Single-dose pharmacokinetics of temocillin in plasma and soft tissues of healthy volunteers after intravenous and subcutaneous administration: a randomized crossover microdialysis trial

Abstract

Background The antibiotic temocillin has recently been rediscovered as a promising therapeutic option against MDR Gram-negative bacteria. However, some aspects of the pharmacokinetic (PK) profile of the drug are still to be elucidated: subcutaneous administration of temocillin might be of interest as an alternative to the intravenous route in selected patients. Similarly, information on the penetration of temocillin into human soft tissues is lacking. Objectives To investigate the feasibility and plasma PK of subcutaneous dosing as well as soft tissue PK of temocillin after intravenous administration to healthy volunteers. Methods Eight healthy volunteers received 2 g of temocillin both as intravenous and subcutaneous infusion in a randomized two-period crossover study. Concentration–time profiles of total temocillin in plasma (after both routes) and of unbound temocillin in plasma, muscle and subcutis (only after intravenous dosing) were determined up to 12 h post-dose. Results Subcutaneous dosing caused some infusion site discomfort but resulted in sustained drug concentrations over time with only slightly decreased overall exposure compared with intravenous dosing. Plasma protein binding of temocillin showed concentration-dependent behaviour and was higher than previously reported. Still, unbound drug concentrations in muscle and subcutis determined by microdialysis markedly exceeded those in plasma, suggesting good tissue penetration of temocillin. Conclusions The subcutaneous administration of temocillin is a valid and feasible alternative to intravenous dosing. With the description of plasma protein binding and soft tissue PK of temocillin in healthy volunteers, this study provides important information that adds to the ongoing characterization of the PK profile of temocillin and might serve as input for PK/PD considerations.

Population Pharmacokinetics of Temocillin Administered by Continuous Infusion in Patients with Septic Shock Associated with Intra-Abdominal Infection and Ascitic Fluid Effusion

“…The plasma unbound concentration of temocillin was best described by a two-compartment model, as previously published [ 32 ], and an additional compartment was added to describe unbound concentration in ascitic fluid (-2LL = 1497, AIC = 1514). Ascitic fluid was eliminated via a drain, thus, non-renal elimination from this additional compartment (CL30) was associated with a significant reduction of -2LL and AIC (Δ-2LL = 10, AIC = 1506).…”

“…For highly protein-bound drugs, including antibiotics, it is commonly admitted that the unbound drug is responsible for the activity [ 27 , 28 , 29 ]. In this context, it is important to note that temocillin shows a saturable and highly variable [ 30 , 31 ] plasma protein binding, ranging from around 85% in adult healthy volunteers [ 15 , 32 ] to a mean value of 59% (range: 19 to 85%) in critically-ill patients [ 33 ]. A previous PK study in critically-ill patients showed that a daily dose of 6 g given as continuous infusion allows to sustainably maintain unbound serum concentrations above 16 mg/L in the vast majority of the patients [ 34 ].…”

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

“…From a PK/PD perspective, SC administration is especially interesting for the administration of beta-lactam drugs, as it results in time above the MIC similar if not greater than IV administration of the same dose (3)(4)(5)8). This suggests that SC administration of beta-lactams should be as efficient as IV administration, although there is a dearth of high-level clinical evidence.…”

“…Spacing drug administration is desirable in this setting, but it should respect the PK/PD requirements of each drug to ensure treatment efficacy. It has been shown that the subcutaneous (SC) route may facilitate drug administration in patients compared with IV route, while preserving the PK/PD objectives of beta-lactams (3)(4)(5)(6)(7)(8). Combining infrequent administration and SC route could be a way to facilitate prolonged suppressive outpatient therapy with beta-lactams, but there is limited information on this practice.…”

Subcutaneous Antibiotic Therapy: The Why, How, Which Drugs and When

“…SC administration of ampicillin, cefepime, and temocillin present a similar PK profile to that of the other studied antibiotics, characterized by a delayed T max but similar AUCs. 45,49,65 However, these studies were performed in healthy volunteers and with single-dose PK analysis.…”