Augmented Renal Clearance in the ICU

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Changes in the pharmacokinetics of piperacillin in febrile neutropenic patients have been reported to result in suboptimal exposures. This study aimed to develop a population pharmacokinetic model for piperacillin and perform dosing simulation to describe optimal dosing regimens for hematological malignancy patients with febrile neutropenia. Concentration-time data were obtained from previous prospective observational pharmacokinetic and interventional therapeutic drug monitoring studies. Nonparametric population pharmacokinetic analysis and Monte Carlo dosing simulations were performed with the Pmetrics package for R. A twocompartment model, with between-subject variability for clearance (CL), adequately described the data from 37 patients (21 males, age of 59 Ϯ 12 years [means Ϯ standard deviations] and weight of 77 Ϯ 16 kg). Parameter estimates were CL of 18.0 Ϯ 4.8 liters/h, volume of distribution of the central compartment of 14.3 Ϯ 7.3 liters, rate constant for piperacillin distribution from the central to peripheral compartment of 1.40 Ϯ 1.35 h Ϫ1 , and rate constant for piperacillin distribution from the peripheral to central compartment of 4.99 Ϯ 7.81 h Ϫ1 . High creatinine clearance (CL CR ) was associated with reduced probability of target attainment (PTA). Extended and continuous infusion regimens achieved a high PTA of Ͼ90% for an unbound concentration of piperacillin remaining above the MIC (fT ϾMIC ) of 50%. Only continuous regimens achieved Ͼ90% PTA for 100% fT ϾMIC when CL CR was high. The cumulative fraction of response (FTA, for fractional target attainment) was suboptimal (Ͻ85%) for conventional regimens for both empirical and directed therapy considering 50% and 100% fT ϾMIC . FTA was maximized with prolonged infusions. Overall, changes in piperacillin pharmacokinetics and the consequences on therapeutic dosing requirements appear similar to those observed in intensive care patients. Guidelines should address the altered dosing needs of febrile neutropenic patients exhibiting high CL CR or with known/presumed infections from high-MIC bacteria.KEYWORDS febrile neutropenia, piperacillin, population pharmacokinetics

Section: Discussionsupporting

confidence: 79%

Using Population Pharmacokinetic Modeling and Monte Carlo Simulations To Determine whether Standard Doses of Piperacillin in Piperacillin-Tazobactam Regimens Are Adequate for the Management of Febrile Neutropenia

Sime

Hahn

Warner

et al. 2017

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“…Given that cefepime is predominantly eliminated unchanged via glomerular filtration (21), the similarities to healthy individuals' data are sensible as all patients in this study exhibited normal renal function (Table 1). However, augmented renal clearance is not uncommon in febrile neutropenic patients with normal renal function; therefore, higher than usual clearance of cefepime is a possibility in such cases (32). Considering the conservative PK/PD target of 60% fT ϾMIC , unbound cefepime concentrations were greater than the highest anticipated MIC of susceptible organisms (8 mg/liter) for all patients in this study.…”

Section: Discussionmentioning

confidence: 93%

Adequacy of High-Dose Cefepime Regimen in Febrile Neutropenic Patients with Hematological Malignancies

Sime

Roberts

Tiong

et al. 2015

i While guidelines recommend empirical cefepime therapy in febrile neutropenia, the mortality benefit of cefepime has been controversial. In light of this, recent reports on pharmacokinetic changes for several antibiotics in febrile neutropenia and the consequent suboptimal exposure call for a pharmacokinetic/pharmacodynamic evaluation of current dosing. This study aimed to assess pharmacokinetic/pharmacodynamic target attainment from a 2-g intravenous (i.v.) every 8 h (q8h) cefepime regimen in febrile neutropenic patients with hematological malignancies. Cefepime plasma concentrations were measured in the 3rd, 6th, and 9th dosing intervals at 60% of the interval and/or trough point. The selected pharmacokinetic/pharmacodynamic targets were the proportion of the dosing interval (60% and 100%) for which the free drug concentration remains above the MIC (fT >MIC ). Target attainment was assessed in reference to the MIC of isolated organisms if available or empirical breakpoints if not. The percentage of fT >MIC was also estimated by log-linear regression analysis. All patients achieved >60% fT >MIC in the 3rd and 6th dosing intervals. A 100% fT >MIC was not attained in 6/12, 4/10, and 4/9 patients in the 3rd, 6th, and 9th dose intervals, respectively, or in 14/31 (45%) of the dosing intervals investigated. On the other hand, 29/31 (94%) of trough concentrations were at or above 4 mg/liter. In conclusion, for patients with normal renal function, a high-dose 2-g i.v. q8h cefepime regimen appears to provide appropriate exposure if the MIC of the organism is <4 mg/liter but may fail to cover less susceptible organisms.T he introduction of cefepime into clinical practice was widely accepted due to its broad-spectrum activity. Cefepime is active against such organisms as Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacteriaceae with relatively low MICs compared to those of other broad-spectrum ␤-lactam antibiotics (1, 2). Therefore, it is considered a good choice for the empirical management of febrile neutropenia, either as a monotherapy agent or as part of combination regimens (3, 4).While several comparative outcome trials suggest cefepime is clinically as effective as other ␤-lactam antibiotics, meta-analyses (5, 6) of data from these trials report an increased risk of mortality associated with cefepime therapy, which was particularly high in febrile neutropenic patients (7). Conversely, a later meta-analysis by the U.S. Food and Drug Administration (FDA), which included several additional unpublished trials, concluded that there is no such association (8, 9). In addition, specific analysis of trials of febrile neutropenic patients did not show any statistically significant increase in mortality (9). The controversy continues as the methodological issues of the FDA's and previous meta-analyses are challenged and debated (7,(10)(11)(12). However, there is little biological plausibility for the claimed risk of mortality, which was originally suggested to be related to unrecognized toxicity or poor in viv...

“…Augmented renal clearance-defined as a sustained elevation of CL CR (Ͼ130 ml/min/1.73 m 2 )-manifests in over 65% of critically ill patients in the first week of admission into an ICU (25) and, as seen in this study, is likely to affect the probability of attainment of therapeutic exposures of renally cleared antibiotics. Renal insufficiency is associated with dramatically higher fosfomycin concentrations, and two patients consistently had CL CR values of Ͻ50 ml/min/1.73 m 2 .…”

Section: Discussionmentioning

confidence: 95%

Population Pharmacokinetics of Fosfomycin in Critically Ill Patients

Parker

Frantzeskaki

Wallis

et al. 2015

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e This study describes the population pharmacokinetics of fosfomycin in critically ill patients. In this observational study, serial blood samples were taken over several dosing intervals of intravenous fosfomycin treatment. Blood samples were analyzed using a validated liquid chromatography-tandem mass spectrometry technique. A population pharmacokinetic analysis was performed using nonlinear mixed-effects modeling. Five hundred fifteen blood samples were collected over one to six dosing intervals from 12 patients. The mean (standard deviation) age was 62 (17) years, 67% of patients were male, and creatinine clearance (CL CR ) ranged from 30 to 300 ml/min. A two-compartment model with between-subject variability on clearance and volume of distribution of the central compartment (V c ) described the data adequately. Calculated CL CR was supported as a covariate on fosfomycin clearance. The mean parameter estimates for clearance on the first day were 2.06 liters/h, V c of 27.2 liters, intercompartmental clearance of 19.8 liters/h, and volume of the peripheral compartment of 22.3 liters. We found significant pharmacokinetic variability for fosfomycin in this heterogeneous patient sample, which may be explained somewhat by the observed variations in renal function.