Pharmacokinetics of Cefamandole in Patients with Renal Impairment

Cefamandole pharmacokinetics were investigated in 24 adult males with stable renal function and creatinine clearances of 0 to 139 ml/min. After intramuscular injection of 1.0 g of cefamandole, peak plasma concentrations were achieved between 1 and 2 h. Maximum plasma concentration and drug half-life increased as creatinine clearance decreased; i.e., with normal renal function the half-life was 1.49 +/- 0.10 h, and in anephrics the half-life was 11.48 +/- 1.91 h. The greatest increase in half-life occurred when the creatinine clearance was less than 20 ml/min. At these levels of renal impairment, there was significant variance in calculated half-life among patients. The maximum urine concentration and rate of cefamandole urinary excretion decreased as renal function declined. Evidence suggesting renal and nonrenal methods of drug elimination is presented. Hemodialysis resulted in increased cefamandole elimination.     

Pharmacokinetics of Cefamandole in the Presence of Renal Failure and in Patients Undergoing Hemodialysis

The pharmacology of cefamandole in seven patients with stable renal insufficiency and in eight patients undergoing hemodialysis was determined. All patients had creatinine clearances less than 5 ml/min. The half-life of cefamandole in those patients with stable chronic renal failure was 7.7 ± 2.2 h. The mean venous level 1 h after intravenous injection of a 1-g dose was 85.3 ± 32.0 μg/ml. The mean venous half-life of cefamandole during hemodialysis was 6.1 h. The venous serum level after 5.5 of hemodialysis was 50.4 ± 20.8 μg/ml. The mean coefficient of extraction was 0.155, and the mean clearance was 34.7 ml/min. The time interval between doses of cefamandole administered intravenously should be lengthened to 24 h in the presence of stable renal failure. No major change in dosage schedule is necessary for patients undergoing dialysis.     

Pharmacokinetics of Cefamandole in Patients with Normal and Impaired Renal Function

The pharmacokinetics of cefamandole, a new cephalosporin, were investigated in 23 patients with urinary tract infections and normal or varying degrees of impairment of renal function. A daily dose of 1.5 to 3.0 g administered intramuscularly was tolerated well and resulted in very high urine concentrations. The pharmacokinetics of the antibiotic were compared with isotopically labeled [¹³¹I]hippurate and [¹²⁵I]iothalamate, which were used for determination of effective renal plasma flow and glomerular filtration rate, respectively. It was shown that cefamandole was excreted by glomerular filtration as well as by active tubular secretion. Probenecid inhibited the tubular secretion of cefamandole. The serum half-life of cefamandole in patients with normal renal function was approximately 1.5 h and increased in patients along with increasing impairment of renal function. Our studies indicate that a dosage regimen of 1 g of cefamandole every 8 h in patients with normal renal function results in urine concentrations sufficiently high for treatment of most common urinary tract infections. In patients with impaired renal function, the dosage interval should be increased or the dosage lowered according to the serum creatinine values.     

Pharmacokinetics of Nafcillin in Patients with Renal Failure

Nafcillin, a pencillinase-resistant penicillin, is frequently used for treatment of staphylococcal infections in hemodialysis patients. Despite its widespread use, there is a paucity of available data regarding the pharmacokinetics of nafcillin in hemodialysis patients. Therefore, sodium nafcillin, 25 mg/kg, was given intravenously over a 5- to 15-min period to 12 hemodialysis patients. Eleven patients were studied during dialysis, and eight of these were studied again during the interdialysis period. The initial serum half-life for nafcillin was 0.208 h during dialyses and 0.278 h between dialyses. The terminal half-life was 1.48 h during dialyses and 1.89 h between dialyses. There was no statistically significant difference between these values. These data indicate that renal failure does not appreciably affect the serum half-life of nafcillin, and hemodialysis does not accelerate the rate of clearance of nafcillin from the blood. Therefore, no modification of the usual nafcillin dosage is necessary when using this drug in hemodialysis patients.     

Pharmacokinetics of Cefaclor in Normal Subjects and Patients with Chronic Renal Failure

We studied the pharmacokinetics of cefaclor, a new cephalosporin antibiotic, in normal subjects and subjects with chronic renal failure. Cefaclor was largely, but not entirely, eliminated by the kidneys. The cefaclor half-life in normal subjects was 40 to 60 min; in subjects with essentially no renal function, it increased to 3 h. In normal subjects, 50 to 70% of a 250-mg dose was excreted in the urine within 8 h. The linear relationship between the elimination constant and creatinine clearance allowed the construction of a useful dosage modification nomogram.     

Pharmacokinetics of Cefamandole in Patients Undergoing Hemodialysis and Peritoneal Dialysis

The pharmacokinetics of cefamandole nafate, a new parenteral cephalosporin derivative, were evaluated in 11 patients with chronic renal failure (creatinine clearance less than 5 ml/min), including five patients during hemodialysis, four patients during routine peritoneal dialysis, and two patients during the interdialytic period. Peak serum levels of cefamandole were comparable to those observed in patients with normal renal function. Clearance of the drug during the interdialytic period and during hemodialysis and peritoneal dialysis was minimal, with a resultant significant prolongation of serum half-life. The nondialyzability of cefamandole is in contrast with reported studies of cephalothin, where significant reduction of the serum half-life was achieved during hemodialysis but not peritoneal dialysis. The concentration of cefamandole in the peritoneal dialysate after parenteral administration was observed to be bactericidal for many gram-negative pathogens and, with the exception of Streptococcus faecalis, most gram-positive organisms found in bacterial peritonitis in patients with severe renal failure. The present data suggest that if stable bactericidal serum levels of cefamandole are to be maintained during hemodialysis and peritoneal dialysis, a parenteral loading dose must be administered followed by one-half the loading dose every half-life.     

Pharmacokinetics of Minocycline in Renal Failure

The pharmacokinetics of minocycline have been studied after single intravenous infusions and repeated oral doses to human subjects with varying degrees of renal impairment. There was no evidence of reduced drug clearance with reduced renal function after intravenous doses although there appeared to be an increase in the tissue distribution of antibiotic in the body in uremia. After identical multiple oral dosage regimens serum levels of antibiotic were comparable in normal and mildly uremic subjects. There was no evidence of renal toxicity in normal or uremic subjects with the repeated dosage regimen used.     

Pharmacokinetics of Meropenem in Critically Ill Patients with Acute Renal Failure Treated by Continuous Hemodiafiltration

The pharmacokinetics of meropenem were studied in nine anuric critically ill patients treated by continuous venovenous hemodiafiltration. Peak levels after infusion of 1,000 mg over 30 min amounted to 103.2 ± 45.9 μg/ml, and trough levels at 12 h were 9.6 ± 3.8 μg/ml. A dosage of 1,000 mg of meropenem twice a day provides plasma drug levels covering intermediately susceptible microorganisms. Further reductions of the dosage might be appropriate for highly susceptible bacteria or when renal replacement therapies with lower clearances are applied.     

Pharmacokinetics of Cefamandole in Infants and Children

In infants less than 3 months of age, the serum concentration of cefamandole during therapy was higher and more prolonged than that in children older than 1 year. A dosage of 37 mg/kg administered intravenously at 6-h intervals provided a serum concentration in excess of the minimum inhibitory concentrations of common bacterial pathogens for 4 h, and in young infants for 5 h, after dosing.     

In Vitro Activity and Pharmacokinetics in Patients of Cefamandole, a New Cephalosporin Antibiotic

Cefamandole nafate, a new cephalosporin for parenteral use, was evaluated in vitro against 231 recent clinical isolates and in 12 patients. Cefamandole had activity equivalent to cefazolin against Staphylococcus aureus, Escherichia coli, and Klebsiella pneumoniae. Cefamandole was more active than cephalothin or cefazolin against Proteus mirabilis. Both cefamandole and cefazolin were as active as cephalothin against S. aureus, were slightly more active against K. pneumoniae, and were considerably more active against E. coli. All strains of indole-positive Proteus sp. were inhibited by 6.3 mug of cefamandole per ml but only 20% were inhibited by 25 mug of cefazolin or cephalothin per ml. Eighty-eight percent of Enterobacter sp. was inhibited by 25 mug of cefamandole per ml, but only 20 and 5% were inhibited by the same concentration of cefazolin and cephalothin, respectively. Peak levels of cefamandole ranged from 6.0 to 110 mug/ml in serum and levels ranged from 440 to 16,800 mug/ml in a 4- to 6-h collection of urine after a 500-mg or 1-g intramuscular dose (6.1 to 17.3 mg/kg) in patients with endogenous creatinine clearances of >/=31 ml/min. These levels were done after the first dose, at mid-therapy, and at the end of therapy. There was no evidence of accumulation with the 500-mg or 1-g dose given every 4 to 6 h. The percentage of the dose excreted in the urine within the first 4 to 6 h after administration of cefamandole was >/=43%. The half-life of cefamandole in serum was 49 to 126 min.     

Pharmacokinetics and Safety of Cefamandole in Newborn Infants

Cefamandole, a new parenteral cephalosporin antibiotic, was administered to 23 newborn infants with pustular skin infection due to Staphylococcus aureus for an average duration of 7.5 days. All the patients improved clinically. Elevation of serum glutamic oxaloacetic transaminase and eosinophilia were observed in nine infants each transiently during treatment. There were no abnormalities of renal functions and Coombs' test results remained negative. The levels of cefamandole in serum after either intravenous or intramuscular administration were higher and the mean life was longer than those previously reported in older infants, children, and adults.     

Pharmacokinetics of Sulfobutylether-Beta-Cyclodextrin and Voriconazole in Patients with End-Stage Renal Failure during Treatment with Two Hemodialysis Systems and Hemodiafiltration

Sulfobutylether-beta-cyclodextrin (SBECD), a large cyclic oligosaccharide that is used to solubilize voriconazole (VRC) for intravenous administration, is eliminated mainly by renal excretion. The pharmacokinetics of SBECD and voriconazole in patients undergoing extracorporeal renal replacement therapies are not well defined. We performed a three-period randomized crossover study of 15 patients with end-stage renal failure during 6-hour treatment with Genius dialysis, standard hemodialysis, or hemodiafiltration using a high-flux polysulfone membrane. At the start of renal replacement therapy, the patients received a single 2-h infusion of voriconazole (4 mg per kg of body weight) solubilized with SBECD. SBECD, voriconazole, and voriconazole-N-oxide concentrations were quantified in plasma and dialysate samples by high-performance liquid chromatography (HPLC) and by HPLC coupled to tandem mass spectrometry (LC-MS-MS) and analyzed by noncompartmental methods. Nonparametric repeated-measures analysis of variance (ANOVA) was used to analyze differences between treatment phases. SBECD and voriconazole recoveries in dialysate samples were 67% and 10% of the administered doses. SBECD concentrations declined with a half-life ranging from 2.6 ± 0.6 h (Genius dialysis) to 2.4 ± 0.9 h (hemodialysis) and 2.0 ± 0.6 h (hemodiafiltration) (P < 0.01 for Genius dialysis versus hemodiafiltration). Prediction of steady-state conditions indicated that even with daily hemodialysis, SBECD will still exceed SBECD exposure of patients with normal renal function by a factor of 6.2. SBECD was effectively eliminated during 6 h of renal replacement therapy by all methods, using high-flux polysulfone membranes, whereas elimination of voriconazole was quantitatively insignificant. The SBECD half-life during renal replacement therapy was nearly normalized, but the average SBECD exposure during repeated administration is expected to be still increased.Voriconazole (VRC), a triazole broad-spectrum antifungal agent, is used for systemic treatment of severe fungal infections, including invasive aspergillosis and invasive candidiasis (6, 9). For intravenous administration, sulfobutylether-beta-cyclodextrin (SBECD) is used as a solvent. SBECD is a cyclic oligosaccharide composed of 1,4-linked glucopyranose molecules that form a truncated cone with a hydrophilic outer surface and a hydrophobic cavity (10, 15). This structure leads to an inclusion complex with the lipophilic voriconazole in its center (4). SBECD appears to be well tolerated in humans, but in animal studies, vacuolation of epithelial cells of the urinary tract as well as an activation of macrophages in liver and lung was observed after repeated doses of SBECD (5). SBECD is a pharmacologically inert agent. The terminal half-life of SBECD in humans with normal renal function is 1.8 h (1), and the steady-state volume of distribution is approximately 0.2 liter/kg of body weight, which is similar to extracellular fluid volume in humans and evidence of very little penetration into the tissues (17). SBECD is renally excreted (95% of the compound), and its clearance is linearly correlated with creatinine clearance. An increased SBECD exposure has been observed in patients with moderate renal impairment and renal failure (1, 19). Preliminary data from four patients with end-stage renal failure on intermittent hemodialysis indicated an extracorporeal SBECD clearance of 3.3 liters/h and removal of approximately 46% of SBECD during 4 h of hemodialysis (12).Voriconazole is extensively metabolized by the hepatic cytochromes CYP2C19, CYP2C9, and CYP3A4 with a terminal elimination half-life (T_1/2) of approximately 7 h. The main metabolite, voriconazole-N-oxide, has only minimal antifungal activity, but its role in voriconazole-associated toxicity is unclear. Extracorporeal voriconazole clearance by hemodialysis is reported as 7.3 liters/h (17) but is considered clinically irrelevant due to the large apparent volume of distribution. Only 2% of a voriconazole dose is excreted unchanged renally. Voriconazole exhibits nonlinear pharmacokinetics, presumably due to saturation of metabolism, which can be described by a two-compartment model with saturable elimination (8).During hemodialysis, solutes are removed by diffusion over a semipermeable membrane, whereas in hemofiltration, removal of solutes is achieved by convective transport over the membrane by ultrafiltration. In intermittent hemodialysis, as used for patients with end-stage renal disease, a low ultrafiltration rate is used to remove excess water from the body (convective transport of solutes is of limited importance here). In intermittent hemodiafiltration, a higher ultrafiltration rate is used, which usually leads to an increase in extracorporeal solute clearance (excessively removed water is replaced in parallel). Genius dialysis is a special kind of hemodialysis with a single batch system where the whole dialysate is contained in one tank (3). Dialysis settings differ between countries. In Germany, dialysis durations of 4 to 5 h and blood flow rates between 200 and 300 ml/min are usually applied, whereas in the United States, dialysis durations of 3 to 4 h and blood flow rates over 300 ml/min are commonly used (13).SBECD and voriconazole pharmacokinetics in patients with renal failure undergoing different renal replacement therapies are still unknown. The aim of the present study was to determine the pharmacokinetics of SBECD and voriconazole in patients undergoing Genius dialysis, hemodialysis, or hemodiafiltration.     

Pharmacokinetics of Netilmicin in Patients with Renal Impairment and in Patients on Dialysis

The pharmacokinetics of netilmicin were examined in 25 adult subjects, 7 normal subjects, and 18 patients with renal impairment. Five were dialysis patients who were studied on and off dialysis. Netilmicin, 2 mg/kg, was infused intravenously over 1 h. The peak serum concentration ranged from 9 to 11 μg/ml. The mean biological half-life of netilmicin for subjects with a creatinine clearance (Ccr) > 70 ml/min was 2.7 h, for those with Ccr > 25 < 70 ml/min it was 10 h, for those with Ccr > 4 < 25 ml/min it was 32 h, and for those who were anephric it was 42 h. Ccr was correlated positively with the elimination constant and the drug's serum clearance. It was negatively correlated with the drug's volume of distribution. The dialyzer clearance of netilmicin was positively correlated with plasma flow rate and was similar to values previously reported for gentamicin. Netilmicin behaves in a fashion similar to other aminoglycosides. Therapeutic guidelines are suggested.     

Population Pharmacokinetics of Colistin Methanesulfonate and Colistin in Critically Ill Patients with Acute Renal Failure Requiring Intermittent Hemodialysis

Colistin is increasingly used as a last option for the treatment of severe infections due to Gram-negative bacteria in critically ill patients requiring intermittent hemodialysis (HD) for acute renal failure. Our objective was to characterize the pharmacokinetics (PK) of colistin and its prodrug colistin methanesulfonate (CMS) in this population and to suggest dosing regimen recommendations. Eight intensive care unit (ICU) patients who were under intermittent HD and who were treated by CMS (Colimycine) were included. Blood samples were collected between two consecutive HD sessions. CMS and colistin concentrations were measured by a specific chromatographic assay and were analyzed using a PK population approach (Monolix software). Monte Carlo simulations were conducted to predict the probability of target attainment (PTA). CMS nonrenal clearance was increased in ICU-HD patients. Compared with that of ICU patients included in the same clinical trial but with preserved renal function, colistin exposure was increased by 3-fold in ICU-HD patients. This is probably because a greater fraction of the CMS converted into colistin. To maintain colistin plasma concentrations high enough (>3 mg/liter) for high PTA values (area under the concentration-time curve for the free, unbound fraction of a drug [fAUC]/MIC of >10 and fAUC/MIC of >50 for systemic and lung infections, respectively), at least for MICs lower than 1.5 mg/liter (nonpulmonary infection) or 0.5 mg/liter (pulmonary infection), the dosing regimen of CMS should be 1.5 million international units (MIU) twice daily on non-HD days. HD should be conducted at the end of a dosing interval, and a supplemental dose of 1.5 MIU should be administered after the HD session (i.e., total of 4.5 MIU for HD days). This study has confirmed and complemented previously published data and suggests an a priori clear and easy to follow dosing strategy for CMS in ICU-HD patients.     

Influence of Renal Failure on Ciprofloxacin Pharmacokinetics in Rats

Ciprofloxacin pharmacokinetics have been shown to be modified in patients with renal failure (e.g., the intestinal secretion of ciprofloxacin is increased). This study investigated the influence of renal failure on the pharmacokinetics of ciprofloxacin following oral and parenteral administration to rats of a dose of 50 mg/kg of body weight. After parenteral administration, only renal clearance (CL_R) was reduced in nephrectomized rats (5.3 ± 1.4 versus 17.8 ± 4.7 ml/min/kg, P < 0.01, nephrectomized versus control rats). However, nonrenal clearance was increased in nephrectomized rats (32 ± 4 versus 15 ± 5 ml/min/kg, P < 0.01, nephrectomized versus control rats), suggesting compensatory mechanisms for reduced renal function. After oral administration, apparent total clearance and CL_R were reduced (P < 0.01) in nephrectomized rats (117 ± 25 and 6.8 ± 4.4 ml/min/kg, respectively) compared with the values for control rats (185 ± 9 and 22.6 ± 5.3 ml/min/kg, respectively) and the area under the concentration-time curve was higher (P < 0.01) for nephrectomized rats (436.3 ± 90.5 mg · min/liter) than for control rats (271.3 ± 14.3 mg · min/liter). Terminal elimination half lives in the two groups remained constant after oral and parenteral administration. These results suggest an increased bioavailability of ciprofloxacin in nephrectomized rats, which was confirmed by a nonlinear mixed-effect model.     

Cefamandole: In Vitro and Clinical Pharmacokinetics

Cefamandole has a broader spectrum and greater potency than the other cephalosporins. It includes Haemophilus influenzae, most strains of Enterobacter, and many strains of indole-positive Proteus and Bacteroides, with a lower minimal inhibitory concentration for Escherichia coli, Klebsiella, etc. Concentrations of drug in the serum after the parenteral injection of cefamandole exceed manyfold the minimal inhibitory concentrations of over 82% of the bacteria studied. Approximately 65 to 85% is excreted in a biologically active form in the urine. This antibiotic offers advantages of antibacterial effectiveness and at the same time retains the safety of penicillin G and cephalothin in animals.     

慢性肾功能衰竭患者性功能障碍

血液透析或腹膜透析能解除患者生命之虞，慢性肾功能衰竭（CRF）患者常常合并性功能障碍，已成为影响其生活质量的一个重要问题，却很少得到关注。本文就有关慢性肾功能衰竭患者性功能障碍的病因、诊断、治疗方法等进行综述如下。     

Pharmacokinetics and Safety of Cefamandole in Infants and Children

Cefamandole, a new cephalosporin antibiotic, has greater activity against common pathogens, including Escherichia coli, Haemophilus influenzae, and Proteus (including indole-positive strains), than available cephalosporin drugs. We have evaluated the safety and pharmacokinetics of this drug in 30 infants and children. Blood levels and urinary excretion of the drug were similar to those previously found in adults. The only side effects were mild and transient elevation of serum glutamic oxalacetic transaminase in 12 patients and of blood urea nitrogen in 1 patient in whom serum creatinine remained normal and unchanged.     

The Pharmacokinetics and Pharmacodynamics of Methylprednisolone in Chronic Renal Failure

Methylprednisolone (MP) pharmacokinetics and its directly suppressive effects on cortisol secretion, circulating T-cells, and basophils in blood were compared in six chronic renal failure (CRF) subjects and six healthy controls after an IV administration of MP 0.6 mg kg(minus sign1) as the sodium succinate ester. The CRF subjects were studied between hemodialysis treatments. The total clearance of methylprednisolone sodium succinate (the prodrug) was reduced by 40% in CRF; however, the pharmacokinetics of methylprednisolone remained unchanged. Methylprednisolone clearance was approximately 280 ml h(minus sign1) kg(minus sign1) and volume of distribution was about 1.1 L kg(minus sign1). Physiological pharmacodynamic models were applied for the immediate effects of MP, based on the premise that receptor binding is followed by rapid suppression of the secretion of cortisol and recirculation of basophils, T-helper cells, and T-suppressor cells, which persist until inhibitory concentrations (IC(50)) of methylprednisolone disappear. The difference in IC(50) for each pharmacodynamic parameter was not statistically significant, suggesting no difference in the responsiveness of these factors to methylprednisolone in CRF. As the pharmacokinetics of other corticosteroids are altered in CRF, the lack of pharmacokinetic and pharmacodynamic changes of methylprednisolone may engender a therapeutic advantage for this corticosteroid in CRF.