Antibiotic exposure at the infection site in periprosthetic joint infections

Prosthetic joint infections (PJI, periprosthetic infection) is a serious
complication of joint replacement surgery, leading to prosthesis failure. The
standard treatment of PJI consists of a one-stage two-stage arthroplasty
exchange, which includes a six-weeks course of orally and intravenously
administered antimicrobial therapy. In practice, antibiotic regimens and the
therapeutic efficacy are optimized by measuring concentrations in plasma.
However, through this method it remains unclear whether effective
concentrations of the antibiotics have reached the site of PJI, although
adequate target site concentrations are important to achieve effective
eradication of the micro-organism causing the PJI. Furthermore, antibiotic
concentrations vary depending on individual patient characteristics such as
body mass, renal function and bowel absorption. Additionally, the comparison of
studies on the penetration of surgical prophylactic antibiotics in bone and
joint tissue indicates a large variation in the antibiotic concentrations at
the target site in extremities, making antibiotic dosage recommendations
supported by limited evidence. Despite these insights, knowledge is lacking
regarding the target site concentrations of the antibiotics, administered as
part of the one-stage or two-stage arthroplasty exchange, with respect to the
dosage and plasma concentrations. The overall aim of this proposed study is to
gain insight into the target attainment of the administered antibiotics during
the two-stage arthroplasty exchange, in order to determine the efficacy in
relation to the minimal inhibitory concentration (MIC) of the pathogen causing
the infection. Additionally, by comparing the target site concentrations of
orally and intravenously (IV) administered antibiotics we can determine whether
a need exists per patient for both oral and IV administration of antibiotics,
or if one route of administration is sufficient enough.

To develop a pharmacokinetic (PK) model for the relationship between dosage,
blood concentration and infection site concentration, estimating covariates to
determine differences in antibiotic concentrations in synovial fluid, synovial
tissue and bone between different types of antibiotics and knee versus hip.

Cross-sectional observational study

This study is relevant since effective concentrations of the applied
antibiotics at the site PJI are of importance for not only the optimization of
the treatment efficacy, but also to decrease the incidence of unnecessary
antibiotic-related adverse events. Patients have to undergo study related
procedures which are minimally invasive; risks and burdens associated with
participation are minimized by combining them with procedures for standard
care, as much as possible. Therefore, only undergoing venous blood sampling and
joint punctures for collecting synovial fluid outside of the surgeries can be
considered invasive and a burden for the patient. To reduce the extend of the
burden on the patients these joint punctures will be combined with the periodic
hospital visitations of the patients after prosthesis extraction; if not
possible additional hospital visits will be necessary and unavoidable. Adverse
events of joint punctures may include pain, bleeding, bruising and joint
swelling; however, these events are rare making joint punctures a
well-tolerated procedure. The individual patients participating in this study
have no direct benefits. The possible risks associated with the study are
outweighed by its benefits for the study population.