The influence of food on itraconazole pharmacokinetics was evaluated for 27 healthy male volunteers in a single-dose (200 mg) crossover study with capsules containing itraconazole-coated sugar spheres. This study was followed by a study of the steady-state pharmacokinetics for the same subjects with 15 days of administration of itraconazole at 200 mg every 12 h. Concentrations of itraconazole and hydroxyitraconazole, the active main metabolite, were measured in plasma by high-performance liquid chromatography. The results of the food interaction segment showed that a meal significantly enhances the amount of itraconazole absorbed. The mean maximum concentration in plasma of unmetabolized itraconazole after fasting (140 ng/ml) was about 59%o that after the standard meal (239 ng/ml). The rate of elimination was not affected (terminal half-life, approximately 21 h). The mean maximum concentration in plasma of hydroxyitraconazole after fasting was about 72% the postmeal concentration (287 and 397 ng/ml, respectively). The terminal half-life of hydroxyitraconazole was approximately 12 h. Steady-state concentrations of itraconazole and hydroxyitraconazole were reached after 14 or 15 days of daily dosing. The average steady-state concentrations were approximately 1,900 ng/ml for itraconazole and 3,200 ng/ml for hydroxyitraconazole. The shape of the elimination curve for itraconazole after the last dose was indicative of saturable elimination. This conclusion was confirmed by the sevenfold increase in the area under the curve from 0 to 12 h at steady state compared with the area under the curve from 0 h to infinity after a single dose. It was furthermore confirmed by the larger-than-expected number of half-lives required to achieve steady-state plasma drug levels.

The term “dementia” describes various neurodegenerative disorders that effect cognition, including Alzheimer disease, vascular dementia, and others. This article reviews the diagnosis and management of common types of dementia and comorbidities. Dementias are differentiated clinically by history, symptom presentation, and exclusion of other causes through laboratory and imaging studies. Cholinesterase inhibitors are useful but may not be effective for all types of dementia and provide only modest benefits. Certain medical comorbidities may increase the risk of dementia, although genetics are also important in its etiology. Psychiatric comorbidities in dementia include delirium, which is treated primarily by addressing underlying medical disorders, but antipsychotics can be useful for symptom management and patient comfort. Nonpharmacologic interventions are first-line treatments for other psychiatric comorbidities, although drug therapy may be useful in some cases. The management of patients with dementia presents many challenges and will continue to do so unless agents with pronounced disease-modifying capabilities are developed.

To better define the pharmacokinetics and serum bactericidal activity (SBA) of ciprofloxacin and other antimicrobial agents in the elderly, six healthy elderly (>65 years) volunteers with normal renal function were given ciprofloxacin alone orally, ciprofloxacin plus rifampin orally, ciprofloxacin plus clindamycin orally, rifampin alone orally (three volunteers), and, for comparison of SBA against gram-positive cocci, vancomycin intravenously. Mean peak ciprofloxacin concentrations and other pharmacokinetic parameters were not altered significantly by coadministration of either rifampin or clindamycin. Ciprofloxacin had somewhat greater SBA against the oxacillin-susceptible and oxacillin-resistant Staphylococcus aureus strains tested than did vancomycin, but rifampin was by far the most active single agent tested. The SBA of rifampin against S. aureus was modestly antagonized during combination therapy with ciprofloxacin, but substantial SBA still was present. The ciprofloxacin SBA against S. aureus was completely antagonized by clindamycin if the strains were susceptible to the latter agent. Ciprofloxacin had modest SBA against group A streptococci and no SBA against the three pneumococcal strains tested. All of the regimens had poor to absent SBA against Enterococcus faecalis. By contrast, ciprofloxacin had excellent SBA against Escherichia coli and Klebsiella pneumoniae and moderate SBA against Pseudomonas aeruginosa. Combination therapy with rifampin or clindamycin in general enhanced the SBA against the nonenterococcal streptococci and had no effect on the SBA against the gram-negative bacilli.

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To better define the pharmacokinetics and serum bactericidal activity (SBA) of the expanded-spectrum cephalosporins in the elderly, we administered single 2-g intravenous infusions of cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime to six healthy volunteers over the age of 65 years. Serum was collected over 24 h, and concentrations were determined by high-performance liquid chromatography; pharmacokinetic parameters were determined for each drug. SBA was measured against representative strains of Staphylococcus aureus, Escherichia coli, KiebsieUa pneumoniae, Enterobacter aerogenes, and Pseudomonas aeruginosa. All agents tested had excellent SBAs against E. coil and K. pneumoniae, often for a longer duration than would be expected on the basis of conventional dosing regimens. Ceftazidime had the greatest SBA against E. aerogenes and was the only agent with a substantial SBA against P. aeruginosa. Although ceftizoxime had the greatest SBA against S. aureus, none of these cephalosporins had substantial antistaphylococcal SBAs. Pharmacokinetic analysis revealed that cefoperazone and ceftriaxone had markedly different concentration-time profiles in the elderly volunteers than would have been expected on the basis of existing data from younger volunteers. For older patients, dosing guidelines for these two agents may need to be altered.The broad-spectrum cephalosporins cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime are administered commonly to elderly patients. Although the pharmacokinetics of these cephalosporins have been well studied (1), there have been no crossover pharmacokinetic trials in the elderly.Conventional in vitro susceptibility tests measure only inhibitory antimicrobial activity under standard laboratory conditions. An alternative to conventional susceptibility tests, the serum bactericidal test (SBT), may provide a more meaningful measure of the potential usefulness of antimicrobial agents (7,22,43,47,(52)(53)(54). The SBT takes into consideration the achievable concentration of the antimicrobial agent in serum as well as its inherent antibacterial activity, and guidelines for a standard test method have been published recently (35). In studies in which serum bactericidal testing has been used in young volunteers, differences in the broad-spectrum cephalosporins have been shown, including pharmacokinetics, in vitro activity, and serum bactericidal activity (SBA) (3,4,15,17,18,23,38,49,50). Although elderly individuals may exhibit altered metabolism and pharmacokinetics of these antimicrobial agents (1,19,21,24,26,27,(31)(32)(33)42), no studies of SBA have been done in this population. Therefore, we administered single 2-g doses of cefoperazone, cefotaxime, ceftriaxone, ceftazidime, and ceftizoxime to six healthy elderly volunteers and studied both the pharmacokinetics and SBAs of these agents.* Corresponding author. MATERIALS AND METHODSStudy subjects. Six healthy elderly volunteers (three males, three females) participated in the study. They had the following...