Assessment of cefepime toxicodynamics: comprehensive examination of pharmacokinetic/pharmacodynamic targets for cefepime-induced neurotoxicity and evaluation of current dosing guidelines.

BACKGROUND: Cefepime-induced neurotoxicity (CIN) is an increasingly reported adverse event; however, the toxicity threshold remains unclear. This study was conducted to provide a comprehensive examination of the most appropriate threshold for CIN, and evaluate the ability of current dosing regimens to attain therapeutic targets. METHODS: Data of the incidence of CIN and cefepime plasma concentrations were collected retrospectively from patients administered cefepime. Population pharmacokinetic modelling was used to determine daily cefepime trough concentration (Cmin), maximum serum concentration and area under the concentration-time curve. The ability of each pharmacokinetic parameter to predict CIN was evaluated using receiver operating characteristic (ROC) curves, from which optimal toxicity thresholds were determined. Pharmacokinetic simulation was used to evaluate the ability of cefepime dosing guidelines to meet established efficacy targets, whilst maintaining exposure below the determined CIN threshold. RESULTS: In total, 102 cefepime courses were evaluated, with CIN reported in 10. ROC analyses showed that all cefepime pharmacokinetic parameters were strongly predictive of CIN. Cmin of 49 mg/L was identified as the optimal toxicity target, based on its predictive ability (0.88, 95% confidence interval 0.758-0.999, P<0.001) and ease of clinical use. Assessment of cefepime dosing regimens predicted that only 29% of simulated patients achieve therapeutic targets, with patients with impaired renal function more likely to exhibit subtherapeutic concentrations (89%), and patients with normal renal function likely to have potentially toxic exposure (64%). CONCLUSIONS: The findings from this study provide evidence that cefepime exposure is highly predictive of CIN, with Cmin of 49 mg/L being the most appropriate toxicity threshold. Further research is required to optimize cefepime dosing in the context of this therapeutic target.

Evaluation of the geographical utility of Eastern Russell's viper (Daboia siamensis) antivenom from Thailand and an assessment of its protective effects against venom-induced nephrotoxicity.

BACKGROUND: Daboia siamensis (Eastern Russell's viper) is a medically important snake species found widely distributed across Southeast Asia. Envenomings by this species can result in systemic coagulopathy, local tissue injury and/or renal failure. While administration of specific antivenom is an effective treatment for Russell's viper envenomings, the availability of, and access to, geographically-appropriate antivenom remains problematic in many rural areas. In this study, we determined the binding and neutralizing capability of antivenoms manufactured by the Thai Red Cross in Thailand against D. siamensis venoms from four geographical locales: Myanmar, Taiwan, China and Thailand. METHODOLOGY/PRINCIPLE FINDINGS: The D. siamensis monovalent antivenom displayed extensive recognition and binding to proteins found in D. siamensis venom, irrespective of the geographical origin of those venoms. Similar immunological characteristics were observed with the Hemato Polyvalent antivenom, which also uses D. siamensis venom as an immunogen, but binding levels were dramatically reduced when using comparator monovalent antivenoms manufactured against different snake species. A similar pattern was observed when investigating neutralization of coagulopathy, with the procoagulant action of all four geographical venom variants neutralized by both the D. siamensis monovalent and the Hemato Polyvalent antivenoms, while the comparator monovalent antivenoms were ineffective. These in vitro findings translated into therapeutic efficacy in vivo, as the D. siamensis monovalent antivenom was found to effectively protect against the lethal effects of all four geographical venom variants preclinically. Assessments of in vivo nephrotoxicity revealed that D. siamensis venom (700 µg/kg) significantly increased plasma creatinine and blood urea nitrogen levels in anaesthetised rats. The intravenous administration of D. siamensis monovalent antivenom at three times higher than the recommended scaled therapeutic dose, prior to and 1 h after the injection of venom, resulted in reduced levels of markers of nephrotoxicity and prevented renal morphological changes, although lower doses had no therapeutic effect. CONCLUSIONS/SIGNIFICANCE: This study highlights the potential broad geographical utility of the Thai D. siamensis monovalent antivenom for treating envenomings by the Eastern Russell's viper. However, only the early delivery of high antivenom doses appears to be capable of preventing venom-induced nephrotoxicity.

[Renal failure in the medicolegal evaluation of civil invalidity and social security disability (INPS)].

After a quick description of the anatomopathology and physiopathology of renal failure, the Authors delve into the problem of assessing its medicolegal aspects in the fields of civil invalidity and social security. In Italy, civil invalidity involves protecting the psychological and physical welfare of the disabled, as sanctioned by law 118 of 1971; this law protects all citizens with a debilitating condition, including those who do not work or are not of working age. A disabled person is someone who, if of working age (between 18 and retirement) has a reduction of more than ⅓ (34%) of their general work capacity; if under or over the retirement age, they have a persistent difficulty in carrying out age-appropriate functions and tasks. In support of an application for being awarded civil invalidity, people can also refer to law no. 104 of 1992, which assesses social, relational and work disadvantages of a disabled person. INPS (Italian Social Security Institute) protection, on the other hand, is a social security protection based on health requirements (having a capacity for work which is reduced by more than ⅓, as established by law no. 222 of 1984), as well as on the following administrative requirement: having paid, as a worker, at least 260 weekly contributions, equivalent to five years of contribution and insurance, of which 156, equal to three years of contribution and insurance, were made in the five-year period preceding the date of submitting the application. If this is the case, the protected person, thus insured, can enjoy protection for their illness by virtue of the stipulations for social security.

Assessment of Hepatic Cytochrome P450 3A Activity Using Metabolic Markers in Patients with Renal Impairment.

BACKGROUND: The renal function of individuals is one of the reasons for the variations in therapeutic response to various drugs. Patients with renal impairment are often exposed to drug toxicity, even with drugs that are usually eliminated by hepatic metabolism. Previous study has reported an increased plasma concentration of indoxyl sulfate and decreased plasma concentration of 4ß-hydroxy (OH)-cholesterol in stable kidney transplant recipients, implicating indoxyl sulfate as a cytochrome P450 (CYP) inhibiting factor. In this study, we aimed to evaluate the impact of renal impairment severity-dependent accumulation of indoxyl sulfate on hepatic CYP3A activity using metabolic markers. METHODS: Sixty-six subjects were enrolled in this study; based on estimated glomerular filtration rate (eGFR), they were classified as having mild, moderate, or severe renal impairment. The plasma concentration of indoxyl sulfate was quantified using liquid chromatography-mass spectrometry (LC-MS). Urinary and plasma markers (6ß-OH-cortisol/cortisol, 6ß-OH-cortisone/cortisone, 4ß-OH-cholesterol) for hepatic CYP3A activity were quantified using gas chromatography-mass spectrometry (GC-MS). The total plasma concentration of cholesterol was measured using the enzymatic colorimetric assay to calculate the 4ß-OH-cholesterol/cholesterol ratio. The correlation between variables was assessed using Pearson's correlation test. RESULTS: There was a significant negative correlation between MDRD eGFR and indoxyl sulfate levels. The levels of urinary 6ß-OH-cortisol/cortisol and 6ß-OH-cortisone/cortisone as well as plasma 4ß-OH-cholesterol and 4ß-OH-cholesterol/cholesterol were not correlated with MDRD eGFR and the plasma concentration of indoxyl sulfate. CONCLUSION: Hepatic CYP3A activity may not be affected by renal impairment-induced accumulation of plasma indoxyl sulfate.

Dose-response assessment of nephrotoxicity from a twenty-eight-day combined-exposure to melamine and cyanuric acid in F344 rats.

The adulteration of pet food with melamine and derivatives, including cyanuric acid, has been implicated in the kidney failure and death of cats and dogs in the USA and other countries. In a previous 7-day dietary study in F344 rats, we established a no-observed-adverse-effect level (NOAEL) for a co-exposure to melamine and cyanuric acid of 8.6 mg/kg bw/day of each compound, and a benchmark dose lower confidence limit (BMDL) of 8.4-10.9 mg/kg bw/day of each compound. To ascertain the role played by the duration of exposure, we treated F344 rats for 28 days. Groups of male and female rats were fed diet containing 0 (control), 30, 60, 120, 180, 240, or 360 ppm of both melamine and cyanuric acid. The lowest dose that produced histopathological alterations in the kidney was 120 ppm, versus 229 ppm in the 7-day study. Wet-mount analysis of kidney sections demonstrated the formation of melamine cyanurate spherulites in one male and two female rats at the 60 ppm dose and in one female rat at the 30 ppm dose, establishing a NOAEL of 2.1mg/kg bw/day for males and <2.6 mg/kg bw/day for females, and BMDL values as low as 1.6 mg/kg bw/day for both sexes. These data demonstrate that the length of exposure is an important component in the threshold of toxicity from a co-exposure to these compounds and suggest that the current risk assessments based on exposures to melamine alone may not reflect sufficiently the risk of a co-exposure to melamine and cyanuric acid.

Effectiveness and cost of replacing a calcineurin inhibitor with sirolimus to slow the course of chronic kidney disease in renal allografts.

Renal grafts suffer a progressive decrease in glomerular filtration rate (GFR) because of several factors including calcineurin inhibitor (CNI) nephrotoxicity. Switching CNIs to sirolimus may improve this adverse prognosis. We performed a prospective, open-label clinical trial among 18 kidney transplant patients with more than 12 months of evolution (range, 385-1826 days), showing progressive GFR decreases and biopsies with interstitial fibrosis and tubular atrophy (IFTA). Immunosuppressive treatment included cyclosporine, ketoconazole, and steroids associated with azathioprine or mycophenolate mofetil. After signing an Institutional Review Board-approved written consent, cyclosporine was switched to sirolimus seeking to achieve a trough blood sirolimus concentration of 6-15 ng/mL. Wilcoxon and Student's t-tests were used to compare the values in the annual periods before and after the switch. GFR was estimated by the Modification of Diet in Renal Disease formula. There were no acute rejection episodes. Estimated GFR on the day of the switch was 38.0 +/- 12.1 mL/min. After CNI switch, the slope of the estimated GFR significantly improved from -6.5 +/- 9.2 to 8.1 +/- 14.0 mL/min/year (P < .01). The estimated GFR 1 year after the switch was 47.2 +/- 16.9 mL/min (P = .003 vs baseline). Total expenditures increased. The ratio of post-switch versus baseline total expenditures was 1.93 (95% confidence interval, 1.54-2.31) and the ratio of sirolimus to CNI cost was 2.16 (95% confidence interval, 1.53-2.78). Switching from CNI to sirolimus for kidney transplants with decreasing GFR and a biopsy with IFTA changes, suggesting progressive graft nephropathy, almost doubled total expenses. It is necessary to conduct trials using clinical end points to definitively validate this therapeutic intervention.