Mean Peak Serum Concentration Research Articles

Clinical Efficacy, Tolerance and Pharmacokinetics of Temocillin in Patients with Respiratory Tract Infections

In this study 13 patients with a history of chronic respiratory disease were treated with temocillin for severe infection of the lower respiratory tract. Eleven patients were clinically improved or cured at the end of treatment and 4 remained free of infection at follow up. However, the 2 remaining patients failed to respond clinically and bacteriologically to temocillin. Blood and sputum pharmacokinetics were studied in patients receiving temocillin at 12-hourly intervals in doses of either 1g by intravenous bolus or 2g by intravenous infusion. On the first day of treatment the mean peak serum concentration was 102 mg/L for the 1g dose and 220 mg/L for the 2g dose, falling to 11 mg/L (1g) and 18.8 mg/L (2g) at 12 hours. Similar results were recorded on the last day of treatment. Temocillin concentrations in the sputum ranged from 1.5 to 2.8 mg/L, with no difference being found in the sputum concentrations of the 2 doses. Temocillin was well tolerated and was found to be an effective treatment for Gram-negative bacterial infections of the lower respiratory tract.

Clinical pharmacokinetics of aztreonam in cancer patients.

The pharmacokinetics of aztreonam were studied in 25 adult patients with hematological malignancies. Two groups of nine patients each received aztreonam (1 or 2 g every 8 h) prophylactically, and seven infected patients received a therapeutic regimen of aztreonam (1.5 g every 4 h). The mean peak serum concentration after a 1-g dose of aztreonam (given over 0.5 h on day 1) was 75.5 micrograms/ml; after a 2-g dose it was 177.2 micrograms/ml. The mean peak serum concentration after a 1.5-g dose of aztreonam (given over 2 h on day 1) was 68.5 micrograms/ml. The serum half-life ranged between 1.7 and 2.0 h for all regimens studied. The urinary concentration of the metabolite of aztreonam, SQ 26,992, increased during 1 week of administration of the drug; however, serum levels of the metabolite were barely detectable.

Pharmacokinetics of clindamycin phosphate in the first year of life

The pharmacokinetics of intravenously administered clindamycin phosphate was studied in 40 children less than 1 year of age. Mean peak serum concentrations were 10.92 micrograms/ml in premature infants less than 4 weeks of age, 10.45 micrograms/ml in term infants greater than 4 weeks, and 12.69 micrograms/ml in term infants less than 4 weeks of age. Mean trough concentrations were 5.52, 2.8, and 3.03 micrograms/ml, respectively, in the same groups. Serum half-life was significantly longer (8.68 vs 3.60 hours) in premature compared with term infants less than 4 weeks of age. Both premature and term infants less than 4 weeks had significantly decreased clearance when compared with infants greater than 4 weeks (0.294 and 0.678, respectively, vs 1.58 L/hr). Clearance was significantly greater (1.919 vs 0.310 L/hr) and serum half-life less (1.75 vs 7.57 hours) in infants with body weight greater than 3.5 kg. On the basis of these data it is recommended that in infants greater than 4 weeks or greater than 3.5 kg, intravenous clindamycin dosage be 20 mg/kg/day in four divided doses. In premature neonates less than 4 weeks, the dose should be reduced to 15 mg/kg/day in three divided doses. Term infants greater than 1 week of age may also receive 20 mg/kg/day in four doses.

In Vitro and Clinical Evaluation of Ceforanide

Ceforanide, a new cephalosporin antibiotic with a long half-life (three hours), was evaluated for its antimicrobial activity, pharmacology, and clinical efficacy Fifty-two patients with 56 infections due to susceptible organisms received ceforanide, 0.5g, 1g, or 2g, intramuscularly or intravenously every 12 hours for four to 60 days (average: 14.1 days). The in vitro studies of our clinical isolates showed that 12.0μg/ml or less of ceforanide inhibited all Streptococcus pneumoniae, beta hemolytic streptococci group A, B, F Staphylococcus aureus. Staphylococcus epidermidis, Escherichia coli, Klebsiella pneumoniae, Proteus mirabilis and Hemophilus influenzae. After a 1 gram intramuscular dose, the mean peak serum concentration at one hour was 44.0μg/ml, and at 12 hours was 3.8μg/ml. After a 1 gram intravenous dose, the mean peak serum concentration was 65.0μg/ml, and the mean trough serum concentration at 12 hours was 9.6μg/ml. The infections treated included ten pneumonias, ten urinary tract infections, seven bacteremias, two osteomyelitis, and 35 skin-soft tissue infections. Of the 56 evaluable infections treated, 52 had a clinical cure with only four failures. Ceforanide was well tolerated, with no patients developing thrombophlebitis, or liver or renal abnormalities. Three patients developed abnormal Coombs’ reactions and one had diarrhea.

Antimicrobial activity of latamoxef (moxalactam) against both Bacteroides fragilis and Escherichia coli in an intraperitoneal abscess model.

The antimicrobial activity of latamoxef (moxalactam) was examined against Bacteroides fragilis and Escherichia coli individually and in combination in an intraperitoneal tissue capsule animal model during ten days of therapy given at 40 mg/kg/day. Mean peak serum concentration was 32.8 mg/l. Mean capsular latamoxef concentrations during samplings on days three, seven and ten were 1.8 mg/l for Bact. fragilis, 0.7 mg/l for E. coli, less than 0.5 mg/l for polymicrobial infection and 3.4 mg/l in uninoculated controls. Capsular colony counts for Bact. fragilis and E. coli monomicrobial infections decreased by 2.2 and 4.0 log10 cfu respectively and 1.9 and 3.6 log10 cfu in polymicrobial infections. Latamoxef concentrations necessary to eliminate viable bacteria in both monomicrobial and polymicrobial capsules were not achieved.

Serum and sputum concentrations of ceftazidime in patients with cystic fibrosis.

The pharmacokinetic parameters of ceftazidime were assessed in six cystic fibrotic patients during eight courses administered for acute exacerbations of pulmonary infection. In order to assess the initial and steady state concentrations of ceftazidime at a dose of 35 mg/kg and to determine the levels found after a higher dose, each ten day course of ceftazidime consisted of eight doses of 35 mg/kg followed by 22 doses of 50 mg/kg, all administered at 8-hourly intervals. Samples of blood and sputum were collected following the 1st, 8th and 9th doses for ceftazidime assay. The mean peak serum concentrations of ceftazidime were 97, 110 and 147 mg/l respectively with corresponding mean concentrations in sputum of 2.7, 2.6 and 1.6 mg/l. The mean clearance rate was calculated on a two compartment model to be 197 ml/min/50 kg lean body mass, the mean volume of distribution was 281/50 kg lean body mass and the mean half life was 1.57 h. There were large inter-patient differences in the pharmacokinetic parameters, however, which suggests that the clinical condition of the patient affects the pharmacokinetics of ceftazidime in cystic fibrosis. In all the patients, even after the doses of 50 mg/kg, the trough serum concentrations were low. Samples of blood were also collected for adverse effects before, during and after each course; there was no evidence of renal, hepatic or haematological changes in response to the drug.

Extravascular penetration of tobramycin and netilmicin in a subcutaneous visking chamber model in rabbits.

Netilmicin and tobramycin penetration in a rabbit Visking chamber model was studied after administration of multiple intramuscular doses of 2 mg of either drug per kg every 4 h in a double-crossover design. The mean serum half-life, mean peak concentration in serum, and mean area under the plasma concentration curve were similar. The mean peak concentration in the chamber and mean area under the plasma concentration curve were likewise not significantly different.

Erythromycin absorption in healthy volunteers from single and multiple doses of enteric-coated pellets and tablets.

The absorption of erythromycin from two different enteric-coated preparations was evaluated in three groups of healthy volunteers. After a single dose, taken after an overnight fast, absorption was significantly better from enteric-coated pellets than from tablets; both the mean peak serum concentration and the peak mean level were higher (p less than 0.01) in all three groups, and the mean area under the serum concentration-time curve (AUC) was at least 65% larger. Eight out of 23 subjects showed no or only a very low serum concentration after the enteric-coated tablets. In a follow-up study, 250 mg doses were given 6-hourly for 3 days, and again the mean maximum serum concentration was significantly higher (p less than 0.05) after the pellets. In conclusion, enteric-coated pellets led to more regular and predictable absorption of erythromycin than did coated tablets.

Absorption and excretion of azodisal sodium and its metabolites in man after rectal administration of a single 2-g dose.

The behaviour of azodisal sodium (ADS) and its metabolites after a single 2-g rectal dose was investigated in 10 healthy volunteers. Blood samples were drawn frequently, and urine was collected during intervals of 24 h. The ADS absorption gave a mean peak serum concentration of 2.1 (SD +/- 0.7) microgram/ml. The urinary excretion of ADS was 0.8% of the given dose. After rectal administration 5-aminosalicylic acid (5-ASA) could be detected in the serum only in two of the subjects, with a mean concentration of less than 0.5 microgram/ml. Ac-5-ASA was present in increasing serum concentrations, being 0.93 microgram/ml at 24 h. The mean 24-h urinary excretion of these two metabolites was only 2.7% of the given dose. In another study the azo bond of ADS has been shown to be split by anaerobic and aerobic bacteria. The low absorption of its metabolites indicates that ADS is a suitable molecule for delivering the presumed pharmacologically active moiety, 5-ASA.

Clinical pharmacology of ceftriaxone in patients with neoplastic disease.

Pharmacological studies of ceftriaxone, a new semisynthetic cephalosporin, were conducted in 35 cancer patients. This antibiotic was administered in a variety of doses and schedules with no observed toxicity. Intramuscular administration of 500 mg of ceftriaxone to seven patients produced mean peak serum concentrations of 32.9 mug/ml 2.0 h after administration. The terminal serum half-life was 10.9 h. Intravenous infusion of 500 mg of ceftriaxone over 5 min to the same group of seven patients produced a mean peak concentration of the drug in serum of 83 mug/ml at the end of administration which decreased to 16.8 mug/ml at 8 h. A dose of 1 g of ceftriaxone given in identical fashion to the same group of seven patients produced mean peak concentrations in serum of 130 mug/ml at the end of administration and 17.3 mug/ml at 12 h. The mean percentages of drug recovered in urine 12 h after single intravenous doses of 500 mg and 1 g were 30 and 20%, respectively. A 1-g dose of ceftriaxone was administered every 8 h to 10 patients, and a 2-g dose was administered every 12 hours to 9 patients. Drug concentrations in serum were measured for each patient after drug administration on day 1, day 3 or 4, and day 7 or 8. The 1-g dose produced an observed mean peak concentration of 154 mug/ml and a mean terminal-phase half-life of 5.6 h on day 3 or 4. The 2-g dose produced a mean peak concentration in serum of 262 mug/ml and a terminal-phase serum half-life of 6.3 h on day 3 or 4. Continuous infusion studies were performed in nine neutropenic patients for up to 8 days by using a loading dose of 1 g over 30 min, followed by 2 g every 8 h. Mean concentrations in serum were maintained at about 135 mug/ml during the infusion period.

Pharmacokinetics of cefoperazone in patients with normal and impaired hepatic and renal function.

The pharmacokinetics of cefoperazone in normal subjects and in patients with hepatic and renal dysfunction are reviewed. Peak serum concentrations and areas under serum level-time curves are linearly related to dose. The range of mean peak serum concentrations after a 2-g dose of cefoperazone is 202-375 micrograms/ml with iv injection or infusion and 111 micrograms/ml with im injection. The serum half-life is 1.6-2.6 hr. Urinary excretion is rapid, but only 15%-37% of the dose is recovered in urine. The drug is not metabolized significantly. Levels of drug in bile are many times higher than serum levels, and biliary excretion represents the major pathway of cefoperazone elimination. Serum kinetics of cefoperazone are not significantly altered by renal impairment. However, hepatic dysfunction is associated with a two- to fourfold increase in serum half-life. Even in these patients, drug accumulation was not observed after repeated administration of 1 g of cefoperazone at 12-hr intervals. Major dosage modification should only be required with concomitant renal and hepatic dysfunction.

Clinical results and pharmacokinetics of ceftazidime treatment in patients with cystic fibrosis.

Ceftazidime (50 mg/kg/8 h) alone or combined with tobramycin (5 mg/kg/8 h) was given to 14 patients with cystic fibrosis. Ten courses were given with ceftazidime alone and 6 courses with a combined therapy. All patients were chronically colonized with Pseudomonas aeruginosa and were hospitalized because of lower respiratory tract infections. Using an agar-well diffusion technique, the concentration of ceftazidime was determined in serum and sputum. The mean (+/- S.E.M.) peak serum concentration of ceftazidime was 142 +/- 16 mg/l during the second to third day of treatment and 114 +/- 18 mg/l on the fifth to sixth day of treatment. In the combined therapy the corresponding values were 104 +/- 20 mg/l and 74 +/- 8 mg/l, respectively. The range of the mean half life was 1.2 to 1.4 h. The maximum concentration of ceftazidime in sputum was usually obtained 1 h after the infusion, ranging from 0.7 to 9.8 mg/l. All patients improved during treatment. Non-mucoid strains of Ps. aeruginosa were eradicated in nearly half of the courses, mucoid strains less often. No side reactions were noted.

Clinical effect and pharmacokinetics of trimethoprim-sulphadiazine in children with urinary tract infections

The clinical effect and pharmacokinetics of the combination trimethoprim (TMP)-sulphadiazine (SD) were studied in 18 children with acute urinary tract infections (UTI), aged 2-56 months. A suspension of TMP-SD (9 + 41 mg/ml) was taken orally twice daily for 10 days. Various doses of TMP (2.9-3.7 mg/kg/day) and SD (12.9-16.7 mg/kg/day) were also given to children of different ages. After 2-4 days of treatment, bacterial cultures of urine were negative and C-reactive protein in serum, WBC count and ESR in all patients had become normal. Steady state serum levels for both components were reached after 4 or more days of treatment. At steady state, mean peak serum concentrations of TMP and SD of 1.4 micrograms/ml and 27 micrograms/ml, respectively, were found within 2-4 h after a fasting morning dose. The biological half-lives of TMP and SD were of the same order of magnitude, but the total clearance of TMP was 5 times greater than that of SD. The concentrations of TMP-SD in urine were invariably more than 10 times the minimum inhibitory concentrations (MIC) for the causative organisms (tested at the ratios 1:20 and 1:4 of TMP and SD). Non-metabolized SD constituted 77% of total SD in urine of infants, and 55% of total SD in children of 1 year or more. The TMP-SD combination showed a satisfactory clinical effect and favourable pharmacokinetic properties in children with UTI.

Pharmacokinetics of intravenous metronidazole in man.

Metronidazole (500 mg) was infused over 20 min. to five patients. At the end of the infusion blood samples were drawn at brief intervals. After subsequent metronidazole analysis the curve plotted for the elimination of the drug showed a bi-exponential profile. Mean peak serum concentrations reached 15 micrograms per ml. At the end of the distribution phase, which was 20 to 30 min. after the infusion, the concentrations had fallen to 10 micrograms per ml. A two-compartment model was used to calculate the kinetic parameters. The elimination half-life ranged from 4.7 to 15.8 hours, the total clearance from 43 to 193 ml per min., and the peripheral distribution volume from 41.5 to 79.11 1. The areas under the serum level curves exhibited a four-fold variation, due to differences in either metabolism or elimination rate.

Pharmacologic interactions among chloramphenicol, phenytoin and phenobarbital

Bioactive chloramphenicol was measured in the sera of 34 infants and children receiving intravenous chloramphenicol succinate (25 mg/kg/dose) as therapy for meningitis, pneumonia, brain abscess or Rocky Mountain spotted fever. In 17 children receiving chloramphenicol succinate alone, mean peak and trough serum concentrations of chloramphenicol were 25.3 and 13.4 micrograms/ml, respectively. Concurrent administration of chloramphenicol succinate and phenobarbital in six patients resulted in reduced peak and trough concentrations of chloramphenicol of 16.6 and 7.5 micrograms/ml, respectively (P less than 0.05). Concurrent administration of chloramphenicol succinate and phenytoin in six patients resulted in an elevated mean peak serum concentration of chloramphenicol of 41.7 micrograms/ml (P less than 0.05). Five other patients treated with phenytoin had indeterminate serum chloramphenicol half-lives with chloramphenicol concentrations of 29 to 90 micrograms/ml. Potentially toxic chloramphenicol concentrations occurred in 9 of 17 controls, 0 of 6 patients who had received phenobarbital (P = 0.001) and 11 of 11 patients who had received phenytoin (P = 0.008). Patients receiving combined chloramphenicol succinate and anticonvulsant therapy require monitoring of serum concentrations of drug and adjustments in the dose of chloramphenicol succinate administered.

Pharmacokinetics of cefotaxime in newborn infants.

The pharmacokinetics of cefotaxime were determined in newborn infants who were 1 to 7 days of age. Mean peak serum concentrations of 116 and 132 micrograms/ml were observed at completion of a 10-min intravenous infusion of 50 mg of cefotaxime per kg in low and average birth weight infants, respectively. The mean elimination half-lives were 4.6 and 3.4 h and rates of clearance from serum were 23 and 44 ml/min per 1.73 m2, respectively. A dosage schedule for cefotaxime in newborn infants is presented.

Pharmacokinetics of a new cephalosporin, cefotaxime (HR 756) in patients with different renal functions.

The pharmacokinetics of intramuscular doses of 1.0 g cefotaxime (HR 759) was studied in 19 persons with normal or reduced renal function. Quantitation was done by both microbiological and high pressure liquid chromatography (HPLC) methods. The HPLC determined unchanged cefotaxime and desacetyl cefotaxime and up to 2 more metabolites in serum, whether unchanged or biotransformed. Patients with renal functions within the normal range (inulin clearance above 100 ml/min) had a mean serum peak concentration of 24.5 ± 10.5 μg/ml. In renal failure, both serum concentrations and the terminal serum half-life (t½β) increased. The mean terminal serum half-life was 2.1 h according to the microbiological assay and 1.5 h according to the HPLC procedure at a glomerular filtration rate (GFR) of 100 ml/min. At an inulin clearance of 10 ml/min, the serum half-life was 6.0 h for the total microbiologically assayed activity and 3.6 h for unchanged drug. There is a linear relationship between log serum half-life of the three moieties of unchanged cefotaxime, total antimicrobial activity (agar diffusion assay with Escherichia coli as indicator), and the major metabolite desacetyl cefotaxime and log clearance of both inulin (ClI) and p-amino-hippuric acid (CIPAH) down to CII, of 10 ml/min. The excretion of unchanged drug in urine during 24 h was reduced gradually upon reduction in renal function from a mean of 59.4 ± 10.2% (range 52.1–77.1) in 5 subjects with GFR above 100 ml/min. The area volume of distribution, e.g. the area of the one-compartment linear open model or during the β-phase of the two-compartment model, Vd,area, was 34.3 ± 10.4 litres according to the microbiological assay and 27.3 ± 13.4 litres for unchanged cefotaxime in patients with renal function within the normal range. The patients with reduced renal function had only insignificantly different distribution volumes. The volumes in normal individuals correspond to 53% of the body weight. The deasacetyl cefotaxime metabolite is excreted more slowly than the parent compound and elimination is relatively longer compared to the parent compound in patients with reduced renal functions. Doses for patients with reduced renal function are discussed. Because nonrenal mechanisms of elimination assume importance when the renal route becomes inefficient, elimination is only moderately prolonged, even in patients with severe renal impairment. Therefore, only moderate reduction in dosage seems necessary.

Oral Chloromycetin

The recent study by Yogev et al1 nicely demonstrates that therapeutic concentrations of chloramphenicol in serum and CSF are achieved following oral administration of chloramphenicol palmitate. However, the authors' pharmacokinetic interpretation of their data is open to question. The apparent longer half-life and higher mean peak and trough serum concentrations most likely reflect greater bioavailability and prolonged absorption of the oral dosage form compared to the intravenous preparation rather than a difference in elimination half-life.

Kinetics of an orally absorbed aldose reductase inhibitor, sorbinil.

Kinetics of sorbinil, an orally absorbed reductase inhibitor, were examined in man. Peak plasma concentrations were 0.95 micrograms/ml after a single 50-mg oral dose and 3.6 micrograms/ml after a 250-mg dose. The apparent volume of distribution was 840 ml/kg. Elimination from plasma was slow with a terminal half-life between 6 and 24 hr after dose of 34 to 52 hr and a renal clearance of 6.0 ml/min/1.73 m2. Administration of 50 mg/day for 5 days induced a mean peak serum concentration of 1.9 micrograms/ml. A dose of 250 mg/day for 10 days induced a peak serum concentration of 10.6 micrograms/ml. A mean of one-third of the dose was ultimately recovered unchanged in urine. Sorbinil kinetics make it suitable for once-a-day dosing.

Phase I study of ceftizoxime, a new cephalosporin. Single-dose study.

A phase I study of ceftizoxime, a new cephalosporin, was performed in 29 subjects. No abnormalities were observed in subjective symptoms, laboratory test results, or physical test results at estimated therapeutic doses of 500 mg intramuscularly, 500 and 1000 mg intravenously, and 2000 mg drip infusion. It is concluded, therefore, that the drug is safe for clinical use. The mean peak serum concentration was dose dependent. The mean serum concentrations of ceftizoxime in man at 5 minutes after 500 and 1000 mg by intravenous bolus were 58.4 and 112.8 micrograms/ml, respectively, which exceed the MIC80 against most pathogens tested. Thus, 500 or 1000 mg was estimated to be the therapeutic dose. The distribution volume of ceftizoxime was 16.0 to 18.6 liters, the total clearance was 135.6 to 154.9 ml/min, and the half-life in the beta-phase was 1.36 to 1.39 hours. Ceftizoxime is mainly excreted in the urine as unchanged drug, at an excretion rate in the 24-hour urine of approximately 80 per cent.