Pharmacokinetic/pharmacodynamic model-based optimization of temocillin dosing strategies for the treatment of systemic infections.

BACKGROUND: Temocillin is increasingly considered as an alternative to carbapenems. However, there is no consensus on optimal dosing strategies and limited data on temocillin efficacy in systemic infections. OBJECTIVES: We compared temocillin dosing strategies using pharmacokinetic/pharmacodynamic (PK/PD) modelling and simulation based on plasma exposure and in vitro time-kill data. METHODS: Temocillin effects on four Escherichia coli strains were evaluated using static time-kill experiments and the hollow-fibre infection model, in which unbound plasma concentrations following intermittent and continuous infusion regimens of 4 and 6 g daily were replicated over 72 h. A PK/PD model was developed to describe the time-kill data. The PK/PD model was coupled to a population PK model of temocillin in critically ill patients to predict bacterial killing and resistance development following various dosing regimens. RESULTS: Amplification of resistant subpopulations was observed within 24 h for all strains. The PK/PD model described the observed bacterial kill kinetics and resistance development from both experimental systems well. Simulations indicated dose-dependent bacterial killing within and beyond the currently used daily dose range, and a superiority of continuous compared with intermittent infusions. However, regrowth of resistant subpopulations was frequently observed. For two strains, bacteriostasis over 72 h was predicted only with doses that are higher than those currently licensed. CONCLUSIONS: Continuous infusions and 6 g daily doses of temocillin kill E. coli more effectively than 4 g daily doses and intermittent infusions, and may increase efficacy in the treatment of systemic infections. However, higher daily doses may be required to suppress resistance development.

Pharmacokinetics and pharmacological target attainment of standard temocillin dosing in non-critically ill patients with complicated urinary tract infections.

OBJECTIVES: Temocillin, a carbapenem-sparing ß-lactam antibiotic, is commonly used at the standard 4 g/day dosage for treating complicated urinary tract infections (cUTIs). However, pharmacokinetic/pharmacodynamic (PK/PD) data supporting this regimen is limited. This study evaluated the plasma pharmacokinetics (PK) and PTA of temocillin in non-critically ill cUTI patients with varying degrees of renal insufficiency (RI). METHODS: In this single-centre clinical study, 22 cUTI patients received a fixed 4 g/day (2 g q12h, intravenously) temocillin dose, irrespective of renal function (no RI: n = 5, mild RI: n = 8, moderate RI: n = 9). Plasma samples were collected post-dosing for LC-MS analysis of total and unbound temocillin levels. Monte Carlo simulations were performed based on the established PK/PD target of ≥35% fT > MIC (minimal inhibitory concentration). RESULTS: Among patients, the highest plasma drug exposure and PK/PD target attainment were observed in those with moderate RI (median AUC0-12h = 1143 h.mg/L and %fT > MIC = 68%), followed by mild RI patients (median AUC0-12h = 918 h.mg/L and %fT > MIC = 34%), and the lowest in those with healthy kidney function (median AUC0-12h = 692 h.mg/L and %fT > MIC = 26%). Simulations indicated that the 4 g/day temocillin dose achieves 90% PTA only for glomerular filtration rate < 60 mL/min and MIC ≤ 8 mg/L. CONCLUSION: The standard temocillin dose may need to be increased from 4 to 6 g/day to treat non-critically ill cUTI patients, in line with recent EUCAST recommendations. For patients with moderate RI, who experience higher exposure due to reduced renal drug clearance, 4 g/day temocillin remains appropriate.

Population pharmacokinetics and dosing simulations of total and unbound temocillin in the plasma and CSF of neurocritically ill patients with external ventricular drain-related cerebral ventriculitis.

BACKGROUND: Cerebral ventriculitis might be caused by Gram-negative bacteria, including ESBL producers. Temocillin may be a useful treatment option in this scenario; however, no consistent data are available regarding its penetration into the CSF. OBJECTIVES: To describe the population pharmacokinetics of temocillin in plasma and CSF and to determine the probability for different simulated dosing regimens to achieve pharmacokinetic/pharmacodynamic (PK/PD) targets in the CSF. METHODS: Ten post-neurosurgical critically ill adult patients requiring continuous drainage of CSF were included in this monocentric, prospective, open-label, non-randomized study. They received 2 g loading dose temocillin over 30 min IV infusion, followed by a 6 g continuous infusion over 24 h. Total and unbound concentrations were measured in plasma (n = 88 and 86) and CSF (n = 88 and 88) samples and used to build a population PK model. Monte Carlo simulations were performed to estimate the PTA at 100% Css>MIC (steady state concentration above the MIC) in CSF. RESULTS: All patients were infected with Enterobacterales with temocillin MICs ≤8 mg/L. The median (min-max) temocillin penetration in CSF was 12.1% (4.3-25.5) at steady state. Temocillin unbound plasma pharmacokinetics were best described by a one-compartment model. PTA for the applied dosing regimen was >90% for bacteria with MIC ≤ 4 mg/L. CONCLUSIONS: The currently approved dose of 6 g by continuous infusion may be adequate for the treatment of ventriculitis by Enterobacterales with MIC ≤ 4 mg/L if considering 100% Css>MIC as the PK/PD target to reach. Higher maintenance doses could help covering higher MICs, but their safety would need to be assessed.

Binding of temocillin to plasma proteins in vitro and in vivo: the importance of plasma protein levels in different populations and of co-medications.

BACKGROUND: Temocillin plasma protein binding (PPB) in healthy individuals is reported to be ∼85% but had not been studied in patients. OBJECTIVES: To obtain normative data on temocillin PPB in patients in relation to infection and impact of co-medications widely used in ICU. METHODS: Plasma was obtained from healthy individuals (Group #1), non-ICU patients with UTI (Group #2), ICU patients with suspected/confirmed ventriculitis (Group #3) or with sepsis/septic shock (Group #4). Total and unbound temocillin concentrations were measured in spiked samples from temocillin-naive donors (in vitro) or in plasma from temocillin-treated subjects (in vivo). The impact of diluting plasma, using pharmaceutical albumin, or adding drugs potentially competing for PPB was tested in spiked samples. Data were analysed using a modified Hill-Langmuir equation taking ligand depletion into account. RESULTS: Temocillin PPB was saturable in all groups, both in vitro and in vivo. Maximal binding capacity (Bmax) was 1.2-2-fold lower in patients. At 20 and 200 mg/L (total concentrations), the unbound fraction reached 12%-29%, 23%-42% and 32%-52% in Groups #2, #3, #4. The unbound fraction was inversely correlated with albumin and C-reactive protein concentrations. Binding to albumin was 2-3-fold lower than in plasma and non-saturable. Drugs with high PPB but active at lower molar concentrations than temocillin caused minimal displacement, while fluconazole (low PPB but similar plasma concentrations to temocillin) increased up to 2-fold its unbound fraction. CONCLUSIONS: Temocillin PPB is saturable, 2-4-fold lowered in infected patients in relation to disease severity (ICU admission, hypoalbuminaemia, inflammation) and only partially reproducible with albumin. Competition with other drugs must be considered for therapeutic concentrations to be meaningful.

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

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.

Dose optimization of ß-lactam antibiotics in children: from population pharmacokinetics to individualized therapy.

INTRODUCTION: ß-Lactams are the most widely used antibiotics in children. Their optimal dosing is essential to maximize their efficacy, while minimizing the risk for toxicity and the further emergence of antimicrobial resistance. However, most ß-lactams were developed and licensed long before regulatory changes mandated pharmacokinetic studies in children. As a result, pediatric dosing practices are poorly harmonized and off-label use remains common today. AREAS COVERED: ß-Lactam pharmacokinetics and dose optimization strategies in pediatrics, including fixed dose regimens, therapeutic drug monitoring, and model-informed precision dosing are reviewed. EXPERT OPINION/COMMENTARY: Standard pediatric doses can result in subtherapeutic exposure and non-target attainment for specific patient subpopulations (neonates, critically ill children, e.g.). Such patients could benefit greatly from more individualized approaches to dose optimization, beyond a relatively simple dose adaptation based on weight, age, or renal function. In this context, Therapeutic Drug Monitoring (TDM) and Model-Informed Precision Dosing (MIPD) emerge as particularly promising avenues. Obstacles to their implementation include the lack of strong evidence of clinical benefit due to the paucity of randomized clinical trials, of standardized assays for monitoring concentrations, or of adequate markers for renal function. The development of precision medicine tools is urgently needed to individualize therapy in vulnerable pediatric subpopulations.

The Microbiological Profile and Antibiotic Susceptibility of Fracture Related Infections in a Low Resource Setting Differ from High Resource Settings: A Cohort Study from Cameroon.

Fracture-related infection (FRI) is a common and devastating complication of orthopedic trauma in all settings. Data on the microbiological profile and susceptibility of FRI to antibiotics in low-income countries are scarce. Therefore, this study aimed to investigate the microbial patterns and antimicrobial susceptibility of FRI in a sub-Saharan African setting in order to provide guidance for the formulation of evidence-based empirical antimicrobial regimens. We conducted a retrospective analysis of patients treated for FRI with deep tissue sampling for microbiological culture from January 2016 to August 2023 in four tertiary-level hospitals in Yaoundé, Cameroon. There were 246 infection episodes in 217 patients. Cultures were positive in 209 (84.9%) cases and polymicrobial in 109 (44.3%) cases. A total of 363 microorganisms from 71 different species were identified, of which 239 (65.8%) were Gram-negative. The most commonly isolated pathogens were Staphylococcus aureus (n = 69; 19%), Enterobacter cloacae (n = 43; 11.8%), Klebsiella pneumoniae (n = 35; 9.6%), Escherichia coli (n = 35; 9.6%), and Pseudomonas aeruginosa (n = 27; 7.4%). Coagulase-negative staphylococci (CoNS) were isolated in only 21 (5.9%) cases. Gram-negative bacteria accounted for the majority of the infections in early (70.9%) and delayed (73.2%) FRI, but Gram-positive bacteria were prevalent in late FRI (51.7%) (p < 0.001). Polymicrobial infections were more frequent in the early (55.9%) and delayed (41.9%) groups than in the late group (27.6%) (p < 0.001). Apart from Staphylococcus aureus, there was no significant difference in the proportions of causative pathogens between early, delayed, and late FRI. This study found striking resistance rates of bacteria to commonly used antibiotics. MRSA accounted for 63% of cases. The most effective antibiotics for all Gram-positive bacteria were linezolid (96.4%), vancomycin (92.5%), clindamycin (85.3%), and fucidic acid (89.4%). For Gram-negative bacteria, only three antibiotics displayed a sensitivity >50%: amikacin (80.4%), imipenem (74.4%), and piperacillin + tazobactam (57%). The most effective empirical antibiotic therapy (with local availability) was the combination of vancomycin and amikacin or vancomycin and imipenem. In contrast to the literature from high-resource settings, this study revealed that in a sub-Saharan African context, Gram-negative bacteria are the most common causative microorganisms of FRI. This study revealed striking resistance rates to commonly used antibiotics, which will require urgent action to prevent antimicrobial resistance in low and middle-income countries.

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

Temocillin is active against Gram-negative bacteria, including many extended-spectrum ß-lactamase (ESBL)-producing Enterobacterales. We studied its pharmacokinetics in plasma and ascitic fluid after intravenous administration of a loading dose of 2 g over 30 min, followed by continuous infusion of 6 g/24 h, to 19 critically-ill patients with septic shock associated with complicated intra-abdominal infection. We established a pharmacokinetic model describing unbound temocillin concentrations in plasma and ascitic fluid and performed Monte-Carlo simulations to evaluate the probability of target attainment (PTA) of unbound concentrations (100% fT > MIC, i.e., unbound concentrations remaining above the MIC during 100% of the time) for the applied and hypothetical dosing regimens. The temocillin AUC in ascitic fluid was 46% of the plasma AUC. Plasma unbound concentrations were best described by a two-compartment model, and an additional compartment was added to describe unbound concentration in ascitic fluid, with renal clearance as a covariate. Dosing simulations showed that 90% PTA was achieved in the plasma with the current dosing regimen for MIC ≤ 16 mg/L (EUCAST susceptibility breakpoint) but not in the ascitic fluid if renal clearance was ≥40 mL/min. Hypothetical dosing with a higher (a) loading dose or (b) infused dose allowed to reach target concentrations in ascitic fluid (a) more rapidly or (b) sustainably, but these simulations need to be evaluated in the clinics for safety and efficacy.

Validation of a HPLC-MS/MS assay for the determination of total and unbound concentration of temocillin in human serum.

OBJECTIVES: The aim of this study was to develop and validate a HPLC-MS/MS assay to determine total and unbound concentrations of temocillin in serum samples. DESIGN AND METHODS: Methanolic protein precipitation and ultrafiltration were used for total and unbound concentration extraction, respectively. Extract was injected into a LC-MS/MS system. Reversed phase chromatography was performed on a phenyl grafted column in gradient mode. Temocillin and internal standard (ticarcillin) were identified in positive electrospray ionization mode using ion transitions of m/z 415.34>339.1 and 385.31>160.3, respectively. RESULTS: Temocillin total and unbound concentration quantification assays were linear over concentrations ranging from 1 to 500 mg/L and from 0.5 to 300 mg/L, respectively. Both assays presented acceptable intra and inter-assay precision and accuracy <13.9%. Limits of quantification and detection were of 1 and 0.10mg/L, and 0.5 and 0.05 mg/L for total and unbound concentration respectively. Total temocillin concentration recovery ranged from 85.80 to 99.40%. Temocillin ion suppression effect was <36.2 % in both assays. CONCLUSION: The method described is fast, sensitive and selective, with no interferences. This method may be used for both pharmacokinetic studies and therapeutic drug monitoring purposes.