Multiple dose pharmacokinetics, safety, and effects on faecal microflora, of cefepime in healthy volunteers.

In a randomized, double-blind, placebo-controlled study in 12 healthy volunteers pharmacokinetics, safety and impact on the faecal microflora of cefepime were determined. For eight days eight volunteers received cefepime 1000 mg bd by constant infusion over 30 min, four volunteers received placebo. Concentrations of cefepime in serum and urine were measured by bioassay and HPLC. The correlation between the two methods was good and the bioassay results were used for pharmacokinetic calculations. The faecal flora was analysed twice before the study, twice during the study and four times after cefepime administration. There were no significant differences in the pharmacokinetic parameters between days 1 and 8. The following values (mean +/- S.D.) represent day 1. The maximum concentration of 72.69 +/- 12.2 mg/L immediately after infusion decreased to 0.56 +/- 0.17 mg/L after 12 h. The mean 12 h recovery in urine was 93.69 +/- 2.14%. Pharmacokinetic parameters based on an open two-compartment model were as follows (mean +/- S.D.): area under the curve, 142.65 +/- 18.35 mg.h/L; elimination half-life 110.3 +/- 8.3 min; steady state volume of distribution 16.0 +/- 1.9 L/70 kg; total clearance, 107.0 +/- 16.0 mL/min; renal clearance 103.0 +/- 15.2 mL/min. No accumulation was observed during the eight day study period with cefepime at this dosage; trough levels on days 2-7 ranged from 0.52 +/- 0.26 mg/L to 0.90 +/- 0.33 mg/L. In the cefepime treated group the following side-effects were noted: headache (5), fatigue (4), nausea/stomach ache (2), soft stool (2), transient scotoma (1). Side-effects in the placebo group were: headache (2) fatigue (3), nausea/stomach-ache (1), soft stool (2) and photophobia (1). During cefepime administration a decrease in the number of Escherichia coli and bifidobacteria in faeces was observed, whereas Bacteroides spp. and clostridia showed a slight increase. The numbers of faecal bacteria returned to normal 20 to 48 days after the study was completed.     

Comparison of the effects of food on the pharmacokinetics of cefprozil and cefaclor.

The objective of this study was to assess the effects of food on the pharmacokinetics of cefprozil and cefaclor. A group of 12 healthy male volunteers received a single 250-mg dose of cefprozil or cefaclor under fasting conditions as well as after the intake of food. There was a 1-week washout period between each treatment. Serial blood samples were collected and assayed for cefprozil or cefaclor by specific high-pressure liquid chromatographic methods. The mean +/- standard deviation peak concentration (Cmax) of cefprozil in plasma was 6.13 +/- 1.22 micrograms/ml under the fasting condition and 5.27 +/- 1.06 micrograms/ml after breakfast, and these values were not significantly different from each other. The corresponding median time to reach Cmax was prolonged after food intake, but this difference was not significant. The mean Cmax values of cefaclor decreased significantly from 8.70 +/- 2.72 micrograms/ml under the fasting condition to 4.29 +/- 1.52 micrograms/ml after breakfast, and the corresponding median times to reach Cmax were significantly prolonged. The mean half-lives of cefprozil and cefaclor were nearly identical for the two treatments, suggesting that the elimination kinetics of these cephalosporins remained unaltered when the drugs were administered with food. The area under the plasma-concentration-versus-time curves for fasted and fed conditions were not significantly different for both drugs. The results of this study indicate that the extent of absorption and rate of elimination of both cephalosporins remain unaltered in the presence of food. However, the absorption rate of cefaclor is significantly reduced in the presence of food, while that of cefprozil remains unaltered. As a result, the Cmax of cefaclor is significantly reduced in the presence of food, whereas that of cefprozil is not significantly affected. Cefprozil can be administered with a meal without markedly affecting levels in blood.     

Absolute bioavailability of cefprozil after oral administration in beagles.

The absolute bioavailability of cefprozil, a new oral cephalosporin, in four beagles was evaluated. In this two-way crossover study, each dog received a 125-mg dose of cefprozil either as an oral aqueous solution or as a 15-min intravenous infusion. A high-performance liquid chromatographic assay with UV detection was employed for the determination of cefprozil concentrations in plasma and urine. Key pharmacokinetic parameters were calculated by noncompartmental methods. Cefprozil was well absorbed after oral administration, and peak concentrations of 17.6 to 26.6 micrograms/ml were attained at 60 min after drug administration. The apparent elimination half-life of cefprozil was about 70 min. The renal clearance was about 60% of total body clearance and is suggestive of significant nonrenal clearance. The absolute bioavailability of cefprozil ranged from 67.1 to 79.1% in the dogs.     

Comparative efficacy and safety of cefprozil and cefaclor in the treatment of acute uncomplicated urinary tract infections.

Cefprozil is a new oral semi-synthetic cephalosporin with broad antibacterial spectrum and prolonged serum elimination half-life. In vitro, cefprozil demonstrates excellent activity against common urinary tract pathogens such as Escherichia coli and Klebsiella pneumoniae. Cefprozil, 500 mg once a day, was compared to cefaclor, 250 mg three times a day, in an open, randomized, comparative, clinical trial for the treatment of acute, uncomplicated, urinary tract infection. One hundred and two adult patients were eligible for safety evaluation; four patients were excluded due to side-effects (abdominal discomfort, nausea and vomiting). Ninety-eight patients were eligible for evaluation of efficacy. Clinical and bacteriological responses were comparable for both antibiotics. Leucopenia, nausea, and vaginal yeast infections were slightly more common in the cefprozil group. Cefprozil, 500 mg once daily, appears to be an appropriate alternative for the treatment of acute, uncomplicated urinary tract infections.     

Comparative efficacy and safety of cefprozil (BMY-28100) and cefaclor in the treatment of acute group A beta-hemolytic streptococcal pharyngitis.

Cefprozil (BMY-28100) is a semisynthetic cephalosporin with broad-spectrum antibacterial activity and prolonged serum elimination half-life allowing for once-a-day oral administration. In vitro, cefprozil demonstrates excellent activity against Staphylococcus aureus, Streptococcus pyogenes, Haemophilus influenzae, and Moraxella catarrhalis. Cefprozil (500 mg once daily) was compared to cefaclor (250 mg three times daily) in an open, randomized, comparative trial for the treatment of acute group A beta-hemolytic streptococcal pharyngitis. Ninety-four patients were enrolled in this study; 53 patients were evaluable for clinical and bacteriological response assessment. Seventy-eight patients were evaluable for safety assessment. Three patients (all in the cefprozil treatment group) required disenrollment because of side effects, mainly nausea. Clinical and bacteriological responses were comparable for both study drugs. Leukopenia and nausea, the most common side effects observed, were more common in the cefprozil-treated group. Cefprozil appears to be an appropriate alternative to cefaclor for the treatment of acute group A beta-hemolytic streptococcal pharyngitis. However, because of the small number of patients eligible for efficacy assessment, a large type II (beta) error was expected in our study, which may have resulted in a potential failure to detect a difference between both treatment groups. A larger study would be required to determine the proper role of cefprozil in the treatment of group A beta-hemolytic streptococcal infections.     

Multiple-dose pharmacokinetics of ceftazidime and its influence on fecal flora.

Eight healthy volunteers each received 2.0 g of ceftazidime by constant intravenous infusion over 20 min twice daily every 12 h for 8 days. Concentrations of ceftazidime in serum and urine were measured by a microbiological assay and by high-pressure liquid chromatography. Qualitative and quantitative studies on aerobic and anaerobic fecal flora were carried out before, during, and 2 weeks after the end of treatment. The mean (+/- standard deviation) maximum drug concentration in serum at the end of the 20-min infusion (day 1) was 185.5 +/- 28.5 micrograms/ml, decreasing to 0.8 +/- 0.4 microgram/ml after 12 h. The mean recovery of drug in urine at 12 h was 71.5 +/- 12.2%. Pharmacokinetic parameters calculated on the basis of a two-compartment model were as follows: elimination half-life, 110.5 +/- 15.2 min; volume of distribution at steady state, 21.2 +/- 2.6 liters/100 kg; volume of distribution by the area method, 26.2 +/- 4.0 liters/100 kg; area under the serum concentration-time curve, 293.3 +/- 47.8 micrograms X h/ml; total body clearance, 116.4 +/- 20.3 ml/min per 70 kg; renal clearance, 82.2 +/- 15.1 ml/min per 70 kg. The agar diffusion test and high-pressure liquid chromatographic analysis showed a good correlation of results. Metabolites of ceftazidime could not be detected by high-pressure liquid chromatography in serum or urine. No accumulation of ceftazidime could be observed during the 8-day study period. Mean maximum drug levels in serum were 185.5 to 214.5 micrograms/ml, and mean trough levels were 0.8 to 1.1 micrograms/ml (days 1 to 8). No severe side effects were noted. During ceftazidime treatment, anaerobes were left intact, whereas members of the family Enterobacteriaceae could be isolated from stool in only three of eight subjects. Two weeks after discontinuation of the drug, all stool specimens contained ampicillin- and cefazolin-resistant gram-negative rods.     

Pharmacokinetics of single-dose cefmetazole following intramuscular administration of cefmetazole sodium to healthy male volunteers.

The tolerance and pharmacokinetics of cefmetazole were studied in healthy male volunteers who received a placebo (sterile saline) or a single dose of cefmetazole sodium intramuscularly. Drug-treated volunteers received one of four doses, 0.375, 0.750, 1, or 2 g. The drug was well tolerated, with no adverse medical events or laboratory changes observed during the study that could affect the pharmacokinetic interpretation of the data. Cefmetazole concentrations were determined by using a specific high-performance liquid chromatographic method. Serum cefmetazole concentrations were well described by a one-compartment open model with first-order absorption and elimination. Cefmetazole was rapidly absorbed in most volunteers, with a mean time to maximum concentration in serum of 1.24 +/- 0.12 h (+/- standard error of the mean), and the mean maximum concentration in serum increased from 17.0 +/- 1.6 to 74.2 +/- 9.5 micrograms/ml over the 0.375- to 2-g dose range. Maximum concentrations in serum, areas under serum concentration-time curve, and urinary excretion of intact drug increased in proportion to cefmetazole sodium dose. Times at which maximum concentrations in serum occurred, apparent volumes of distribution, steady-state volumes of distribution, absorption and elimination half-lives, and systemic clearances did not change significantly (P greater than 0.05) with drug dose. Although absorption and elimination half-lives were not significantly different in 10 of 40 volunteers (P greater than 0.05), in a majority of subjects elimination half-lives were approximately 10 times longer than absorption half-lives. The mean recovery of intact drug in urine ranged from 68.8 to 86.0% over the dose range studied, with a mean recovery over all doses of 77.1 +/- 2.4%. Rental clearances were significantly lower (P < 0.05) for the two lowest doses (93.0 and 84.3 versus 115.0 and 118.0 ml/min); these differences are not considered clinically important. The results of this study indicate that cefmetazole pharmacokinetics are linear after administration of single intramuscular doses ranging from 0.375 to 2 g, that clinically relevant concentrations of cefmetazole in serum (1 to 2 micrograms/ml) persist in a majority of volunteers for more than 8 h after administration of 0.750-g or higher doses, and that clinically relevant concentrations of cefmetazole continue to be excreted in urine 8 to 12 h after administration of 0.375- to 2-g doses.     

Impairment of mycophenolate mofetil absorption by iron ion

OBJECTIVE: We sought to evaluate the effect of iron ion on the absorption of mycophenolate mofetil, which is an immunosuppressive agent. The pharmacokinetics of mycophenolic acid were studied. METHODS: A randomized crossover design with two phases was used. A 7-day washout period separated the two treatment conditions. In the first phase, the volunteers received 1.0 g of mycophenolate mofetil alone (study 1); in the second phase, the volunteers received 1.0 g of mycophenolate mofetil and 2 tablets of iron ion preparations concomitantly (study 2). The serum concentration of mycophenolic acid, which is a pharmacologically active metabolite, was measured by reverse-phase HPLC. RESULTS: The area under the plasma concentration-time curve from 0 to 12 hours and the maximum concentration of mycophenolic acid in study 2 were significantly less than in study 1 (area under the curve, 32.9 +/- 14.7 versus 2.92 +/- 0.883 microg x h/mL, P < .001, maximum concentration, 20.1 +/- 9.21 versus 1.30 +/- 0.367 microg x h/mL, P < .001). CONCLUSIONS: This finding shows that when mycophenolate mofetil and iron ion preparations were administered concomitantly, a remarkable decrease of mycophenolate mofetil absorption was observed. Therefore it seems to be clear that we must avoid the concomitant administration of mycophenolate mofetil and iron ion preparations.     

Excretion of cefprozil into human breast milk.

The excretion of cefprozil into breast milk in nine healthy, lactating female subjects was investigated. Each subject received a single 1,000-mg oral dose of cefprozil consisting of cis and trans isomers in an approximately 90:10 ratio. Serial blood, urine, and breast milk samples were collected and analyzed for the concentrations of the cis and trans isomers by a specific high-pressure liquid chromatography-UV assay. The mean pharmacokinetic parameters for both isomers were essentially the same. The mean peak concentrations in plasma for the cis isomer were 14.8 micrograms/ml, and the area under the concentration curve was 54.8 micrograms.h/ml. The mean values of elimination half-life, renal clearance, and urinary excretion for the cis isomer were 1.69 h, 164 ml/min, and 60%, respectively. The mean concentrations in milk of the cis isomer over a 24-h period ranged from 0.25 to 3.36 micrograms/ml, with the maximum concentration appearing at 6 h after dosing. The average maximum concentration in milk of the trans isomer was less than 0.26 micrograms/ml. The concentrations of the trans isomer in plasma and in breast milk were about 1/10 of those for the cis isomer. Less than 0.3% of the dose was excreted in breast milk for both isomers of cefprozil. Even if one assumes that the concentration of cefprozil in milk remains constant at 3.36 micrograms/ml (the highest concentration of cefprozil observed in breast milk), an infant ingesting an average of 800 ml of milk per day will be exposed to a maximum amount of about 3 mg of cefprozil per day. This value represents about 0.3% of the maternal dose. Low excretion of cefprozil in breast milk and the excellent safety profile of cefprozil suggest that this cephalosporin may be administered to nursing mothers when indicated.     

Penetration of cefprozil into middle ear fluid of patients with otitis media.

Penetration of cefprozil into the middle ear fluid was investigated in patients with chronic otitis media. A total of 89 patients ranging from 7 months to 11 years old participated in the study. The middle ear fluid was removed by ventilation tubes inserted through the tympanic membrane at times ranging from 0.38 to 5.97 h after oral administration of a single dose of 15 or 20 mg/kg of body weight. A blood sample was also collected as soon as the middle ear fluid was removed. Plasma samples were analyzed for the concentration of cefprozil by a high-performance liquid chromatographic assay. Middle ear fluid samples were analyzed for the concentration of cefprozil by a microbiological assay. The concentrations of cefprozil in plasma ranged from 0.38 to 15.97 micrograms/ml at the 15-mg/kg dose level and from 1.28 to 21.47 micrograms/ml at the 20-mg/kg dose level. The corresponding middle ear fluid concentrations of cefprozil ranged from 0.06 to 4.44 micrograms/ml and from 0.17 to 8.67 micrograms/ml, respectively. Cefprozil penetrates well into middle ear fluid in patients with chronic otitis media.     

Pharmacokinetics of dirithromycin in patients with mild or moderate cirrhosis.

The pharmacokinetics of dirithromycin were determined over a 72-h period following oral administration of a single 500-mg dose to 8 healthy volunteers and to 16 cirrhotic patients (8 patients with class A cirrhosis and 8 patients with class B cirrhosis according to Pugh's & Child's classification). Drug levels in plasma and urine were determined by microbiological assay. The mean maximum concentrations of drug in serum obtained 3 to 4 h after administration were 0.29 +/- 0.22 mg/liter in volunteers and 0.48 +/- 0.21 and 0.52 +/- 0.38 mg/liter in patients with class A and class B cirrhosis, respectively. The elimination half-life (t1/2beta) was 23.3 +/- 7.6 h in healthy subjects and 35.2 +/- 11.8 h and 39.5 +/- 11.0 h in patients with class A and class B cirrhosis, respectively. The mean area under the concentration-time curve (AUC) and t1/2beta were significantly higher in patients with class A and B cirrhosis than in healthy controls, while total and renal clearances were markedly reduced (P < 0.01). The time to the maximum concentration of drug in serum and the volume of distribution values appeared to be similar in all groups, and the mean recovery in urine at 72 h ranged from 3.7 to 5.7%, without significant differences among groups. These results demonstrate that some dirithromycin kinetic parameters are significantly different in cirrhotic patients in comparison to those in healthy volunteers. However, an increase in the t1/2beta or AUC, which is also observed with other semisynthetic macrolides (e.g., azithromycin), does seem to be not clinically relevant if one takes into account both the high therapeutic indices of these antibiotics and the usually short duration of therapy. Therefore, on the limited basis of single-dose administration, no modifications of dirithromycin dosage seem to be required even for patients with class B liver cirrhosis.     

Gentamicin penetration into cerebrospinal fluid in experimental Haemophilus influenzae meningitis.

We studied the effect of meningitis and the method of parenteral gentamicin administration (intramuscular injection, a 30-min intravenous infusion, or intravenous bolus administration) on achievable concentrations of drug in cerebrospinal fluid (CSF). In normal animals, only intravenous bolus administration of 2 to 8 mg/kg produced a gentamicin concentration of greater than 0.1 microgram/ml in CSF in some animals. All CSF samples contained less than the limit of detection (0.1 microgram/ml) after the intramuscular administration of 6 mg/kg. In animals with meningitis, gentamicin penetration into cisternal CSF was increased significantly after a bolus administration of 6 mg/kg (mean, 0.197 +/- 0.063 microgram/ml in normal animals versus 1.68 +/- 0.38 micrograms/ml in animals with meningitis; P less than 0.01). In meningitic animals that received 6 mg/kg as an intravenous bolus, lumbar CSF had the highest maximum concentration (4.25 +/- 1.08 micrograms/ml), in comparison with ventricular CSF (3.10 +/- 0.66 micrograms/ml). The gentamicin concentration in cisternal CSF decreased more slowly than it did in serum (elimination half-life, 238.70 +/- 64.56 min in cisternal CSF versus 82.73 +/- 2.91 min in serum), yielding a relative increase in the percentage of penetration. We conclude that maximum penetration by gentamicin into CSF occurs after intravenous bolus administration and that the maximum concentration occurs in lumbar CSF.     

Pharmacokinetics of cefpodoxime proxetil and interactions with an antacid and an H2 receptor antagonist.

Cefpodoxime proxetil is a new oral esterified cephem antibiotic with a broad antibacterial spectrum. The dissolution of cefpodoxime proxetil is pH dependent. The objectives of this study were to characterize the pharmacokinetics of cefpodoxime proxetil in two different oral doses and to examine possible interactions with an antacid, aluminum magnesium hydroxide (Maalox 70), and an H2 receptor antagonist, famotidine. Two studies involving the same 10 healthy volunteers were performed. In the first study, cefpodoxime proxetil was administered in two doses, 0.1 and 0.2 g. In the second study, two interventions were performed in a randomized crossover design. For one intervention, the volunteers were pretreated with 40 mg of famotidine 1 h before 0.2 g of cefpodoxime proxetil was administered. In the second trial, participants were given 10 ml of Maalox 70 2 h and 10 ml of Maalox 70 15 min before they received 0.2 g of cefpodoxime proxetil. Serum and urine concentrations were determined by high-performance liquid chromatography. For the statistical evaluation, these data were tested by using the pharmacokinetics of 0.2 g of cefpodoxime proxetil from the first study. The maximum concentrations were 1.19 +/- 0.32 mg/liter after 0.1 g of cefpodoxime proxetil and 2.54 +/- 0.64 mg/liter after 0.2 g of cefpodoxime proxetil. The elimination half-lives were 149 min for 0.1 g and 172 min for 0.2 g of cefpodoxime proxetil. The total increase in the area under the concentration-time curve (AUC) was dose dependent. Combination with Maalox 70 caused a reduction in the AUC from 14.0 +/- 3.9 to 8.44 +/- 1.85 mg.h/liter. After famotidine, the AUC decreased to 8.36 +/- 2.0 mg . h/liter. Corresponding changes were registered for the maximum concentration of drug in serum, 24-h urine recovery, and the time to maximum concentration of drug serum. Cefpodoxime proxetil was well tolerated without any seriously adverse drug reactions.     

In-vitro activity of cefprozil (BMY 28100) and loracarbef (LY 163892) against pathogens obtained from middle ear fluid

We compared the in-vitro activities of cefprozil, a novel oral cephalosporin, and of loracarbef, a new oral carbacephem, with other agents against middle ear fluid isolates obtained from children with acute otitis media. These included Streptococcus pneumoniae, Haemophilus influenzae and Branhamella catarrhalis. Cefprozil activity (MIC50 and MIC90) against S. pneumoniae was 0.25 and 0.50 mg/l; against H. influenzae 8 and 16 mg/l; against B. catarrhalis 2 and 2 mg/l. Loracarbef activity (MIC50 and MIC90) against S. pneumoniae was 1 and 2 mg/l; against H. influenzae 8 and 16 mg/l; against B. catarrhalis 1 and 8 mg/l. Cefprozil was four-fold more active against S. pneumoniae than loracarbef but similar to amoxycillin, amoxycillin/clavulanate, cefaclor, cefixime, cefuroxime and trimethoprim/sulfamethoxazole (TMP/SMX). Against H. influenzae, cefprozil was similar to loracarbef and other agents through less active than TMP/SMX and cefixime. Against B. catarrhalis, cefprozil was four-fold more active than loracarbef, cefaclor and cefixime but similar to the comparative antibiotics. Cefprozil and loracarbef activities were unaffected at pH 6 and 8 or in the presence of human serum, but there was a major diminution of activity for both agents at pH 5 and at inoculum sizes greater than or equal to 10(7) cfu/ml. Cefoprozil and loracarbef have consistent activity against middle ear pathogens and further pharmacokinetic and clinical studies appear warranted.     

Hyperresponse to Thyrotropin-Releasing Hormone Accompanying Small Decreases in Serum Thyroid Hormone Concentrations

To determine whether pituitary thyrotropin (TSH) responsiveness to thyrotropin-releasing hormone (TRH) is enhanced by small decreases in serum thyroxine (T4) and triiodothyronine (T3), 12 euthyroid volunteers were given 190 mg iodide po daily for 10 days to inhibit T4 and T3 release from the thyroid. Basal serum T4, T3, and TSH concentrations and the serum T4 and TSH responses to 400 mug TRH i.v. were assessed before and at the end of iodide administration. Iodide induced small but highly significant decreases in basal serum T4 (8.0+/-1.6 vs. 6.6+/-1.7 mug/100 ml; mean +/- SD) and T3 (128+/-15 vs. 110+/-22 ng/100 ml) and increases in basal serum TSH (1.3+/-0.9 vs. 2.1+/-1.0 muU/ml). During iodide administration, the TSH response to TRH was significantly increased at each of seven time points up to 120 min. The maximum increment in serum TSH after TRH increased from a control mean of 8.8+/-4.1 to a mean of 13.0+/-2.8 muU/ml during iodide administration. As evidence of the inhibitory effect of iodide on hormonal release, the increment in serum T3 at 120 min after TRH was significantly lessened during iodide administration (61+/-42 vs. 33+/-24 ng/100 ml). These findings demonstrate that small acute decreases in serum T4 and T3 concentrations, resulting in values well within the normal range, are associated both with slight increases in basal TSH concentrations and pronounced increases in the TSH response to TRH. These results demonstrate that a marked sensitivity of TSH secretion and responsiveness to TRH is applicable to decreasing, as well as increasing, concentrations of thyroid hormones.     

Pharmacokinetic comparison of 5 g of azlocillin every 8 h and 4 g every 6 h in healthy volunteers.

To compare the multiple-dose pharmacokinetics of two dosage regimens of azlocillin, we studied 12 healthy volunteers via a randomized, crossover design with a 2-week washout phase between regimens. Serum and urine samples were collected for 8 h following the fifth dose of a regimen of 4 g every 6 h and the fourth dose of a regimen of 5 g every 8 h. Data for concentrations in serum were fitted to a two-compartment open model by nonlinear regression. Statistically significant differences (P less than 0.05) were observed in the following parameters (mean +/- standard deviation) for the 4- and 5-g regimens, respectively: area under the serum concentration-time curve during the dosing interval, 592 +/- 140 versus 772 +/- 151 micrograms.h/ml; terminal elimination rate constant, 0.5364 +/- 0.0912 versus 0.4758 +/- 0.0486 h-1; renal clearance, 87.6 +/- 16.1 versus 76.1 +/- 13.5 ml/min; maximum drug concentration in serum, 381 +/- 89 versus 473 +/- 90 micrograms/ml; and minimum drug concentration in serum, 19 +/- 10 versus 8 +/- 4 micrograms/ml. No significant differences were seen in the following parameters: V1, V beta, k10, k12, k21, total systemic clearance, and nonrenal clearance. These data support the presence of saturable renal elimination of azlocillin, as well as the feasibility of an 8-h dosing interval.     

Multiple-dose pharmacokinetics of sparfloxacin and its influence on fecal flora.

In a randomized, double-blind, placebo-controlled, multiple-dose pharmacokinetic study, the safety and effect on intestinal flora of sparfloxacin (SPX) were determined in 12 healthy male volunteers (8 received SPX and 4 received a placebo). Following fasting and oral administration of 400 mg on day 1 and 200 mg on days 2 to 8, concentrations of the free drug in serum, urine, and feces were measured by high-performance liquid chromatography; serum and urine were also evaluated by a microbiological assay. All results, except those for renal excretion, exclude the glucuroconjugate metabolite. A mean peak concentration in serum (400-mg dose) of 0.56 +/- 0.13 mg/liter was measured 3.52 +/- 0.98 h after administration. Pharmacokinetic parameters (measured by high-performance liquid chromatography) were based on an open, one-compartment model and resulted in the following day 1 (calculated for the 200-mg dose), day 4 (recalculated for a single dose), and day 8 values (mean +/- standard deviation): area under the curve, 16.4 +/- 2.3 (day 1) and 18.3 +/- 5.1 (day 4) mg.h/liter; elimination half-life, 18.3 +/- 3.9 h; steady-state volume of distribution, 4.7 +/- 1.4 (day 1) and 4.3 +/- 1.2 (day 8) liters/kg; apparent total clearance, 201 +/- 31 (day 1) and 190 +/- 51 (day 4) ml/min; renal clearance, 19.1 +/- 5.8 (day 1) and 23.2 +/- 19.4 (day 4) ml/min. Recovery in urine on day 1 was 5.89% +/- 1.4% of the dose in 24 h for the parent compound and 18.4% +/- 6.8% for the SPX glucuronide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Lack of interaction between lomefloxacin and caffeine in normal volunteers.

Sixteen healthy, nonsmoking adult males participated in a randomized, double-blind, placebo-controlled, two-way crossover study to evaluate the influence of chronic lomefloxacin administration on the disposition of caffeine and its major metabolite, paraxanthine, at steady-state conditions. Lomefloxacin (400 mg) or placebo was administered orally once daily for 5 days to xanthine-free volunteers after an overnight fast. Caffeine (200 mg orally) was administered simultaneously with lomefloxacin on days 3 through 5. After a 2-day washout period, subjects were crossed over to the alternate 5-day regimen with caffeine, which was again given on the final 3 days. Blood samples for caffeine, paraxanthine, and lomefloxacin concentration determinations were serially collected for 48 h following the last dose of each regimen. All compounds were analyzed by high-performance liquid chromatography. For the placebo versus lomefloxacin-containing treatments, maximum caffeine concentrations in plasma (4.35 +/- 0.63 versus 4.07 +/- 0.56 micrograms/ml), areas under the concentration-time curve from time zero to 24 h at steady state (30.3 +/- 6.9 versus 29.7 +/- 6.6 micrograms.h/ml), and elimination half-lives of caffeine (4.8 +/- 1.1 versus 4.8 +/- 1.2 h) were not significantly different. In addition, there were no significant changes in the disposition parameters of paraxanthine as a result of lomefloxacin administration. The frequencies of central nervous system-related effects for the two treatments were not statistically different. We conclude that lomefloxacin has no significant effect on the disposition of caffeine in young healthy volunteers.     

Phase I study of multiple-dose cefprozil and comparison with cefaclor.

The objectives of this study were to assess the safety and tolerance of cefprozil, to characterize the pharmacokinetics of cefprozil after administration of multiple doses of the drug, and to compare these pharmacokinetic parameters with those obtained with cefaclor. The volunteers received 28 doses of 250, 500, or 1,000 mg of cefprozil or 500 mg of cefaclor every 8 h for 10 days. Serial blood samples and the total volume of urine voided by each individual were collected for pharmacokinetic evaluation on days 1, 5, and 10. Both cephalosporins were well tolerated after multiple oral dosing. The peak levels in plasma (Cmax) of cefprozil ranged from 5.7 to 18.3 micrograms/ml after oral administration of 250- to 1,000-mg doses. The regression analysis of Cmax on cefprozil dose showed a dose-linear response. The mean Cmax of cefaclor ranged from 15.2 to 16.7 micrograms/ml and did not change significantly on multiple dosing. The overall mean terminal half-life of cefprozil was 1.2 h and was invariant with respect to dose or duration of dosing. The area under the plasma-concentration-versus-time curve from 0 h to infinity (AUC0-infinity) of cefprozil increased in a dose-proportional manner with an increase in dose. The overall urinary recovery (61% of dose) and renal clearance values of cefprozil were generally invariant with respect to dose and duration of dosing. While cefprozil was apparently absorbed less rapidly and achieved lower Cmax values than cefaclor, the AUC0-infinity of cefprozil was nearly twofold greater than that of cefaclor. The half-life of cefprozil was also twofold longer than that observed for cefaclor. Although the urinary recovery of cefaclor (75% of dose) was significantly higher than that of cefprozil (61% of dose), the concentrations of cefprozil in urine remained significantly higher than those of cefaclor from 2 to 8 h postdosing. If the therapeutic concept is maintained that levels of beta-lactam antibiotics in plasma should exceed the MIC for the offending organisms over a period that approximates the dosing interval, then cefprozil would appear to be suitable for twice-daily administration, whereas cefaclor should probably be administered three or even four times a day.     

The pharmacokinetics of teicoplanin in varying degrees of renal function

The pharmacokinetics of teicoplanin, a new glycopeptide antibiotic with activity against aerobic gram-positive bacteria, were characterized after intravenous administration of a single 3 mg/kg dose in five healthy volunteers and six patients with various degrees of stable renal insufficiency. Serum and urine samples were collected during a 15-day period and drug concentrations were assayed microbiologically. The mean elimination half-life of teicoplanin was 162.6 +/- 69.8 hours in healthy volunteers and was prolonged with decreased renal function. The mean plasma and renal clearances of teicoplanin in healthy subjects were 11.4 +/- 1.5 ml/min and 10.0 +/- 1.0 ml/min, respectively. Both values decreased in patients with renal failure and correlated significantly with measured creatinine clearances (r2 = 0.938 and 0.884, respectively). A nomogram for dosage adjustment in patients with varying degrees of renal failure is presented.