fosfomycin and Soft-Tissue-Infections

Osteomyelitis, or bone infection, is often induced by antibiotic resistant Staphylococcus aureus strains of bacteria. Although debridement and long-term administration of antibiotics are the gold standard for osteomyelitis treatment, the increase in prevalence of antibiotic resistant bacterial strains limits the ability of clinicians to effectively treat infection. Bacteriophages (phages), viruses that in a lytic state can effectively kill bacteria, have gained recent attention for their high specificity, abundance in nature, and minimal risk of host toxicity. Previously, we have shown that CRISPR-Cas9 genomic editing techniques could be utilized to expand temperate bacteriophage host range and enhance bactericidal activity through modification of the tail fiber protein. In a dermal infection study, these CRISPR-Cas9 phages reduced bacterial load relative to unmodified phage. Thus we hypothesized this temperate bacteriophage, equipped with the CRISPR-Cas9 bactericidal machinery, would be effective at mitigating infection from a biofilm forming S. aureus strain in vitro and in vivo. In vitro, qualitative fluorescent imaging demonstrated superiority of phage to conventional vancomycin and fosfomycin antibiotics against S. aureus biofilm. Quantitative antibiofilm effects increased over time, at least partially, for all fosfomycin, phage, and fosfomycin-phage (dual) therapeutics delivered via alginate hydrogel. We developed an in vivo rat model of osteomyelitis and soft tissue infection that was reproducible and challenging and enabled longitudinal monitoring of infection progression. Using this model, phage (with and without fosfomycin) delivered via alginate hydrogel were successful in reducing soft tissue infection but not bone infection, based on bacteriological, histological, and scanning electron microscopy analyses. Notably, the efficacy of phage at mitigating soft tissue infection was equal to that of high dose fosfomycin. Future research may utilize this model as a platform for evaluation of therapeutic type and dose, and alternate delivery vehicles for osteomyelitis mitigation.

Topics: Animals; Anti-Bacterial Agents; Bacteriophages; Biofilms; CRISPR-Cas Systems; Disease Models, Animal; Female; Fosfomycin; Gene Editing; Longitudinal Studies; Osteomyelitis; Rats; Rats, Sprague-Dawley; Soft Tissue Infections; Staphylococcal Infections; Staphylococcus aureus; Vancomycin

Complicated skin and soft tissue infections constitute a heterogeneous group of severe disorders, with surgical site infections being the most common hospital-acquired ones. The aim of our study was to investigate the synergistic and bactericidal activities of antimicrobial combinations of fosfomycin with rifampicin and tigecycline against Enterococcus faecalis, Enterococcus faecium and methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates, and also to evaluate their in vivo effects in a mouse wound infection model. In in vitro studies, the combinations of fosfomycin with rifampicin and tigecycline were both synergistic. These synergies were confirmed in in vivo studies: the drug combinations showed the highest antimicrobial effects compared to monotherapy. In conclusion, the efficacy of fosfomycin combinations, also confirmed in our in vivo model, may suggest new directions in the treatment of infected skin and a possible alternative way to control bacterial skin infection.

Topics: Animals; Anti-Bacterial Agents; Enterococcus faecalis; Enterococcus faecium; Fosfomycin; Gram-Positive Cocci; Humans; Male; Methicillin-Resistant Staphylococcus aureus; Mice; Mice, Inbred BALB C; Microbial Sensitivity Tests; Minocycline; Rifampin; Skin Diseases, Bacterial; Soft Tissue Infections; Surgical Wound Infection; Tigecycline

Topics: Aged; Amikacin; Anti-Bacterial Agents; Bacterial Proteins; beta-Lactamases; Ciprofloxacin; Colonic Diseases; Drug Synergism; Drug Therapy, Combination; Enterobacter cloacae; Enterobacteriaceae Infections; Female; Fosfomycin; Hernia, Abdominal; Herniorrhaphy; Humans; Intestinal Fistula; Minocycline; Postoperative Complications; Prosthesis-Related Infections; Soft Tissue Infections; Surgical Mesh; Tigecycline