To Örebro University

INTRODUCTION: Studies have shown promising results using bone graft as a carrier for local administration of antibiotics to reduce the risk of prosthetic joint infection (PJI). The objective of this clinical trial is to determine if tobramycin and vancomycin-impregnated bone graft is safe and effective in reducing the rate of PJI after total hip arthroplasty (THA).

METHODS AND ANALYSIS: This study is an international, randomised, double-blinded, placebo-controlled clinical drug trial. Patients scheduled for THA (n=1100) requiring bone grafting (excluding revisions due to an ongoing infection) are randomised in a 1:1 ratio to prophylactic treatment with tobramycin and vancomycin or placebo-impregnated bone graft.The primary outcome is the time to reoperation due to infection or diagnosis of PJI, expressed as a relative risk difference between the two groups. A risk reduction of at least 50% is considered clinically relevant. Secondary outcomes are time to and reason for reoperation and implant revision, type of micro-organism and antibiotic susceptibility pattern within 2 and 5 years after surgery. Safety outcomes are the number of adverse events and revision rate due to aseptic loosening. The primary analysis will be performed using proportional hazard models.

ETHICS AND DISSEMINATION: The study has been approved under the Clinical Trial Regulation No 536/2014 (EU CT; 2024-510921-25-00). Results will be published in open-access peer-reviewed journals and disseminated to patient organisations and the media, and de-identified individual participant data will be curated and shared on reasonable request in accordance with the Findability, Accessibility, Interoperability and Reuse principles, subject to the laws and regulations governing data protection in each participating country.

TRIAL REGISTRATION NUMBER: NCT05169229.

BACKGROUND AND OBJECTIVES: Dalbavancin, a lipoglycopeptide with a half-life of 150-200 h, is a promising treatment option for prosthetic joint infections (PJIs) and other orthopaedic implant-associated infections (IAIs) caused by multidrug-resistant staphylococci. However, in vitro studies have shown that when exposed to low concentrations of dalbavancin, staphylococcal strains resistant to dalbavancin can emerge, potentially affecting its effectiveness in cases of recurrent infection. To investigate whether dalbavancin-resistant staphylococci emerge in vivo following long-term dalbavancin treatment for PJIs or orthopaedic IAIs.

PATIENTS AND METHODS: Nineteen patients who had received long-term dalbavancin treatment (≥12 weeks) following PJI or orthopaedic IAI and 25 control patients scheduled for elective prosthetic joint surgery were sampled from the nares and perineum. Each sample was subcultured on Mueller-Hinton II agar plates containing various concentrations of dalbavancin (0.0, 0.125, 0.5, and 2.0 mg/L). The growth of staphylococcal colonies was analysed using MALDI-TOF, and the MIC values of dalbavancin were determined using the gradient test method.

RESULTS: Among dalbavancin-treated patients, 4 out of 19 displayed staphylococcal species resistant to dalbavancin (MIC value >0.25 mg/L according to EUCAST breakpoint tables). These four were all Staphylococcus epidermidis isolates, three from the nares and one from the perineum, and displayed MIC values of 0.38, 0.38, 0.5, and 0.75 mg/L. No resistant staphylococci were detected in the samples from the control group (P = 0.029, Fisher's exact test).

CONCLUSIONS: The present study demonstrated the emergence of dalbavancin-resistant staphylococci following long-term treatment.

BACKGROUND: Corynebacterium is a widespread and abundant bacterial genus on human skin. Occasionally, corynebacteria are isolated from clinical specimens associated with infection. In this study, 56 bacterial isolates were examined. These isolates were obtained from 52 patients with diverse infections such as keratitis, osteitis/osteomyelitis, mastitis, (suspected) foreign body associated infections (spine, prosthetic joint), suspected meningitis, post-operative infections, among others. These isolates were identified as corynebacteria by MALDI-TOF mass spectrometry but could not be reliably assigned to a specific species. To resolve this issue, the isolates were genome-sequenced, and species identification was done with different approaches, including digital DNA-DNA hybridization, phylogenomic tree placement and Average Nucleotide Identity (ANI) calculations. A subset of 34 strains was further investigated by biochemical characterization and antimicrobial susceptibility testing (AST).

RESULTS: The 56 isolates belonged to 28 distinct corynebacterial species. Species identification was particularly ambiguous for 13 isolates as the ANIs were below 95% to the closest identified reference genomes. Two isolates represented potentially novel species, since no close relative could be identified (ANI < 90%). The majority of isolates belonged to the Corynebacterium marquesiae/tuberculostearicum (n = 10) and Corynebacterium kroppenstedtii/parakroppenstedtii (n = 9) complexes. Biochemical tests and AST revealed species- and strain-level variability. AST demonstrated extensive antimicrobial resistance (AMR), particularly among C. marquesiae, C. tuberculostearicum, C. lehmanniae, C. hesseae and C. resistens, with resistances observed against penicillin, clindamycin, ciprofloxacin, and rifampin. Resistance was frequently associated with acquired AMR genes, such as erm(X), tet(W) and genes encoding aminoglycoside-modifying enzymes. Among the tested antibiotics, clindamycin resistance was most common, detected in 23 of 34 tested strains (64.7%).

CONCLUSIONS: This study expands our knowledge of Corynebacterium isolates derived from clinical specimens, particularly those differing from well-characterized species. It underscores the extensive geno- and phenotypic variability within most Corynebacterium species and challenges current species boundary definitions. The extensive level of detected AMR may complicate treatment of underlying infections. However, it remains uncertain whether these isolates represent true infectious agents or contaminants derived from the skin of the patients.

OBJECTIVES: Perioperative antibiotic prophylaxis is crucial for preventing detrimental postoperative prosthetic joint infections (PJIs). Guidelines aim to prevent infection with methicillin-susceptible staphylococci-in Sweden through administering cloxacillin, at fixed doses with minimal consideration to kidney function or patient weight. Over- and under-dosing could have adverse effects, negative effects on the microbiome, or increase the risk of PJI. We aimed primarily to evaluate whether the current uniform prophylactic regimen of cloxacillin in hip and knee arthroplasty is adequate.

PATIENTS AND METHODS: Patients subjected to elective prosthetic joint surgery (N = 204) were included in a prospective study. Free plasma concentrations of cloxacillin were measured on three occasions throughout arthroplasty surgery. Samples were analysed using a validated HPLC-MS/MS method. A free concentration of <2 mg/L was deemed a theoretically appropriate concentration to suppress growth of methicillin-susceptible staphylococci in bone. A sensitivity analysis with values of 1 and 4 mg/L was included.

RESULTS: Potentially subtherapeutic concentrations (≤2 mg/L) at the end of surgery were found in 31 cases (15%). The corresponding numbers for 1 and 4 mg/L were 3 and 88 (1% and 43%). In multivariable logistic regression analysis, an ASA (American Association of Anesthesiologists physical status) score of I (relatively healthy patients), estimated glomerular filtration rate >90 mL/min/1.73 m2, body weight >100 kg and long duration of surgery significantly predicted suboptimal concentrations.

CONCLUSIONS: Current cloxacillin dosing in hip and knee arthroplasty surgery results in a risk for subtherapeutic levels in patients with high body weight and preserved renal function. Therefore, dosing guidelines for cloxacillin prophylaxis in arthroplasty should be reviewed.

OBJECTIVES: To characterize the population pharmacokinetics of unbound cloxacillin in patients undergoing total arthroplasty of the hip (THA) or knee (TKA), and to explore alternative dosing regimens for cloxacillin prophylaxis.

METHODS: Plasma concentrations of total and unbound cloxacillin from 200 patients undergoing primary elective THA (n & 95) or TKA (n & 105) were analysed. Intravenous cloxacillin doses of 2 g were administered pre-surgery, and repeated after 2 and 6 hours. Samples (n & 496) were analysed using HPLC-MS/MS. Non-linear mixed-effects modelling was performed to develop a population pharmacokinetic model describing unbound cloxacillin exposure. Using this model, alternative prophylaxis regimens were explored with Monte Carlo simulations.

RESULTS: A two-compartment model with non-linear protein binding adequately described the data. Estimated glomerular filtration rate (eGFR) and body weight (kg) were significant covariates on unbound cloxacillin clearance. In 13% of patients sampled at the end of surgery (n & 25/187), unbound cloxacillin <2 mg/L was observed. A model-predicted 18-22% (n & 36-43/200) of patients failed to sustain plasma levels ≥2 mg/L throughout the two-hour dosing interval with the current regimen. In contrast, a continuous 1 g/h infusion after a 1 g loading dose would ensure target attainment in >99% of patients, according to the model predictions.

CONCLUSIONS: For many THA and TKA patients, the current cloxacillin prophylaxis regimen may fail to provide adequate target site concentrations during the entire surgical procedure. Transitioning to a prolonged infusion protocol could increase attainment of PK/PD targets without exceeding the currently recommended total perioperative dose amounts.

Staphylococcus pettenkoferi has increasingly been reported as a human pathogen, with virulence potential recently confirmed in vivo. However, its genomic diversity and antimicrobial resistance remain insufficiently characterized. This study, conducted within the PETTENK-OS project of the ESCMID Study Group for Staphylococci and Staphylococcal Diseases (ESGS), aimed to characterize the genomic diversity and resistome of this underrecognized coagulase-negative staphylococcus (CoNS). Whole-genome sequencing was performed on 61 European clinical isolates (mainly bloodstream infections and osteomyelitis) from 17 hospitals in five countries, plus two reference strains. Antimicrobial susceptibility profiles were determined by disk diffusion and broth microdilution (2025 EUCAST breakpoints). Phylogenetic analyses clustered the 63 isolates into two major clades: Clade I (n = 51; subclades I-A, n = 47, and I-B, n = 4) and Clade II (subclades II-A, n = 8, and II-B, n = 3). Susceptibility rates were below 70% for cefoxitin, erythromycin, and levofloxacin, whereas high susceptibility (>90%) was observed for vancomycin, teicoplanin, dalbavancin, aminoglycosides, oxazolidinones, trimethoprim-sulfamethoxazole, fusidic acid, and tetracycline. Nearly all isolates (92.1%) were fosfomycin-resistant. Daptomycin MIC50/90 values (1/2 mg/L) were elevated, including eight resistant isolates carrying mutations in walKR, cls1, and/or cls2 genes. Twenty-two isolates (35.4%) were multidrug-resistant, and 18 (28.6%) were methicillin-resistant, all in subclade I-A and mecA-positive within SCCmec type IV. This study provides a comprehensive genomic and phenotypic assessment of antimicrobial resistance in S. pettenkoferi, revealing widespread multidrug-resistant lineages, including ceftobiprole- and daptomycin-resistant isolates across distinct clades. These findings underscore the need for continued surveillance and improved diagnostics for this increasingly encountered CoNS species.

Background and objectives: Staphylococcus epidermidis is a major cause of prosthetic joint infections (PJIs). Multidrug resistant (MDR), hospital-adapted clones constitute most cases globally, though regional differences in lineage dissemination likely exist. The aim was to explore the population structure of S. epidermidis from PJIs in Sweden and France, with a focus on the presence of antimicrobial resistance (AMR).

Methods: This study included genome sequence data from 191 clinical S. epidermidis isolates collected from patients with PJI in central Sweden (2007-16; n = 138) and the Lyon region in France (2015-20; n = 53).

Results: Hospital-adapted lineages with a high burden of AMR dominated the cases in both countries. However, the ST2 lineage was significantly more prevalent in Sweden (43% versus 11% in France), while ST5 and ST87 were more common in France (55% versus 10% in Sweden). ST215 was only present in Sweden (25%). A significantly higher prevalence of streptogramin resistance genes [vat(B), vga(A), vga(B)] was found in French (26%) versus Swedish (2%) isolates. These genes were present in all ST87 isolates and in 20% of the French ST5 isolates. The erm(C) gene (resistance to streptogramin A, macrolides and lincosamides) was also more common in the French isolates (77% versus 55% of Swedish isolates), and so was the fusidic acid resistance gene fusB (France: 66%, Sweden: 39%).

Conclusions: This study highlights significant regional differences in S. epidermidis variants causing PJI. Despite similar MDR levels, certain AMR genes, particularly those related to streptogramin resistance, were significantly more prevalent among French isolates. This suggests that S. epidermidis undergoes local adaptation to region-specific antibiotic usage.

BACKGROUND: There is limited knowledge regarding how long prepared sterile goods can wait before becoming contaminated. We investigated whether surgical goods could be prepared the day before surgery and kept sterile overnight in the operating room, if protected by sterile covers.

METHODS: Sterile surgical goods for open-heart surgeries (n=70) were randomized to preparation on the morning of the operation or on the previous evening. Exposure time was the total time between preparation and use. Primary outcome was bacterial growth reported as colony forming units (cfu), isolated on 840 agar plates. The protocol was registered with ClinicalTrials.gov (NCT05597072).

RESULTS: When the agar plates were protected with sterile covers, exposure time had no impact (intervention group: 7 cfu, control group: 17 cfu). Without protection, longer exposure time was associated with more cfu (p=0.016). A total of 499 cfu were isolated, displaying 59 different types of bacteria including 13 resistant Staphylococcus epidermidis, 6 (46%) of which were multidrug resistant.

CONCLUSIONS: Sterile goods could wait in the operating room for at least 15 hours before use without increased risk of bacterial air contamination, if protected with sterile covers. However, if the goods were not covered, bacterial air contamination occurred over time.

PURPOSE: To describe the clinical characteristics of exogenous episodes of endophthalmitis from which Staphylococcus epidermidis was isolated by vitreous cultures. We also explored the genomic traits of these S. epidermidis isolates and their relatedness to S. epidermidis originating from carriers and from prosthetic joint infections in the same geographical region.

METHODS: S. epidermidis isolated from cases of exogenous endophthalmitis (n = 33) were genome sequenced. Clinical features were retrospectively collected from medical records. The isolates were compared with previously sequenced S. epidermidis isolates from the nares of healthy individuals (n = 151) and from prosthetic joint infections (n = 138).

RESULTS: The most common ophthalmological procedure preceding the endophthalmitis was a posterior segment surgery (76%; 25/33), mainly intravitreal injection (70%; 23/33). These patients displayed a significantly shorter time to symptoms compared to those with an anterior segment surgery (median 3 vs. 9 days; p < 0.001), and significantly less phenotypic methicillin resistance (8%, n = 2/25 vs. 50%, n = 4/8; p = 0.02). Most isolates of S. epidermidis originating from endophthalmitis cases did not belong to known healthcare-associated lineages and did not cluster with isolates from prosthetic joint infections. Rather, they were more similar to isolates from the nares of healthy individuals.

CONCLUSIONS: Genomic data suggest that the S. epidermidis isolated from the vitreous of Swedish cases of postsurgical endophthalmitis may originate from the commensal flora of the individual, and not from the healthcare facilities. The type of preceding surgical procedure (anterior vs. posterior segment) may influence both symptom delay and the presence or absence of methicillin resistance.