Sandbox/v46

# Overview
Acute bacterial meningitis is a medical emergency; commence empiric treatment after obtaining blood and/or cerebrospinal fluid (CSF) cultures if the possibility of bacterial meningitis becomes evident. Once a bacterial etiology has been identified on a CSF Gram stain, treatment regimen should be optimized accordingly. Further modifications may be required after the culture and/or in vitro susceptibility results are available.  Neuroimaging (such as CT scan and MRI) or lumbar puncture must not delay antimicrobial therapy.

# Principles of Therapy for Bacterial Meningitis

### Factors Determining Antimicrobial Activity
- Factors determine the acitivity of antimicrobial agents include pharmacodynamics, pharmacokinetics, penetration into the CSF, and bactericidal activity within the CSF.
- Beta-lactams, aminoglycosides, glycopeptides, linezolid, and daptomycin are considered to have poor penetration into the CSF, while fluoroquinolones, chloramphenicol, aztreonam, and tigecycline generally achieve minimum inhibitory concentration (MIC) in the CSF at standard dosage.
- Aminoglycosides and fluoroquinolones express a concentration-dependent manner of bactericidal activity; beta-lactams typically follow a a time-dependent antimicrobial pattern (i.e., the activity is dependent on the time that CSF concentration exceeds MIC as a proportion of the dosing interval).
- Penetration into the CSF is less prominent for drugs with a high molecular weight, high protein-binding ability, low lipid solubility, and drugs that are subject to active transport in the choroid plexus such as penicillins and cephalosporins. Toxicity due to dose escalation may limit the usage the aminoglycosides, glycopeptides, and polymyxins, thus intrathecal or intraventricular administration might be occasionally required (see table below).

### Duration of Antimicrobial Therapy
- The duration of therapy in patients with bacterial meningitis has not been well-supported by evidence-based data.
- The IDSA Practice Guideline provides recommendations on the duration of antimicrobial agents based on microorganisms (see table below). However, the duration of antimicrobial therapy should be individualized in accordance with patient's clinical response.
- Maximum parenteral dosage should be maintained throughout the recommended duration of therapy to ensure adequate bactericidal concentrations are attained since antimicrobial entry attenuates as meningeal inflammation subsides, especially when dexamethasone is co-administered.

### Adjunctive Dexamethasone Therapy
- Evidences for beneficial effects of dexamethasone are variable. In some studies, adjunctive use of dexamethasone for bacterial meningitis in selected groups are associated with an improved survival or prognosis. However, other studies fail to demonstrate a substantial reduction of death or neurological disability. The occurrence of delayed cerebral thrombosis with dexamethasone therapy has been reported.
- In infants and children with Haemophilus influenzae type b meningitis, the IDSA Practice Guideline supports the use of adjunctive Dexamethasone at 0.15 mg/kg q6h for 24 days with the first dose administered 1020 minutes prior to, or at least concomitant with, the first antimicrobial dose.
- In adults with suspected or proven Streptococcus pneumoniae meningitis, the IDSA also recommends Dexamethasone at 0.15 mg/kg q6h for 24 days with the first dose administered 1020 minutes prior to, or at least concomitant with, the first antimicrobial dose. Dexamethasone should only be continued if the CSF Gram stain reveals Gram-positive diplococci, or if blood or CSF cultures are positive for S. pneumoniae. In this scenario, certain authorities advocate the addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin pending culture results and in vitro susceptibility testing.
- Dexamethasone should not be given to patients who have already received animicrobial therapy because it is unlikely to improve clinical outcome.

# Empiric Therapy Adapted from Lancet. 2012;380(9854):1693-702. and N Engl J Med. 2010;362(2):146-54.

# CSF Gram Stain-Based Therapy Adapted from Lancet. 2012;380(9854):1693-702. and Clin Infect Dis. 2004;39(9):1267-84.

# Pathogen-Based Therapy Adapted from Lancet. 2012;380(9854):1693-702. and Clin Infect Dis. 2004;39(9):1267-84.