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Infection

Case Report

Treatment of Meningitis Caused by Methicillin-Resistant Staphylococcus aureus with Linezolid A.T. Kessler, A.P. Kourtis

Abstract Methicillin-resistant Staphylococcus aureus (MRSA) is increasing in prevalence both in nosocomial and in community settings. Treatment of such infections, particularly in the central nervous system (CNS), is problematic, as available options are limited. Linezolid is a new antibiotic with activity against Gram-positive cocci, including MRSA, and has good penetration into the cerebrospinal fluid. To our knowledge, there are only three case reports of successful treatment of CNS infections caused by MRSA with linezolid; we report herein a fourth such case. Clinical trials to address the role of linezolid in CNS infections are urgently needed.

Infection 2007; 35: 271–274 DOI 10.1007/s15010-007-6211-z

Introduction Staphylococcus aureus is one of the most common causes of nosocomial infections, but also increasing in prevalence among community-acquired infections [1]. Resistance to methicillin among staphylococcal strains (MRSA) represents a growing threat in the hospital setting, and in particular in surgical and intensive care patients [2]. Linezolid belongs to the oxazolidinone class of antibiotics that has non-bactericidal activity against Gram-positive cocci such as enterococci (including vancomycin-resistant strains), Streptococcus pneumoniae, coagulase-negative staphylococci and S. aureus, including MRSA strains [3, 4]. Therapy with linezolid does not induce resistance rapidly in bacteria; such resistance is mainly observed in Enterococcus species, with only one report thus far concerning a S. aureus strain [5]. Vancomycin and teichoplanin, the two glycopeptide antibiotics that the majority of MRSA strains remain susceptible to, both achieve low concentrations in the cerebrospinal fluid, thus severely limiting treatment options for central nervous system (CNS) infections caused by Gram-positive resistant organisms [1]. Linezolid, on the other hand, has excellent cerebrospinal fluid (CSF) penetration. Its CSF to plasma ratio is 0.7:1 at peak and

Infection 35 Æ 2007 Æ No. 4 Ó URBAN & VOGEL

2:1 at trough [6, 7]. Linezolid, like vancomycin, is bacteriostatic. There has been limited clinical experience with use of linezolid for the treatment of CNS infections caused by resistant Gram-positive bacteria, and even more limited for such infections caused by MRSA. We report here on a case of MRSA meningitis in a patient who could not tolerate vancomycin that was successfully treated with intravenous linezolid.

Case Report The patient was a 48-year-old Caucasian female who was previously healthy with the exception of chronic back pain due to degenerative joint disease, for which she was not on any therapy. Six days prior to admission she had an uncomplicated epidural block; two days prior to admission she had the onset of progressive headache, fever and neck pain. On presentation the patient had a fever of 102 F, photophobia and severe headache and neck stiffness. A lumbar puncture was performed and revealed a white blood cell count of 957/mm3 with 50% neutrophils; protein was 48 mg/dl and glucose was 67 mg/dl. The Gram stain of the cerebrospinal fluid had many white blood cells but no organisms but the primary culture plates grew S. aureus resistant to oxacillin (MIC > 2) and sensitive to Vancomycin (MIC < 4), levofloxacin (MIC < 2), gentamicin (MIC < 4), Rifampin (MIC < 1) and Trimethoprim/Sulphamethoxazole (MIC < 2/38); susceptibility to erythromycin and clindamycin were not assessed. A magnetic resonance imaging study of the head and spine showed no evidence of an epidural or brain abscess, discitis or vertebral osteomyelitis. She was started on intravenous vancomycin but shortly thereafter she developed a severe generalized maculopapular rash and the vancomycin had to be discontinued on the third day of therapy. Intravenous linezolid was started (600 mg every 12 h) and the patient was successfully treated with a 3-week course of intravenous linezolid

A.T. Kessler Dept. of Medicine, Northside-Cherokee Hospital, Atlanta, GA, USA A.P. Kourtis Dept. of Obstetrics/Gynecology, Eastern Virginia Medical School, Norfolk, VA, USA A.T. Kessler (corresponding author) 15 Reinhardt College Parkway, Canton, GA 30013, USA; Phone: (+1/770) 704 9499, Fax: 352 0943, e-mail: [email protected] Received: August 3, 2006 Æ Revision accepted: February 26, 2007 Published online: July 23, 2007

271

272

Gram-positive bacteria (two cases)

MRSA

MRSA

MRSE

MRSE (two cases), S. pneumoniae (one case), ‘‘Gram-positive cocci’’ (one case), MRSA (one case)

MRSE

MRSE

VRE

VREF

VREF

Sabbatani et al. [15]

Amod et al. [16]

Our case

Gill et al. [10]

Viale et al. [14]

Lalueza et al. [8]

Krueger et al. [9]

Shaikh et al. [6]

Steinmetz et al. [11]

Hachem et al. [12]

28 days IV

3 weeks IV

4 weeks IV

6 weeks IV

17 days

15 days IV and 5 days PO

21 days, 14 days, 21 days, 13 days (patient died of acute heart failure) 20 days IV and 8 days PO

32 days

21 days IV

21 days

7 weeks and 10 days IV

42 days IV and 14 days PO

Duration of treatment

Resolution

Resolution; but patient expired due to his malignancy and its complications

Resolution

Resolution

Resolution

Resolution

Resolution in all cases; one patient died from unrelated cause

Resolution

Resolution

Resolution

Resolution

Resolution

Outcome

Meningitis in immunosuppressed patient with parasitic infection (Strongyloides stercoralis in stool and sputum – no prior neurosurgical procedure

Meningitis post neurosurgical procedure with VP-shunt placement; 5 days of IV gentamicin was also given

Meningitis post neurosurgical procedure with VP-shunt placement

Meningitis post neurosurgical procedure with ventriculostomy

Meningitis post lumbar CSF drainage placement

Meningitis post neurosurgical procedure with external lumbar CSF drainage

Three cases of meningitis, one ventriculitis and one case of brain abscess, all post neurosurgical procedures, three of which with CSF drainage devices in place

VP-shunt infection

Meningitis post epidural block

Ventriculitis post insertion of VP-shunt; received intrathecal vancomycin

One case of post-neurosurgical brain abscess and one post-neurosurgical meningitis

Endocarditis with disseminated cerebritis – no prior neurosurgical procedure; vancomycin and amikacin were continued and given concurrently with linezolid

Comments

MRSA: Methicillin-resistant Staphylococcus aureus; MRSE: methicillin-resistant Staphylococcus epidermidis; VRE: Vancomycin-resistant Enterococcus; VREF: Vancomycin-resistant Enterococcus fecium; VP: ventriculo-peritoneal; CSF: cerebrospinal fluid; IV: intravenous; PO: per os

VREF

MRSA

Pistella et al. [17]

Zeana et al. [13]

Infecting Organism

Reference

Table 1 Cases of central nervous system infections caused by Gram-positive cocci successfully treated with linezolid.

A.T. Kessler, A.P. Kourtis MRSA Meningitis Treated with Linezolid



with complete resolution of symptoms and no relapse of the infection at 3 months of follow-up.

Discussion The experience with use of linezolid in treating CNS infections due to resistant Gram-positive bacteria is limited to case reports and two case series. The bacteria involved included coagulase-negative staphylococci, Enterococci, Streptococcus pneumoniae and MRSA. We will briefly review these by organism (Table 1): Treatment of Staphylococcus epidermidis meningitis with linezolid has been described in three case reports [8–10]; all were in patients who had undergone neurosurgical procedures and had foreign material such as ventriculo-peritoneal-shunts. Successful treatment of vancomycin-resistant enterococcal meningeal and ventricular infections with linezolid has been described in four case reports [5, 11–13]. Viale et al. [14] reported on five patients with Gram-positive CNS infections subsequent to neurosurgical procedures, who either failed or did not tolerate a glycopeptide regimen; in all cases linezolid was used and resulted in resolution of the infection. The infections were caused by S. epidermidis in two cases, S. pneumoniae in one case, MRSA in one case and unspecified gram-positive cocci in one case. Sabbatani et al. [15] reported on one case of post-surgical brain abscess and one case of post-surgical meningitis due to resistant Gram-positive bacteria that responded to salvage linezolid therapy. To our knowledge, there have been only three case reports of CNS infections due to S. aureus that have been successfully treated with linezolid: Amod et al. [16] from South Africa recently described a case of ventriculitis due to a strain of S. aureus resistant to methicillin and intermediate to vancomycin that was successfully treated with intravenous linezolid (for 3 weeks) and intrathecal vancomycin. Pistella et al. [17] reported on a case of disseminated cerebritis complicating communityacquired MRSA endocarditis unresponsive to vancomycin and amikacin that was successfully treated when linezolid (for 42 days IV and for 14 days PO) was added to the regimen. Even though some earlier in vitro data had suggested possible antagonism between vancomycin and linezolid against some MRSA isolates [4], the case by Pistella et al. demonsrates that in vivo linezolid did not result in clinical antagonism with vancomycin and amikacin. The third case reported is that described in the case series by Viale et al. [14], and mentioned earlier; a case of post-surgical meningitis due to MRSA unresponsive to vancomycin, where change of therapy to linezolid (for 28 days) led to prompt improvement and final resolution of the infection. Our case is thus the fourth case described in the literature of a patient with MRSA meningitis successfully treated with intravenous linezolid; the infection was possibly introduced through the earlier epidural injection and the patient could not tolerate vancomycin.


In conclusion, it appears that linezolid can be efficacious in treating CNS infections due to MRSA. As other authors have also urged, we believe that clinical trials of linezolid in post-surgical CNS infections or in CNS infections caused by Gram-positive cocci resistant to betalactams are needed, in order to rigorously assess the efficacy/toxicity/resistance profile of linezolid in comparison with other available agents and thus determine the role of this antibiotic in the treatment of these increasingly prevalent and difficult to treat infections.

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