Pharmacokinetics of Ceftriaxone in Patients Undergoing Continuous Veno‐Venous Hemofiltration

Kroh, U.; Lennartz, H; Edwards, David J.; Stoeckel, Klaus

doi:10.1002/j.1552-4604.1996.tb04164.x

Cited by 37 publications

(19 citation statements)

References 13 publications

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“…The median (range) simulated free fraction in our patients was 11 (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19) % and 14 (9-41) %, for doses of 1 and 2 g, respectively. The simulated trough concentration and time > MIC following a single dose of ceftriaxone at 1 or 2 g in patients with different degrees of renal function are presented in Table 4.…”

Section: Dosing Simulationsmentioning

confidence: 72%

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Garot

Respaud

Lanotte

et al. 2011

Brit J Clinical Pharma

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WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Intensive care unit patients exhibit altered pharmacokinetics for many drugs and suboptimal exposure may be detrimental. • Despite frequent use of ceftriaxone in critically ill patients, its pharmacokinetics have not been studied in large cohorts of critically ill patients. • Population pharmacokinetic analysis provides pharmacokinetic parameter estimates, estimates of inter-individual and intra-individual variability in these parameters and allows patient characteristics explaining inter-individual variability to be quantified. • Coupled with pharmacodynamic analysis, this approach can help in simulating an optimal dosing regimen based on individual characteristics. WHAT THIS STUDY ADDS • Our population model characterized the pharmacokinetic profile of ceftriaxone in patients with highly variable characteristics • Creatinine clearance was identified as the main covariate influencing ceftriaxone pharmacokinetics, particularly for high values. Haemofiltration had no effect. • Model-based simulations showed that the risk of being under threshold concentrations is low for infections due to common pathogens, but exists in patients with high glomerular filtration rates. AIMS To investigate the population pharmacokinetics of ceftriaxone in critically ill patients suffering from sepsis, severe sepsis or septic shock. METHODS Blood samples were collected at preselected times in 54 adult patients suffering from sepsis, severe sepsis or septic shock in order to determine ceftriaxone concentrations using high-performance liquid chromatography-ultraviolet detection. The pharmacokinetics of ceftriaxone were assessed on two separate occasions for each patient: on the second day of ceftriaxone therapy and 48 h after catecholamine withdrawal in patients with septic shock, or on the fifth day in patients with sepsis. The population pharmacokinetics of ceftriaxone were studied using nonlinear mixed effects modelling. RESULTS The population estimates (interindividual variability; coefficient of variation) for ceftriaxone pharmacokinetics were: a clearance of 0.88 l h-1 (49%), a mean half-life of 9.6 h (range 0.83-28.6 h) and a total volume of distribution of 19.5 l (range 6.48-35.2 l). The total volume of distribution was higher than that generally found in healthy individuals and increased with the severity of sepsis. However, the only covariate influencing the ceftriaxone pharmacokinetics was creatinine clearance. Dosage simulations showed that the risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold was low. CONCLUSIONS Despite the wide interpatient variability of ceftriaxone pharmacokinetic parameters, our results revealed that increasing the ceftriaxone dosage when treating critically ill patients is unnecessary. The risk of ceftriaxone concentrations dropping below the minimum inhibitory concentration threshold is limited to patients with high glomerular filtration rates or infections with high minimum inhibitory concentration pathogens (...

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Section: Dosing Simulationsmentioning

confidence: 72%

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Garot

Respaud

Lanotte

et al. 2011

Brit J Clinical Pharma

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“…Patients with sepsis/severe sepsis may also substantially differ from patients with septic shock: septic shock patients may exhibit higher Vd due to capillary leakage and aggressive fluid resuscitation as compared with critically ill patients without septic shock. In spite of this, some of the available studies include patients with sepsis/severe sepsis and acute kidney injury [21,33-35,37,49,50] but not those with septic shock.…”

Section: Main Limitations Of Available Pharmacokinetic Studiesmentioning

confidence: 99%

Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy

et al. 2014

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Although early and appropriate antibiotic therapy remains the most important intervention for successful treatment of septic shock, data guiding optimization of beta-lactam prescription in critically ill patients prescribed with continuous renal replacement therapy (CRRT) are still limited. Being small hydrophilic molecules, beta-lactams are likely to be cleared by CRRT to a significant extent. As a result, additional variability may be introduced to the per se variable antibiotic concentrations in critically ill patients. This article aims to describe the current clinical scenario for beta-lactam dosing in critically ill patients with septic shock and CRRT, to highlight the sources of variability among the different studies that reduce extrapolation to clinical practice, and to identify the opportunities for future research and improvement in this field. Three frequently prescribed beta-lactams (meropenem, piperacillin and ceftriaxone) were chosen for review. Our findings showed that present dosing recommendations are based on studies with drawbacks limiting their applicability in the clinical setting. In general, current antibiotic dosing regimens for CRRT follow a one-size-fits-all fashion despite emerging clinical data suggesting that drug clearance is partially dependent on CRRT modality and intensity. Moreover, some studies pool data from heterogeneous populations with CRRT that may exhibit different pharmacokinetics (for example, admission diagnoses different to septic shock, such as trauma), which also limit their extrapolation to critically ill patients with septic shock. Finally, there is still no consensus regarding the %T>MIC (percentage of dosing interval when concentration of the antibiotic is above the minimum inhibitory concentration of the pathogen) value that should be chosen as the pharmacodynamic target for antibiotic therapy in patients with septic shock and CRRT. For empirically optimized dosing, during the first day a loading dose is required to compensate the increased volume of distribution, regardless of impaired organ function. An additional loading dose may be required when CRRT is initiated due to steady-state equilibrium breakage driven by clearance variation. From day 2, dosing must be adjusted to CRRT settings and residual renal function. Therapeutic drug monitoring of beta-lactams may be regarded as a useful tool to daily individualize dosing and to ensure optimal antibiotic exposure.

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“…Most drugs will fall in the 20-25 ml/min range, but this may increase to 25-50 ml/min with higher effluent volumes in modern CRRT protocols. Since CRRT is often started somewhat earlier in the course of an illness than prior practice, residual renal function can also be significant in clearing some drugs [48]. This method will perform well for many drugs and, aside from estimation of creatinine clearance, is not reliant on individualised pharmacokinetic knowledge, such as V d , Cl NR or the extent of protein binding.…”

Section: Adjusting Drug Dosage Based On Estimated Total Creatinine CLmentioning

confidence: 95%

Drug Dosing in Continuous Renal Replacement Therapy (CRRT)

Gallagher

Murray

2016

Core Concepts in Dialysis and Continuous Therapies

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Pharmacokinetics of Ceftriaxone in Patients Undergoing Continuous Veno‐Venous Hemofiltration

Cited by 37 publications

References 13 publications

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Population pharmacokinetics of ceftriaxone in critically ill septic patients: a reappraisal

Beta-lactam dosing in critically ill patients with septic shock and continuous renal replacement therapy

Drug Dosing in Continuous Renal Replacement Therapy (CRRT)

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