Covariate determinants of effective dosing regimens for time-dependent beta-lactam antibiotics for critically ill patients

Abstract

Aims. Critically ill patients undergoing aggressive fluid resuscitation and treated empirically with hydrosoluble timedependent beta-lactam antibiotics are at risk for sub-therapeutic plasma concentrations. The aim of this study was to assess the impact of two covariates -creatinine clearance (Cl cr ) and cumulative fluid balance (CFB) on pharmacokinetics/pharmacodynamics (PK/PD) target attainment within a week of treatment with meropenem (ME) or piperacillin/ tazobactam (PIP/TZB). Methods. In this prospective observational pharmacokinetic (PK) study, 18 critically ill patients admitted to a surgical Intensive Care Unit (ICU) were enrolled. The primary PK/PD target was free antibiotic concentrations above MIC at 100% of the dosing interval (100%fT>MIC) to obtain maximum bactericidal activity. Drug concentration was measured using liquid chromatography-tandem mass spectrometry. Results. The treatment of both 8 septic patients with IV extended ME dosing 2 g/3 h q8 h and 10 polytraumatized patients with IV intermittent PIP/TZB dosing 4.0/0.5 g q8 h was monitored. 8/18 patients (44%) manifested augmented renal clearence (ARC) where Cl cr ≥130 mL/min/1.73m 2 . Maximum changes were reported on days 2-3: the median positive CFB followed by the large median volume of distribution: Vd me =70.3 L (41.9-101.5), Vd pip = 46.8 L (39.7-60.0). 100%fT me >MIC was achieved in all patients on ME (aged ≥60 years), and only in two patients (non-ARC, aged ≥65 years) out of 10 on PIP/TZB. A mixed model analysis revealed positive relationship of CFB pip with Vd pip (P=0.021). Conclusion. Assuming that the positive correlation between CFB and Vd exists for piperacillin in the setting of the pathological state, then CFB should predict Vd pip across subjects at each and every time point.

Quantification of total and unbound cefuroxime in plasma by ultra‐performance liquid chromatography tandem mass spectrometry in a cohort of critically ill patients with hypoalbuminemia and renal failure

“…Low protein binding in ICU patients is caused by reduced albumin binding and competition with endogenous substrates, such as urea and bilirubin, that accumulate due to reduced renal clearance . An increase in volume of distribution by fluid resuscitation in septic patients may also account for higher unbound fractions of beta‐lactam antibiotics …”

“…[17][18][19] An increase in volume of distribution by fluid resuscitation in septic patients may also account for higher unbound fractions of beta-lactam antibiotics. 20 A major strength of our study was the inclusion of a heterogeneous group of ICU patients, and blood samples were taken at random times. All ICU patients underwent standard care, making our results generalizable to other compatible ICU cohorts.…”

Augmented Renal Clearance: What Have We Known and What Will We Do?

“…Compared to patients with normal kidney function, ARC patients have higher clearances and shorter half-lives of drugs, which promote drug concentrations to fall rapidly. Standard doses make it challenging to meet treatment requirements in these cases ( Kaska et al, 2018 ; Chen and Nicolau, 2020 ). Some studies have attempted to obtain sufficient drug exposure by changing the way of infusion, altering the frequency of administration, or using drug combinations.…”