Bone Marrow Transplantation (2003) 31, 65–67 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00 www.nature.com/bmt Case report Successful treatment of meningoencephalitis caused by methicillin-resistant Staphylococcus aureus with intrathecal vancomycin in an allogeneic peripheral blood stem cell transplant recipient

H Matsubara1, A Makimoto1,2, T Higa1, H Kawamoto1, Y Kanda2, M Kami2, R Tanosaki2, S Mineishi2, M Ohira1 and Y Takaue2

1Divisions of Pediatric Oncology, National Cancer Center Hospital, Tokyo, Japan; and 2Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan

Summary: Case report

Methicillin-resistant Staphylococcus aureus (MRSA) A 4-year-old boy was hospitalized in August 2000 because is a common infectious pathogen during stem cell trans- of newly diagnosed acute myeloid leukemia (AML). plantation. We report a case of meningoencephalitis He had previously had bilateral retinoblastoma, which with multiple abscess formation caused by MRSA, which developed at the age of 13 months. For this, he received occurred in a 4-year-old boy soon after allogeneic peri- external beam radiotherapy (40 Gy)to both eyes, followed pheral blood stem cell transplantation. We successfully by systemic chemotherapy. The interval between the cured the infection with a combination of intravenous and onset of AML and the end of his last chemotherapy was intrathecal vancomycin. 2 years. He achieved complete remission after one course Bone MarrowTransplantation (2003) 31, 65–67. of induction chemotherapy, and continued to receive doi:10.1038/sj.bmt.1703799 intensification chemotherapy until February 2001, when Keywords: methicillin-resistant Staphylococcus aureus; he underwent allogeneic PBSCT from an HLA one- meningoencephalitis; sepsis; vancomycin; peripheral blood locus-mismatched uncle. The conditioning regimen con- allogeneic stem cell transplantation sisted of busulfan (140 mg/m2  4)and cyclophosphamide (60 mg/kg  2), followed by the infusion of unmanipulated allogeneic PBSC that contained 5.7  106/kg CD34+ cells. Infectious complications caused by methicillin-resistant Cyclosporin A (3 mg/kg)and a short course of methotrex- Staphylococcus aureus (MRSA)are a serious problem in ate (10 mg/m2 on day 1, and 7 mg/m2 on days 3 and 6)were patients who receive intensive chemotherapy with or with- given as graft-versus-host disease prophylaxis. Although out stem cell transplantation. Although vancomycin is the the patient had a history of MRSA infection 6 months prior most promising agent for the management of such infec- to transplantation, follow-up cultures for MRSA were tions, it is often difficult to achieve an effective therapeutic all negative. Therefore, he did not receive prophylactic level in cerebrospinal fluid (CSF)by intravenous (i.v.)infu- antibacterial treatment for MRSA up-front. Only intra- sion because of poor penetration of vancomycin through venous acyclovir and oral amphotericin B were used. the blood–brain barrier. Direct instillation of vancomycin On day 6 of the transplant, he developed chills and a into the CSF is a possible alternative to achieve adequate high temperature of up to 401C. Empiric antibiotic therapy CSF concentrations and eventual success in controlling this with i.v. piperacillin 100 mg/kg/day divided into three infection. Several investigators have reported the successful doses and i.v. aztreonam 100 mg/kg/day divided into use of intraventricular vancomycin to shunt-related ven- three doses was started. The next day, these were replaced triculitis or meningitis mainly caused by coagulase-negative with a combination of i.v. panipenem/betamipron and 1,2 Staphylococci. However, there has been no report on the i.v. vancomycin (VCM), based on the isolation of Gram- use of this procedure with MRSA meningoencephalitis in positive cocci from the blood and stool. These strains were an immunosuppressed patient. We report a 4-year-old boy later proven to be MRSA. Despite neutrophil engraftment who underwent allogeneic peripheral blood stem cell (40.5  109/l)on post-transplant day 12, high fever transplantation (PBSCT). The post-transplant course was continued and he gradually became drowsy and agitated. complicated by MRSA meningoencephalitis, which was Computed tomography (CT)scan of the brain did not successfully treated with a protracted course of intrathecal show any signs of inflammatory disease on day 12, while vancomycin. lumbar puncture performed on the same day revealed that the CSF contained 454 cells/mm3 consisting of 84% Correspondence: Dr A Makimoto, Division of Pediatric Oncology, mononuclear cells and 16% neutrophils. The CSF showed National Cancer Center Hospital, 1-1 Tsukiji 5-Chome, Chuo-ku, Tokyo 104-0045, Japan protein 77 mg/dl, glucose 69 mg/dl and LDH 145 IU/l, and Received 15 March 2002; accepted 18 September 2002 CSF culture was positive for MRSA, which had the same MRSA meningoencephalitis in Allo-PBSCT recipient H Matsubara et al 66 drug-sensitivity pattern as that of the strain isolated from Discussion the blood. A magnetic resonance imaging (MRI)scan of the brain taken on day 17 revealed multiple small nodules To the best of our knowledge, there have been no previous in the white matter of the brain, and a diagnosis of reports of successfully treated MRSA meningitis or meningoencephalitis with abscess formation was con- encephalitis developing after stem cell transplantation. In firmed. The minimal inhibitory concentrations (MIC)of our case, the prompt use of i.v. VCM failed to control the VCM and arbekacin (ABK)for the MRSA strains iso- MRSA infection and, consequently, brain abscesses devel- lated were 2 and 3.13 mg/ml, respectively. From day 18, oped. Based on the data reported by Redfield et al3 i.v. after obtaining consent from his parents, i.v. ABK 100 VCM may not achieve adequate CSF levels to treat central mg/kg/day and intrathecal (i.t.)5 mg VCM were started. nervous system (CNS)infection, especially when there is no The next day, the CSF concentrations of VCM and ABK meningitis. Therefore, i.t. VCM was given in an effort to were 4.7 and 1.1 mg/ml, respectively. In an attempt to raise maintain an adequate therapeutic level of VCM in the CSF. the CSF level of ABK to above the MIC, we gave Several investigators have conducted pharmacokinetic three doses of i.t. ABK 5 mg while i.t. VCM was with- studies after the i.t. VCM.1–4 Bayston et al1 successfully held for the following 3 days. Although his conscious- treated 18 of 33 patients with ventriculitis who failed to ness level and general condition improved, the high fever respond to i.v. VCM with intraventricular VCM. Based on and leukocytosis in the CSF continued. Therefore, on day their data, they recommended a dose of 10–20 mg of 22 we restarted i.t. VCM and administered ABK intra- intraventricular VCM every 24 h in adults. Reesor et al2 venously. CSF culture for MRSA became negative after measured CSF levels once or twice daily in patients day 17. MRI showed multiple ring-enhancing small receiving intraventricular VCM therapy. They recom- lesions in the whole brain on FLAIR (Figure 1)when mended initial treatment with 8–10 mg to achieve a peak evaluated on day 25. His mental status had completely CSF concentration of 30–50 mg/ml. Based on these data, we normalized by day 27. CSF leukocytosis resolved around decided to use a dose of 5 mg i.t. VCM. During the day 40 and his fever lessened. The multiple small nodules biweekly i.t. injections, trough levels of VCM in the CSF had disappeared on MRI examination on day 40. Levels of ranged between 2.9 and 9.8 mg/ml. Since the MIC of VCM VCM in the CSF were carefully monitored (2.9–9.9 mg/ml) for the MRSA strains isolated in this patient was 2.0 mg/ml, to maintain a therapeutic level. Intrathecal VCM was given a dose of 5 mg i.t. VCM was considered to be adequate to biweekly until day 43 to a total of 10 doses, with a manage the CNS infection. cumulative dose of 50 mg. VCM was then administered i.v. Although several reports have indicated possible side until day 63. effects associated with i.t. VCM, including changes in the No adverse events directly related to the i.t. VCM or mental status5 and severe headache,6 our patient had no ABK were noted. MRSA infection did not recur up to day evidence of neurological problems secondary to VCM. 185, when he died of bronchiolitis obliterans secondary to Since the severity of the side effects appears to be related to allogeneic PBSCT, without evidence of GVHD. Autopsy the peak VCM level in the CSF,5,7,8 we suggest that careful was not performed. monitoring of the CSF VCM level could prevent excessive adverse events. We noted failure of response to i.t. ABK with MRSA meningoencephalitis. A possible explanation would be the fact that the antibacterial activity of aminoglycosides is pH- dependent, with increased activity at higher pH, and it has been shown that in cases of meningitis the CSF becomes acidic.9 The emergence of glycopeptide-resistant coagulase-nega- tive staphylococci in patients treated for long periods with VCM and teicoplanin has been increasingly documented.10 In vitro, linezolid, quinupristin-dalfopristin, moxifloxacin and trovafloxacin, which are new antibiotics, reveal good activity against MRSA and methicillin-resistant and teicoplanin- intermediate coagulase negative staphylococci.11 In parti- cular, linezolid has an acceptable safety profile for both i.v. and oral administration and has proven effective in the treatment of infections caused by methicillin-resistant staphylococcal species in critically ill patients.12 Intravenous linezolid also appears to be a safe and effective therapy for vancomycin-resistant enterococcus meningitis13–15 and line- zolid achieved sufficient CSF concentrations to bring about clinical and bacteriological cure.16,17 Based on our experience and the data reported to date, Figure 1 Magnetic resonance imaging on FLAIR. Multiple ring- i.t. VCM might be a safe and effective second-line enhancing small lesions in the whole brain on FLAIR when evaluated on treatment for Staphylococcal CNS infections in immuno- day 25. compromised patients. For rational use of i.t. VCM, with

Bone Marrow Transplantation MRSA meningoencephalitis in Allo-PBSCT recipient H Matsubara et al 67 maximum efficacy and minimum toxicity, we recommend 7 Congeni BL, Tan J, Salstrom SJ, et al. Kinetics of vancomycin that CSF drug levels should be closely monitored and the (V)after intraventricular and intravenous administration dose should be adjusted to reasonably exceed the MIC of (abstract). Pediatr Res 1979; 13: 459. the target bacterial strain. 8 Pfausler B, Haring HP, Kampfl A et al. Cerebrospinal fluid (CSF)pharmacokinetics of intraventricular vancomycin in patients with Staphylococcal ventriculitis associated with external CSF drainage. Clin Infect Dis 1997; 25: 733–735. Acknowledgements 9 Biavasco F, Vignaroli C, Varaldo PE. Glycopeptide resistance in coagulase-negative staphylococci. Eur J Clin Microbiol The authors thank Michihiro Shino and Yoshiko Kawamoto, Infect Dis 2000; 19: 403–417. Department of Pharmacy, for analyzing the pharmacokinetics of 10 Guerra-Romero L, Tauber MG, Fournier MA et al. Lactate VCM. This research was supported by a Grant-in-Aid for and glucose concentrations in brain interstitial fluid, cere- Scientific Research from the Ministry of Health, Labor and brospinal fluid, and serum during experimental pneumococcal Welfare. meningitis. J Infect Dis 1992; 166: 546–550. 11 Betriu C, Redondo M, Boloix A et al. Comparative activity of linezolid and other new agents against methicillin-resistant References Staphylococcus aureus and teicoplanin-intermediate coagulase- negative Staphylococci. J Antimicrob Chemother 2001; 48: 911– 1 Bayston R, Hart CA, Barnicoat M. Intraventricular vanco- 913. mycin in the treatment of ventriculitis associated with 12 Chein JW, Kucia ML, Salata RA. Use of linezolid, an cerebrospinal fluid shunting and drainage. J Neurol Neurosurg oxazolidinone, in the treatment of multidrug-resistant gram- Psychiatr 1987; 50: 1419–1423. positive bacterial infections. Clin Infect Dis 2000; 30: 146–151. 2 Reesor C, Chow AW, Kureishi A et al. Kinetics of 13 Zeane C, Kubin CJ, Della-Latta P et al. Vancomycin-resistant intraventricular vancomycin in infections of cerebrospinal Enterococcus faecium meningitis successfully managed with fluid shunts. J Infect Dis 1988; 158: 1142–1143. linezolid: case report and review of the literature. Clin Infect 3 Redfield DC, Underman A, Normal D et al. Cerebrospinal Dis 2001; 33: 477–482. fluid penetration of vancomycin in bacterial meningitis. In: 14 Steinmetz MP, Vogelbaum MA, De Georgia MA et al. Nelson JD, Grassi C (eds). Current Chemotherapy and Successful treatment of vancomycin-resistant enterococcus Infectious Disease. Proceedings of the International Congress meniongitis with linezolid: case report and review of the of Chemotherapy and the 19th Interscience Conference on literature. Crit Care Med 2001; 29: 2383–2385. Antimicrobial Agents and Chemotherapy, Vol 1. Am Soc 15 Hachem R, Afif C, Gokaslan Z et al. Successful treatment of Microbiol: Washington, DC, 1980, pp 638–640. vancomycin-resistant enterococcus meningitis with linezolid. 4 Luer MS, Hatton J. Vancomycin administration into the Eur J Clin Microbiol Infect Dis 2001; 20: 432–434. cerebrospinal fluid: a review. Ann Pharmacother 1993; 27: 912– 16 Shaikh ZH, Peloquin CA, Ericsson CD. Successful treatment 921. of vancomycin-resistant Enterococcus faecium meningitis with 5 Golledge CL, McKenzie T. Monitoring vancomycin concen- linezolid: case report and literature review. Scand J Infect Dis trations in CSF after intraventricular administration. J 2001; 33: 375–379. Antimicrob Chemother 1988; 21: 262–263. 17 Villani P, Regazzi MB, Marubbi F et al. Cerebrospinal fluid 6 Sutherland GE, Palitang EG, Marr JJ et al. Sterilization of linezolid concentrations in postneurosurgical central nervous Ommaya reservoir by instillation of vancomycin. Am J Med system infections. Antimicrob Agents Chemother 2002; 46: 1981; 71: 1068–1070. 936–937.

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