No abstract

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,(24)(25)(26). 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.( 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 1...

The 6-substituted 2-(3',4'-dichlorophenoxy)-2H-pyrano[2,3-b]pyridines MDL 20,610 (6-SO2CH3), MDL 20,646 (6-Br), and MDL 20,957 (6-Cl) are potent antirhinovirus compounds with median plaque 50% inhibitory concentrations (IC1/2s) of 0.03, 0.006, and 0.006 micrograms/ml, respectively, against the 32 serotypes evaluated. The 6-halogenated analogs produced 99% reductions in progeny virion yields at concentrations as low as 0.004 micrograms/ml. However, these analogs perturbated HeLa cell metabolism at lower concentrations (at or above 5 micrograms/ml) than did the 6-methylsulfonyl analog (at or above 20 micrograms/ml). Compound MDL 20,610 was also active against human, simian, and bovine rotaviruses (cytopathic effect IC1/2s of 0.8 to 1.5 micrograms/ml) and possessed variable enterovirus and paramyxovirus activity.

Teicoplanin pharmacokinetics were evaluated after multiple-dose intravenous administration to healthy male volunteers by using a randomized, double-blind, parallel design. Doses of 3, 12, or 30 mg of teicoplanin per kg of body weight were administered every 24 h for 14 days as 60-min constant-rate intravenous infusions. Blood and urine samples were collected over 21 days and analyzed by a microbiological assay. Twenty-three subjects were included in the pharmacokinetic analysis. The median pharmacokinetic parameters upon multiple-dose intravenous administration of 3, 12, and 30 mg/kg included steady-state volumes of distribution of 0.94, 0.77, and 0.68 liter/kg; total clearances of 11.9, 12.0, and 13.2 ml/h/kg; and terminal disposition half-lives of 143, 166, and 96 h, respectively. Renal clearance accounted for approximately 95% of total clearance. No dose-related differences existed for teicoplanin total or renal clearance. The steady-state volume of distribution decreased significantly with increasing doses. As a result of the decrease in the volume of distribution, the terminal disposition half-life at 30 mg/kg was significantly decreased. However, the decreases in the volume of distribution and terminal disposition half-life are of limited clinical importance, since steady-state trough concentrations in serum increase in proportion to dose. Combined results of all multiple-dose studies with similar durations of sample collection indicate no dose-related differences for any pharmacokinetic parameters from 3 to 12 mg/kg. As observed in the present study, no dose-related differences exist for teicoplanin total and renal clearances from 3 to 30 mg/kg. However, at 30 mg/kg, a significant decrease in the steady-state volume of distribution is observed. As a consequence of the reduction in the volume of distribution at 30 mg/kg with no change in clearance, the terminal disposition half-life is decreased.Teicoplanin is a new glycopeptide antibiotic, chemically related to vancomycin and ristocetin. It is active against aerobic and anaerobic gram-positive bacteria (4,8,12,15). Its effect on susceptible bacteria is bactericidal, and like vancomycin, it interferes with cell wall synthesis (18).In earlier studies, the pharmacokinetics of teicoplanin were determined on the basis of plasma concentration-time profiles obtained over 3 to 4 days (22, 24). A review of these studies has recently been published (16). In more recent studies, the duration of sample collection has been extended up to 3 weeks, resulting in a more complete characterization of the serum concentration-time profile (1,11,14,21). As a result of the increase in the duration of sample collection, teicoplanin total clearance was found to be slightly less and the volumes of distribution and terminal disposition half-life were found to be greater than previously reported. Results from these more recent studies indicate that the pharmacokinetics of teicoplanin upon multiple-dose intravenous administration are linear over the range of 3 to 12 mg/kg of body wei...

Nineteen phenoxypyridinecarbonitriles were initially evaluated for their in vitro activity against rhinoviruses (RV) 1A, 2, and 64 and coxsackievirus (Cox) A21 and for their oral prophylactic and therapeutic activity in Swiss albino mice challenged with Cox A21. On the basis of the results of these studies, one compound, 6-(3,4-dichlorophenoxy)-3-(ethylthio)-2-pyridinecarbonitrile, was selected for further evaluation. Expanded in vitro spectrum of activity studies showed that the MIC causing a 50% reduction in viral cytopathic effect in infected cultures (MIC50) was 3.0 ,ug/ml or less against 11 of 20 RV serotypes tested. The compound was only moderately active (MIC50, 5 to 7 ,ug/ml) against four of the RV serotypes evaluated, while RV 4, 5, 8, 13 and Hank's were relatively resistant to compound inhibition. Of the nine enteroviruses studied, only Cox A21, echovirus 12, poliovirus 2, and enterovirus 70 were inhibited at compound concentrations of less than 2.0 ,ug/ml. The compound provided significant protection to mice infected with a normally lethal dose of Cox A21 when administered in a single oral dose of 150 mg/kg (P < 0.01) and during a regimen of continuous oral doses of 37.5 mg/kg per day (P < 0.001). Mechanism of action studies indicated that the compound inhibited picornavirus uncoating or some earlier virus-host cell-associated event.