Comparative study of piperacillin, ticarcillin, and carbenicillin pharmacokinetics.

Piperacillin, ticarcillin, and carbenicillin were administered intravenously to 10 healthy volunteers in a three-way, crossover study. The pharmacokinetics of the three drugs were in general quite similar. The peak serum concentration of piperacillin achieved at the end of a 30-min intravenous infusion was 63.5 +/- 27.6 microgram/ml. During the first 8 h, 67.5% of the dose of piperacillin was excreted in the urine, and the urinary concentration was extremely high. All three penicillins had high volumes of distribution. The serum half-life of the beta elimination phase of carbenicillin was lower than that of either piperacillin or ticarcillin. The volunteers experienced no adverse reactions from the administration of the drugs.     

Therapy of experimental Pseudomonas endocarditis with high-dose amikacin and ticarcillin

Right-sided infective endocarditis due to Pseudomonas aeruginosa was induced in 130 rabbits. Animals received either: (1) no therapy (controls); (2) standard-dose amikacin (AMK) (15 mg/kg/day) plus ticarcillin (300 mg/kg/day), or (3) high-dose AMK (20 or 25 mg/kg/day) plus ticarcillin, for 20 days. Animals in each treatment group were evaluated at 10 days after therapy for bacteriologic relapse. Both standard- and high-dose AMK regimens significantly decreased mortality and Pseudomonas aeruginosa vegetation titers versus controls (p less than 0.01, p less than 0.05, respectively). Despite significantly higher serum AMK levels at 25 mg/kg/day, there was no significant difference in mean vegetation titers, percent of vegetations sterilized, or posttherapy bacteriologic relapse in the three treatment groups. AMK at 20 or 25 mg/kg/day (but not at 15 mg/kg/day) significantly reduced the incidence of pulmonary infarction versus untreated controls (p less than 0.01).     

Comparative pharmacokinetics and serum bactericidal activity of mezlocillin, ticarcillin and piperacillin, with and without gentamicin

We compared the serum levels, pharmacokinetics and serum bactericidal activity after intravenous infusions of 5 g of each of three anti-pseudomonal penicillins--ticarcillin, mezlocillin and piperacillin alone and in combination with 80 mg gentamicin in normal volunteers. Gentamicin levels were significantly lower when administered with ticarcillin than when administered with mezlocillin or piperacillin. Serum levels of ticarcillin and piperacillin immediately after the infusion were similar (approximately 450 mg/l) and were higher than mezlocillin at 350 mg/l, but by 6 h, levels of all three penicillins were less than 10 mg/l. Overall, the geometric mean bactericidal titres produced in the serum against organisms which commonly infect cancer patients with granulocytopenia were highest with the piperacillin-gentamicin combination. However, except for the mezlocillin-gentamicin combination against Pseudomonas aeruginosa, serum bactericidal titres of all three penicillin-gentamicin regimes were greater than 1:8 at zero and 2 h after the infusion against the organisms tested. It is unlikely that these differences in the three penicillin-gentamicin combinations will be apparent in the outcome of clinical trials for empiric therapy of fever in the cancer patient with granulocytopenia.     

Comparative bactericidal effects of azlocillin and ticarcillin against Pseudomonas aeruginosa.

Azlocillin was relatively ineffective against actively growing cultures of Pseudomonas aeruginosa in tests of bacteriolytic and bactericidal activity in which ticarcillin demonstrated pronounced bactericidal effects over a wide range of concentrations. Microscopic observation showed that azlocillin generally induced the formation of filamentous cells of P. aeruginosa which lysed only slowly, but ticarcillin caused the production of spheroplasts and subsequent rapid lysis. During the course of the bactericidal tests, azlocillin was inactivated, presumably by the beta-lactamase produced by P. aeruginosa, and the filamentous cells resumed normal cell division and growth. In contrast, there was no loss of ticarcillin activity, and there was no evidence of resumption of growth of P. aeruginosa in the presence of ticarcillin. These results suggest that the different bactericidal effects demonstrated by azlocillin and ticarcillin against P. aeruginosa are related primarily to dose-related differences in inhibition of cell wall synthesis and secondarily to the instability of azlocillin to pseudomonal beta-lactamase.     

Pharmacokinetic evaluations of low- and high-dose zidovudine plus high-dose acyclovir in patients with symptomatic human immunodeficiency virus infection.

The pharmacokinetics of zidovudine were evaluated in 41 patients with Centers for Disease Control HIV class IVA infection. The patients were assigned escalating doses of zidovudine (300, 600, or 1,500 mg daily) and were randomized to receive either zidovudine alone or zidovudine with a high dose of acyclovir (4,800 mg per day). Single and multiple intravenous- and oral-dose pharmacokinetic studies were performed on days 1 and 7 and weeks 6 and 12 of therapy. Zidovudine concentrations were analyzed by high-pressure liquid chromatography. Pharmacokinetic parameters were estimated by noncompartmental methods. Zidovudine concentrations in serum declined in a biphasic manner, with half-lives ranging from 1 to 2 h, and were independent of acyclovir administration or length of zidovudine therapy. The median time of peak concentrations in serum following oral doses was 0.75 h (range, 0.25 to 3 h). Accumulation of zidovudine in serum was not observed, but the maximum concentration of drug in serum (Cmax) and the area under the concentration-time curve increased proportionally with increased zidovudine doses. Mean day 7 oral Cmax values were 0.20 +/- 0.12, 0.55 +/- 0.33, and 1.0 +/- 0.5 micrograms/ml for 17 patients receiving total daily doses of, respectively, 300, 600, and 1,500 mg of zidovudine alone, whereas Cmax values were, respectively, 0.27 +/- 0.18, 0.43 +/- 0.33, and 1.2 +/- 0.80 micrograms/ml for 15 comparably treated recipients of zidovudine plus acyclovir (P was not significant). The median bioavailability of oral zidovudine was 67% (42 to 120%) and did not vary with dosage. Absolute and apparent total body clearances were similar among the patients given the various zidovudine doses regardless of whether there was concomitant acyclovir therapy. Drug-related toxicities were observed more frequently in the subjects who received high doses of zidovudine than they were in those who received median and low doses of zidovudine (P=0.03). Overall, acyclovir did not influence the disposition of zidovudine over a wide range of zidovudine doses. No unusual toxicities could be attributed to the zidovudine and high-dose acyclovir combination during the 12-week observation period.     

Amikacin pharmacokinetics in patients receiving high-dose cancer chemotherapy.

We retrospectively analyzed amikacin pharmacokinetics in 28 patients (mean age, 47.4 +/- 13.6 years) who received high-dose chemotherapy during a neutropenic febrile episode. Patients received an experimental protocol of high-dose anticancer chemotherapy. Amikacin pharmacokinetic parameters were calculated from two or more concentrations in serum around a single dose by the method of Sawchuck and Zaske (J. Pharmacokinet. Biopharm. 4:183-195, 1976). Predicted parameters were calculated by using standard methods. The observed amikacin volume of distribution and clearance were significantly greater and the elimination half-life was longer than predicted (0.38 +/- 0.13 versus 0.25 liter/kg [P = 0.0001], 1.51 +/- 0.92 versus 1.17 +/- 0.38 liters/h/kg [P = 0.012], and 3.8 +/- 2.4 versus 2.9 +/- 1.1 h [P = 0.011], respectively). Multivariate analysis revealed that albumin correlated negatively and creatinine correlated positively with the volume of distribution and the elimination half-life. Creatinine and the percentage below the ideal body weight correlated negatively and hematocrit correlated positively with clearance. Administration of dosage regimens based on predicted pharmacokinetic parameters yielded subtherapeutic amikacin concentrations in serum in our patients. Because of the increased dosage requirements and the need for adequate antibiotic treatment in this population, we suggest guidelines for empiric dosing for patients with advanced cancer receiving intensive chemotherapy.     

Treatment of streptomycin-susceptible enterococcal experimental endocarditis with combinations of penicillin and low- or high-dose streptomycin.

We used two strains of streptomycin-susceptible enterococci (MIC, 64 and 128 micrograms of streptomycin per ml, respectively) isolated from patients with infective endocarditis. When combined with penicillin, 20 micrograms of streptomycin per ml killed both strains synergistically in vitro whereas combinations of 5 and 10 micrograms of streptomycin per ml did not act synergistically against either strain. By using the rabbit model of enterococcal experimental endocarditis, animals were treated for 3 days with procaine penicillin (1.2 X 10(6) U intramuscularly three times daily) together with low-dose streptomycin (3.5 mg/kg) or high-dose streptomycin (10 mg/kg) intramuscularly three times daily. The peak concentrations of streptomycin in serum at 0.5 h were 9.2 and 26.8 micrograms/ml in the low- or high-dose group, respectively. When combined with procaine penicillin, both dosages of streptomycin were more effective (P less than 0.01) than procaine penicillin alone for the treatment of enterococcal experimental endocarditis. There was no significant difference in the efficacy of procaine penicillin plus low-dose streptomycin versus procaine penicillin plus high-dose streptomycin therapy of enterococcal experimental endocarditis.     

The pharmacokinetics of high-dose carboplatin in pediatric patients with cancer.

Carboplatin disposition was studied in 18 pediatric patients with cancer over a dosage range of 400 to 700 mg/m2 given on an alternate-day schedule (total doses of 1200 to 2100 mg/m2) with high-dose etoposide. Median age was 7.7 years, hepatic functions were normal, and serum creatinine levels were less than or equal to 1.0 mg/dl. Carboplatin pharmacokinetics were determined by atomic absorption spectroscopy. Median pharmacokinetic parameters for ultrafilterable platinum were as follows: clearance 45.8 ml/min/m2 (range, 25.5 to 65.3 ml/min/m2) and a terminal half-life of 3.6 hours (range, 2.1 to 14.2 hours). Carboplatin clearance (CL) values and volume of distribution (VC) were highly correlated to body size (CL = 55 x Body surface area in [BSA, in square meters] - 6.7, r2 = 0.73; VC = 5 x BSA [in square meters] + 0.26, r2 = 0.69). However, carboplatin doses normalized to BSA still resulted in twofold to threefold variability in area under the concentration-time curve. Carboplatin CL was significantly lower in those subjects (n = 9) who had previously received cumulative cisplatin doses of greater than or equal to 960 mg/m2 (p less than 0.05) but was not influenced by age, gender, or diagnosis.     

Comparative in-vitro activities of azlocillin, ticarcillin and ticarcillin plus clavulanic acid against Staphylococcus aureus, Klebsiella pneumoniae and Pseudomonas aeruginosa

Azlocillin (5 g), ticarcillin (5 g) and ticarcillin (5 g) plus clavulanic acid (200 mg) were administered intravenously on separate days to human volunteers. Serum levels 1 h after the infusion were (mean +/- S.E.): 263 +/- 40 mg/1 for azlocillin, 238 +/- 56 mg/l for ticarcillin and 5.5 +/- 1.9 mg/l for clavulanic acid. Serum withdrawn at 0.5 h was titrated against ten strains of Staphylococcus aureus, ten Klebsiella pneumoniae and nine Pseudomonas aeruginosa of which four were resistant to ticarcillin. Against Staph. aureus and K. pneumoniae, median serum bactericidal activity (SBA) and percentage of sera with SBA greater than or equal to 1:8 were greater with ticarcillin plus clavulanic acid (median SBA 1:32 and 85% of sera with SBA greater than or equal to 1:8) than with the other two regimens. There were no differences in activity against Ps. aeruginosa.     

Comparative nephrotoxicities of high-dose netilmicin and tobramycin in rats.

The nephrotoxic potentials of netilmicin and tobramycin given in doses of 180 mg/kg per day for up to 14 days were compared in Fischer rats. At this dosage, tobramycin produced mortality and significant changes in renal structure and function; netilmicin evoked minimal nephrotoxicity.     

Comparative activities of ciprofloxacin, ticarcillin, and tobramycin against experimental Pseudomonas aeruginosa pneumonia.

The therapeutic efficacy of ciprofloxacin, an investigational quinoline derivative, was compared with those of ticarcillin and tobramycin in guinea pigs with experimental Pseudomonas aeruginosa pneumonia. Guinea pigs challenged with tracheal instillations of 10(8) CFU of P. aeruginosa developed acute pneumonia, for which survival rates were: controls, 0%; ticarcillin treatment, 37%; ciprofloxacin treatment, 57%; and tobramycin treatment, 69%. Intrapulmonary killing of P. aeruginosa was greater (P less than 0.05) in animals treated with ciprofloxacin or tobramycin than in groups treated with ticarcillin. A more chronic, nonfatal form of bronchopneumonia caused by P. aeruginosa was induced with agar beads impregnated with bacteria for pulmonary challenge. In this model, ciprofloxacin treatment resulted in significantly (P less than 0.001) greater intrapulmonary killing than did any other therapy. These data suggest that ciprofloxacin may be useful in the treatment of acute and more-chronic forms of pulmonary infection caused by P. aeruginosa.     

Comparative activities of N-formimidoyl thienamycin, ticarcillin, and tobramycin against experimental Pseudomonas aeruginosa pneumonia.

The therapeutic efficacies of disodium ticarcillin, tobramycin sulfate, and N-formimidoyl thienamycin (MK0787) were compared in guinea pigs with experimentally induced Pseudomonas aeruginosa pneumonia. Survival rates were 35% for ticarcillin, 80% for tobramycin, and 75% for N-formimidoyl thienamycin. Numbers of viable Pseudomonas organisms in lungs approximately 3 h after the first dose of drug were nearly 10-fold fewer in tobramycin- or N-formimidoyl thienamycin-treated animals than in ticarcillin-treated animals. Our data suggest that N-formimidoyl thienamycin may have therapeutic efficacy against respiratory infections with P. aeruginosa equivalent to that of tobramycin.     

Carbenicillin and ticarcillin

Carbenicillin and ticarcillin are penicillins which were initially developed as agents to treat serious Pseudomonas infections in the seriously ill hospitalized patient. These drugs have made a major contribution to improved survival in the neutropenic patients with Pseudomonas infection, the burn patient and to the care of the patient with cystic fibrosis. Areas of use for the compounds have enlarged to include aspiration pneumonitis in hospitalized patients, intra-abdominal and pelvic sepsis, and infections due to Proteus and Enterobacter species. Careful attention to the pharmacology of the agents is necessary to achieve clinical and bacteriologic success and to avoid the toxic side-effects such as bleeding and hypokalemia associated with the use of these agents. A decade of use has shown that the agents have remained effective agents in institutions in which their use has not been abused. It is too early to clearly position azlocillin, mezlocillin, and piperacillin. In the next few years the role of these potent compounds will be established. As noted in this review, these three agents have been used with success to treat all of the aforementioned infections. With these drugs it is also essential that the physician closely correlate in vitro data and the human pharmacology of the drugs if he or she wishes to achieve the most effective response from the agents.     

Comparative study of mezlocillin and ticarcillin in the treatment of urinary tract infections

Mezlocillin (1.5 gm) or ticarcillin (2 gm) was administered intramuscularly every six hours for seven days in this prospective, randomized study of 60 men with complicated urinary tract infections. The two patient groups were comparable as to age, weight, and infecting microorganisms. The underlying urologic disorders, which were comparable in the two groups, included hypertrophy of the prostate, carcinoma of the prostate, bladder tumors, and urethral strictures. No patient had an indwelling catheter for more than three days. Both drugs were well tolerated except for mild pain on injection. A cure of the urinary tract infection, defined as a negative urine culture one week after treatment, was obtained in 64% of the mezlocillin group and in 47% of the ticarcillin group. There was no statistical difference between these results. This study demonstrated that mezlocillin and ticarcillin, administered intramuscularly, were safe and effective in the treatment of complicated urinary tract infections.     

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%.     

Comparative pharmacokinetics of apalcillin and piperacillin

The pharmacokinetics of apalcillin and piperacillin, each administered intravenously as a single 2-g dose, were compared in 10 volunteers in a randomized study of crossover design using bioassay and high-pressure liquid chromatographic procedures. The concentrations of both penicillins in serum were determined over a period of 12 h and in urine over 24 h. Concentrations of apalcillin and piperacillin at the end of the 15-min infusion were similar; however, at 8 h, concentrations of piperacillin were below measurable levels, whereas concentrations of apalcillin were still measurable at 10 h. Pharmacokinetic parameters were calculated according to a two-compartment open model. The area under the curve and the half-life for apalcillin were larger than for piperacillin. On the other hand, renal clearance of piperacillin was substantially greater than that of apalcillin. Of the apalcillin excreted via the kidneys, approximately one-fifth was eliminated as two microbiologically inactive penicilloic acid derivatives. The nonrenal clearance of apalcillin was 79% of total clearance. Binding of apalcillin to serum protein was almost twice that of piperacillin.     

Impaired adrenal reserve in men with spinal cord injury: results of low- and high-dose adrenocorticotropin stimulation tests.

OBJECTIVE: To use low- and high-dose adrenocorticotropin (ACTH) tests to assess adrenal reserve in men with spinal cord injury (SCI). DESIGN: After an overnight fast, 1 microg and 200 microg ACTH were injected intravenously at time 0 and 60 minutes between 8 AM and 9 AM. Blood was withdrawn at 30-minute intervals from time 0 to 120 minutes. SETTING: All participants were recruited from the outpatient clinic of a university hospital that is a tertiary referral center. PARTICIPANTS: Forty-two men with traumatic neurologically complete SCI that had occurred more than 1 year before the study. MAIN OUTCOME MEASURES: Serum cortisol response to ACTH at times 0, 30, 60, 90, and 120 minutes. RESULTS: Twenty subjects had a serum cortisol response of <20 microg/dL 30 minutes after a 1-microg ACTH injection; 10 of these remained at this level at 30 minutes after a 200-microg ACTH injection. CONCLUSION: There is a high prevalence of impaired adrenal reserve in persons with chronic SCI. The 1-microg (low dose) ACTH test is more sensitive for detecting subclinical adrenal insufficiency than is the 200-microg (high dose) ACTH test.     

Comparative pharmacokinetics and pharmacodynamics of epoetin alfa and epoetin beta.

Different recombinant human erythropoietin products have been developed. Although they appear to have similar pharmacokinetics and function, these have not been directly compared. This randomized, double-blind, four-period crossover study compared the pharmacokinetics and pharmacodynamics of intravenous and subcutaneous epoetin alfa and epoetin beta in 18 normal male volunteers. As a control, three subjects received placebo treatment. After intravenous administration, the steady-state volume of distribution and beta-phase volume of distribution of epoetin beta were 7.7% and 16.9% larger than for epoetin alfa (p less than 0.05). The terminal elimination half-life after intravenous administration of epoetin beta was 20% longer than the terminal elimination half-life of epoetin alfa. After subcutaneous administration there was a delayed drug absorption with epoetin beta compared with epoetin alfa (p less than 0.05). There was a small but significantly greater absolute reticulocyte response after subcutaneous epoetin beta compared with subcutaneous epoetin alfa. The findings support differences in the pharmacokinetics and function of epoetin alfa and beta that are possibly caused by differences in their glycosylation.