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 Amoxicillin: Dosage Nomogram for Patients with Impaired Renal Function

Amoxicillin pharmacokinetics after intravenous administration were studied in patients with normal renal function, with impaired renal function, and during hemodialysis. The average urinary recovery was 68% in patients with normal renal function. Serum half-life was highly correlated (r = 0.967) with creatinine clearance corrected for body weight. Expected half-life was 71 min for a corrected creatinine clearance of 100 ml/min per 70 kg and 16 h in the anephric patient. Average amoxicillin half-life on hemodialysis was 3.6 h. We present a dosage nomogram for making appropriate adjustments to loading dose based on patient weight and maintenance dose based on corrected creatinine clearance.     

Cinoxacin: pharmacokinetics and tolerance in patients with normal and impaired renal function.

The pharmacokinetics of cinoxacin, a new antibacterial compound related to nalidixic acid and oxolinic acid, were investigated in 22 patients with varying degrees of renal impairment. After oral administration of cinoxacin at 500 mg every 12 h for 7 days to all patients, the drug was found to be well tolerated. The urine concentrations of cinoxacin in all patients far exceeded the minimal inhibitory concentrations for susceptible organisms commonly found in urinary tract infections. The serum half-life of cinoxacin in patients with normal renal function was approximately 2.7 h but increased to approximately 8.5 h in patients with creatinine clearance less than 30 ml/min. No undue drug accumulation was demonstrated in any patient group during the treatment. Highly significant correlations were found between the elimination rate constant and creatinine clearance and also between the elimination half-life and serum creatinine. The bioavailability of cinoxacin was independent of renal function.     

Effects of impaired renal function, hemodialysis, and peritoneal dialysis on the pharmacokinetics of mezlocillin

The pharmacokinetics of mezlocillin were examined in 8 patients with normal renal function (inulin clearance, > 80 ml/min per 1.73 m2), 32 patients with moderately reduced renal function (inulin clearances, 80 to 5 ml/min per 1.73 m2), and 12 patients maintained by hemodialysis or peritoneal dialysis because of severely impaired renal function. A single dose of 60 mg of mezlocillin per kg of body weight was infused intravenously over 30 min. Antibiotic concentrations in plasma, urine, and dialysate were determined by the agar diffusion technique. The half-life of mezlocillin increased with decreasing renal function from an average of 53 min in subjects with normal function to 165 min in oligoanuric patients. The urinary recovery of this drug in 24 h decreased from 65% at a glomerular filtration rate of 92 ml/min to 7.6% at a glomerular filtration rate of 6.7 ml/min. Volume of distribution was not changed by the renal insufficiency, amounting on the average to 22.5% of body weight. Intermittent hemodialysis or peritoneal dialysis contributed to only a minor degree to the 24-h mezlocillin kinetics. The pharmacokinetic properties of mezlocillin permit a normal dosage over wide ranges of renal insufficiency; however, when the glomerular filtration rate is below 10 ml/min, the dosage interval should be increased from 8 to 12 h.     

Altered tobramycin pharmacokinetics during chemoprophylaxis in bladder surgery.

The effect of bladder surgery on the pharmacokinetics of tobramycin in hospitalized patients was studied. Fourteen patients with vesical neoplasia undergoing urinary tract surgery were given tobramycin in a dose of 2 mg/kg of body weight. Each patient received the dose at the induction of anesthesia, about 1 h before surgical incision. For seven patients, the drug was also administered 3 weeks later when nutritional conditions were normal. The pharmacokinetic parameters were determined by a two-compartment open model. Except for renal clearance, no significant difference appeared between pharmacokinetic parameters determined from serum data during peri- and postoperative periods. During this work, tobramycin excretion in urine was studied. Twenty-four hours after drug administration, the mean urine tobramycin levels were 25.5 +/- 9.06 and 41.6 +/- 21.5 micrograms/ml after peri- and postoperative administration, respectively; these values were higher than the MICs for most urinary tract pathogens. Seventy-two hours after perioperative administration, the mean value was still elevated (3.54 micrograms/ml), but 72 h after postoperative administration, the urinary tobramycin concentration was not detectable. The percentages of tobramycin recovered unchanged in urine were 54 and 79% after peri- and postoperative administration, respectively. When tobramycin was administered during surgery, a long terminal log-linear phase, with a mean half-life of 25.6 h, was detected. The ratio of renal clearance to total body clearance was 0.52 and 0.79 after peri- and postoperative administration, respectively.     

Pharmacokinetics of aztreonam in patients with gram-negative infections.

Aztreonam pharmacokinetics were assessed in seven patients treated for urinary (n = 6) or lower respiratory (n = 1) tract infections. Each patient was studied twice, at the beginning and end of therapy (7 to 10 days). The patients enrolled had normal to moderately impaired renal function; a good correlation (r2 = 0.90) between serum aztreonam clearance (CL) and creatinine clearance (CLCR) was observed (mean CL/CLCR ratio = 1.11). CL ranged from 21.6 to 121 ml/min per 70 kg, and the half-life ranged from 1.6 to 8.9 h. The mean steady-state volume of distribution (0.16 +/- 0.05 [standard deviation] liter/kg) approximated the extracellular fluid volume. Protein binding of aztreonam in serum (mean, 30%) was lower than that reported in healthy adults. CL increased significantly from the first to the last day of the study, probably reflecting increasing renal function. After multiple dosing (1 g every 8 h), no significant accumulation of aztreonam was observed. Overall, the disposition of aztreonam is comparable in infected and noninfected subjects, and dosing adjustments in patients with renal impairment should be facilitated by the good correlation between CL and CLCR.     

Gentamicin pharmacokinetics in 1,640 patients: method for control of serum concentrations.

The pharmacokinetics and dosage requirements of gentamicin were studied in 1,640 patients receiving treatment for gram-negative infections. A wide interpatient variation in the kinetic parameters of the drug occurred in all patients and in patients who had normal serum creatinine or normal creatinine clearance. The half-life ranged from 0.4 to 32.7 h in 331 patients who had normal creatinine clearance. The factors related to the elimination rate constant were creatinine clearance, age, distribution volume, weight, gender, and hematocrit. The daily dose necessary to obtain therapeutic serum concentrations ranged from 0.5 to 25.8 mg/kg in patients with normal serum creatinine and from 0.7 to 25.8 mg/kg in patients with normal creatinine clearance. In 13 patients (0.9%), a significant change in base-line serum creatinine (greater than or equal to 0.5 mg/dl) occurred during or after treatment, which may have been gentamicin-associated toxicity. Overt cochlear or vestibular toxicity did not occur in these patients. The method of individualizing dosage regimens provided a clinically useful means of rapidly attaining therapeutic peak and trough serum concentrations.     

Ciprofloxacin pharmacokinetics in patients with normal and impaired renal function.

The pharmacokinetics of ciprofloxacin following single oral doses of 500 and 750 mg in 32 patients with various degrees of renal function impairment were investigated in an open, randomized crossover fashion. Ciprofloxacin was administered after overnight fasting; the washout time between the two doses was 1 week. Serum and urine samples were collected serially between 0 and 24 h and subjected to bioassay and high-performance liquid chromatography. Pharmacokinetic parameters were analyzed, assuming an open two-compartment model with first-order input and elimination. A distinct difference was observed in pharmacokinetic parameters between patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) and those with normal renal function (creatinine clearance, greater than or equal to 50 ml/min per 1.73 m2). For the former group, the area under the curve of serum concentration versus time was doubled, the renal clearance of ciprofloxacin was cut to one-fourth, the total and nonrenal ciprofloxacin clearance was reduced by 50%, and the elimination half-life was prolonged by a factor of approximately 1.7. The correlation between renal drug clearance and creatinine clearance was highly significant (r = 0.890; P less than 0.001). On the basis of these findings, it appears that a 50% dose reduction of ciprofloxacin in patients with impaired renal function (creatinine clearance, less than 50 ml/min per 1.73 m2) may be indicated to achieve concentrations in serum similar to those observed in normal individuals. As the concentration of ciprofloxacin in urine after 24 h remained above the MIC for most urinary pathogens, this drug appears to be of potential benefit for the treatment of urinary tract infections in patients with impaired renal function.     

Oral antiviral drugs in experimental herpes simplex keratitis

Serum kinetics of amikacin were investigated in 17 severely ill patients. During both the first and last dose intervals of therapy, the serum concentration time course of every patient was documented by 17 blood samples. Six of the patients had moderate to severe renal insufficiency (serum creatinine greater than 1.5 mg/100 ml). In this group of patients, a pronounced rise in serum half-life of amikacin was observed, increasing from a mean of 11.2 to 21.5 h for the first and last interval, respectively. In contrast, mean half-life remained stable in the group of 11 patients with normal renal function. No change in mean serum creatinine occurred in either group, when data from the beginning and the end of therapy were compared. Therefore, the increase of amikacin half-life is apparently not due to a reduction of the glomerular filtration rate, but rather to a decrease of the ratio of amikacin to creatinine clearance. Indeed, a significant reduction of this ratio could be shown in the seven patients in which 24-h creatinine clearance was determined during the first and last day of therapy. This phenomenon is discussed in the context of aminoglycoside accumulation in deep compartments. We conclude that the daily dose of amikacin has to be reduced during therapy in patients with impaired, but stable, renal function.     

Netilmicin treatment of complicated urinary tract infection in patients with renal function impairment.

The efficacy and tolerance of netilmicin was studied in 28 elderly male patients with varying degrees of renal function impairment who suffered from complicated urinary tract infections. Doses of netilmicin, equivalent to 2 mg/kg divided by milligrams of creatinine per 100 ml, were administered every 12 h. A 62% cure rate, defined as negative urine culture at 1-week follow-up, was obtained. Treatment failure correlated with impaired renal function. Nephrotoxic reaction, defined as any significant increase in serum creatinine during treatment, was found in 6 of 28 patients (21%). The increase in serum creatinine was transient in all except one of these patients. Apart from the finding of a significant correlation between nephrotoxic reaction to netilmicin and postoperative urinary tract infection, no clinical or therapeutic features correlated with nephrotoxicity; trough concentrations correlated with serum creatinine.     

Comparative nephrotoxicity of gentamicin and tobramycin: pharmacokinetic and clinical studies in 201 patients.

A total of 201 critically ill patients were studied during 267 courses of gentamicin or tobramycin treatment (139 gentamicin courses and 128 tobramycin courses). Of these 267 courses, pharmacokinetic and clinical data were obtained for 240 (120 gentamicin and 120 tobramycin). The data collected for pharmacokinetic analysis included measurements of serial blood and urine levels, urinary excretion of beta 2-microglobulin, protein levels, and granular casts. A two-compartment model was used to assess tissue accumulation, and in 89 courses the predicted accumulation was confirmed by cumulative urine collection or postmortem tissue analysis. As groups, the patients given gentamicin and tobramycin did not differ in age, weight, creatine clearance, total dose given, duration of treatment, initial aminoglycoside through serum levels, number of dosage adjustments, concurrent use of furosemide, or concurrent cephalosporins. Previous aminoglycoside treatment (usually gentamicin) had occurred more frequently in the tobramycin treated patients (P less than 0.01), and more males than females received tobramycin (P less than 0.05). Pharmacokinetic assessments of renal damage were based on both changes in glomerular filtration rate (serum creatinine levels, creatinine clearance) and renal tubular damage (beta 2-microglobin, casts), but only patients with elevated aminoglycoside tissue levels leading to renal tubular damage and subsequent creatinine clearance decreases were considered to have experienced aminoglycoside nephrotoxicity. In the pharmacokinetic analysis of nephrotoxicity, 29 gentamicin courses (24%) and 12 tobramycin courses (10%) were complicated by nephrotoxicity (P less than 0.01). The 201 study patients were also evaluated independently for clinical nephrotoxicity (defined as a serum creatinine level increase of 0.5 mg/dl or more). Clinical nephrotoxicity occurred at rates of 37% in the gentamicin-treated group and 22% in the tobramycin-treated group (P less than 0.02). In these similar groups of critically ill patients, tobramycin was less nephrotic than gentamicin.     

The pharmacokinetics of once-daily dosing of ceftriaxone in critically ill patients

The aim of this study was to determine the pharmacokinetic profile of the normal recommended dose of ceftriaxone in critically ill patients and to establish whether the current daily dosing recommendation maintains plasma concentrations adequate for antibacterial efficacy. Ceftriaxone at a recommended dose of 2 g iv was administered od to 12 critically ill patients with severe sepsis and normal serum creatinine concentrations. Blood samples were taken at pre-determined intervals over the first 24 h and on day 3 for measurement of ceftriaxone concentrations. There was wide variability in drug disposition, explained by the presence of variable renal function and identified by the measurement of creatinine clearance. In nine patients with normal renal function, there was a high level of creatinine clearance (mean +/- S.D., 41 +/- 12 mL/min) and volume of distribution (20 +/- 3.3 L), which resulted in an elimination half-life of 6.4 +/- 1.1 h. In comparison with normal subjects, ceftriaxone clearance was increased 100%, volume of distribution increased 90% and the elimination half-life was similar. Three patients had substantially suboptimal plasma ceftriaxone concentrations. We confirm previous findings that ceftriaxone clearance in critically ill patients correlates with renal clearance by glomerular filtration. The elimination half-life is prolonged (21.4 +/- 9.8 h) in critically ill patients with renal failure when compared with previously published data in non-critically ill patients with renal failure. We conclude that in critically ill patients with normal renal function, inadequate plasma concentrations may result following od bolus dosing of ceftriaxone. Drug accumulation may occur in critically ill patients with renal failure.     

Elimination kinetics of ceftizoxime in humans with and without renal insufficiency.

The pharmacokinetics of a single 500-mg intramuscular dose of ceftizoxime were studied in 11 healthy adult volunteers and in 22 patients with various degrees of renal dysfunction. The mean serum half-life of ceftizoxime was 1.44 h in normal subjects and 30.2 h in hemodialysis patients. A significant correlation (P less than 0.001) between the elimination rate constant of ceftizoxime and creatinine clearance was demonstrated. The mean urinary recovery in normal subjects was 75.6% within 6 h of dosage; recovery decreased progressively with reduced renal function.     

Multiple-dose pharmacokinetics of cefonicid in patients with impaired renal function.

The pharmacokinetics of multiple-dose administration of cefonicid to patients with normal and impaired renal function were studied by using high-performance liquid chromatography to measure serial serum and urine concentrations. Eighteen patients received an initial dose of 15 mg/kg intravenously over 12 min plus two or three subsequent modified doses at intervals of 24 to 72 h, depending upon the degree of renal impairment. Six patients chronically requiring hemodialysis and 12 nondialysis subjects (creatinine clearance, 10 to 80 ml/min per 1.73 m2) were studied. The concentrations of cefonicid in serum after the initial dose were best described by an open two-compartment model. The elimination half-life of cefonicid ranged between 5.5 and 84.9 h. Mean peak and trough concentrations in serum for all patients were 178.2 +/- 29.3 micrograms/ml (plus or minus standard deviation) and 39.0 +/- 17.5 micrograms/ml, respectively. Trough concentrations were higher in patients requiring hemodialysis than in nondialysis subjects, but the difference was clinically insignificant. The renal clearance/plasma clearance ratio of cefonicid was linearly related to creatinine clearance and decreased with impaired renal function. Therefore, nonrenal mechanisms of elimination become more important as renal function declines. Since cefonicid concentrations were within the therapeutic range for nearly all dosing intervals, we conclude that the guidelines used for dosage reduction and interval prolongation in this study result in therapeutically adequate concentrations in serum and, at the same time, result in no significant drug accumulation.     

Evaluation of cefoxitin nephrotoxicity in experimentally induced renal failure.

The nephrotoxicity of cefoxitin was studied in a rat model of impaired renal function. Two levels of renal impairment were produced: "moderate," with blood urea concentrations of 100 to 150 mg/100 ml (16.7 to 25.1 mmol/liter) and glomerular filtration rates 25 to 35% of normal, and "severe," with blood urea concentrations greater than 150 mg/100 ml (greater than 25.1 mmol/liter) and glomerular filtration rates 10 to 20% of normal. Sham-operated animals were used as controls. Three dose schedules of cefoxitin were administered to these controls--500, 1,000, and 2,500 mg/kg per day administered as a divided dose for 5 days. Doses given to the moderately and severely uremic animals were adjusted so that serum levels of cefoxitin were similar to those attained in the sham-operated control animals. Concentrations of urea and creatinine in blood, glomerular filtration rates, and the urinary concentrating capacities of the experimental animals were monitored before and after cefoxitin treatment. There was no evidence of nephrotoxicity in even the most challenging experiment, in which blood serum levels of cefoxitin reached 2,000 microgram/ml in animals, with 15% renal function. These findings support available clinical data, suggesting that cefoxitin can be administered safely to patients with compromised renal function.     

Renal function in rats with essential fatty acid deficiency

1. Renal function was studied in 50-, 70-, 90- and 200-day-old rats with essential fatty acid deficiency. The pharmacokinetics of tobramycin was investigated in 90-day-old essential fatty acid-deficient rats. 2. A higher glomerular filtration rate and a higher serum concentration of urea were seen in 50-day-old essential fatty acid-deficient rats compared with age-matched controls. Later, the glomerular filtration rate progressively deteriorated in parallel with a decline in effective renal plasma flow and with a concomittant rise in serum levels of urea and creatinine. The serum concentration of protein was lower in the rats with essential fatty acid deficiency and that of sodium was higher than in the control rats. The non-renal clearance of tobramycin was increased in the rats with essential fatty acid deficiency. 3. The early hyperfiltration in essential fatty acid-deficient rats with the subsequent fall in glomerular filtration rate, which was paralleled by a rise in serum levels of urea and creatinine, as well as the increased non-renal clearance of tobramycin, are in accordance with the clinical manifestations of cystic fibrosis. Rats with essential fatty acid deficiency might be a useful model with which to study the pathophysiological renal changes in cystic fibrosis related to the progressive essential fatty acid deficiency in this disease.     

Pharmacokinetics and dosage adjustment of cefotiam in renal impaired patients

The pharmacokinetics of cefotiam were investigated after intravenous administration of 1 g to 2 healthy volunteers with normal renal function and to 16 patients whose creatinine clearance ranged from 4.7 to 0.1 l/h (78 to 1.66 ml/min). The elimination half-life varied from 1.1 h in normal subjects to 13 h in patients and the total plasma clearance from 21 to 0.6 l/h (350 to 10 ml/min). The urinary recovery decreased from 62% of the dose in normal subjects to 1.1% in patients, and the renal clearance from 15 to 0.01 l/h (250 to 0.5 ml/min). Plasma and renal clearances of cefotiam correlated well with the creatinine clearance. The dosage schedule for cefotiam in patients with normal renal function can be used in the presence of renal failure when the creatinine clearance is equal to or greater than 1 l/h (16.6 ml/min). For patients whose creatinine clearance is less than 1 l/h, the dose must be decreased to 75% of that for a patient with normal renal function only when it is given every 6 or 8 h.     

Pharmacokinetics of Netilmicin in the Presence of Normal or Impaired Renal Function

A pharmacokinetic study of netilmicin was conducted in 12 healthy subjects and 24 subjects with chronic renal failure. After intramuscular administrations of 2 and 3 mg of netilmicin per kg in normal subjects, the mean peak serum concentrations were 5.46 and 8.83 μg/ml, respectively. After intravenous infusions of identical doses, the mean maximum serum levels, occurring at the end of the infusion, were 11.79 and 15.75 μg/ml, respectively. The pharmacokinetic data were very similar via the two routes of administration and for the two doses. The elimination half-life was 2.20 h, and 80 to 90% of the injected dose was recovered in urine during the first 24 h. After intramuscular administration of 2 mg/kg in subjects with chronic renal impairment, the elimination half-life increased to 29.48 h, and urinary elimination was inversely related to the degree of impairment. A study was conducted throughout hemodialysis sessions: serum concentrations decreased by 63.3%. The linear relationships between the elimination rate constant and creatinine clearance and the elimination half-life and serum creatinine allowed us to establish dosage schedules according to the degree of renal failure.     

Pharmacokinetics of Carbenicillin in Neonates of Normal and Low Birth Weight

A single intramuscular dose of 100 mg carbenicillin/kg produced measured peak concentrations of approximately 150 to 175 mug/ml in newborn infants. The carbenicillin serum half-life of 1.0 hr in normal adults was prolonged to 2.7 hr in infants of normal birth weight and to 4.0 hr in babies of low birth weight in the first week of life. One-third of a dose administered to babies of low birth weight and two-thirds of that given to babies weighing over 2,500 g was excreted by the kidney in 12 hr. Postadministration 6-hr urinary carbenicillin concentrations averaged 1,399 mug/ml after an intramuscular dose of 50 mg/kg and 2,689 mug/ml after a 100 mg/kg injection. Although carbenicillin is excreted by both glomerular and tubular mechanisms in adults, serum half-life and urinary carbenicillin excretion correlated well with creatinine clearance. Recommendations for dosage of carbenicillin and intervals of administration in the neonatal period are made based upon mathematical predictions from pharmacokinetic data.     

Ceftriaxone pharmacokinetics in patients with various degrees of renal impairment

The effects of renal impairment on the pharmacokinetics of ceftriaxone in humans were examined after intravenous infusion of a 1-g dose over 15 min to 30 renally impaired patients. The study included 12 dialysis patients and 18 patients with severe, moderate, or mild renal impairment. Plasma and, where appropriate, urine and dialysate samples were collected at predetermined times and analyzed for ceftriaxone by high-pressure liquid chromatography. The elimination half-life (group mean ranged from 11.7 to 17.3 h) and plasma clearance (group mean ranged from 529 to 705 ml/h) did not correlate linearly with creatinine clearance. The renal clearance and fraction of dose excreted unchanged in urine were related linearly, however weakly, with creatinine clearance. Ceftriaxone was not removed from plasma to a significant extent during hemodialysis. The half-life was prolonged twofold, the plasma clearance was lowered less than 50%, and the volume of distribution was relatively unchanged in renally impaired patients compared with young or elderly healthy subjects with normal renal function at an equivalent dose. Since these changes are moderate, adjustment in the dosage regimen of ceftriaxone for patients with impaired renal function should not be necessary when ceftriaxone dosage is 2 g or less per day (2 g every 24 h or 1 g every 12 h). It was reported that the elimination half-life of ceftriaxone is substantially prolonged in a small percentage of patients with end-stage renal disease maintained on hemodialysis. Therefore, plasma concentrations of ceftriaxone should be monitored in dialysis patients to determine whether dosage adjustments are necessary.