Swabs versus tissue samples for infected diabetic foot ulcers: the CODIFI2 RCT.

Background: Foot ulcers affecting people with diabetes (diabetic foot ulcers) often become infected, potentially leading to amputation. Suspected diabetic foot ulcer infection is treated with immediate empiric antimicrobials, with wound samples for culture and sensitivity collected to optimise antibiotic therapy. Collecting samples with swabs is easier than obtaining tissue, but this reports fewer pathogens and more contaminants. Compared with standard culture and sensitivity laboratory methods, molecular microbiology identifies more organisms. How these differences affect clinical decisions or outcomes is currently unknown. To determine if taking tissue samples versus swabs from suspected infected diabetic foot ulcer affects ulcer healing, antibiotic prescribing, costs of care and patient safety. Substudy 1: To determine the agreement between microbiology results from culture and sensitivity versus molecular techniques and to assess whether intention of prescribers to change antimicrobials differs based on sampling methods. Substudy 2: A health-economic perspective of the expected application of empiric and/or targeted treatment regimens and the cost consequences of treatment decisions based on substudy 1. Substudy 3: To compare questionnaire response rates for theoretically informed versus standard participant letters. Substudy 4: To explore clinician perspectives on diabetic foot ulcer sampling and processing techniques. Design: Randomised controlled trial of results of performing tissue sampling versus swabbing of wounds in people with suspected mild or moderate infected diabetic foot ulcer. Individually randomised (allocation concealed), 1 : 1, tissue or swab sampling for suspected diabetic foot ulcer infection. Follow-up is 12-24 months. A priori sample size estimate is 730. Substudy 1: Cross-sectional agreement study of microbiology results from molecular versus culture and sensitivity techniques and virtual clinic. Diabetic foot ulcers sampled for standard microbiology and central laboratory analysis (molecular). Substudy 2: Exploratory cost-consequence analysis of molecular processing and the likelihood of empiric and targeted treatment based on treatment decisions from substudy 1. Substudy 3: Randomised trial of theoretically informed versus standard participant letters. Substudy 4: Qualitative study explored clinicians' perspectives regarding sampling and processing techniques. Setting and participants: Twenty-one United Kingdom diabetic foot ulcer clinics. Participants with suspected mild or moderate infected diabetic foot ulcers. Time to ulcer healing (primary outcome blinded assessment), proportion of ulcers healed, antibiotic usage, ulcer area reduction at 4 weeks, hospitalisation duration, time to death, quality of life and cost-effectiveness. Substudy 1: Extent of agreement regarding presence or absence of pathogens from standard versus molecular microbiology. Decision to revise antimicrobials based on sampling method. Substudy 2: Modelled costs (from virtual clinic) of antimicrobial change for standard or molecular analysis. Substudy 3: Response rate for questionnaires. Results: The trial was stopped early, after enrolling only 149 participants, due to poor recruitment. The hazard ratio for wound healing for patients undergoing tissue versus swab sampling was 1.01 (95% confidence interval 0.65 to 1.55). The swab group had both higher quality-adjusted life-years and lower costs across most time points. Substudy 1: Agreement between culture and sensitivity and molecular microbiology was low. A higher proportion of molecular versus culture and sensitivity vignettes led to recommendations to change antimicrobials [difference 20.5% (95% confidence interval 8.9% to 31.1%)]. Substudy 2: The modelled costs of molecular processing versus culture and sensitivity were £120 higher per wound. Substudy 3: Response rates were 14.8% higher at 52 weeks (95% confidence interval -3.2% to 31.2%) using a theoretically informed versus standard cover letter. Substudy 4: Clinicians were not confident about replacing culture and sensitivity with molecular microbiology, as the result reporting was unfamiliar to them. Limitations: The trial was underpowered. Conclusions: Trial recruitment was challenging during the COVID pandemic and its aftermath. While the results leave substantial uncertainty regarding differences in healing between the sampling methods, tissue sampling appeared to be costlier and was associated with lower quality-adjusted life-years than swabbing. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 16/163/04.