Pharmacokinetics Of Penicillin Research Articles

Особенности фармакокинетики антибактериальных антибиотиков при беременности

Представлена современная информация о фармакокинетических особенностях отдельных антибактериальных антибиотиков у беременных, включающая увеличение объема распределения, почечного клиренса и снижение степени связывания с белками крови. Показано, что существует прямая зависимость между антибактериальной активностью препарата и степенью его связывания с белками: чем больше препарата находится в связанном состоянии, тем меньше его антибактериальная активность. Приведены особенности фармакокинетики пенициллинов, цефалоспоринов, аминогликозидов, макролидов у беременных, которые предопределяют необходимость изменения режима дозирования этих препаратов. Рассмотрены аспекты безопасности применения антибиотиков для плода.

Pharmacokinetics of Penicillin G in Preterm and Term Neonates

Group B streptococci are common causative agents of early-onset neonatal sepsis (EOS). Pharmacokinetic (PK) data for penicillin G have been described for extremely preterm neonates but have been poorly described for late-preterm and term neonates. Thus, evidence-based dosing recommendations are lacking. We describe the PK of penicillin G in neonates with a gestational age (GA) of ≥32 weeks and a postnatal age of <72 h. Penicillin G was administered intravenously at a dose of 25,000 or 50,000 IU/kg of body weight every 12 h (q12h). At steady state, PK blood samples were collected prior to and at 5 min, 1 h, 3 h, 8 h, and 12 h after injection. Noncompartmental PK analysis was performed with WinNonlin software. With those data in combination with data from neonates with a GA of ≤28 weeks, we developed a population PK model using NONMEM software and performed probability of target attainment (PTA) simulations. In total, 16 neonates with a GA of ≥32 weeks were included in noncompartmental analysis. The median volume of distribution (V) was 0.50 liters/kg (interquartile range, 0.42 to 0.57 liters/kg), the median clearance (CL) was 0.21 liters/h (interquartile range, 0.16 to 0.29 liters/kg), and the median half-life was 3.6 h (interquartile range, 3.2 to 4.3 h). In the population PK analysis that included 35 neonates, a two-compartment model best described the data. The final parameter estimates were 10.3 liters/70 kg and 29.8 liters/70 kg for V of the central and peripheral compartments, respectively, and 13.2 liters/h/70 kg for CL. Considering the fraction of unbound penicillin G to be 40%, the PTA of an unbound drug concentration that exceeds the MIC for 40% of the dosing interval was >90% for MICs of ≤2 mg/liter with doses of 25,000 IU/kg q12h. In neonates, regardless of GA, the PK parameters of penicillin G were similar. The dose of 25,000 IU/kg q12h is suggested for treatment of group B streptococcal EOS diagnosed within the first 72 h of life. (This study was registered with the EU Clinical Trials Register under EudraCT number 2012-002836-97.).

Clinical pharmacokinetics of penicillins in the neonate: a review of the literature

Sepsis is common in neonates and a major cause of morbidity and mortality. Sixty percent of preterm neonates receive at least one antibiotic during the first week of life, with penicillins being the most frequently administered antibiotics. The clearance (Cl), serum half-life (t((1/2))) and volume of distribution (Vd) of penicillins are different in the neonate than in the adult. As such, the pharmacokinetics of penicillins need be studied in neonates in order to optimise therapy in this age class with these drugs. The aim of this study was to review the published data on the pharmacokinetics of penicillins in the neonate in order to provide a critical analysis of the literature and, consequently, a useful tool in the hands of the physician. The bibliographic search was performed electronically using the PubMed and EMBASE databases as search engines. An initial search was performed with the keywords "pharmacokinetics", "penicillins" and "neonates". Secondly, other searches were performed using the keywords "pharmacokinetics" and "neonates", followed by the name of a single antibiotic. The search included articles up to 2007. There have been few pharmacokinetic studies on the use of penicillins in neonates. The results from those few studies that have been carried out suggest that the Cl is reduced and t((1/2)) prolonged in the neonate as compared with the more mature infant. There is little variation in Vd during the first week of life. In the premature neonate, Cl is reduced compared to the full-term infant. As postnatal age proceeds, the Cl of penicillins increases. More pharmacokinetic studies are required to provide a sound scientific basis for planning a dosage regimen with penicillins in the neonate.

Pharmacokinetics of Penicillin G in Infants with a Gestational Age of Less than 32 Weeks

The pharmacokinetics of penicillin G were studied in 20 preterm neonates with a gestational age of less than 32 weeks on day 3 of life by using a population approach performed with the nonlinear mixed effects modeling program NONMEM. The derived population estimates and the correlation matrix of these estimates were used to perform Monte Carlo simulations and obtain the probability of target attainment (PTA). The pharmacokinetics of penicillin G were best described by a two-compartment pharmacokinetic model. The population estimates of the central volume of distribution, the peripheral volume of distribution, the intercompartmental clearance, and the total body clearance were 0.359 +/- 0.06 liter, 0.152 +/- 0.03 liter, 0.774 +/- 0.28 liter/h, and 0.103 +/- 0.01 liter/h (mean +/- standard error), respectively. The terminal half-life was 3.9 h. Clearance increased significantly with increasing birth weight. Assuming the percentage of time that the concentration of unbound drug remained above the MIC of 50% for preterm neonates, the susceptibility breakpoint based on a 100% PTA was < or =4 mg/liter, simulating the current dosing regimen of 50,000 U/kg every 12 h. This regimen is therefore adequate for the treatment of common infections in neonates on the third day of life.

Pharmacokinetics of Penicillin G in Very-Low-Birth-Weight Neonates

Data on the pharmacokinetics (PKs) of penicillin G (PEN) in neonates date back to the 1970s and do not include data for very-low-birth-weight (VLBW) neonates. The aim of this study was to describe the steady-state PKs and to establish an optimal regimen for the dosing of PEN in neonates with gestational ages of less than 28 weeks and birth weights of less than 1,200 g. Two PEN dosing regimens were studied: 50,000 IU (30 mg)/kg of body weight every 12 h (q12h) (group 1; n = 9) and 25,000 IU (15 mg)/kg q12h (group 2; n = 9). Samples for PK analysis were drawn before the injection of PEN and at 2 and 30 min and 1.5, 4, 8, and 12 h after intravenous injection of the third to eighth PEN doses. The PEN concentration was measured by a high-performance liquid chromatography with UV detection technique. The median peak and trough concentrations of PEN were 147 mug/ml (lower and upper quartiles, 109 and 157 mug/ml, respectively) and 7 mug/ml (lower and upper quartiles, 5 and 13 mug/ml, respectively) after administration of the dose of 50,000 IU and 59 mug/ml (lower and upper quartiles, 53 and 78 mug/ml, respectively) and 3 mug/ml (lower and upper quartiles, 3 and 4 mug/ml, respectively) after administration of the dose of 25,000 IU. The PEN half-life (median and lower and upper quartiles for group 1, 3.9 h and 3.3 and 7.0 h, respectively; median and lower and upper quartiles for group 2, 4.6 h and 3.8 and 5.6 h, respectively) was longer in VLBW neonates than in adults and term infants. PEN renal clearance correlated with creatinine clearance (R(2) = 0.309596; P = 0.038). Only a median of 34% (lower and upper quartiles, 28 and 37%, respectively) of the administered dose was excreted in urine within the following 12 h. We conclude that in VLBW infants a PEN dose of 25,000 IU (15 mg)/kg q12h is safe and sufficient to achieve serum concentrations above the MIC(90) for group B streptococci for the entire dosing interval.

P1370 Pharmacokinetics of penicillin G in infants with a gestational age of less than 32 weeks

P1370 Pharmacokinetics of penicillin G in infants with a gestational age of less than 32 weeks

Bioequivalence study in calves of three commercial penicillin/dihydrostreptomycin fixed combination products for intramuscular injection.

A bioequivalence study with three penicillin/dihydrostreptomycin fixed combination products for intramuscular administration was performed in dairy calves. In addition to plasma concentrations of penicillin and dihydrostreptomycin, creatine phosphokinase concentrations were determined during a period of 72 h after administration of the drug products. Considerable differences were observed in the pharmacokinetics of penicillin from the three products. Although the extent of absorption was similar for all products, one product showed a significantly slower release from the site of injection. Except for the AUC, the 90% confidence intervals for these parameters exceeded the acceptable range of 0.80-1.20. Therefore, these products are not bioequivalent with respect to the rate of absorption of penicillin. Concerning the pharmacokinetics of dihydrostreptomycin in calves, it could not be concluded that the products were bioequivalent, since the 90% confidence intervals of the ratios for Cmax, tmax and MRT exceeded the range of 0.80-1.20. From this study in calves, it was also found that the product with the slowest release of penicillin from the injection site caused the most severe tissue damage, based on plasma creatine phosphokinase concentrations. Comparing the results from this study in calves with those from a previous study in rabbits, it can be concluded that the rabbit is a good animal model that could substitute for large animals, at least calves, in bioequivalence studies for penicillin/dihydrostreptomycin fixed combination products.

Ampicillin vs. penicillin for in utero therapy

The pharmacokinetics of penicillin G and ampicillin are reviewed as they pertain to their potential use in in vitro therapy. © 1996 Wiley-Liss, Inc.

Ampicillin Vs. Penicillin for In Utero Therapy

The pharmacokinetics of penicillin G and ampicillin are reviewed as they pertain to their potential use in in vitro therapy.

Experimental Streptococcus pneumoniae infection in mice for studying correlation of in vitro and in vivo activities of penicillin against pneumococci with various susceptibilities to penicillin.

The purpose of the study was to investigate the correlation of in vitro activity with the in vivo effect and the pharmacokinetics of penicillin in the treatment of infections with pneumococci with various susceptibilities to penicillin. We used 10 pneumococcal strains for which penicillin MICs ranged from 0.016 to 8 micrograms/ml. Time-kill curve experiments were performed with all strains. We found that the effect of penicillin in vitro is concentration independent, with a maximum effect at two to four times the MIC for penicillin-susceptible as well as penicillin-resistant pneumococci. The mouse peritonitis model with an inoculum of approximately 10(6) CFU, to which mucin was added, resulted in a reproducible lethal infection with the pneumococci. The 50% effective dose was determined for each strain, and we found a highly significant correlation between the log MIC and the log 50% effective dose of penicillin against these strains (P < 0.01). Furthermore, it was shown that the most important pharmacokinetic parameter determining the effect of penicillin in vivo was the time that the concentration of penicillin in serum was greater than the MIC.

Malnutrition and Pharmacokinetics of Penicillin in Ethiopian Children

Penicillin was given to 104 children with different nutritional status, normal, underweight, marasmus and kwashiorkor. Penicillin was given either intravenously, intramuscularly or orally and the plasma concentration was followed at regular times after administration. There was a significantly decreased plasma clearance of penicillin in all malnourished groups compared to the normal weight-for-age group. The half-lives of penicillin were, however, not significantly different between the nutritional groups. This was explained by the fact that also the volume of distribution was decreased in the malnourished group with a net result that the half-life was unchanged. The bioavailability was decreased if penicillin was given to non-fasting individuals. The greatest difference between fasting and non-fasting was seen in the severely malnourished children with marasmus and kwashiorkor. Therefore, it is advised that, if penicillin is given orally to very sick and undernourished children, the dose should be increased and preferably be given in the fasting state.

Effects of experimentally induced Streptococcus suis infection on the pharmacokinetics of penicillin G in pigs

The pharmacokinetics of potassium penicillin G were studied in both healthy (n = 8) and experimentally Streptococcus-suis-infected (n = 6) pigs following intramuscular administration (15,000 iu/kg). Streptococcus-suis infection was induced artificially in young cross-bred pigs by subcutaneous inoculation with 9 x 10(8) to 10(9) colony-forming units of S. suis. The rectal temperature of infected pigs was significantly increased (P less than 0.01) before penicillin G injection and this was maintained for 8 h after the drug was given. Other clinical symptoms were also present. The serum concentration-time data for penicillin were found to fit a one-compartment open model with first-order absorption in the two groups of pigs. Significant changes were not observed between healthy and diseased pigs in following parameters: A, Ka, Ke and Tmax. However, in diseased pigs, significant increases (P less than 0.01) were found in Vd and ClB, and significant decreases (P less than 0.01) in Cmax and AUC occurred. The increased body clearance (ClB) and greater apparent volume of distribution (Vd) of penicillin G could partly explain why the serum values of the drug were much lower in diseased pigs than in healthy pigs.

Effect of ethanol on the pharmacokinetics of penicillin in the rat.

The effect of a single intraperitoneal dose of ethanol (2 g/kg) given 30. min. prior to intravenous administration of benzylpenicillin (20, 40 and 80 mg/kg) was studied in rats. Ethanol pretreated animals showed lower blood and brain tissue levels of penicillin, 15 and 30 min. after the administration of the two lower penicillin doses. This difference was not observed when the penicillin dose was raised to 80 mg/kg. The quotient between brain and serum concentrations was increased 45 min. after the injection of 20 mg/kg of penicillin. Urine collection during the following 2 days showed an increased urine volume during the first 4-hour period in animals pretreated with ethanol. During the same time period they excreted less benzylpenicillin than the controls.

The pharmacokinetics of penicillin in osteomyelitic canine bone.

The pharmacokinetics of penicillin in osteomyelitic canine bone.

Drug residues in food animals. III. Plasma and tissue kinetics of potassium penicillin G in young cross‐bred swine

Twenty‐two young cross‐bred swine were treated either intravenously or orally with potassium penicillin G. The pharmacokinetics of penicillin G were determined in plasma and tissues. The plasma half‐life of penicillin G in swine was found to be 19.45±1.69 min, and the distribution and elimination kinetics were found to fit a classical two‐compartment model. The volume of distribution was found to be 0.53±0.12 1/kg, and the body clearance was found to be 19.06±5.06 ml/min/kg which exceeded the effective renal plasma flow of 16.50±2.73 ml/min/kg, suggesting that the drug was eliminated both by tubular excretion and glomerular filtration. The elimination rate constants (Beta) for the major organs were as follows: muscle, 0.00343 min‐1; lung, 0.0310 min‐1; fat, 0.0394 min‐1; and kidney, 0.0213 min‐1, which compared favorably with the elimination rate constant found in plasma (0.0320 min‐1). These values were found to be significantly similar at the level of P &lt; 0.005 in muscle, spleen and fat, and at a level of P &lt; 0.025 in lung tissue. The data indicates that blood plasma would be a satisfactory body fluid for estimating this drug in tissue.