J Korean Neurosurg Soc.  2020 Jan;63(1):45-55. 10.3340/jkns.2019.0161.

Evaluation of Cumulative and Conditional Antibiotic Release from Vancomycin-Embedded Fibrin Sealant and Its Antibacterial Activity : An In Vitro Study

Affiliations
  • 1Department of Neurological Surgery, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
  • 2Neuroscience & Radiosurgery Hybrid Research Center, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
  • 3Department of Laboratory Medicine, Inje University Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea
  • 4Department of Neurosurgery, Inje University Seoul Paik Hospital, Inje University College of Medicine, Seoul, Korea

Abstract


Objective
: Fibrin sealants have been used for hemostasis, sealant for cerebrospinal fluid leakage, and adhesive barrier in neurosurgery. Further, as its clinical use and role of an effective drug delivery vehicle have been proposed. This study was performed to measure antibacterial activity and continuous local antibiotic release from different concentrations of vancomycin-impregnated fibrin sealant in vitro.
Methods
: Antibacterial activity was investigated by disk diffusion test by measuring the diameter of the growth inhibition zone of bacteria (methicillin-resistant Staphylococcus aureus, ATCC29213) from vancomycin-embedded fibrin sealant disc diluted at five different concentrations (C1–C5; 8.33, 4.167, 0.83, 0.083, and 0.0083 mg/disc, respectively). Continuous and conditioned release of vancomycin concentration (for 2 weeks and for 5 days, respectively) were also measured using high-performance liquid chromatography (HPLC) method. To mimic the physiologic wound conditions with in vitro, conditioned vancomycin release in phosphate buffer solution (PBS) was measured and replaced PBS for five consecutive days, half a day or completely daily.
Results
: In the disk diffusion test, the mean diameters of bacterial inhibition zone were 2.54±0.07 cm, 2.61±0.12 cm, and 2.13±0.15 cm (C1, C2, and C3 respectively) but 1.67±0.06 cm and 1.23±0.15 cm in C4 and C5, respectively. Continuous elution test elicited the peak release of vancomycin from the fibrin sealant at 48 hours, with continued release until 2 weeks. However, conditioned vancomycin release decreased to half or more on day 2, however, the sustainable release was measured over the therapeutic dose (10–20 μg/mL) for 5 days and 4 days in assays of half and total exchange of PBS.
Conclusion
: This study suggests that fibrin sealant can provide an efficient vehicle for antibiotic drug release in a wide range of neurosurgical procedures and the safe and effective therapeutic dose will be at the concentration embedded of 4.167 mg/disc or more of vancomycin.

Keyword

Drug delivery system; Fibrin tissue adhesive; Disk diffusion antimicrobial tests; High-performance liquid chromatography; Surgical wound infection

Figure

  • Fig. 1. Comparison of disk diffusion test inoculated with Staphylococcus aureus (MRSA, ATCC29213) on Blood Agar Plates for (A) control (fibrin sealant without vancomycin) on the left and (B) concentration 1 (C1, fibrin sealant with vancomycin) on the right. The diameter of the clear zone was measured after 24 hours (arrow).

  • Fig. 2. HPLC measurement for ① cumulative vancomycin release for 2 consecutive weeks and ② two different Conditional vancomycin release each of daily total and half PBS exchange from day 1 to day 2 and sample collection for analysis. HPLC : high-performance liquid chromatography, PBS : phosphate buffer solution.

  • Fig. 3. Relationship between peak area and concentration of vancomycin release measured and the process of calibrating concertation of vancomycin release in each PBS sampling for HPLC analysis. RSD : relative standard deviation, PBS : phosphate buffer solution, HPLC : high-performance liquid chromatography.

  • Fig. 4. Comparison in zone of inhibition test for five different concentrations with respective standard deviation. *p<0.05 in one way ANOVA, post-hoc analysis by Tukey’s HSD showed p<0.05 except for C1–C2 and C4–C5. ANOVA : analysis of variance.

  • Fig. 5. Continuous release test - average vancomycin concentration with standard deviation (μg/mL) from vancomycin loaded fibrin sealant for C1 and C2 over 2 weeks of study periods.

  • Fig. 6. Average vancomycin release (μg/mL) from vancomycin loaded fibrin sealant in C1 and C2 with total solution exchange every 24 hours for 5 days (e.g., rapid drainage by JP drain or significant bleeding in operation field).

  • Fig. 7. Average vancomycin release (μg/mL) from vancomycin loaded fibrin sealant in C1 and C2 with half solution exchange every 24 hours for 5 days (e.g., natural drainage by JP drain or slowly body fluid exchange).


Reference

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