Eur J Cardiothorac Surg 2003;23:765-770
© 2003 Elsevier Science NL
Topical vancomycin applied on closure of the sternotomy wound does not prevent high levels of systemic vancomycin
Joel Desmond*,
Andy Lovering,
Chris Harle,
Tatiana Djorevic,
Russell Millner
Blackpool Victoria Hospital, Southmead Hospital, Bristol, UK
Received 25 November 2002;
received in revised form 15 January 2003;
accepted 16 January 2003.
* Corresponding author. Manchester Royal Infirmary, Flat 13, Lexington House, 42 Chorlton Street, Manchester M1 3HW, UK. Tel.: +44-780-1548-122; fax: +44-780-1548-122
e-mail: joeldesmond{at}doctors.org.uk
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Abstract
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Objective: Vancomycin is effective in reducing the risk of mediastinits and topical vancomycin has been hypothesised to give high local dose concentrations while avoiding high systemic levels, thus avoiding the risk of bacterial resistance to this second-line antibiotic. However, this theory has never been tested and the degree to which vancomycin is absorbed systemically is unknown. Methods: Fourteen patients undergoing elective coronary artery bypass grafts (CABG) received 500 mg of topical vancomycin prior to sternotomy closure. Serum samples were taken at 30, 60, 120, 180 and 720 min post-operatively. In addition, samples were taken from the drain bottles and urine samples taken daily for 5 days. Vancomycin levels were measured by fluorescence polarisation immunoassay, using the reverse dilution method to give a detection limit of 0.8 mg/l. Results: Vancomycin was detected in almost all serum samples. Peak concentration was at 30 min and the mean value was 2.96 mg/l (range, 0.99–5.00 mg/l). This mean fell to 1.32 mg/l at 6 h. Of the 500 mg of vancomycin applied, a mean of only 8.8 mg was found to have been lost into the drain bottles in the first 24 h (range, 0.17–12.5 mg). When 5 consecutive days of urine collection was achieved, a mean of 151 mg of vancomycin was excreted (range, 40–195 mg) and vancomycin was detectable in the urine till day 5. The mean concentration of vancomycin in the urine was maximal on day 1 and was 24.4 mg/l (range, 4.49–44.98 mg/l). Conclusions: Topical vancomycin causes significant systemic concentrations in the 6 h post-surgery and can be detected in the urine for up to 5 days post-surgery.
Key Words: Thoracic surgery • Vancomycin • Mediastinitis • Drug resistance • Staphylococcus aureus • Coronary artery bypass
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1. Introduction
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Mediastinitis is an uncommon but life-threatening complication following cardiac surgery. The incidence reported in large series varies from 0.4 to 5% for deep sternal wound infection, and the mortality in these patients approaches 50% [1–6]. Therefore, several prophylactic antibiotic regimes are instituted worldwide in order to attempt to reduce this serious complication, which is most commonly due to Staphylococcus aureus or Staphylococcus epidermidis [7]. One regime that is in common usage is to supplement cephalosporin intravenous antibiotics by taking the powder used to make up intravenous vancomycin and spreading it directly into the sternotomy wound. The theoretical basis behind this is that high concentrations of vancomycin will be achieved locally without requiring high systemic doses, thus avoiding the undesirable complications of intravenous vancomycin such as bacterial resistance. This regime was found by Vander Salm et al. [6] to reduce the incidence of mediastinitis from 3.6 to 0.5% in a single blinded prospective randomised clinical trial of 416 patients.
Vancomycin is a bactericidal glycopeptide antibiotic, and it is known that renal excretion of the unmetabolised drug is its major route of elimination (80–90%) if given intravenously, with hepatic elimination being of little importance [8]. Furthermore, it is known that up to 30% of total vancomycin clearance is by non-renal pathways [9] and that some of this elimination is by breakdown to an inactive crystalline degredation product (CDP-1) rather than by metabolism [10]. However, there have been no studies to examine the pharmaco-kinetics of vancomycin used in this topical fashion and several questions remain unanswered: to what extent is vancomycin absorbed systemically? How much of the vancomycin exits the chest cavity via the chest drains in the first 24 h? To what extent is vancomycin excreted in the urine after its single usage in the chest cavity? And is there still a risk of inducing vancomycin resistance in these patients? We, therefore, sought to answer these questions in a cohort of elective patients undergoing coronary surgery.
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2. Materials and methods
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2.1. Patients and setting
Fourteen patients undergoing elective coronary arterial surgery were prospectively studied, attending Blackpool Victoria Hospital, over a 4-month period from April 2002. A single surgeon (R.W.J.M.) performed all the operations.
2.2. Ethics
Ethical approval was obtained from Blackpool Victoria Local Ethics Committee and written consent was obtained from each patient.
2.3. Methods
Usual intravenous prophylaxis was given at the start of the operation. At the end of the procedure, patients were randomised to receive either 500 mg of vancomycin powder or 500 mg of vancomycin powder dissolved in 10 ml of 0.9% normal saline. These two methods of applying the vancomycin are in common usage in the UK and we, therefore, decided to use both methods to see if there was any difference between the two. The treatments were placed into the sternotomy wound, ensuring that the sternal edges received liberal amounts of the vancomycin.
After the operation, samples were taken for measurement of vancomycin levels. Serum samples were taken at: 30, 60, 120, 180 and 720 min in seven patients and at 60 and 180 min in the other seven. In four patients, samples were taken from each chest drain prior to removal and the volume in these drains documented. Ten patients had urine samples taken at day 1 post-surgery and four had daily urine sampling for 5 days, all with urine volume documentation. It is to be noted that the original protocol did not include the 5-day urine and drain collection and we elected to change the protocol towards the end of the study as we felt that this would provide additional interesting data.
2.4. Measurement
The samples were processed by fluorescence polarisation immunoassay using the Abbott FLX system and Abbott kits. For serum samples, the reverse dilution method was used with a sample volume of 5 µl [11]. The detection limit using the reverse dilution procedure was 0.8 mg/l. Urine samples were processed using the standard procedure with a detection limit of 2.0 mg/l.
2.5. Statistics
Descriptive statistics were performed using SPSS version 10.1. Comparison of vancomycin powder vs. solution was performed using repeated measures analysis of variance (ANOVA).
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3. Results
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The demographics of our patient cohort are shown in Table 1. Repeated measures ANOVA was used to search for a between group difference and between powdered and solution methods of applying the vancomycin. The serum samples were found not to be significantly different between groups (P=0.874). In addition, no difference was found in the concentrations of vancomycin excreted in the urine (P=0.982) between these groups. We, therefore, continued to analyse the data without differentiating between methods of application.
Vancomycin was easily detectable in the serum samples of all patients post-surgery. Peak levels were seen at 30 min post-surgery, when a mean level of 2.96 mg/l (range, 0.99–5.00 mg/l) was detected. At 6 h post-surgery, the mean level detected was 1.32 mg/l (0.56–2.17 mg/l), giving a half-life of 5 h (Fig. 1
).
Samples were taken from the chest drains in four patients to assess whether vancomycin was lost in large volumes immediately post-surgery. The mean concentration detected in the drains was 11.3 mg/l (range, 0.52–29.4 mg/l). For each drain, the volume of fluid collected was also measured allowing us to calculate the amount of vancomycin that was lost into the drains. The mean amount of vancomycin lost into the drain was 11.5 mg (range, 0.17–12.5 mg, see Fig. 2
).
Urine samples were taken from all patients on day 1. The mean concentration detected on day 1 was 24.4 mg/l (range, 4.49–45.0 mg/l). Urine volume in 24 h was measured in all patients allowing the absolute amount of vancomycin excreted in those 24 h to be estimated. On day 1, the mean level of vancomycin excreted was 68.3 mg (range, 0–157 mg). In four patients, daily samples were taken up to day 5. On day 5, the absolute amount of vancomycin excreted was calculable in two of these patients, with 1.55 and 10.9 mg of vancomycin being excreted in the two patients, respectively (concentrations of 1.94 and 5.74 mg/l, respectively, see Fig. 3
).
In the four patients where drain and 5 days of urine samples were taken and the amount of vancomycin excreted calculated, we detected a mean loss of 162 mg (range, 50–213 mg) through the drains and urine, of the 500 mg of vancomycin given to each patient. We thus conclude that around 340 mg of the vancomycin is eliminated by alternative biological pathways. We can, of course, not make any conclusions about the time scale of this elimination. The tabulated results of this study are presented in Table 2.
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4. Discussion
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We have found that topical vancomycin applied directly to the sternotomy wound does cause significant systemic levels of vancomycin, and vancomycin can be detected in significant concentrations in the urine for up to 5 days post-surgery. Recommended systemic trough concentrations of vancomycin for treatment are 5–10 mg/l [12]. We have found a mean serum level of 3 mg/l and the maximum level of vancomycin detected was 5 mg/l. More strikingly, we found very high concentrations of vancomycin in the urine, with a mean concentration of 24.4 mg/l on day 1, which was detectable for up to 5 days. Interestingly, we found only very small amounts of vancomycin being lost into the chest drains in the first 24 h post-operation. Of the 500 mg applied, only a mean of 11 mg was lost into the drain.
Prior to our study, we contacted the manufacturers of vancomycin [12]. They had no data on the pharmaco-kinetics of topical vancomycin. Our own literature review found no papers of relevance, but a letter by El Oakley et al. was found to be useful [13]. This letter reported that they had measured the level of vancomycin in the serum of four patients after topical administration of 1 g of vancomycin. They found a maximal level at 3 h post-administration and the mean level was 2.2 mg/l (range, 1–4.4 mg/l). No papers measuring levels of urine or chest drain vancomycin were found.
It is, however, known that if vancomycin is given by an intracolonic route (for pseudomembranous colitis), this may cause significant levels of systemic vancomycin, thus indicating that intravenous absorption has been shown in other specialties [14].
Our study was conducted prospectively but our patient number is small. In addition, as our study progressed, we discovered that our measurement of 24-h urine on the wards was in some patients not reliable, leading to a number of measurements being left as missing variables (Table 2). Also, as the study progressed, we were surprised by the high vancomycin levels in urine and thus decided to continue collection for 5 days in the last four patients. In addition, it was suggested that it might be interesting to look at the concentrations of vancomycin in the chest drains, and thus this data was collected only in the last four patients. However, as our study is the first to look at the pharmaco-dynamics of topical vancomycin, we feel that the data that we collected is important and reliable and the only effect of the small number of patients is to cause wider confidence intervals around our results.
We report that after close daily monitoring of vancomycin elimination from the chest drains and urine in four patients, we only detected the elimination of 160 mg, leaving 340 mg to be eliminated by ‘alternative pathways’. There are several possibilities for the nature of these pathways. Vancomycin is known to be sequestered by many medical devices and this has been shown during cardiac surgery [15], thus loss on the drain tubing, gloves, swabs etc. will account for some loss. We agree with other authors who have found that there is a significant non-renal elimination pathway [9], which may account for around 30% of our total and hypothesise that the remainder will be locked into the deep-tissues and continue to be released after 5 days as active vancomycin or is released as the inactive degredation product CDP-1 [10].
The major concern over the prophylactic usage of vancomycin in cardiac surgery is the emergence of vancomycin resistance. Reduced vancomycin sensitivity has been documented in methicillin-resistant S. aureus, and the first report of this was after a cardiac operation [16–18]. The minimum inhibitory concentration (MIC) of vancomycin for these isolates was 8 mg/l and these bacteria were termed vancomycin-intermediate S. aureus (VISA). In addition, eight of these patients have now been reported in the US [19]. However in July 2002, the Centre for Disease Control and Prevention described the first case of fully vancomycin-resistant S. aureus (VRSA), which was isolated from the catheter and foot ulcer of a patient in Michigan [19]. This has caused widespread concern as already one-third of enterococci in US intensive care units are vancomycin-resistant (VRE) and this outbreak in Michigan demonstrates that S. aureus is also able to generate fully resistant strains [20].
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5. Conclusion
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Our study has demonstrated that topical vancomycin will routinely expose patients to systemic and urinary vancomycin in significant doses. Of further concern is that this exposure is often below the dose required to inhibit S. aureus growth and, therefore, this bacteria may be proliferating while being exposed to vancomycin, which increases markedly the potential to develop vancomycin resistance. If this practise continues, then it may only be a matter of time, therefore, before we see the first case of VRSA in a cardiac unit in the UK.
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Acknowledgments
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No funding or support was received from any commercial company and no authors were funded in part or in whole by any commercial company.
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References
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Abstract
1. Introduction
