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

Case report

Restricted access

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.
Article Information

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.
Headings
References
  • 1

    Baptista JPSousa EMartins PJPimentel JM: Augmented renal clearance in septic patients and implications for vancomycin optimisation. Int J Antimicrob Agents 39:4204232012

    • Search Google Scholar
    • Export Citation
  • 2

    Baptista JPUdy AASousa EPimentel JWang LRoberts JA: A comparison of estimates of glomerular filtration in critically ill patients with augmented renal clearance. Crit Care 15:R1392011

    • Search Google Scholar
    • Export Citation
  • 3

    Beer RLackner PPfausler BSchmutzhard E: Nosocomial ventriculitis and meningitis in neurocritical care patients. J Neurol 255:161716242008

    • Search Google Scholar
    • Export Citation
  • 4

    Beer RPfausler BSchmutzhard E: Infectious intracranial complications in the neuro-ICU patient population. Curr Opin Crit Care 16:1171222010

    • Search Google Scholar
    • Export Citation
  • 5

    Craig WA: Pharmacokinetic/pharmacodynamic parameters: rationale for antibacterial dosing of mice and men. Clin Infect Dis 26:1121998

    • Search Google Scholar
    • Export Citation
  • 6

    Di Giantomasso DMay CNBellomo R: Norepinephrine and vital organ blood flow. Intensive Care Med 28:180418092002

  • 7

    Di Giantomasso DMay CNBellomo R: Vital organ blood flow during hyperdynamic sepsis. Chest 124:105310592003

  • 8

    Jeffres MNIsakow WDoherty JAMcKinnon PSRitchie DJMicek ST: Predictors of mortality for methicillin-resistant Staphylococcus aureus health-care-associated pneumonia: specific evaluation of vancomycin pharmacokinetic indices. Chest 130:9479552006

    • Search Google Scholar
    • Export Citation
  • 9

    Kees MGHilpert JWGnewuch CKees FVoegeler 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 36:5455482010

    • Search Google Scholar
    • Export Citation
  • 10

    Kumar ARoberts DWood KELight BParrillo JESharma S: Duration of hypotension before initiation of effective antimicrobial therapy is the critical determinant of survival in human septic shock. Crit Care Med 34:158915962006

    • Search Google Scholar
    • Export Citation
  • 11

    Lozier APSciacca RRRomagnoli MFConnolly ES Jr: Ventriculostomy-related infections: a critical review of the literature. Neurosurgery 51:1701822002

    • Search Google Scholar
    • Export Citation
  • 12

    McKinnon PSPaladino JASchentag 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 31:3453512008

    • Search Google Scholar
    • Export Citation
  • 13

    McWhinney BCWallis SCHillister TRoberts JALipman JUngerer JP: Analysis of 12 beta-lactam antibiotics in human plasma by HPLC with ultraviolet detection. J Chromatogr B Analyt Technol Biomed Life Sci 878:203920432010

    • Search Google Scholar
    • Export Citation
  • 14

    Moise-Broder PAForrest ABirmingham MCSchentag JJ: Pharmacodynamics of vancomycin and other antimicrobials in patients with Staphylococcus aureus lower respiratory tract infections. Clin Pharmacokinet 43:9259422004

    • Search Google Scholar
    • Export Citation
  • 15

    Nau RSörgel FEiffert H: Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections. Clin Microbiol Rev 23:8588832010

    • Search Google Scholar
    • Export Citation
  • 16

    Pujal MSoy DCodina CRibas J: Are higher vancomycin doses needed in ventricle-external shunted patients?. Pharm World Sci 28:2152212006

    • Search Google Scholar
    • Export Citation
  • 17

    Ricard JDWolff MLacherade JCMourvillier BHidri NBarnaud 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 44:2502552007

    • Search Google Scholar
    • Export Citation
  • 18

    Roberts JAKruger PPaterson DLLipman J: Antibiotic resistance—what's dosing got to do with it?. Crit Care Med 36:243324402008

    • Search Google Scholar
    • Export Citation
  • 19

    Roberts JALipman J: Pharmacokinetic issues for antibiotics in the critically ill patient. Crit Care Med 37:8408512009

  • 20

    Roberts JANorris RPaterson DLMartin JH: Therapeutic drug monitoring of antimicrobials. Br J Clin Pharmacol 73:27362012

  • 21

    Roberts JATaccone FSUdy AAVincent JLJacobs FLipman J: Vancomycin dosing in critically ill patients: robust methods for improved continuous-infusion regimens. Antimicrob Agents Chemother 55:270427092011

    • Search Google Scholar
    • Export Citation
  • 22

    Roberts JAUlldemolins MRoberts MSMcWhinney BUngerer JPaterson DL: Therapeutic drug monitoring of beta-lactams in critically ill patients: proof of concept. Int J Antimicrob Agents 36:3323392010

    • Search Google Scholar
    • Export Citation
  • 23

    Rybak MJ: The pharmacokinetic and pharmacodynamic properties of vancomycin. Clin Infect Dis 42:Suppl 1S35S392006

  • 24

    Sen JBelli AAlbon HMorgan LPetzold AKitchen N: Triple-H therapy in the management of aneurysmal subarachnoid haemorrhage. Lancet Neurol 2:6146212003

    • Search Google Scholar
    • Export Citation
  • 25

    Teasdale GJennett B: Assessment of coma and impaired consciousness. A practical scale. Lancet 2:81841974

  • 26

    Tunkel ARHartman BJKaplan SLKaufman BARoos KLScheld WM: Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 39:126712842004

    • Search Google Scholar
    • Export Citation
  • 27

    Udy ABoots RSenthuran SStuart JDeans RLassig-Smith M: Augmented creatinine clearance in traumatic brain injury. Anesth Analg 111:150515102010

    • Search Google Scholar
    • Export Citation
  • 28

    Udy ARoberts JABoots RJLipman J: You only find what you look for: the importance of high creatinine clearance in the critically ill. Anaesth Intensive Care 37:11132009

    • Search Google Scholar
    • Export Citation
  • 29

    Udy AARoberts JABoots RJPaterson DLLipman J: Augmented renal clearance: implications for antibacterial dosing in the critically ill. Clin Pharmacokinet 49:1162010

    • Search Google Scholar
    • Export Citation
  • 30

    Udy AARoberts JALipman J: Implications of augmented renal clearance in critically ill patients. Nat Rev Nephrol 7:5395432011

  • 31

    Udy AAVarghese JMAltukroni MBriscoe SMcWhinney BCUngerer JP: Sub-therapeutic initial β-lactam concentrations in select critically ill patients: association between augmented renal clearance and low trough drug concentrations. Chest 142:30392012

    • Search Google Scholar
    • Export Citation
  • 32

    Wan LBellomo RMay CN: The effects of normal and hypertonic saline on regional blood flow and oxygen delivery. Anesth Analg 105:1411472007

    • Search Google Scholar
    • Export Citation
TrendMD
Cited By
Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 302 230 16
Full Text Views 254 52 1
PDF Downloads 127 37 1
EPUB Downloads 0 0 0
PubMed
Google Scholar