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Dynamic PET-facilitated modeling and high-dose rifampin regimens for Staphylococcus aureus orthopedic implant-associated infections.

ABSTRACT: Staphylococcus aureus is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat S. aureus orthopedic implant–associated infections. Rifampin, however, has limited bone penetration. Here, dynamic ¹¹C-rifampin positron emission tomography (PET) performed in prospectively enrolled patients with confirmed S. aureus bone infection (n = 3) or without orthopedic infection (n = 12) demonstrated bone/plasma area under the concentration-time curve ratio of 0.14 (interquartile range, 0.09 to 0.19), exposures lower than previously thought. PET-based pharmacokinetic modeling predicted rifampin concentration-time profiles in bone and facilitated studies in a mouse model of S. aureus orthopedic implant infection. Administration of high-dose rifampin (human equipotent to 35 mg/kg per day) substantially increased bone concentrations (2 mg/liter versus <0.2 mg/liter with standard dosing) in mice and achieved higher bacterial killing and biofilm disruption. Treatment for 4 weeks with high-dose rifampin and vancomycin was noninferior to the recommended 6-week treatment of standard-dose rifampin with vancomycin in mice (risk difference, −6.7% favoring high-dose rifampin regimen). High-dose rifampin treatment ameliorated antimicrobial resistance (0% versus 38%; P = 0.04) and mitigated adverse bone remodeling (P < 0.01). Last, whole-genome sequencing demonstrated that administration of high-dose rifampin in mice reduced selection of bacterial mutations conferring rifampin resistance (rpoB) and mutations in genes potentially linked to persistence. These data suggest that administration of high-dose rifampin is necessary to achieve optimal bone concentrations, which could shorten and improve treatments for S. aureus orthopedic implant infections.

SUBMITTER: Gordon O

PROVIDER: S-EPMC8693472 | biostudies-literature | 2021 Dec

REPOSITORIES: biostudies-literature

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Dynamic PET-facilitated modeling and high-dose rifampin regimens for Staphylococcus aureus orthopedic implant-associated infections.

Gordon Oren O Lee Donald E DE Liu Bessie B Langevin Brooke B Ordonez Alvaro A AA Dikeman Dustin A DA Shafiq Babar B Thompson John M JM Sponseller Paul D PD Flavahan Kelly K Lodge Martin A MA Rowe Steven P SP Dannals Robert F RF Ruiz-Bedoya Camilo A CA Read Timothy D TD Peloquin Charles A CA Archer Nathan K NK Miller Lloyd S LS Davis Kimberly M KM Gobburu Jogarao V S JVS Jain Sanjay K SK

Science translational medicine 20211201 622

Staphylococcus aureus is a major human pathogen causing serious implant–associated infections. Combination treatment with rifampin (10 to 15 mg/kg per day), which has dose-dependent activity, is recommended to treat S. aureus orthopedic implant–associated infections. Rifampin, however, has limited bone penetration. Here, dynamic 11C-rifampin positron emission tomography (PET) performed in prospectively enrolled patients with confirmed S. aureus bone infection ( ...[more]

PMID: 34851697

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Project description:BACKGROUND:This study assessed incidence, risk factors, and outcomes of Staphylococcus aureus infections (SAI) following endoprosthetic hip or knee, or spine surgeries. METHODS:Adult patients with at least one of the selected surgeries from 2012 to 2015 captured in a German sickness fund database were included. SAI were identified using S. aureus-specific ICD-10 codes. Patients with certain prior surgeries and infections were excluded. Cumulative incidence and incidence density of post-surgical SAI were assessed. Risk factors, mortality, healthcare resource utilization and direct costs were compared between SAI and non-SAI groups using multivariable analyses over the 1 year follow-up. RESULTS:Overall, 74,327 patients who underwent a knee (28.6%), hip (39.6%), or spine surgery (31.8%) were included. The majority were female (61.58%), with a mean age of 69.59 years and a mean Charlson Comorbidity Index (CCI) of 2.3. Overall, 1.92% of observed patients (20.20 SAI per 1000 person-years (PY)) experienced a SAI within 1 year of index hospitalization. Knee surgeries were associated with lower SAI risk compared with hip surgeries (Hazard Ratio (HR) = 0.8; p = 0.024), whereas spine surgeries did not differ significantly from hip surgeries. Compared with non-SAI group, the SAI group had on average 4.4 times the number of hospitalizations (3.1 vs. 0.7) and 7.7 times the number of hospital days (53.5 vs. 6.9) excluding the index hospitalization (p < 0.001). One year post-orthopedic mortality was 22.38% in the SAI and 5.31% in the non-SAI group (p < 0.001). The total medical costs were significantly higher in the SAI group compared to non-SAI group (42,834€ vs. 13,781€; p < 0.001). Adjusting for confounders, the SAI group had nearly 2 times the all-cause direct healthcare costs (exp(b) = 1.9; p < 0.001); and 1.72 times higher risk of death (HR = 1.72; p < 0.001). CONCLUSIONS:SAI risk after orthopedic surgeries persists and is associated with significant economic burden and risk of mortality. Hence, risk reduction and prevention methods are of utmost importance.

Project description:IntroductionTreating orthopedic implant-associated infections, especially those caused by Staphylococcus aureus (S. aureus), remains a significant challenge. S. aureus has the ability to invade host cells, enabling it to evade both antibiotics and immune responses during infection, which may result in clinical treatment failures. Therefore, it is critical to identify the host cell type of implant-associated intracellular S. aureus infections and to develop a strategy for highly targeted delivery of antibiotics to the host cells.ObjectivesIntroduced an antibody-antibiotic conjugate (AAC) for the targeted elimination of intracellular S. aureus.MethodsThe AAC comprises of a human monoclonal antibody (M0662) directly recognizes the surface antigen of S. aureus, Staphylococcus protein A, which is conjugated with vancomycin through cathepsin-sensitive linkers that are cleavable in the proteolytic environment of the intracellular phagolysosome. AAC, vancomycin and vancomycin combined with AAC were used in vitro intracellular infection and mice implant infection models. We then tested the effect of AAC in vivo and in vivo by fluorescence imaging, in vivo imaging, bacterial quantitative analysis and bacterial biofilm imaging.ResultsIn vitro, it was observed that AAC captured extracellular S. aureus and co-entered the cells, and subsequently released vancomycin to induce rapid elimination of intracellular S. aureus. In the implant infection model, AAC significantly improved the bactericidal effect of vancomycin. Scanning electron microscopy showed that the application of AAC effectively blocked the formation of bacterial biofilm. Further histochemical and micro-CT analysis showed AAC significantly reduced the level of bone marrow density (BMD) and bone volume fraction (BV/TV) reduction caused by bacterial infection in the distal femur of mice compared to vancomycin treatment alone.ConclusionsThe application of AAC in an implant infection model showed that it significantly improved the bactericidal effects of vancomycin and effectively blocked the formation of bacterial biofilms, without apparent toxicity to the host.

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Dynamic PET-facilitated modeling and high-dose rifampin regimens for Staphylococcus aureus orthopedic implant-associated infections.

Publications

Dynamic PET-facilitated modeling and high-dose rifampin regimens for <i>Staphylococcus aureus</i> orthopedic implant-associated infections.

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