Population pharmacokinetics and probability of target attainment of ertapenem administered by subcutaneous or intravenous route in patients with bone and joint infection

International audienceBackground: Ertapenem is a therapeutic option in patients with Gram-negative bone and joint infection (BJI). The subcutaneous (sc) route of administration is convenient in the outpatient setting and has shown favourable pharmacokinetics (PK), but available data on ertapenem are limited. Objectives: To perform population PK analysis and pharmacokinetic/pharmacodynamic (PK/PD) simulation of ertapenem administered by the intravenous (iv) or sc route to patients with BJI. Patients and methods: This was a retrospective analysis of PK data collected in patients with BJI who received iv or sc ertapenem. Measured ertapenem concentrations were analysed with a non-parametric population approach. Then, simulations were performed based on the final model to investigate the influence of ertapenem route of administration, dosage and renal function on the probability of achieving a pharmacodynamic (PD) target, defined as the percentage of time for which free plasma concentrations of ertapenem remained above the MIC (fT\textgreaterMIC) of 40%. Results: Forty-six PK profiles (13 with iv and 33 with sc ertapenem) with a total of 133 concentrations from 31 subjects were available for the analysis. A two-compartment model with linear sc absorption and linear elimination best fitted the data. Creatinine clearance was found to significantly influence ertapenem plasma clearance. Simulations showed that twice daily dosing, sc administration and renal impairment were associated with an increase in fT\textgreaterMIC and target attainment. Conclusions: Our results indicate that 1 g of ertapenem administered twice daily, by the iv or sc route, may optimize ertapenem exposure and achievement of PK/PD targets in patients with BJI

Seventeen Cases of Daptomycin-Induced Eosinophilic Pneumonia in a Cohort of Patients Treated for Bone and Joint Infections: Proposal for a New Algorithm

Background: Daptomycin is increasingly used in the treatment of bone and joint infections (BJIs) and may be responsible for daptomycin-induced eosinophilic pneumonia (DIEP), a potentially severe adverse drug reaction. The aim of this study was to describe DIEP in patients treated at a referral center for the management of BJI, and to revisit current definitions of this disease.Methods: Patients treated from 1 January 2012 to 31 March 2021 were included in a prospective cohort (NCT02817711), in which all potential serious adverse events are prospectively recorded. Patients diagnosed with DIEP were retrospectively analyzed using different definitions.Results: In a total of 4664 patients included in the cohort during the study period, 1021 patients (21.9%) received daptomycin, of whom 17 (1.7%) were diagnosed with DIEP. Most patients were male (n = 11 [64.7%]), and periprosthetic joint infection was the commonest BJI (n = 12 [70.6%]). Only 1 patient had bronchoalveolar lavage (BAL) eosinophil count ≥25%, while most patients had peripheral blood eosinophilia (n = 15 [88.2%]). Chest computed tomography (CT) was compatible with eosinophilic pneumonia in 13 of 14 cases (92.9%). All patients recovered upon discontinuation of daptomycin. Using the different definitions available, only a minority of cases fulfilled existing criteria for DIEP. We propose a new algorithm that includes specific CT scan signs, and systemic instead of BAL eosinophilia.Conclusions: DIEP is a rare event that requires prompt discontinuation of the causative antibiotic. Current criteria to diagnose definite DIEP are too restrictive and not easily applicable in clinical practice. A new algorithm is proposed here (Lyon algorithm) to facilitate the early identification of DIEP

Correction of linezolid-induced myelotoxicity after switch to tedizolid in a patient requiring suppressive antimicrobial therapy for multidrug-resistant staphylococcus epidermidis prosthetic-joint infection

A 71-year-old man (85 kg) has a past history of vitiligo, ischemic myocardiopathy, and bilateral knee arthroplasties. A 1-stage exchange of the right prosthetic-joint infection (PJI) was done in 2016 for a mechanical prosthetic loosening. A massive constrained prosthetic joint was used to compensate for the bone loss (Supplementary Figure S1A). Iterative postoperative dislocations were followed by occurrence of a fistula in January 2017 and prosthetic loosening (Supplementary Figure S1B) without any pain. Because it was impossible to imagine a 2-stage exchange, a debridement and implant retention (DAIR) procedure followed by suppressive antimicrobial therapy was proposed. Daptomycin (700 mg/day) and ceftaroline (1200 mg/ day) were prescribed after the surgery. A multidrug-resistant Staphylococcus epidermidis, which is only susceptible to dap-tomycin, vancomycin, fosfomycin, and linezolid, was found in culture from all operative samples. After 6 weeks of intravenous antimicrobial therapy, 600 mg of linezolid bid was prescribed in August 2017. Concomitant medications were ramipril, bisopr-olol, furosemide, and aspirin. Under therapy, the patient experienced a progressive decrease of hemoglobin and hematocrit (without decrease of white blood cells or platelets). Five months after linezolid introduction, the patient developed asthenia related to anemia, with a decrease of hemoglobin to 65 mg/dL, and without leucopenia or thrombocytopenia (Figure 1). The patient did not take any treatment with potential bone marrow toxicity, except linezolid. The patient has no other adverse drug reactions. A blood transfusion (2 bags) was performed, which led to an immediate increase of the hemoglobin level to 84 mg/ dL, and linezolid was switched to 200 mg of tedizolid once a day. In May 2018, 9 months after the DAIR surgery and 4 months after the switch, the patient was perfectly fine, walked despite rupture of the right knee extensor apparatus (video S2), without any pain, without any local signs of relapse (Supplementary Figure S1C), without clinical signs of neuropathy, and he experienced a continuous increase of the hemoglobin to 14 mg/dL under tedizolid therapy. No other treatment was changed or introduced