Intrathecal penetration of meropenem and vancomycin administered by continuous infusion in patients suffering from ventriculitis—a retrospective analysis
- 321 Downloads
Vancomycin and meropenem are frequently used as empiric treatment for ventriculitis. Penetration into the cerebrospinal fluid (CSF) depends on various factors with a high inter-individual variability. Because attaining and maintaining adequate concentrations of meropenem and vancomycin in the CSF is crucial for their bactericidal effect, we introduced a routine therapeutic drug monitoring (TDM) from CSF and serum for both antibiotics. We studied the antibiotic penetration into the CSF.
Patient data including serum and CSF concentrations for meropenem and vancomycin were collected in a retrospective fashion. Antibiotic CSF penetration ratio was calculated for each patient. Antibiotics were administered by continuous infusion aiming for serum target concentrations of 20–30 mg/L for vancomycin and 16–32 mg/L for meropenem.
Twenty-two patients with 36 CSF/serum pairs for meropenem and 43 pairs for vancomycin were studied. No patient suffered from renal or liver insufficiency. Mean vancomycin serum concentration was 22 ± 8 mg/L and the mean CSF concentration 4.5 ± 2.6 mg/L. CSF penetration was 20 ± 11% (coefficient of determination (R2) 0.02). For meropenem, the mean serum concentration was 30.7 ± 14.9 mg/L, mean CSF concentration 5.5 ± 5.2 mg/L, and a penetration of 18 ± 12%, R2 = 0.42.
Penetration of meropenem and vancomycin into the CSF is low while showing a high interindividual variability. Various patients in our study cohort were at risk for insufficient target attainment in CSF. Continuous administration of antibiotics under routine TDM appears to be a feasible and reasonable approach for optimization of intrathecal drug levels in patients suffering from ventriculitis. TDM might guide individual dosing adaptation and efforts to predict the CSF penetration of meropenem and vancomycin in cases of ventriculitis.
KeywordsCritical care Drug monitoring Pharmacokinetics Meropenem Vancomycin Cerebral ventriculitis
European Committee on Antimicrobial Susceptibility Testing
External ventricular drain
Gamma glutamyl transpeptidase
Glasgow Outcome Scale
High-performance liquid chromatography with ultra violet detection
Minimal inhibitory concentration
- SAPS II
Simplified Acute Physiology Score II
Therapeutic drug monitoring
MMM helped to design the study and to write the manuscript and acquired the data. PC helped to design the study and helped with the data acquisition. CK interpreted the data and helped to write the manuscript. VF helped to write the manuscript and to interpret the data. SK and MW helped with the interpretation and revised the manuscript. JG designed the study, wrote the manuscript, and helped to acquire the data. All authors read and approved the final manuscript.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. For this type of study, formal consent is not required.
- 1.Albanese J, Leone M, Bruguerolle B, Ayem ML, Lacarelle B, Martin C (2000) Cerebrospinal fluid penetration and pharmacokinetics of vancomycin administered by continuous infusion to mechanically ventilated patients in an intensive care unit. Antimicrob Agents Chemother 44:1356–1358CrossRefGoogle Scholar
- 3.Blassmann U, Roehr AC, Frey OR, Vetter-Kerkhoff C, Thon N, Hope W, Briegel J, Huge V (2016) Cerebrospinal fluid penetration of meropenem in neurocritical care patients with proven or suspected ventriculitis: a prospective observational study. Crit Care 20:343. https://doi.org/10.1186/s13054-016-1523-y CrossRefPubMedPubMedCentralGoogle Scholar
- 5.CDC/NHSN (2018) CDC/NHSN surveillance definitions for specific types of infections. https://www.cdc.gov/nhsn/PDFs/pscManual/17pscNosInfDef_current.pdf. Accessed August 3, 2018
- 6.Chen K, Wu Y, Wang Q, Wang J, Li X, Zhao Z, Zhou J (2015) The methodology and pharmacokinetics study of intraventricular administration of vancomycin in patients with intracranial infections after craniotomy. J Crit Care 30:218.e211–218.e215. https://doi.org/10.1016/j.jcrc.2014.09.020 CrossRefGoogle Scholar
- 7.Dulhunty JM, Roberts JA, Davis JS, Webb SA, Bellomo R, Gomersall C, Shirwadkar C, Eastwood GM, Myburgh J, Paterson DL, Starr T, Paul SK, Lipman J (2015) A multicenter randomized trial of continuous versus intermittent beta-lactam infusion in severe sepsis. Am J Respir Crit Care Med 192:1298–1305. https://doi.org/10.1164/rccm.201505-0857OC CrossRefPubMedGoogle Scholar
- 15.McKinnon PS, Paladino JA, Schentag JJ (2008) 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 31:345–351. https://doi.org/10.1016/j.ijantimicag.2007.12.009 CrossRefPubMedGoogle Scholar
- 18.No Authors (2000) The management of neurosurgical patients with postoperative bacterial or aseptic meningitis or external ventricular drain-associated ventriculitis. Infection in Neurosurgery Working Party of the British Society for Antimicrobial Chemotherapy. Br J Neurosurg 14:7–12CrossRefGoogle Scholar
- 21.Roberts JA, Paul SK, Akova M, Bassetti M, De Waele JJ, Dimopoulos G, Kaukonen KM, Koulenti D, Martin C, Montravers P, Rello J, Rhodes A, Starr T, Wallis SC, Lipman J (2014) DALI: defining antibiotic levels in intensive care unit patients: are current beta-lactam antibiotic doses sufficient for critically ill patients? Clin Infect Dis 58:1072–1083. https://doi.org/10.1093/cid/ciu027 CrossRefPubMedGoogle Scholar
- 22.Roberts JA, Abdul-Aziz MH, Davis JS, Dulhunty JM, Cotta MO, Myburgh J, Bellomo R, Lipman J (2016) Continuous versus intermittent beta-lactam infusion in severe sepsis. A meta-analysis of individual patient data from randomized trials. Am J Respir Crit Care Med 194:681–691. https://doi.org/10.1164/rccm.201601-0024OC CrossRefPubMedGoogle Scholar
- 23.Rybak M, Lomaestro B, Rotschafer JC, Moellering R Jr, Craig W, Billeter M, Dalovisio JR, Levine DP (2009) Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 66:82–98. https://doi.org/10.2146/ajhp080434 CrossRefGoogle Scholar
- 24.Shah SS, Ohlsson A, Shah VS (2012) Intraventricular antibiotics for bacterial meningitis in neonates. Cochrane Database Syst Rev:Cd004496. https://doi.org/10.1002/14651858.CD004496.pub3
- 26.Sorgel F, Hohl R, Glaser R, Stelzer C, Munz M, Vormittag M, Kinzig M, Bulitta J, Landersdorfer C, Junger A, Christ M, Wilhelm M, Holzgrabe U (2017) Pharmacokinetics and pharmacodynamics of antibiotics in intensive care. Med Klin Intensivmed Notfmed 112:11–23. https://doi.org/10.1007/s00063-016-0185-5 CrossRefPubMedGoogle Scholar
- 27.Tangden T, Enblad P, Ullberg M, Sjolin J (2011) Neurosurgical gram-negative bacillary ventriculitis and meningitis: a retrospective study evaluating the efficacy of intraventricular gentamicin therapy in 31 consecutive cases. Clin Infect Dis 52:1310–1316. https://doi.org/10.1093/cid/cir197 CrossRefPubMedGoogle Scholar
- 28.Testing ECoAS (2018) Clinical breakpoints - bacteria (v8.1). http://www.eucast.org/clinical_breakpoints/. Accessed June 7, 2018
- 29.Tunkel AR, Hasbun R, Bhimraj A, Byers K, Kaplan SL, Michael Scheld W, van de Beek D, Bleck TP, Garton HJ, Zunt JR (2017) 2017 Infectious Diseases Society of America’s clinical practice guidelines for healthcare-associated ventriculitis and meningitis. Clin Infect Dis. https://doi.org/10.1093/cid/ciw861 CrossRefGoogle Scholar
- 31.Wang JH, Lin PC, Chou CH, Ho CM, Lin KH, Tsai CT, Wang JH, Chi CY, Ho MW (2014) Intraventricular antimicrobial therapy in postneurosurgical gram-negative bacillary meningitis or ventriculitis: a hospital-based retrospective study. J Microbiol Immunol Infect 47:204–210. https://doi.org/10.1016/j.jmii.2012.08.028 CrossRefPubMedGoogle Scholar