EXPAND Cdiff international group of infectious disease specialists propose changing criteria for initial and sustained response to antibiotic treatment.
Accurately determining an initial response rather than seeking a putative clinical cure could lead to more efficient antibiotic trials and treatment of patients infected with Clostridioides difficle, according to a recent proposal from the EXPAND Cdiff international group of infectious disease specialists.
"Threshold-based definitions of initial cure have shifted in the last 10 years to more restrictive definitions that risk misclassifying CDI (C difficile infection) treatment response as failed," observed proposal lead author Anne Gonzales-Luna, PharmD, Department of Pharmacy Practice and Translational Research, University of Houston College of Pharmacy, Houston, TX, and colleagues.
Consequences of applying current criteria of clinical cure at the completion of an investigational antibiotic regimen, according to the EXPAND Cdiff group, include requiring greater number of participants for sufficient statistical power to reveal initial benefit over comparator, and the unnecessary eliminating of participants who could demonstrate sustained clinical response.
The group finds several faults with current bacteriological and clinical endpoints for defining a successful antibiotic regimen for CDI. Regarding the former, they note that cultures are not routinely performed, that organism and toxin presence in the stool is not diagnostic of infection, that the antimicrobial does not eradicate spores from the host and, "the complex interplay of pathogen and host microbiome is not accounted for."
Regarding the clinical endpoint of the absence of diarrhea, commonly defined as ≤3 unformed bowel movements (UBMs) in 24 hours, they note that it has not been validated as cure, it is inconsistently characterized, and is difficult to apply across age groups and populations or those with comorbidities with different baseline frequency of bowel movements.
Instead, the group proposes the "less restrictive definition of initial response to increase the validity of sustained response," of any substantial improvement in diarrhea; characterized as any of the following, assessed by day 2 after antibiotic regimen for CDI:
"We highlight the use of the term response in this short-term outcome assessment since we prefer to reserve the term cure for people who do not have any recurrence," the group indicated.
They propose that a sustained response is determined by no requirement for retreatment by day 30 after completion of the typical 10-day primary CDI antibiotic regimen; although pointing out that it is not uncommon to have CDI recurrence up to 8 weeks after primary infection.
"We acknowledge that a range of events could occur in an 8-week follow-up period that confound the investigators' ability to discern a given antibiotic's treatment effect, such as exposure to non-CDI treatment antibiotics," they noted.
Although their proposal pertains to clinical trials of antibiotics for CDI, Gonzales-Luna and colleagues also acknowledge that other modes of treatment are emerging, including vaccination, fecal microbiota transplantation, and microbiota-based biotherapeutics.
Appropriate criteria of response are needed for these investigations as well, they advise, "to ensure the accurate measurement of each treatment's effect, either alone or in combination with other therapies."