Background: Chlorhexidine gluconate (CHG) and povidone-iodine (PI) are commonly used to prevent prosthetic joint infection (PJI) during total joint replacement; however, their effective concentrations and impact on biofilms are not well defined. Aim: To determine: (1) the in-vitro minimum inhibitory concentration of CHG and PI against model PJI-causing organisms and clinical isolates; (2) their impact on biofilm formation; (3) whether there is a synergistic benefit to combining the two solutions; and (4) whether adding the antibiotic vancomycin impacts antiseptic activity. Methods: We measured in-vitro growth and biofilm formation of Staphylococcus epidermidis, , meticillin-sensitive and meticillin-resistant Staphylococcus aureus, , Escherichia coli, , Pseudomonas aeruginosa and Candida albicans, , as well as recent clinical isolates, in the presence of increasing concentrations of CHG and/or PI. Checkerboard assays were used to measure potential synergy of the solutions together and with vancomycin. Findings: CHG and PI inhibited growth and biofilm formation of all model organisms tested at concentrations of 0.0004% and 0.33% or lower, respectively; highly dilute concentrations paradoxically increased biofilm formation. The solutions did not synergize with one another and acted independently of vancomycin. Conclusion: CHG and PI are effective at lower concentrations than typically used, establishing baselines to support further clinical trials aimed at optimizing wound disinfection. There is no synergistic advantage to using both in combination. Vancomycin is effective at inhibiting the growth of S. epidermidis and S. aureus; ; however, it stimulates P. aeruginosa biofilm production, suggesting in the rare case of P. aeruginosa PJI, it could exacerbate infection. (c) 2024 The Authors. Published by Elsevier Ltd on behalf of The Healthcare Infection Society. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to subinhibitory concentrations of antibiotics increases the formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits the growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce interleukin-1β (IL-1β) production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross-resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues synergize with penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants.

As the number of effective antibiotics dwindled, antibiotic resistance (AR) became a pressing concern. Some Pseudomonas aeruginosa isolates are resistant to all available antibiotics. In this review, we identify the mechanisms that P. aeruginosa uses to evade antibiotics, including intrinsic, acquired, and adaptive resistance. Our review summarizes many different approaches to overcome resistance. Antimicrobial peptides have potential as therapeutics with low levels of resistance evolution. Rationally designed bacteriophage therapy can circumvent and direct evolution of AR and virulence. Vaccines and monoclonal antibodies are highlighted as immune‐based treatments targeting specific P. aeruginosa antigens. This review also identifies promising drug combinations, antivirulence therapies, and considerations for new antipseudomonal discovery. Finally, we provide an update on the clinical pipeline for antipseudomonal therapies and recommend future avenues for research.

As the number of effective antibiotics dwindled, antibiotic resistance (AR) became a pressing concern. Some Pseudomonas aeruginosa isolates are resistant to all available antibiotics. In this review, we identify the mechanisms that P. aeruginosa uses to evade antibiotics, including intrinsic, acquired, and adaptive resistance. Our review summarizes many different approaches to overcome resistance. Antimicrobial peptides have potential as therapeutics with low levels of resistance evolution. Rationally designed bacteriophage therapy can circumvent and direct evolution of AR and virulence. Vaccines and monoclonal antibodies are highlighted as immune-based treatments targeting specific P. aeruginosa antigens. This review also identifies promising drug combinations, antivirulence therapies, and considerations for new antipseudomonal discovery. Finally, we provide an update on the clinical pipeline for antipseudomonal therapies and recommend future avenues for research.