Optimization of tigecycline dosage regimen for different infections in the patients with hepatic or renal impairment.

OBJECTIVE: The objective of this study was to investigate the cumulative fraction of response (CFR) of various tigecycline dosing regimens in patients with hepatic or renal impairment. METHODS: Monte Carlo simulations were performed using pharmacokinetic parameters and microbiological data to evaluate various tigecycline regimens in patients with hepatic or renal impairment. RESULTS: For HAP and cIAI, the regimen of 25 mg q12h achieved CFR values of >90% in Child-Pugh C patients against Gram-positive bacteria and partial Gram-negative bacteria (Escherichia coli and Klebsiella oxytoca). However, dose increases of tigecycline was mostly required for Enterobacter cloacae, Klebsiella pneumoniae and Acinetobacter baumanni. The conventional tigecycline regimen (50 mg q12h) was effective for HAP and cIAI caused by Gram-positive bacteria and Escherichia coli in patients with renal impairment. For HAP caused by Klebsiella pneumoniae and Enterobacter cloacae, patients with severe renal failure can use the standard dose regimen 50 mg q12h, and other patients need to increase the dose of tigecycline. However, when treating cSSSI caused by Acinetobacter baumannii, Enterobacter cloacae and Klebsiella pneumoniae, all tigecycline maintenance doses have a CFR <90%. CONCLUSIONS: It is necessary to optimize tigecycline dosage regimens in patients with hepatic or renal impairment in order to maximise clinical response and minimise the probability of exposure-related toxicity.

Body composition and components of energy expenditure in children with end-stage liver disease.

BACKGROUND: Better understanding of body composition and energy metabolism in pediatric liver disease may provide a scientific basis for improved medical therapy aimed at achieving optimal nutrition, slowing progression to end-stage liver disease (ESLD), and improving the outcome of liver transplantation. METHODS: Twenty-one children less than 2 years of age with ESLD awaiting liver transplantation and 15 healthy, aged-matched controls had body compartment analysis using a four compartment model (body cell mass, fat mass, extracellular water, and extracellular solids). Subjects also had measurements of resting energy expenditure (REE) and respiratory quotient (RQ) by indirect calorimetry. Nine patients and 15 control subjects also had measurements of total energy expenditure (TEE) using doubly labelled water. RESULTS: Mean weights and heights were similar in the two groups. Compared with control subjects, children with ESLD had higher relative mean body cell mass (33 +/- 2% vs 29 +/- 1% of body weight, P < 0.05), but had similar fat mass, extracellular water, and extracellular solid compartments (18% vs 20%, 41% vs 38%, and 7% vs 13% of body weight respectively). Compared with control subjects, children with ESLD had 27% higher mean REE/body weight (0.285 +/- 0.013 vs 0.218. +/- 0.013 mJ/kg/24h, P < 0.001), 16% higher REE/unit cell mass (P < 0.05); and lower mean RQ (P < 0.05). Mean TEE of patients was 4.70 +/- 0.49 mJ/24h vs 3.19 +/- 0.76 in controls, (P < 0.01). CONCLUSIONS: In children, ESLD is a hypermetabolic state adversely affecting the relationship between metabolic and nonmetabolic body compartments. There is increased metabolic activity within the body cell mass with excess lipid oxidation during fasting and at rest. These findings have implications for the design of appropriate nutritional therapy.

The low-dose monoethylglycinexylidide test: assessment of liver function with fewer side effects.

The hepatic metabolism of lidocaine (1 mg/kg intravenously) to its metabolite monoethylglycinexylidide (MEG-X) is the basis of the standard MEG-X test. To reduce the lidocaine-induced side effects, we evaluated the MEG-X formation after 0.5 and 1 mg/kg lidocaine intravenously in subjects with normal (n = 5) and severely impaired liver function (n = 7) (study I). From this study, a low-dose test (MEG-X concentration 30 minutes after 50 mg lidocaine intravenously [MEG-X30min] normalized to standard MEG-X test results) was developed. Sensory side effects from this low dose and from the standard MEG-X test were compared in a double-blind, randomized, cross-over study (study II) comprising 15 individuals with normal liver function and 45 patients with cirrhosis (15 Child A, 15 Child B, and 15 Child C). In study I, MEG-X formation rate was dose-independent in patients with severely impaired liver function. In study II, normalized MEG-X test results (ranging from < or = 4 to 120 microg/L) were virtually identical to the standard test results (mean difference: -1.9 microg/L; 95% confidence interval [CI]: -5.3; 1.5 microg/L). Fewer individuals experienced side effects (30% vs. 53%) with the low-dose test (P = .0013). In a multivariate analysis, the Child-Pugh score was inversely related to the occurrence of side effects. The low-dose MEG-X test gives almost identical results to the standard MEG-X test and is associated with fewer side effects, which occur less often in individuals with more severely compromised liver function.