Binding of teicoplanin to human serum albumin

Teicoplanin is a glycopeptide antibiotic with a mode of action and spectrum of activity similar to those of vancomycin. Its efficacy and tolerability as empiric therapy and its pharmacokinetic properties in neutropenic patients are being studied in a double-blinded, randomized trial in comparison with those of vancomycin. We report here a modified agar diffusion bioassay which is suitable for monitoring levels of either teicoplanin or vancomycin in serum during combination therapy with ,-lactams, aminoglycosides, and amphotericin B. Serum samples spiked with either teicoplanin or vancomycin gave reproducible results (mean coefficient of variation, 8.8%) regardless of the presence of tobramycin, amikacin, piperacillin, ceftazidime, amphotericin B, or their combinations. Among 25 patients who received teicoplanin at a dosing schedule of 6 mg/kg every 24 h intravenously, steady state was reached after 14.2 ± 4.0 days, and 1-h peak and trough concentrations of teicoplanin in serum at steady state were 40.8 ± 15.0 and 12.5 ± 3.2 mg/liter, respectively. In contrast, among 25 patients who received vancomycin at a dosing schedule of 15 mg/kg every 12 h intravenously, steady state was reached by 24 h, and the 1-h peak and trough concentrations in serum were 37.5 ± 15.6 and 8.3 ± 3.8 mg/liter, respectively. The elimination half-lives for teicoplanin estimated by two separate approaches agreed closely with each other: 80.5 ± 21.5 h by an accumulation model (M. Gilbaldi and D. Perrier, Pharmacokinetics, 2nd ed., p. 121, 1982) and 87.3 ± 19.3 h as predicted from the degree of renal function (M. Rowland, Clin. Pharmacokinet. 18:184-209, 1990). These values were 14-to 15-fold higher than that for vancomycin (5.61.8 h). Since considerable variability was noted in the pharmacokinetic parameters for both teicoplanin and vancomycin among the individual patients, our data further emphasized the need for frequent monitoring of these drugs during empiric therapy of the febrile neutropenic patient.

Section: Methodsmentioning

confidence: 99%

Application of a modified bioassay for monitoring serum teicoplanin and vancomycin in febrile neutropenic patients

Kureishi

Jewesson

Bartlett

et al. 1990

“…Unlike teicoplanin, vancomycin affects the permeability of the cell membrane and impairs RNA synthesis in protoplasts (11). Teicoplanin has been shown to be more highly protein bound than vancomycin (1). Early in vivo studies with low-dose teicoplanin for the treatment of infective endocarditis (21) and severe staphylococcal infections (4,5) found high failure rates.…”

mentioning

confidence: 99%

Protein binding and serum bactericidal activities of vancomycin and teicoplanin

Dykhuizen

Harvey

Stephenson

et al. 1995

In a randomized crossover study, the protein binding and serum bactericidal activities (SBAs) of vancomycin and teicoplanin against Staphylococcus aureus and Streptococcus pyogenes were investigated in six healthy volunteers. Total concentrations in serum 1 h postadministration of vancomycin and teicoplanin were 25.5 ؎ 2.7 and 10.8 ؎ 8.9 mg/liter, respectively; mean free concentrations were 14.6 ؎ 2.0 and 0.6 ؎ 0.9 mg/liter, respectively. Protein binding for vancomycin was 36.9% ؎ 2.87%, and that for teicoplanin was 97.4% ؎ 2.6%. SBA determined in pooled human serum at 1 h against S. aureus ranged from 1:8 to 1:32 for both vancomycin and teicoplanin. Against S. pyogenes SBA at 1 h ranged from 1:16 to 1:128 for vancomycin and 1:256 to 1:2,048 for teicoplanin. In vitro kill curve studies showed that vancomycin is slowly bactericidal and that teicoplanin is bacteriostatic. Despite having less in vitro cidal activity against the study isolates and having low or unrecordable levels of free drug in serum, teicoplanin demonstrated a similar or better SBA than vancomycin. SBA was more closely related to the total drug level (r ‫؍‬ 0.77 for S. aureus and r ‫؍‬ 0.79 for S. pyogenes) than the free level of teicoplanin (r ‫؍‬ 0.59 for S. aureus and r ‫؍‬ 0.56 for S. pyogenes). The high level of protein binding of teicoplanin did not seem to impair its antibacterial activity as measured by its SBA.

“…MDL 63,246 was distributed in a similar volume as MDL 63,476 and was cleared quite slowly compared with the clearance of the natural compound. A high level of protein binding of the drug in plasma, possibly higher than the approximately 90% estimated for teicoplanin (1), is a possible explanation for the low CL from plasma in the rat. A relatively small amount of drug, the fraction not bound to plasma protein, is available at all times for distribution and elimination (6,12,13).…”

Section: Discussionmentioning

confidence: 85%

Pharmacokinetics of MDL 63,246, a new semisynthetic glycopeptide antibiotic, in the rat

Borgonovi¹,

Cavenaghi²,

Borghi³

et al. 1995

Following intravenous administration in the rat, the concentration of MDL 63,246 in plasma was high and long-lasting. Concentrations fell with an apparent three-exponential decay. MDL 63,246 was distributed in a high volume and was cleared quite slowly. The pharmacokinetics of MDL 63,246 in the rat appear to be dose proportional in the dose range of 20 to 50 mg/kg of body weight. When administered subcutaneously, MDL 63,246 was slowly absorbed from the injection site, and the extent of availability was good, being 70.1%. MDL 63,246 was eliminated slowly by both renal and fecal excretion. MDL 63,246 is rapidly and extensively distributed into the tissues. At 0.5 h after drug administration, radioactivity was detected in all organs examined. At 24 h after administration, the total concentrations of radioactivity still increased in some organs which represent a slowly equilibrating compartment, but only the kidneys and liver showed a higher total concentration of radioactivity than plasma. Between 24 and 192 h after treatment, total concentrations of radioactivity decreased very slowly, and finally, apart from brain, all tissues showed higher concentrations than plasma, indicating a very high affinity of MDL 63,246 for tissues. The ratio of the concentration of radioactivity in blood to that in plasma ratio was 0.58, indicating that MDL 63,246 does not diffuse into erythrocytes and that binding to the erythrocyte membrane does not occur. All of these findings appear to correlate with the excellent in vitro and in vivo activities of the compound, suggesting that MDL 63,246 could be therapeutically efficacious at lower dosages and longer treatment intervals than those currently used for vancomycin and teicoplanin.The antibiotic MDL 63,246 (11) is the dimethylaminopropylamide derivative of natural glycopeptide MDL 62,476 (A40926) (9), in which the N-acyl-glucuronic acid is selectively reduced to N-acyl-glucosamine (Fig. 1). MDL 63,246 has better in vitro activity than MDL 62,476, teicoplanin, and vancomycin, particularly against Staphylococcus aureus and coagulase-negative staphylococci (8,10). It also has excellent activity against streptococci and teicoplanin-susceptible enterococci and against some VanA enterococcal isolates. The compound is more active than teicoplanin and vancomycin against acute staphylococcal, streptococcal, and enterococcal septicemia in immunocompetent and neutropenic mice. It is highly efficacious in reducing the heart bacterial load in staphylococcal endocarditis experiments in rats and the bacterial load of Staphylococcus epidermidis in a thigh infection model in neutropenic mice (8). We present preliminary data on the kinetics in plasma, distribution in tissue, and excretion of MDL 63,246 in the rat following intravenous (i.v.) administration and on its availability after subcutaneous (s.c.) administration.(Many of the data included in this report were presented at the 33rd Interscience Conference on Antimicrobial Agents and Chemotherapy, New Orleans, La., 17 to 20 October 1993 [3a].) MAT...