We report on 28 patients who underwent voriconazole monitoring because of disease progression or toxicity. A relationship (P < 0.025) between disease progression and drug concentration was detected. Favorable responses were observed in 10/10 patients with concentrations above 2.05 g/ml, while disease progressed in 44% (n ‫؍‬ 18) of patients with concentrations below 2.05 g/ml.Most drugs display linear pharmacokinetic profiles. Drugs with nonlinear elimination characteristics that also have narrow therapeutic toxicity widows are candidates for monitoring. This is especially true in the circumstance where low drug exposures are life threatening and high drug exposures result in significant toxicities. Voriconazole is a triazole antifungal with enhanced activity against a broad spectrum of fungal pathogens, including Aspergillus and Candida species (11, 26). We provide a succinct review of voriconazole's pharmacokinetics (PK) and present new PK-pharmacodynamic (PD) data relating drug concentration to therapeutic response.The pharmacokinetics of voriconazole in volunteers and patients have shown that voriconazole exhibits a nonlinear pharmacokinetic profile, secondary to saturable clearance (6,16,24,25). Voriconazole is metabolized by the cytochrome P450 system, with less than 2% of the dose excreted unchanged (12,13,24,25). Most voriconazole metabolism is mediated through CYP2C19. Allelic polymorphisms of CYP2C19 have been shown to be the most important determinants of the clearance of voriconazole, resulting in two phenotypes: poor and extensive metabolizers (both homozygous and heterozygous). There is extensive genetic variability in the incidence of poor and extensive metabolizers (5,10,18,28). The proportions of CYP2C19 extensive metabolizers in the U.S. population are estimated to be 2% homozygous extensive and 26% heterozygous extensive. Homozygous extensive metabolizers have a twofold lower exposure than heterozygous extensive metabolizers and fourfold lower drug exposure than poor metabolizers (12, 13).In 10 trials, the median values for the average and maximum voriconazole plasma concentrations in individual patients (n ϭ 1,121) were 2.51 g/ml and 3.79 g/ml, respectively (6,16,23,24,25). The values for area under the plasma concentrationtime curve on day 10 in 200-and 300-mg administration groups were approximately 5.8 and 3.8 times higher, respectively, among the poor metabolizers than among the extensive metabolizers. Trough concentrations also suggested that poor metabolizers were exposed to higher concentrations than were extensive metabolizers. The pharmacokinetics exhibited minimal intrapatient variation but marked interpatient variation, which was postulated to be secondary to genetic factors, enzyme inhibition and induction, old age, and liver disease.

The extra direct costs associated with nosocomial CAUTI found in this prospective study, which was done in the era of managed care during the late 1990s, are substantially lower than those reported in the largest comparable studies done more than 15 years ago, most of which were retrospective, reflecting the powerful impact of cost-containment measures that are now implemented in managed care.

Background. The epidemiology of candiduria in renal transplantation is unknown. Methods. We performed a nested case-control study to evaluate the epidemiology of candiduria in renal transplant recipients at the University of Wisconsin (Madison) over an 8-year period.Results. Renal transplantations were performed on 1738 patients during this period, 192 of whom had 276 episodes of candiduria. Candida glabrata, which was recovered from 98 (51%) of 192 case patients, was the most common pathogen identified. Most case patients were asymptomatic. Independent predictors of candiduria were female sex (odds ratio [OR], 12.5; 95% confidence interval [CI], 6.7-23.0), intensive care unit admission (OR, 8.8; 95% CI, 2.3-35.0), antibiotic use during the month before candiduria (OR, 3.8; 95% CI, 1.7-8.3), presence of an indwelling bladder catheter (OR, 4.4; 95% CI, 2.1-9.4), diabetes (OR, 2.2; 95% CI, 1.3-3.9), neurogenic bladder (OR, 7.6; 95% CI, 2.1-27), and malnutrition (OR, 2.4; 95% CI, 1.3-4.4). Log-rank testing of KaplanMeier curves revealed that 60-day, 90-day, and cumulative survival rates were significantly different between case and control patients; there was no difference in the survival rate during the first 30 days after transplantation. A variety of regimens were used for treatment; 119 case patients (62%) underwent removal of the indwelling bladder catheter within 1 week after diagnosis of candiduria. Candiduria cleared in 148 case patients (77%). Treatment of candiduria was not associated with an improved survival rate.Conclusions. Candiduria occurs commonly in renal transplant recipients. Risk factors for candiduria in such persons are similar to those in hospitalized patients who have not received a transplant. Candiduria is associated with reduced survival rates among persons who have undergone renal transplantation; this is likely a marker for severity of illness. Treatment of asymptomatic candiduria in renal transplant recipients does not appear to result in improved outcome.

Among recipients of intra-abdominal solid-organ transplants, bloodstream infections (BSIs) are a major cause of mortality. We undertook a retrospective cohort study of recipients of kidney, pancreas, and/or liver transplants with BSIs at a single center over an 11-year period. Multivariate analysis using logistic regression was used to determine independent predictors of 15-day mortality and clinical cure, with a focus on the use of statins. Three hundred and eleven recipients of solid-organ transplants had 604 episodes of BSI. Forty-four (14%) died within 15 days of BSI. Sixteen percent did not achieve clinical cure. In the multivariate model, each one point increase in the APACHE score was associated with a 1.09-fold increased risk of death (95% confidence interval [CI] 1.00-1.18, P = 0.03). The lack of appropriate antibiotic therapy was associated with a four-fold higher risk of death within 15 days (odds ratio [OR] 4.65, 95% CI 1.46-14.78, P = 0.009). Statin use was protective (OR 0.18, 95% CI 0.04-0.78). Patients with high APACHE scores, nosocomial rather than community source of BSI, lack of appropriate antibiotic therapy, and mental status changes were less likely to achieve clinical cure of their BSIs. In conclusion, appropriate antibiotic therapy and statin use are associated with lower risk of mortality from BSIs in this patient population.

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