Pharmacokinetics and tissue penetration of vancomycin in patients undergoing prosthetic mammary surgery
R. Luzzatia,*,
A. Sannab,
B. Allegranzia,
S. Nardia,
M. Bertic,
D. Barisonib and
E. Conciaa
a Department of Immunology and Infectious Diseases, and
b Department of Plastic and Reconstructive Surgery, Università ed Azienda Ospedaliera di Verona, Verona;
c B.T. Biotecnica, Varese, Italy
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Abstract
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Vancomycin concentrations in periprosthetic breast tissues were evaluated in 24 women undergoing reconstructive surgery after mastectomy for breast cancer. Patients were given a single prophylactic dose of vancomycin (1 g iv) 18 h before surgery, and mean capsular and pericapsular tissue concentrations were measured by HPLC. Vancomycin was not detectable in the majority of patients belonging to the 13 h post-dose groups, whereas in the 48 h post-dose groups, mean capsular and pericapsular concentrations were as follows: at 4 h, 4.0 mg/kg and 5.9 mg/kg; at 6 h, 4.1 mg/kg and 4.8 mg/kg; at 8 h, 5.9 mg/kg and 11.1 mg/kg, respectively. Vancomycin tissue concentrations thus were equal to or exceeded the breakpoint of 4 mg/L in most samples collected 48 h after dosing. In conclusion, our data suggest that appropriate timing of vancomycin prophylaxis should be considered to allow the maintenance of adequate tissue concentrations throughout the surgical procedure.
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Introduction
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Infection following breast implant surgery is an uncommon but devastating event. Indeed, severe infection generally results in the removal of the mammary prosthetic material and the deferring of its replacement for at least 6 months.1 Antibiotic prophylaxis is thus indicated in clean surgery involving grafts or prosthetic devices such as breast implants. Staphylococci, mostly Staphylococcus aureus and Staphylococcus epidermidis, are responsible for the majority of post-operative wound infections in this setting.2 In addition, S. epidermidis may cause subclinical prosthetic infection and late firmness secondary to capsular contracture,3 which has been reported to constitute the most common reason for reoperation after breast implantation.4 As methicillin-resistant staphylococci have frequently been reported in nosocomial infections, the glycopeptide antibiotics vancomycin and teicoplanin are commonly used for the prevention of infections after implant surgery in a number of institutions. The aim of this study was to investigate the extent and duration of vancomycin penetration into breast periprosthetic tissues following pre-operative single-dose prophylaxis.
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Materials and methods
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Patients undergoing mammary reconstruction after subcutaneous mastectomy for breast cancer were consecutively enrolled into the study. The pharmacokinetic research was performed at the second surgical procedure when the temporary tissue expander had to be explanted and replaced with a permanent breast implant. The study was approved by the local Research Ethics Committee and all patients gave written informed consent. Exclusion criteria included renal impairment, evidence of active mammary infection and any complication during the expanding phase of the reconstruction procedure. Vancomycin was pre-operatively administered as a single dose of 1 g, infused iv over 1 h. No additional prophylaxis was given to the patients. For each patient, two tissue specimens were obtained, one from the capsular tissue and one from the adjacent soft tissue surrounding the removed silicone expander and near the surgical incision, respectively. The timing of the surgical procedure was planned to obtain simultaneous blood and tissue specimens in the 18 h interval after the end of vancomycin infusion. All specimens were stored at 80°C until drug assays were performed. Serum and tissue concentrations of vancomycin were measured using an adaptation of a previously described HPLC method.5 Briefly, the HPLC system consisted of an LC10 compact system equipped with a binary pump (Shimadzu, Tokyo, Japan), UV detector set at 230 nm, column oven and autosampler. Separation was on a Supelcosil C18 column (250 mm x 4.6 mm, 5 µm, Supelco, Bellefonte, PA, USA). Mobile phase (50 mM phosphate buffer, pH 5, and acetonitrile, 92:8) was run isocratically at a flow rate of 1.5 mL/min. Tissue samples were homogenized in 1 mL of cold water, and centrifuged twice at 12,550g. To 500 µL of serum or tissue homogenate, 20 µL of internal standard cefodizime (200 mg/L) was added. The sample was then applied to C18 SPE cartridges (100 mg, J. T. Baker, Deventer, The Netherlands) conditioned just before use by washing with 1 mL of methanol and 1 mL of water. Vancomycin and the internal standard were eluted with 300 µL of methanolwater (50:50). The eluate was centrifuged at 12,550g and 50 µL was injected into the HPLC system. The calibration curve was linear in the range 0.440 mg/L with R2 better than 0.998. At 2 and 20 mg/L, precision [relative standard deviation (r.s.d.), %] was 2.68% and 1.14%, and accuracy was 106% and 109%. For each patient, tissue serum concentration ratios were calculated by using vancomycin concentrations in tissues and serum obtained at sampling times during the surgical procedures. Serum and tissue concentrations of vancomycin, and tissue/serum ratios are presented as their means ± standard deviations (s.d.) for each time-point.
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Results
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A total of 24 patients, aged between 32 and 68 years (mean 47.3 years), took part in the study. Mean body weight was 67.8 ± 16.2 kg and mean serum creatinine was 76 ± 12 mmol/L. Duration of surgery was 85 ± 12 min. No patient experienced post-operative infection up to 3041 months after surgery. The concentrations of vancomycin in serum, capsular and pericapsular tissue, and tissue/serum ratios are summarized in the Table.
Vancomycin diffused slowly into both tissues surrounding the mammary expander, particularly into the capsular tissue. Indeed, seven and three of the 12 patients belonging to the 13 h post-dose groups did not have detectable concentrations of vancomycin in the capsular and pericapsular tissue, respectively. Afterwards, vancomycin penetrated well into both mammary tissues, with the highest capsular and pericapsular tissue concentrations (mean ± s.d. concentrations 5.9 ± 1.1 mg/kg and 11.1 ± 5.3 mg/kg, respectively) being observed 8 h after the end of drug infusion. Penetration of vancomycin into the capsular was lower than that into the pericapsular tissue, with tissue/serum ratios ranging, respectively, from 0.16 to 0.32 and from 0.27 to 0.47 in the 4 h post-dose group, and from 0.50 to 1.48 and from 0.7 to 2.8 in the 8 h post-dose group. To evaluate the potential prophylactic efficacy of vancomycin concentrations achieved at the different sampling times after drug infusion, capsular tissue concentrations were assessed with regard to the breakpoint for vancomycin (4 mg/kg). Only a few patients belonging to the 13 h post-dose groups achieved that tissue concentration. In contrast, most of the patients belonging to the 48 h post-dose groups exhibited tissue concentrations equal to or exceeding the breakpoint.
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Discussion
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Vancomycin has been reported to be widely distributed throughout the body and to penetrate into most body fluids and tissues.6 So far, no study has evaluated the penetration of vancomycin into adjacent implant segments. Our data demonstrate the diffusion of vancomycin into the tissues surrounding breast implants after single-dose administration during mammary reconstruction surgery. High inter-subject variation in both serum and tissue concentrations is apparent and, in part, could be accounted for by differences in the weight of patients. The drug penetrated slowly into mammary surgical sites and achieved concentrations approximating those found in serum 68 h post-dose. Vancomycin concentrations were below the limit of detection in the majority of capsular samples taken in patients in the 13 h post-dose groups. Interestingly, penetration of vancomycin, expressed as the tissue to serum ratio, was lower in the capsular than in the pericapsular tissue at all time periods examined. This finding could be due to the fact that the capsule is a poorly vascularized tissue constituting a collagenous sheath around the breast implant. Capsular tissue is a critical site, as subclinical infection of silicone implants occurring at the time of surgery may be associated with the late contracture of the adjacent capsule.3 This phenomenon was found to constitute the most frequent local complication (i.e. 14.6% of total breasts operated on) leading to surgery after breast implantation according to a recent series.4 The effectiveness of pre-operative antibiotic prophylaxis against wound infections following mammary implantation was reported in 1983.7 More recently, a number of surgeons reported that post-operative infection rates ranged from 0.3% to 0.6% in women undergoing breast reconstruction with pre-operative antibiotic prophylaxis.3 There is general agreement that the initial dose of parenteral antibiotic used in prophylaxis needs to be given at the onset of the procedure, to ensure high concentrations at the surgical site at the time of possible contamination. As vancomycin bacterial killing is characterized by time-dependent activity,8 adequate serum and tissue concentrations of vancomycin should be maintained throughout the surgical procedure. In this study vancomycin achieved and maintained periprosthetic tissue concentrations that equalled or exceeded the breakpoint 4 h after the end of drug infusion. In conclusion, our data suggest that for appropriate timing of vancomycin prophylaxis, drug administration at least 4 h before surgery should be considered. This regimen would allow the maintenance of adequate tissue concentrations of vancomycin even in the capsule and thus help to reduce the rate of devastating breast implant infections.
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Notes
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* Correspondence address. Divisione Clinicizzata di Malattie Infettive, Ospedale Civile Maggiore, Piazzale Stefani 1, 37126 Verona, Italy. Tel: +39-045-8073295; Fax: +39-045-8340223; E-mail: luzzati{at}borgotrento.univr.it

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Received 2 June 1999;
returned 8 September 1999; revised 27 September 1999;
accepted 11 October 1999