Polymyxin B 10,000units/g / Bacitracin 500units/g ointment

IntroductionIntra-articular antibiotics have been proposed as a treatment for septic arthritis to allow for high local concentrations without subjecting a patient to the toxicity/side effects of systemic therapy. However, there is concern for chondrotoxicity with intra-articular use of these solutions in high concentrations. The purpose of this systematic review was to evaluate the intra-articular use of antibiotics and antiseptic solutions, and to determine their association with chondrolysis following in vitro or in vivo administration.MethodsA systematic review was conducted following PRISMA guidelines through PubMed, Clinical Key, OVID, and Google Scholar. Studies in English were included if they evaluated for chondrotoxicity following antibiotic exposure.ResultsThe initial search resulted in 228 studies, with 36 studies meeting criteria. These 36 studies included manuscripts that studied 24 different agents. Overall, 7 of the 24 (29%) agents were non-chondrotoxic: minocycline, tetracycline, chloramphenicol, teicoplanin, pefloxacin, linezolid, polymyxin-bacitracin. Eight (33%) agents had inconsistent results: doxycycline, ceftriaxone, gentamicin, vancomycin, ciprofloxacin, ofloxacin, chlorhexidine, and povidone iodine. Chondrotoxicity was evident with 9 (38%) agents, all of which were also dose-dependent chondrotoxic based on reported estimated half maximal inhibitory concentrations (est. IC50): amikacin (est. IC50 = 0.31-2.74 mg/mL), neomycin (0.82), cefazolin (1.67-3.95), ceftazidime (3.16-3.59), ampicillin-sulbactam (8.64 - >25), penicillin (11.61), amoxicillin (14.01), imipenem (>25), and tobramycin (>25). Additionally, chondroprotective effects of doxycycline and minocycline were reported.ConclusionsThis systematic review identified agents that may be used in the treatment of septic arthritis. Nine agents should be avoided due to their dose-dependent chondrotoxic effects. Further studies are needed to clarify the safety of these medications for human intra-articular use.

Abstract licence: CC BY-NC-ND

Bacitracin is a macrocyclic peptide antibiotic that is widely used as a topical treatment for infections caused by gram-positive bacteria. Mechanistically, bacitracin targets bacteria by specifically binding to the phospholipid undecaprenyl pyrophosphate (C55PP), which plays a key role in the bacterial lipid II cycle. Recent crystallographic studies have shown that when bound to C55PP, bacitracin adopts a highly ordered amphipathic conformation. In doing so, all hydrophobic side chains align on one face of the bacitracin-C55PP complex, presumably interacting with the bacterial cell membrane. These insights led us to undertake structure-activity investigations into the individual contribution of the nonpolar amino acids found in bacitracin. To achieve this we designed, synthesized, and evaluated a series of bacitracin analogues, a number of which were found to exhibit significantly enhanced antibacterial activity against clinically relevant, drug-resistant pathogens. As for the natural product, these next-generation bacitracins were found to form stable complexes with C55PP. The structure-activity insights thus obtained serve to inform the design of C55PP-targeting antibiotics, a key and underexploited antibacterial strategy.

Abstract licence: CC BY-NC-ND

Antibiotic resistance is a major challenge in modern medicine. The unique double membrane structure of Gram-negative bacteria limits the efficacy of many existing antibiotics and adds complexity to antibiotic development by limiting transport of antibiotics to the bacterial cytosol. New methods to mimic this barrier would enable high-throughput studies for antibiotic development. In this study, we introduce an innovative approach to modify outer membrane vesicles (OMVs) from Aggregatibacter actinomycetemcomitans, to generate planar supported lipid bilayer membranes. Our method first involves the incorporation of synthetic lipids into OMVs using a rapid freeze-thaw technique to form outer membrane hybrid vesicles (OM-Hybrids). Subsequently, these OM-Hybrids can spontaneously rupture when in contact with SiO2 surfaces to form a planar outer membrane supported bilayer (OM-SB). We assessed the formation of OM-Hybrids using dynamic light scattering and a fluorescence quenching assay. To analyze the formation of OM-SBs from OM-Hybrids we used quartz crystal microbalance with dissipation monitoring (QCM-D) and fluorescence recovery after photobleaching (FRAP). Additionally, we conducted assays to detect surface-associated DNA and proteins on OM-SBs. The interaction of an antimicrobial peptide, polymyxin B, with the OM-SBs was also assessed. These findings emphasize the capability of our platform to produce planar surfaces of bacterial outer membranes, which in turn, could function as a valuable tool for streamlining the development of antibiotics.

Abstract licence: CC BY-NC-ND

Antibiotic resistance genes (ARGs) pose a significant threat, exacerbated by climate change impacts on polar regions, particularly melting glaciers and permafrost. While ancient antibiotic resistance exists in the environments, the release and dissemination of ARGs remain poorly understood. This study investigated ARG composition and distribution in 43 metagenomes from Arctic and Antarctic glacier forelands. We identified 154 ARGs, predominantly bacitracin resistance, followed by rifamycin, fosfomycin, vancomycin, tetracycline, and beta-lactam resistance genes. Significant correlations were observed between ARGs and mobile genetic elements (MGEs), with 20 ARGs associated with tnpA MGEs. Actinomycetota and Pseudomonadota were the primary ARG-carrying phyla. Metagenome-assembled genomes revealed Mycobacterium sp., Pseudomonas sp., and Tatlockia sp. as major ARG-harboring pathogens in the glacier forelands. Evolutionarily adapted, distinct ancient ARGs were abundant in the polar environments, varying between different geographic regions. The environmental parameters such as pH and total organic carbon significantly influenced the ARG distribution in the Arctic and Antarctic glacier forelands. This study provides crucial baseline data on antimicrobial resistance, highlighting potential risks associated with rapid environmental change in the regions.ImportanceAntibiotic resistance poses a significant global health threat, exacerbated by the release of antibiotic resistance genes from melting glaciers and permafrost due to climate change. This study provides crucial baseline data on the composition and distribution of antibiotic resistance genes in these vulnerable polar environments, which is essential for understanding and mitigating the risks associated with their release. The findings have far-reaching implications for global health security and emphasize the need for further research to address this emerging threat.

Abstract licence: CC BY