Advertisement

AAPS PharmSciTech

, 20:5 | Cite as

Brain Microdialysis Study of Vancomycin in the Cerebrospinal Fluid After Intracerebroventricular Administration in Mice

  • Yusuke Miura
  • Yuki Fuchigami
  • Sakiko Nomura
  • Koyo Nishimura
  • Masayori Hagimori
  • Shigeru KawakamiEmail author
Brief/Technical Note

Abstract

Vancomycin (VCM) is an important antibiotic for treating methicillin-resistant Staphylococcus aureus (MRSA) infections. To treat bacterial meningitis caused by MRSA, it is necessary to deliver VCM into the meninges, but the rate of VCM translocation through the blood–brain barrier is poor. Additionally, high doses of intravascularly (i.v.) administered VCM may cause renal impairments. Thus, VCM is sometimes administered intracerebroventricularly (i.c.v.) for clinical treatment. However, information on the VCM pharmacokinetics in cerebrospinal fluid (CSF) after i.c.v. administration is lacking. In the present study, we evaluated the VCM pharmacokinetics in the CSF and systemic circulation after i.c.v. compared to that after i.v. administration, using the brain microdialysis method in mice. VCM administered via i.c.v. showed a highly selective distribution in the CSF, without migration to systemic circulation. Moreover, to assess renal impairments after i.c.v. administration of VCM, we histologically evaluated damage to the mouse kidney by hematoxylin and eosin staining. No significant morphological change in the kidney was observed in the i.c.v. administration group compared to that in the i.v. administration group. Our results demonstrate that i.c.v. administration of VCM can be partially prevented from entering the systemic circulation to prevent renal impairments caused by VCM.

KEY WORDS

intracerebroventricular administration vancomycin microdialysis pharmacokinetics 

Notes

Funding information

This work was partly supported by JSPS KAKENHI Grant Number 16K18862.

References

  1. 1.
    Pfausler B, Spiss H, Beer R, Kampl A, Engelhardt K, Schober M, et al. Treatment of staphylococcal ventriculitis associated with external cerebrospinal fluid drains: a prospective randomized trial of intravenous compared with intraventricular vancomycin therapy. J Neurosurg. 2003;98:1040–4.CrossRefGoogle Scholar
  2. 2.
    Wang Q, Shi Z, Wang J, Shi G, Wang S, Zhou J. Postoperatively administered vancomycin reaches therapeutic concentration in the cerebral spinal fluid of neurosurgical patients. Surg Neurol. 2008;69:126–9.CrossRefGoogle Scholar
  3. 3.
    Lodise TP, Lomaestro B, Graves J, Drusano GL. Larger vancomycin doses (at least four grams per day) are associated with an increased incidence of nephrotoxicity. Antimicrob Agents Chemother. 2008;52:1330–6.CrossRefGoogle Scholar
  4. 4.
    Costa e Silva VT, Marçal LJ, Burdmann EA. Risk factors for vancomycin nephrotoxicity: still a matter of debate*. Crit Care Med. 2014;42:2635–6.CrossRefGoogle Scholar
  5. 5.
    Chavada R, Ghosh N, Sandaradura I, Maley M, Van Hal SJ. Establishment of an AUC0-24 threshold for nephrotoxicity is a step towards individualized vancomycin dosing for methicillin-resistant Staphylococcus aureus bacteremia. Antimicrob Agents Chemother. 2017;61:1–8.CrossRefGoogle Scholar
  6. 6.
    Barceló-Vidal J, Rodríguez-García E, Grau S. Extremely high levels of vancomycin can cause severe renal toxicity. Infect Drug Resist. 2018;11:1027–30.CrossRefGoogle Scholar
  7. 7.
    Fuchigami Y, Fu X, Ikeda R, Kawakami S, Wada M, Kikura-Hanajiri R, et al. Evaluation of the neurochemical effects of methoxetamine using brain microdialysis in mice. Forensic Toxicol. 2015;33:374–9.CrossRefGoogle Scholar
  8. 8.
    Miura Y, Fuchigami Y, Hagimori M, Sato H, Ogawa K, Munakata C, et al. Evaluation of the targeted delivery of 5-fluorouracil and ascorbic acid into the brain with ultrasound-responsive nanobubbles. J Drug Target. 2018;26:684–91.CrossRefGoogle Scholar
  9. 9.
    Usman M, Hempel G. Development and validation of an HPLC method for the determination of vancomycin in human plasma and its comparison with an immunoassay (PETINIA). Springerplus. 2016;5:124.CrossRefGoogle Scholar
  10. 10.
    Ambrose PG, Bhavnani SM, Rubino CM, Louie A, Gumbo T, Forrest A, et al. Pharmacokinetics-pharmacodynamics of antimicrobial therapy: it’s not just for mice anymore. Clin Infect Dis. 2007;44:79–86.CrossRefGoogle Scholar
  11. 11.
    Spassky N, Merkle FT, Flames N, Tramontin AD, García-Verdugo JM, Alvarez-Buylla A. Adult ependymal cells are postmitotic and are derived from radial glial cells during embryogenesis. J Neurosci. 2005;25:10–8.CrossRefGoogle Scholar
  12. 12.
    Rosenberg GA, Kyner WT, Estrada E. Bulk flow of brain interstitial fluid under normal and hyperosmolar conditions. Am J Phys. 1980;238:F42–9.Google Scholar
  13. 13.
    Pullen RG, DePasquale M, Cserr HF. Bulk flow of cerebrospinal fluid into brain in response to acute hyperosmolality. Am J Phys. 1987;253:F538–45.Google Scholar
  14. 14.
    Takigawa M, Masutomi H, Kishimoto Y, Shimazaki Y, Hamano Y, Kondo Y, et al. Time-dependent alterations of vancomycin-induced nephrotoxicity in mice. Biol Pharm Bull. 2017;40:975–83.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Yusuke Miura
    • 1
  • Yuki Fuchigami
    • 1
  • Sakiko Nomura
    • 1
  • Koyo Nishimura
    • 1
  • Masayori Hagimori
    • 1
  • Shigeru Kawakami
    • 1
    Email author
  1. 1.Department of Pharmaceutical Informatics, Graduate School of Biomedical SciencesNagasaki UniversityNagasakiJapan

Personalised recommendations