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OBJECTIVE: To compare the relative bioavailability of a single atovaquone 750 mg suspension oral dose when administered in the fasting state, after a normal breakfast, and after an enteral nutrition supplement. DESIGN: Ten healthy volunteers received a single dose of atovaquone suspension 750 mg/5 mL while fasting. At 2-week intervals, the subjects were then randomized in a crossover design to receive the atovaquone dose within 1 hour of consuming a normal breakfast (fat content 21 g) and 16 oz. of Sustacal Plus (fat content 28 g). Blood samples were collected at seven time points after each atovaquone dose. HPLC was used to determine the atovaquone concentrations in plasma. RESULTS: Administering atovaquone suspension with either a normal breakfast or an enteral nutrition supplement, such as Sustacal Plus, significantly increased the oral relative bioavailability. The mean AUC0-24 after the fasting dose was 43.4 micrograms.h/mL. The mean AUC0-24 values with breakfast (103.8 micrograms.h/mL) and Sustacal Plus (118.8 micrograms.h/mL) were significantly greater compared with fasting (p < 0.0001). CONCLUSIONS: This study has shown that the new atovaquone oral suspension also has significantly greater bioavailability when administered after food or a nutrition supplement that has a moderate fat content. Patients who require atovaquone therapy can use Sustacal Plus without risk of reduced absorption.

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The serum disposition, antimicrobial activity, and stability of ceftazidime continuously infused with an elastomeric infusion device (Homepump, Block Medical) were studied. Twelve healthy adult volunteers were given a 500-mg bolus dose of ceftazidime infused i.v. over two minutes, followed by a continuous i.v. infusion of 3 g over 24 hours. Blood samples were drawn five minutes before and at intervals up to 24 hours after the start of the bolus infusion. Samples were collected from the infusers immediately before and at the end of the 24-hour infusion. Infusers were insulated with ice packs. Ceftazidime concentrations were determined by high-performance liquid chromatography. Minimum inhibitory concentrations (MICs), serum inhibitory titers (SITs), and serum bactericidal titers (SBTs) were determined by the microdilution technique. Mean +/- S.D. serum ceftazidime concentrations ranged from 39.50 +/- 6.92 micrograms/ml at peak (30 minutes after the start of the bolus infusion) to 15.30 +/- 2.83 micrograms/mL at trough (24 hours after the start). The ceftazidime MIC for Pseudomonas aeruginosa was 1 microgram/mL; this MIC was exceeded 100% of the time. Serum ceftazidime concentrations achieved a median SIT and SBT of 1:32 and 1:16, respectively, at 30 minutes and 1:8 and 1:8, respectively, at 24 hours. Six infusers met or exceeded the 24-hour infusion time; ceftazidime was stable in these infusers. A 500-mg i.v. bolus of ceftazidime followed by a continuous infusion (3 g over 24 hours) delivered by an elastomeric infusion device produced serum drug concentrations that were constantly above the MIC for P. aeruginosa and maintained serum bactericidal activity against that organism. Adequate stability of ceftazidime was ensured by placing an ice pack next to the infuser.

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Meta-analysis is increasingly performed to try and answer clinical questions around which controversy exists. We performed meta-analyses using three different methods as examples to illustrate problems and points to consider when doing such work. The questions of interest were comparing frequency of nephrotoxicity and clinical effectiveness with once-daily aminoglycoside regimens versus multiple-daily dose aminoglycoside regimens. Inclusion and exclusion criteria were established. Studies were obtained from literature searches, and included published studies and abstracts. The overall odds ratio (95% confidence interval) for nephrotoxicity and clinical effectiveness meta-analyses of these studies using the Mantel-Haenszel-Peto method were 0.70 (0.51-0.94, p = 0.042) and 0.79 (0.59-1.07, p = 0.09), respectively. Analyzing the data by Fisher's combined test and the Mean-P method showed agreement with the other methods' conclusions for nephrotoxicity but not for clinical effectiveness. Meta-analysis is not an exact procedure and contains various problems and inconsistencies. Combining studies of poor quality is not ideal for answering unresolved clinical questions.

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Zidovudine (ZDV) and clarithromycin (CLR) are often used simultaneously in the management of patients with AIDS. While pharmacokinetic studies show decreased absorption of ZDV when it is administered with CLR, it is unknown if CLR affects the intracellular metabolism of ZDV. We investigated the effects of CLR on the intracellular metabolism of ZDV in vitro. CEM-T4 cells were coincubated with a microM ZDV ([3 H] ZDV, 3 microCi/ml) either alone or with 1 or 10 microM CLR. Cells were also grown in the presence of CLR for 48 h prior to exposure to ZDV. Samples were analyzed for mono-, di-, and triphosphate metabolites of [3 H] ZDV by high-performance liquid chromatography separation and radiochemical detection. There were no significant differences in levels of intracellular metabolites of ZDV following exposure to ZDV, either alone or with 1 or 10 microM CLR and under both coincubated and preincubated conditions. These results show that treatment with CLR does not alter the formation of phosphorylated metabolites of ZDV in this cell line.

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The Society of Infectious Diseases Pharmacists (SIDP) is an organization, comprised mainly of Pharm D.s in academia, industry, and hospital practice, whose professional orientation is in the area of infectious disease pharmacotherapy. SIDP membership has deemed it necessary to produce position statements on issues of concern to the infectious disease community. This article is an overview of SIDP, along with a description of their guidelines for position statement development. The value of any organization's position statement(s) is influenced by a multitude of factors (e.g., author's expertise, accuracy, evidence, opinion, etc.); thus, some degree of scrutiny is advised.

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The pharmacodynamics of dosage regimens of piperacillin alone or in combination with tazobactam against piperacillin-resistant or -susceptible bacteria were studied in an in vitro model of infection. Experiments were conducted by using a fixed daily exposure of 12 g of piperacillin, given as 3 g alone or in combination with tazobactam at 0.375 g every 6 h, or the same total dose of the combination given as 4 g of piperacillin plus 0.5 g of tazobactam every 8 h. The addition of tazobactam to piperacillin, irrespective of the dosing interval, did not alter the killing of piperacillin-susceptible organisms (Escherichia coli J53 and Pseudomonas aeruginosa ATCC 27853). In contrast, experiments with an isogenic TEM-3-containing transconjugant of E. coli J53 (E. coli J53.2-TEM-3) that was resistant to piperacillin (MIC, 128 micrograms/ml) showed that the addition of tazobactam resulted in bacterial killing similar to that observed with the wild-type strain. Although tazobactam concentrations fell to less than 4 mg/liter (the concentration associated with a reduction in the piperacillin MIC from 128 to 2 mg/liter) 2 to 3 h after a dose, a similar degree of bacterial killing was observed when the same total 24-h dose of piperacillin-tazobactam was fractionated into dosing intervals of every 6 or 8 h. Investigations with Staphylococcus aureus 7176 (piperacillin MIC, 128 micrograms/ml) showed that the addition of tazobactam, again irrespective of dosing interval, also resulted in net bacterial killing which was not seen with piperacillin alone. These data support the use of extended dosing intervals (every 8 h) of piperacillin-tazobactam in the treatment of infections caused by piperacillin-resistant bacteria.

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