No detectable resistance to tenofovir disoproxil fumarate in HBeAg+ and HBeAg- patients with chronic hepatitis B after 8 years of treatment.

A major hurdle in the long-term treatment of chronic hepatitis B (CHB) patients is to maintain viral suppression in the absence of drug resistance. To date, no evidence of resistance to tenofovir disoproxil fumarate (TDF) has been observed. A cumulative evaluation of CHB patients who qualified for resistance surveillance over 8 years of TDF treatment was conducted. Patients in studies GS-US-174-0102 (HBeAg-) and GS-US-174-0103 (HBeAg+) were randomized 2:1 to receive TDF or adefovir dipivoxil (ADV) for 48 weeks followed by open-label TDF through year 8. Population sequencing of HBV pol/RT was attempted for all TDF-treated patients at baseline and, annually if viremic, at discontinuation, or with addition of emtricitabine. Overall, 88/641 (13.7%) patients qualified for sequence analysis at one or more time points. The percentage of patients qualifying for sequence analysis declined over time, from 9 to 11% in years 1-2 to <4% over years 3-8. Forty-one episodes of virologic breakthrough (VB) occurred throughout the study, with most (n=29, 70%) associated with nonadherence to study medication. Fifty-nine per cent of VB patients with an opportunity to resuppress HBV achieved HBV DNA resuppression. A minority of patients who qualified for sequencing had polymorphic (41/165, 24.8%) or conserved (17/165, 10.3%) site changes in pol/RT, with six patients developing lamivudine and/or ADV resistance-associated mutations. No accumulation of conserved site changes was detected. The long-term treatment of CHB with TDF monotherapy maintains effective suppression of HBV DNA through 8 years, with no evidence of TDF resistance or accumulation of conserved site changes.

Prevention of adverse events in hospitalized patients using an antimicrobial review program.

OBJECTIVE: To evaluate whether an antimicrobial review system is associated with a reduction in antimicrobial-associated adverse events. DESIGN: All antimicrobial medication orders for patients hospitalized over a two-year period were evaluated. High-level interventions intended to prevent adverse antimicrobial events were collated. Based on literature estimates of adverse antimicrobial events, potential reduction of high-level adverse antimicrobial events was estimated. SETTING: Department of Clinical Pharmacy and Division of Infectious Diseases at a tertiary care teaching hospital. RESULTS: A total of 452 interventions were classified as "high-level." The incidence of preventable adverse antimicrobial events requiring intervention was 16 per 1000 antimicrobial orders. The incidence of high-level errors necessitating intervention was 4.4 per 1000 antimicrobial orders. An estimated 125 to 198 high-level adverse events were avoided. CONCLUSION: An antimicrobial review program has the potential to reduce significant adverse events in hospitalized patients.

Cross-reactivity in HIV-infected patients switched from trimethoprim-sulfamethoxazole to dapsone.

STUDY OBJECTIVE: To evaluate the cross-reactivity of dapsone after a documented hypersensitivity reaction to trimethoprim-sulfamethoxazole (TMP-SMX) during prophylaxis for Pneumocystis carinii pneumonia. DESIGN: Retrospective, chart review, cohort study. SETTING: Two university-affiliated teaching hospitals. PATIENTS: Sixty patients infected with the human immunodeficiency virus. MEASUREMENTS AND MAIN RESULTS: Thirteen patients (21.7%) had cross-reactivity to dapsone after the reaction to TMP-SMX. No significant risk factors for this response were identified. Most reactions were of mild or moderate severity and rated as possibly or probably caused by one of the agents. Of the 13 patients, 4 (30.8%) continued therapy. CONCLUSIONS: Although cross-reactivity can occur, dapsone may be considered in patients with mild hypersensitivity reactions to TMP-SMX.

Grepafloxacin pharmacokinetics in individuals with hepatic dysfunction.

The pharmacokinetics of grepafloxacin, a new broad spectrum fluoroquinolone antibiotic, were studied in 2 trials involving 14 healthy volunteers, 10 individuals with mild (Child-Pugh Class A) impairment of liver function, and 12 with moderate (Child-Pugh Class B or C) hepatic impairment. All participants received an oral dose of grepafloxacin 400 mg, daily for 7 days, and plasma and urine grepafloxacin concentrations were measured over 7 days. The pooled data from participants with impaired liver function showed that, compared with healthy individuals, peak plasma grepafloxacin concentrations, area under the plasma concentration-time curve and proportion of the dose excreted in the urine were increased. In addition, apparent total clearance was reduced in the presence of hepatic dysfunction. Peak concentrations were increased by 36% and 48% in individuals with Class A and B disease, respectively; the corresponding reductions in clearance were 33% and 55%, respectively. Child-Pugh scores and components of the scores showed no correlation with any pharmacokinetic variables. Based on these findings, we recommend a daily grepafloxacin dose of 400 mg in patients with mild hepatic impairment, irrespective of the severity of infection. Grepafloxacin should not be used in patients with moderate or severe liver disease.

Famciclovir for treatment of herpesvirus infections.

OBJECTIVE: To discuss the antiviral activity, pharmacokinetics, clinical efficacy, and adverse effect profile of famciclovir, the oral prodrug of penciclovir (PCV), and to compare these features of famciclovir with those of acyclovir in the treatment of herpesvirus infections. DATA SOURCES: Literature was identified by MEDLINE search, and abstracts from recent meetings were included where relevant. Data provided by the manufacturer were also used. STUDY SELECTION: Data regarding antiviral activity were included if accepted and widely used methods were followed. Clinical trials in which a comparison with acyclovir or placebo was performed were given the highest priority. DATA SYNTHESIS: In comparison with acyclovir, PCV has similar antiviral activity although its mode of action is not identical. When administered orally, faMciclovir, the oral prodrug of PCV, is better absorbed than acyclovir, yielding an absolute bioavailability of PCV of 77%. The predominant route of PCV elimination is via the kidneys, with a half-life of approximately 2.5 hours. In trials comparing famciclovir with acyclovir for the treatment of herpes zoster in immunocompetent individuals, comparable results were obtained. Famciclovir is also effective as therapy for recurrent episodes of genital herpes and may prove useful for chronic suppressive therapy. The most common adverse effects of famciclovir are headache and gastrointestinal upset. The dosage of famciclovir for herpes zoster in immunocompetent individuals is 500 mg po tid for 7 days; for recurrent genital herpes a dosage of 125 mg po bid for 5 days is recommended. Dosage adjustments are necessary in patients with renal dysfunction. CONCLUSIONS: Given its comparable efficacy, similar adverse effect profile, and less frequent dosing schedule than acyclovir, famciclovir represents a viable alternative for treatment of herpes zoster and for episodic therapy of recurrent genital herpes in immunocompetent adults. Specific recommendations for other uses of famciclovir await the publication of recent clinical trial results.

Protein binding of clindamycin in sera of patients with AIDS.

Patients with AIDS have altered pharmacokinetics of clindamycin compared with those of healthy control subjects. In an attempt to better understand these differences, we undertook a study of protein binding of clindamycin in sera of patients with AIDS. Fifteen patients with AIDS and 15 healthy volunteers were given a single 600-mg dose of clindamycin orally and intravenously, and serum samples were collected at three time points corresponding to high, midpoint, and low clindamycin concentrations. Protein binding was determined by ultrafiltration, and total and unbound clindamycin concentrations were measured with a gas chromatography assay. AIDS patients had alpha 1-acid glycoprotein values approximately twice those of healthy volunteers (mean +/- standard deviation, 103 +/- 27 versus 61 +/- 11 mg/dl; P = 0.001). Overall, serum protein binding levels were higher in AIDS patients (mean +/- standard deviation, 83 +/- 7 versus 78% +/- 8%; P = 0.0001), which is likely the result of increased alpha 1-acid glycoprotein levels in these patients. Total concentrations of clindamycin in plasma were significantly higher in AIDS patients at most time points studied, while unbound serum clindamycin concentrations did not differ among the groups at each sampling time after both oral and intravenous dosing. Increased protein binding may partly explain the altered pharmacokinetic disposition of clindamycin in AIDS patients; however, other factors cannot be excluded.

Recruitment and funding for clinical pharmacy residency and fellowship programs.

A survey was conducted to determine if a shortage exists of graduates interested in residency and fellowship training, and whether program preceptors experience difficulty maintaining funding. Questionnaires were mailed to 195 preceptors listed in the American College of Clinical Pharmacy Directory of Residencies and Fellowships, and responses from 143 (73%) were compiled. Average numbers of applicants interviewed per available position were 3.1, 3.3, and 2.6 for general clinical residency, specialized residency, and fellowship positions, respectively. Approximately 20% of specialty residency and fellowship positions were reported to be unfilled, and 70% of preceptors of these programs expressed the opinion that a shortage of interested graduates exists. Difficulty maintaining funding was most frequently reported by fellowship preceptors (54%), and several sources of funding were required to maintain such programs.

Roxithromycin disposition in patients on continuous ambulatory peritoneal dialysis.

Roxithromycin is a macrolide antibiotic with a spectrum of activity similar to erythromycin. Roxithromycin has been shown to have a favourable pharmacokinetic profile with more reliable absorption and higher, prolonged plasma and tissue concentrations compared with erythromycin. The pharmacokinetics and dialysis clearance of roxithromycin were studied in twelve patients with end-stage renal disease on continuous ambulatory perionteal dialysis. Following a single 300 mg oral dose, multiple blood, dialysate and urine samples were collected over 48 h and assayed for roxithromycin by a microbiological method. Peak plasma concentrations were attained between 0.5 and 5 h, and ranged from 2.3 to 6.8 mg/L. The mean elimination half-life was 20.6 +/- 8.7 h, compared with 10 to 14 h previously reported in healthy volunteers given a single 300 mg dose. Plasma clearance relative to bioavailability (Clp/F) ranged from 37.3 to 118.3 mL/min. The percentage of the dose recovered in the dialysate and net dialysis clearance were low, ranging from 1.0 to 3.1% and 0.9 to 1.8 mL/min, respectively. Only 1% of the dose was recovered in the urine. These results demonstrate that roxithromycin is not substantially removed by continuous ambulatory peritoneal dialysis, and its elimination is prolonged in renal failure, possibly due to impaired nonrenal elimination.

Nocardial brain abscess: treatment strategies and factors influencing outcome.

The successful management of nocardial brain abscess remains problematic. The authors report 11 cases of nocardial brain abscess treated between 1971 and 1993 and review 120 cases reported since 1950. The clinical findings included focal deficits in 55 patients (42%), nonfocal findings in 36 (27%), and seizures in 39 (30%). Extraneural nocardiae were present in 66% of the cases; pulmonary (38%) and cutaneous/subcutaneous (20%) locations were the most frequent. The abscesses were single in 54% of the patients, multiple in 38%, and of unknown number in 8%. Forty-four of 131 patients (34%) were immunocompromised; since 1975, 18 of 40 immunocompromised patients (45%) were transplant recipients and six (15%) had human immunodeficiency virus. The mortality rate was 24% after initial craniotomy and excision (11/45), 50% after aspiration/drainage (17/34), and 30% after nonoperative therapy (7/23); 29 cases (22%) were diagnosed at autopsy. The mortality rate was 33% in patients with single abscesses and 66% in those with multiple abscesses (P < 0.0003). There was no difference in the mortality rates of immunocompromised and nonimmunocompromised patients treated before computed tomography (CT) was available; since the advent of CT, however, the mortality rate has been significantly higher in immunocompromised patients (55% vs. 20%, P < 0.05). Although the mortality rate for nocardial brain abscesses has dropped almost 50% since the advent of CT, it has remained virtually unchanged in immunocompromised patients and is three times higher than that of other bacterial brain abscesses (30% vs. 10%). The authors recommend image-directed stereotactic aspiration for diagnosis; however, craniotomy and total excision are necessary in most cases, because nocardial abscesses are usually multiloculated. Patients with minimal neurological deficits or small abscesses may be treated initially with antibiotics alone. Sulfonamides, alone or in combination with trimethoprim, are most effective and should be continued for at least 1 year. Minocycline, imipenem, or aminoglycoside in combination with a third-generation cephalosporin may be used with reasonably good success as second-line agents in cases of allergy or nonresponsiveness to sulfa agents.

Atovaquone: a review.

OBJECTIVE: To review the chemistry, pharmacology, pharmacokinetics, clinical efficacy, and safety of atovaquone. DATA IDENTIFICATION: An English-language literature search using MEDLINE (1984-1993), programs and abstracts of the 30th, 31st, and 32nd Interscience Conferences on Antimicrobial Agents and Chemotherapy, program and abstracts of the VIII International Conference on AIDS, and unpublished information from Burroughs Wellcome, the manufacturer of atovaquone. STUDY SELECTION: All available pharmacokinetic and clinical trials were reviewed. DATA EXTRACTION: Study quality was assessed by a critical appraisal of study design and methods. Pharmacokinetic studies were evaluated for sampling, methods used to determine pharmacokinetic properties, and the presence of concentration-response and concentration-toxicity relationships. Clinical trials were assessed primarily for comparative efficacy and toxicity. RESULTS: Atovaquone is a novel hydroxynaphthoquinone with potent activity against Pneumocystis carinii and Toxoplasma gondii. Its pharmacokinetic properties are characterized by relatively poor bioavailability, excretion almost exclusively through the feces, lack of hepatic metabolism and urinary excretion, low steady-state plasma concentrations, high protein binding, and a long elimination half-life (50-70 h). Results from comparative clinical trials in AIDS patients with mild-to-moderate P. carinii pneumonia (PCP) reveal similar overall treatment success rates for atovaquone, trimethoprim/sulfamethoxazole (TMP/SMX), and pentamidine. Treatment failure because of lack of therapeutic response was significantly greater in patients who received atovaquone compared with those treated with TMP/SMX (p = 0.002). More atovaquone-patients experienced treatment failure compared with their pentamidine-treated counterparts, although statistical significance was not achieved. Treatment failure secondary to drug toxicity was significantly higher in the TMP/SMX- and pentamidine-treated patients (p < or = 0.01). Atovaquone has not been studied for PCP prophylaxis. Limited data exist on the use of atovaquone for toxoplasmic encephalitis (TE); however, results from an open trial reveal that the drug may be useful in treating this disorder. To date, atovaquone has been well tolerated by most patients administered the drug. The most common adverse effects include maculopapular rash, gastrointestinal disturbances, and fever. Atovaquone is considerably more costly than other oral agents used to treat PCP. CONCLUSIONS: Atovaquone appears to be better tolerated but less effective than TMP/SMX and pentamidine in the treatment of mild-to-moderate PCP. There is not enough information available on the use of atovaquone for PCP prophylaxis or the treatment of TE to definitively describe its efficacy. Comparative clinical trials are needed to assess its role in this clinical setting.

Use of intrathecally administered morphine in the treatment of postoperative pain after lumbar spinal surgery: a prospective, double-blind, placebo-controlled study.

Improved control of postoperative pain is now known to reduce the incidence of morbidity. Although spinally administered narcotics have found a clear role in chest and abdominal surgery, their role in lumbar spinal surgery is debated. We conducted a prospective, double-blind, randomized, placebo-controlled trial of intrathecally administered morphine sulfate after lumbar spinal surgery in 56 patients. Patients received 0, 0.125, 0.25, or 0.5 mg of intrathecally administered morphine during extradural lumbar spinal operations, and the effects on postoperative analog pain scores, narcotic consumption, complications, and length of hospitalization were assessed. As compared with systemic narcotic administration, intrathecally administered morphine provided superior analgesia in a dose-dependent fashion without an increase in narcotic side effects. Consumption of parenteral narcotics on the first postoperative day and over the total hospitalization period decreased in correlation with increasing doses of intrathecally administered morphine. Mean length of hospitalization was significantly decreased, as compared with the control group, in patients receiving 0.25 or 0.5 mg of intrathecally administered morphine. When proper precautions are observed, intrathecally administered morphine can improve the postoperative care of patients undergoing lumbar spinal surgery.

The Social Rhythm Metric. An instrument to quantify the daily rhythms of life.

The Social Rhythm Metric (SRM) is an instrument designed to quantify an individual's daily social rhythms. Social rhythms are important both as a way of structuring the day cognitively and as time cues (or zeitgebers) that drive the biological clock (circadian system). The development of the SRM and its pilot testing in 50 healthy control subjects is described, along with measurements of reliability and validity. The potential of the SRM for integrating psychosocial and biological research and its clinical applicability are discussed.

Influence of coadministration on the pharmacokinetics of mezlocillin and cefotaxime in healthy volunteers and in patients with renal failure.

The pharmacokinetic disposition of cefotaxime, desacetyl cefotaxime, and mezlocillin after the administration of each drug singly and in combination was examined in eight healthy volunteers and in five anuric patients with end-stage renal disease (ESRD). In the presence of ESRD, the total body clearance of cefotaxime decreased from 256.7 +/- 41.5 to 65.4 +/- 42.0 ml/min, and its elimination half-life (t1/2) increased from 1.1 to 3.6 hours as compared with healthy volunteers. Concomitant administration of mezlocillin in healthy volunteers decreased the total body clearance of cefotaxime by 42% and increased its steady-state volume of distribution. This reduction in clearance was reflected by a decrease in both renal and nonrenal clearances. In the presence of ESRD, coadministration of mezlocillin increased the t1/2 of cefotaxime to 5.8 hours. Desacetyl cefotaxime accumulated in ESRD with a prolongation of its elimination t1/2 to 18.7 hours from 1.7 hours in healthy volunteers. Desacetyl cefotaxime peak plasma concentrations occurred later with the combination regimen in the presence of ESRD. The clearance of mezlocillin was reduced and t1/2 prolonged in ESRD from 194.6 +/- 31.9 to 76.4 +/- 38.8 ml/min and 1.4 to 2.3 hours, respectively. Concomitant administration of cefotaxime did not alter the pharmacokinetics of mezlocillin. These data suggest that in the presence of normal renal function, lower doses of cefotaxime may be adequate to maintain similar cefotaxime plasma concentrations when mezlocillin is coadministered compared to when cefotaxime is given alone. Additional pharmacodynamic and clinical studies with this combination are warranted to further elucidate the clinical impact of this pharmacokinetic interaction.

Pharmacokinetics of esmolol and ASL-8123 in renal failure.

The effect of renal function on the pharmacokinetics of esmolol, an ultra-short-acting beta-adrenergic blocker, and its major metabolite, ASL-8123, was examined in six healthy control subjects, six patients maintained on hemodialysis, and six patients on continuous ambulatory peritoneal dialysis (CAPD). In addition, the impact of hemodialysis and CAPD on removal of esmolol and ASL-8123 was determined. Multiple blood, urine, and dialysate samples were collected during a 72-hour period and assayed for esmolol and ASL-8123 by HPLC. The pharmacokinetic disposition of esmolol was not significantly altered by renal failure. Mean (+/- SD) total body clearance for esmolol was 171.4 +/- 69.8, 249.8 +/- 176.3, and 265.3 +/- 143.1 ml/min/kg for the control, hemodialysis, and CAPD patients, respectively. Mean elimination half-life (t1/2) was 7.2 minutes in control subjects compared with 7.1 and 8.0 minutes for the hemodialysis and CAPD groups, respectively. The apparent volume of distribution of esmolol did not differ significantly among the three groups. ASL-8123 was shown to accumulate in patients with renal failure, as evidenced by a mean maximum blood concentration of 42.8 +/- 12.2 micrograms/ml in the control group compared with 76.1 +/- 23.9 and 87.1 +/- 20.4 micrograms/ml in the hemodialysis and CAPD groups, respectively (p less than 0.05). The elimination t1/2 of ASL-8123 was prolonged in patients with renal failure, averaging more than 42 hours compared with only 4 hours in the control subjects. Approximately 20% of the esmolol dose as ASL-8123, was removed by either hemodialysis or CAPD, contributing minimally to the elimination of the drug.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparative pharmacokinetics and serum inhibitory activity of clindamycin in different dosing regimens.

The comparative pharmacokinetics and serum inhibitory effects of clindamycin were evaluated in six healthy male subjects given multiple-dose infusions of the following regimens in a crossover fashion: 600 mg every 6 h, 900 mg every 8 h, and 1,200 mg every 12 h. Serial blood samples were obtained after the last dose in each regimen and analyzed for clindamycin by a sensitive and specific high-performance liquid chromatography assay technique. Clindamycin pharmacokinetics were estimated by using noncompartmental methods, and serum inhibitory titers were serially determined against Bacteroides fragilis ATCC 25285 and evaluated by using area under the serum inhibitory curve (AUIC). Maximum and minimum concentrations in plasma averaged 12.2 +/- 1.6 and 1.2 +/- 0.6, 16.3 +/- 4.0 and 0.9 +/- 0.5, and 16.8 +/- 2.5 and 0.4 +/- 0.2 micrograms/ml for the 600-, 900-, and 1,200-mg regimens, respectively. Clindamycin plasma clearance and elimination half-life averaged 23.3 +/- 4.0 liters/h and 1.9 +/- 0.4 h for the 600-mg regimen, 25.6 +/- 8.2 liters/h and 2.1 +/- 0.4 h for the 900-mg regimen, and 26.4 +/- 4.7 liters/h and 2.1 +/- 0.4 h for the 1,200-mg regimen. These results were not significantly different. Apparent volume of distribution increased significantly for the 1,200-mg regimen compared with the 600-mg regimen. Mean maximum reciprocal serum inhibitory titers were 96 +/- 35, 101 +/- 43, and 160 +/- 78 for the 600-, 900-, and 1,200-mg regimens, respectively. Minimum reciprocal serum inhibitory titers averaged 12 +/- 4, 6 +/- 3, and 5 +/- 2 for the low-, medium-, and high-dose regimens, respectively. Mean AUIC increased roughly in proportion to dose. Similar daily values for the area under the concentration-time curve and for AUIC for each of the regimens suggest similar daily drug exposure and serum inhibitory activity. A regimen of 1,200 mg every 12 h may represent an alternative dosing strategy for clindamycin.

Effect of dose on pharmacokinetics and serum bactericidal activity of mezlocillin.

Mezlocillin is subject to dose-dependent pharmacokinetics. Previous studies have examined the pharmacokinetic but not the pharmacodynamic aspects of this effect. The pharmacokinetic disposition of mezlocillin was determined in eight healthy volunteers in a randomized, crossover fashion after single infusions of 50 and 80 mg of mezlocillin per kg of body weight. Plasma and urine were assayed with a specific high-pressure liquid chromatography assay and analyzed by noncompartmental methods. Pharmacodynamic (bactericidal) effects were evaluated from serial serum bactericidal titers obtained after each dose by using the area under the bactericidal activity curve method. The mean mezlocillin total body clearance decreased from 203.6 +/- 36.2 ml/min after the 50-mg/kg dose to 171.7 +/- 42.1 ml/min after the 80-mg/kg dose (P, 0.01). The decreased clearance was reflected by a decrease in nonrenal clearance only (108.9 +/- 20.0 to 77.9 +/- 23.5 ml/min, respectively; P, 0.001). Mean areas under the curve for concentration in plasma versus time normalized to the 50-mg/kg dose were 314 +/- 73 and 375 +/- 64 micrograms X h/ml for the low and high doses, respectively (P, 0.01). No significant changes were observed in the steady-state volume of distribution or elimination half-life. Mean areas under the bactericidal activity curve were 100 +/- 77 and 244 +/- 143 for the 50- and 80-mg/kg doses, respectively. The decrease in mezlocillin clearance and the disproportionate increase in the area under the curve for concentration in plasma versus time, coupled with the observed prolonged bactericidal effects of the 80-mg/kg dose, lend support for administration of mezlocillin at a higher dose less frequently (e.g., 5 g every 8 h). Clinical trials with the higher-dose regimen are warranted to validate these observations.

Pharmacokinetics of cefoperazone and tobramycin alone and in combination.

Certain beta-lactams have been shown to increase the clearance of tobramycin. We evaluated the pharmacokinetics of cefoperazone and tobramycin, alone and in combination, in healthy volunteers. No significant alteration in pharmacokinetic behavior was noted for cefoperazone or tobramycin alone or in combination.

Comparative pharmacokinetics of low- and high-dose ticarcillin.

Certain antipseudomonal penicillins, such as mezlocillin, exhibit a nonlinear pharmacokinetic disposition with increasing doses. We evaluated the effect of a single low dose (50 mg/kg) compared with a high dose (80 mg/kg) on the pharmacokinetics of ticarcillin in a crossover trial of eight healthy volunteers. No significant alteration in plasma clearance (130.1 +/- 36.5 versus 120.5 +/- 38.0 ml/min), nonrenal clearance (36.5 +/- 8.4 versus 33.4 +/- 18.5 ml/min), or volume of distribution at steady state (12.8 +/- 3.5 versus 12.3 +/- 4.5 liters) was observed between the low- and high-dose regimens, respectively. The elimination half-life remained unchanged between the two doses (67.9 +/- 14.3 versus 68.0 +/- 12.2 min). Unlike other newer antipseudomonal penicillins, ticarcillin did not display dose-dependent pharmacokinetic behavior with the range of doses used in the clinical setting.