β-Lactam therapeutic drug monitoring in the critically ill: optimising drug exposure in patients with fluctuating renal function and hypoalbuminaemia

Self Cite

199

144

cThe use of therapeutic drug monitoring (TDM) to optimize beta-lactam dosing in critically ill patients is growing in popularity, although there are limited data describing the potential impact of altered protein binding on achievement of target concentrations. The aim of this study was to compare the measured unbound concentration to the unbound concentration predicted from published protein binding values for seven beta-lactams using data from blood samples obtained from critically ill patients. From 161 eligible patients, we obtained 228 and 220 plasma samples at the midpoint of the dosing interval and trough, respectively, for ceftriaxone, cefazolin, meropenem, piperacillin, ampicillin, benzylpenicillin, and flucloxacillin. The total and unbound beta-lactam concentrations were measured using validated methods. Variabilities in both unbound and total concentrations were marked for all antibiotics, with significant differences being present between measured and predicted unbound concentrations for ceftriaxone and for flucloxacillin at the mid-dosing interval (P < 0.05). The predictive performance for calculating unbound concentrations using published protein binding values was poor, with bias for overprediction of unbound concentrations for ceftriaxone (83.3%), flucloxacillin (56.8%), and benzylpenicillin (25%) and underprediction for meropenem (12.1%). Linear correlations between the measured total and unbound concentrations were observed for all beta-lactams (R 2 ‫؍‬ 0.81 to 1.00; P < 0.05) except ceftriaxone and flucloxacillin. The percent protein binding of flucloxacillin and the plasma albumin concentration were also found to be linearly correlated (R 2 ‫؍‬ 0.776; P < 0.01). In conclusion, significant differences between measured and predicted unbound drug concentrations were found only for the highly protein-bound beta-lactams ceftriaxone and flucloxacillin. However, direct measurement of unbound drug in research and clinical practice is suggested for selected beta-lactams.

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confidence: 99%

Protein Binding of β-Lactam Antibiotics in Critically Ill Patients: Can We Successfully Predict Unbound Concentrations?

Wong

Briscoe

Adnan

et al. 2013

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199

144

“…TDM and subsequent dose adjustments to meet patient PK alterations provide a more individual approach to antimicrobial therapy and are increasingly used in the intensive care unit (ICU) (13). Furthermore, extended or continuous infusion of the antibiotic given has been suggested to maximize antibiotic exposure and to better achieve the pharmacokinetic-pharmacodynamic (PK/PD) targets required (14).…”

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confidence: 99%

Population Pharmacokinetics of Piperacillin in the Early Phase of Septic Shock: Does Standard Dosing Result in Therapeutic Plasma Concentrations?

Öbrink-Hansen

Juul

Storgaard

et al. 2015

e Antibiotic dosing in septic shock patients poses a challenge for clinicians due to the pharmacokinetic (PK) variability seen in this patient population. Piperacillin-tazobactam is often used for empirical treatment, and initial appropriate dosing is crucial for reducing mortality. Accordingly, we determined the pharmacokinetic profile of piperacillin (4 g) every 8 h, during the third consecutive dosing interval, in 15 patients treated empirically for septic shock. We developed a population pharmacokinetic model to assess empirical dosing and to simulate alternative dosing regimens and modes of administration. Time above the MIC (T>MIC) predicted for each patient was evaluated against clinical breakpoint MIC for Pseudomonas aeruginosa (16 mg/liter). Pharmacokinetic-pharmacodynamic (PK/PD) targets evaluated were 50% fT>4؋MIC and 100% fT>MIC. A population PK model was developed using NONMEM, and data were best described by a two-compartment model. Central and intercompartmental clearances were 3.6 liters/h (relative standard error [RSE], 15.7%) and 6.58 liters/h (RSE, 16.4%), respectively, and central and peripheral volumes were 7.3 liters (RSE, 11.8%) and 3.9 liters (RSE, 9.7%), respectively. Piperacillin plasma concentrations varied considerably between patients and were associated with levels of plasma creatinine. Patients with impaired renal function were more likely to achieve predefined PK/PD targets than were patients with preserved or augmented renal function. Simulations of alternative dosing regimens showed that frequent intermittent bolus dosing as well as dosing by extended and continuous infusion increases the probability of attaining therapeutic plasma concentrations. For septic shock patients with preserved or augmented renal function, dose increment or prolonged infusion of the drug needs to be considered. (This study has been registered at ClinicalTrials.gov under registration no. NCT02306928.) A ppropriate early antimicrobial therapy is of utmost importance for reducing mortality in critically ill patients with sepsis and septic shock (1-3). Pathophysiological changes associated with the septic process, such as changes in volume of distribution (V), drug clearance (CL), decrease in plasma protein concentration, and organ dysfunction, lead to pharmacokinetic (PK) changes that may alter the efficacy of the antimicrobial given (4). As a consequence, antibiotic plasma concentrations are variable and hard to predict in these patients, which makes optimal antibiotic exposure a challenge, especially in the early phase of treatment (5, 6). In septic shock patients, appropriate dosing is of greater importance, as effective antimicrobial therapy within the first hour of documented hypotension is associated with increased survival to hospital discharge (7).Piperacillin-tazobactam is a ␤-lactam-␤-lactamase inhibitor combination with a broad spectrum of antibacterial activity (8), frequently used for empirical treatment in critically ill patients. It is an antibiotic with time-dependent antibacterial activit...

“…In recent years, therapeutic drug monitoring (TDM) has become increasingly available as a routine analysis method in the daily clinical setting. As the pharmacokinetics of ␤-lactams has been shown to be unpredictable and display considerable interindividual variation, particularly in critically ill patients (27,28), TDM is expected to optimize PK-PD target attainment and thus ultimately improve the treatment of serious infections (29)(30)(31).…”

Section: Discussionmentioning

confidence: 99%

Continuous versus Short-Term Infusion of Cefuroxime: Assessment of Concept Based on Plasma, Subcutaneous Tissue, and Bone Pharmacokinetics in an Animal Model

Tøttrup

Bibby

Hardlei

et al. 2015

The relatively short half-lives of most ␤-lactams suggest that continuous infusion of these time-dependent antimicrobials may be favorable compared to short-term infusion. Nevertheless, only limited solid-tissue pharmacokinetic data are available to support this theory. In this study, we randomly assigned 12 pigs to receive cefuroxime as either a short-term or continuous infusion. Measurements of cefuroxime were obtained every 30 min in plasma, subcutaneous tissue, and bone. For the measurements in solid tissues, microdialysis was applied. A two-compartment population model was fitted separately to the drug concentration data for the different tissues using a nonlinear mixed-effects regression model. Estimates of the pharmacokinetic parameters and time with concentrations above the MIC were derived using Monte Carlo simulations. Except for subcutaneous tissue in the short-term infusion group, the tissue penetration was incomplete for all tissues. T he relatively short half-lives of most ␤-lactams suggest that extended infusion (EI) or continuous infusion (CI) of these time-dependent antimicrobials may be favorable compared to short-term infusion (STI). Nevertheless, different meta-analyses evaluating CI versus STI of various time-dependent antimicrobials have failed to convincingly demonstrate improved clinical outcomes on mortality and clinical cure (1-6). It is noteworthy, however, that in the majority of studies included in these metaanalyses, the total daily dose of antimicrobials was lower for patients treated with EI or CI (1, 2, 5). In a subset of randomized controlled trials (RCTs) in which the total daily dose was equivalent in the two intervention arms, the clinical failure rate was lower for patients treated with CI (1).Inferences about the dosing regimens of antimicrobials are commonly based on plasma pharmacokinetics-pharmacodynamics (PK-PD) indices, despite the fact that the majority of bacterial pathogens reside in the interstitial space of solid tissues. However, incomplete and uneven tissue distribution was eventually demonstrated in a number of studies for different combinations of drug and tissue (7-13). As the gap between steady-state plasma concentrations and MICs may be rather limited using CI, incomplete tissue penetration may partly explain why improved clinical outcomes for CI have been difficult to demonstrate, particularly when the total daily dose is reduced.Deep-seated orthopedic infections, like osteomyelitis and implant-associated infections (IAI), are difficult to treat, often requiring extensive surgical debridement and long-lasting antimicrobial therapy (14). In a recent porcine study, we demonstrated substantially impaired bone and subcutaneous tissue (SCT) penetration of cefuroxime (15). The pharmacokinetic profiles suggested that EI or CI of the drug might attain increased time with tissue concentrations above the MIC (TϾMIC) for relevant microorganisms.Ultimately, the dosing regimens of antimicrobials should be based on results of RCTs for a specific combination of drug, bug...