Intraoperative Vancomycin Pharmacokinetics in Cardiac Surgery With or Without Cardiopulmonary Bypass

Paolo Cotogni MD; Roberto Passera PharmD PhD; Cristina Barbero MD; Angela Gariboldi BSc; Donatella Moscato BSc; Gennaro Izzo, Mauro Rinaldi MD

Disclosures

The Annals of Pharmacotherapy. 2013;47(4):455-463. 

In This Article

Abstract and Introduction

Abstract

Background: Vancomycin is administered as antimicrobial prophylaxis to patients undergoing cardiac surgery, an intervention that usually requires cardiopulmonary bypass (CPB). Previous studies reported that CPB modifies vancomycin pharmacokinetic parameters.

Objective: To investigate intraoperative vancomycin pharmacokinetic changes in a large population of patients undergoing cardiac surgery with CPB (on-pump) and without CPB (off-pump).

Methods: In this prospective study, patients undergoing cardiac surgery received a single dose of vancomycin 1000 mg in a 60-minute intravenous infusion, with skin incision performed between 16 and 120 minutes after the end of the infusion. For the on-pump group, arterial samples were drawn before CPB (end of infusion, skin incision), during CPB (5, 30, and 60 minutes, and then every 60 minutes until CPB end), and after CPB (wound closure). For the off-pump group, arterial samples were drawn time-matched to the CPB period of the on-pump group.

Results: Two hundred thirty-six consecutive patients were enrolled: 215 in the onpump group and 21 in the off-pump group. A total of 1682 serum vancomycin concentrations (median 7/patient) were measured. Vancomycin maximum concentration ([C max ] on-pump, 45.6 mg/L; off-pump, 47.3 mg/L); area under the concentration-time curve, zero to 8 hours ([AUC 0–8 ] on-pump, 104.6 mg*h/L; offpump, 96.1 mg*h/L); volume of distribution ([V d ] on-pump, 31 L; off-pump, 28.2 L); and total body clearance ([Cl] on-pump, 6.23 L/h; off-pump, 7.05 L/h) were similar. Moreover, C max and AUC 0-∞ (AUC, zero to infinity) showed values comparable to those found in previous studies performed on noncardiac surgery patients.

Conclusions: In our study there were no significant differences in vancomycin C max , AUC 0–8 , V d , and Cl between the on-pump and off-pump groups. CPB does not seem to significantly modify intraoperative vancomycin pharmaco ki netics in patients undergoing cardiac surgery. The results of this study may contribute to increased knowledge of vancomycin pharmacokinetics.

Introduction

The incidence of surgical site infections ([SSIs] sternal wound and underlying mediastinum) ranges between 0.4% and 4% of cardiac surgical procedures. SSIs, mainly mediastinitis, are associated with increased morbidity, prolonged length of stay, increased cost, and in-hospital mortality rates of 10–20%.[1]

Antimicrobial prophylaxis benefits in cardiac surgery were clearly demonstrated in placebo-controlled studies.[2] Therefore, prophylactic intravenous antibiotics were routinely administered to patients undergoing cardiac surgery. Selection of an appropriate antibiotic would be directed toward staphylococci (aureus and coagulase-negative), which is the most common cause of bacterial infections, and against gram-negative bacteria. However, the optimal antimicrobial prophylaxis concerning cardiac surgery (eg, antibiotic choice and duration of administration) remains controversial.[1,3] The guidelines of the Society of Thoracic Surgeons recommended that in the setting of the institutional presence of a "high incidence" of methicillin-resistant Staphylo coccus aureus (MRSA), it would have been reasonable to combine a ®-lactam (cefazolin) with a glycopeptide (vancomycin) for prophylaxis (class IIB recommendation, level of evidence C).[1]

Likewise, optimal dosage regimens for vancomycin are undetermined. Indeed, the Society of Thoracic Surgeons mentioned that any of the following doses and durations may be used (1000 mg, 1500 mg, or 15 mg/kg; and 24 hours vs 48 hours or 1 dose vs 2 doses).[1,3]Moreover, while intraoperative redosing of prophylactic cefazolin appeared to reduce the infection risk in cardiac surgery,[4] because of vancomycin's long half-life, there is still controversy over the impact of intraoperative redosing of vancomycin on infection risk.[1,3]

In clinical practice, trough serum vancomycin concentrations are the most accurate method to monitor the effectiveness of vancomycin administration (level of evidence IIB).[5] Indeed, the steady-state trough concentration is not achieved until before the fourth dose of vancomycin is given. Based on evidence suggesting that S. aureus exposure to trough serum vancomycin concentrations less than 10 mg/L can produce strains with vancomycin-intermediate S.aureus (VISA)-like characteristics, it is recommended that trough therapeutic serum concentrations of vancomycin be maintained above 10 mg/L to avoid development of resistance (level of evidence IIIB).[5] On the contrary, there are no accepted recommendations indicating standards in monitoring pharmacokinetics and target serum vancomycin trough concentrations to achieve at wound closure for effective antimicrobial prophylaxis.

Cardiopulmonary bypass (CPB) is the extracorporeal circulation technique that provides blood flow and oxygen to tissues when the cardiac surgical procedure requires that the heart pumping action stops. CPB has significant effects on the pharmacokinetic profile of a variety of drugs, including vancomycin.[6] In the past 20 years, 6 studies investigated vancomycin pharmacokinetics, reporting a reduction in blood concentration due to several physiologic and pharmacokinetic alterations occurring immediately after the CPB start or during CPB.[7–12] However, these studies enrolled small numbers of patients, without control groups undergoing cardiac surgery without CPB. Furthermore, their conclusions were controversial regarding the cause of vancomycin pharmacokinetic alterations during CPB.

In 2005, the choice to combine cefazolin with vancomycin for antimicrobial prophylaxis in patients undergoing cardiac surgery was adopted in our Division of Cardiovascular Surgery. The rationale for using vancomycin was an increased prevalence of MRSA infections, which exceeded 60% of hospital-wide and 95% of isolates in cardiac surgery patients with SSIs. Since 2007, our Hospital Infection Control Committee reported some cases of S. aureus isolates in patients who underwent cardiac surgery having vancomycin minimum inhibitory concentration (MIC) of 1–2 mg/L. In 2008, 2 patients with S. aureus isolates had a vancomycin MIC of 4 mg/L (ie, a VISA strain).

The aim of our study was to investigate intraoperative vancomycin pharmacokinetic changes in a large population of patients undergoing cardiac surgery with CPB (onpump) and without CPB (off-pump). The primary objective was to investigate whether or not CPB could cause a difference in vancomycin pharmacokinetics. The second objective was related to a public health grant we had been awarded to evaluate intraoperative serum vancomycin concentrations regarding our policy of antimicrobial prophylaxis using a single 1000-mg vancomycin dose.

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