Background/Objectives: Almost all orthopedic infections require a combination of surgical debridement with targeted antimicrobial treatment. The number of debridement procedures may vary considerably between infection episodes. The case mix is large, and so-called “second looks” are frequent. We investigate which bacteria are associated with second looks to achieve local infection control. Methods: We used a composite database stemming from three prospective randomized controlled trials (RCTs) from 2019 to 2025 with protocoled surgical debridement (initial debridement). In these RCTs, we allowed additional debridement only in the case of persistent or progressive local infection. Results: Overall, 201/1067 (18.8%) orthopedic infections required multiple debridement procedures. The median number of additional debridement procedures was two across all pathogen groups, with a range of 2–8 interventions. Gram-negative pathogens revealed the highest risk for “second looks” (28.2%), followed by implant-related infections (25.4%). Cutibacteria yielded the lowest risk (11.7%). In the multivariable logistic regression model, Gram-negative infections (OR 2.04, 95%CI 1.20–3.47) and infected implants (OR 2.18, 95%CI 1.56–3.03) were independently associated with multiple interventions, in contrast to Staphylococcus aureus, Enterococci, or Streptococci. Conclusions: Gram-negative pathogens were significantly associated with the need for second looks in orthopedic infections. The findings support preoperative counseling, antibiotic stewardship, and operative planning for staged management in infection cases with a high risk of clinical failure. Trials registrations: NCT04048304, NCT04081792, NCT05499481.

Background/Objectives: Almost all orthopedic infections require a combination of surgi-cal debridement with targeted antimicrobial treatment. The number of debridement may vary considerably between infection episodes. The case-mix is enormous and so-called "second looks" are frequent. We investigate which bacteria are associated with second looks to achieve local infection control. Methods: We used a composite database stem-ming from three prospective randomized-controlled trials (RCTs) 2019-2025 with proto-colled surgical debridement (initial debridement). In these RCTs, we allowed additional debridement only in case of persistent (during several days) or progredient local infection. Results: Overall, 201/1,067 (18.8%) orthopedic infections required multiple debridement (median two second looks, range 2–8 surgeries). Gram-negative pathogens revealed the highest risk for "second looks" (28.2%), followed by implant-related infections (25.4%). Cutibacteria yielded the lowest risk (11.7%). In the multivariable logistic regression model, Gram-negative infections (odds ratio 2.04, 95%CI 1.20-3.47) and infected implants (OR 2.18, 95%CI 1.56-3.03) were independently associated to multiple interventions, in con-trast to Staphylococcus aureus, enterococci or streptococci. Conclusions: When analyzing orthopedic infections included in prospective RCTs, Gram-negative pathogens groups significantly associate with the need for second looks, which matches our own experience. Today findings support preoperative counseling, antibiotic stewardship, and operative planning for a staged management in infection cases with a high risk of clinical failure. Trials registrations: NCT04048304, NCT04081792, NCT05499481.