Cefuroxime levels were measured in cerebrospinal fluid (CSF) and serum of four patients with traumatic brain injury following the implantation of intraventricular catheters. The levels ranged from 0.15 to 2.03 μg/mL in CSF and from 1.8 to 66.9 μg/mL in serum. No ventriculostomy related infections were detecte

Hans, V.

Imhof, H.-G

Joos, B.

Kossmann, T.

Morganti-Kossmann, M. C.

Stocker, R.

Trentz, O.

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Journal of Antimicrobial Chemotherapy (1996) 37, 161-167Penetration of cefuroxime into the cerebrospinal fluid of patients withtraumatic brain injuryT. Kossmann', V. Hans', R. Stocker', H.-G. Imhof*, B. Joos', O. Trentz' andM. C. Morganti-Kossmann*-*"Department of Surgery, Division of Trauma Surgery; bDepartment of Neurosurgery;'Department of Internal Medicine, Division of Infectious Diseases, University of Zurich,Medical School, CH-8091 Zurich, SwitzerlandCefuroxime levels were measured in cerebrospinal fluid (CSF) and serum of fourpatients with traumatic brain injury following the implantation of intraventricularcatheters. The levels ranged from 0.15 to 2.03//g/mL in CSF and from 1.8 to66.9 /ig/mL in serum. No ventriculostomy related infections were detected.IntroductionIntracranial pressure (ICP) monitoring is fundamental in the treatment of patients withsevere traumatic brain injury (TBI). Intraventricular catheters (IVC) allow continuousICP monitoring as well as drainage of ventricular cerebrospinal fluid (CSF) in orderto reduce elevated ICP. However, the risk of ventriculostomy related infections (VRI)exists (Rosner & Becker, 1976; Mayhall et ah, 1984; Clark et al., 1989). In order toprevent VRI, an absolute aseptic surgical technique and sterile management is necessarywhile the catheter is in place. Detailed information on penetration of antibiotics intoCSF of patients with TBI is lacking so the advantage of prophylaxis remainscontroversial (Mayhall et al., 1984; Clark el al., 1989). However, cefuroxime is routinelyused in our clinic as a prophylactic antibiotic in patients with TBI during the time ofventricular ICP monitoring and may be of benefit. Cefuroxime levels were monitoredin CSF and serum of patients with severe TBI who underwent ventriculostomy.Relevant antibiotic concentrations were detected in CSF independently from theintegrity of the blood brain barrier.Materials and methodsPatientsIn 1994 a total of 31 patients with severe TBI received IVC at the Division of TraumaSurgery, University of Zurich, Switzerland. All of them had a Glasgow Coma Score(GCS) ^ 8 on arrival (Teasdale & Jennett, 1976) and showed varying abnormalities inthe computed tomography (CT). Table I shows the clinical details of four patients•Corresponding author: Telephone: +4I-<I)-2551111; Fax: +41-(l)-2554406.1610305-7453/96/010161 + 06 $12.00/0 © 1996 The British Society for Antimicrobial Chemotherapy162 T. Kossmann et at.included in this study. After surgical treatment the patients were transferred to theintensive care unit (ICU). The therapy followed a standardized protocol (Stocker et al.,1995). VRI was diagnosed according to Mayhall (Mayhall et al., 1984) and pneumoniawas diagnosed according to the protocol (Stocker et al., 1995). The study was approvedby the University Hospital Medical Ethics Board, Zurich.Intraventricular catheter insertionIVC (Becker External Drainage, Pudenz-Schulte Medical Corporation, Goleta, CA,USA) were used in brain injured patients for monitoring as well as for therapeuticrelease of CSF when ICP exceeded 15 mmHg. The IVC were inserted under asepticconditions in the operating room.Cefuroxime treatmentCefuroxime (Zinacef*, Glaxo AG, Schoenbuehl, Switzerland) was given in all patientsprior to IVC implantation in doses of 1.5 g intravenously and continued at the samedosage every 8 h for 10-25 days (Table I). Cefuroxime was administered asrecommended by the manufacturer.Specimen collection and microbiologyThe serum and CSF samples were drawn on day 2, 4 and 6 of the treatment period atapproximately 1.5 and 6 h (99 ± 13 min and 355 ± 8 min respectively, mean ± S.E.M.)after the first dose of cefuroxime. The specimens were centrifuged at 170 g at 4°C for10 min, divided into aliquots and frozen at — 70°C until analysis.On a routine basis CSF samples were drawn every three to four days and screenedfor bacterial infections. The IVC tips were tested after removal for bacterial colonisationat the Institute for Medical Microbiology, University of Zurich.Albumin analysis and blood brain barrier functionAlbumin levels were measured in CSF and serum by automatized laser photometry(BNA Automat, Behring Werke, Marburg, Germany). The CSF/serum albumin ratio(QA) was utilized as a parameter for blood brain barrier (BBB) integrity (Reiber &Felgenhauer, 1987).High performance liquid chromatography (HPLC) analysisCefuroxime levels were determined by a reversed phase HPLC system (Waters-MilliporeCorp., Milford, MA, USA) using 40% methanol in 5 mM tetrabutylammoniumphos-phate as mobile phase and photodiode array detection. The variability of the assay was< 3 % , linearity was tested at 1.5-150 jig/mL, detection limits for serum and CSFsamples were 0.2 and 0.1 /ig/mL respectively.Antibiotic prophylaxis in brain injured patients 163Results and discussionAt our institution cefuroxime is used as a standard prophylactic antibiotic not only inpatients with severe TBI. In this study all patients received an IVC for measurementand treatment of elevated ICP. Additionally the IVC offered the possibility of acontinuous monitoring of cefuroxime levels in the cerebral compartment. Table Isummarizes the clinical data. The IVC was in place for 20 to 26 days. Patient selectionwas based on the single antibiotic prophylaxis with cefuroxime which was given fromthe day of insertion and continued for at least 10 days (Table I). Our results clearly showthat cefuroxime enters the CSF of patients with TBI. Cefuroxime concentrations in CSFranged from 0.35 to 1.76 fig/mL at approximately 1.5 h after the first daily applicationof cefuroxime (day 2, 4 and 6), whereas after about 6 h the levels ranged from 0.15 to2.03 /ig/mL (Figure). The corresponding levels of cefuroxime in serum ranged between2.0 and 61.7 /ig/mL after 1.5 h and between 1.8 and 66.9 /Jg/mL after 6 h. As indicatedin the figure, two samples (patient 2 at day 6 and patient 4 at day 2) were collected later(after the second daily dose) and therefore these concentrations were higher. Thecefuroxime levels in the serum of our patients were highly variable. The use of IVC inthe treatment of brain injured patients is nowadays well established (Stocker et al.,1995), despite the risk of infections (Mayhall et al., 1984; Clark et al., 1989). The devicemust be implanted under aseptic conditions and the removal of CSF has to beperformed under sterile conditions.The use of prophylactic antibiotics in patients with IVC is controversal (Mayhallet al., 1984; Clark et al., 1989), chiefly due to the fact that the penetration of antibioticsin the CSF of patients with severe TBI has not been studied, whereas numerouspharmacokinetic studies have been performed in patients with meningitis (Ristuccia &Le Frock, 1992).Cefuroxime is a second generation cephalosporin with a broad antimicrobialspectrum (Ristuccia & Le Frock, 1992) and is active against frequently encounteredbacteria, which can cause meningitis following neurosurgical procedures (Mayhall et al.,1984). Cefuroxime reaches therapeutic concentrations in many body compartments(Daikos et al., 1977), has a very low toxicity, and is excreted unmetabolized by theurinary tract (Ristuccia & Le Frock, 1992). In meningitis cefuroxime has superiorpenetration into the CSF compared to other cephalosporins (Daikos et al., 1977;Ristuccia & Le Frock, 1992). In children with bacterial meningitis mean cefuroximeconcentrations in the CSF were 6.4 and 3.6 /ig/mL 2 h following iv doses of 50 mg/kgof cefuroxime on days 2 and 14 of treatment. Without meningeal inflammation meancefuroxime concentration in CSF was 1.34 /ig/mL (Sirinavin et al., 1984). This findingis comparable with our results. The minimal inhibitory concentration for sensitivestaphylococci and streptococci ranges from 0.1 to 1.4/ig/mL. Therefore, cefuroximeconcentrations in CSF of our patients are likely sufficient to inhibit most of the bacteriafound in VRI (Mayhall et al., 1984).No patient in this study had a VRI, which was confirmed by microbiological analysisof the CSF samples every 3 to 4 days during the period the IVC was in place.Furthermore, the IVC-tips of all patients were analyzed after removal for bacterialcolonisation, but no bacterial infection was detected.Systemic infections occurred during their treatment period in the ICU. The onsetof these infections was more than a week (7-14 days) following TBI. Three out of fourpatients had pneumonia (Table II). The cefuroxime monotherapy was supplementedTable I. Clinical details of the four patients studiedPatient1i34Sex/age(years)M/41F/23M/16F/18Other injuriesfractures of humerus, tibia.calcaneus and patellafracture of radiusfacial fracturesfracture of radiusDurationIVO (days)20242620Days inICU*31352831GOS'5545VRI"nonononoAntibioticprophylaxiscefuroximecefuroximecefuroximecefuroximeDuration(days)212510161a3"Duration of intraventncular catheter in place.Intensive care unit.Glasgow Outcome Score at 6 months after trauma (Jennett el «/.. 1976)''Ventnculostomy related infections.Antibiotic prophylaxis in brain injured patients 16521.5l10.5nDay 2_-MLI )ay 4 Day ti(di•~Day 2Day 2 Day 1 Day 670HO50•103020100Day 4 Day 61 1 1 ! 1 1^ _ ( h iuDay 2 Dav 4 Day 6Figure. Cefuroxime concentrations (//g/mL) in CSF ((a)-(d)) and serum ((e)-(h)) of four brain injuredpatients. Black columns show values after 1.5 h (99 ± 13 min) and white columns after 6 h (355 ± 8 min).As indicated by asterisk (•) two samples (patient 2 at day 6 and patient 4 at day 2) were drawn after thesecond daily administration of cefuroxime The CSF and serum levels reflect concentrations 45 min(patient 2) and immediately (patient 4) after the second daily infusion of cefuroxime.with different antibiotics according to microbiological evaluation of the broncho-alveolar lavage and may have delayed the occurrence of VRI. However, previously theonset of VRI has been reported predominantly within 5 days after insertion of theIVC (Mayhall el al., 1984; Clark el al., 1989).After a 6 month period the patients were examined again and none showed clinicalsigns of late onset intracerebral infection. They had recovered to a varied extent andhad a GOS between 4 and 5 (Jennet el al., 1976).In order to determine the influence of BBB function on the availability of cefuroximewe analyzed the CSF/serum albumin ration (QA)- With the exception of patient 2, whoshowed a moderate dysfunction of the BBB during the first 48 h, the QA of all patientswere below 0.007 indicating normal BBB function. Therefore, cefuroxime may reach theCSF of these patients by diffusion or via active transport. Further studies are warrantedregarding the transport mechanisms of cefuroxime via the BBB.166 T. Kossmann et al.Table II. Systemic infections and treatmentPatient1234Onseton day8914713Systemicinfectionspneumoniapneumoniapneumoniatracheo-bronchialcolonisationvaginal-mycosisMicrobiologyPseudomonas aeruginosaSerratia marcescensP. aeruginosaCandida albicansP. aeruginosaC. albicansStreptococcus consiellatusKlebsiella spp.Enterobacter cloacaeStenotrophomonas maltophiliaTreatmentnetilmicinciprofloxacinamoxicillin +clavulanic acidnetilmicinceftazidimepiperacillinco-trimoxazoleciprofloxacinamoxicillin +clavulanic acidceftazidimevancomycineconazolIn summary, our data show that cefuroxime reaches the CSF, suggesting that thismay be a suitable prophylactic antibiotic for the prevention of VRI in patients with TBI.However, aseptic implantation of intraventricular catheters as well as sterilemanagement of the device are essential. A follow-up study will focus on elucidating theexact pharmacokinetics of cefuroxime in the CSF of patients with TBI.AcknowledgementsThis study was supported by a grant from the Swiss National Fund No. 31-36375.92and by Glaxo AG, Schoenbuehl, Switzerland. We gratefully thank Prof. Dr RuediLiithy and Dr Philipp Lenzlinger for critically reviewing the manuscript.ReferencesClark, W. C, Muhlbauer, M. S., Lowrey. R., Hartman, M.. Ray, M. W. & Watridge, C. B.(1989). Complications of intracranial pressure monitoring in trauma patients Neurosurgerv25, 20-4.Daikos, G. K.., Kosmidis, J., Stathakis, C , Anyfantis, A., Plakoutsis, T. & Papathanassiou, B.(1977). Bioavailability of cefuroxime in various sites including bile, sputum and bone.Proceedings of the Royal Society of Medicine 70, Suppl. 9, 38-41.Jennett, B., Teasdale, G., Braakman, R., Minderhoud, J. & Knill-Jones, R. (1976). Predictingoutcome in individual patients after severe head injury. Lancet i, 1031-4.Mayhall, C. G., Archer, N. H., Lamb, V. A., Spadora, A. C , Baggett, J. W., Ward, J D. et al.(1984). Ventriculostomy-related infections. A prospective epidemiologic study. New EnglandJournal of Medicine 310, 553-9.Reiber, H. & Felgenhauer, K.. (1987). Protein transfer at the blood cerebrospinal fluid barrier andthe quantitation of the humoral immune response within the central nervous system. ClinicaChimica Ada 163, 319-28.Ristuccia, A M. & Le Frock, J. L. (1992). Cerebrospinal fluid penetration of antimicrobials.Antibiotics and Chemotherapy 45, 118-52.Antibiotic prophylaxis in brain injured patients 167Rosner, M. J. & Becker, D. P. (1976). ICP monitoring: complications and associated factors.Clinical Neurosurgerv 23, 494-519.Sirinavin, S., Chiemchanya, S., Visudhipan, P. & Lolekha, S. (1984). Cefuroxime treatment ofbacterial meningitis in infants and children. Antimicrobial Agents and Chemotherapy 25,273-5.Stocker, R., Bernays, R., Kossmann, T. & Imhof, H. G. (1995). Monitonng and treatment ofacute head injury in Update in Intensive Care and Emergency Medicine, Vol. 22 (Goris,R. J. A. & Trentz, O., Eds), pp. 196-219. Springer-Verlag, Berlin.Teasdale, G. & Jennett, B. (1976). Assessment and prognosis of coma after head injury. AdaNeurochirurgica 34, 45-55.(Received 24 March 1995; returned 2 May 1995; revised 21 June 1995; accepted 22 August 1995)

Penetration of cefuroxime into the cerebrospinal fluid of patients with traumatic brain injury

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