Pharmacokinetics and Pharmacodynamics of Temocillin

Abstract

Temocillin, a 6-α-methoxy derivative of ticarcillin, is a forgotten antibiotic that has recently been rediscovered, and issues about clinical breakpoints and optimal therapeutic regimens are still ongoing. Temocillin spectrum is almost restricted to Enterobacteriaceae. The addition of the α-methoxy moiety on ticarcillin confers resistance to hydrolysis by Ambler classes A and C β-lactamases (extended spectrum β-lactamases, Klebsiella pneumoniae carbapenemase and AmpC hyperproduced enzymes). Temocillin is bactericidal, and the effect of inoculum size on its activity is relatively mild. The proportion of spontaneous resistant mutants in vitro to temocillin is low, as found in vivo. After intravenous infusion, temocillin showed a prolonged elimination half-life of approximately 5 h. The percentage of protein binding of temocillin is high (approximately 80%), and is concentration-dependent. Temocillin clearance is mainly renal, and urinary recovery is high, ranging from 72 to 82% after 24 h. Furthermore, the penetration of temocillin into bile and peritoneal fluid is high, but poor into cerebrospinal fluid. The cumulative percentage of a 24-h period during which the free drug concentration exceeds the minimum inhibitory concentration (fT > MIC) at steady-state pharmacokinetic conditions seems to be the best pharmacokinetic/pharmacodynamic (PK/PD) index correlating with temocillin efficacy. An fT > MIC of 40-50% is associated with antibacterial effect and survival in vivo. Monte Carlo simulations performed in critically ill patients showed that the 2 g every 12 h and 2 g every 8 h regimens provide a 95% probability of target attainment of 40% fT > MIC up to an MIC of 8 mg/L. In less severely ill patients or in specific foci of infection, such as urinary tract infection, a 4 g daily regimen should be adequate for strains with temocillin MIC up to 16 mg/L. Data regarding actual wild-type MIC distribution, clinical efficacy, PK profiling in volunteers or patients, and PD targets are scarce, and further studies are required to support appropriate dosing recommendations and determination of clinical breakpoints.

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

“…On the one hand, this confirms the concentration-dependent nature of plasma protein binding of temocillin. 11,20,23 On the other hand, it highlights a degree of plasma protein binding markedly above the previously assumed value of 85% for almost the entire concentration range observed in the present study in healthy volunteers. However, preliminary data from an in-depth analysis of temocillin's binding characteristics have already illustrated that the unbound fraction might be markedly higher in patients compared with healthy subjects, most likely due to Temocillin microdialysis JAC hypoalbuminaemia and pharmacokinetic drug-drug interactions in the former population.…”

“…In terms of PK, the concentration-time curves and key PK parameters of temocillin in plasma of healthy volunteers after intravenous infusion did not show relevant deviations from previous data. 11,20,22 Subcutaneous administration achieved a very good overall exposure, as denoted by an AUC 0-1 even higher than that observed after intravenous dosing. As a limitation in this context, it should be noted that AUC 0-1 calculation was possible only with large extrapolated fractions, making the resulting relative bioavailability of 112% potentially prone to bias.…”

“…Unbound temocillin levels exceeding those in plasma have already been reported in bile and intraperitoneal fluid. 20 High concentrations of unbound temocillin were also found in pancreatic tissue of a critically ill patient receiving temocillin as a continuous intravenous infusion. 24 When trying to relate the mentioned measures of drug exposure to therapeutic efficacy, one must consider that many aspects of the PK/PD profile of temocillin are still fragmentary.…”

“…An fT >MIC of 40%-50% was reported to be required for antibacterial effect and survival in animal infection models. 20 However, the magnitude of fT >MIC required for optimal efficacy awaits more comprehensive definition.…”

“…19 Previously described MIC 90 values for relevant ESBL and AmpC producers (8 and 16 mg/L, respectively) were used. 20,21 Statistical analysis was performed using version 20 of a commercially available computer program (SPSS, IBM, Armonk, NY). The Shapiro-Wilk test was used to test for normal distribution.…”