Bayesian pharmacokinetics of gentamicin in a haemodialysis population

BACKGROUND: Aminoglycosides are commonly used in the haemodialysis population. Standard pharmacokinetic approaches require multiple sampling to describe the parameters of drug distribution and elimination in the intra- and interdialytic periods. OBJECTIVE: To characterise the pharmacokinetics of gentamicin in a haemodialysis population by using Bayesian pharmacokinetic methods and only two plasma concentrations. DESIGN AND PARTICIPANTS: Prospective case series of 13 adult (aged 36-70 years) haemodialysis patients (Fresenius F80 dialysers were used) receiving gentamicin. METHODS: Patients with suspected or confirmed Gram-negative infections were given gentamicin. At 48 hours after receiving the dose (at the next haemodialysis session), patients provided two blood samples, one immediately before the dialysis session and another 1 hour after haemodialysis. Data on dosage, timing and plasma concentrations for all subjects were analysed with PASTRX version 10.6 and Bayesian pharmacokinetic analysis. Volume of distribution (Vd), interdialytic elimination rate constant (k(inter)), interdialytic elimination half-life (t1/2beta, inter)) and interdialytic clearance (CL(inter)) were determined from a single predialysis plasma concentration. Elimination rate constant (k(dial)), elimination half-life (t1/2beta, dial)) and clearance (CL(dial)) during 3.5-4 hours of dialysis were also determined from the pre- and post-plasma concentrations. RESULTS: Pharmacokinetic parameters (mean +/- SD) were: Vd 0.288 +/- 0.002 L/kg, k(inter) 0.015 +/- 0.004h(-1), t1/2beta, inter) 48 +/- 11h, CL(inter) 5.9 +/- 2.4 mL/min, k(dial) 0.25 +/- 0.05 h(-1), t1/2beta, dial) 3.0 +/- 1.0h and CL(dial) 91 +/- 24 mL/min. CONCLUSIONS: The rate of elimination of gentamicin was 17-fold greater (95% CI 13.7-20.7) on haemodialysis with a Fresenius F80 than off haemodialysis. All of the pharmacokinetic parameters of interest were determined using Bayesian pharmacokinetic procedures and only two plasma gentamicin concentrations.     

Prevalence of Antimicrobial Resistance in Respiratory Tract Isolates of Streptococcus pneumoniae: Results of a Canadian National Surveillance Study

From October 1997 to November 1998, 1,180 respiratory tract isolates of Streptococcus pneumoniae were collected from 18 medical centers in 9 of the 10 Canadian provinces. Penicillin-intermediate and -resistant isolates occurred at rates of 14.8 and 6.4%, respectively, and these rates varied considerably by geographic region. Trimethoprim-sulfamethoxazole, tetracycline, and macrolide rates of nonsusceptibility were 12.2, 10.6, and 8.0 to 9.3%, respectively. The most potent agents studied were newer fluoroquinolones.     

Does warfarin safely prevent clotting of hemodialysis catheters? a review of efficacy and safety.

This article reviews the efficacy and safety of warfarin to prevent tunneled cuffed catheter (TCC) thrombosis in the hemodialysis population. Literature searches of PubMed, EMBASE, the Cochrane Library and Google Scholar were performed until April 1, 2007. Bibliographies of relevant articles were reviewed for additional publications. Minidose (1 mg/day) warfarin is ineffective in preventing TCC malfunction. Warfarin titrated to an international normalized ratio (INR) of 1.5-2.0, 1.8-2.5, and 2.0-3.0 was found to decrease the rate of thrombosis in selected patients. Early initiation of warfarin after catheter placement may be advantageous. Despite evidence of efficacy, safety is of greater concern. There were no major bleeds reported at an INR range of 1.5-2.5 specifically in catheter studies. However, an increase in major bleeding episodes has been reported with INR ranging from 1.4 to 3.0 in patients receiving warfarin for other indications (e.g., graft patency or cardiovascular indications). There is insufficient evidence to recommend the routine use of warfarin to prevent TCC thrombosis in all patients, primarily because of safety concerns. There is an increased risk of bleeding associated with warfarin use in the hemodialysis population. If a decision is made to use warfarin on a case-by-case basis, literature to date suggests that an INR target of 1.5-2.5 should suffice. Bleeding must be monitored carefully in this population, especially in patients using antiplatelet medications for concurrent conditions.     

A mechanical evaluation of TiO2-gritblasted and Ca-P magnetron sputter coated implants placed into the trabecular bone of the goat: Part 1

The influence of Ca-P magnetron sputter coated implants on the mechanical anchorage was evaluated in a goat model. Therefore, uncoated and coated screw designed commercially pure titanium TiO2-blasted implants were inserted into the trabecular bone of the femoral condyles of 12 goats. The thicknesses of the coatings were 0.1 micron (CaP-0.1), 1.0 micron (CaP-1) and 4.0 microns (CaP-4). In addition, uncoated TiO2-blasted implants (Ti) were used as control. Evaluation of the interface strength and appearance, using torque test and scanning electron microscopy, was done at implantation periods of 6 and 12 weeks. Although, especially at 6 weeks of implantation, the Ca-P coated implants showed higher failure torque values than the TiO2 blasted implants, the observed differences for type of implant and evaluation period were not significant (P > 0.1). SEM evaluation showed that all implants with failure values of more than 100 N conducted bone growth into their screw threads. In addition, we observed that the fracture plane for the CaP-4 implants was situated at the coating-implant interface or inside the coating. For the CaP-1 and CaP-0.1 the fracture line could not be determined definitely. For the Ti implants, the fracture torque testing resulted in failure at the bone-implant interface. Therefore, we conclude that all implants resulted in a good bonding strength with the surrounding bone. The sputtered Ca-P coatings seemed to improve the initial fixation of the TiO2 blasted implants.     

A histological evaluation of TiO2-gritblasted and Ca-P magnetron sputter coated implants placed into the trabecular bone of the goat: Part 2

The aim of this study was to investigate the synergetic influence of surface topography and chemical composition of oral implant materials on bone response. For the experiment screw designed implants were used. The implants were grit-blasted with TiO2 particles. The implants were left uncoated (Ti) or provided with three different amorphous/crystalline Ca-P magnetron sputter coatings, resp. 0.1 micron (CaP-0.1), 1 micron (CaP-1) and 4 microns (CaP-4), in thickness. The implants were inserted in the medial femoral condyles of 12 goats. Each femur received 2 implants. After implantation periods of 6 and 12 weeks the implants were retrieved and prepared for histological and histomorphometrical evaluation (bone contact and bone mass). The light microscopy revealed that bone response to CaP-4 and CaP-1 implants was similar. For example, after 12 weeks, screw threads were almost completely covered with bone. In contrast to CaP-0.1 and Ti implants, where bone apposition was less pronounced. Histomorphometry demonstrated that the bone-to-implant contact for the CaP-1 and CaP-4 implants was significantly higher (P < 0.05) than for the CaP-0.1 and Ti implants. This difference existed already after 6 weeks and was even enhanced after 12 weeks. The bone mass measurements revealed that only at 12 weeks CaP-4 implants had significantly more bone contact inside the screw threads than non-coated Ti-implants (P < 0.05). Supported by our findings, we conclude that the additional application of a 1-4 microns thick Ca-P magnetron sputter coating can further improve the healing response to surface roughened oral implants placed into trabecular bone.     

Oxidation of cardiac myoglobin in vivo by sodium nitrite or hydroxylamine

A non-vascularized fish heart model was used to assess the oxidation of cardiac myoglobin in vivo by compounds known to cause methemoglobinemia. Buffalo sculpin (Enophrys bison) were cannulated from the afferent branchial artery to permit repeated blood sampling and injected intraperitoneally with sodium nitrite, hydroxylamine or aniline. Methemoglobin was formed by sublethal levels of sodium nitrite or hydroxylamine. For hydroxylamine, the time to peak effect was less than 1 h. For sodium nitrite, the onset was less rapid and the effect more prolonged. Aniline had no effect on hemoglobin at any concentration tested. Cardiac myoglobin, assayed at the time of peak effect on hemoglobin, was oxidized in a dosedependent manner by sodium nitrite or hydroxylamine. At high doses of sodium nitrite (50 and 100 mg/kg), the oxidation of myoglobin exceeded that of hemoglobin. The reverse was true of hydroxylamine at all concentrations tested. This study suggests the possibility that cardiac myoglobin is oxidized in occupational or other exposures to sodium nitrite, hydroxylamine and related compounds.