Staphylococcus aureus meningitis: barriers to treatment

Staphylococcus aureus is a common pathogen with a wide range of clinical presentations, causing significant morbidity and mortality especially with rising rates of methicillin-resistant S. aureus (MRSA) [1]. Although S. aureus is an uncommon cause of bacterial meningitis, accounting for up to 10% of cases, it is associated with a mortality rate of up to 36% [2, 3]. There are two types of S. aureus meningitis, and management differs according to the cause. S. aureus meningitis may be hematogenous or associated with either neurosurgical procedures or trauma. Hematogenous S. aureus meningitis follows dissemination from a non-central nervous system (CNS) focus of infection, as illustrated by the case reported by Whaby et al. [4]. In a recent case series spanning the years 1999–2008, MRSA was isolated in 48% of patients with hematogenous S. aureus meningitis, with evidence of an increased incidence in the latter years of the study supporting concern about the increasing rates of MRSA isolates [2].

In general, hematogenous S. aureus meningitis is more commonly community-acquired, occurs in patients with more comorbidities, and is associated with infection outside the CNS and S. aureus bacteremia. It has a worse prognosis than post-operative S. aureus meningitis. As illustrated by the case presented by Whaby et al. [4], treatment of MRSA meningitis is challenging due to the limited available active drugs, the reduced blood–brain barrier penetration of those antimicrobials, often resulting in low therapeutic drug levels at the primary site of infection, and the potential for drug-related side-effects. Vancomycin is considered the first-line antimicrobial for MRSA meningitis despite its poor CNS penetration, as this increases in the setting of meningeal inflammation [5, 6]. Alternative agents include daptomycin, linezolid or trimethoprim–sulfamethoxazole. Recently, daptomycin has been used to successfully treat MRSA meningitis in one case report [7]. In an animal model of meningitis, daptomycin was more successful than vancomycin in sterilizing cerebrospinal fluid (CSF) [8]. However, Whaby et al. [4] have demonstrated low CNS penetration of daptomycin, which resulted in clinical failure necessitating a change in therapy to linezolid. Although there are more reports of success with linezolid for MRSA meningitis [3], likely due to its better CNS penetration, this drug has dose-dependent myelotoxicity [5]. This is a significant drawback in patients with hematological malignancies receiving chemotherapy, although the myelosuppression is reversible [5]. There is some evidence for combination therapy for MRSA meningitis with the addition of rifampicin. In a recent case series, the mortality rate in patients treated with vancomycin and rifampicin was 33%, in comparison to 45% in those who received vancomycin alone [2], and the authors recommended the use of combination therapy in the setting of severe disease.

The management of MRSA meningitis, especially hematogenous meningitis, should include the aggressive search for an extra-CNS focus of infection, especially if associated with a concurrent bacteremia. Vancomycin remains the first-line agent, with administration of a loading dose to achieve maximum CSF therapeutic levels. Serum levels of vancomycin are a surrogate guide, and levels between 15 and 20 μg/L are the target. Combination therapy should be considered if the clinical situation is severe, and an alternative agent such as linezolid if there is vancomycin resistance or poor response to vancomycin. Guidelines recommend 2 weeks of treatment for MRSA meningitis, but the final duration of treatment should be determined by the presence of any other foci of S. aureus infection requiring treatment [5] and severity of immunosuppression. The case reported by Whaby et al. [4] is a timely reminder of the challenges of managing infections in the era of increasing antimicrobial resistance with limited treatment options.

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