Is the Healthcare Facility Level Sufficient for Assessing the Impact of 2-Step Clostridioides difficile Testing? Free

(See the Major Article by Turner et al. on pages 1043–9.)

The title question is based on the adequacy of healthcare facility–level data to provide sufficient information to address all the nuances of assessing the diagnosis of hospital-onset Clostridioides difficile infection (CDI). As demonstrated very effectively by Turner et al [1] in the current issue of Clinical Infectious Diseases, healthcare facility data for CDI test results using a 2-step laboratory procedure of nucleic acid amplification testing (NAAT) followed by enzyme immunoassay (EIA) for presence of toxin in stool of NAAT-positive specimens can be employed successfully for NAAT-positive/toxin-positive results in multiple hospitals and document significant reduction of the number of patients diagnosed with hospital-onset CDI (HO-CDI). These data at the facility level confirm similar previous patient-level cohort studies of CDI testing.

The rationale for this 2-step algorithm is that it employs a highly sensitive NAAT test followed by a more specific but less sensitive EIA toxin test. Only the NAAT-positive/toxin-positive results are interpreted to be diagnostic of CDI. NAAT testing increases the number of positive stool tests by 43%–67% compared to toxin EIA [2]. As a result, use of NAAT-positive followed by EIA toxin algorithm places a very large number of specimens in the NAAT-positive/toxin-negative category, often more than twice the number that are in the NAAT-positive/toxin-positive category. How to interpret these NAAT-positive/toxin-negative specimens has been the subject of debate for at least the last decade and is a limitation of healthcare-level reporting since it requires patient-level clinical data to try to distinguish active CDI from C. difficile colonization. These patients have been the subject of patient-level studies with conflicting conclusions as to what proportion are CDI vs C. difficile colonization. There are 2 concerns in the debate, both linked to treatment: overtreatment of colonized patients who do not require treatment, and undertreatment of CDI patients who may incur clinical deterioration from lack of treatment. If patients are colonized, they should not be treated for CDI as it is only temporarily effective in resolving colonization and needless vancomycin treatment further compromises the normal microbiota [3, 4]. If patients have CDI, some patients will require treatment and some with mild illness may be managed without specific antibiotic treatment, although this is debatable.

Turner et al [1] examined trends in HO-CDI and, using available healthcare facility–level data, were able to measure CDI-specific antibiotic use and emergent colectomy rates as proxies for treatment and safety of 2-step testing in terms of estimating the number of patients treated and avoidance of complications in untreated CDI patients. Of the 2 measures, CDI-specific antibiotic use suggests that treatment of CDI decreased proportional to the number of reduced HO-CDI cases; however, total emergent colectomy rates are unlikely to detect complications of untreated CDI as colectomies due to CDI are rare events and could easily be obscured by the much more common emergent colectomies due to bowel obstructions and perforations, colon cancer, inflammatory bowel disease, and diverticulitis. Patient-level data are required to evaluate complications of CDI and the need for treatment in NAAT-positive/toxin-negative patients.

One of the earliest trials in the debate cited by Turner et al [1] found that these NAAT-positive/toxin-negative patients more closely resemble NAAT-negative/toxin-negative patients than NAAT-positive/toxin-positive patients in terms of CDI complications and mortality [5]. No CDI-related complications were found in the NAAT-positive/toxin-negative group. Despite not reporting the NAAT-positive result to clinicians in this study, 40.8% of them received some CDI treatment, 27.8% received partial treatment (1–9 days), and 13.0% received full treatment (≥10 days), suggesting that at least some clinicians considered a diagnosis of CDI and treated despite a negative toxin test. In the Turner et al study, additional treatment information from a subset of sites found that treatment of all NAAT-positive/toxin-negative patients (not just HO-CDI, which likely comprises <10% of all CDI cases) was just 16% consistent with the proportional change in CDI-specific antibiotic use. In contrast, a large multicenter preliminary report from the Centers for Disease Control and Prevention Emerging Infections Program presented at IDWeek in 2022 found that the test sequence of NAAT followed by toxin testing of NAAT-positive patients resulted in treatment of 77% of patients with a NAAT-positive/toxin-negative test result [6].

Can these discrepant treatment frequencies of NAAT-positive/toxin-negative patients be explained by smaller patient-level studies? Zou et al [7] had antimicrobial stewardship program clinicians review clinical data on patients who tested NAAT positive/toxin negative and concluded that 56% of patients had CDI and 44% were likely colonized. The CDI-related complication rate was 9% in 110 NAAT-positive/toxin-negative patients. Untreated colonized patients did not have increased adverse outcomes compared to treated CDI patients at 8 weeks of follow-up. Similar results were found in a somewhat larger retrospective study of the first 6 months of implementation of the NAAT followed by toxin test algorithm by Miller et al [8] in a tertiary center. Of 352 patients who tested positive, 112 were NAAT positive/toxin positive and 240 were NAAT positive/toxin negative. CDI-related complications (megacolon [n = 2], colectomy [n = 1], and intensive care unit admission [n = 22]) occurred in 9.6% of NAAT-positive/toxin-negative patients. In multivariate analysis, increased odds of CDI-related complications were found for baseline severe CDI disease (Infectious Diseases Society of America criteria), baseline fulminant colitis, and fever >38.5°C. Complete CDI treatment was given to 72%, incomplete treatment to 17%, and no treatment to 11% of NAAT-positive/toxin-negative patients. Among those given incomplete or no treatment, failure occurred in 15%. Comparison of 112 NAAT-positive/toxin-positive to 173 NAAT-positive/toxin-negative patients with complete treatment showed no difference in CDI-related complications, 60-day all-cause mortality, or CDI recurrence. Of interest is that infectious diseases consultation resulted in reduced treatment in this study.

How can such markedly different interpretations of NAAT-positive/toxin-negative patients occur? One possibility is the laboratory reporting language used to convey test results to the clinician. Turner et al [1] did a careful education program for their participating sites regarding the significance of NAAT-positive/toxin-negative test results. Their suggested laboratory reporting language placed colonization as the most likely interpretation: “Likely represents colonization. Evaluate the patient before treating. Consider treatment if severe or nonresolving symptoms and no other apparent cause of symptoms.” Limited data on treatment of a subset of patients in this study indicated that only 16% were treated for CDI. Hecker et al [9] also recently published a smaller study in which clinicians blinded to CDI test results estimated the likelihood of CDI as probable, possible, unlikely, or indeterminate using clinical and laboratory criteria they developed. Treatment feedback to clinicians was given only for the 21% of patients deemed unlikely to have CDI. Laboratory reporting of NAAT-positive/toxin-negative test results was more neutral: “Possible C. difficile infection or carriage of (toxigenic) C. difficile.” Treatment occurred in 79% of NAAT-positive/toxin-negative patients, including 42% classified as unlikely CDI. Could reporting language result in such large differences in treatment? Controlled trials are needed.

This question of how to interpret NAAT-positive/toxin-negative results is soon to become sharply focused. The National Healthcare Safety Network is updating the healthcare facility–onset CDI surveillance definition to incorporate antibiotic treatment in addition to test results (ie, healthcare facility–onset, treated CDI). The updated definition is still undergoing validation, but it will involve a combination of any positive test for C. difficile plus initiation of antibiotics specifically for treatment of CDI [10]. This will place treatment of HO-CDI squarely in the calculation of CDI standard infection ratio and will be an opportunity for infection preventionists, hospital epidemiologists, and antimicrobial stewardship experts to carefully study the need for treatment of NAAT-positive/toxin-negative patients.

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Author notes