Mississippi mud no more: cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity

OBJECTIVE: To determine the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin to prevent nephrotoxicity. An analysis was performed for subpopulations of patients receiving nephrotoxic agents (aminoglycosides, amphotericin, and acyclovir), those in the intensive care unit, and those on the oncology service. METHODS: Decision analysis was used to model the cost-effectiveness of pharmacokinetic dosage adjustment of vancomycin. The reference case was determined, in part, by a retrospective review of 200 patients randomly selected from our clinical pharmacology consultation service. Patients were aged 18 years or older and had received intravenous vancomycin for at least 48 hours, with at least two--one peak and one trough--vancomycin serum concentrations obtained during therapy. Results of published clinical trials were used to determine the probability of vancomycin-induced nephrotoxicity. RESULTS: The mean cost of treating nephrotoxicity was 11,233 dollars at our institution. The mean cost for all patients was 25,166 dollars (sensitivity analysis 15,000-27,500 dollars)/nephrotoxic episode prevented. The subgroup analysis revealed a cost of 8,363 dollars (sensitivity analysis 4,368-10,500 dollars)/nephrotoxic episode prevented in intensive care patients, 5,000 dollars (sensitivity analysis 1,687-13,250 dollars ) in oncology patients, and a dominant strategy showing a cost savings of 5,564 dollars (sensitivity analysis 2,724-12,428 dollars) in those receiving concomitant nephrotoxins. CONCLUSION: Although pharmacokinetic monitoring and dosage adjustment are effective methods for reducing the toxicity of many drugs, controversy exists regarding the necessity of such monitoring with vancomycin. Evaluation by decision analysis over a range of assumptions, varying probabilities, and costs reveals that pharmacokinetic monitoring and vancomycin dosage adjustment to prevent nephrotoxicity are not cost-effective for all patients. However, such dosage adjustment demonstrates cost-effectiveness for patients receiving concomitant nephrotoxins, intensive care patients, and probably oncology patients.     

Determinants of aciclovir-induced nephrotoxicity in children

BACKGROUND: Aciclovir is the drug of choice for severe systemic herpes virus infections. Nephrotoxicity is one of the clinically significant adverse effects of this drug, but studies examining nephrotoxicity in children are scarce. OBJECTIVE: To identify risk factors for aciclovir-associated nephrotoxicity in the pediatric population. PATIENTS AND METHODS: A retrospective review was conducted on all children (mean age 81 months; n = 126 [74 boys]) who were treated with aciclovir in a tertiary center between July 2005 and January 2006 and who met our inclusion criteria. Glomerular filtration rate (GFR) was calculated on the first day of treatment and at the peak measured creatinine level while on therapy, using Schwartz's method. RESULTS: Aciclovir therapy was associated with a significant increase in serum creatinine levels and a parallel decrease in GFR (n = 93; both p 相似文献   

Drug safety evaluation of adefovir in HBV infection

INTRODUCTION: Several nucleos(t)ide analogs (NUC) are available for the management of patients with chronic hepatitis B (CHB). In most patients, NUC need to be administered on a long-term basis, thus increasing the risk of adverse effects. Adefovir dipivoxil (ADV), the first nucloeotide analog developed to treat CHB, may indeed cause nephrotoxicity. AREAS COVERED: The pharmacokinetic mechanism of action, potential mechanism of renal damage and long-term safety profile of ADV in CHB patients have been reported. The current monitoring modalities, together with dosage adjustments, treatment of patients with ADV-related kidney impairment and the therapeutic algorithm in place at the authors' Liver Center are also summarized. Although, in short-term clinical trials, a daily dose of 10 mg of ADV was safe owing to a low rate of negligible nephrotoxic effects, the same dose may be associated with a usually reversible, proximal renal tubular toxicity as reflected by hypophosphatemia and elevated creatinine levels. Occasionally, Fanconi syndrome occurred in ADV-treated patients. EXPERT OPINION: Renal function at baseline and during treatment should be carefully assessed in all patients receiving ADV to adjust the dose according to creatinine clearance, aimed to prevent or minimize nephrotoxicity.     

Peak antifactor xa activity produced by dalteparin treatment in patients with renal impairment compared with controls

STUDY OBJECTIVE: To evaluate the relationship between impaired renal function and antifactor Xa activity in patients receiving dalteparin. DESIGN: Open-label prospective study. SETTING: Inpatient and outpatient units of a large teaching hospital. SUBJECTS: Eleven patients with renal impairment and 11 control subjects with normal renal function. INTERVENTION: Subjects were administered dalteparin at a dosage of approximately 100 U/kg subcutaneously every 12 hours. MEASUREMENTS AND MAIN RESULTS: Peak steady-state antifactor Xa levels were compared between the groups. Mean +/- SD levels were similar for patients with and without renal impairment: 0.47 +/- 0.25 and 0.55 +/- 0.20 U/ml, respectively. A test of equivalency showed statistical significance (p=0.0001). CONCLUSION: No meaningful difference in peak antifactor Xa activity was found between patients with renal impairment and control subjects. To the extent that peak antifactor Xa levels can be used as markers for adjusting doses of dalteparin, these data suggest that such adjustments are not necessary for patients with renal impairment who are not receiving dialysis.     

Pregnancy and renal failure: the case for application of dosage guidelines.

Pregnancies in women with renal disease, undergoing dialysis treatment or with kidney transplants are increasingly observed. Serious problems with drug dose adjustment may arise in pregnant women with renal impairment. This review gives a practical overview on the risks of drug use during gestation, the recommended drugs of choice (e.g. methyldopa, cyclosporin), and provides some proposals for dosage adjustments in pregnant women with renal impairment. In normal pregnancy, the glomerular filtration rate and plasma volume increase, whereas plasma protein binding and liver function may be impaired. An increase in dosage is needed for cyclosporin and for methadone because of increased hepatic clearance. The dosage of erythropoetin must be increased because of lower potency in pregnant women. Little more is known on the impact of gestation on drug dose, since pharmacokinetic studies are rarely done in pregnant women. The dosages of magnesium, lithium and morphine must be reduced in renal impairment. Dose adjustment to renal function is critical and is essential for anti-infective agents (e.g. ceftazidime, ganciclovir). Basing drug dose on estimated creatinine clearance might be the most practical solution in pregnant women with renal impairment.     

Antibacterial-induced nephrotoxicity in the newborn.

Antibacterials are the primary cause of drug-induced kidney disease in all age groups and these agents bring about renal damage by 2 main mechanisms, namely, direct and immunologically mediated. For some antibacterials (aminoglycosides and vancomycin) nephrotoxicity is very frequent but generally reversible upon discontinuation of the drug. However, the development of acute renal failure with these agents is possible and its incidence in the newborn seems to be increasing. Antibacterials are very often used in the neonatal period especially in very low birthweight neonates. The role of neonatal age in developing nephrotoxicity has still to be defined. Since the traditional laboratory parameters of nephrotoxicity are abnormal only in the presence of substantial renal damage, the identification of early non-invasive markers of the renal damage (urinary microglobulins, enzymes and growth factors) is of importance. Aminoglycosides and glycopeptides are still frequently used, either alone or in combination, despite their low therapeutic index. Numerous factors intervene in bringing about the kidney damage induced by these 2 classes of antibacterials, such as factors related to the antibacterial itself and others related to the associated pathology as well as pharmacological factors. Nephrotoxicity can be caused by the beta-lactams and related compounds. Their potential to cause nephrotoxicity decreases in the order: carbapenems > cephalosporins > penicillins > monobactams. Third generation cephalosporins are frequently used in neonates. However, they are well tolerated compounds at the renal level. The nephrotoxicity of other classes of antibacterials is not discussed either because they are only used in neonates in exceptional circumstances, for example, chloramphenicol and cotrimoxazole (trimethoprim-sulfamethoxazole) or are not associated with significant nephrotoxicity, for example macrolides, clindamicin, quinolones, rifampicin (rifampin) and metronidazole. Antibacterial-induced nephrotoxicity is an important parameter to be considered when treating the newborn and this is particularly true when use of a combination of different antibacterials and/or drugs with a nephrotoxic potential is being considered. However, other parameters, such as antibacterial spectrum, pharmacokinetics, post-antibacterial effect, clinical efficacy, general adverse effect profile and cost, must also be considered in the choice of antibacterial therapy in the neonate. Knowledge of the renal safety of antibacterials and the correct approach to therapeutic drug monitoring may be useful elements for preventing iatrogenic renal disorders.     

Drug safety evaluation of adefovir in HBV infection

Introduction: Several nucleos(t)ide analogs (NUC) are available for the management of patients with chronic hepatitis B (CHB). In most patients, NUC need to be administered on a long-term basis, thus increasing the risk of adverse effects. Adefovir dipivoxil (ADV), the first nucloeotide analog developed to treat CHB, may indeed cause nephrotoxicity.

Areas covered: The pharmacokinetic mechanism of action, potential mechanism of renal damage and long-term safety profile of ADV in CHB patients have been reported. The current monitoring modalities, together with dosage adjustments, treatment of patients with ADV-related kidney impairment and the therapeutic algorithm in place at the authors’ Liver Center are also summarized. Although, in short-term clinical trials, a daily dose of 10 mg of ADV was safe owing to a low rate of negligible nephrotoxic effects, the same dose may be associated with a usually reversible, proximal renal tubular toxicity as reflected by hypophosphatemia and elevated creatinine levels. Occasionally, Fanconi syndrome occurred in ADV-treated patients.

Expert opinion: Renal function at baseline and during treatment should be carefully assessed in all patients receiving ADV to adjust the dose according to creatinine clearance, aimed to prevent or minimize nephrotoxicity.     

Resurgence of colistin use.

PURPOSE: The role of colistin in the treatment of infections caused by multidrug-resistant gram-negative microorganisms is discussed. SUMMARY: Colistin is structurally and pharmacologically related to polymyxin B, the other commercially available drug from the polymyxin class. Colistin is bactericidal in nearly all strains of gram-negative bacilli. As with all antibiotics, resistance is of paramount concern. Resistance to colistin has not been frequently documented. Colistin must be administered parenterally, as it is not absorbed from the gastrointestinal tract, mucous membranes, or intact or denuded skin. Parenteral colistin has been replaced by less-toxic antibiotics and should be reserved for life-threatening infections caused by organisms resistant to preferred drugs. A number of published studies and case reports have reevaluated the safety and efficacy of parenteral colistin use in patients with multidrug-resistant infections. In three case series, 58-74% of patients exhibited a clinical response to colistin. Although colistin was previously viewed as reasonably effective but highly nephrotoxic, recent studies have suggested that nephrotoxicity may not be as severe as once thought. Frequent renal function monitoring is necessary in patients receiving colistin, since adverse renal effect may occur, regardless of the dosage given. The recommended dosage of parenteral colistin for adults and children with normal renal function is 2.5-5 mg/kg/day, administered as two to four divided doses. Doses must be adjusted for renal impairment, and dosing recommendations for patients undergoing renal replacement therapy have not been well established. CONCLUSION: With vigilant monitoring of renal function and the avoidance of concomitant neurotoxic medications, colistin can be used safely and effectively with minimal adverse outcomes.     

Effect of severe renal impairment on the pharmacokinetics of azimilide following single dose oral administration

AIMS: To assess the influence of severe renal impairment on azimilide pharmacokinetics. METHODS: A single oral dose of 125 mg azimilide dihydrochloride was administered to subjects with normal and severely impaired renal function. Blood and urine samples were collected for 22-28 and 10 days, respectively. RESULTS: Azimilide renal clearance decreased in subjects with renal impairment (mean 14 vs 4.8 ml h-1 kg-1, 95% confidence interval on the ratio 0.23, 0.50). However, no change in any other pharmacokinetic parameter including oral clearance (mean 109 vs 104 ml h-1 kg-1, 95% confidence interval on the ratio 0.67, 1.36) was observed. CONCLUSIONS: Since azimilide blood concentrations are essentially unaffected by renal function, an a priori dosage regimen adjustment is not required in patients with renal impairment.     

Differences in kinetic properties of drugs: implications as to the selection of a particular drug for use in patients with renal failure with special emphasis on antibiotics and beta-adrenoceptor blocking agents

Adjustment of dosage of a renally excreted drug (or active metabolite) for patients with severe renal failure still causes some difficulties. It is therefore helpful to select, within a given therapeutic group of drugs, a compound that is particularly safe and easy to use and, if possible, does not require adjustment of dosage. This is 'the drug of choice for renal patients'. Such a drug would ideally meet the following pharmacokinetic criteria: normal urinary excretion less than 30% of the administered dose, predominant biliary and intestinal removal, disposition essentially unaffected by parameters likely to be modified in renal failure (e.g. changes in serum proteins or fluid compartments: receptor sensitivity, etc), and pharmacokinetics not complicated by the formation of active or toxic metabolites that depend on urinary elimination. Above all, the drug should have a wide therapeutic margin and must be free of nephrotoxicity. Examples of drugs of choice for patients with impaired renal function are given for some important therapeutic groups and special emphasis is placed on antibiotics and beta-adrenoceptor blocking agents.     

Pharmacokinetics and pharmacodynamics of pegfilgrastim in subjects with various degrees of renal function

A phase I study was conducted to evaluate the effects of renal function on the pharmacokinetics and pharmacodynamics (absolute neutrophil count [ANC]) of pegfilgrastim in nonneutropenic subjects. Thirty subjects categorized into 5 renal function groups (normal, mildly impaired, moderately impaired, severely impaired, and end-stage renal disease) received 1 subcutaneous injection of pegfilgrastim at 6 mg. The ANC profiles after pegfilgrastim administration were similar across different renal function groups. No discernable correlation between pharmacokinetic parameter values and degree of renal impairment was observed; the mean values ranged from 147 to 201 ng/mL for C(max) and from 7469 to 8513 ng x h/mL for AUC. Results suggest that the kidney has no important role in the elimination of pegfilgrastim. Therefore, no dosage adjustment for renal impairment is indicated for pegfilgrastim.     

Pharmacodynamic dose adjustment in renal failure: importance of the Hill coefficient

OBJECTIVE: The most commonly applied pharmacodynamic model is the sigmoid E(max) model which can be applied for evaluation of dose adjustment schemes in renal failure. It is not known whether the Hill coefficient (H) is a shape factor that only improves the mathematical fit or whether the Hill coefficient is a pharmacodynamic parameter that independently affects drug effects and drug dosage adjustment. METHODS: We performed simulations applying a mechanism-based mathematical pharmacokinetic-pharmacodynamic model for antimicrobial drugs. For the case of renal failure, two dose adjustment rules were evaluated. RESULTS: Administering the drug as 3 dose fractions per day increased the predicted total effect in the case of H = 1 but decreased the predicted total effect in the case of H = 2 compared to once-daily dosing. In renal failure, administration of the normal dose and prolongation of the interval leads to an increased total effect for the simulated drugs for both cases, namely H = 1 and H = 2. However, reducing the dose in renal failure might produce underdosage for a drug with a high Hill coefficient. CONCLUSION: The predicted effects of once- versus thrice-daily dose fractions as well as the predicted effects of dose reduction versus interval prolongation in renal failure critically depend on the Hill coefficient. Methods to estimate the Hill coefficient more precisely should be explored.     

Tigecycline: a new glycylcycline antimicrobial agent.

PURPOSE: The pharmacology, spectrum of activity, pharmacokinetics, clinical efficacy, adverse events, dosage and administration, drug interactions, and place in therapy of tigecycline are reviewed. SUMMARY: Tigecycline is the first of a new class of antimicrobials, the glycylcyclines, to receive approved labeling from the Food and Drug Administration. Similar to tetracyclines, glycylcyclines contain the central four-ring carbocyclic skeleton, with a substitution at the D-9 position. This substitution confers expanded broad-spectrum activity and defense against antimicrobial efflux pumps and ribosomal protection mechanisms. Tigecycline covers a broad spectrum of gram-positive (including resistant isolates), gram-negative (including extended-spectrum beta-lactamase producing organisms), and anaerobic pathogens. It does not exhibit activity against Pseudomonas aeruginosa and Proteus species. Clinical efficacy has been demonstrated in complicated skin and skin structure infections and intraabdominal infections. Tigecycline is administered intravenously and exhibits linear pharmacokinetics. The drug does not undergo extensive metabolism and works independently of the cytochrome P-450 isoenzyme system and therefore does not affect medications metabolized by these enzymes. Tigecycline is administered as a 100-mg i.v. loading dose followed by 50 mg i.v. every 12 hours. Hepatic dosage adjustment is necessary for severe disease; however, no dosage adjustments are necessary for patients with renal impairment. CONCLUSION: Tigecycline is an alternative agent available for the treatment of resistant gram-negative and gram-positive infections, especially in patients with a history of a penicillin allergy or antimicrobial-related toxicities.     

Pharmacokinetics and safety of a single oral dose of once-daily alfuzosin, 10 mg,in male subjects with mild to severe renal impairment

The effect of renal impairment on the safety and pharmacokinetics of a once-daily formulation of alfuzosin, 10 mg, was evaluated. In an open, single-dose study, 26 volunteers, ages 18 to 65 years, were classified as having normal renal function (n = 8) or mild (n = 6), moderate (n = 6), or severe (n = 6) renal impairment. Mean Cmax values increased by a factor of 1.20, 1.52, and 1.20 in subjects with mild, moderate, or severe renal impairment, respectively, compared with controls. Values for AUC(0-infinity) were 1.46, 1.47, and 1.44, respectively. The t(1/2z) was increased only in the group with severe renal impairment. Emergent vasodilatory adverse events were reported by 4 of 26 subjects. No discontinuations due to adverse events occurred. Laboratory parameters were satisfactory in all groups. In conclusion, once-daily alfuzosin, 10 mg, could be safely administered to patients with impaired renal function, and dosage adjustment does not seem necessary.     

Antiretroviral drugs and the kidney: dosage adjustment and renal tolerance

BACKGROUND: Acquired immunodeficiency syndrome (AIDS)-related kidney disorders concern 30% of those patients and can lead to end-stage renal disease (ESRD; 0.6 to 1%). Therefore, administration of antiretroviral drugs in human immunodeficiency virus (HIV) patients with nephropathy is not uncommon. AIM OF THE REVIEW: Since renal insufficiency is not uncommon among HIV-infected patients treated with antiretroviral drugs, guidelines on how to use these drugs in the pattern of an altered renal function are mandatory. This review provides such guidelines established on the basis of pharmacokinetic and clinical studies reported in the international literature. In addition, some of these drugs may be nephrotoxic. Mechanisms and clinical and/or biological manifestations are reviewed to help monitor renal tolerance in patients receiving these drugs. CONCLUSION: Antiretroviral drugs' dosage in HIV-infected patients with altered renal function should be cautiously determined. Drug dosage should not be systematically reduced since dosage adjustment is not mandatory for all therapies (ie. protease inhibitors). Furthermore, when dose reduction is necessary, pharmacokinetic and clinical data from the literature allows to establish practical guidelines on how to use these drugs in such patients.     

Drug prescribing in renal failure.

Drug prescribing for patients with renal failure should incorporate adjustment of dosage regimens in order to avoid accumulation and thus adverse effects. Drugs usually eliminated by the kidneys require the most modification. Since immediate therapeutic efficacy is of importance, the initial or loading dose is essentially unaltered for patients with renal dysfunction. Maintenance doses can be adjusted by either lengthening the interval between doses of by reducing the size of individual doses. In clinical practice, a combination of both methods is used. Serum levels should be used as guides whenever possible. In interpreting these levels, recognition of decreased plasma protein binding and prolonged elimination half-lives in renal failure is imperative. In patients requiring dialysis, consideration must be given to adjustments for drug removal by the artificial membrane. Small molecules unbound to proteins are most easily removed. Specific guidelines for therapy with common drugs prescribed for patients with renal failure are given. These include: (1) narcotics and analgesics; (2) psychotherapeutic drugs; (3) cardiovascular drugs; and (4) antimicrobial agents.     

急性肾损伤并肺部感染患者的抗菌方案阶段性调整探析

目的：对急性肾损伤并肺部感染患者临床抗菌方案进行评价和调整。方法：利用PK/PD理论优化抗菌治疗的综合评价参数的定量范围,以及根据CCr值（内生肌酐清除率）对用药方案进行调整。结果及结论：急性肾损伤初期处于肾衰阶段的患者,CCr大幅下降,全程使用PIP/TAZ（哌拉西林/他唑巴坦）4.5 g q8h的给药方案,其给药剂量或给药频次明显超量。对该类患者,建议初期采用PIP/TAZ 4.5 g q24h～q36h的给药方案,逐步过渡到4.5 g q8h。     

Nephrotoxicity of N-(3,5-dihalophenyl)succinimides in Fischer 344 rats

Previous studies have demonstrated that N-(3,5-dichlorophenyl)succinimide (NDCPS) is the most nephrotoxic compound among the N-(mono- or dichlorophenyl)succinimides. The purpose of this study was to examine the nephrotoxic potential of the different N-(3,5-dihalophenyl)succinimides (NDHPS) to determine the importance of the halogen species for NDHPS-induced nephrotoxicity. Male Fischer 344 rats were administered a single intraperitoneal injection of an NDHPS (0.4, 0.8, or 1.0 mmol/kg) or vehicle (2.5 ml/kg), and renal function was monitored at 24 and 48 h. NDCPS or N-(3,5-diiodophenyl)succinimide administration produced the greatest nephrotoxic response. Nephrotoxicity was characterized by diuresis, increased proteinuria, glucosuria, increased kidney weight and blood urea nitrogen (BUN) concentration, decreased accumulation of p-aminohippurate (PAH) and tetraethylammonium (TEA) by renal cortical slices and proximal tubular necrosis. N-(3,5-Dibromophenyl)succinimide injection produced mild nephrotoxicity, while N-(3,5,-difluorophenyl)succinimide administration did not result in nephrotoxicity. These results indicate that the halogen species can influence the nephrotoxicity produced by the NDHPS. In addition, nephrotoxic potential did not correlate with fungicidal efficacy, which suggests that the nephrotoxic and fungicidal mechanisms of these compounds might be different.     

Azthreonam in the treatment of urinary tract infection: evaluation of efficacy, renal effects and nephrotoxicity

The efficacy, renal effects and nephrotoxicity of a short course of treatment with azthreonam were evaluated in 11 adult patients with urinary tract infection. Azthreonam was administered for 5 days at a daily dose adjusted to the residual renal function of the patients. In the pre-treatment period, during treatment and 10 days after completion of therapy, urine cultures, urinalysis and routine renal function tests (clearance of creatinine, urea and uric acid) were performed and urinary enzymes (alanine-aminopeptidase, gamma-glutamyl-transpeptidase, N-acetyl-beta-D-glucosaminidase, lysozyme) were determined. Renal haemodynamics (glomerular filtration rate and effective renal plasma flow) were measured in the pretreatment period and on the 5th day of therapy. The results confirm the efficacy of azthreonam for treatment of urinary tract infection. Results of renal function tests and measurements of urinary enzymes remained unchanged during and after treatment with azthreonam. These data support the conclusion that azthreonam is an effective antimicrobial agent which does not influence renal function or cause nephrotoxic effects.