Caspofungin: Pharmacodynamics, pharmacokinetics, clinical uses and treatment outcomes.

Over the past decade, echinocandins have emerged as first-line antifungal agents for many Candida infections. The echinocandins have a unique mechanism of action, inhibiting the synthesis of ß-1,3-d-glucan polymers, key components of the cell wall in pathogenic fungi. Caspofungin was the first echinocandin antifungal agent to become licensed for use. The objectives of this review are to summarize the existing published data on caspofungin, under the subject headings of chemistry and mechanism of action, spectrum of activity, pharmacodynamics, pharmacokinetics, clinical studies, safety, drug interactions, dosing, and an overview of the drug's current place in therapy.

Efavirenz plasma concentrations and cytochrome 2B6 polymorphisms.

BACKGROUND: Interpatient variability in efavirenz concentrations may be due to CYP2B6 genetic polymorphisms. Efavirenz concentration and pharmacogenomic data are scarce in Latino patients. OBJECTIVE: To evaluate the difference in trough and midpoint efavirenz plasma concentrations between HIV-positive Latino and white patients. In addition, this study evaluated the association between efavirenz concentrations and CYP2B6 polymorphisms in Latino and white HIV-positive subjects. METHODS: This pilot study included 10 Latinos and 10 whites. Two efavirenz blood concentrations were determined: a trough and a midpoint. CYP2B6 genetic polymorphisms were analyzed at the 516 (G to T) and 785 (A to G) codons. The Mann-Whitney test was used to determine whether efavirenz concentrations varied with ethnicity. The Kruskal-Wallis test was used to determine whether efavirenz concentrations varied with CYP2B6 genetic polymorphisms. Efavirenz concentrations were expressed as medians (minimum, maximum). RESULTS: Midpoint concentrations were 1.58 µg/mL (1.36, 6.02) and 3.14 µg/mL (1.74, 7.72) for whites and Latinos, respectively (p < 0.05). Trough concentrations did not vary as a function of ethnicity. Ten percent of Latinos and whites tested positive for homozygous variants of CYP2B6-516 and CYP2B6-785. One white subject tested positive for the homozygous variant of CYP2B6-1459. Trough concentrations for 516TT, 516GT, and 516GG (wild type) were 5.13 µg/mL (4.13, 6.12), 2.13 µg/mL (1.33, 3.37), and 1.44 µg/mL (0.59, 2.92), respectively (p < 0.05). Trough concentrations for 785GG, 785AG, and 785AA (wild type) were 5.12 µg/mL (4.13, 6.12), 1.98 µg/mL (1.33, 3.37), and 1.27 µg/mL (0.59, 2.92), respectively (p < 0.05). None of the patients took concomitant medications that impacted CYP2B6 metabolism. CONCLUSIONS: Trough efavirenz concentrations were significantly higher in patients with the 785 (A to G) and 516 (G to T) variants. Midpoint efavirenz concentrations in Latinos were significantly higher than those of whites.

Use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population.

PURPOSE: The use of maximum-dose simvastatin or atorvastatin in an ethnically diverse population was studied. METHODS: This retrospective analysis was conducted at a publicly funded teaching institution whose predominant patient population consists of Hispanics and Asians. A computer-generated report was used to identify outpatients who received a prescription for maximum-dose simvastatin or atorvastatin between January 1, 2002, and January 1, 2004. Data evaluated included demographic information; metabolic syndrome elements; coronary heart disease (CHD) risk equivalents; clinical characteristics placing patients at very high risk of having a CHD event; 10-year Framingham risk score; documentation of hepatotoxicity, myalgia, myositis, or rhabdomyolysis during maximum-dose therapy; concomitant medication during maximumdose therapy; relevant laboratory test values; and physician response to biochemical abnormalities or adverse events associated with maximum-dose therapy. RESULTS: Of the 232 outpatients identified, 173 were eligible for study inclusion. A total of 135 patients were classified as having a high or very-high risk of developing CHD (68 and 67, respectively). The success rates for low-density-lipoprotein (LDL) cholesterol goal attainment by very-high-risk patients and high-risk patients were 19.4% and 44.1%, respectively. Thirteen patients developed myalgia. Alanine transaminase levels were monitored for 38.8% of the study patients. Approximately 9% of patients were prescribed one interacting medication while on maximum-dose simvastatin or atorvastatin. The most commonly prescribed interacting drug was gemfibrozil. CONCLUSION: Despite the use of maximum-dose simvastatin or atorvastatin, target LDL cholesterol goals were not achieved and statin use was not adequately monitored in an ethnically diverse population with a high or very high risk of developing CHD.

Hepatotoxicity of antifungal agents.

Antifungal agents have been implicated in numerous cases of hepatotoxicity throughout the past few decades. Hepatotoxic reactions to antifungal agents range from slight, asymptomatic abnormalities in liver function tests to potentially fatal fulminant hepatic failure. Clinically significant hepatic injury resulting from antifungal therapy most commonly manifests as acute hepatocellular, cholestatic or mixed hepatocellular-cholestatic reactions. In general, reactions usually resolve on cessation of therapy, but some antifungal agents may induce chronic liver damage. This review will summarize the hepatotoxicity profiles of the major classes of antifungal agents and will provide recommendations for drug monitoring in order to minimize the risk of hepatotoxicity.

Ertapenem-associated seizures in a peritoneal dialysis patient.

OBJECTIVE: To report a case of a patient undergoing peritoneal dialysis who developed refractory seizures after 2 doses of ertapenem. CASE SUMMARY: A 56-year-old white man with end-stage renal disease requiring continuous ambulatory peritoneal dialysis experienced 5 seizures following 2 doses of ertapenem 500 mg given intravenously. The first generalized tonic-clonic seizure occurred 16 hours after the second ertapenem dose and lasted 3 minutes. Three hours after his first seizure, the patient experienced 2 more seizures 15 minutes apart, lasting 3 minutes each. After suffering a fifth seizure, the patient became apneic and pulseless and was not resuscitated, as he had previously requested a "do not resuscitate" status. DISCUSSION: Carbapenem treatment has been associated with simple partial, complex partial, and generalized tonic-clonic seizures, with generalized seizures representing the most frequently occurring type. Safety data from 7 published clinical trials of ertapenem revealed a seizure incidence of 0.18%. To our knowledge, there are no previously published reports of ertapenem neurotoxicity in patients undergoing peritoneal dialysis. Moreover, little information is available regarding the pharmacokinetics of carbapenems in end-stage renal disease. Ertapenem pharmacokinetics were not tested in any patients receiving peritoneal dialysis during published clinical trials. CONCLUSIONS: Our patient experienced 5 seizures, possibly induced by ertapenem, as validated by the Naranjo probability scale. Clinicians administering ertapenem to patients undergoing peritoneal dialysis should use caution, as clinical experience with the agent is limited and pharmacokinetic data are lacking.

Anaphylactoid reaction to ciprofloxacin.

OBJECTIVE: To report a case of anaphylactoid reaction in an HIV-negative patient associated with the administration of intravenous ciprofloxacin. CASE SUMMARY: A 79-year-old Armenian man developed an anaphylactoid reaction following a first-time exposure to intravenous ciprofloxacin. This reaction was characterized by severe hypotension, wheezing, tachypnea, tachycardia, and pruritus. The patient had complete recovery once ciprofloxacin treatment was terminated and supportive care was provided. DISCUSSION: Fluoroquinolones are important therapeutic agents in the management of infectious diseases and are generally safe and well tolerated. Anaphylactoid and anaphylactic reactions have been documented as adverse effects of ciprofloxacin, ofloxacin, norfloxacin, levofloxacin, and moxifloxacin. To date, >33 cases have been reported with ciprofloxacin, of which at least 10 occurred in HIV-positive patients. In Europe, 15 cases of anaphylactoid reactions to ofloxacin have been reported and, more recently, with moxifloxacin. Since anaphylactoid reactions are potentially life threatening, the administration of fluoroquinolones to patients who have experienced a prior reaction to any of these agents should be avoided, unless tolerance has been confirmed by oral challenge tests. CONCLUSIONS: The anaphylactoid reaction in our patient was probably induced by ciprofloxacin as validated by the Naranjo probability scale. Although anaphylactoid/anaphylactic reactions are rare adverse effects of ciprofloxacin and other fluoroquinolones, clinicians should be aware of this potentially fatal event.

Clinical pharmacokinetics and selective pharmacodynamics of new angiotensin converting enzyme inhibitors: an update.

The angiotensin converting enzyme (ACE) inhibitors are widely used in the management of essential hypertension, stable chronic heart failure, myocardial infarction (MI) and diabetic nephropathy. There is an increasing number of new agents to add to the nine ACE inhibitors (benazepril, cilazapril, delapril, fosinopril, lisinopril, pentopril, perindopril, quinapril and ramipril) reviewed in this journal in 1990. The pharmacokinetic properties of five newer ACE inhibitors (trandolapril, moexipril, spirapril, temocapril and imidapril) are reviewed in this update. All of these new agents are characterised by having a carboxyl functional groups and requiring hepatic activation to form pharmacologically active metabolites. They achieve peak plasma concentrations at similar times (t(max)) to those of established agents. Three of these agents (trandolapril, moexipril and imidapril) require dosage reductions in patients with renal impairment. Dosage reductions of moexipril and temocapril are recommended for elderly patients, and dosages of moexipril should be lower in patients who are hepatically impaired. Moexipril should be taken 1 hour before meals, whereas other ACE inhibitors can be taken without regard to meals. The pharmacokinetics of warfarin are not altered by concomitant administration with trandolapril or moexipril. Although imidapril and spirapril have no effect on digoxin pharmacokinetics, the area under the concentration-time curve of imidapril and the peak plasma concentration of the active metabolite imidaprilat are decreased when imidapril is given together with digoxin. Although six ACE inhibitors (captopril, enalapril, fosinopril, lisinopril, quinapril and ramipril) have been approved for use in heart failure by the US Food and Drug Administration, an overview of 32 clinical trials of ACE inhibitors in heart failure showed that no significant heterogeneity in mortality was found among enalapril, ramipril, quinapril, captopril, lisinopril, benazepril, perindopril and cilazapril. Initiation of therapy with captopril, ramipril, and trandolapril at least 3 days after an acute MI resulted in all-cause mortality risk reductions of 18 to 27%. Captopril has been shown to have similar morbidity and mortality benefits to those of diuretics and beta-blockers in hypertensive patients. Captopril has been shown to delay the progression of diabetic nephropathy, and enalapril and lisinopril prevent the development of nephropathy in normoalbuminuric patients with diabetes. ACE inhibitors are generally characterised by flat dose-response curves. Lisinopril is the only ACE inhibitor that exhibits a linear dose-response curve. Despite the fact that most ACE inhibitors are recommended for once-daily administration, only fosinopril, ramipril, and trandolapril have trough-to-peak effect ratios in excess of 50%.