Pharmacokinetics of total and unbound ertapenem in healthy elderly subjects

Ertapenem is a new once-a-day parenteral carbapenem antimicrobial agent. The pharmacokinetics of unbound and total concentrations of ertapenem in plasma were investigated in elderly subjects and compared with historical data from young adults. In a single- and multiple-dose study, healthy elderly males and females (n = 14) 65 years old or older were given a 1-g intravenous (i.v.) dose once daily for 7 days. Plasma and urine samples collected for 24 h on days 1 and 7 following administration of the 1-g doses were analyzed by reversed-phase high-performance liquid chromatography. Areas under the concentration-time curve from 0 h to infinity (AUC(0- infinity )) for elderly females and males were similar following administration of 1-g single i.v. doses, and thus, the genders were pooled in subsequent analyses. Concentrations in plasma and the half-life of ertapenem were generally higher and longer, respectively, in elderly subjects than in young adults. The mean AUC(0- infinity ) of total ertapenem in the elderly was 39% higher than that in young subjects following administration of a 1-g dose. The differences were slightly greater for the mean AUC(0- infinity ) of unbound ertapenem (71%). The unbound fraction of ertapenem in elderly subjects ( approximately 5 to 11%) was generally greater than that in young adults ( approximately 5 to 8%). As in young adults, ertapenem did not accumulate upon multiple dosing in the elderly. The pharmacokinetics of ertapenem in elderly subjects, while slightly different from those in young adults, do not require a dosage adjustment for elderly patients.     

Comparison of single-dose fosfomycin and a 7-day course of nitrofurantoin in female patients with uncomplicated urinary tract infection

This multicenter clinical trial compared single-dose fosfomycin tromethamine with a 7-day course of nitrofurantoin for the treatment of acute uncomplicated lower urinary tract infection (UTI) in female patients. Healthy females with symptoms of acute uncomplicated UTI were enrolled in a double-masked, randomized clinical trial. Assessable patients had >10(5) colony-forming units per milliliter of a uropathogen in a clean-voided midstream urine sample. Patients received a single 3-g dose of fosfomycin tromethamine plus 7 days of placebo capsules or a single 3-g dose of placebo plus 7 days of nitrofurantoin monohydrate/macrocrystal 100-mg capsules. Treatment efficacy was assessed by both bacteriologic and clinical response 5 to 11 days after the initial treatment dose (visit 2) and 5 to 11 days (visit 3) and 4 to 6 weeks (visit 4) after the last day of medication. Of the 749 patients initially enrolled in the study, 375 received fosfomycin and 374 received nitrofurantoin. There were no clinical differences in patient characteristics between the 2 groups at study entry. Overall, 94% of pretreatment isolates were susceptible to fosfomycin and 83% were susceptible to nitrofurantoin. Bacteriologic cure rates at the first follow-up visit (5 to 11 days after initiation of treatment) were 78% and 86% for fosfomycin and nitrofurantoin, respectively (P = 0.02). At visit 3 (1 week posttreatment), they were 87% and 81% for fosfomycin and nitrofurantoin, respectively (P = 0.17). Both treatment groups had an 80% overall clinical success rate (cure and improvement). Twenty patients (5.3%) who received fosfomycin and 21 patients (5.6%) who received nitrofurantoin reported an adverse effect related to study medication. The most common side effects related to fosfomycin treatment were diarrhea (2.4%), vaginitis (1.8%), and nausea (0.8%). Both bacteriologic and clinical cure rates observed with a single 3-g dose of fosfomycin were comparable to those achieved with a 7-day course of nitrofurantoin in female patients with acute uncomplicated UTI.     

Pharmacokinetics of molsidomine and of its active metabolite, SIN-1 (or linsidomine), in the elderly

The pharmacokinetics of molsidomine were investigated in six young (25.5 +/- 0.6 years) and in six elderly healthy volunteers (81.1 +/- 3.1 years). After a 2 mg oral administration, molsidomine elimination half-life was prolonged in elderly subjects (1.9 +/- 0.2 h versus 1.2 +/- 0.1 h, P less than 0.05) because of a decrease in its plasma clearance (15.1 +/- 3.2 l.h-1 versus 41.8 +/- 2.5 l.h-1 (P less than 0.01) in young volunteers). The elimination half-life of the active metabolite, SIN-1 or linsidomine was also prolonged in elderly subjects (1.8 +/- 0.2 h versus 1.0 +/- 0.08 h, P less than 0.05). AUCs of both molsidomine and SIN-1 were increased in the elderly subjects, but the increase in the former was greater (x 3.4) than the increase in the latter (x 1.6). These results suggest that pharmacokinetics and metabolism of molsidomine are impaired in elderly subjects.     

Comparative single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride in young and elderly adults

The single-dose pharmacokinetics of amantadine hydrochloride and rimantadine hydrochloride were compared in a randomized, two-period, crossover study involving six young (less than or equal to 35 years) and six elderly (less than or equal to 60 years) adults. Subjects ingested single 200-mg oral doses after an overnight fast, and serial plasma (0 to 96 h), nasal mucus (0 to 8 h), and urine (0 to 24 h) samples were collected for assay of drug concentration by electron capture gas chromatography. For both groups combined, rimantadine differed significantly from amantadine in peak plasma concentration (mean +/- standard deviation, 0.25 +/- 0.06 versus 0.65 +/- 0.22 micrograms/ml), plasma elimination half-life (36.5 +/- 15 versus 16.7 +/- 7.7 h), and percentage of administered dose excreted unchanged in urine (0.6 +/- 0.8 versus 45.7 +/- 15.7%). No significant age-related differences were noted for rimantadine. Urinary excretion (0 to 24 h) of rimantadine and its hydroxylated metabolites averaged 19% of the administered dose. The maximum nasal mucus drug concentration was similar for both drugs (0.42 +/- 0.25 versus 0.45 +/- 0.32 micrograms/g), and the ratio of maximum nasal mucus to plasma concentration was over twofold higher after rimantadine than after amantadine. These findings may in part explain the clinical effectiveness of rimantadine in influenza A virus infections at dosages that have lower toxicity than those of amantadine.     

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.     

Pharmacokinetics and dose proportionality of cefmetazole in healthy young and elderly volunteers.

The pharmacokinetics and dose proportionality of cefmetazole were studied in 24 healthy volunteers (12 young and 12 elderly). Each volunteer received single 0.5-, 1-, and 2-g doses of cefmetazole administered intravenously over 5 min according to a three-way crossover design. Serial plasma and urine samples were collected over a 24-h period following dosing and assayed for cefmetazole by a high-performance liquid chromatography method. Results of the dose proportionality portion of the study indicated that cefmetazole pharmacokinetics are linear and proportional with dose in both age groups. Comparisons of pharmacokinetic parameters between the young and elderly groups indicated that the systemic clearance was significantly lower in elderly than in young volunteers (92.4 versus 112 ml/min). Additionally, creatinine clearance was significantly lower in elderly (74.1 ml/min) than in young (92.9 ml/min) subjects. No significant differences between age groups were observed for volume of distribution, urinary recovery, terminal half-life, nonrenal clearance, or renal clearance, although half-life was slightly prolonged in elderly volunteers relative to that in young volunteers (1.54 versus 1.34 h), and renal clearance was slightly lower in elderly than in young volunteers (83.7 versus 96.1 ml/min). Both systemic and renal clearance were significantly correlated with creatinine clearance. These results indicate that the observed age-related differences in the pharmacokinetics of cefmetazole are most likely due to differences in renal function between the two age groups. The small reduction in cefmetazole elimination in the elderly would not warrant dose adjustment in this population.     

In vivo activity and pharmacodynamics of amoxicillin in combination with fosfomycin in fibrin clots infected with highly penicillin-resistant Streptococcus pneumoniae.

Using a clinical pneumococcal strain for which MICs were 4, 2, and 32 mg/liter for penicillin, amoxicillin, and fosfomycin, respectively, we studied the efficacies of these antibiotics alone and their combinations in the treatment of prolonged (48-h) experimental fibrin clot infection in rabbits. Treatments were as follows: amoxicillin IV at 20 mg/kg of body weight in one dose (Amo20), 50 mg/kg in one dose (Amo50), or two doses 6 h apart (Amo20 x 2 and Amo50 x 2); fosfomycin IV at a fixed dose of 50 mg/kg in one dose (Fos50) or two divided doses 6 h apart (Fos50 x 2); or the combinations of amoxicillin and fosfomycin with the same schedules. Maximum concentrations in clots were 2.03 +/- 1.02 and 2.13 +/- 0.33 mg/liter for Amo20 regimens, 3.7 +/- 1.9 and 4 +/- 1.3 mg/liter for Amo50 regimens, and 24 +/- 7 and 40 +/- 8 mg/liter for fosfomycin regimens, respectively. The mean half-lives of elimination from clots were between 2 and 3 h for amoxicillin regimens and between 5 and 7 h for fosfomycin. We observed the highest bacterial reductions (log10 CFU/gram) for Amo50 in two divided doses with or without fosfomycin. A significantly higher bacterial reduction than that with each monotherapy was observed when Amo20 was combined with fosfomycin in either one dose or two doses 6 h apart (0.16 +/- 0.8 and 1.64 +/- 1.6 log10 CFU/g for Amo20 in one and two doses, respectively, and 0.93 +/- 0.81 and 0.61 +/- 0.56 log10 CFU/g for fosfomycin in one and two doses, respectively, versus 3.46 +/- 1.26 and 3.16 +/- 1.31 log10 CFU/g for Amo20 plus fosfomycin in one and two doses, respectively [P < 0.001]). A time-dependent effect was observed with amoxicillin regimens. The time of regrowth was significantly delayed when amoxicillin was combined with fosfomycin. By using a multivariate analysis, we demonstrated that the most important parameter correlated to efficacy of the combination amoxicillin-fosfomycin was the length of the period during which the concentration of amoxicillin remained above the MIC. We demonstrated that the in vivo efficacy of the combination of amoxicillin and fosfomycin gave higher antibacterial effect than each monotherapy.     

Pharmacokinetics of intravenous cefetamet (Ro 15-8074) and oral cefetamet pivoxil (Ro 15-8075) in young and elderly subjects.

The purpose of this investigation was to evaluate the effect of advanced age on the pharmacokinetics of cefetamet and its prodrug, cefetamet pivoxil. A secondary objective of this study was to assess the effect of food on the absorption of cefetamet pivoxil in the elderly. Twenty-four healthy subjects (twelve young and twelve elderly) received (in a Latin square design) a single-dose, 515-mg infusion of cefetamet, a single 1,000-mg oral dose of cefetamet pivoxil during fasted conditions, and a single 1,000-mg oral dose of cefetamet pivoxil 10 min after a standardized low-fat breakfast. Serial blood and urine samples were collected over a 36-h period and analyzed by high-performance liquid chromatography. Intravenous and oral pharmacokinetic parameters were obtained by using model-independent techniques. The systemic clearance and renal clearance of cefetamet were significantly lower (P less than 0.05) in elderly subjects compared with in young controls after intravenous administration. No significant difference was observed in the apparent volumes of distribution at steady state between the two groups. Consequently, half-life and mean residence time were prolonged. A trend toward a lower renal clearance/creatinine clearance ratio was observed in our elderly population. Oral clearance of cefetamet was only slightly reduced in our elderly subjects, consistent with an increase in plasma half-life. Otherwise, oral pharmacokinetic parameters were comparable between elderly and young subjects. Additionally, the same effects of food were observed on the absorption characteristics of cefetamet (no change in maximum concentration of drug in plasma and an increase in both time to maximum concentration of drug in plasma and bioavailability) in our elderly subjects as in our young volunteers. Age did not appear to alter the deesterification and bioavailability of cefetamet pivoxil. We conclude that the small reduction in the elimination of cefetamet in the elderly would not require dose adjustment for this population.     

Pharmacokinetics and tolerance of lomefloxacin after sequentially increasing oral doses.

The pharmacokinetics of five dose levels of lomefloxacin (100, 200, 400, 600, and 800 mg) were examined in a single-dose, double-blind, placebo-controlled study involving 40 subjects. There were eight subjects in each group: five received active drug and three received placebo; each subject was given only one dose. All subjects completed the study, and lomefloxacin was well tolerated at all doses. No drug crystals were noted in the urine at 3 and 6 h after the dose. The mean maximum concentration in serum (Cmax) ranged from 1.11 to 7.46 micrograms/ml for the 100- to 800-mg doses, respectively, and the AUC increased proportionally with the dose. The mean time to Cmax (Tmax) values averaged 64.8 +/- 28.8 min. The elimination half-life and plasma clearance averaged 7.7 +/- 0.52 h and 259 +/- 37 ml/min, respectively. Mean concentrations in urine were highest during the first 4 h after the dose and ranged from 104 to 713 micrograms/ml following the 100- and 800-mg doses, respectively. Concentrations above 20 micrograms/ml in urine were observed in most subjects over 24 h at the three lower doses and averaged over 120 micrograms/ml during the 12- to 24-h interval at the 400-mg dose, thus supporting once-per-day dosing. Excretion rates from urine and the cumulative amount excreted increased in a dose-related fashion. Renal clearance decreased moderately at the higher doses. Thus, lomefloxacin was well tolerated, and dose proportionality was demonstrated by most pharmacokinetic parameters. The 400-mg dose produced concentrations in plasma and urine above the MIC for susceptible pathogens.     

Antibiotic abscess penetration: fosfomycin levels measured in pus and simulated concentration-time profiles

The present study was performed to evaluate the ability of fosfomycin, a broad-spectrum antibiotic, to penetrate into abscess fluid. Twelve patients scheduled for surgical or computer tomography-guided abscess drainage received a single intravenous dose of 8 g of fosfomycin. The fosfomycin concentrations in plasma over time and in pus upon drainage were determined. A pharmacokinetic model was developed to estimate the concentration-time profile of fosfomycin in pus. Individual fosfomycin concentrations in abscess fluid at drainage varied substantially, ranging from below the limit of detection up to 168 mg/liter. The fosfomycin concentrations in pus of the study population correlated neither with plasma levels nor with the individual ratios of abscess surface area to volume. This finding was attributed to highly variable abscess permeability. The average concentration in pus was calculated to be 182 +/- 64 mg/liter at steady state, exceeding the MIC(50/90)s of several bacterial species which are commonly involved in abscess formation, such as streptococci, staphylococci, and Escherichia coli. Hereby, the exceptionally long mean half-life of fosfomycin of 32 +/- 39 h in abscess fluid may favor its antimicrobial effect because fosfomycin exerts time-dependent killing. After an initial loading dose of 10 to 12 g, fosfomycin should be administered at doses of 8 g three times per day to reach sufficient concentrations in abscess fluid and plasma. Applying this dosing regimen, fosfomycin levels in abscess fluid are expected to be effective after multiple doses in most patients.     

Multiple-dose pharmacokinetics of rimantadine in elderly adults.

To assess the possible effect of aging on rimantadine hydrochloride pharmacokinetics, single- and multiple-dose kinetics were determined in 18 healthy adults with ages between 51 and 79 years. Subjects ingested single 100-mg oral doses of rimantadine after an overnight fast, followed after 5 days by a dosage of 100 mg twice a day for 9.5 days. No differences were observed among the age-stratified groups in measured or derived pharmacokinetic parameters. Peak concentrations in plasma (mean +/- standard deviation) following the single- and multiple-dose regimens, respectively, were 89 +/- 25 and 417 +/- 129 ng/ml for subjects who were 50 to 60 years of age (group 1), 92 +/- 24 and 401 +/- 84 ng/ml for those 61 to 70 years of age (group 2), and 100 +/- 14 and 538 +/- 51 for those 71 to 79 years of age (group 3). The elimination half-life in plasma following multiple doses averaged 33.5 h for group 1, 32.5 h for group 2, and 38.6 h for group 3. Steady-state concentrations in nasal mucus developed by day 5 of dosing (1.5-fold higher than concentrations in plasma), and rimantadine remained detectable in secretions for 5 days after the last dose in 65% of subjects. Stepwise regression analysis suggested that changes in maximum concentration in plasma and area under the concentration-time curve at steady state may be related to creatinine clearance. The results indicate that no important differences in rimantadine multiple-dose pharmacokinetics exist among healthy elderly adults with ages between 51 and 79 years.     

High-pressure liquid chromatographic assay and pharmacokinetics of HR 810 after intramuscular injection in rabbits.

A high-pressure liquid chromatographic assay was developed for the detection of HR 810 in rabbit plasma. There was no interference in the high-pressure liquid chromatographic assay from other antibiotics. The method was accurate, reproducible, and capable of detecting less than 1 microgram of HR 810 per ml in plasma. The assay correlated with the microbiological assay (correlation coefficient, 0.93) and was used to quantitate the concentration of HR 810 in rabbit plasma and determine its half-life subsequent to a 20-mg/kg intramuscular dose. The peak concentration of HR 810 was 51.2 +/- 8.0 micrograms/ml at 1 h postdose. The half-life of the absorption phase (mean +/- standard deviation) was 0.35 +/- 0.10 h, and the half-life of the elimination phase was 0.75 +/- 0.06 h. This is 54% less than the half-life of elimination of 1.38 h previously reported for the intravenous dose.     

The dynamics of intraperitoneal growth and elimination of Escherichia coli and Bacteroides fragilis in porcine faecal peritonitis treated with fosfomycin.

The kinetics of intraperitoneal killing of proliferating bacteria was studied in pigs given fosfomycin. Eight animals were given intra-abdominal injection of Escherichia coli and Bacteroides fragilis (10(9) cfu of each species) mixed in sterile faces. Three hours later, half of the animals received an intravenous dose of 1 g fosfomycin (0.05 g/kg). Host defences rapidly decreased the density of E. coli in all animals in the first hour. After 2h, growth of E. coli started and continued throughout the experiment in pigs not receiving fosfomycin. B. fragilis was slowly eliminated in the first 5 6 h, then numbers increased in all animals. Fosfomycin caused a reduction in E. coli density, by 10(2.19) +/- 0.29 (mean +/- S.E.M.) cfu/ml, or more than 150 times within 1 h, while the concentration of B. fragilis was unaltered. After 10 h the difference in E. coli density between fosfomycin treated and untreated animals was 10(4.96) cfu/ml (P less than 0.01). Fosfomycin eradicated E. coli in faecal peritonitis but not B. fragilis, which is resistant in vitro. There was a prolonged elimination of the drug from peritoneal exudate in pigs infected with bacteria in sterile faeces compared to the elimination in uninfected pigs or pigs infected only with bacteria.     

Pharmacokinetics of acyclovir suspension in infants and children.

Eighteen children from 3 weeks to 6.9 years of age were given an oral acyclovir suspension for herpes simplex or varicella-zoster virus infections. Thirteen patients who were 6 months to 6.9 years old received 600 mg/m2 per dose, and three infants and two children less than 2 years old were given 300 mg/m2 per dose. The drug was given four times a day, except to one infant who was treated with three doses a day. Among the 13 children who received the 600-mg/m2 dose, the maximum concentration in plasma (Cmax) was 0.99 +/- 0.38 microgram/ml (mean +/- standard deviation), the time to maximum concentration (Tmax) was 3.0 +/- 0.86 h, the area under the curve (AUC) was 5.56 +/- 2.17 micrograms.h/ml, and the elimination half-life (t1/2) was 2.59 +/- 0.78 h. The three infants less than 2 months of age who received the 300-mg/m2 dose had a Cmax of 1.88 +/- 1.11 micrograms/ml, a Tmax of 4.10 +/- 0.48 h, an AUC of 6.54 +/- 4.32 micrograms.h/ml, and a t1/2 of 3.26 +/- 0.33 h. The acyclovir suspension was well tolerated by young children. No adverse effects requiring discontinuation of the drug occurred.     

Pharmacokinetics, protein binding, and predicted extravascular distribution of moxalactam in normal and renal failure subjects

Ten normal subjects and ten patients with chronic renal failure requiring hemodialysis were given intravenous infusions of moxalactam ranging from 500 mg to 2 g. Serum and urine concentrations were measured for up to 12 h. Renal failure subjects were given doses both during and between hemodialysis treatments. Protein binding of moxalactam in both normal and uremic serum was determined by ultracentrifugation. The serum half-life in normal subjects was 2.1 and 2.3 h for the 1- and 2-g doses, respectively. The half-life of moxalactam in patients with renal failure was 13.9 h on the 500-mg dose and 13.3 h on the 1.0-g dose. During hemodialysis the serum half-life fell to 4.4 and 5.7 h, respectively. Moxalactam protein binding ranged from 52% in normal serum to 36% in renal failure patient serum. Unbound moxalactam appeared to distribute with the entire body water based on the serum pharmacokinetics and antibiotic serum protein binding determined in this study.     

Pharmacokinetics and electrocardiographic effect of ebastine in young versus elderly healthy subjects

The objective of this study was to compare the single- and multiple-dose pharmacokinetics and electrocardiographic effect of a 10-mg oral dose of ebastine in elderly (ages, 65-85 years) and young (ages, 18-35 years) healthy volunteers. Thirty-seven subjects completed this randomized, double-blind, multiple-dose, placebo-controlled, parallel group study. The elderly group consisted of 18 subjects, with 13 subjects receiving 10 mg ebastine and 5 receiving matching placebo. The young group consisted of 19 subjects, with 13 subjects receiving 10 mg ebastine and 6 receiving matching placebo. On study days 1 and 3 through 10, each subject received a single 10-mg dose of ebastine or matching placebo in the morning with a standard breakfast. No drug was administered on study day 2 because of pharmacokinetic sampling. Blood samples were collected at selected times postdose on study days 1, 2, and 10. Plasma samples were analyzed for ebastine and its active metabolite, carebastine, using a validated high-performance liquid chromatography method. No plasma ebastine concentrations were detected, suggesting essentially complete metabolic conversion of ebastine to its metabolites. Analysis of variance showed no statistically significant differences between young and elderly single- and multiple-dose carebastine pharmacokinetics with respect to area under the plasma concentration-time curve, maximum concentration (Cmax ), terminal elimination rate constant, apparent oral clearance, or apparent volume of distribution. The mean time of maximum concentration value for young subjects was 1 hour longer than that for elderly subjects after single-dose administration but was comparable after multiple-dose administration. Within-group comparisons of both the young and elderly showed that pharmacokinetics between single dose and steady state were not statistically different. However, the mean steady-state carebastine Cmax values were approximately twofold greater than the mean Cmax values obtained after single-dose administration. A twofold increase in Cmax values between single-dose and steady-state administration is predicted for drugs such as carebastine, because its input interval is approximately equal to its elimination half-life. Twelve-lead electrocardiography was performed before dosing on day 1 and repeated 4 hours postdose on days 1, 5, and 10. Twenty-four hour Holter monitoring was also performed before and at the end of the study. No clinically relevant findings were found by electrocardiography or Holter monitoring between ebastine and placebo in the elderly and young subjects.     

Single-dose pharmacokinetics of fosfomycin during continuous venovenous haemofiltration

OBJECTIVES: Dosage recommendations for fosfomycin are available for haemodialysed patients but there are no data for patients undergoing continuous renal replacement therapy. Therefore, the present study was designed to determine the concentration-versus-time profile of fosfomycin in continuous venovenous haemofiltration (CVVH). PATIENTS AND METHODS: A total of 12 anuric intensive care patients (10 males and 2 females) with suspected or proven infection requiring parenteral antibiotic therapy were included in the study. All patients underwent CVVH. Blood samples were drawn from the arterial (input) and venous (output) line of the extracorporeal circuit after application of a single dose of 8 g of fosfomycin. Ultrafiltration samples were collected from the outlet of the ultrafiltrate compartment of the haemofilter. Fosfomycin in the samples was quantified by gas chromatography. RESULTS: The peak serum concentration was 442.7+/-124 mg/L at the arterial port. The trough serum level was 103.1+/-36.6 mg/L at the arterial port after 720 min. The mean value of the area under the concentration-versus-time curve from 0 to 12 h (AUC0-12) was 2159.4+/-609.8 mg.h/L. Mean total removal of the drug was 76.7+/-6.2%. The mean calculated clearance was 1.1+/-0.2 L/h for CLHF. Mean CLtot was 6.4+/-7.7 L/h. CONCLUSIONS: A regimen of 8.0 g of fosfomycin every 12 h, which is usually used in patients with intact renal function, should be an appropriate antimicrobial treatment for patients undergoing CVVH.     

Pharmacokinetics of ceftizoxime in patients undergoing continuous ambulatory peritoneal dialysis.

The pharmacokinetics of ceftizoxime were studied in 12 patients on continuous ambulatory peritoneal dialysis. After a 3-g intravenous dose, the steady-state volume of distribution was 0.23 +/- 0.05 liter kg-1, with an elimination half-life of 9.7 +/- 5.1 h. The peritoneal clearance of ceftizoxime (2.8 +/- 0.7 ml min-1) contributed modestly to the overall serum clearance of the drug (17.1 +/- 7.4 ml min-1) and was greater than the renal clearance (0.8 +/- 0.8 ml min-1). The peritoneal concentration rose to 91 +/- 29 micrograms ml-1 at 6 h, which was 0.61 +/- 0.17 of the serum concentration. A 3-g intravenous dose of ceftizoxime given every 48 h would result in adequate activity against most susceptible organisms, but more frequent dosing may be necessary for less susceptible organisms.     

Repaglinide pharmacokinetics in healthy young adult and elderly subjects.

In this open-label, single-center, pharmacokinetic study of repaglinide, 12 healthy volunteers (6 men, 6 women) were enrolled in each of 2 groups (total, 24 volunteers). One group consisted of young adult subjects (18 to 40 years), and the other group consisted of elderly subjects (> or = 65 years). On day 1, after a 10-hour fast, all 24 subjects received a single 2-mg dose of repaglinide. Starting on day 2 and continuing for 7 days, subjects received a 2-mg dose of repaglinide 15 minutes before each of 3 meals. On day 9, subjects received a single 2-mg dose of repaglinide. Pharmacokinetic profiles, including area under the curve, maximum concentration (Cmax), time to Cmax, and half-life, were determined at completion of the single-dose and multiple-dose regimens (days 1 and 9, respectively). Trough repaglinide values were collected on days 2 through 7 to assess steady state. The single-dose and multiple-dose pharmacokinetic variables of serum repaglinide were not significantly different between young adult and elderly subjects. Repaglinide was well tolerated in both groups. Hypoglycemic events occurred in 5 young adult and 5 elderly subjects. This study demonstrates that the pharmacokinetics of repaglinide are similar in healthy young adult and elderly subjects.     

Phase 1 safety and pharmacokinetic study of chimeric murine-human monoclonal antibody c alpha Stx2 administered intravenously to healthy adult volunteers

Hemolytic-uremic syndrome (HUS) is a serious complication of infection by Shiga toxin-producing Escherichia coli. Shiga toxin type 2 (Stx2) is responsible for the renal toxicity that can follow intestinal infection and hemorrhagic colitis due to E. coli. A chimeric mouse-human antibody, designated c alpha Stx2, that has neutralizing activity in a mouse model was produced and tested in healthy adult volunteers. In this phase I dose escalation study, c alpha Stx2 was generally well tolerated. Pharmacokinetic studies indicated that clearance was stable over the dose range of 1.0 to 10 mg/kg of body weight (0.249 +/- 0.023 ml/kg/h) but was higher for the 0.1-mg/kg dose (0.540 +/- 0.078 ml/kg/h), suggesting saturable elimination. A similar nonlinear trend was observed for the volume of distribution, where average values ranged from 0.064 +/- 0.015 liter/kg for the 1.0- to 10-mg/kg doses and 0.043 +/- 0.005 for the 0.01-mg/kg dose. The relatively small volume of distribution suggests that the antibody is limited to the vascular (plasma) compartment. The mean half-life was 165 +/- 66 h, with lowest values observed for the 0.1-mg/kg dose (56.2 +/- 9.7 h) and the highest values reported for the 10.0-mg/kg dose (206.4 +/- 12.4 h). Future studies are needed to confirm the safety of this c alpha Stx2, and innovative clinical trials will be required to measure its efficacy in preventing or treating HUS.