Glycopeptide pharmacokinetics in current paediatric cardiac surgery practice

European Journal of Cardio-thoracic Surgery 32 (2007) 577—581 www.elsevier.com/locate/ejcts Glycopeptide pharmacokinetics in current paediatric cardiac surgery practice§ Nobuaki Shime a,e,*, Yuko Kato a, Tadashi Kosaka b, Takatoshi Kokufu b, Masaaki Yamagishi c, Naohisa Fujita d,e Department of Intensive Care and Anaesthesiology, Kyoto Prefectural University of Medicine, Kyoto, Japan b Department of Pharmacy, Kyoto Prefectural University of Medicine, Kyoto, Japan c Department of Paediatric Cardiac Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan d Department of Laboratory Medicine, Kyoto Prefectural University of Medicine, Kyoto, Japan e Department of Infection Control and Prevention, Kyoto Prefectural University of Medicine, Kyoto, Japan Received 24 April 2007; received in revised form 5 July 2007; accepted 9 July 2007; Available online 8 August 2007 Abstract Objective: To examine the evolution of serum concentrations of prophylactic glycopeptides administered during state-of-the-art cardiopulmonary bypass (CPB) and vigorous haemodiafiltration in paediatric patients undergoing cardiac surgery. Methods: We enrolled infants and children <3 years of age who, based on the preoperative microbiological screening, age and surgical complexity, were at high risk of methicillinresistant Staphylococcus aureus (MRSA) infection. Antimicrobial prophylaxis with glycopeptides was administered to 22 patients, randomly assigned to vancomycin (VAN; n = 11) versus teicoplanin (TEC; n = 11). Fixed doses of each drug (15 mg/kg for VAN and 8 mg/kg for TEC) were administered immediately before the operation, at the time of priming of the extracorporeal circuit, upon admission to the intensive care unit and for 48 h thereafter, q. 8 h for VAN, and once daily for TEC. Vigorous haemodiafiltration was applied during and briefly after CPB. Results: The second dose of drug added to the prime prevented a fall in serum drug concentrations at the onset of CPB in both groups. A 77% decrease in VAN, versus 53% in TEC concentrations, was observed after the conclusion of CPB. Serum concentrations of TEC > 10 mg/ml were observed throughout the treatment period in 91% of patients, while 55% of patients assigned to VAN had serum concentrations consistently >5 mg/ml ( p = 0.08). Therapeutic serum concentrations were maintained throughout the intraoperative period, particularly with TEC, administered before the first surgical incision, followed by a supplemental bolus in the priming fluid of CPB. Postoperative surgical wound infections occurred in neither group. Conclusions: The prophylactic use of glycopeptides in paediatric patients at high risk of MRSA infection undergoing cardiac surgery was safe and effective. TEC might be the drug of choice, since stable, therapeutic serum concentrations were easily maintained throughout the treatment period. # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. Keywords: Paediatric cardiac surgery; Cardiopulmonary bypass; Antimicrobial prophylaxis; Teicoplanin; Vancomycin 1. Introduction Lowering the rates of perioperative infections and associated morbidity has been a priority in the management of paediatric patients after cardiac surgery. The perioperative prophylactic administration of antimicrobial agents has been effective in preventing infections, particularly at the surgical site. Staphylococcus aureus is a predominant pathogen among patients undergoing cardiac surgery. In settings where methicillin-resistant Staphylococcus aureus § This study was performed in the paediatric intensive care unit of University Hospital, Kyoto Prefectural University of Medicine. * Corresponding author. Address: Department of Intensive Care and Anaesthesiology, Kyoto Prefectural University of Medicine, 465 Kajii-cho, Kamigyoku, Kyoto 602-8566, Japan. Tel.: +81 75 251 5633; fax: +81 75 253 5843. E-mail address: (N. Shime). (MRSA) is endemic, glycopeptides might be recommended for surgical antimicrobial prophylaxis [1]. The intraoperative concentrations of antimicrobials have a prominent influence on rates of postoperative infection. Antibiotics should be administered within 1 h preceding the first surgical incision, and continued in doses sufficient to maintain effective serum concentrations over the subsequent 24 h postoperatively [2,3]. The pharmacokinetics of the two synthetic glycopeptides available for surgical prophylaxis, vancomycin (VAN) and teicoplanin (TEC) have not been thoroughly studied in the setting of paediatric cardiac surgery. To the best of our knowledge, a study of six patients treated with VAN is the only report of the clinical application of glycopeptides in paediatric patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) [4]. The purpose of this study was to examine the evolution of blood concentrations of VAN and TEC administered 1010-7940/$ — see front matter # 2007 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejcts.2007.07.008 a 578 N. Shime et al. / European Journal of Cardio-thoracic Surgery 32 (2007) 577—581 prophylactically, during state-of-the-art CPB and vigorous haemodiafiltration, in paediatric patients at high risk of postoperative MRSA infections undergoing cardiac surgery. 2. Materials and methods 2.1. Indications for prophylactic glycopeptides The 24 patients identified as candidates for surgical prophylaxis with glycopeptides fulfilled the following criteria: (1) carriage of MRSA in the nasal cavity, preoperatively confirmed by sampling the anterior nare [5], or (2) a history of MRSA infection in (a) a neonate or <3-month-old infant hospitalised since birth, or (b) a patient presenting with a major cardiac disorder, according to the cardiac complexity classification for paediatric cardiac surgery [6]. 2.2. Drug administration Patients were randomly assigned to receive either VAN (Shionogi & Co., Ltd., Osaka, Japan) or TEC (Astellas Pharma Inc., Tokyo, Japan). Based on the information provided by the pharmaceutical companies and certified by the Japanese Ministry of Health, Welfare, and Labour, VAN (molecular weight = 1485) and TEC (molecular weight = 1564—1893) were administered in fixed doses of 15 and 8 mg/kg, respectively. A first dose of antimicrobial was administered after the induction of general anaesthesia, within 1 h before the first surgical incision, and a second, identical dose was added to the priming solution of CPB, based on an approximately doubled plasma volume at the onset of extracorporeal circulation (Table 1). Postoperatively, the same dose was given upon admission to the PICU, and repeated every 8 h for VAN and every 24 h for TEC, each for 48 h. An intranasal ointment of mupirocin was applied three times a day, for 3 days before the operation. The serum concentrations of the drugs were measured in 1 ml of arterial blood centrifuged at 3000 rpm for 5 min. A fl (...truncated)