Antibacterial therapeutic drug monitoring in cerebrospinal fluid: difficulty in achieving adequate drug concentrations

Case report

Dagan O. Lonsdale M.B.B.S., B.Sc.(Hon), M.R.C.P. 1 , Andrew A. Udy B.H.B., M.B.Ch.B., F.C.I.C.M. 1 , 2 , Jason A. Roberts B.Pharm.(Hon), Ph.D., F.S.H.P. 1 , 3 , 2 , and Jeffrey Lipman M.B.B.Ch., D.A., F.F.A., M.D., F.C.I.C.M. 1 , 2
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  • 1 Department of Intensive Care Medicine and
  • 3 Pharmacy Department, Royal Brisbane and Women's Hospital, Herston, Queensland; and
  • 2 Burns, Trauma, and Critical Care Research Center, University of Queensland, Herston, Queensland, Australia
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This report illustrates the difficulty in managing CNS infection in neurosurgical patients, the altered drug pharmacokinetics associated with critical illness, and the role that therapeutic drug monitoring (TDM) of CSF can play in assisting clinical decision making.

The authors present a case of external ventricular drain–related ventriculitis in a critically ill patient who initially presented with a subarachnoid hemorrhage. They discuss the physiological changes found in such patients, in particular augmented renal clearance (demonstrated in this patient by a measured creatinine clearance of 375 ml/min/1.73 m2), noting the effect this had on drug pharmacokinetics and leading to dosing requirements 2–3 times those recommended in standard regimens.

The authors consider the bacterial “kill” characteristics of 2 different antibacterial agents (meropenem and vancomycin) and describe the unique approach of using plasma and CSF TDM to achieve optimal drug exposure at the site of infection while limiting toxic side effects. The authors demonstrate that simply using plasma TDM as a surrogate marker for drug concentration in the CNS may lead to underdosing, exemplified in this patient by CSF vancomycin concentrations as little as 13% of that in plasma. Finally, by measuring CSF and plasma ratios, the authors illustrate the disparity in pharmacokinetic properties between drugs, reminding the clinician of the importance of CNS penetration when selecting antibacterial agents in such cases.

This work raises an important hypothesis in the accurate prescription of antibacterial agents in neurosurgical critical care, namely underdosing in the context of augmented elimination and impaired target site penetration. However, prior to any recommendations regarding empirical dose modification, more data are clearly needed, particularly with respect to the safety and efficacy of such an approach. In this respect, the authors would advocate further research using TDM in the management of CNS infection in this setting, in addition to work defining plasma and CSF concentrations associated with antibacterial efficacy and toxicity.

Abbreviations used in this paper:ARC = augmented renal clearance; AUC = area under the curve; CLCR = creatinine clearance; E = eye response; EVD = external ventricular drain; GCS = Glasgow Coma Scale; M = motor response; MIC = minimum inhibitory concentration; SAH = subarachnoid hemorrhage; TDM = therapeutic drug monitoring; V = verbal response.

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Contributor Notes

Address correspondence to: Jeffrey Lipman, M.D., Department of Intensive Care Medicine, Level 3 Ned Hanlon Building, Royal Brisbane and Women's Hospital, Herston, Queensland, 4029, Australia. email: j.lipman@uq.edu.au.

Please include this information when citing this paper: published online November 2, 2012; DOI: 10.3171/2012.10.JNS12883.

  • 1

    Baptista JP, , Sousa E, , Martins PJ, & Pimentel JM: Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents 39:420423, 2012

    • Search Google Scholar
    • Export Citation
  • 2

    Baptista JP, , Udy AA, , Sousa E, , Pimentel J, , Wang L, & Roberts JA, : A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care 15:R139, 2011

    • Search Google Scholar
    • Export Citation
  • 3

    Beer R, , Lackner P, , Pfausler B, & Schmutzhard E: Nosocomial ventriculitis and meningitis in neurocritical care patients. J Neurol 255:16171624, 2008

    • Search Google Scholar
    • Export Citation
  • 4

    Beer R, , Pfausler B, & Schmutzhard E: Infectious intracranial complications in the neuro-ICU patient population. Curr Opin Crit Care 16:117122, 2010

    • Search Google Scholar
    • Export Citation
  • 5

    Craig WA: Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:112, 1998

    • Search Google Scholar
    • Export Citation
  • 6

    Di Giantomasso D, , May CN, & Bellomo R: Norepinephrine and vital organ blood flow. Intensive Care Med 28:18041809, 2002

  • 7

    Di Giantomasso D, , May CN, & Bellomo R: Vital organ blood flow during hyperdynamic sepsis. Chest 124:10531059, 2003

  • 8

    Jeffres MN, , Isakow W, , Doherty JA, , McKinnon PS, , Ritchie DJ, & Micek ST, : Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 130:947955, 2006

    • Search Google Scholar
    • Export Citation
  • 9

    Kees MG, , Hilpert JW, , Gnewuch C, , Kees F, & Voegeler S: Clearance of vancomycin during continuous infusion in Intensive Care Unit patients: correlation with measured and estimated creatinine clearance and serum cystatin C. Int J Antimicrob Agents 36:545548, 2010

    • Search Google Scholar
    • Export Citation
  • 10

    Kumar A, , Roberts D, , Wood KE, , Light B, , Parrillo JE, & Sharma S, : Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:15891596, 2006

    • Search Google Scholar
    • Export Citation
  • 11

    Lozier AP, , Sciacca RR, , Romagnoli MF, & Connolly ES Jr: Ventriculostomy-related infections: a critical review of the literature. Neurosurgery 51:170182, 2002

    • Search Google Scholar
    • Export Citation
  • 12

    McKinnon PS, , Paladino JA, & Schentag JJ: Evaluation of area under the inhibitory curve (AUIC) and time above the minimum inhibitory concentration (T>MIC) as predictors of outcome for cefepime and ceftazidime in serious bacterial infections. Int J Antimicrob Agents 31:345351, 2008

    • Search Google Scholar
    • Export Citation
  • 13

    McWhinney BC, , Wallis SC, , Hillister T, , Roberts JA, , Lipman J, & Ungerer JP: Analysis of 12 beta-lactam antibiotics in human plasma by HPLC with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci 878:20392043, 2010

    • Search Google Scholar
    • Export Citation
  • 14

    Moise-Broder PA, , Forrest A, , Birmingham MC, & Schentag JJ: Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 43:925942, 2004

    • Search Google Scholar
    • Export Citation
  • 15

    Nau R, , Sörgel F, & Eiffert H: Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 23:858883, 2010

    • Search Google Scholar
    • Export Citation
  • 16

    Pujal M, , Soy D, , Codina C, & Ribas J: Are higher vancomycin doses needed in ventricle-external shunted patients?. Pharm World Sci 28:215221, 2006

    • Search Google Scholar
    • Export Citation
  • 17

    Ricard JD, , Wolff M, , Lacherade JC, , Mourvillier B, , Hidri N, & Barnaud G, : Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study. Clin Infect Dis 44:250255, 2007

    • Search Google Scholar
    • Export Citation
  • 18

    Roberts JA, , Kruger P, , Paterson DL, & Lipman J: Antibiotic resistance—what's dosing got to do with it?. Crit Care Med 36:24332440, 2008

    • Search Google Scholar
    • Export Citation
  • 19

    Roberts JA, & Lipman J: Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 37:840851, 2009

  • 20

    Roberts JA, , Norris R, , Paterson DL, & Martin JH: Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol 73:2736, 2012

  • 21

    Roberts JA, , Taccone FS, , Udy AA, , Vincent JL, , Jacobs F, & Lipman J: Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother 55:27042709, 2011

    • Search Google Scholar
    • Export Citation
  • 22

    Roberts JA, , Ulldemolins M, , Roberts MS, , McWhinney B, , Ungerer J, & Paterson DL, : Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 36:332339, 2010

    • Search Google Scholar
    • Export Citation
  • 23

    Rybak MJ: The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 42:Suppl 1 S35S39, 2006

  • 24

    Sen J, , Belli A, , Albon H, , Morgan L, , Petzold A, & Kitchen N: Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2:614621, 2003

    • Search Google Scholar
    • Export Citation
  • 25

    Teasdale G, & Jennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:8184, 1974

  • 26

    Tunkel AR, , Hartman BJ, , Kaplan SL, , Kaufman BA, , Roos KL, & Scheld WM, : Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 39:12671284, 2004

    • Search Google Scholar
    • Export Citation
  • 27

    Udy A, , Boots R, , Senthuran S, , Stuart J, , Deans R, & Lassig-Smith M, : Augmented creatinine clearance in traumatic brain injury. Anesth Analg 111:15051510, 2010

    • Search Google Scholar
    • Export Citation
  • 28

    Udy A, , Roberts JA, , Boots RJ, & Lipman J: You only find what you look for: the importance of high creatinine clearance in the critically ill. Anaesth Intensive Care 37:1113, 2009

    • Search Google Scholar
    • Export Citation
  • 29

    Udy AA, , Roberts JA, , Boots RJ, , Paterson DL, & Lipman J: Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 49:116, 2010

    • Search Google Scholar
    • Export Citation
  • 30

    Udy AA, , Roberts JA, & Lipman J: Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol 7:539543, 2011

  • 31

    Udy AA, , Varghese JM, , Altukroni M, , Briscoe S, , McWhinney BC, & Ungerer JP, : Sub-therapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 142:3039, 2012

    • Search Google Scholar
    • Export Citation
  • 32

    Wan L, , Bellomo R, & May CN: The effects of normal and hypertonic saline on regional blood flow and oxygen delivery. Anesth Analg 105:141147, 2007

    • Search Google Scholar
    • Export Citation

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