Teicoplanin pharmacokinetics in critically ill paediatric patients

Amelia Sánchez, Jesús López-Herce*, Elisa Cueto, Angel Carrillo and Ramón Moral

Paediatric Intensive Care Section, Gregorio Marañón University General Hospital, Madrid, Spain


    Abstract
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twenty-one critically ill children aged between 7 days and 12 years were treated with teicoplanin (three loading dosages of 10 mg/kg at 12 h intervals, followed by a maintenance dosage of 10 mg/kg/day). Serum teicoplanin concentrations were monitored by HPLC. Mean concentrations in plasma 30 min after drug administration were 20 ± 16.1 mg/L. The volume of distribution was 0.30 L/kg and the terminal half-life was 17.41 h. Only 11% of trough values were >10 mg/L (established as desirable values). In critically ill children a dosage of 10 mg/kg/day does not assure serum trough values >10 mg/L.


    Introduction
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Teicoplanin is a drug with a similar spectrum to vancomycin. Its easy administration and dosage make it advantageous for use in children. Its long half-life permits administration in a single daily dose.1 The adverse effects of telcoplanin are less frequent than those of vancomycin.1

The recommendations for teicoplanin dosage have been inferred from studies in healthy adult volunteers.2 There are few studies that analyse the pharmacokinetics of teicoplanin in children.3,4,5,6,7 Critically ill patients present physiopathological alterations (haemodynamic, renal, hepatic, protein concentrations) that can alter antibiotics' distribution, metabolism, elimination and interaction with receptors. Thus, it was necessary to analyse the pharmacokinetics of teicoplanin in critically ill children.


    Materials and methods
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
The study was subject to parental informed consent and ethical approval by the Institutional Review Board. The patients to be included in the study were critically ill children aged between a few days and 15 years, admitted to the paediatric intensive care unit (PICU) requiring treatment with teicoplanin. Three doses of teicoplanin (10 mg/kg by iv bolus) every 12 h followed by one daily dosage of 10 mg/kg were administered. Blood was extracted in order to beasure the levels of teicoplanin at 30 min, 2.6 h and 12 h after the first dose, and before the next dose after 24 h, 48 h, 72 h and on the seventh day of treatment.

Teicoplanin levels were measured by high-performance liquid chromatography (HPLC). Although serum levels of teicoplanin >5 mg/L can be considered as therapeutic, we accepted values of >10 mg/L as being desirable levels.3,4,5,6 The assay specificity was 1 mg/L.

The pharmacokinetic study was performed by compartmental pharmacokinetic analysis. Blood was taken for full blood count, renal function tests (creatinine and urea), hepatic function tests (ALT, AST, gammaglutamyltranspeptidase, alkaline phosphatase, total bilirubin and direct bilirubin), total protein, and albumin before the initiation of treatment and every 48–72 h afterwards, throughout the duration of the study. Adverse reactions that could potentially be attributed to teicoplanin were noted.


    Results
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
Twenty-one children admitted to our PICU with nosocomial infection treated with teicoplanin were included in the study. Fourteen were boys and seven were girls, aged between 7 days and 12 years (seven patients were younger than 3 months, seven patients were between 3 and 12 months and seven patients were older than 12 months). The patients weighed between 2.7 and 40 kg (mean 8.1 ± 9.3 kg).

Eighteen patients were admitted to the PICU in the postoperative period for cardiac surgery, the remaining three for rejection of cardiac transplant, heart failure and encephalitis. Teicoplanin was started because of sepsis in 10 patients, pneumonia in eight, surgical wound infection in four and mediastinitis in one (two patients had infections at two sites). No patient presented alteration of hepatic function before treatment. Only one patient had a moderate alteration in renal function (plasma creatinine 1.6 mg/L, clearance of creatinine 55 mL/min per 1.73 m2) which did not require a modification in the therapeutic schedule. The teicoplanin concentrations in this patient were not different from those of the other patients. Teicoplanin was well tolerated, with no adverse effects or alteration in the laboratory parameters attributable to the teicoplanin.

The mean values of serum teicoplanin levels are presented in Table I. Pharmacokinetic analysis demonstrated that the model that best represented the data was the open bicompartmental model. The pharmacokinetic values are shown in Table II. Only 60% of all the teicoplanin concentrations were >5 mg/L and 25% were >10 mg/L. Only 11% of trough values were >10 mg/L. There were no significant differences in the mean serum concentrations and pharmacokinetic characteristics between children >3 months 3–12 months and >12 months. The two neonates (7 and 10 days old) did not have different levels from the other patients.


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Table I. Serum teicoplanin concentrations(mg/L) in 21 critically ill children
 

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Table II. Pharmacokinetic indices for teicoplanin in 21 critically ill children
 

    Discussion
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 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
We found that teicoplanin has a rapid initial disposition phase, with a mean half-life of 0.79 h, indicating that the initial concentrations of the drug in the central compartment decrease rapidly, mostly due to distribution of the drug to the peripheral compartment and elimination from the central compartment. The values of the distribution volumes CCV and Vss indicate that the drug occupies a large proportion of tissues. Few studies have been carried out on the pharmacokinetics of teicoplanin in paediatric patients3,4,5 and only one in critically ill children.6 Terragna et al.4 found in their study that the clearance of teicoplanin in children was similar to that reported for adults, but Dufort et al.3 and Tarral et al.5 found increased clearances—although less than demonstrated in our study. In a study of 12 critically ill children, Reed et al. found teicoplanin serum levels similar to ours but with minor clearance values.6 The pharmacokinetics of teicoplanin in adults shows important individual variation. Individual variations are greater in children and in critical care patients. These facts could explain in part the differences in pharmacokinetic values found between our study and others.

Although there are few studies that relate the serum concentrations of teicoplanin to its efficiency, several authors consider that stable concentrations of >10 mg/L should be achieved.3 In neonates, most of whom were premature, Cmin values were higher after a 15 mg/kg dose on day one followed by 8 mg/kg daily than with 10 mg/kg on day one and 6 mg/kg daily thereafter, but the clinical efficacy was similar.7 The few studies available on paediatric patients have conflicting results. Peller et al.8 and Lemerle et al.,9 for children in a stable clinical situation, used a dosage of 10 mg/kg/day and obtained mean teicoplanin concentrations of >10 mg/L (although not all the patients achieved concentrations of >10 mg/L). In contrast, our study found that with a dosage of 10 mg/kg/day the mean concentration of teicoplanin in a steady state was 9.4 mg/L and the mean Cmin was 5.8 mg/L, with most patients not achieving a concentration >10 mg/L. Our study in critically ill children agrees with the results of Dufort et al.3 for children undergoing bone marrow transplant, where the teicoplanin dosage of 10 mg/kg/day was not sufficient to achieve concentrations >10 mg/L.4 When these authors used maintenance doses of 20 mg/kg/day all the patients reached concentrations of 10–21 mg/L.4 Critically ill children frequently receive volume expansion treatment, diuretics and multiple drug infusions. They also frequently present alterations in the plasma protein concentrations in the blood—and the teicoplanin is 90% protein bound. These facts might explain the lower levels of teicoplanin found in our study. We conclude that in critically ill children the teicoplanin maintenance dosage of 10 mg/kg/day is not sufficient to achieve serum concentrations >10 mg/L. Studies are necessary to evaluate the pharmacokinetics and levels of teicoplanin at higher doses.


    Notes
 
* Correspondence address. Arzobispo Morcillo 52 9° C, 28029 Madrid, Spain. Tel: +34-9-1-3145613; Fax: +34-9-1-5868018; E-mail: pielvi{at}mx4.redestb.es Back


    References
 Top
 Abstract
 Introduction
 Materials and methods
 Results
 Discussion
 References
 
1 . Brogden, R. N. & Peters, D. H. (1994). Teicoplanin: a reappraisal of its antimicrobial activity, pharmacokinetic properties and therapeutic efficacy. Drugs 47, 823–54.[ISI][Medline]

2 . Thompson, G. A., Smithers, J. A., Kenny, M. T., Dulworth, J. K. & Kulmala, H. K. (1992). Pharmacokinetics of teicoplanin upon multiple dose intravenous administration to normal healthy male volunteers. Biopharmaceutics and Drug Disposition 13, 213–20.[ISI][Medline]

3 . Dufort, G., Ventura, C., Olivé, T. & Ortega, J. (1996). Teicoplanin pharmacokinetics in pediatric patients. Paediatric Infectious Diseases Journal 15, 494–8.[ISI][Medline]

4 . Terragna, A., Ferrea, G., Loy, A., Danese, A., Bernareggi, A., Cavenaghi, L. et al. (1988). Pharmacokinetics of teicoplanin in pediatric patients. Antimicrobial Agents and Chemotherapy 32 , 1223–6.[ISI][Medline]

5 . Tarral, E., Jehl, F., Tarral, A., Simeoni, U., Monteil, H., Willard, D. et al. (1988). Pharmacokinetics of teicoplanin in children. Journal of Antimicrobial Chemotherapy 21, Suppl. A, 47–51.[ISI][Medline]

6 . Reed, M. D., Yamashita, T. S, Myers, C. M. & Blumer, J. L. (1997). The pharmacokinetics of teicoplanin in infants and children. Journal of Antimicrobial Chemotherapy 39, 789–96.[Abstract]

7 . Kacet, N., Bubos, J.-P., Roussel-Devallez, M., Storme, L. & Pierrat, V. (1993). Teicoplanin and amikacin in neonates with staphylococcal infection. Paediatric Infectious Diseases Journal 12, S10–3.

8 . Peller, P., Aizchholzer, B., Fell, J. & Dietrich, H.-A. (1993). Safety and efficacy of teicoplanin in the treatment of Gram-positive infections in pediatric patients in Germany. Paediatric Infectious Disease Journal 12, S7–9.

9 . Lemerle, S., de la Rocque, F., Lamy, R., Fremaux, A., Bernaudin, F., Lobut, J. B. et al. (1988). Teicoplanin in combination therapy for febrile episodes in neutropenic and non-neutropenic paediatric patients. Journal of Antimicrobial Chemotherapy 21, Suppl. A, 113–6.[Abstract]

Received 8 December 1998; returned 15 February 1999; revised 8 March 1999; accepted 24 March 1999





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