Meningitis medical therapy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [2], Sheng Shi, M.D. [3]

Principles of Therapy for Bacterial Meningitis

• Acute bacterial meningitis is a medical emergency; commence empiric treatment after obtaining blood and/or cerebrospinal fluid (CSF) cultures once the possibility of bacterial meningitis becomes evident. Antibiotic regimen should be adjusted according to the culture results.

• Neuroimaging (such as CT scan and MRI) or lumbar puncture must not delay antimicrobial therapy.

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).

• Adequate parenteral dosage should be maintained throughout the course to ensure adequate bactericidal concentration since antimicrobial entry attenuates as meningeal inflammation subsides, especially when adjunctive dexamethasone is co-administered.

• 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).

Recommended Doses of Selected Antimicrobial Agents Administered by the Intraventricular Route.

Antimicrobial Agent	Daily Intraventricular Dose
▸ Vancomycin	5—20 mg/day; 10—20 mg/day has been used in most studies
▸ Gentamicin	4—8 mg/day in adults; 1—2 mg/day in infants and children
▸ Tobramycin	5—20 mg/day
▸ Amikacin	5—50 mg/day; the usual daily dose is 30 mg/day
▸ Polymyxin B	5 mg/day in adults; 1—2 mg/day in infants and children
▸ Colistimethate sodium	10 mg q24h or 5—10 mg q12h
▸ Quinupristin/Dalfopristin	2—5 mg/day
▸ Teicoplanin	5—40 mg/day; 5—10 mg q48—72h in one study
▸ Amphotericin B	0.1—0.5 mg/day for Candida shunt infection

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 2—4 days with the first dose administered 10—20 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 2—4 days with the first dose administered 10—20 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 Advances in treatment of bacterial meningitis. Lancet. 2012;380(9854):1693-702. and Nosocomial bacterial meningitis. N Engl J Med. 2010;362(2):146-54.

Community-Acquired Meningitis  ▸   Newborns, Age <1 Week  ▸   Newborns, Age 1—4 Weeks  ▸   Infants & Children  ▸   Adults, Age <50 Years  ▸   Adults, Age >50 Years  ▸   Immunocompromised  ▸   Recurrent   Nosocomial Meningitis  ▸   Postneurosurgical Infection  ▸   CSF Shunt Infection  ▸   Penetrating Trauma  ▸   Basilar Skull Fracture

Newborns, Age <1 Week Preferred Regimen ▸ Ampicillin 50 mg/kg IV q8h PLUS ▸ Cefotaxime 100—150 mg/kg/day IV q8—12h Alternative Regimen ▸ Ampicillin 50 mg/kg IV q8h PLUS ▸ Gentamicin 2.5 mg/kg IV q12h Newborns, Age 1—4 Weeks Preferred Regimen ▸ Ampicillin 200 mg/kg/day IV q6—8h PLUS ▸ Cefotaxime 150—200 mg/kg/day IV q6—8h Alternative Regimen ▸ Ampicillin 200 mg/kg/day IV q6—8h PLUS ▸ Gentamicin 2.5 mg/kg IV q8h OR ▸ Tobramycin 2.5 mg/kg IV q8h OR ▸ Amikacin 10 mg/kg IV q8h Infants & Children Preferred Regimen ▸ Vancomycin 15 mg/kg IV q6h (trough: 15—20 μg/mL) PLUS ▸ Cefotaxime 225—300 mg/kg/day IV q6—8h OR ▸ Ceftriaxone 80—100 mg/kg/day IV q12—24h Alternative Regimen ▸ Vancomycin 15 mg/kg IV q6h (trough: 15—20 μg/mL) PLUS ▸ Meropenem 40 mg/kg IV q8h   Add Ampicillin 50 mg/kg IV q6h if suspecting Listeria monocytogenes. Adults, Age <50 Years Preferred Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Cefotaxime 8—12 g/day IV q4—6h OR ▸ Ceftriaxone 2 g IV q12h Alternative Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Meropenem 2 g IV q8h   Add Ampicillin 2 g IV q4h if suspecting Listeria monocytogenes. Adults, Age >50 Years Preferred Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Ampicillin 2 g IV q4h PLUS ▸ Cefotaxime 8—12 g/day IV q4—6h OR ▸ Ceftriaxone 2 g IV q12h Alternative Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Aztreonam 6—8 g/day IV q6—8h PLUS ▸ TMP/SMZ 10—20 mg/kg/day IV q6—12h (TMP component) Immunocompromised Preferred Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Ampicillin 2 g IV q4h PLUS ▸ Cefepime 2 g IV q8h OR ▸ Meropenem 2 g IV q8h Recurrent Preferred Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Cefotaxime 8—12 g/day IV q4—6h OR ▸ Ceftriaxone 2 g IV q12h Postneurosurgical Infection Preferred Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Cefepime 2 g IV q8h OR ▸ Ceftazidime 2 g IV q8h OR ▸ Meropenem 2 g IV q8h Alternative Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Aztreonam 2 g IV q6—8h OR ▸ Ciprofloxacin 400 mg IV q8—12h CSF Shunt Infection Preferred Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Cefepime 2 g IV q8h OR ▸ Ceftazidime 2 g IV q8h OR ▸ Meropenem 2 g IV q8h Alternative Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Aztreonam 2 g IV q6—8h OR ▸ Ciprofloxacin 400 mg IV q8—12h Penetrating Trauma Preferred Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Cefepime 2 g IV q8h OR ▸ Ceftazidime 2 g IV q8h OR ▸ Meropenem 2 g IV q8h Alternative Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Aztreonam 2 g IV q6—8h OR ▸ Ciprofloxacin 400 mg IV q8—12h Basilar Skull Fracture Preferred Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Ceftriaxone 2 g IV q12h OR ▸ Cefotaxime 2 g IV q4—6h Alternative Regimen ▸ Vancomycin 15 mg/kg IV q8—12h (trough: 15—20 μg/mL) PLUS ▸ Aztreonam 2 g IV q6—8h OR ▸ Ciprofloxacin 400 mg IV q8—12h