Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients

Schleibinger, Michael; Steinbach, Cathérine Louise; Töpper, Christoph; Kratzer, Alexander; Liebchen, Uwe; Kees, Frieder; Salzberger, Bernd; Kees, Martin G.

doi:10.1111/bcp.12636

Cited by 87 publications

(76 citation statements)

References 30 publications

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“…As for pharmacokinetics, a dose-dependent effect of alteplase on stroke outcome has been shown in different studies with significant higher rates of ICH rate with doses above 0.95 mg/kg, which has led to a licensed dose for administration of 0.9 mg/kg body weight [16]. The drug is predominantly metabolized by the liver and is eliminated via urine [16], as is ceftriaxone [17]. However, to date no data comparing both pharmacokinetic profiles have been published.…”

Section: Discussionmentioning

confidence: 99%

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

et al. 2016

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Background: The Preventive Antibiotics in Stroke Study (PASS), a randomized open-label masked endpoint trial, showed that preventive ceftriaxone did not improve functional outcome at 3 months in patients with acute stroke (adjusted common OR 0.95; 95% CI 0.82-1.09). Post-hoc analyses showed that among patients who received intravenous thrombolysis (IVT), patients who received ceftriaxone had a significantly better outcome as compared with the control group. This study aimed to gain more insight into the characteristics of these patients. Methods: In PASS, 2,550 patients were randomly assigned to preventive antibiotic treatment with ceftriaxone or standard care. In current post-hoc analysis, 836 patients who received IVT were included. Primary outcome included functional status on the modified Rankin Scale, analyzed with adjusted ordinal regression. Secondary outcomes included infection rate and symptomatic intracerebral hemorrhage (sICH) rate. Results: For all patients in PASS, the p value for the interaction between IVT and preventive ceftriaxone regarding functional outcome was 0.03. Of the 836 IVT-treated patients, 437 were administered ceftriaxone and 399 were allocated to the control group. Baseline characteristics were similar. In the IVT subgroup, preventive ceftriaxone was associated with a significant reduction in unfavorable outcome (adjusted common OR 0.77; 95% CI 0.61-0.99; p = 0.04). Mortality at 3 months was similar (OR 0.75; 95% CI 0.48-1.18). Preventive ceftriaxone was associated with a reduction in infections (OR 0.43; 95% CI 0.28-0.66), and a trend towards an increased risk for sICH (OR 3.09; 95% CI 0.85-11.31). Timing of ceftriaxone administration did not influence the outcome (aOR 1.00; 95% CI 0.98-1.03; p = 0.85). Conclusions: According to the post-hoc analysis of PASS, preventive ceftriaxone may improve the functional outcome in IVT-treated patients with acute stroke, despite a trend towards an increased rate of post-IVT-sICH.

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Section: Discussionmentioning

confidence: 99%

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

et al. 2016

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“…When compared with healthy volunteers, the unbound fraction in our group was significantly higher (14-43% vs 5-15%) (370), but lower than other published data on critically ill patients (23% vs 33%) (369). Higher unbound concentration was seen in our patients with hyperbilirubinaemia and diabetes, which is in agreement with previous studies (369,371), however, we did not find a correlation between hypoalbuminaemia and unbound fraction. The lower CL and V dss seen in our group may have provided an explanation for the high fC 720 observed.…”

Section: Discussionsupporting

confidence: 88%

“…A dramatically lower V dss was observed in our subjects when compared with other published data on critically ill patients (10.4 vs 20.2, 20.0 L) (368,369). When compared with healthy volunteers, the unbound fraction in our group was significantly higher (14-43% vs 5-15%) (370), but lower than other published data on critically ill patients (23% vs 33%) (369).…”

Section: Discussioncontrasting

confidence: 72%

“…When compared with other studies on critically ill patients, our subjects achieved a significantly lower CL against those with similar CrCL (112 mL/min vs 98 mL/min, CL 0.88 vs 2.4 L/h respectively) (368). Compared with those with lower CrCL (112 mL/min vs 26, 63 mL/min), a similar or lower CL is observed in our subjects (0.88 vs 1.2, 0.96 L/h) (368,369), which suggests a lower non-renal CL, either due to less hepatic CL or unspecified interethnic differences. Furthermore, the lack of relationship between the CrCL and ceftriaxone recovered in urine as well as between CL and CrCL may be a result of the small sample size of this study, but it may also suggest differences in PK between this patient group and others.…”

Section: Discussionsupporting

confidence: 63%

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Improving antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis

Tsai¹

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Sepsis is a major health issue in the Australian Indigenous population. Unfortunately, the high rates of mortality and morbidity caused by sepsis or severe sepsis in this population have not significantly reduced over recent decades. Research into the role of optimisation of antibiotic therapy for improving patient outcomes is certainly an important area of need. In other patient populations, there is increasing evidence of an improvement of clinical cure rates and survival in patients with severe sepsis when antibiotic dosing results in therapeutic concentrations, that is, achieves pharmacokinetic/pharmacodynamic (PK/PD) targets. However, numerous PK changes caused by the altered physiology associated with critical illness may reduce the likelihood of such effective dosing.Previous studies have identified a number of physiological characteristics in the Australian Indigenous population which suggest that interethnic PK differences are likely in comparison with the non-Indigenous. As most PK data of antibiotics were obtained from healthy Caucasian volunteers, whether these data can be extrapolated to the critically ill Indigenous patients requires investigation.The aims of this thesis are to describe the PK of meropenem, ceftriaxone, vancomycin and piperacillin in severely septic Indigenous patients; compare the PK with existing data from nonIndigenous patients; design optimised dosing regimens for each of the study antibiotics; and quantify the variation in renal function of critically ill Indigenous patients. This thesis consists of nine Chapters:Chapter one provides an overview of the current clinical challenges encountered in antibiotic dosing in critically ill patients. It also discusses specific physiological characteristics of Australian Indigenous patients which may lead to different PK compared with non-Indigenous comparators.Chapter two comprises of a narrative review which discusses the PK/PD factors that should be considered when prescribing antibiotics to critically ill patients. This Chapter summarises data which describe an improvement in clinical outcome when antibiotics achieve PK/PD targets. ThisChapter concludes to support an individualised approach to dosing antibiotics as opposed to the 'one dose fits all' approach that is common to clinical practice.ii Chapter three incorporates a systematic review which investigates the published data describing differences in antibiotic PK between different ethnic groups. No reports on PK in Indigenous Australians were found. The predominant data described differences in PK between the Asian and Caucasian ethnicities. Typically, Asian subjects manifested higher antibiotic concentrations for antibiotics that have significant hepatic metabolism, are substrates to p-glycoprotein or other forms of active transport and/or have high alpha-1-acid glycoprotein binding.Chapter four incorporates a study which described the renal function of critically ill Australian Indigenous patients. This study found a numerically higher incidence of augmented renal clea...

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“…Studies in ICU septic patients have shown very high variability in the main PK parameters of CTX, with changes in renal clearance representing the main cause [11]. No data is reported concerning increased elimination of CTX due to loss of GFB perm-selectivity.…”

Section: Introductionmentioning

confidence: 99%

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

Selmi¹,

Loriga²,

Vitali³

et al. 2016

J Transl Med

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BackgroundSepsis is characterized by the loss of the perm-selectivity properties of the glomerular filtration barrier (GFB) with consequent albuminuria. We examined whether the pharmacokinetics–pharmacodynamics (PK/PD) of ceftriaxone (CTX), an extensively protein-bound 3rd generation cephalosporin, is altered during early sepsis and whether an increase in urinary loss of bound-CTX, due to GFB alteration, can occur in this condition.MethodsA prospective, experimental, randomized study was carried out in adult male Sprague–Dawley rats. Sepsis was induced by cecal ligation and puncture (CLP). Rats were divided into two groups: Sham-operated and CLP. CTX (100 mg i.p., equivalent to 1 g dose in humans) was administered in order to measure plasma and lung CTX concentrations at several time-points: baseline and 1, 2, 4 and 6 h after administration. CTX was measured by High Performance Liquid Chromatography (HPLC). The morphological status of the sialic components of the GFB barrier was assessed by lectin histo-chemistry. Monte Carlo simulation was performed to calculate the probability of target attainment (PTA >90%) for 80 and 100% of Tfree > minimum inhibitory concentration (MIC) for 80 and 100% of dosing interval.Measurements and main resultsAfter CLP, sepsis developed in rats as documented by the growth of polymicrobial flora in the peritoneal fluid (≤1 × 101 CFU in sham rats vs 5 × 104–1 × 105 CFU in CLP rats). CTX plasma concentrations were higher in CLP than in sham rats at 2 and 4 h after administration (difference at 2 h was 47.3, p = 0.012; difference at 4 h was 24.94, p = 0.004), while lung penetration tended to be lower. An increased urinary elimination of protein-bound CTX occurred (553 ± 689 vs 149 ± 128 mg/L, p < 0.05; % of bound/total CTX 22 ± 6 in septic rats vs 11 ± 4 in sham rats, p < 0.01) and it was associated with loss of the GFB sialic components. According to Monte Carlo simulation a PTA > 90% for 100% of the dosing interval was reached neither for sham nor CLP rats using MIC = 1 mg/L, the clinical breakpoint for Enterobacteriacee.ConclusionsSepsis causes changes in the PK of CTX and an alteration in the sialic components of the GFB, with consequent loss of protein-bound CTX. Among factors that can affect drug pharmacokinetics during the early phases of sepsis, urinary loss of both free and albumin–bound antimicrobials should be considered.

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Protein binding characteristics and pharmacokinetics of ceftriaxone in intensive care unit patients

Cited by 87 publications

References 30 publications

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

Preventive Ceftriaxone in Patients with Stroke Treated with Intravenous Thrombolysis: Post Hoc Analysis of the Preventive Antibiotics in Stroke Study

Improving antibiotic dosing in critically ill Australian Indigenous patients with severe sepsis

Changes in ceftriaxone pharmacokinetics/pharmacodynamics during the early phase of sepsis: a prospective, experimental study in the rat

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