What constitutes a true polymicrobial periprosthetic joint infection? From multiple detections to organism-level causality.

Polymicrobial periprosthetic joint infection (PJI) is often defined by recovery of two or more microorganisms from the same clinical episode, but this numerical definition is biologically incomplete. A second organism may represent a true co-pathogen, colonization, contamination, reagent background, nonviable DNA after antimicrobial exposure, or an analytically plausible signal of uncertain clinical importance. Established PJI definitions determine whether infection is present but do not provide a validated organism-level rule for assigning causality to every detection. We therefore propose a sequential approach: first establish PJI using accepted episode-level criteria, then adjudicate each detected microorganism separately before classifying the episode as polymicrobial. This Mini Review examines evidence relevant to organism-level causal attribution, including sampling integrity, reproducibility across independent deep specimens, anatomical coherence, orthogonal confirmation, quantitative and temporal signal, organism biology, and clinical concordance. We also consider how tissue culture, synovial fluid culture, sonication, blood culture, PCR, and metagenomic sequencing generate different interpretive challenges, particularly after antimicrobial exposure. Finally, we propose a pragmatic four-category vocabulary-strongly supported participant, probable participant, uncertain detection, and likely contaminant-to make organism-level causal confidence explicit in multidisciplinary interpretation and research reporting. This framework is intended as an interpretive aid rather than a validated diagnostic score. Whether it improves inter-rater consistency, antimicrobial precision, or organism-specific outcomes requires prospective validation.