Innovative Approaches Against Planktonic and Biofilm-Producing Clostridium perfringens Associated with Necrotic Enteritis.

Necrotic enteritis (NE), caused by the Gram-positive, anaerobic bacterium Clostridium perfringens (C. perfringens; CP), is one of the most economically important diseases affecting the poultry industry worldwide. The pathogenicity of C. perfringens is attributed to the production of more than twenty extracellular toxins and enzymes, with strains classified into seven toxinotypes (A-G) based on their major toxin genes. While the alpha-toxin gene (cpa) is present across all C. perfringens toxinotypes, netB is recognized as the primary virulence determinant of avian NE. However, toxin-gene carriage alone does not establish toxin expression or disease causation. Cpb2 and tpeL have also been associated with virulence in some C. perfringens isolates, although their independent contributions to NE pathogenesis remain less firmly established. The increasing prevalence of antimicrobial-resistant C. perfringens strains, including multidrug-resistant (MDR), extensively drug-resistant (XDR), and pandrug-resistant (PDR) isolates, together with the organism's ability to form biofilms, has complicated disease prevention and treatment by enhancing environmental persistence and tolerance to antimicrobial agents. Distinct from reviews that primarily address NE pathogenesis or antibiotic alternatives as broad terms, this review integrates antimicrobial resistance with planktonic and biofilm-associated C. perfringens. Furthermore, it critically evaluates alternative interventions based on their activity against these bacterial states and the strength of supporting in vitro, in vivo, and field evidence. In conclusion, this review highlights the urgent need for sustainable, antibiotic-free strategies to combat NE. Advancing the development and field validation of these alternative approaches may contribute to reducing antimicrobial resistance, limiting biofilm-associated persistence, and improving poultry health and productivity.