Jan 21, 1991 - MICHAEL J. RYBAK,1 2,3,4* STEPHEN A. LERNER,2'4 DONALD P. ... PAM L. McNEIL,4'5 GARY A. THOMPSON,6 MICHAEL T. KENNY,7 ...
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Apr. 1991, p. 696-700
Vol. 35, No. 4
0066-4804/91/040696-05$02.00/0 Copyright © 1991, American Society for Microbiology
Teicoplanin Pharmacokinetics in Intravenous Drug Abusers Being Treated for Bacterial Endocarditis MICHAEL J. RYBAK,1 2,3,4* STEPHEN A. LERNER,2'4 DONALD P. LEVINE,2'45 LISA M. ALBRECHT,1 3t PAM L. McNEIL,4'5 GARY A. THOMPSON,6 MICHAEL T. KENNY,7 AND LIANNG YUH6 College of Pharmacy and Allied Health Professions1 and School of Medicine,2 Wayne State University, Departments of Pharmacy3 and Internal Medicine,5 Detroit Receiving Hospital and University Health Center, and Division of Infectious Diseases, Department of Medicine, Harper Hospital,4 Detroit, Michigan 48201; Merrell Dow Research Institute, Cincinnati, Ohio 452156; and Merrell Dow Research Institute, Indianapolis, Indiana 462687 Received 20 June 1990/Accepted 21 January 1991
The pharmacokinetics of teicoplanin were determined after multiple 30-min intravenous infusions of 10 to 15 mg/kg every 12 to 24 h in 11 intravenous drug abuse (IVDA) patients being treated for bacterial endocarditis. Multiple serum samples were obtained over 7 to 14 days. Twenty-four-hour urine collections were obtained on days 1 and 5. Serum concentration-time data were analyzed by using multiple-dose pharmacokinetic analysis (NONLIN84). Results were compared with pharmacokinetic parameters derived from previous studies in normal healthy volunteers following multiple intravenous infusions of teicoplanin (3 to 6 mg/kg/day). Total and renal clearances of teicoplanin in IVDA patients were found to be significantly greater and more highly variable than those observed previously in normal healthy volunteers. As a result, predicted steady-state trough concentrations in serum may vary up to fivefold. The mechanism responsible for this variation appears to be related to the glomerular filtration rate. In IVDA patients, individualized teicoplanin dosage may be required in the treatment of bacterial endocarditis.
Teicoplanin is an investigational glycopeptide which is chemically related to vancomycin. Like vancomycin, it is active against gram-positive aerobic and anaerobic bacteria, including methicillin-resistant staphylococci (6, 8, 9, 21, 2426). The in vivo activity of teicoplanin for serious staphylococcal infections has been established in experimental animal models (5, 10, 23). Clinical evaluations of teicoplanin for serious infections caused by gram-positive bacteria have demonstrated the potential efficacy of the drug, although clinical failures with low-dosage regimens have contributed to doubts regarding its ultimate utility (4, 13, 17, 28). Unlike vancomycin, teicoplanin can be administered intramuscularly, and it has a long terminal elimination half-life which permits extended dosing intervals. Furthermore, teicoplanin may have a lower toxicity profile (2, 4, 26). In a preliminary comparative efficacy trial of teicoplanin versus vancomycin for intravenous drug abuse (IVDA)associated bacterial endocarditis at Detroit Receiving Hospital, teicoplanin concentrations in serum were consistently lower than expected based on the pharmacokinetics of teicoplanin in normal healthy volunteers (Fig. 1). As a result of this observation, we determined the pharmacokinetics of teicoplanin in IVDA-associated bacterial endocarditis, in order to explore the possible mechanisms responsible for these findings. (The results of this study were presented in part at the 29th Interscience Conference on Antimicrobial Agents and Chemotherapy [20].)
University Health Center for treatment of suspected infective endocarditis and who completed at least 7 days of teicoplanin blood sampling. Informed consent was obtained from each patient prior to participation in the study. After entry into the study, continuation in the protocol required isolation in blood culture of a gram-positive pathogen (methicillin-susceptible or methicillin-resistant staphylococcus, or streptococcus) which was susceptible to teicoplanin. The exclusion criteria were compromised renal function (serum creatinine level, >1.5 mg%), elevated liver transaminase (more than four times normal), pregnancy or lactation, known hypersensitivity to vancomycin, or concomitant antibiotic use. Dosage administration. Teicoplanin (10 to 15 mg/kg of actual body weight) was administered as a constant intravenous infusion over 30 min every 12 h for up to 10 doses (loading dose regimen), followed by 10 to 15 mg/kg every 24 h (maintenance dose regimen). Dosages were increased (to a maximum daily dose of 30 mg/kg) if trough concentrations of teicoplanin in serum were less than 10 mg/liter (target trough concentrations, 10 to 25 mg/liter) for doses 3, 5, or 7 of the loading dose regimen. Blood and urine samples. Blood samples were collected serially from a central intravenous catheter at the following times from the start of the infusion for the first and last loading doses: 0, 30, 35, and 45 min and 1, 2, 4, 6, 8, 10, and 12 h. An additional sample was drawn 24 h after the last loading dose. Three serum samples (peak, trough, and one additional timed sample obtained between 2 and 20 h postinfusion) were obtained during the loading dose procedure for doses 3, 5, 7, and 9. Serum samples for peak and trough determinations were obtained every 5 to 7 days thereafter during the remaining maintenance regimen. Blood for peak and trough determinations were drawn immediately after a 30-min infusion and 30 min prior to the next dose, respectively. Blood samples were allowed to clot for approximately 45 min before centrifugation. A 24-h total urine collection
MATERIALS AND METHODS Patients. We evaluated patients with a history of IVDA who were admitted to the Detroit Receiving Hospital and * Corresponding author. t Present address: College of Pharmacy, University of Illinois, Chicago, IL 60680.
696
TEICOPLANIN PHARMACOKINETICS IN IVDA
VOL. 35, 1991
697
quantitation for teicoplanin in serum and urine were 0.19 and 3.0 mg/liter, respectively. Pharmacokinetic analysis. By using NONLIN84 (22), serum concentration-time data were fit to a three- and fourexponential function as described by the following equation:
30
o 20 B A
z
z
k
E
E
8 10.10
C=
C
E D
C D
cn-
D
4 TIME (DAYS)
2
{Dj/Dl x Cl( - Li x TIj)
j=1 i=1 x
6
n
E E
6
8
FIG. 1. Mean (bars indicate the range) predicted trough serum concentration-time profile (dashed line) upon intravenous administration of 6 mg/kg every 12 h for 10 doses followed by 6 mg/kg every 24 h based on the pharmacokinetics of teicoplanin in normal, healthy volunteers (18) and observed trough concentrations in serum of IVDA patients being treated for suspected endocarditis. The letters A to E represent the observed serum trough concentrations in serum of five different IVDA patients being treated for endocarditis.
obtained in two collection increments (0 to 12 and 12 to 24 h) following the first and last doses of the loading dose regimen for the determination of creatinine clearance (CLCR) and teicoplanin renal clearance (CLR). Serum and urine samples were stored at or below -20°C until the time of teicoplanin assay. Analytical methods. Serum and urine were analyzed for teicoplanin by a bioassay (Bacillus subtilis ATCC 6633) (7). Serum containing beta-lactams (subject 11) was pretreated with the appropriate P-lactamase (15). For urine, samples were diluted 1:10 in 0.1 M phosphate buffer (pH 7.4) supplemented with 1% normal human serum (Flow Laboratories, McLean, Va.). Within- and between-run coefficients of variation were less than 10% for the serum assay (control samples, 38 and 0.19 mg/liter) and
