The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

Abdulla, Alan; Ewoldt, Tim M J; Hunfeld, Nicole; Muller, Anouk E.; Rietdijk, Wim; Polinder, Suzanne; Gelder, Teun van; Endeman, Henrik; Koch, Birgit C. P.

doi:10.1186/s12879-020-4781-x

Cited by 69 publications

(73 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Routine TDM with same-day antibiotic dose adaptation using immunoassays over the more commonly used chromatographic methods could contribute to overcoming these barriers in routine clinical practice [45]. However, pending a large randomized trial investigating the effect of TDM of beta-lactam antibiotics on clinical outcome in critically ill patients [46], the clinical impact on patient's prognosis using this strategy is not yet fully demonstrated. In view of the fact that target attainment is observed in only about 60-65% of critically ill patients receiving antibiotics and considering the increasing resistance to antibiotics worldwide, higher dosing in these patients could be an alternative strategy to obtain better target attainment when TDM is not available.…”

Section: Discussionmentioning

confidence: 99%

“…However, with the exception of ceftriaxone, the protein binding of most antibiotics in this study is too low to be clinically affected by, for example, a decreased serum albumin. Moreover, we analyzed unbound concentration of ceftriaxone in another cohort of critically ill patients [46] to support the clinical feasibility of calculating unbound fractions using an average PPB value. The mean fraction of ceftriaxone unbound plasma concentrations (n = 34) in the range of 0.05-40 mg/L was 12.3% [IQR 8.5-20] (unpublished observations), which is comparable to the calculated unbound concentration used in this study and previously published data [31].…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

et al. 2020

Self Cite

View full text Add to dashboard Cite

Background Early and appropriate antibiotic dosing is associated with improved clinical outcomes in critically ill patients, yet target attainment remains a challenge. Traditional antibiotic dosing is not suitable in critically ill patients, since these patients undergo physiological alterations that strongly affect antibiotic exposure. For beta-lactam antibiotics, the unbound plasma concentrations above at least one to four times the minimal inhibitory concentration (MIC) for 100% of the dosing interval (100%ƒT > 1–4×MIC) have been proposed as pharmacodynamic targets (PDTs) to maximize bacteriological and clinical responses. The objectives of this study are to describe the PDT attainment in critically ill patients and to identify risk factors for target non-attainment. Methods This prospective observational study was performed in two ICUs in the Netherlands. We enrolled adult patients treated with the following beta-lactam antibiotics: amoxicillin (with or without clavulanic acid), cefotaxime, ceftazidime, ceftriaxone, cefuroxime, and meropenem. Based on five samples within a dosing interval at day 2 of therapy, the time unbound concentrations above the epidemiological cut-off (ƒT > MICECOFF and ƒT > 4×MICECOFF) were determined. Secondary endpoints were estimated multivariate binomial and binary logistic regression models, for examining the association of PDT attainment with patient characteristics and clinical outcomes. Results A total of 147 patients were included, of whom 63.3% achieved PDT of 100%ƒT > MICECOFF and 36.7% achieved 100%ƒT > 4×MICECOFF. Regression analysis identified male gender, estimated glomerular filtration rate (eGFR) ≥ 90 mL/min/1.73 m2, and high body mass index (BMI) as risk factors for target non-attainment. Use of continuous renal replacement therapy (CRRT) and high serum urea significantly increased the probability of target attainment. In addition, we found a significant association between the 100%ƒT > MICECOFF target attainment and ICU length of stay (LOS), but no significant correlation was found for the 30-day survival. Conclusions Traditional beta-lactam dosing results in low target attainment in the majority of critically ill patients. Male gender, high BMI, and high eGFR were significant risk factors for target non-attainment. These predictors, together with therapeutic drug monitoring, may help ICU clinicians in optimizing beta-lactam dosing in critically ill patients. Trial registration Netherlands Trial Registry (EXPAT trial), NTR 5632. Registered on 7 December 2015.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, protein binding of ciprofloxacin is too low to be clinically affected by the decrease of serum albumin for instance, making the calculation of unbound concentrations from published protein binding values acceptable. We analyzed plasma protein unbound fractions in another cohort of ICU patients [48] to clarify the clinical feasibility of calculating unbound fractions using an average PPB value. The mean fraction of ciprofloxacin unbound plasma concentrations (n = 36) in the range of 0.1-12.5 mg/L was 70.5% ± 4.7% SD (data not published yet).…”

Section: Discussionmentioning

confidence: 99%

Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients

Abdulla

Rogouti

Hunfeld

et al. 2020

Eur J Clin Pharmacol

View full text Add to dashboard Cite

Purpose To develop and validate a population pharmacokinetic model of ciprofloxacin intravenously in critically ill patients, and determine target attainment to provide guidance for more effective regimens. Methods Non-linear mixed-effects modelling was used for the model development and covariate analysis. Target attainment of an ƒAUC 0-24 /MIC ≥ 100 for different MICs was calculated for standard dosing regimens. Monte Carlo simulations were performed to define the probability of target attainment (PTA) of several dosing regimens. Results A total of 204 blood samples were collected from 42 ICU patients treated with ciprofloxacin 400-1200 mg/day, with median values for age of 66 years, APACHE II score of 22, BMI of 26 kg/m 2 , and eGFR of 58.5 mL/min/1.73 m 2. The median ƒAUC 0-24 and ƒC max were 29.9 mg•h/L and 3.1 mg/L, respectively. Ciprofloxacin pharmacokinetics were best described by a two-compartment model. We did not find any significant covariate to add to the structural model. The proportion of patients achieving the target ƒAUC 0-24 /MIC ≥ 100 were 61.9% and 16.7% with MICs of 0.25 and 0.5 mg/L, respectively. Results of the PTA simulations suggest that a dose of ≥ 1200 mg/day is needed to achieve sufficient ƒAUC 0-24 /MIC ratios. Conclusions The model described the pharmacokinetics of ciprofloxacin in ICU patients adequately. No significant covariates were found and high inter-individual variability of ciprofloxacin pharmacokinetics in ICU patients was observed. The poor target attainment supports the use of higher doses such as 1200 mg/day in critically ill patients, while the variability of inter-individual pharmacokinetics parameters emphasizes the need for therapeutic drug monitoring to ensure optimal exposure.

show abstract

“…16 Pharmacokinetic parameters in our patient population were generally similar between the start of vancomycin and SS, further bolstering the validity of using first-dose pharmacokinetic calculations in critically ill patients with relatively stable renal function. The firstdose pharmacokinetic approach was shown to be beneficial for vancomycin, but may have utility with other antibiotics as well, such as betalactams, 17 given the time-critical nature of pharmacokinetic / pharmacodynamic target attainment in critically ill patients. Additionally, this approach may be suitable for high-risk patients admitted to non-intensive care unit (ICU) services.…”

Section: Discussionmentioning

confidence: 99%

First‐Dose Vancomycin Pharmacokinetics Versus Empiric Dosing on Area‐Under‐the‐Curve Target Attainment in Critically Ill Patients

et al. 2020

View full text Add to dashboard Cite

Background Early attainment of target area under the curve (AUC) to minimum inhibitory concentration (MIC) ratios have been associated with clinical success, as well as lower incidence of acute kidney injury (AKI), in patients receiving vancomycin for methicillin-resistant Staphylococcus aureus (MRSA). Critically ill patients are particularly vulnerable to poor outcomes from infection and face multiple risk factors for AKI, thus early precision dosing of vancomycin is vital in this population. We hypothesized that a personalized dosing approach, using vancomycin levels obtained after the first dose to guide further dosing, would be superior to empiric dosing in terms of AUC target attainment assessed at steady state (SS). Methods A retrospective cohort study of 66 critically ill adult patients admitted to the medical intensive care unit without AKI and receiving vancomycin with at least two SS concentrations obtained for AUC calculation was performed. Patients were separated into cohorts based on whether they had two concentrations assessed after the first dose of vancomycin and were subsequently dosed based on personalized pharmacokinetic calculations (first-dose kinetics) or whether they were empirically dosed using population estimates. The primary outcome was AUC target attainment (400-600 mg hour/L) at SS. Results Compared with patients receiving empiric dosing by population estimates, using first-dose kinetics to guide subsequent dosing resulted in significantly greater AUC target attainment at SS (58.6% first-dose vs 32.4% empiric; p=0.033). Patients dosed empirically yielded more variable AUC values across a wide range compared with the first-dose kinetics group (coefficient of variation 40.7% empiric vs 26.1% first-dose). There was no difference in AKI up to 48 hours after SS concentrations between the two dosing schemes. Conclusions A dosing strategy using two vancomycin serum concentrations after the first dose and calculating personalized pharmacokinetic parameters to guide subsequent dosing is associated with greater AUC target attainment at SS compared with empiric dosing of vancomycin in critically ill adults with relatively stable renal function. KEY WORDS vancomycin, pharmacokinetics, area under the curve, critical care, dosing, therapeutic drug monitoring.

show abstract

The effect of therapeutic drug monitoring of beta-lactam and fluoroquinolones on clinical outcome in critically ill patients: the DOLPHIN trial protocol of a multi-centre randomised controlled trial

Cited by 69 publications

References 33 publications

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Failure of target attainment of beta-lactam antibiotics in critically ill patients and associated risk factors: a two-center prospective study (EXPAT)

Population pharmacokinetics and target attainment of ciprofloxacin in critically ill patients

First‐Dose Vancomycin Pharmacokinetics Versus Empiric Dosing on Area‐Under‐the‐Curve Target Attainment in Critically Ill Patients

Contact Info

Product

Resources

About