The Comparison of Serum Teicoplanin Trough Concentrations Under Two Different Loading Doses

Background: As one of the first-line therapy for multiresistant Gram-positive infections, teicoplanin exhibits time-dependant killing. Due to the reduced susceptibility to teicoplanin within the past decade, the minimum inhibitory concentrations of clinical methicillin-resistant Staphylococcus aureus isolates increased to 2 mg/L in these years. It is the gold standard to maintain a trough concentration at least 10 mg/L, even 20 mg/L. However, it is known that teicoplanin is high protein binding. Current standard dose, 3-6 mg/Kg, often produces a serum trough level of < 10 mg/L. There is also no commercially avalible drug monitoring method in Taiwan. Because delay in effective therapy is detrimental to clinical outcomes, this study was designed to identify appropriate loading dose to obtain therapeutic concentrations as soon as possible.

Methods: A prospective, single-blinded clinical trial was carried out in a medical center. The sample size was determined by a preliminary observation performed during Febunary 2004 to January 2005. The drug concentrations of these 10 patients were analyzed by high performance liquid chromatography. Patients with suspected moderate gram-positive infections were enrolled during June 2005 to January 2006. A loading dose of 6 or 12 mg/Kg was given every 12 hours for three times and then 24 hours after the third dose. From day 4, patients received a maintenance dose of 6 mg/Kg. The dosing interval was 1 to 3 days according to their creatinine clearance (CLCr). Serum samples before dose 3, 4, 5 and day 9 and 14 were collected to determine the trough concentrations of teicoplanin by fluorescence polarization immunoassay.

Results: Twelve patients were allocated to each group as randomly as possible. The proportions of patints achieving 10 mg/L or higher during the first five doses differed significantly between two groups (18% vs. 92% before the third dose; 17% vs. 91% before the fourth dose; 33% vs. 82% before the fifth dose). Hemodialysis patients or those with CLCr < 20 mL/min/1.73m2 even achieved > 20 mg/L in the higher loading dose group. Obviously, loading dose was the crucial factor for the serum teicoplanin concentrations. Creatinine clearance (β=-0.11, p=0.0043) and the ratio of actual body weight and ideal body weight (β=21.61, p=0.0008) also influenced the trough levels on the third day, indicating actual body weight might not be the approapriate dosing weight.
Besides, looking into the pattern of the changes in the trough concentrations further, higher maintenance dose might be necessary. Patients receiving loading dose of 6 mg/Kg had consitantly low trough concentrations, which half was not higher than 8.5 mg/L. Those in the other group declined over time. A total of 3 patients had trough concentrations below 10 mg/L in two weeks. Dosing interval was determined by creatinine clearance. The cutpoint was 60 and 40 mL/min/1.73m2. Hemodialysis patients kept target concentrations when they received 6 mg/Kg every three days. But 6 mg/Kg every other day might be too small to keep the target trough concentrations during continuous hemofiltration. A total of 8 adverse effects occurred on 7 study subjects (29%). There were no relationship between serum trough concentrations and the occurance of side effects.

Conclusion: Loading doses of 12 mg/Kg would achieve the serum trough concentrations higher than 10 mg/L, even higher than 20 mg/L on patients with CLCr < 20 mL/min/1.73m2 or during hemodialysis in the early treatment period. Higher maintenance dose might be necessary. It was acceptable to adjust the dosing interval of maintainence dose to two and three days for patients with CLCr 40-60 and <40 mL/min/1.73m2, respectively. As for hemodialysis patients, 6 mg/Kg every 3 days was enough. But 6 mg/Kg every other day was not enough to keep target concentrations during continuous hemofiltration. In view of large variation of serum teicoplanin concentrations in different patients, therapeutic drug monitoring was recommended.