagnosis.

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Section: Why Do Studies Of Symptoms and Clinical Outcomes In Patientsmentioning

confidence: 99%

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confidence: 99%

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Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

2017

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“…The approach generates three categorical results: (i) CDI very likely (where toxin is detected), (ii) CDI very unlikely (where GDH or NAAT is negative), and (iii) CDI possible (where GDH and/or NAAT are positive but toxin assay is negative). A "CDI possible" result may be useful for distinguishing patients who are potentially shedding toxigenic organism (13). It might also prove important for the clinical management of patients with a high likelihood of CDI or in whom symptoms of diarrhea persist or progress.…”

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confidence: 99%

Quantitative Fecal Lactoferrin in Toxin-Positive and Toxin-Negative Clostridium difficile Specimens

et al. 2013

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Quantitative fecal lactoferrin was measured in 112 patients tested for toxigenic Clostridium difficile using glutamate dehydrogenase (GDH) and toxin immunoassays combined with tcdB PCR. Lactoferrin levels were higher in the GDH-positive/toxin-positive group (79 g/ml) than in the GDH-positive/toxin-negative/PCR-positive (21 g/ml) and the GDH-negative groups (13 g/ ml). Differences in fecal lactoferrin levels suggest variable presence or severity of C. difficile infection among toxin-positive and toxin-negative patients. Diagnostic testing for Clostridium difficile infection (CDI) may be accomplished through (i) organism detection by anaerobic culture or glutamate dehydrogenase (GDH) immunoassay with subsequent confirmation of toxigenicity, (ii) toxin detection by cell cytotoxicity neutralization assay (CCNA) or enzyme immunoassay (EIA), and (iii) nucleic acid amplification tests (NAAT) for tcdA, tcdB, and/or other C. difficile genes. Given that the rate of positivity of NAAT assays and GDH immunoassays approaches that of toxigenic culture (1, 2), while those of CCNA and EIA are significantly lower (3), universal testing by NAAT or by multistep GDH screening algorithms is endorsed by IDSA/ SHEA consensus (4). Because toxin production is necessary for organism pathogenesis, however, debate persists as to whether direct toxin measurements may offer a theoretical advantage with respect to clinical specificity (5, 6). If toxin positivity were a better indicator of CDI than NAAT positivity, it would follow that levels of fecal lactoferrin (a measure of colonic inflammation) should be higher in toxin-positive patients than in NAAT-positive/toxinnegative patients. The aim of this study, therefore, was to assess fecal lactoferrin values among toxin-positive, NAAT-positive/ toxin-negative, and NAAT-negative/toxin-negative patients.Based upon results from a single academic medical center of a routine, two-step C. difficile diagnostic algorithm (7), which incorporates GDH and toxin A/B lateral flow EIA (C. Diff Quick Check Complete; TechLab, Blacksburg, VA) with tcdB PCR (Gene Xpert; Cepheid, Sunnyvale, CA), 112 previously frozen, unique patient stool samples were selected for study inclusion. Fecal lactoferrin levels were determined for all samples using quantitative enzyme-linked immunosorbent assay (ELISA) (IBD Scan; TechLab, Blacksburg, VA) as per the manufacturer's instruction with a modification (to improve assay precision) that initial specimen aliquots were weighed to the nearest 0.001 g and diluted 1:10 (wt/vol) in kit diluent. A final dilution of 1:500 was used for all samples. Patient electronic medical records were queried to determine history of immunosuppression, inflammatory bowel disease (IBD) and/or prior bowel surgery, results of other stool studies, and peripheral white blood cell (WBC) count within 48 h of C. difficile testing. Data were analyzed using a statistical software program (Minitab 16), and Mann-Whitney U test and Fisher's exact test were used to study group differences in lactoferrin levels.Coe...

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“…In routine practice, providers often test for C. difficile despite the absence of diarrhea. In North American studies, diarrhea has been reported to be absent in up to 39.0% of patients tested for C. difficile and up to 66.5% of patients diagnosed with CDI (13)(14)(15)(16)(17). Laxative therapy was also documented in up to 50% of patients undergoing testing or diagnosed with CDI in some studies (13,14,16).…”

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confidence: 99%

Real-Time Electronic Tracking of Diarrheal Episodes and Laxative Therapy Enables Verification of Clostridium difficile Clinical Testing Criteria and Reduction of Clostridium difficile Infection Rates

et al. 2017

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Health care-onset health care facility-associated Clostridium difficile infection (HO-CDI) is overdiagnosed for several reasons, including the high prevalence of C. difficile colonization and the inability of hospitals to limit testing to patients with clinically significant diarrhea. We conducted a quasiexperimental study from 22 June 2015 to 30 June 2016 on consecutive inpatients with C. difficile test orders at an academic hospital. Real-time electronic patient data tracking was used by the laboratory to enforce testing criteria (defined as the presence of diarrhea [Ն3 unformed stools in 24 h] and absence of laxative intake in the prior 48 h). Outcome measures included C. difficile test utilization, HO-CDI incidence, oral vancomycin utilization, and clinical complications. During the intervention, 7.1% (164) and 9.1% (211) of 2,321 C. difficile test orders were canceled due to absence of diarrhea and receipt of laxative therapy, respectively. C. difficile test utilization decreased upon implementation from an average of 208.8 tests to 143.0 tests per 10,000 patient-days (P Ͻ 0.001). HO-CDI incidence rate decreased from an average of 13.0 cases to 9.7 cases per 10,000 patient-days (P ϭ 0.008). Oral vancomycin days of therapy decreased from an average of 13.8 days to 9.4 days per 1,000 patient-days (P ϭ 0.009). Clinical complication rates were not significantly different in patients with 375 canceled orders compared with 869 episodes with diarrhea but negative C. difficile results. Realtime electronic clinical data tracking is an effective tool for verification of C. difficile clinical testing criteria and safe reduction of inflated HO-CDI rates.KEYWORDS Clostridium difficile, data tracking, evidence-based medicine, verification C lostridium difficile is the most common identifiable cause of antibiotic-associated diarrhea (1). Clostridium difficile infection (CDI) is estimated to be the most expensive health care-associated infection, costing the U.S. health system $5.4 billion annually (2). A major challenge with accurate diagnosis of CDI is the high prevalence of C. difficile colonization. Studies indicate that 4.4% to 21% of hospitalized patients are asymptomatically colonized with toxigenic C. difficile (3-10, 30). In the absence of disease-specific

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Clinical and Infection Control Implications of Clostridium difficile Infection With Negative Enzyme Immunoassay for Toxin

Cited by 62 publications

References 11 publications

Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

Point-Counterpoint: What Is the Optimal Approach for Detection of Clostridium difficile Infection?

Quantitative Fecal Lactoferrin in Toxin-Positive and Toxin-Negative Clostridium difficile Specimens

Real-Time Electronic Tracking of Diarrheal Episodes and Laxative Therapy Enables Verification of Clostridium difficile Clinical Testing Criteria and Reduction of Clostridium difficile Infection Rates

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