Decreased Linezolid Serum Concentrations in Three Critically Ill Patients: Clinical Case Studies of a Potential Drug Interaction between Linezolid and Rifampicin

Linezolid is a valuable treatment option for treating infections caused by multi-resistant gram-positive pathogens. Lack of effective linezolid levels due to the co-administration of rifampicin has been described in healthy subjects. However, the clinical significance of this potential drug interaction (DI) for critically ill patients is still unclear. This was a retrospective analysis of 3 critically ill patients with the combination therapy of linezolid and rifampicin or rifampicin pre-treatment. Despite increasing the dose of linezolid, the majority of observed linezolid trough concentrations in all 3 patients were below 2 mg/l. Furthermore, linezolid trough concentrations remained below 2 mg/l after discontinuation of rifampicin. This potential DI between linezolid and rifampicin could lead to treatment failure. Therefore, we strongly recommend that linezolid serum concentrations be monitored in patients with rifampicin co-administration or rifampicin pretreatment. (C) 2016 S. Karger AG, Base

Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study

Background: Ventriculitis is a complication of temporary intraventricular drains. The limited penetration of meropenem into the cerebrospinal fluid (CSF) is well known. However, ventricular CSF pharmacokinetic data in patients with ventriculitis are lacking. The aim of this study was to evaluate meropenem pharmacokinetics in the serum and CSF of neurocritical care patients with proven or suspected ventriculitis. Methods: We conducted an observational pharmacokinetic study of neurocritical care patients with proven or suspected ventriculitis receiving meropenem. Multiple blood and CSF samples were taken and were described using nonparametric pharmacokinetic modelling with Pmetrics. Results: In total, 21 patients (median age 52 years, median weight 76 kg) were included. The median (range) of peak and trough concentrations in serum were 20.16 (4.40-69.00) mg/L and 2.54 (0.00-31.40) mg/L, respectively. The corresponding peak and trough concentrations in CSF were 1.20 (0.00-6.20) mg/L and 1.28 (0.00-4.10) mg/L, respectively, with a median CSF/serum ratio (range) of 0.09 (0.03-0.16). Median creatinine clearance ranged from 60. 7 to 217.6 ml/minute (median 122.5 ml/minute). A three-compartment linear population pharmacokinetic model was most appropriate. No covariate relationships could be supported for any of the model parameters. Meropenem demonstrated poor penetration into CSF, with a median CSF/serum ratio of 9 % and high interindividual pharmacokinetic variability. Conclusions: Administration of higher-than-standard doses of meropenem and therapeutic drug monitoring in both serum and CSF should be considered to individualise meropenem dosing in neurocritical care patients with ventriculitis

Pharmacokinetics of tigecycline in critically ill patients with liver failure defined by maximal liver function capacity test (LiMAx)

Background: In critically ill patients, tigecycline (TGC) remains an important therapeutic option due to its efficacy against multiresistant Gram-positive and Gram-negative bacteria. TGC is metabolized and eliminated predominantly by the liver. Critical illness-induced liver failure may have a profound impact on the pharmacokinetic of TGC. In the present study, we aimed to establish a link between the degree of liver dysfunction and TGC plasma concentration using the novel maximum liver function capacity (LiMAx) test, as a dynamic liver function test. Materials/methods: The prospective study included 33 patients from a surgical ICU with the clinical indication for antibiotic therapy with TGC. The patients received 100 mg loading dose of TGC followed by intermittent standard doses of 50 mg q12. Blood samples for TGC plasma concentration were collected at 0.3, 2, 5, 8 and 11.5 h in a steady-state condition after at least 36 h post-standard dosage. The results were analyzed by means of a high-performance liquid chromatography (HPLC) method. Within the same day, the LiMAx test was carried out and routine blood parameters were measured. Results: Peak plasma concentrations of TGC were significantly higher in patients with severe liver failure (LiMAx  300 µg/kg/h). The pharmacokinetic curves revealed higher values in severe liver failure at any measured point. Moreover, LiMAx and total bilirubin were the only liver-related parameters that correlated with TGC Cmax. Conclusions: The present study demonstrates a high variability of TGC plasma concentrations in critically ill patients. The results show a significant correlation between the degree of liver dysfunction, measured by the LiMAx test, and TGC Cmax. LiMAx test may be a helpful tool beyond others for adjusting the required dosage of hepatic metabolized antibiotics in critically ill patients. Trial registry DRKS—German clinical trials register; Trial registration number: DRKS00008888; Date of registration: 07-17-2015; Date of enrolment of the first participant to the trial: 12-10-201

Anti-infective drugs during continuous hemodialysis - using the bench to learn what to do at the bedside

Purpose: The main objective of this study was to investigate the clearance of 11 selected anti-infectives in an in vitro model of continuous veno-venous hemodialysis (CVVHD), in order to suggest rational dosing strategies for clinical practice. Methods: Ceftazidime, ciprofloxacin, flucloxacillin, gentamicin, linezolid, meropenem, metronidazole, piperacillin, rifampicin, vancomycin and voriconazole were studied in two different solvents (sodium chloride 0.9% and HSA 5%) using a multifiltrate dialysis device by Fresenius Medical Care (Bad Homburg, Germany). For each solution, prefilter, postfilter, and dialysate samples were drawn simultaneously during one hour of dialysis and were assayed. Results: The clearance of all drugs except rifampicin in sodium chloride 0.9% was comparable (mean 1.76 ± 0.11 l/h). The clearance of these agents in human serum albumin solution 5% was reduced by between 5.3% and 72.2%. The unbound drug fraction correlated with a lower clearance in HSA 5% (Pearson correlation coefficient r = 0.933; p = 0.00008). No correlation between clearance in HSA 5% and the drugs’ molecular weight was found (Pearson correlation coefficient r = 0.388; p = 0.268). Rifampicin was detected to bind to the surface of the polysulfone filter used. Dialysis clearance of ceftazidime, gentamicin, linezolid, meropenem, metronidazole, piperacillin and vancomycin during CVVHD accounted for over 25% of the total body clearance of population pharmacokinetic data for renally impaired patients. Conclusions: The results from this study highlight that dose adaptations are needed for most of the drugs under investigation for patients undergoing CVVHD. In combination with polysulfone filters, rifampicin should be used with care in this setting

Development of a dosing nomogram for continuous-infusion meropenem in critically ill patients based on a validated population pharmacokinetic model

Optimal antibiotic exposure is a vital but challenging prerequisite for achieving clinical success in ICU patients.To develop and externally validate a population pharmacokinetic model for continuous-infusion meropenem in critically ill patients and to establish a nomogram based on a routinely available marker of renal function.A population pharmacokinetic model was developed in NONMEM® 7.3 based on steady-state meropenem concentrations (CSS) collected during therapeutic drug monitoring. Different serum creatinine-based markers of renal function were compared for their influence on meropenem clearance (the Cockcroft-Gault creatinine clearance CLCRCG, the CLCR bedside estimate according to Jelliffe, the Chronic Kidney Disease Epidemiology Collaboration equation and the four-variable Modification of Diet in Renal Disease equation). After validation of the pharmacokinetic model with independent data, a dosing nomogram was developed, relating renal function to the daily doses required to achieve selected target concentrations (4/8/16 mg/L) in 90% of the patients. Probability of target attainment was determined for efficacy (CSS ≥8 mg/L) and potentially increased likelihood of adverse drug reactions (CSS >32 mg/L).In total, 433 plasma concentrations (3.20-48.0 mg/L) from 195 patients (median/P0.05 - P0.95 at baseline: weight 77.0/55.0-114 kg, CLCRCG 63.0/19.6-168 mL/min) were used for model building. We found that CLCRCG best described meropenem clearance (CL = 7.71 L/h, CLCRCG = 80 mL/min). The developed model was successfully validated with external data (n = 171, 73 patients). According to the nomogram, daily doses of 910/1480/2050/2800/3940 mg were required to reach a target CSS = 8 mg/L in 90% of patients with CLCRCG = 20/50/80/120/180 mL/min, respectively. A low probability of adverse drug reactions

What are the predictors for achieving therapeutic levetiracetam serum concentrations in adult neurological patients?

Emerging studies suggest that levetiracetam pharmacokinetics can be difficult to predict in certain special patient populations, including the elderly, critically ill patients, and pregnant women.To determine clinical characteristics that predict the attainment of target serum concentrations in a heterogeneous group of patients prescribed levetiracetam.A retrospective observational study was conducted in adult neurological patients prescribed levetiracetam for the treatment or prophylaxis of seizures. Serum samples were collected after steady-state was reached, with a trough/steady-state serum concentration between 6 and 20 mg/L considered therapeutic. Logistic regression was used to identify significant predictors associated with the attainment of therapeutic concentrations.One-hundred and thirty patients (63 male) were included. The median (interquartile ranges, IQR) serum trough/steady-state concentration (Cmin/ss) was 16.2 (9.8 - 26.1) mg/L. The dose-normalized median (IQR) Cmin/ss was 11.5 (7.0 - 16.5) mg/L. The coefficient of variation (CV) of Cmin/ss and dose-normalized Cmin/ss were 69.4% and 64.2%, respectively. A weak correlation was observed between levetiracetam Cmin/ss and patient age (r = 0.21; p = 0.020), creatinine clearance (r = - 0.26; p = 0.004), and daily dose (r = 0.42;