Pharmacokinetic/Pharmacodynamic Dosage Individualization of Suppressive Beta-Lactam Therapy Administered by Subcutaneous Route in Patients With Prosthetic Joint Infection

Abstract

Suppressive parenteral antibiotic therapy with beta-lactams may be necessary in patients with Gram-negative bone and joint infection (BJI). Subcutaneous drug administration can facilitate this therapy in outpatient setting, but there is limited information about this practice. We have developed an original approach for drug dosing in this context, based on therapeutic drug monitoring (TDM) and pharmacokinetic/pharmacodynamic (PK/PD) principles. The objective of this study was to describe our approach and its first results in a case series. We analyzed data from patients who received suppressive antibiotic therapy by subcutaneous (SC) route with beta-lactams as salvage therapy for prosthetic joint infection (PJI) and had TDM with PK/PD-based dose adjustment. Ten patients (six women and four men with a mean age of 77 years) were included from January 2017 to May 2020. The drugs administered by SC route were ceftazidime (n = 4), ertapenem (n = 4), and ceftriaxone (n = 2). In each patient, PK/PD-guided dosage individualization was performed based on TDM and minimum inhibitory concentration (MIC) measurements. The dose interval could be prolonged from twice daily to thrice weekly in some patients, while preserving the achievement of PK/PD targets. The infection was totally controlled by the strategy in nine out the 10 patients during a median follow-up of 1,035 days (~3 years). No patient acquired carbapenem-resistant Gram-negative bacteria during the follow-up. One patient presented treatment failure with acquired drug resistance under therapy, which could be explained by late MIC determination and insufficient exposure, retrospectively. To conclude, our innovative approach, based on model-based TDM, MIC determination, and individualized PK/PD goals, facilitates, and optimizes suppressive outpatient beta-lactam therapy administered by SC route for PJI. These encouraging results advocate for larger clinical evaluation.

Limitations of Antibiotic MIC-Based PK-PD Metrics: Looking Back to Move Forward

“…This problem is minimized in animal infection model or dynamic in vitro infection model studies aimed at elucidating the predictive PK-PD index and target values for various magnitudes of bacterial kill by ensuring that several bacterial strains are included in the study to inform setting of PK-PD targets and breakpoints (Zhao et al, 2016;Mouton et al, 2018b;Jorda and Zeitlinger, 2020). However, an inaccurate estimate from a single determination of MIC for an isolate from a particular patient is problematic in the clinical application of MIC-based PK-PD targets within the framework of what has been described as therapeutic drug monitoring (TDM) (Mouton et al, 2018b;Roberts et al, 2019;Märtson et al, 2020;Seeger et al, 2021a;Goutelle et al, 2021;Jorgensen et al, 2021;Moser et al, 2021). Thus, if an isolate from an infected patient returns an MIC estimate from an assay which has a typical error range of two dilutions (i.e., potentially a 4-fold range of reported MIC values), it follows that the PK-PD driven target plasma concentration for that patient would vary 4-fold if the PK-PD index for the antibiotic is fAUC/MIC or fC max /MIC.…”

“…Clearly, if the "true" MIC of the isolate is at the top of the error range but the reported MIC is at the bottom of the range, there is substantial risk of under dosing the patient. If the converse applied for an antibiotic of low therapeutic index, there may be increased risk of treatment-related toxicity if the reported MIC resulted in the decision to increase the dosage regimen (Märtson et al, 2020;Goutelle et al, 2021). Either of these outcomes may decrease the probability of achieving a good clinical outcome for the patient.…”

A Systematic Review of the Effect of Therapeutic Drug Monitoring on Patient Health Outcomes during Treatment with Carbapenems

“…The included studies are summarised in Table S3 [ 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 , 76 , 77 , 78 , 79 ]. Best practice for carbapenem TDM is not known, which has led to differences in the way it is carried out, particularly concerning pharmacological targets, dose-adjustment protocols, and frequency of antibiotic concentration measurement.…”

The Subcutaneous Administration of Beta-Lactams: A Case Report and Literary Review—To Do Small Things in a Great Way

“…The prolonged t 1/2 associated with the s.c. administration of beta-lactams and the potential for patient self-medication make this route of administration very attractive, especially for infections requiring long-term antibiotic therapy, such as prosthetic joint infections. In our review, we included two case series describing the use of beta-lactams (ceftriaxone, ceftazidime, ertapenem) administered via the s.c. route for the treatment of chronic osteoarticular infections [11,14]. The s.c. administration of beta-lactams could be particularly useful for the treatment of chronic infections caused by Gram-negative bacteria, which are difficult to treat without inducing susceptibility to oral antibiotics, a very common situation in countries where MDR Gram-negative bacteria are frequently isolated.…”

“…In this case, the issue was the lack of knowledge regarding the ertapenem minimum inhibitory concentration (MIC) for E. cloacae at the onset of treatment. Subsequently, it was discovered that the MIC value was 0.38 mg/L, and the PK profile revealed that the thrice-weekly regimen did not achieve a sufficient fraction of time above the MIC (fT > MIC) [14].…”