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 μg/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 μg/ml at the end of administration which decreased to 16.8 μg/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 μg/ml at the end of administration and 17.3 μg/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 μg/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 μg/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 μg/ml during the infusion period.     

Clinical pharmacology of moxalactam in patients with malignant disease.

Pharmacological studies of moxalactam were conducted with 37 cancer patients. Intramuscular administration of 500 mg of moxalactam to 10 patients produced a mean peak serum concentration of 12.4 micrograms/ml. The serum terminal-phase half-life was 3.9 h. Intravenous administration of 500 mg of moxalactam over 5 min to the same 10 patients produced a mean serum concentration of 42.0 micrograms/ml at 15 min, which decreased to 3.3 micrograms/ml at 6 h. A dose of 1 g of moxalactam was given in an identical manner to the same 10 patients. The mean serum concentration was 69.7 micrograms/ml at 15 min and 7.4 micrograms/ml at 6 h. The mean proportions of a drug recovered in the urine by 12 h after administration were 59% after the intramuscular dose and 61 and 55% after the single intravenous doses. Multiple-dose intravenous studies were also conducted. The serum terminal-phase half-life varied from 2.0 to 3.2 h. Continuous infusion studies were performed by up to 9 days by using a loading dose of 1 g over 0.5 h, followed by 2 g every 6 h. Serum concentrations were maintained at about 30.0 micrograms/ml during the study period.     

Pharmacokinetics and pharmacodynamics of cefoperazone-sulbactam in patients on continuous ambulatory peritoneal dialysis.

This study was conducted to determine the pharmacokinetics of the fixed combination antibiotic cefoperazone-sulbactam in patients receiving continuous ambulatory peritoneal dialysis (CAPD). In addition, the pharmacodynamic profile of this combination was determined by the use of mean bactericidal titers against selected bacterial strains. Six noninfected CAPD patients were given a fixed dose of cefoperazone (2 g) and sulbactam (1 g) either intravenously or intraperitoneally over 10 min in a randomized, two-way crossover fashion. The mean peak cefoperazone concentration in serum after intravenous administration was 280.9 micrograms/ml. The mean peak concentration in serum after intraperitoneal cefoperazone administration was 38.9 micrograms/ml and occurred 2 to 4 h postdose. The mean peak sulbactam concentration in serum after intravenous administration was 82.2 micrograms/ml. The mean peak concentration in serum after intraperitoneal sulbactam administration was 24.4 micrograms/ml and occurred at 6 h. The absolute bioavailability of the intraperitoneal dose was 61% for cefoperazone and 70% for sulbactam. Cefoperazone total body and renal clearances were unaffected by renal failure and dialysis. However, both clearance values for sulbactam were reduced markedly. Only intraperitoneal dosing provided peak inhibitory and bactericidal titers in dialysate for all organisms tested. Intravenous dosing provided satisfactory dialysate titers only for very susceptible bacterial strains. End-stage renal disease and CAPD do not alter cefoperazone pharmacokinetics; however, sulbactam dosing may need to be adjusted.     

Piperacillin kinetics.

Piperacillin was administered to normal, healthy volunteers by an intravenous infusion over 30 min at dosage regimens of 12 gm daily (4 gm every 8 hr) and 24 gm daily (6 gm every 6 hr) for 5 consecutive days. Mean peak serum level after 12 gm daily was 244 +/- 24 (SE) microgram/ml and after 24 gm daily, 353 +/- 7 microgram/ml. After infusion the serum level declined monoexponentially in most subjects. On the 12-gm daily dosage mean values were 60 min for half-life (t1/2), 16 1 for volume of distribution, 188 ml/min for body clearance, and 139 ml/min for renal clearance. The same values on day 4 were 47 min, 12 1, 181 ml/min, and 125 ml/min; the volume of distribution was lower than on day 1. On the 24-gm daily dosage regimen, t1/2 was 60 min; volume of distribution, 16 1; body clearance, 183 ml/min; and renal clearance, 101 ml/min on day 1 compared to 68 min, 15 1, 148 ml/min, and 71 ml/min on day 4, the last 2 being significantly lower than on day 1. High renal clearance values were observed at low serum concentrations and vice versa, suggesting saturation of the tubular secretion process at high piperacillin concentrations in serum.     

New schedule for tobramycin administration.

Ten patients received a loading dose of tobramycin of 60 mg/m2 intravenously over 0.5 h followed immediately by 60 mg/m2 over 2 h every 4 h. The highest mean serum concentration (at the end of the loading dose) was 6.0 +/- 0.3 microgram/ml (range, 3.2 to 10.9 microgram/ml). The mean serum concentration 2 h after the end of the initial 2-h infusion was 3.0 +/- 0.2 microgram/ml (range, 1.6 to 3.9 microgram/ml). This schedule of tobramycin was used to treat 117 patients with presumed or proven infection. There were no differences in the mean serum concentrations of tobramycin at comparable times on days 3 to 4 and 6 to 7. Only 60% of patients had serum levels between 3 micrograms/ml (trough) and 10 micrograms/ml (peak). This intermittent schedule of administration resulted in substantial fluctuations in serum concentrations of tobramycin and produced trough concentrations which were too low or peak concentrations which were too high in some patients.     

Piperacillin pharmacokinetics in subjects with chronic renal failure

The pharmacokinetic parameters of piperacillin sodium were studied in eight volunteer subjects with chronic renal failure. Subjects were given a single 30-min intravenous infusion of 70 mg/kg (lean body weight) on their off-dialysis day. Blood was drawn from the contralateral arm at 15 and 30 min and 1, 3, 6, 9, and 12 h from the start of the infusion. Kinetic parameters were determined during the elimination phase with a one-compartment open model for linear kinetics. The following pharmacokinetic parameters (mean +/- standard deviation) were determined for the eight subjects: elimination half-life = 3.33 +/- 0.99 h, elimination rate constant = 0.22 +/- 0.06 h-1, apparent volume of distribution = 0.18 +/- 0.05 liters per kg, and total body clearance = 0.041 +/- 0.019 liters per kg/h. The mean peak serum concentration was 372 +/- 125 microgram/ml, and mean trough at 12 h was 39 +/- 27 microgram/ml. A dose of 70 mg/kg (lean body weight) or a dose of 4 g appears to provide adequate serum concentrations against susceptible organisms for a 12-h interval. No adverse reactions were noted in any subject throughout the study.     

Comparative pharmacokinetics of cefoperazone and cefamandole

The pharmacokinetics of cefoperazone, a new beta-lactam antibiotic, were studied in normal volunteers and compared with the pharmacokinetics of cefamandole. After a 30-min infusion of 2 g of cefoperazone, the mean serum level was 256 micrograms/ml; at 4 h, the serum level was 20 micrograms/ml, and at 24 h, the level was 1.25 micrograms/ml, compared with levels of cefamandole of 188 micrograms/ml at the end of infusion, 1.8 micrograms/ml at 4 h, and none detected thereafter. The mean half-life of cefoperazone was 1.6 h, compared with 0.7 h for cefamandole. The area under the curve was 356 micrograms/ml per h for cefoperazone, which was three times that for cefamandole. The apparent volume of distribution for cefoperazone was 9.9 liters/1.73 m2 compared with 12.5 liters/1.73 m2 for cefamandole. Serum clearance of cefoperazone was 85 ml/min, and renal clearance was 25 ml/min, compared with a serum clearance of 224 ml/min and a renal clearance of 213 ml/min for cefamandole. Urine levels exceeded 25 micrograms/ml in the first 8 h after injection. Renal recovery of cefoperazone was only 29%.     

Pharmacokinetics and tissue penetration of cefpirome, a new cephalosporin

The pharmacokinetics and tissue penetration (as measured by a blister fluid model) of cefpirome were studied in six male volunteers following a 1 g intravenous dose. A mean peak serum concentration (at 5 min) of 97.4 mg/l was followed by rapid distribution into an apparent volume of 21.3 1. The serum elimination half-life was 2.3 h. Cefpirome penetrated rapidly into inflammatory fluid with a mean peak concentration of 39.2 mg/l at 1.9 h. The mean inflammatory fluid elimination half-life was 2.5 h. The availability of the drug in inflammatory fluid was high with a mean per cent penetration of 123%. The plasma and renal clearances were 109.5 and 82.1 ml/min respectively. Twenty-four hour urinary recovery was 75.5% of the administered dose. This study suggests that a twice daily dosage may be sufficient to treat tissue infections with susceptible pathogens.     

Pharmacokinetics of Cefaclor in Patients with End Stage Renal Disease and During Hemodialysis

A single 1.0-g dose of cefaclor administered to patients with stable end stage renal disease whose creatinine clearances were <5 ml/min produced a mean peak serum concentration of 48.3 ± 19.8 μg/ml. The half-life was 2.3 ± 0.3 h. Hemodialysis shortened the half-life of a similar dose to 1.6 ± 0.3 h. Approximately one-third (340 mg) of the administered drug was recovered in the dialysate. Multiple doses of 500 mg every 6 h between hemodialysis sessions produced effective serum concentrations and no bioassay evidence of drug accumulation.     

Pharmacokinetics of cefoperazone in the parturient.

Limited pharmacokinetic data for cefoperazone are available from the parturient. Because cefoperazone has a dual excretory pattern, primarily via the biliary system and secondarily via the kidney, pregnancy-induced physiologic alterations can influence its deposition and clearance. Twelve term parturients receiving cefoperazone prophylaxis after cesarean section were selected for study. After 2 g of cefoperazone was administered for 1 h intravenously, serial blood samples were assayed by high-pressure liquid chromatography. Plasma protein binding of cefoperazone was studied in vitro. The mean peak cefoperazone concentration +/- standard deviation was 169.9 +/- 60.4 micrograms/ml. The mean half-life was 152 min. Total serum clearance was 80.8 +/- 30.8 ml/min. The steady-state volume of distribution was 14.2 +/- 6.0 liters. All subjects had detectable trough levels at the end of the dosage interval, with a mean value of 6.5 +/- 5.2 micrograms/ml. Protein binding of cefoperazone for parturients was 74.3 +/- 10.9%, compared with 87.7 +/- 3.2% in nonpregnant controls (P less than 0.05). These data suggest that cefoperazone deposition can be greatly influenced by pregnancy. However, unlike several other new antimicrobial agents whose excretions are mainly renal, the cefoperazone half-life and thus trough concentration for the parturient more closely resemble that for the nonpregnant subject.     

Cefotaxime and desacetylcefotaxime pharmacokinetics in infants and children with meningitis.

The pharmacokinetics and cerebrospinal fluid (CSF) penetration of cefotaxime (Ctx) and desacetylcefotaxime (dCtx) were evaluated in 13 infants and children with meningitis after dose 6 of Ctx in a multiple-dose intermittent intravenous infusion regimen (50 mg/kg every 6 h). Model-dependent and noncompartmental pharmacokinetic parameters were determined and were found to be congruous. The disposition of both Ctx and dCtx was described adequately by a one-compartment, open model. Noncompartmental pharmacokinetic parameters are reported. The mean Ctx serum concentration at 0.25 h postinfusion was 121.2 micrograms/ml, and the mean CSF concentration at 1 h postinfusion was 6.2 micrograms/ml. The CSF/serum ratio was variable (0 to 20%), with a mean penetration of 10.1%. The mean Ctx elimination half-life, apparent steady-state volume of distribution, and total body clearance were 0.8 h, 0.361 liter/kg, and 0.289 liter/h per kg, respectively. For Ctx, 61% of the dose was excreted unchanged in the urine during the 6-h postinfusion period, and the estimated renal clearance was 0.174 liter/h per kg. No significant correlations were observed between Ctx pharmacokinetic parameters and demographic parameters. The mean peak concentration of dCtx in serum (21.6 micrograms/ml) occurred at approximately 1.5 h postinfusion, and the mean concentration in CSF at 1 h postinfusion was 5.6 micrograms/ml. The CSF/serum ratio was extremely variable (0 to 103%), and the mean penetration was 28.8%. The mean apparent elimination half-life for dCtx was 2.1 h. In infants and children with normal renal function, a 50-mg/kg dose of Ctx administered every 6 h should provide adequate concentrations in serum and CSF in the majority of patients with meningitis.     

Pharmacokinetics of cefotaxime.

The pharmacokinetics of cefotaxime after intramuscular injection and intravenous infusion were determined. The mean peak serum level after the 500-mg intramuscular dose was 11.7 micrograms/ml, and it was 20.5 micrograms/ml after a 1,000-mg dose. The serum half-life was 1.2 and 1.3 h, respectively for the two doses. The apparent fractional volumes of distribution of 32 and 37 liters were not significantly different for the two doses, and the fractional serum clearance was approximately 315 ml/min per 1.73 m2 for both doses. The mean peak serum level after 1,000 mg administered by intravenous infusion over 30 min was 41.1 micrograms/ml. The half-life was 1.13 h, apparent volume of distribution was 33 liters, serum clearance 341 ml/min per 1.73 m2, and renal clearance was 130 ml/min per 1.73 m2. The pharmacology of cefotaxime is similar to the pharmacology of other cephalosporin antibiotics, but the low inhibitory levels which it has against gram-positive and gram-negative bacteria suggest that lower dosage regimens should be possible.     

Pharmacokinetics of piperacillin in patients with moderate renal failure and in patients undergoing hemodialysis.

The pharmacokinetics of piperacillin administered intravenously were studied in five patients with stable mild to moderate renal impairment and in five patients undergoing hemodialysis. Patients with stable renal failure given 1 g of piperacillin intravenously had peak serum concentrations within 30 min ranging from 78 to 280 micrograms/ml. The mean serum half-life was 3.57 +/- 1.36 h; the mean apparent volume of distribution was 28.6 +/- 13.5 liters/100 kg; and the plasma clearance was 4.10 +/- 1.46 liters/h per 1.73 m2. Neither serum half-life nor clearance correlated with serum creatinine, implying significant nonrenal elimination. Patients undergoing hemodialysis had peak serum concentrations within 30 min of 66 to 138 micrograms/ml after 1 g of piperacillin infused intravenously. During hemodialysis, the serum half-life was 3.6 +/- 2.5 h; the mean apparent volume of distribution was 26.7 +/- 16.7 liters/100 kg; and the plasma clearance was 3.28 +/- 0.76 layers/h per 1.73 m2. Mean hemodialysis clearance was 0.484 +/- 0.282 liters/h per 1.73 m2, and only 10.0 +/- 5.3% of the total dose could be recovered in the dialysate.     

Pharmacology, Safety, and efficacy of cefamandole in childhood infections.

We used cefamandole in the initial treatment of 34 children (10 months to 15 years of age) with suspected bone, joint, or soft tissue infections. The minimal inhibitory concentration of organisms encountered ranged between 0.015 and 2 microgram/ml. At 1 h after intravenous infusion of 25 mg/kg, the mean serum level of cefamandole was 26.2 microgram/ml (range, 8.9 to 47.5 microgram/ml), and at 3 h the level was 1.8 microgram/ml (range, 0.6 to 4.4 microgram/ml), which is above the minimal inhibitory concentration for most of the organisms encountered. However, when the drug was given intravenously every 6 h, the mean level after a 37-mg/kg dose was 0.9 microgram/ml (range, less than 0.5 to 1.9 microgram/ml) at 4 h and, by extrapolation, would have fallen below 0.1 microgram/ml at 6 h. The mean serum half-life was 34 min. Cefamandole appeared to diffuse well into synovial fluid, with joint fluid levels between 5 and 40 microgram/ml. The drug was tolerated well. Cefamandole appears to be a reasonable alternative in the initial treatment of skeletal infections in children, but need to be administered every 4 h to maintain suprainhibitory serum levels between doses.     

Pharmacokinetic studies with dibekacin, a new aminoglycoside, after intravenous and intramuscular administration to human volunteers

The pharmacokinetics of dibekacin, a new aminoglycoside antibiotic, was studied in volunteers given the same dose (100 mg) intramuscularly on two separate occasions and intravenously at two different rates of infusion. The kinetic parameters (t 1/2, 2.24 h, and Vd, 0.136 liter/kg, as the overall mean) observed after intramuscular administration appear to be compatible with those of other aminoglycosides and fairly reproducible within the same individuals. Dibekacin was rapidly absorbed (tmax, 0.84 h), yielding a peak level of 10.4 microgram/ml after the 100-mg intramuscular dose. After the 30- or 60-min infusion, the concentrations of dibekacin in serum fell bi-exponentially, giving an elimination half-life (t 1/2 beta) of 2.50 to 2.88 h. The highest serum levels after th 30- and 60-min infusions were 15.2 +/- 0.9 and 12.1 +/- 1.8 microgram/ml, respectively. Serum levels at 6 h after completion of infusions were 1.9 +/- 0.3 and 1.7 +/- 0.4 microgram/ml, respectively.     

Clinical Pharmacology of Ticarcillin (α-Carboxyl-3-Thienylmethyl Penicillin, BRL-2288)

Clinical pharmacological studies of ticarcillin (alpha-carboxyl-3-thienylmethyl penicillin, BRL-2288) were conducted in patients with metastatic cancer and leukemia.After administration of 0.5 g intramuscularly, 1 g intramuscularly, and 1 g intravenously, the mean peak concentrations in serum were 18, 35, and 106 mug/ml, respectively. Greater than 80% of ticarcillin was excreted in the urine during the subsequent 6-h period. The mean concentrations in the serum of patients 15 min after they received an intravenous injection of 4 g of ticarcillin with and without probenecid were 508 and 519 mug/ml, respectively. Serum levels were determined in patients who received ticarcillin for therapy of infection in doses of 5 g every 6 h. The mean drug concentration in serum 15 min after the rapid administration of the first dose was 433 mug/ml. Subsequent doses were given during a 2-h infusion and the study was repeated 2 days later. The average initial serum level (4 h after the completion of the preceding dose) was 19 mug/ml, and the mean serum level at 15 min was 213 mug/ml. Drug concentrations in the serum of patients receiving ticarcillin by infusion in doses of 3.5 g every 4 h were also determined. In patients with normal renal function, the average initial serum level (2 h after completion of the preceding dose) was 49 mug/ml and the mean level at 15 min was 210 mug/ml. Drug concentrations in the serum of patients with impaired renal function were considerably higher. No detectable levels of ticarcillin were found in the cerebrospinal fluid.     

Pharmacology of aztreonam after intravenous infusion

The pharmacokinetics of aztreonam, a monocyclic beta-lactam which inhibits most members of the family Enterobacteriaceae at concentrations of less than 1 microgram/ml and most Pseudomonas aeruginosa isolates at concentrations of less than 16 micrograms/ml, were examined in healthy male volunteers after 30-min intravenous infusions of 0.5, 1, and 2 g of the drug. Mean peak levels of the drug in serum at the end of infusion were 65.5, 164, 255 micrograms/ml after 0.5 1, and 2 g, respectively, with levels of the drug in serum of 1.8, 3, and 8.5 micrograms/ml at 8.5 h for the three doses, respectively. The half-life was approximately 2 h for all three doses. The total serum clearance averaged 1 ml/min per kg. The apparent volume of distribution averaged 0.17 liter/kg for the three doses. Overall excretion of the drug in urine was 61%, with mean levels in urine of 23, 52, and 109 micrograms/ml at 8.5 to 12.5 h after 0.5, 1, and 2 g of aztreonam, respectively. Concentrations of the drug in serum after a 1-g dose exceeded the minimal inhibitory concentration for 90% of the members of the Enterobacteriaceae by four- to eightfold for 8 h and exceeded the minimal inhibitory concentration for P. aeruginosa isolates for 4 h.     

Piperacillin pharmacokinetics in pediatric patients.

The pharmacokinetics of piperacillin were studied in 15 pediatric patients (age range, 3.3 to 14.3 years). Piperacillin was administered in a dosage of 1.5 +/- 0.4 g/m2 (mean +/- standard deviation) every 4 to 6 h. Peak serum concentrations ranged from 69 to 354 micrograms/ml. The mean elimination half-life was 37.0 +/- 13.3 min, which is shorter than that observed in most adults with normal renal function. The mean elimination half-life in three patients with renal impairment was 60.1 +/- 12.4 min, and the mean ratio of renal clearance to total clearance was 0.57. These results suggest a significant nonrenal elimination of piperacillin. Based on these data, a dosage of 1.5 g/m2 given as a 30-min infusion every 4 h is suggested for children with normal renal function. For patients with renal impairment, the daily dosage could be calculated as follows: corrected dose = normal dose x (0.35 + [0.65 x (ClCr/0.06)]), where ClCr is the creatinine clearance expressed as liters per minute per square meter.     

Effect of pancreatitis on ampicillin excretion in pancreatic fluids of dogs.

Pancreatic excretion of ampicillin was evaluated in normal dogs and in dogs with induced pancreatis. A 100-mg/kg ampicillin dose administered intravenously induced mean peak serum levels of 100 micrograms/ml, and a 200-mg/kg intravenous dose induced a mean peak serum level of 273 microgram/ml. Ampicillin serum levels did not differ between the group of normal dogs and those with pancreatitis. In normal dogs, the peak pancreatic fluid ampicillin concentration after the 100-mg/kg dose was 0.4 microgram/ml, and that after the 200-mg/kg dose was 2.7 micrograms/ml. In dogs with pancreatitis, the mean peak ampicillin concentration in the pancreatic fluid after the 100 mg/kg dose was 19 micrograms/ml, and that after the 200-mg/kg dose was 38.5 micrograms/ml. Pancreatic fluid ampicillin concentrations were therapeutic in dogs with pancreatitis and subtherapeutic in normal dogs.     

Pharmacokinetics of cefoperazone in full-term and premature neonates.

The pharmacokinetics of cefoperazone were evaluated in 28 newborn infants who were being treated for sepsis. A dose of 50 mg/kg was administered intravenously on days 0 to 2 in all, with a second dose administered on days 5 to 7 in 14 infants. Cerebrospinal fluid penetration was also studied in seven neonates. The mean peak concentration of cefoperazone in the serum of premature infants less than 33 weeks of gestational age, 159 (standard deviation, +/- 22) micrograms/ml, was higher than concentrations in premature infants 33 to 36 weeks of age and full-term infants (110 +/- 41 and 109 +/- 29 micrograms/ml, respectively). The mean concentrations 24 h after dosage were similar in all three groups, 13 to 17 micrograms/ml. The mean serum half-lives were similar in the three subgroups and ranged from 7 to 9 h. After the dose at 5 to 7 days, mean blood levels in the subgroups at 0.5 h were 149, 112, and 112 micrograms/ml; 24-h levels ranged from 9 to 12 micrograms/ml. The mean serum half-lives ranged from 5 to 7 h. Cerebrospinal fluid levels in patients with meningitis ranged from 2.8 to 9.5 micrograms/ml and in patients without meningitis from 1 to 7 micrograms/ml. Peak blood levels were 15 to 1,000 times higher than the 90% minimal inhibitory concentration of common pathogens found in newborns. These observations support the potential efficacy of cefoperazone in treatment of infections, including meningitis, in newborn infants.