Estimation of cefepime, piperacillin, and tazobactam clearance with iohexol-based glomerular filtration rate in paediatric patients.

PURPOSE: Estimated glomerular filtration rate (eGFR) equations reflect kidney function imprecisely. We aimed to describe whether iohexol-based GFR or eGFRs predict clearance of cefepime, piperacillin, and tazobactam in pharmacokinetic (PK) models in this population and its clinical significance. METHODS: Hospitalized patients (0.5-25 years) with haemato-oncological disease and infection receiving cefepime or piperacillin/tazobactam were included. PK samples were collected at a steady state concomitantly with samples for iohexol-based GFR. PK models were developed in NONMEM. Weight, postmenstrual age, iohexol-based GFR, different eGFR equations (Schwartz updated, Lund-Malmö revised, CKD-EPI, Bouvet, Schwartz cystatin C-based) were tested as covariates. Probabilities of neurotoxic/therapeutic concentrations were assessed by simulations. RESULTS: Fifteen patients receiving cefepime and 17 piperacillin/tazobactam were included (median (range) age 16.2 (1.9-26.0) and 10.5 (0.8-25.6) years, iohexol-based GFR 102 (68-140) and 116 (74-137) mL/min/1.73 m2, respectively). Two-compartment model provided the best fit for all drugs. Weight was covariate for central and peripheral compartment, clearance and intercompartmental clearance (only tazobactam), and postmenstrual age for clearance (excluding cefepime). Iohexol-based GFR was the best predictor of clearance. The model of cefepime without vs with iohexol-based GFR underestimated the probability of neurotoxic concentrations (28.3-28.6% vs 52.1-69.3%) and overestimated the probability of therapeutic concentrations (> 90% vs 81.9-87.1%) in the case of iohexol-based GFR 70-80 and 130-140 mL/min/1.73 m2, respectively. CONCLUSION: Iohexol-based GFR can predict better than eGFRs the clearance of cefepime, piperacillin, and tazobactam in children and young adults with haemato-oncological disease and infection, warranting further investigation as an indicator of renal function to improve targeting of therapeutic window. TRIAL REGISTRATION NUMBER AND DATE OF REGISTRATION: EudraCT 2015-000,631-32, EudraCT 2016-003,374-40 (24.10.2016).

Changes in adipokine levels and metabolic profiles following bariatric surgery.

BACKGROUND: Bariatric surgery is considered to be the most effective treatment option for weight reduction in obese patients. Abdominal obesity is frequently accompanied by metabolic syndrome (MS). Adipokines are cell signaling proteins that have direct impact upon the metabolic homeostasis. The purpose of this analysis was to evaluate the effect of bariatric surgery, including laparoscopic sleeve gastrectomy (LSG) and laparoscopic gastric bypass (LRYGB) on the adipokine levels and metabolic profile as well as MS and status of type 2 diabetes (T2D). METHODS: We analyzed anthropometric parameters, blood levels of adipokines, vitamins, lipids and inflammatory markers in 30 bariatric surgery patients with obesity of class II or III 1 month before and 1 year after surgery as well as in 60 obese patients from general practice (GP) and 15 patients with normal body mass (control). RESULTS: The BMI was significantly higher among patients before surgery and GP patients in comparison to control and post-surgery patients. The levels of glucose, cholesterol and LDL-cholesterol, triglyceride and hs-CRP were the highest in patients before surgery but decreased significantly after surgery, while the level of HDL-cholesterol increased after surgery. The levels of adiponectin increased and that of leptin decreased after surgery. The significant difference in the concentration of resistin was revealed between LSG and LRYGB methods. The relationship between resistin and vitamin D was also found. The patients with MS and T2D displayed significantly greater reduction in lipid markers and adipokine levels than the rest of patients. CONCLUSION: Remarkable changes in levels of adipokines after bariatric surgery appear like increase in adiponectin and decrease in leptin levels. Significant improvement in anthropometric parameters, metabolic and inflammatory markers occurs, suggesting high potential for reduction of metabolic syndrome and risk for type 2 diabetes. We have shown for the first time ever that level of vitamin D may be involved in resistin regulation.

Glomerular filtration rate in children and young adults with haemato-oncological disease and infection is best described by three-compartment iohexol model.

BACKGROUND: Children with cancer and infection may develop glomerular hyperfiltration. With the aim to determine the prevalence of glomerular hyperfiltration in children and young adults with haemato-oncological disease and infection, we developed population pharmacokinetic model of iohexol. We further aimed to assess the accuracy of estimated glomerular filtration rate (eGFR) equations and single- or two-point measured GFR (mGFR) formulas compared with GFR based on iohexol clearance from our population pharmacokinetic model (iGFR). PROCEDURE: Hospitalised patients (0.5-25 years) with haemato-oncological disease and infection were included if their eGFR was ≥80 ml/min/1.73 m2 at the screening visit. Iohexol plasma concentrations were described by population pharmacokinetic model. Bias, precision and accuracy of 23 eGFR equations and 18 mGFR formulas were calculated. RESULTS: Total of 32 iohexol administrations were performed in 28 patients. Median (range) eGFR was 136 ml/min/1.73 m2 (74-234) and age 15.1 years (0.8-26.0). Three-compartment model with allometric scaling of central, one peripheral compartment and clearance (with power 0.75) to weight fitted the best. Median (range) iGFR was 103 ml/min/1.73 m2 (68-140). All except one eGFR equation overestimated GFR. Lund-Malmö revised eGFR equation performed the best, followed by Gao equation. Of single- or two-point mGFR formulas, 15 overestimated iGFR. Modified Jacobsson formula at 5.5 hours performed the best, followed by Fleming formula at 3 hours. CONCLUSIONS: In children and young adults with haemato-oncological disease and infection, renal function is best described by iohexol clearance from three-compartment pharmacokinetic model, while eGFR equations and single- and two-point mGFR formulas overestimate iGFR.

The Pharmacokinetic Profile and Bioavailability of Enteral N-Acetylcysteine in Intensive Care Unit.

Background and Objectives: N-acetylcysteine (NAC) is a mucolytic agent used to prevent ventilator-associated pneumonia in intensive care units. This study aimed to evaluate the oral bioavailability of NAC in critically ill patients with pneumonia, isolated acute brain injury and abdominal sepsis. Materials and Methods: This quantitative and descriptive study compared NAC's pharmacokinetics after intravenous and enteral administration. 600 mg of NAC was administered in both ways, and the blood levels for NAC were measured. Results: 18 patients with pneumonia, 19 patients with brain injury and 17 patients with abdominal sepsis were included in the population pharmacokinetic modelling. A three-compartmental model without lag-time provided the best fit to the data. Oral bioavailability was estimated as 11.6% (95% confidence interval 6.3-16.9%), similar to bioavailability in healthy volunteers and patients with chronic pulmonary diseases. Conclusions: The bioavailability of enteral NAC of ICU patients with different diseases is similar to the published data on healthy volunteers.

Long-Term Elevated Inflammatory Protein Levels in Asymptomatic SARS-CoV-2 Infected Individuals.

The clinical features of SARS-CoV-2 infection range from asymptomatic to severe disease with life-threatening complications. Understanding the persistence of immune responses in asymptomatic individuals merit special attention because of their importance in controlling the spread of the infections. We here studied the antibody and T cell responses, and a wide range of inflammation markers, in 56 SARS-CoV-2 antibody-positive individuals, identified by a population screen after the first wave of SARS-CoV-2 infection. These, mostly asymptomatic individuals, were reanalyzed 7-8 months after their infection together with 115 age-matched seronegative controls. We found that 7-8 months after the infection their antibodies to SARS-CoV-2 Nucleocapsid (N) protein declined whereas we found no decrease in the antibodies to Spike receptor-binding domain (S-RBD) when compared to the findings at seropositivity identification. In contrast to antibodies to N protein, the antibodies to S-RBD correlated with the viral neutralization capacity and with CD4+ T cell responses as measured by antigen-specific upregulation of CD137 and CD69 markers. Unexpectedly we found the asymptomatic antibody-positive individuals to have increased serum levels of S100A12, TGF-alpha, IL18, and OSM, the markers of activated macrophages-monocytes, suggesting long-term persistent inflammatory effect associated with the viral infection in asymptomatic individuals. Our results support the evidence for the long-term persistence of the inflammation process and the need for post-infection clinical monitoring of SARS-CoV-2 infected asymptomatic individuals.