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.

Cost-effectiveness of prospective and continuous parenteral antibiotic control: experience at the Palo Alto Veterans Affairs Medical Center from 1987 to 1989.

PURPOSE: Controlling inappropriate antibiotic usage is a major focus for hospital quality assurance and cost-containment programs. We assessed the impact of strengthening a parenteral antibiotic control policy and instituting continuous infectious disease service (IDS) reviews of the appropriateness of antimicrobial therapy on cost and patient outcomes. PATIENTS AND METHODS: All patients receiving intravenous antibiotics during a 3.5-year period from 1986 to 1989 were included in either the pre- or post-policy study group. Antibiotic costs 16 months before were compared with antibiotic costs 26 months after implementation of a new policy to restrict inappropriate usage of (1) broad-spectrum antibiotics when not necessary, (2) expensive agents when a less costly agent could be used, and (3) an excessive dosage or interval. Patient subgroups treated 4 months before and 4 months after policy implementation were compared further within diagnosis-related group (DRG) assignments using patient demographic, cost, and outcome measures. RESULTS: The average monthly antibiotic costs during the 26-month post-policy period were $7,600 less than during the 16-month pre-policy period (p less than 0.0001), resulting in an average yearly drug cost reduction of $91,200. The IDS team altered therapy in 611 (34.5%) of 1,769 reviews of antibiotic usage during the 26-month period. The comparisons among similar patient groups by DRG classification revealed the average number of antibiotic doses per study patient admission was decreased 24% (p = 0.005) and drug costs were reduced 32% (p = 0.004) after policy implementation. In two DRG categories (i.e., respiratory infections plus pneumonia), patients in the post-policy group had a 33% decrease in average number of doses (p = 0.05) and 45% decrease in antibiotic costs (p = 0.04) compared with the pre-policy group. Similar trends were observed in most DRG categories. There was an average $70 per admission decrease in drug cost and a reduction of eight antibiotic doses per admission after policy initiation. The overall prevalence of deaths (p = 0.22) and average length of antibiotic therapy (p = 0.29) were less in the post-policy period despite group similarities in patient characteristics and lengths of hospital stay. CONCLUSION: Antibiotic control policies can be developed to ensure quality care and can be designed to select for cost-effective agents. Prospective and continuous monitoring of antibiotic usage by the IDS resulted in a significant and sustained reduction in antibiotic costs without detrimental effect on the length of therapy or deaths.

Altered pharmacokinetics of antibiotics during vascular surgery.

Prophylactic antibiotics significantly decrease the incidence of infection in various surgical procedures. Although antibiotics must be administered preoperatively to be effective, it is unknown whether therapeutic concentrations are necessary throughout the operation to prevent infection. Furthermore, the pharmacokinetics of antibiotics during surgical procedures is not well understood. Several factors, including blood loss, fluid redistribution, and changes in renal blood flow may alter the pharmacokinetic disposition of the antibiotic. In a controlled investigation of intraoperative antibiotic pharmacokinetics, cefamandole was studied in eight patients undergoing elective surgery of the abdominal aorta and peripheral vasculature. Both elimination half-life (67 +/- 19 minutes versus 93 +/- 23 minutes) and the volume of distribution (16.8 +/- 5.3 liters versus 25.2 +/- 11.9 liters) increased when compared with the preoperative state. The increased volume may be due, in part, to redistribution of fluid. Plasma concentrations of antibiotic were low at the time of graft placement in those patients with normal renal function. Additional antibiotic dosing may be warranted prior to prosthesis insertion in these patients.

Comparison of antibiotic activities by using serum bactericidal activity over time.

In evaluating antimicrobial agents with similar spectra of activity, it is difficult to determine equivalent dosage regimens. In vitro potency, pharmacokinetic disposition, and other factors determine the usual dosing regimen. Knowledge of the serum bactericidal activity over time may assist in defining the potency of comparative antimicrobial agents. Cefoxitin and ceftizoxime, cephalosporins with gram-negative aerobic and anaerobic activity, have been promoted as monotherapy in the treatment of intra-abdominal infection. In a randomized, crossover study, six healthy volunteers received single 30-mg/kg doses of cefoxitin and ceftizoxime. Greater serum activity against Escherichia coli and Bacteroides fragilis was observed with ceftizoxime than with cefoxitin. The results suggest that ceftizoxime can be administered in a lower daily dosage than cefoxitin. We propose that the present study may serve as a prototype for future studies attempting to assess equivalent dosing regimens for antibiotics with similar spectra of activity.

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.