Penetration of ceftriaxone into human pleural fluid.

The pharmacokinetics of ceftriaxone were studied for seven patients with pleural effusion of various etiologies. All patients received 1 g of antibiotic, administered as an intravenous bolus. The pleural fluid had a high total protein content (6.0 g/dl). Ceftriaxone levels in plasma and in pleural fluid were determined by the agar well diffusion technique. Total and free drug concentrations in pleural fluid reached 7 to 8.7 and 3.8 to 2.3 micrograms/ml, respectively, in 4 to 6 h. The disappearance of the drug from the pleural fluid was very slow. In these patients, therapeutic ceftriaxone levels were present for at least 53 h in pleural fluid.     

Analysis of ceftriaxone and ceftazidime distribution in cerebrospinal fluid of and cerebral extracellular space in awake rats by in vivo microdialysis.

In vivo microdialysis was used to estimate the extracellular concentrations of ceftazidime and ceftriaxone, two expanded-spectrum cephalosporins commonly used in the treatment of bacterial meningitis, in two brain regions (the right corpus striatum and the left lateral ventricle_ of awake, freely moving rats. Antibiotics were administered by constant intravenous infusion at 18 mg/h until steady-state levels were reached. Ceftriaxone levels measured at the steady state in the extracellular space of the corpus striatum (0.80 +/- 0.17 micrograms/ml) were statistically equivalent to those obtained in the cerebrospinal fluid of the lateral ventricle (0.71 +/- 0.15 micrograms/ml). The ratios of these levels in the brain to the steady-state levels in plasma were 0.5 +/- 0.1% for both regions. The postinfusion concentrations of ceftriaxone in the brain declined monoexponentially, with an elimination half-life similar to that obtained in plasma. However, the mean antibiotic concentration of ceftazidime in the striatum (2.2 +/- 0.4 micrograms/ml) was lower (P < 0.001) than that in the lateral ventricle (3.8 +/- 0.5% and 4.0 +/- 1.8%, respectively) were higher than those obtained with ceftriaxone. Moreover, the half-life of ceftazidime elimination from plasma was lower than that obtained in the two brain regions. It was concluded that the in vivo microdialysis technique yields useful data on antibiotic distribution in the extracellular space of the brain, that the distribution may not be homogeneous, and that the decay of postinfusion concentrations in the brain may be different from the decay of postinfusion concentrations in plasma.     

Pulmonary disposition of roxithromycin (RU 28965), a new macrolide antibiotic.

The penetration of roxithromycin (RU 28965), an ether oxime derivative of erythromycin, into the cells and fluid lining the epithelial surface of the lower respiratory tract was studied by performing fiber-optic bronchoscopy with bronchoalveolar lavage on eight patients who had received roxithromycin at 300 mg perorally every 12 h for 5 days. The apparent volume of epithelial lining fluid recovered by bronchoalveolar lavage was determined by using urea as an endogenous marker. There was a significant relationship (r = 0.75; P less than 0.02) between roxithromycin levels in plasma and epithelial lining fluid, with a correlation whose slope suggested that the level of drug penetration into the lining fluid was 0.2. Concentrations of the antibiotic in cells recovered by bronchoalveolar lavage (21 +/- 10 micrograms/ml) were 2 and 10 times higher than in plasma (11.4 +/- 5.7 micrograms/ml) and epithelial lining fluid (2.0 +/- 1.7 micrograms/ml), respectively. Thus, when administered perorally in humans, roxithromycin is markedly accumulated by resident alveolar macrophages in concentrations largely exceeding the MBCs of the drug for most facultative intracellular pathogens including Legionella pneumophila, despite low concentrations in the epithelial lining fluid.     

Single-dose pharmacokinetics of ceftriaxone in patients with end-stage renal disease and hemodialysis

We report the pharmacokinetic parameters of ceftriaxone in 11 patients on hemodialysis with end-stage renal disease (ESRD; creatinine clearance less than 5 ml/min/1.73 m2). The patients were studied during the interdialysis period and during 4 h of hemodialysis. The mean age was 53.4 years. After the administration of 1 g of ceftriaxone during a constant intravenous infusion over a 30-min period, t 1/2 was 16.6 h, beta was 0.0418 +/- 0.0106 h-1, VD was 14.5 +/- 3.0 liters/1.73 m2 and Clp was 0.40 +/- 0.05 liters/h for the interdialysis period. Hemodialysis started 24 h after the infusion. The initial plasma ceftriaxone concentration was 68.6 +/- 10.8 micrograms/ml. This value dropped to 40.4 +/- 4.7 micrograms/ml at the end of the 4th hour, indicating a significant 41% decay in blood levels during hemodialysis (p less than 0.001). The t 1/2 decreased to 4.88 h, kel rose to 0.142 +/- 0.0250 h-1 and Clp increased to 1.73 +/- 0.44 liters/h. All values were highly significantly different (p less than 0.001) from those during the interdialysis period. The plasma ceftriaxone concentration of 40.4 +/- 4.7 micrograms/ml at the end of hemodialysis was well within the therapeutic range of the drug. We conclude that ceftriaxone has a moderated increase in t 1/2 in patients with ESRD. Ceftriaxone is significantly dialyzable, however, the plasma concentrations are in the therapeutic range by the end of a 4-hour hemodialysis, 28 h after the administration of the drug. We propose that 1 g given intravenously before each hemodialysis will be sufficient to keep the patient's plasma concentrations within the therapeutic range until the next hemodialysis.(ABSTRACT TRUNCATED AT 250 WORDS)     

Gingival crevicular fluid levels of clindamycin compared with its minimal inhibitory concentrations for periodontal bacteria

Clindamycin concentrations in gingival crevicular fluid and in blood were determined over a 7-h period and were related to the minimal inhibitory concentrations of this agent for 340 bacterial strains isolated from diseased periodontal sites. The clindamycin levels after administration of single 300-mg oral doses were measured in gingival crevicular fluids by using an agar diffusion bioassay. Minimal inhibitory concentrations were determined by agar dilution techniques for 30 species of periodontal bacteria. With the exception of Eikenella corrodens and Actinobacillus actinomycetemcomitans, most of the bacteria were inhibited by a concentration of 1.0 microgram of clindamycin per ml or less. The peak concentrations in crevicular fluid (2.0 +/- 0.3 microgram/ml) and in blood (1.9 +/- 0.3 micrograms/ml) were approximately the same. However, crevicular fluid levels of 1.0 micrograms/ml and above were present for up to 6 h, whereas blood concentrations dropped below 1.0 micrograms/ml within 2 h after administration. Based on its minimal inhibitory concentrations, clindamycin at crevicular fluid levels of 1.0 micrograms/ml or above should inhibit most bacteria associated with diseased periodontal sites.     

Pharmacokinetics of Ceftriaxone in Pediatric Patients With Meningitis

Pharmacokinetics of ceftriaxone after a single dose of 50 or 75 mg/kg were determined in 30 pediatric patients with bacterial meningitis. Data for doses of 50 and 75 mg/kg, respectively, were as follows (mean +/- standard deviation): maximum plasma concentrations, 230 +/- 64 and 295 +/- 76 mug/ml; elimination rate constant, 0.14 +/- 0.06 and 0.14 +/- 0.04 h(-1); harmonic elimination half-life, 5.8 +/- 2.8 and 5.4 +/- 2.1 h; plasma clearance, 51 +/- 24 and 55 +/- 18 ml/h per kg; volume of distribution, 382 +/- 129 and 387 +/- 56 ml/kg; mean concentration in cerebrospinal fluid 1 to 6 h after infusion, 5.4 and 6.4 mug/ml. A dosage schedule of 50 mg/kg every 12 h for bacterial meningitis caused by susceptible organisms is suggested for pediatric patients over 7 days of age.     

Pharmacokinetics of mezlocillin in pleural fluid

Mezlocillin concentrations in the pleural fluid and serum of six patients with malignant pleural effusion were determined following administration of 10 g mezlocillin over 30 minutes as a rapid infusion. Thirty minutes and eight hours after the infusion had been completed, concentrations of the active ingredient in the pleural fluid were 36.44 micrograms/ml and 112 micrograms/ml respectively; in the serum the respective values were 777.89 micrograms/ml and 44.22 micrograms/ml. The concentrations of active ingredient in the pleural fluid exceed the MIC for clinically significant pathogenic germs. The elimination half-life of mezlocillin in malignant pleural effusion is prolonged.     

Pharmacokinetics of meropenem in patients with intra-abdominal infections.

Noncompartmental and compartmental analyses of meropenem disposition in patients receiving 1-g intravenous intermittent infusions every 8 h were performed. Twelve patients (one woman and 11 men) participated in the meropenem pharmacokinetic analysis. Operative findings included perforated appendicitis (five patients), gangrenous appendicitis (five patients), peri-appendical abscess (one patient), and gunshot wound to the abdomen (one patient). The most common associated adverse drug reactions to meropenem were diarrhea and increased liver enzymes. The estimated noncompartmental pharmacokinetic parameters, mean +/- standard deviation, are as follows: maximum drug concentration in plasma, 47.58 +/- 17.59 micrograms/ml; half-life, 1.04 +/- 0.19 h; elimination rate constant, 0.68 +/- 0.12 h-1; area under the concentration-time curve from 0 h to infinity, 57.5 +/- 20.12 micrograms x ml/h; total plasma clearance, 315.40 +/- 71.94 ml/min; renal clearance, 136.7 +/- 89.20 ml/min; volume of distribution at steady state, 26.68 +/- 6.88 liters; and mean residence time, 1.47 +/- 0.28 h. The two-compartment model best described meropenem disposition in our patients. Our findings differed from estimates for healthy volunteers possibly because of the physiologic changes as a result of surgery. Our findings suggest that meropenem (1,000 mg) administered intravenously every 8 h provides adequate concentrations for most intra-abdominal infections.     

Kinetics of gentamicin in plasma of nonpregnant, pregnant, and fetal guinea pigs and its distribution in fetal tissues.

Nonpregnant and pregnant guinea pigs in the last third of gestation were injected intramuscularly with 4 mg of gentamicin per kg, and drug concentrations in plasma were determined by radioimmunoassay at several intervals after injection. The maximum gentamicin concentration was lower in pregnant than in nonpregnant animals (14.6 +/- 0.7 micrograms/ml versus 21.6 +/- 0.7 micrograms/ml), and the peak time occurred significantly later (0.57 +/- 0.12 h versus 0.13 +/- 0.02 h). Four hours after gentamicin injection, drug concentrations in plasma were 2.1 +/- 0.8 and 0.3 +/- 0.1 micrograms/ml in pregnant and nonpregnant animals, respectively. Pregnant animals therefore eliminated the drug from their plasma more slowly. These data provide good evidence that the kinetics of plasma gentamicin varies in pregnant females because its volume of distribution was larger in pregnant than in nonpregnant animals. Detectable but small amounts of gentamicin (less than or equal to 0.50 microgram/ml) were found in the plasma of 46 of 57 fetuses. However, no net variations in these concentrations were observed during the period between 15 min and 6 h after injection to the mother. Gentamicin concentrations were also determined in the kidneys, liver, lungs, heart, and brain of fetal guinea pigs after administration to their mothers of one daily injection of 4 mg/kg for 7 days. Gentamicin was present in all these fetal organs; however, as in the adult organs, the kidneys contained far more than any of the others. Gentamicin concentrations were not significantly different in the kidney cortex and medulla (1.79 +/- 0.16 versus 1.48 +/- 0.92 micrograms/g), indicating that, contrary to what is observed for adults, renal accumulation of gentamicin in the fetus does not occur preferentially in the cortex.     

Moxalactam kinetics during continuous ambulatory peritoneal dialysis after intraperitoneal administration.

Moxalactam kinetics during continuous ambulatory peritoneal dialysis (CAPD) was followed in eight patients after a single intraperitoneal dose of 1 g. Approximately 60% of the dose was absorbed after a dwell time of 4 h. Dialysis solutions were exchanged at 4-h intervals with an overnight dwell of 8 h. The mean (+/- standard deviation) elimination half-life was 13.2 +/- 2.9 h, and the mean apparent volume of distribution was 0.22 +/- 0.08 liters/kg. Mean total clearance was 11.5 +/- 2.4 ml/min, with a mean dialysis clearance of 2.3 +/- 0.5 ml/min. The maximum concentration in plasma ranged from 24.5 to 54.1 micrograms/ml. Moxalactam concentrations in the peritoneal dialysis fluid were above 80 micrograms/ml during the first exchange and above 2 micrograms/ml for a further three exchanges. A suggested intraperitoneal dose regimen for patients undergoing CAPD is 1 g initially, followed by 15 to 25% of the recommended dose for normal patients given at the same time intervals, or 30 to 50% of the recommended dose at twice the usual intervals. Moxalactam is suggested for initial treatment of peritonitis in CAPD patients who do not have ready access to the antibiotic of choice.     

Effects of macro- and microcirculatory functions on ceftriaxone concentrations in tissues of patients with stage IV peripheral arterial occlusive disease.

The objective of the study was to determine the ceftriaxone levels achievable within lesions (toe or forefoot area) in patients with septic gangrene and to investigate the relationship between macro- and microcirculatory parameters and antibiotic concentration. Fifteen patients with severe chronic peripheral occlusive disease received an intravenous injection of 2 g of ceftriaxone. Antibiotic levels in venous and capillary blood and in an exudative part of the lesion were measured. Macrocirculatory functions were assessed by Doppler sonography, plethysmography, and angiography; microcirculatory functions were assessed by quantitative capillaroscopy and fluorescence video microscopy. The mean antibiotic concentrations measured between 4 and 8 h after injection were 92 +/- 26 micrograms/ml in venous blood and 84 +/- 46 micrograms/ml in capillary blood. The concentration in tissue reached its maximum 4 h after injection; the average concentration at between 2 and 8 h was 95 +/- 55 micrograms/ml. Only dynamic capillary parameters showed significant (P < 0.01) correlations to antibiotic levels in tissue. Significantly (P < 0.01) higher levels in tissue were observed in patients with adequate microcirculatory functions (138 +/- 48 micrograms/ml) than in patients with poor microcirculatory function (51 +/- 26 micrograms/ml). Microcirculatory dysfunction appears to be the limiting factor for tissue antibiotic levels. However, even those patients with poor microcirculatory function showed tissue antibiotic levels that were above the MICs for the pathogens most frequently isolated from gangrenous lesions. Therefore, intravenous application was found to be adequate and additional measures such as intra-arterial therapy or Bier's occlusion are basically unnecessary. Our finding that microcirculatory function is the limiting factor for the tissue antibiotic concentration is corroborated by computations based on a three-compartment model.     

Pharmacokinetics of cefpimizole in normal humans after single- and multiple-dose intravenous infusions

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were determined after single- and multiple-dose 20-min intravenous infusions of 1, 2, and 4 g. The kinetics of single-dose administration of cefpimizole correspond to a two-compartment model with an average apparent volume of distribution of 20.0 +/- 3.5 liters, a distribution rate constant of 2.24 +/- 1.00 h-1, and a terminal rate constant of 0.358 +/- 0.036 h-1 (half-life, 1.9 h). The total body clearance was 118.6 +/- 20.2 ml/min. The primary route of elimination for cefpimizole was the renal route, with approximately 80% of the administered dose excreted as the parent compound. The elimination rate constant, as calculated from urinary excretion data, was 0.339 +/- 0.043 h-1, which is in close agreement with the terminal rate constant for plasma. Renal clearance of cefpimizole was 96.2 +/- 17.3 ml/min. Dose proportionality over the three dose levels was obtained from area under the plasma curve and cumulative urinary excretion data. The results of the multiple-dose study indicated that no apparent change in the distribution or elimination kinetics of cefpimizole occurred after the administration of 1-, 2-, and 4-g doses for 7 days, three times a day. The kinetics from the multiple-dose study were in close agreement with those from the single-dose study. No accumulation of cefpimizole occurred, and nondetectable levels was observed 24 h after administration of the last dose. Peaks that could be attributed to metabolites of cefpimizole were not observed during high-pressure liquid chromatographic analysis of either plasma or urine specimens.     

Pharmacokinetics of cefuroxime in infants and children with bacterial meningitis.

A total of 38 patients with bacterial meningitis received either 50 or 75 mg of cefuroxime per kg of body weight given as a 15-min intravenous infusion during the first to third days of therapy. The mean peak plasma concentrations of cefuroxime after doses of 50 and 75 mg/kg were 105 and 152 micrograms/ml, respectively. In five patients, pharmacokinetic values were determined after multiple doses of 50 mg of cefuroxime per kg every 6 h. The mean peak plasma concentrations were 120 micrograms/ml after the first dose and 130 micrograms/ml after the last dose. The concentrations at 6 h were 3.25 and 11.0 micrograms/ml after the first and last doses, respectively. The elimination half-life was approximately 1.5 h, and the apparent volume of distribution was 650 ml/kg. The plasma clearance rate was 195 to 198 ml/min per 1.73 m2. Penetration into the cerebrospinal fluid, expressed as the ratio of the cerebrospinal fluid to serum areas under the curve times 100, was 6.4% in patients given 50 mg of cefuroxime per kg and 10% in those who received 75 mg/kg. The cerebrospinal bactericidal activity in 27 patients was less than or equal to 1:8; only 2 patients had bactericidal activity of less than or equal to 1:2.     

Difference in blister fluid penetration after single and multiple doses of ceftriaxone.

Plasma and suction skin blister fluid concentrations of ceftriaxone were studied in 12 subjects after intravenous administration of 1 g of ceftriaxone every 12 h (q12h) and 2 g every 24 h (q24h) after single and multiple doses. Ceftriaxone concentrations were determined by high-pressure liquid chromatography. Mean peak plasma concentrations (at the end of the 5-min infusion) were 254.0 and 374.8 micrograms/ml after administration of 1 g q12h after single and multiple doses, respectively. Similarly, with 2 g q24h, maximum levels were 409.6 and 443.5 micrograms/ml. Forty-eight hours after the last dose of ceftriaxone, plasma concentrations were still detectable: 1.2 micrograms/ml after 1 g q12h and 3.0 micrograms/ml after 2 g q24h. Higher ceftriaxone concentrations were observed in blister fluid after multiple doses than after a single dose. Peak concentrations almost doubled in the blister fluid after multiple doses: 36.0 versus 67.0 micrograms/ml and 38.6 versus 68.9 micrograms/ml for 1 g q12h and 2 g q24h, respectively. Elimination half-life of ceftriaxone in the blister (8.3 and 11.5 h) was longer than plasma half-life (6.3 h). With the area under the concentration-time curve ratio, a 113% increase in tissue penetration was observed after multiple doses for the 1 g q12h regimen. The free plasma and blister fluid ceftriaxone concentrations observed at the end of the dosing interval of the 2 g q24h regimen were higher than the MIC for 90% of the susceptible microorganisms and justified the once-a-day use of ceftriaxone.     

Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.     

Pharmacokinetics of cefpodoxime in plasma and skin blister fluid following oral dosing of cefpodoxime proxetil.

The single-dose and steady-state pharmacokinetics of cefpodoxime were assessed in plasma and skin blister fluid (SBF) after oral dosing of 200 mg (n = 8) and 400 mg (n = 8) of cefpodoxime proxetil (doses are expressed as cefpodoxime equivalents) in healthy subjects in an open-label, parallel-design study. Skin blisters were formed by air suction on the midvolar forearm by a previously validated method. After single-dose administration, serial plasma and SBF samples were collected over 24 h for measurement of cefpodoxime by microbiological assays. After a 1-week washout, subjects received the same doses of antibiotic every 12 h for 5 days, with plasma and SBF sampling on day 5. After 200 mg of cefpodoxime proxetil, average peak concentrations (Cmax) in plasma and SBF were 2.18 +/- 0.52 and 1.55 +/- 0.59 micrograms/ml, respectively, after a single dose and 2.33 +/- 0.74 and 1.56 +/- 0.55 micrograms/ml, respectively, at steady state. After 400 mg of cefpodoxime proxetil, Cmax in plasma and SBF averaged 4.16 +/- 1.04 and 2.94 +/- 0.71 micrograms/ml, respectively, following a single dose and 4.10 +/- 0.95 and 2.84 +/- 0.88 micrograms/ml, respectively, at steady state. Cmax occurred 1.1 to 1.6 h later in SBF than in plasma. There was no accumulation of cefpodoxime in plasma or SBF when dosing was done every 12 h. Cefpodoxime blister fluid penetration was estimated to be 67 to 101%, consistent with the relatively low serum protein binding of the drug. Cefpodoxime levels exceeding the MIC for 90% of many skin pathogens, such as Streptococcus species (<1 microgram/ml) or Staphylococcus species (2 to 4 micrograms/ml), were achieved in plasma and SBF following the 200- and/or 400-mg dosing regimens.     

Pharmacokinetics of cefamandole and ampicillin in experimental meningitis.

The penetration of cefamandole and ampicillin into the cerebrospinal fluid of rabbits with and without pneumococcal meningitis was evaluated. In normal animals, a mean maximum concentration of 0.22 +/- 0.13 microgram of cefamandole per ml was measured in the spinal fluid after a dose of 150 mg/kg given intramuscularly; with 25 and 50 mg/kg doses, no antibiotic was detected in the cerebrospinal fluid. With ampicillin, in intramuscular doses of 200 and 300 mg/kg, the mean maximum concentrations encountered in the cerebrospinal fluid were 1.59 +/- 0.4 and 1.47 +/- 0.44 microgram/ml, respectively. Penetration of cefamandole, and to a lesser extent ampicillin, was increased after 24 h of experimental meningitis. With cefamandole, the concentration of drug in the cerebrospinal fluid exceeded the usual inhibitory concentration for Haemophilus influenzae only with the 150 mg/kg dose. After 48 h of meningitis, there was a trend toward higher levels of antibiotic in the cerebrospinal fluid, but the difference between animals infected 24 versus 48 h was not statistically significant. In animals with meningitis, serum concentrations after 150 mg of cefamandole per kg and both ampicillin doses studied were 32 to 38% lower than the serum levels achieved in normal rabbits after identical doses of antibiotic.     

Pharmacokinetics and dose proportionality of cefpimizole in normal humans after intramuscular administration.

The pharmacokinetics of cefpimizole (free acid equivalents of cefpimizole sodium), a broad-spectrum cephalosporin antibiotic, were evaluated after intramuscular administration of single doses (dose range, 100 to 1,000 mg) and multiple doses (dose range, 500 to 2,000 mg) given b.i.d. for 6 or 11 days. The kinetics after intramuscular administration correspond to a one-compartment model with first-order input. The apparent volume of distribution of the absorbed dose averaged 18.6 +/- 3.4 (standard deviation) liters for 58 individuals; the absorption-phase and elimination-phase rate constants averaged 2.53 +/- 1.16 h-1 (half-life, 0.27 h) and 0.338 +/- 0.041 h-1 (half-life, 2.05 h), respectively; and the mean residence time was 3.43 +/- 0.43 h. The total body clearance of the absorbed dose after single-dose intramuscular administration was 102 +/- 13 ml/min. The primary route of elimination was renal with 73 to 83% of the administered dose excreted in the urine as unchanged drug. Renal clearance averaged 81 +/- 13 ml/min. Dose proportionality was obtained from area under the plasma curve, concentration maximum in plasma, and cumulative urinary excretion levels. Multiple-dose evaluation of intramuscular administration of cefpimizole indicated no apparent change in the absorption or elimination phases after b.i.d. dosing for 6 or 11 days. The kinetic parameters determined from multiple-dose plasma and urine levels were in close agreement with the same parameters calculated from single-dose results. No apparent accumulation of cefpimizole occurred, and nondetectable levels of drug were observed in the 24-h plasma and 24- to 48-h urine specimen after administration of the last dose. The kinetics of cefpimizole after intramuscular administration were similar to the kinetics obtained after intravenous infusion.     

Effect of renal impairment on distribution of ofloxacin.

A study was made of the plasma and distribution kinetics of ofloxacin administered at a dosage of 400 mg orally to a group of healthy volunteers and a group of patients with renal impairment. Blood and blister fluid samples were taken at programmed times from all individuals included in the study. The analytical techniques for the determination of ofloxacin in both fluids were a plate diffusion method and a high-performance liquid chromatographic technique. The fitting of the experimental data to the kinetic model used was done with the help of the AUTOAN 2 and NONLIN 84 computer programs. In the groups of healthy volunteers, the elimination half-life mean values were found to be 5.1 and 5.9 h in plasma and blister fluid, respectively. The maximum concentration reached in plasma (3.9 micrograms/ml) proved to be slightly higher than that in interstitial tissue fluid (2.8 micrograms/ml). In the patients with renal impairment, the maximum concentrations in both plasma and blister fluid were significantly increased, in the order of 5 to 8 micrograms/ml in the former and 3 to 4 micrograms/ml in interstitial tissue fluid. The parameters seen to undergo an increase as a result of the renal impairment were the area under the curve of the plasma-time levels, the area under the curve of the blister fluid-time levels, and the elimination half-life in plasma and blister fluid. The degree of absorption and the access capacity of the drug to interstitial tissue fluid remained constant.     

Steady-state pharmacokinetics of intramuscular imipenem-cilastatin in elderly patients with various degrees of renal function.

We studied the concentrations in plasma and pharmacokinetics of imipenem and cilastatin in elderly patients (greater than 65 years old) who had various degrees of renal function and who were hospitalized with soft tissue infections. Three groups of patients received imipenem-cilastatin (500/500 mg) intramuscularly every 12 h: group I consisted of eight patients with a creatinine clearance (CLCR) of greater than 50 ml/min (range, 51 to 84 ml/min; mean, 65.8 ml/min); group II consisted of three patients with a CLCR of 20 to 50 ml/min; and group III consisted of two patients with a CLCR of less than 20 ml/min. Imipenem and cilastatin concentrations were measured at steady state on day 5. Mean peak and trough plasma imipenem concentrations were 5.28 +/- 1.78 and 1.43 +/- 0.76 micrograms/ml in group I, 6.25 +/- 0.78 and 2.50 +/- 0.00 micrograms/ml in group II, and 14.3 +/- 0.71 and 6.85 +/- 1.06 micrograms/ml in group III, respectively. Mean peak and trough plasma cilastatin concentrations were 11.8 +/- 2.85 and 0.31 +/- 0.43 microgram/ml in group I, 15.5 +/- 2.48 and 2.03 +/- 2.05 micrograms/ml in group II, and 24.5 +/- 6.72 and 10.7 +/- 5.94 micrograms/ml in group III, respectively. Mean imipenem AUCss (area under the concentration-time curve over a dosage interval at steady state) values were 38.7 +/- 7.9 micrograms.h/ml for group I, 52.3 +/- 7.3 micrograms.h/ml for group II, and 143.7 +/- 11.9 micrograms.h/ml for group III. Mean cilastatin AUCss values were 45.6 +/- 12.5 micrograms.h/ml for group I, 93.8 +/- 51.2 micrograms.h/ml for group II, and 217.5 +/- 57.8 micrograms.h/ml for group III. Cilastatin mean apparent body clearance values (normalized to weight) were 2.78 +/- 0.67 ml/min for group I, 1.43 +/- 0.81 ml/min for group II, and 0.71 +/- 0.24 ml/min for group III. Imipenem open-lactam metabolite levels were all below the level of detective of the assay (<3.9 micrograms/ml). There was a progressive increase in plasma imipenem and cilastatin levels and AUCss and there was a decline in body clearance as renal function declined.