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

Abstract

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.

Double-blind comparison of teicoplanin versus vancomycin in febrile neutropenic patients receiving concomitant tobramycin and piperacillin: effect on cyclosporin A-associated nephrotoxicity

“…Steady-state levels in serum (mean + standard deviation [SD]) at 1 and 3 h postinfusion and trough levels in serum were 42 + 15, 22 ± 5, and 12 + 3 mg/liter, respectively, for teicoplanin and were 37 ± 15, 20 ± 8, and 8 ± 4 mg/liter, respectively, for vancomycin. The pharmacokinetic data from this study have been fully described elsewhere (16). Mean (+SD) tobramycin levels (mg/liter) at steady state were comparable in both groups, with a Cmax level of 6.7 + 1.4 and a Cmin level of 0.9 ± 0.4 for patients in the teicoplanin group and a Cmax level of 7.0 ± 1.4 and a Cmin level of 1.1 + 0.5 for patients in the vancomycin group.…”

“…Teicoplanin has several potential advantages, including low toxicity (29), good tolerance when administered by i.v. and intramuscular routes (26), and a half-life that is up to 15 times longer than that of vancomycin (2,5,16). However, teicoplanin has a high degree of protein binding (>90%), which makes it more difficult to predict the in vivo clinical response on the basis of in vitro antimicrobial activity alone (4,6).…”

“…Like vancomycin, it is active against most gram-positive organisms (18,(20)(21)(22)32), but it offers several potential advantages over vancomycin, including low toxicity, better tolerance after intravenous (i.v.) or intramuscular administration, and a longer elimination halflife (up to 15 times that of vancomycin) (2,5,16,26). However, teicoplanin is highly protein bound (>90%), and drug resistance appears to develop more readily with it than with vancomycin (1,3,4,6,10).…”

“…to maintain 1-h peak concentrations of 30 to 50 mg/liter and trough concentrations of 5 to 15 mg/liter for both teicoplanin and vancomycin. The vancomycin values obtained by this bioassay were determined to be approximately 20% higher than those obtained by the corresponding fluorescence polarization immunoassay method (TDX; Abbott Laboratories, North Chicago, Ill.) (16). In addition, each patient received piperacillin (3 g q4h i.v.)…”

“…Each of these doses was infused over 1 h. Serum teicoplanin and vancomycin levels were monitored daily for the first 3 days prior to and at 1 and 3 h after the end of infusion, and they then were monitored every 3 to 7 days thereafter. Serum drug levels were determined by a Bacillus subtilis bioassay as described previously by us (16) and were adjusted by an unblinded investigator (P.J.J.) to maintain 1-h peak concentrations of 30 to 50 mg/liter and trough concentrations of 5 to 15 mg/liter for both teicoplanin and vancomycin.…”