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Successful Treatment of Vancomycin-Resistant Enterococcal Ventriculitis in a Pediatric Patient With Linezolid

October 1, 2008

By Maranich, Ashley M Rajnik, Michael

ABSTRACT Although vancomycin-resistant Enterococcus infection of the central nervous system is not common, this organism is becoming an increasing problem in nosocomial infections. We report a 17- month-old male infant with an externalized ventricular peritoneal shunt secondary to infection who subsequently developed a vancomycin- resistant Enterococcus faecium ventriculitis. This infection was successfully treated with a 28-day course of linezolid while monitoring linezolid drug levels in both the cerebral spinal fluid and serum. This case supports the use of linezolid in treating such resistant infections. However, our drug level results suggest that further investigation is needed to determine the optimal dosing of linezolid in treatment of central nervous system infection in pediatric patients. INTRODUCTION

Enterococcal central nervous system (CNS) infections are not common. However, the emergence of vancomycin-resistant Enterococcus species (VRE) has made treatment of these infections challenging. As the spread of VRE species becomes an increasing problem in the hospital setting, it is important that we continue to investigate potential treatments for meningitis caused by this pathogen.

We describe a case of VRE ventriculitis in a hospitalized 17- month-old male with a ventriculoperitoneal shunt (VPS) successfully treated with intravenous (IV) linezolid. Additionally, therapeutic drug monitoring of the serum and cerebral spinal fluid (CSF) was conducted to further elucidate CSF penetration of linezolid in a pediatric patient.

CASE REPORT

Our patient is a 17-month-old male with a history of VPS placement soon after birth secondary to congenital hydrocephalus. Three months following a shunt infection with a coagulase-negative Staphylococcus species and subsequent revision, he presented to the pediatric clinic with fever and emesis. Initial CSF sampling from the shunt was reassuring without pleocytosis, but the patient was empirically started on vancomycin for potential shunt infection. The CSF culture grew a methicillin-sensitive Staphylococcus aureus and he was switched to nafcillin resulting in quick CSF sterilization. In addition, his shunt was externalized on hospital day (HD) 3 with subsequent placement of an external ventricular drain on HD 9.

The patient showed clinical deterioration on HD 14 with antibiotics then changed to vancomycin and meropenem. A new CSF culture grew both Klebsiella oxytoca and a nonmeningitidis Neisseria species. These bacteria were treated with ceftriaxone for 21 days with successful CSF sterilization by HD 17. CSF was subsequently monitored by intermittent sampling and, on HD 21, cultures were positive for Enterococcus faecium. Vancomycin resistance was identified on the VITEK system (bioMerieux, Durham, North Carolina). Further analysis by E-testing and Kirby-Bauer disk diffusion demonstrated resistance to meropenem, ampicillin, and rifampin with possible susceptibility to linezolid (minimum inhibitory concentration (MIC)

Therapy was initiated with linezolid, at a dose of 10 mg/kg given IV every 8 hours. Measurements of linezolid drug levels were obtained on day 3 of linezolid therapy from a commercially available laboratory with achievement of a peak serum level of 5.62 [mu]g/mL and a peak CSF level of 1.51 [mu]g/mL. The CSF was sterile by day 4 of therapy, and his VPS was successfully reinternalized after completing 14 days of linezolid therapy. IV treatment was continued for 18 days, at which time he was transitioned to oral linezolid to complete a 28-day course. The patient tolerated the therapy without any adverse clinical effects. Weekly complete blood counts obtained throughout the treatment period remained at age appropriate levels without myelosuppression. Additionally, chemistry panels and liver function tests were obtained twice while on linezolid therapy. These values, too, showed no abnormalities nor any significant change from values obtained before initiating therapy. At 6 months posthospitalization follow-up, the patient was found to be in his baseline state of health without recurrence of infection.

DISCUSSION

In a recent review of CNS infections caused by Enterococcus species, Pintado et al.1 found only 15 total cases attributable to vancomycin-resistant species. VRE, however, is becoming an increasing problem in hospital settings as a cause of nosocomial infections. It is therefore important that we continue to search for effective therapies to treat the spectrum of VRE disease, to include CNS infections.

A complete review of the literature shows only seven reports of patients with VRE CNS infection successfully treated with linezolid as outlined in Table I. Only one of these patients is in the pediatric age range,2 with ours being the second pediatric patient with VRE CNS infection to achieve sterilization using IV linezolid. Despite the small numbers, these previously reported successes do suggest that linezolid may be an option for treating CNS infections after trauma or surgery in patients at risk for resistant organisms.

Linezolid is a member of the oxazolidinone class of antibiotics that act via inhibition of bacterial protein synthesis by blocking formation of the ribosomal initiation complex. It is bacteriostatic against Gram-positive bacteria, to include resistant strains such as VRE, Streptococcus pneumoniae, and S. aureus. Little has been reported about the pharmacokinetics of this medication in the pediatric population. It is known, however, that more rapid drug clearance occurs in pediatric patients when compared to adults. This increased clearance is the basis for the accepted pediatric dosing recommendation of 10 mg/kg/dose every 8 hours used in our patient.9

Studies of linezolid levels in healthy volunteers have shown CSF/ plasma ratios of 0.7.8 This value was similar to the ratios of 0.5 to 0.8 in case reports of VRE meningitis treated with linezolid by Hachem et al. and Zeana et al.3,8 Additionally, Shaikh et al.5 showed a relatively stable CSF drug level (in comparison to serum levels) throughout a single dosing interval at steady state. Villani et al.9 further examined CSF penetration of linezolid in five postneurosurgical patients on monotherapy with linezolid. In these patients, CSF/serum drug level ratios were always >1, with troughs well in excess of the MIC for identified isolates. All of this data, however, is in adult patients only.

The measured peak drug levels in our patient were much lower than in similar reported measurements in adult patients. Nonetheless, the CSF level likely still exceeded the MIC for our identified isolate as CSF sterility was quickly achieved. Despite the clinical success, the CNS drug levels measured were lower than expected, raising questions about appropriate linezolid dosing in pediatric patients. As the use of linezolid increases for therapy of resistant infections in the pediatric population, it may be necessary to further investigate the appropriate dose to provide sufficient CSF penetration.

CONCLUSIONS

We describe the successful treatment of VRE meningitis with linezolid in a pediatric patient using the current recommended pediatric dosing of 10 mg/kg/dose every 8 hours. Although this option was both efficacious and safe, the unexpectedly low linezolid levels in the CSF, indicate that further research is needed to determine optimal linezolid dosing for pediatric CNS infections.

ACKNOWLEDGMENTS

Report of this case was approved by the Walter Reed Army Medical Center Institutional Review Board.

REFERENCES

1. Pintado V, Cabellos C, Moreno S, Meseguer MA, Ayats J, Viladrich PF: Enterococcal meningitis: a clinical study of 39 cases and review of the literature. Medicine (Baltimore) 2003; 82: 346- 64.

2. Graham PL, Ampofo K, Saiman L: Linezolid treatment of vancomycin-resistant Enterococcus faecium ventriculitis. Pediatr Infect Dis J 2002; 21: 798-800.

3. Hachem R, Afif C, Gokaslan Z, Raad I: Successful treatment of vancomycin-resistant Enterococcus meningitis with linezolid. Eur J Clin Microbiol Infect Dis 2001; 20: 432-4.

4. Kanchanapoom T, Koirala J, Goodrich J, Agamah E, Khardori N: Treatment of central nervous system infection by vancomycin- resistant Enterococcus faecium. Diagn Microbiol Infect Dis 2003; 45: 213-5.

5. Shaikh ZH, Peloquin CA, Ericsson CD: Successful treatment of vancomycin-resistant Enterococcus faecium meningitis with linezolid: case report and literature review. Scand J Infect Dis 2001; 33: 375- 9.

6. Steinmetz MP, Vogelbaum MA, De Georgia MA, Andrefsky JC, Isada C: Successful treatment of vancomycin-resistant Enterococcus meningitis with linezolid: case report and review of the literature. Crit Care Med 2001; 29: 2383-5.

7. Tsai TN, Wu CP, Peng MY, Giian CF, Lee SY, Lu JJ: Short course of linezolid treatment for vancomycin-resistant Enterococcus faecium meningitis. Int J Clin Pract 2006; 60: 740-1.

8. Zeana C, Kubin CJ, Della-Latta P, Hammer SM: Vancomycin- resistant Enterococcus faecium meningitis successfully managed with linezolid: case report and review of the literature. Clin Infect Dis 2001; 33: 477-82.

9. Villani P, Regazzi MB, Marubbi F, et al: Cerebrospinal fluid linezolid concentrations in postneurosurgical central nervous system infections. Antimicrob Agents Chemother 2002; 46: 936-7.

CPT Ashley M. Maranich, MC USA*[dagger]; Lt Col Michael Rajnik, USAF MC* * Department of Pediatrics, F. Edward Herbert School of Medicine, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, MD 20814.

[dagger] Department of Pediatrics, Walter Reed Army Medical Center, 6900 Georgia Avenue NW, Washington, DC 20307.

The views expressed in this article are those of the authors and do not reflect the official policy of the Department of the Army, Department of Defense, or U.S. government.

This manuscript was received for review in August 2007. The revised manuscript was accepted for publication in March 2008.

Copyright Association of Military Surgeons of the United States Sep 2008

(c) 2008 Military Medicine. Provided by ProQuest LLC. All rights Reserved.




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