Treatment of Accidental High Dose Intraventricular Mezlocillin Application by Cerebrospinal ﬂuid Exchange

J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.3.379 on 1 March 1998. Downloaded from J Neurol Neurosurg Psychiatry 1998;64:379–381 379

SHORT REPORT

Treatment of accidental high dose intraventricular mezlocillin application by cerebrospinal ﬂuid exchange

Rudolf A Kristof, Hans Clusmann, Walter Koehler, Klaus B Fink, Johannes Schramm

Abstract drocephalus due to aqueductal stenosis. Thirty An accidental high dose of intraventricu- five years previously she had been operated on lar mezlocillin was given during antibiotic and received local radiation because of a left treatment for pneumonia in a patient parietooccipital glioma, confirmed later to be admitted because of severe traumatic an infantile desmoplastic ganglioglioma. There brain injury and occlusive hydrocephalus. was no epilepsy in her medical history. Because of serial epileptic seizures not At admission cranial CT showed severe responsive to antiepileptic drug treat- brain injury, hydrocephalic enlargement of the ment, CSF exchange was performed. The lateral and third ventricles and a left parieto- CSF was drained through a ventricular occipital postoperative brain defect, not com- catheter, while mock CSF was infused into municating with the lateral ventricles (fig 1). the lumbar subarachnoid space. The pa- Ventriculostomy was immediately performed. tient soon recovered to her clinical status During the next three weeks her clinical condi- previous to intraventricular mezlocillin tion improved slightly. Control cranial CT application. Side eVects of CSF exchange confirmed the contusions and showed normali- were not seen. Under continued antiepi- sation of the ventricle width. Electroencepha- leptic medication no more seizures oc- lography disclosed severe general dysrhythmia curred. It is concluded that high doses of with predominant delta waves. A depression of intraventricular mezlocillin have procon- the right hemisphere was noted and the vulsive eVects. In this patient CSF ex- left hemisphere records showed some alpha change was a suitable means of preventing activity. putatively permanent impairment of At that time mezlocillin treatment was begun brain function caused by serial epileptic because of pneumonia. One night accidentally http://jnnp.bmj.com/ seizures due to intraventricular mezlocil- 4 g mezlocillin dissolved in 50 ml double lin application. distilled water were connected to the ventricu- Department of lostomy catheter, partially delivered into the Neurosurgery, (J Neurol Neurosurg Psychiatry 1998;64:379–381) lateral ventricle, and partially collected directly University of Bonn, in the CSF collecting bag. As soon as the anti- Sigmund-Freud-Strasse Keywords: intrathecal; mezlocillin; seizures; ventricular 25, D-53105 Bonn, drainage complication biotic application terminated, the fault was Germany recognised and during the next nine hours

R A Kristof CSF drainage was accelerated by lowering the on September 24, 2021 by guest. Protected copyright. H Clusmann Therapeutic intravenous and intrathecal peni- drainage height of the ventriculostomy device. W Koehler The CSF and serum mezlocillin concentra- J Schramm cillin application may cause epileptic seizures as a neurotoxic side eVect,1–3 whereas therapeu- tions were determined as described 11 Institute of tic intravenous mezlocillin application does elsewhere. Because of the occurrence of a Pharmacology and not.45 Penicillin applied experimentally to the series of generalised seizures six hours after the Toxicology, University cortex regularly leads to the development of an start of intraventricular mezlocillin application, of Bonn, Reuterstrasse 6–8 which became resistant to phenytoin treat- 2b, D-53113 Bonn, epileptic focus. To our knowledge there is a Germany single case report of therapeutic intrathecal ment, the patient was put on artiﬁcal ventila- K B Fink mezlocillin application, neurotoxic eVects not tion and clonazepam was administered. A CSF being mentioned.910 We therefore report this exchange was initiated 12 hours after the start Correspondence to: case of an accidental high dose intraventricular of intraventricular mezlocillin application, to Dr Hans Clusmann, Neurochirurgische Klinik, mezlocillin application and the management of avoid further spread of mezlocillin from the Sigmund-Freud-Strasse 25, its neurotoxic eVects. ventricles into the subarachnoid space. The D-53105 Bonn, Germany. balanced infusion of mock CSF (composition Telephone 0049 228 287 NaCl 9 g/l, glucose 1 g/l, human albumin 0.15 6518; fax: 0049 228 287 4758. Case report g/l) was started through a newly inserted lum- A 43 year old woman was admitted due to a bar drain and native CSF was drained by pas- Received 25 October 1996 severe traumatic head injury with an initial sive ﬂow out via the ventriculostomy. The CSF and in revised form 11 July 1997 Glasgow coma score of 7, and a previously replacement was stopped 16 hours later, when Accepted 14 July 1997 undiagnosed oligosymptomatic occlusive hy- a turnover of 450 ml was achieved. During that J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.3.379 on 1 March 1998. Downloaded from 380 Kristof, Clusmann, Koehler, et al

ing that time mezlocillin was never detectable in the serum. A cellular meningeal reaction due to mezlocillin infusion did not occur as assessed by daily determinations of CSF pleocytosis and global protein content. Meanwhile the patient recovered to the clinical state before intraventricular mezlocillin application. One week after the event, the EEG showed less sharp components. During the next eight weeks there was little improvement of the patient’s clinical condition: She became contactable and was able to speak a few words, but still needed full time nursing. With continued antiepileptic medication she remained seizure free. The EEG continously showed dysrhythmia, but sharp components disappeared. The insertion of a CSF shunting system became necessary. Eight months later the patient had made a good recovery, being able to take care of herself at home.

Discussion When intravenously applied, penicillin and its semisynthetic acylamino derivate mezlocillin pass the blood-brain barrier, especially when the meninges are inﬂamed.12–15 Penicillin can Figure 1 Cranial CT on emergency admission into the occasionally induce epileptic seizures when hospital after traumatic head injury. Note the left frontotemporoparietal traumatic subarachnoid given in therapeutic doses intravenously or haemorrhage, hydrocephalic enlargement of the lateral and intrathecally.1–3 When applied directly into or the third ventricles due to aqueductal stenosis (no on the cortex, it regularly causes seizures, often enlargement of the fourth ventricle), and the pre-existing left being used as an experimental epileptogenic parieto-occipital brain defect after resection and radiation of 6–8 a glioma 35 years previously. agent. Mezlocillin seems to be less epileptogenic when given intravenously in therapeu- time the intraventricular mezlocillin concentra- tic doses, seizures not having been described as tion had decreased from 1500 mg/l to 483 adverse eVects in large studies.45 To our mg/l. Seizures had ceased under continued knowledge, there is a single reported case of phenytoin medication. Thereafter the EEG was therapeutic intraventricular (and simultaneus dysrhythmic with predominance of delta and intravenous) application of mezlocillin in an theta waves, but exhibited some multifocal infant with therapy resistant ventriculitis.910 sharp slow wave complexes; a few irregular The average intraventricular concentration of spikes were superimposed as well. By further mezlocillin achieved in the mentioned case was passive drainage of 350 ml CSF through the 60 mg/l (range 52–90 mg/l). No worsening of http://jnnp.bmj.com/ ventriculostomy, 108 hours after the beginning the pre-existing epilepsy was noted. The peak of the intraventricular infusion of mezlocillin, CSF concentration of mezlocillin in the case its concentration was lowered to 36 mg/l. Dur- reported here exceeded the value mentioned above by more than 25-fold. 3 Being aware of the deleterious course in a 2 case of intraventricular cefotiam application 3 10 (unpublished data) and because of the occur-

rence of seizures resistant to antiepileptic on September 24, 2021 by guest. Protected copyright. medication, CSF was exchanged via lumbar 3 2 infusion and ventricular drainage to avoid the advance of mezlocillin from the ventricles to 2 10 the subarachnoid space in the period of extremely high mezlocillin concentration, pu- 3 tatively minimising its epileptogenicity. It is 2 known that intrathecally applied substances 16–18 1 hardly pass into the ventricular lumen, 10 Mezlocillin in CSF (mg/l) whereas substances injected into a lateral ven- III III tricle lead to high concentrations at the 3 ependymal and cortical surfaces in contact 2 CSF exchange with CSF.17 19 When considering the incom- 0 10 plete obstructive hydrocephalus being also 0 10 20 30 40 50 60 70 80 90 100 110 present in this case, a penetration of mock CSF Time after intraventricular mezlocillin (h) to the ventricles after lumbar infusion seems Figure 2 Half logarithmic plot of intraventricular mezlocillin concentration over 108 rather unlikely. hours after the beginning of accidental mezlocillin application. The elimination follows a A half logarithmic plot of the mezlocillin ﬁrst degree evasion kinetic, implying a decay proportional to the actual drug concentration. concentration in CSF suggests that mezlocillin Periods of passive CSF drainage (I,III) and active CSF exchange (II) are indicated. The regression lines of the mezlocillin concentration show a steeper decay during active CSF clearance was almost twice as fast during active exchange (t1/2 = 10.7 hours) than passive drainage (t1/2 = 18.7 hours). CSF exchange than during the following J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.64.3.379 on 1 March 1998. Downloaded from Treatment of accidental high dose intraventricular mezlocillin 381

period of passive drainage (fig 2). This ment of Epileptology, Universität Bonn, andDCCedzich, Department of Neurosurgery, Südklinikum Nürnberg, for help- assumption is supported by the higher rate of ful discussions of this case. CSF drainage through the ventriculostomy catheter during lumbar infusion of mock CSF 1 Andriole VT, Ryan JL. An approach to formulary considera- compared with the period of solely passive tion of antimicrobial agents: the penicillins. Hospital drainage. This eVect may be due to a block of Formulary 1981;8:816–21. flow out of ventricular CSF towards the 2 Johnson HC, Walker AE. Intraventricular penicillin. A note of warning. JAMA 1945;127:217–9. subarachnoid space, as supported by the lack of 3 Simon C. Penicilline. In: Simon C, Stille W, eds. Antibiotika- Therapie in Klinik und Praxis. Stuttgart: 1993:35–70. the antibiotic in the serum. Thus dilution and 4 Konopka CA, Arcieri G, Schacht P. Clinical experience with drainage through the ventriculostomy catheter mezlocillin in Europe. J Antimicrob Chemother 1982; seem to be the only way of mezlocillin elimina- 9(suppl A):267–72. 5 Parry MF, Neu HC. The safety and tolerance of mezlocillin. tion, which could be enforced by intrathecal J Antimicrob Chemother 1982;9(suppl A):273–80. mock CSF infusion. 6 Gloor P, Quesney LF, Zumstein H. Pathophysiology of gen- eralized penicillin epilepsy in the cat. The role of cortical To our knowledge there is one previous and subcortical structures. II. Topical application of report of a massive intrathecal methotrexate penicillin to the cerebral cortex and subcortical structures. Electroencephalogr Clin Neurophysiol 1977;43:79–94. overdose treated successfully by CSF replace- 7 Grøndahl TØ, Langmoen IA. Epileptogenic eVect of ment via ventriculolumbar perfusion with nor- antibiotic drugs. J Neurosurg 1993;78:938–43. 20 8 Kataoka N. Regional diVerences in seizure threshold follow- mal saline. Due to the lumbar intrathecal ing systemic and topical administration of penicillin in cats. location of drug overdose in the case cited Hokkaido Igaku Zasshi 1994;69:84–94. 9 Grüneberg RN, Emmerson AM, Ridgway GL. Rifampicin- above, direction of CSF replacement was containing antibiotic combinations in the treatment of dif- opposite to the direction which had to be used ficult infections. J Antimicrob Chemother 1984;13(suppl C):49–55. in the case reported here. 10 Kelsey MC, Emmerson AM, Drabu Y. Flavobacterium It is beyond question that the epileptic meningosepticum ventriculitis: in vivo and in vitro results with the combinations rifampicin-erythromycin and seizures were caused by the high intraventricu- mezlocillin-cefoxitin. Eur J Clin Microbiol 1982;1:138–43. lar mezlocillin concentrations. It remains a 11 Hildebrandt R, Gundert-Remy U. Improved procedure for the determination of the ureidopenicillins azlocillin and matter of discussion to what extent the severe mezlocillin in plasma by high-performance liquid chroma- traumatic brain injury, the previous operation tography. J Chromatogr 1982;228:409–12. 12 Cadeo GP, Barni C, Delaini C, et al. Mezlocillina nel tratta- and radiation of a glioma, and the occlusive mento delle meningiti acute purulente. Giornale Italiano di hydrocephalus facilitated the occurrence of Chemioterapia 1985;32:303–5. 13 Chen MN, Yoshida D, Imaya H, et al. A study on seizures. This is supported by the EEG before penetration of mezlocillin into the cerebrospinal fluid. Jap J the intraventricular mezlocillin application, Antibiot 1986;34–5:1234–6. 14 Friedrich H, Haensel-Friedrich G. Penetration of antibiot- already showing a focus over the right hemi- ics into the cerebrospinal fluid (CSF). Acta Neurochir sphere. The further alteration of the EEG after (Wien) 1980;52:136. 15 Henker J, Scherber A. Theoretische Überlegungen zur drug application reversed without normalisa- Chemotherapie der Meningitis purulenta im Kindesalter. tion, some time after mezlocillin elimination. II. Spezielle Pharmakokinetik der bei der Meningitis purulenta gebräuchlichsten Chemotherapeutika. Kinderärztliche Further epileptic events were not seen under Praxis 1982;6:288–92. continued antiepileptic medication with 16 Rieselbach RE, Di Chiro G, Freireich EJ, et al. Subarach- noid distribution of drugs after lumbar injection. N Engl J phenytoin. Med 1962;267:1273–8. Because of the patient’s pre-existing severe 17 Shapiro WR, Young DF, Mehta BM. Methotrexate: distribution in CSF after iv, ventricular and lumbar brain damage the possibility of eventual injections. N Engl J Med 1975;293:161–6. additional damage due to mezlocillin detect- 18 Yen J, Reis FL, Kimelberg HK, Bourke RS. Direct adminis-

tration of methotrexate into the CNS of primates. Part 2. http://jnnp.bmj.com/ able by CT cannot be assessed. However, it Distribution of 3H methotrexate after intrathecal lumbar seems unlikely, because after mezlocillin appli- injection. J Neurosurg 1978;48:895–902. 19 Kimelberg HK, Kung D, Watson RE, et al. Direct adminis- cation a rise in CSF pleocytosis or global pro- tration of methotrexate into the central nervous system of tein content was not registered. primates. Part 1: distribution and degradation of methotrexate in nervous and systemic tissue after intraventricular injection. J Neurosurg 1978;48:883–94. We thank the Bioscentia Laboratories Ingelheim for the 20 Spiegel RJ, Cooper PR, Blum RH, et al. Treatment of mas- determination of mezlocillin concentrations in the CSF and sive intrathecal methotrexate overdose by ventriculolumbar serum. We also thank Dr A Hufnagel and Dr J Bauer, Depart- perfusion. N Engl J Med 1984;311:386–8. on September 24, 2021 by guest. Protected copyright.