Duration of Perioperative Antibiotic Prophylaxis in Open Fractures:A Systematic Review and Critical Appraisal

Fracture-related infection (FRI) remains a serious complication in open fracture care. Adequate surgical treatment and perioperative antibiotic prophylaxis (PAP) are key factors influencing the outcome. However, data concerning the optimal duration of PAP is scarce. The aim of this systematic review was to provide an overview of current evidence on the association between PAP duration and FRI in open fractures. A comprehensive search on 13 January 2022, in Embase, Medline, Cochrane, Web of Science and Google Scholar revealed six articles. Most studies compared either 1 day versus 5 days of PAP or included a cut-off at 72 h. Although prolonged PAP was not beneficial in the majority of patients, the variety of antibiotic regimens, short follow-up periods and unclear description of outcome parameters were important limitations that were encountered in most studies. This systematic review demonstrates a lack of well-constructed studies investigating the effect of PAP duration on FRI. Based on the available studies, prolonged PAP does not appear to be beneficial in the prevention of FRI in open fractures. However, these results should be interpreted with caution since all included studies had limitations. Future randomized trials are necessary to answer this research question definitively

Staphylococcus aureus From an Acute Fracture-related Infection Displays Important Bacteriological and Histopathologic Differences From a Chronic Equivalent in a Murine Bone Infection Model

Background Staphylococcus aureus is the leading pathogen in fracture-related infection. Previous in vitro experiments, in vivo testing in wax moth larvae, and genomic analysis of clinical S. aureus isolates from fracture-related infection identified low-virulence (Lo-SA5464) and high-virulence (Hi-SA5458) strains. These findings correlated with acute fracture-related infection induced by Hi-SA5458, whereas Lo-SA5464 caused a chronic fracture-related infection in its human host. However, it remains unclear whether and to what extent the causative pathogen is attributable to these disparities in fracture-related infections. Question/purpose Are there differences in the course of infection when comparing these two different clinical isolates in a murine fracture-related infection model, as measured by (1) clinical observations of weight loss, (2) quantitative bacteriology, (3) immune response, and (4) radiographic and histopathologic morphology? Methods Twenty-five (including one replacement animal) female (no sex-specific influences expected), skeletally mature C57Bl/6N inbred mice between 20 and 28 weeks old underwent femoral osteotomy stabilized by titanium locking plates. Fracture-related infection was established by inoculation of high-virulence S. aureus EDCC 5458 (Hi-SA5458) or low-virulence S. aureus EDCC 5464 (Lo-SA5464) in the fracture gap. Each of these groups consisted of 12 randomly assigned animals. Mice were euthanized 4 and 14 days postsurgery, resulting in six animals per group and timepoint. The severity and progression of infection were assessed in terms of clinical observation of weight loss, quantitative bacteriology, quantitative serum cytokine levels, qualitative analysis of postmortem radiographs, and semiquantitative histopathologic evaluation. Results For clinical observations of weight change, no differences were seen at Day 4 between Hi-SA5458- and Lo-SA5464-infected animals (mean -0.6 ± 0.1 grams versus -0.8 ± 0.2 grams, mean difference -0.2 grams [95% CI -0.8 to 0.5 grams]; p =0.43), while at 14 days, the Hi-SA5458 group lost more weight than the Lo-SA5464 group (mean -1.55 ± 0.2 grams versus -0.8 ± 0.3 grams; mean difference 0.7 grams [95% CI 0.2 to 1.3 grams]; p = 0.02). Quantitative bacteriological results 4 days postoperatively revealed a higher bacterial load in soft tissue samples in Hi-SA5458-infected animals than in the Lo-SA5464-infected cohort (median 6.8 x 107 colony-forming units [CFU]/g, range 2.2 x 107 to 2.1 x 109 CFU/g versus median 6.0 x 106 CFU/g, range 1.8 x 105 to 1.3 x 108 CFU/g; difference of medians 6.2 x 107 CFU/g; p = 0.03). At both timepoints, mice infected with the Hi-SA5458 strain also displayed higher proportions of bacterial dissemination into organs than Lo-SA5464-infected animals (67% [24 of 36 organs] versus 14% [five of 36 organs]; OR 12.0 [95% CI 3.7 to 36]; p < 0.001). This was accompanied by a pronounced proinflammatory response on Day 14, indicated by increased serum cytokine levels of interleukin-1β (mean 9.0 ± 2.2 pg/mL versus 5.3 ± 1.5 pg/mL; mean difference 3.6 pg/mL [95% CI 2.0 to 5.2 pg/mL]; p < 0.001), IL-6 (mean 458.6 ± 370.7 pg/mL versus 201.0 ±89.6 pg/mL; mean difference 257.6 pg/mL [95% CI 68.7 to 446.5 pg/mL]; p = 0.006), IL-10 (mean 15.9 ± 3.5 pg/mL versus 9.9 ± 1.0 pg/mL; mean difference 6.0 pg/mL [95% CI 3.2 to 8.7 pg/mL]; p < 0.001), and interferon-γ (mean 2.7 ± 1.9 pg/mL versus 0.8 ± 0.3 pg/mL; mean difference 1.8 pg/mL [95% CI 0.5 to 3.1 pg/mL]; p = 0.002) in Hi-SA5458-infected compared with Lo-SA5464-infected animals. The semiquantitative histopathologic assessment on Day 4 revealed higher grades of granulocyte infiltration in Hi-SA5458-infected animals (mean grade 2.5 ± 1.0) than in Lo-SA5464-infected animals (mean grade 1.8 ± 1.4; mean difference 0.7 [95% CI 0.001 to 1.4]; p = 0.0498). On Day 14, bone healing at the fracture site was present to a higher extent in Lo-SA5464-infected animals than in Hi-SA5458-infected animals (mean grade 0.2 ± 0.4 versus 1.8 ± 1.2; mean difference -1.6 [95% CI -2.8 to -0.5]; p = 0.008). Conclusion Similar to septic infection in a human host, infection with Hi-SA5458 in this murine model was characterized by a higher bacterial load, more-pronounced systemic dissemination, and stronger systemic and local inflammation. Thus, there is strong support for the idea that pathogenic virulence plays a crucial role in fracture-related infections. To confirm our observations, future studies should focus on characterizing S. aureus virulence at the genomic and transcriptomic levels in more clinical isolates and patients. Comparing knockout and wildtype strains in vitro and in vivo, including the S. aureus strains studied, could confirm our findings and identify the genomic features responsible for S. aureus virulence in fracture-related infections. Clinical Relevance For translational use, virulence profiles of S. aureus may be useful in guiding treatment decisions in the future. Once specific virulence targets are identified, one approach to fracture-related infections with high-virulence strains might be the development of antivirulence agents, particularly to treat or prevent septic dissemination. For fracture-related infections with low virulence, prolonged antimicrobial therapy or exchange of an indwelling implant might be beneficial owing to slower growth and persistence capacity

Comparative Genomics Study of Staphylococcus epidermidis Isolates from Orthopedic-Device-Related Infections Correlated with Patient Outcome

Staphylococcus epidermidis has emerged as an important opportunistic pathogen causing orthopedic-device-related infections (ODRI). This study investigated the association of genome variation and phenotypic features of the infecting S. epidermidis isolate with the clinical outcome for the infected patient. S. epidermidis isolates were collected from 104 patients with ODRI. Their clinical outcomes were evaluated, after an average of 26 months, as either “cured” or “not cured.” The isolates were tested for antibiotic susceptibility and biofilm formation. Whole-genome sequencing was performed on all isolates, and genomic variation was related to features associated with “cured” and “not cured.” Strong biofilm formation and aminoglycoside resistance were associated with a “not-cured” outcome (P = 0.031 and P = 0.001, respectively). Based on gene-by-gene analysis, some accessory genes were more prevalent in isolates from the “not-cured” group. These included the biofilm-associated bhp gene, the antiseptic resistance qacA gene, the cassette chromosome recombinase-encoding genes ccrA and ccrB, and the IS256-like transposase gene. This study identifies biofilm formation and antibiotic resistance as associated with poor outcome in S. epidermidis ODRI. Whole-genome sequencing identified specific genes associated with a “not-cured” outcome that should be validated in future studies. (The study has been registered at ClinicalTrials.govwith identifier NCT02640937.

A Trans-Atlantic Perspective on Stagnation in Clinical Translation of Antimicrobial Strategies for the Control of Biomaterial-Implant-Associated Infection

Current regulatory requirements impede clinical translation and market introduction of many new antimicrobial combination implants and devices, causing unnecessary patient suffering, doctor frustration, and costs to healthcare payers. Regulatory requirements of antimicrobial combination implants and devices should be thoroughly revisited and their approval allowed based on enrichment of benefit demonstrations from high-risk patient groups and populations or device components to facilitate their clinical translation. Biomaterial implant and devices equipped with antimicrobial strategies and approved based on enrichment claims should be mandatorily enrolled in global registry studies supervised by regulatory agencies for a minimum five-year period or until statistically validated evidence for noninferiority or superiority of claims is demonstrated. With these recommendations, this trans-Atlantic consortium of academicians and clinicians takes its responsibility to actively seek to relieve the factors that stagnate downward clinical translation and availability of antimicrobial combination implants and devices. Improved dialogue between the various key players involved in the current translational blockade, which include patients, academicians and doctors, policymakers, regulatory agencies, manufacturers, and healthcare payers, is urgently needed.</p

Disease-associated genotypes of the commensal skin bacterium Staphylococcus epidermidis

Some of the most common infectious diseases are caused by bacteria that naturally colonise humans asymptomatically. Combating these opportunistic pathogens requires an understanding of the traits that differentiate infecting strains from harmless relatives. Staphylococcus epidermidis is carried asymptomatically on the skin and mucous membranes of virtually all humans but is a major cause of nosocomial infection associated with invasive procedures. Here we address the underlying evolutionary mechanisms of opportunistic pathogenicity by combining pangenome-wide association studies and laboratory microbiology to compare S. epidermidis from bloodstream and wound infections and asymptomatic carriage. We identify 61 genes containing infection-associated genetic elements (k-mers) that correlate with in vitro variation in known pathogenicity traits (biofilm formation, cell toxicity, interleukin-8 production, methicillin resistance). Horizontal gene transfer spreads these elements, allowing divergent clones to cause infection. Finally, Random Forest model prediction of disease status (carriage vs. infection) identifies pathogenicity elements in 415 S. epidermidis isolates with 80% accuracy, demonstrating the potential for identifying risk genotypes pre-operatively.Peer reviewe

The 2023 Orthopedic Research Society's international consensus meeting on musculoskeletal infection: Summary from the in vitro section

Antimicrobial strategies for musculoskeletal infections are typically first developed with in vitro models. The In Vitro Section of the 2023 Orthopedic Research Society Musculoskeletal Infection international consensus meeting (ICM) probed our state of knowledge of in vitro systems with respect to bacteria and biofilm phenotype, standards, in vitro activity, and the ability to predict in vivo efficacy. A subset of ICM delegates performed systematic reviews on 15 questions and made recommendations and assessment of the level of evidence that were then voted on by 72 ICM delegates. Here, we report recommendations and rationale from the reviews and the results of the internet vote. Only two questions received a ≥90% consensus vote, emphasizing the disparate approaches and lack of established consensus for in vitro modeling and interpretation of results. Comments on knowledge gaps and the need for further research on these critical MSKI questions are included

Development and Characterization of a Subcutaneous Implant-Related Infection Model in Mice to Test Novel Antimicrobial Treatment Strategies

Orthopedic-device-related infection is one of the most severe complications in orthopedic surgery. To reduce the associated morbidity and healthcare costs, new prevention and treatment modalities are continuously under development. Preclinical in vivo models serve as a control point prior to clinical implementation. This study presents a mouse model of subcutaneously implanted titanium discs, infected with Staphylococcus aureus, to fill a gap in the early-stage testing of antimicrobial biomaterials. Firstly, three different inocula were administered either pre-adhered to the implant or pipetted on top of it following implantation to test their ability to reliably create an infection. Secondly, the efficacy of low-dose (25 mg/kg) and high-dose (250 mg/kg) cefazolin administered systemically in infection prevention was assessed. Lastly, titanium implants were replaced by antibiotic-loaded bone cement (ALBC) discs to investigate the efficacy of local antibiotics in infection prevention. The efficacy in infection prevention of the low-dose perioperative antibiotic prophylaxis (PAP) depended on both the inoculum and inoculation method. Bacterial counts were significantly lower in animals receiving the high dose of PAP. ALBC discs with or without the additional PAP proved highly effective in infection prevention and provide a suitable positive control to test other prevention strategies

Development and Characterization of a Subcutaneous Implant-Related Infection Model in Mice to Test Novel Antimicrobial Treatment Strategies

Orthopedic-device-related infection is one of the most severe complications in orthopedic surgery. To reduce the associated morbidity and healthcare costs, new prevention and treatment modalities are continuously under development. Preclinical in vivo models serve as a control point prior to clinical implementation. This study presents a mouse model of subcutaneously implanted titanium discs, infected with Staphylococcus aureus, to fill a gap in the early-stage testing of antimicrobial biomaterials. Firstly, three different inocula were administered either pre-adhered to the implant or pipetted on top of it following implantation to test their ability to reliably create an infection. Secondly, the efficacy of low-dose (25 mg/kg) and high-dose (250 mg/kg) cefazolin administered systemically in infection prevention was assessed. Lastly, titanium implants were replaced by antibiotic-loaded bone cement (ALBC) discs to investigate the efficacy of local antibiotics in infection prevention. The efficacy in infection prevention of the low-dose perioperative antibiotic prophylaxis (PAP) depended on both the inoculum and inoculation method. Bacterial counts were significantly lower in animals receiving the high dose of PAP. ALBC discs with or without the additional PAP proved highly effective in infection prevention and provide a suitable positive control to test other prevention strategies