Bioavailability and population pharmacokinetics of voriconazole in lung transplant recipients.

This study was undertaken to characterize the pharmacokinetics and bioavailability of voriconazole in adult lung transplant patients during the early postoperative period, identify factors significantly associated with various pharmacokinetic parameters, and make recommendations for adequate dosing regimens. Thirteen lung transplant patients received two intravenous infusions (6 mg/kg, twice daily [b.i.d.]) immediately posttransplant followed by oral doses (200 mg, b.i.d.) for prophylaxis. Blood samples (9/interval) were collected during one intravenous and one oral dosing interval from each patient. Voriconazole plasma concentrations were measured by high-pressure liquid chromatography (HPLC). NONMEM was used to develop pharmacokinetic models, evaluate covariate relationships, and perform Monte Carlo simulations. There was a good correlation (R(2) = 0.98) between the area under the concentration-time curve specific for the dose evaluated (AUC(0-∞)) and trough concentrations. A two-compartment model adequately described the data. Population estimates of bioavailability, clearance, V(c), and V(p) were 45.9%, 3.45 liters/h, 54.7 liters, and 143 liters. Patients with cystic fibrosis (CF) exhibited a significantly lower bioavailability (23.7%, n = 3) than non-CF patients (63.3%, n = 10). Bioavailability increased with postoperative time and reached steady levels in about 1 week. V(p) increased with body weight. Bioavailability of voriconazole is substantially lower in lung transplant patients than non-transplant subjects but significantly increases with postoperative time. CF patients exhibit significantly lower bioavailability and exposure of voriconazole and therefore need higher doses. Intravenous administration of voriconazole during the first postoperative day followed by oral doses of 200 mg or 400 mg appeared to be the optimal dosing regimen. However, voriconazole levels should be monitored, and the dose should be individualized based on trough concentrations as a good measure of drug exposure.

Voriconazole pharmacokinetics in liver transplant recipients.

The objective of this study was to evaluate the pharmacokinetics of voriconazole and the potential correlations between pharmacokinetic parameters and patient variables in liver transplant patients on a fixed-dose prophylactic regimen. Multiple blood samples were collected within one dosing interval from 15 patients who were initiated on a prophylactic regimen of voriconazole at 200 mg enterally (tablets) twice daily starting immediately posttransplant. Voriconazole plasma concentrations were measured using high-pressure liquid chromatography (HPLC). Noncompartmental pharmacokinetic analysis was performed to estimate pharmacokinetic parameters. The mean apparent systemic clearance over bioavailability (CL/F), apparent steady-state volume of distribution over bioavailability (Vss/F), and half-life (t1/2) were 5.8+/-5.5 liters/h, 94.5+/-54.9 liters, and 15.7+/-7.0 h, respectively. There was a good correlation between the area under the concentration-time curve from 0 h to infinity (AUC0-infinity) and trough voriconazole plasma concentrations. t1/2, maximum drug concentration in plasma (Cmax), trough level, AUC0-infinity, area under the first moment of the concentration-time curve from 0 h to infinity (AUMC0-infinity), and mean residence time from 0 h to infinity (MRT0-infinity) were significantly correlated with postoperative time. t1/2, lambda, AUC0-infinity, and CL/F were significantly correlated with indices of liver function (aspartate transaminase [AST], total bilirubin, and international normalized ratio [INR]). The Cmax, last concentration in plasma at 12 h (Clast), AUMC0-infinity, and MRT0-infinity were significantly lower in the presence of deficient CYP2C19*2 alleles. Donor characteristics had no significant correlation with any of the pharmacokinetic parameters estimated. A fixed dosing regimen of voriconazole results in a highly variable exposure of voriconazole in liver transplant patients. Given that trough voriconazole concentration is a good measure of drug exposure (AUC), the voriconazole dose can be individualized based on trough concentration measurements in liver transplant patients.

Beneficial pharmacokinetic interaction between cyclosporine and itraconazole in renal transplant recipients.

BACKGROUND: Itraconazole is often given for fungal prophylaxis to renal transplant recipients, who require concomitant cyclosporine in the immediate posttransplant period. We determined the extent of the pharmacokinetic interaction between cyclosporine and itraconazole oral solution in renal transplant recipients and the effect on daily drug costs. METHOD: This was a single-center, open-label, nonrandomized study. Posttransplantation, renal transplant recipients received itraconazole solution 200 mg twice daily and cyclosporine, dosed to achieve target concentrations. Once at steady state, blood samples were collected over 12 hours for pharmacokinetic evaluation of cyclosporine, itraconazole, and hydroxy-itraconazole. Itraconazole was discontinued after approximately a 3-month prophylaxis regimen. Cyclosporine doses were titrated to achieve target concentrations and cyclosporine concentrations were once again determined when steady state was achieved. A noncompartmental analysis was used to analyze cyclosporine pharmacokinetic parameters. The pharmacoeconomic impact was measured based on the percent change in dose of cyclosporine when administered with and without itraconazole. Drug costs were calculated using the average wholesale price. The cost per patient, as well as the average cost, was calculated for the cyclosporine/itraconazole combination, as well as the cyclosporine regimen alone. RESULTS: Eight renal transplant recipients completed the study. All were included for itraconazole analyses and seven for cyclosporine analyses. Mean peak and trough itraconazole levels were 1.64 +/- 0.82 and 1.23 +/- 0.90 microg/mL respectively. Mean peak and trough hydroxy-itraconazole levels were 2.37 +/- 1.55 and 2.20 +/- 1.48 microg/mL, respectively. While on itraconazole, a 48% reduction in the mean total daily dose of cyclosporine was necessary to maintain target concentrations (171 +/- 63.6 versus 329 +/- 103.5 mg, P =.003). This reduction in cyclosporine dose resulted in a discounted itraconazole daily drug cost of approximately 29.5%. CONCLUSION: Administering itraconazole with cyclosporine allows for a decrease in the cyclosporine dose, thus lowering daily drug costs and providing adequate antifungal coverage with itraconazole and hydroxy-itraconazole trough concentrations above the MIC(90) of Candida and Aspergillus spp.

Antibacterials for the prophylaxis and treatment of bacterial endocarditis in children.

Although the overall incidence of infective endocarditis in the paediatric population is considered to be low, over the last 20 years a rising trend in infective endocarditis has been observed among children. This could be due to several reasons including the availability of improved diagnostic techniques, use of continuous central venous catheters and cardiac implants increasing the risk of infection, and the survival of a greater number of infants with congenital heart disease as a result of improved medical management. The predominant causative organisms of paediatric endocarditis include staphylococci and streptococci. There is increased concern surrounding the emergence of endocarditis in children caused by methicillin-resistant Staphylococcus aureus and drug resistant strains of Streptococcus pneumoniae. The treatment approach to paediatric endocarditis is similar to that for adult patients with endocarditis because of similarities in disease pathogenesis and aetiology. The therapeutic goal is to achieve sterilisation of the cardiac vegetations. The choice of antibacterial is dependent upon the susceptibility profile of the causative organism. Vancomycin or gentamicin is recommended for enterococcal endocarditis, according to guidelines from the American Heart Association. For staphylococcal endocarditis in patients with no prosthetic valve, oxacillin or nafcillin with or without gentamicin is the treatment of choice. In the case of endocarditis caused by methicillin-resistant S. aureus, vancomycin is commonly used in patients with no prosthetic valve and a combination of vancomycin, gentamicin and rifampicin (rifampin) for patients with prosthetic material. Cefazolin or ceftriaxone is the treatment of choice for penicillin allergic paediatric patients with endocarditis caused by viridans streptococci. While there have been no major changes in endocarditis therapy for the last decade, the current focus is on the recognition of multiple-drug resistant pathogens and the use of newer agents such as quinupristin/dalfopristin in the treatment of resistant bacterial endocarditis. Prophylactic antibacterial therapy is recommended for procedures thought to be associated with the occurrence of bacteraemia involving organisms commonly associated with endocarditis. These include dental extractions and oral, respiratory tract, genitourinary, gastrointestinal or oesophageal procedures. Prophylactic antibacterials recommended by the American Heart Association during genitourinary and gastrointestinal surgical procedures in high risk patients include ampicillin + gentamicin or vancomycin + gentamicin in high risk patients with penicillin allergy. Ampicillin has been recommended for prophylaxis of bacterial endocarditis in children undergoing oral, respiratory tract or oesophageal procedures. In the case of penicillin allergy in these patients, cephalosporins, clindamycin, azithromycin or clarithromycin have been recommended. The general consensus is that antibacterial prophylaxis during dental procedure is unnecessary, and in fact propagates bacterial resistance.

Incidence and Impact of Swiss Needle Cast in Forest Plantations of Douglas-fir in Coastal Oregon.

An epidemic of Swiss needle cast, caused by the ascomycete Phaeocryptopus gaeumannii, is causing defoliation and growth reductions in Douglas-fir forest plantations along the Oregon Coast. The area of symptomatic plantations has been monitored annually since 1996 by aerial survey; in spring 1999, 119,500 ha were affected. Pathogen and symptom development have also been monitored on nine permanent plots in stands of differing disease severity. Infection levels and symptom severity are greatest in low elevation plantations close to the coast. In areas of severe disease, trees retain only current year needles. Defoliation is proportional to the number of stomata occluded by pseudothecia of the fungus, with needles being shed when about 50% of stomata are occupied, regardless of needle age. Fungus sporulation and premature needle abscission are greatest on the upper branches of trees. Annual application of fungicides increases needle retention significantly. Tree height and diameter growth and total tree volume are reduced by disease, and tree volume is significantly correlated with needle retention on our plot trees. The epidemic continues to be most severe in Douglas-fir plantations established on sites where Sitka spruce and western hemlock or red alder predominated in earlier times.