o14s396X 82/1001-008080200/0, Cope © 1982 by the Congres 9 Nearlogical Surgeons Vol 10,8. 11982 Painted nS. Intraventricular Cerebrospinal Fluid Antibiotic Concentrations in Patients with Intraventricular Infections HE, James, M.D., HD, Wilson, M.D., J.D. Connor, M.D., and J W. Walsh, M.D., Ph.D, Division of Neurosurgery (H.E.1.) and Department of Pediatrics LE. J.CC), Univers of Calforia, San Diego, California, and Department of Pedicircs(H.D.W) and Distsion of Neurosurgery (.W-W), Univers of Kentucky Medical Center, Lexingion. Kentucky The antibiotic concentration of the fluid from either lateral ventricle was determined 104 times in 37 patients through direct ventricular puncture, external ventricular drainage (EVD). or cerebrospinal fluid shunt sampling. The patients were month to 12 years old. When the patients were receiving maximal intravenous antibiotic therapy alone. the concentrations for the most part were below 5 ng/ml. whereas patients receiving an antibiotic through direct ventricular puncture. EVD. ‘ora shunt reservoir usually had concentrations over 5 ug/ml. However. wide variations from patient to patient were found with all forms of treatment despite similar dosages. Clustering of the concentration tended to occur in each individual Patient. The authors conclude that, to obtain a high concentration of an antibiotic in the ventricular uid, one should administer it directly into the ventricle, (Neurosurgery 10:30-54, 1982) Key words: Antibiotic concentration, Cerebrospinal fluid shunt sampling, External ventricular drainage, Intravenous antibiotic, Lateral ventricle, Shunt reservoir, Ventricular puncture INTRODUCTION Intraventricular infection may complicate meningitis of in- fancy and childhood (1. 8, 16) and cerebrospinal fluid (CSF) shunt systems (3, 4, 9. 12, 15, 17. I8) in the presence or absence ‘of myelomeningocele. The incidence of intraventricular infec: tion varies, but it may be as high as 31% in patients with CSF shunts (14). The concentration of an antibiotic in the ventric tlar fluid during therapy for an intraventricular infection, with ‘or without a CSF shunt, has received limited attention (1. 22, 25), and previous work centered around the lumbar subarach- noid levels because of easier access for sampling (26). In a preliminary report, we emphasized the variability of intraven- tricular aniibiotic concentrations in patients with external CSF drainage systems or shunts and indicated that, for optimal ‘management of intraventricular and shunt infections, periodic assessment of the antibiotic concentration is indicated (25). ‘The present report demonstrates that, to obsain elevated anti- biotic levels in the ventricular fluid, one must introduce the anubiotie directly into the ventricle, MATERIALS AND METHODS Thiny-seven patents with ages ranging from 1 month to 12 years who had documented inravenieular infections a5 a Consequence of shunt infection (34 patient) or meningitis 3 Paliens) underwent 104 determinations of anbloictvel in {he CSF from either lateral entice. There mere 25 boys and 12 irl, The measurements were made by eirei ventricular Puncture in 9 patients. by aspiration off rom the reservoir San internal CSF shunt device (venticulopertoneal or ven= teicuojugula in 22 patents or by sampling of the Mu fom an external ventricular druinage (EVD} system in 6 patients All patients during the fire 48 hour of their weatment received inuavenousantitotcs lone. In 1S patents the concentration of antibiotic in the ventricular CSP was obtained when the iniraventricler antibiotic treatment was begun. Samples mere Subsequently obtained at varying times ater the fntaventic: lar amination ofthe dug. and the tiie was recorded {range 61096 hour) “Antibiotics wer selected onthe basis of Gram’ sain ntl and were adjusted according tothe uscepibiity of he lated pathogen. When intraventricular anibvoties were starved. they were given in one daily injection for a minimum of 7 day there was no shunt or external CSF drainage system and twice a day for a minimum of 2 weeks if either of these systems was in place. Throughout these periods, the patients were main- tained on intravenous therapy as well. When the EVD system was used, the antibiotic was injected close to the ventricular catheter and the drainage was interrupted for | hour after the injection. If a shunt was in place, the antibiotic was injected ‘with barbotage through the reservoir and the distal end of the shunt was occluded for 5 minutes. The antibiotic dose for the intraventricular injection of meth- icillin, ampicillin, and cephalothin was | to 2 mg/kg/dose. In fone patient, it was increased 10 3.5 mg/kg/dose because of failure to eradicate the infection, The intravenous dose was 200 mg/kg/day for methicillin, oxacillin, ampicillin, and nafeilin: 150 mg/kg/day for cephalothin; 50 mg/kg/day for chloram- phenicol: 1S mg/kg/day for amikacin; 75 mg/kg/day for Bentamicin; and 400 mg/kg/day for carbenicillin. ‘AIL CSF specimens were frozen at ~70°C until assayed, Antibiotic concentrations were determined by the technique of ‘Simon and Yin (20) or of Braude et al, (2), RESULTS. Inrravenous antibiotics and intraventricular concentrations The oxacillin concentration in six patients was determined after 24 to 48 hours of intravenous therapy: the ventricular CSF concentration ranged from 0 to § ug/ml. For three of these patients, the concentration was below the required min- imal inhibitory concentration (MIC) (Fig. 1). Three patients hhad ventricular CSF concentrations of gentamicin ranging from 0 10 1.2 g/ml: therefore, in wo the MIC was surpassed (Fig. 1). Two patients had been born premavurely and acquired ventricultis during early life. These were treated with carben- icillin and amikacin intravenously. and those concentrations are also listed in Figure 1, One patient received nafeillin (1.7 g/ml) and three received cephalothin (0.0, and | ug/ml) Intraventricular antibiotics and concentrations without CSF drainage systems In six patients. the intraventricular methicillin concentration ranged from 0.8 to 75 yg/ml at 15 to 96 hours after theJanuary 1982 i. \ 938 ge ° 8 P 210 ollie Bosh x ‘Corbenicitin 80 4 i os , : ‘os adminstration, Each symbol represent a different patient. except for the carbeicillin, amikacin, and nafilin measurements (see tex) intraventricular injection of the drug (Fig. 2). These values were well above the 0.3-ng/ml MIC, and they remained at or above 5 g/ml for 20 hours after the antibiotic administration in 12 of 16 injections. In one patient, the level of intraventric- ular cephalothin was $ jg or more for 7 to $4 hours after its intraventricular injection, well above the MIC of less than 0.3, vag/ml (Fig. 2) Intraventricular antibiotics and concentrations with CSF drainage sysiems. The administration of antibiotics through the shunt assembly yielded a wide variation in ventricular concentration, Six 10 31 hours after methicillin was injected into the reservoir of the shunt assembly (dose. 1 to 2 mg/kg) in eight patients, the intraventricular concentration ranged from 0:30 10 100 g/ml (Fig. 3). One patient received cephalothin (dose. | to 2 mg/ kg). and his concentration ranged from 00 10 25 jig/ml (Fig 3). Two patients were treated with ampicillin in their shunts (dose, 1 10 2 mg/kg). The first patient maintained levels of 30 to 40 yig/mal for IT to 16 hours after its administration. The second patient's concentration was 0.3 10 3.0 g/ml for 10 to 12 hours after the intrashunt injection. Even the lowest con- centration of 0.3 pg/ml was 20 times the MIC of 0.015 ag of ampicillin per ml of CSF needed for the patient's pathogen (Hemophilus influenzae Type B) One. patient was treated with methicillin injected via the EVD system on to separate occasions. During the first treat ment. the peritoneal catheter was externalized, and the anti biotic was administered through the scalp reservoir (2 mg/kg/ dose). Dusing the second course of treatment with the same system. the dose was increased to 3.5 mg/kg/dose. Despite the increase in dose. the antibiotic levels in the CSF were 1/10 10 1/100 of the concentration achieved with 2 mg/kg/dose. The infection was eradicated despite this discrepancy (Fig. 4). Three patients received cephalothin via their EVD system. No con: centration consistent from patient to patient was found. but the rug levels of each patient tended to cluster within @ limited INTRAVENTRICULAR CSF ANTIBIOTIC CONCENTRATIONS — SI range. One of these patients was converted from inteashunt to EVD therapy. The concentration varied from 3.0 to 5.0 g/ml of CSF after shunt injection, and after EVD injection the values were extremely high, ranging from 10.000 to 100.000 g/ml, This last method oF treatment eradicated the infection, DISCUSSION In this study, there was considerable variability in the intra ventricular CSF antibiotic concentration in patients who un. derwent treatment by the intravenous route alone or by intra- ventricular antibiotic injection when a shunt or EVD system was present. A more uniform and persistently higher level of intraventricular antibiotic was noted when the intraventricular injection was made in the absence of a shunt or EVD system, The penetration of an intravenous antibiotic into the ventric- ular CSF is determined by its passage from the capillaries of the choroid plexus into the ventricle and possibly from the capillaries of the brain into the interstitium and then through, the ependyma into the ventricle. The amibiotic concentration in the ventricular CSF is determined not only by this, but also by its clearance rate through the ventricular system into the siibarachnoid space following the normal circulation of CSF and possibly by the transependymal movement of the CSE Accordingly. inflammation, scarring. and thickening of the choroid plexus and ependymal walls could diminish the trans- fer of antibiotics from the plasma into the ventricle. Likewise. obstruction to CSF flow, such as occurs in bydrocephalic children, yields higher concentrations for longer periods. Itis thus reasonable to presume that the finding of a persistently high concentration in children treated by the intraventricular injection of the antibiotic without a shunt or EVD system can 110 Cota: © " - ‘h 8 . ait | fe $ S te o rn ry 2 ‘ Eas 2 ut o ene? : o6 ms 2 gf —_@—,-__ ey 5 250 & 20) 5 ae onm E os = @ 1 We 228 «0 TIME IN HOURS, Fic, 2. Methicilin and cephalothin ventricular CSF concentrations and sampling time after intraventeicularinjetions in patients without (CSF drainage ssstems. Each group of sigs corresponds to one patient, Cephalothia MIC: =0.3 jig/ml: methicillin MIC: =0.3 pg/ml. except for Case $ (MIC: =30 ug/ml52 JAMES et al. fs. o S Cephalothin 59) & = Case 9 © os] 2 & z 2 = z = 8 12 16 20 2 2 32 36 40 TIME IN HOURS ic, 3, Methicilin and cephalothin ventricular CSF concentrations and sampling time afer icraventeicular injection i patients with CSF ‘hunts Each group of signs corresponds to one patient, Two patients ‘who were given ampicillin are not included (sce tex) be explained by the fact that 34 of the 37 children had hydrocephalus and thus poor circulation of their CSF. Con- versely. it is also reasonable to state that, in the presence of a shunt or an EVD system, the movement of CSF through these raining devices will inerease the clearance of the antibiotic, Which explains the wider variability in intraventricular ant: biotic concentrations in patients with shunts or EVD systems. With intravenous antibiotics alone, the ventricular concentra tion is most likely determined by the accessibility of the ven: tricle through the choroid plextis and the ependymal lining, The magnitude of these histological changes is, of eourse, very difficult to assess in clinical practice and. therefore. is most unpredictable in any given patient. There is a significant difference in the antibiotic levels sampled when the intravenous route alone was used (Fig. 1) vs. when the antibiotic was injected into the ventricle by direct puncture (Fig. 2). through the shunt (Fig. 3). of by EVD (Fig. 4), The ventricular CSF levels over 5.0 jig/ml afe consistently higher in the last three {groups when compared to the first group. Despite the obvious temptation to treat ventriculitis with single daily injections of intraventricular antibiotics without a CSF drainage system, one must be aware of the risk for patients, with hydrocephalus of sudden neurological deterioration and death due to intracranial hypertension when the CSF circula tion is impaired (7. 10), Because of this concern. the only Neurosurgery, Vol. 10.No. 1 patients treated with this method in this study were those children with open fontanelles and sutures who could tolerate the hydrocephalus that was intermittently decompressed at each daily ventricular puncture, Treatment through an EVD. system or through a shunt system obviates this concern. al though it creates problems ofits own. Complications such as. superinfections from the handling or disconnection of EVD. systems (6, 11) and the inability to eradicate an intraventricular infection in the face of a foreign body (8) should be taken into account in deciding the appropriate therapeutic course. ‘One must always keep in mind the possibility of creating a porencephalic cavity by ventricular puncture. Although this, did not occur in this group of children, as determined by ‘computed tomographic scans before and after shunting. it may ‘occur in any patient who undergoes ventricular taps. and has underlying hydrocephalus: the pressure within the ventricular system may create a dissection through the needle tract and thereby an expansion of the ventricle into the substance of the bain parenchyma (porencephaly), It is therefore important to allow for the removal of a significant amount of CSF at the ‘ime of the ventricular puncture, thus minimizing the potential ofa tract of CSF opening into the parenchyma after removal of the needle ‘These findings indicate that periodic antibiotic assays cou pled with a determination of the pathogen’s MIC should be wr ew cea | tac 50 a Case 18 @ - 3 e132 = a Meibcitin z can tal 0 2 Tral2@ 2 of Zs —— — = 49) 2 30r a 3 2 5 ot E z . 5 5 Z ot 0 2 . z 2 Lire nn nr 2 16 20 2 28 3 36 40 TIME IN HOURS Fio. 4 Methiilin and cephalothin ventricular CSF concentrations and sampling time after intraventsicular ijestions in patients with EVD. Each group of signs corresponds ta one patient. eet for CaseJanuary 1982 done to manage ventricular infections optimally. Where assay procedures are not available, a bactericidal titer using the patient's CSF pathogens can provide an estimate of antibiotic adequacy in the ventricular CSF (24). Antibiotic neurotoxicity was not observed in this study. but hhas been documented (23). We believe that this is a potential hhazard using the current methods for treatment of ventricular CSE shunt infections, Patient 3 developed excessive cephalo: thin concentrations with the same dose that earlier had yielded both safe and effective concentrations. Salmon. using another method to determine antibiotic dose by estimating ventricular volume, had one patient who developed a ventricular cepha- lothin concentration of 800 jig/ml (16). Weiss et al. observed. neurotoxicity in dogs due to penicillin G and cephalothin when, the ventricles were perfused with these antibiotics (23), Similar reactions have occurred in humans receiving intravenous and. intrathecal antibioties (5). The manifestations of neurotoxicity include myoclonus, seizures. coma, fever. and CSF pleceytosis (5, 23). These findings ate easily misdiagnosed in an ill infant with @ CSF shunt infection, Varying doses of intraventricular antibioties have been used in the treatment of ventriculits (21), Perrin and McLaurin recommended 3 mg/kg/dose of methicillin through the shunt (13), and Shurtleff et al. recommended 2.5 10 5.0 mg/kg/dose when using methicillin or 0.5 mg/kg/dose when using oxacillin, (19), Lee et al, used daily doses in neonates of 2 mg for ‘gentamicin, 2 t0 5 mg for rifampin, 10 mg for erythromycin, ‘and 5000 U for penicillin (8). Lorber et al. emphasized the nnced for early intraventricular antibiotic therapy in myelomen: ingocele patients with ventriculitis. with primary emphasis on. levels significantly higher than the MIC of the pathogen. ifthe infection is to be cleared (9), ‘The intraventricular antibiotic dose used in this study re- sulted generally, but not invariably, in adequate antibiot concentrations. However. in older children or adults. the 2 mg/kg dose would probably be excessive. Ventricular size did ‘not have a predictable influence on the CSF antibiotic concen: tration, In the two patients treated with ampicillin, both with the same dose, the infant with massive hydrocephalus had concentrations 10 t0 100 times those of the infant with only ‘moderate enlargement of his ventricles. The dose could have bbeen reduced safely in several cases, whereas in one instance the standard dose was insufficient. For these reasons, we rec ‘ommend periodic assay to determine the antibiotic concentra tion in the ventricular fluid, together with determination of the pathogen’s MIC of determination of the CSF bactericidal tte. This should result in improved management of intraventricular infections, Received for publication, July 14, 1981: accepted, September 29, 1981 Reprint requests: H. E James, M.D. Disision of Neurosurgery H. 893, University Hospital. 225 Dickinson Street, San Diego, California s21as REFERENCES |. Blevins J, Ericksson CD, Ruiz-Palacios G Intraventricular and systemic gentamyein therapy for ventrieulis in children. in Pro ceedings ofthe Interscience Conference on Antilerobial Agents dnd Chemotherapy. Chicago, 1976, Braude Al. Bannister J. Wright N: Use ofthe gradient plate for routine clinical determinations of bacterial sensitivities to antbiot tes, Amtibiot Annu {133-1140 (1988-1985), 3, Drapkin AJ. Michel J. Sucks T, Heller AJ: Postoperative ven teoults in infants. Acta Neurochie (Wien) 3289-100, 1975 4, Evetew ED. Eickhotl TC, Simon RH: Cerebrospinal Nid shunt infections with anaerobic diptheroids (Propionibacterium species} I Neurosurg 4480-584, 197, INTRAVENTRICULAR CSF ANTIBIOTIC CONCENTRATIONS 53 5. Fossieck B Jr. Parker RH: Neurotoxicity during intravenous infiu- sion of penicilin: A review. J Clin Pharmacol 14:S04-512. 1974 6, James HE. Langtit TW, Kumar VS, Ghostine SY: Treatment of itracraniat hypertension: Analysis of 105 consecutive, continuous recordings of intracranial presse, Acta Neurochir (Wien) 36:189 200, 1977, 7, James HE, Schut L: Pitfalls in the diagnosis of arrested hydro- ‘cephalus, Acta Neurochir Wien) 4313-11, 1978 8, Lee EL. Robinson MJ. Thong ML. Putbucheary SD, Ong TH, Ne KK: Intraventricular chemotherapy in nesatal meningitis, J Pe diate 91:991-995. 1977, 9, Lotber J. Kathan SC. MahgrefteB: Treatment of venriculitis with gentamicin and cloxacilin in inanxs born with spina bifida, Arch Dis Child 45:178-188, 1970, 10, MeLaurin RL: Infeced cerebrospinal fluid shunts, Surg Neurot 191-198. 1973, 11, Mori K. Raimondi Al: An analysis external ventricular drainage as. treatment for infected shuts. Childs Brain 1:243-250, 1973 12, Nalsen FE, Becker DP: Control of hydrocephalus by valve-regu- lated shunt: Infections and their prevention. Clin Neurosurg 14 256-273. 196, 13, Perrin JCS, MeLaurin RL: Infected venti method of teaiment 1 Neurosurg 2721-26 14, Robinson JS, Raimond, AJ- Complications of ventriculo-perito- neal shunting procedures for congenial and secondary hydroceph- lus in childhood, Presented at the 42nd Annual Mesting of the American Assocation of Neurological Surgeons, St Louis. Mise ui, April 25, 1974 15, Salmon JH Adult hydrocephalus: Evaluation of shunt therapy in i patients. J Neurosurg 37:423-428, 1972 16, Salmon JH: Venticulitis complicating mes 124335-40, 1972, 17, Sehoenbaum SC. Gardner P, Shillito J: Infections of cerebrospinal fluid shunts: Epidemiology. clinical manifestations. and therapy. 3 Infect Dis 131-543-552, 1975, 18, Shutletf DB. Christie D. Foltz EL: Ventriculoauriculostomy’as- sociated infection: A [2-year study.) Neurosurg 35:686-694, 1971 19, Shurtleif DB. Folt: EL. Weeks RD, Loeser I: Therapy of Staphy Tococcus epidermidis: Infections associated with cerebrospinal uid shunts. Pediatrics 5335-62, 1974 20, Simon HI. Yin El: Mirobioasay of antimicrobial agents. Appl Microbiol 19:573-379, 1970, 21, Simpson PB, Jr, Warren GC. Smith RR: Intraventsicular cepha- Joutin in childhood ventscubis, Surg Neurol 4279-282, 1973, 22 Wald SL, MeLaurin RL: Cerebrospinal Mvid antibiotic levels during treatment of shunt infections, 3 Newtosurg 8241-46, 1980. 23, Weiss MH, Kurze T. Nulsen FE: Antibiotic neurotoxicity” Labo: ratory and clinical study. J Neurosurg 41:480-489, 1974 24, Whang CH. Cauthen IC, Garcia-Bengochea F: Successful eat. rent of venriclitis by continuous intraventricular tigation with {gentamicin solutions, Surg Neurol 2:91-94, (974 25, Wilton HD, Bean JR, James HE, Pendley MM: Cerebrospinal fluid antibiotic concentrations in ventricular shunt infections (Childs Brain 474-82, 1978 26. Wilson HD. Haltain KC: Ampicilin in Haemophilus influenzae meningitis: Clinicopharmacologic evaluation of intramuscular vs intravenous administration. Ams J Dis Child 129-208-215, 1975, itis, Am J Dis Child COMMENT This is @ valuable contribution to our knowledge of the pharmacodynamics of amtibiotis in the CSF. It is not surpris- ing, however, that there was considerable variation in the antibiotic concentrations with intravenous therapy alone be- ‘cause this is largely dependent on the intensity of inflammation present. It might have been of interest to correlate the signs of Inflammation in the CSF with its amtibiotie concentration It is more surprising that the authors found such marked variations of concentration when the antibiotic was adminis- tered intraventricularly. This bas not been our experience. particularly in patients without CSF drainage systems. There may be an explanation in the doses that were used. Although ‘arly in our period of interest in shunt infections, we used the54 JAMES et al body weight as a basis for dosage, we soon concluded that this ‘was not a logical basis because an enlarged ventricular system, in a 3-kg newborn might be the same size as. of even larger than, the ventricles of a 25-kg child. It would be interesting to know whether there was relationship in the patients of James eval The authors report that in some patients the antibiotics were administered «wice daily. Our experience indicates that this is not necessary: We have never seen inadequate trough levels, after 24 hours when adequate doses were used. Neurosurgery, Vol. 10, No. 1 The most valuable part of this paper. in my judgment. is the authors’ plea for monitoring of CSF antibiotic levels during treatment. This is particularly true if one is attempting sterilize an infected shunt in situ. Recently. we have some t© rely more heavily on the use of CSF bactericidal tters rather than antibiotic concentrations. This is particularly useful when multiple synergistic antibiotics ate being used, Robert L. MeLaurin, M.D. Cincinnati, Ohio