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, 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; 10 mg or 20 mg has been used in most studies.
▸ Gentamicin	4–8 mg in adults; 1–2 mg in infants and children
▸ Amikacin	5–50 mg; the usual daily dose is 30 mg.
▸ Polymyxin B	5 mg in adults; 1–2 mg in infants and children
▸ Colistimethate sodium	10 mg q24h or 5–10 mg q12h

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 receive 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.

Community-Acquired Meningitis  ▸   Newborn, Age <1 Week  ▸   Newborn, Age 1—4 Weeks  ▸   Infant & Children  ▸   Adult, Age <50 Years  ▸   Adult, Age >50 Years  ▸   Immunocompromised  ▸   Recurrent

Newborn, 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 Newborn, 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 Infant & Children Preferred Regimen ▸ Vancomycin 15 mg/kg IV q6h (Target trough concentration: 15–20 μg/mL) PLUS ▸ Cefotaxime 225—300 mg/kg/day IV q6–8h OR ▸ Ceftriaxone 80—100 mg/kg/day IV q12–24h   Add Ampicillin 50 mg/kg IV q6h if Listeria monocytogenes is also suspected. Adult, Age <50 Years Preferred Regimen ▸ Vancomycin 30–60 mg/kg/day IV q8–12h (Target trough concentration: 15–20 μg/mL) PLUS ▸ Cefotaxime 8–12 g/day IV q4–6h OR ▸ Ceftriaxone 2 g IV q12h   Add Ampicillin 2 g IV q4h if Listeria monocytogenes is also suspected. Adult, Age >50 Years Preferred Regimen ▸ Vancomycin 30–60 mg/kg/day IV q8–12h PLUS ▸ Ampicillin 2 g IV q4h PLUS ▸ Cefotaxime 8–12 g/day IV q4–6h OR ▸ Ceftriaxone 2 g IV q12h Immunocompromised Preferred Regimen ▸ Vancomycin 30–60 mg/kg/day IV q8–12h 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 PLUS ▸ Cefotaxime 8–12 g/day IV q4–6h OR ▸Ceftriaxone 2 g IV q12h

Healthcare-Associated Meningitis  ▸   Basilar Skull Fracture  ▸   Head Trauma; Post-Neurosurgery

Basilar Skull Fracture Preferred Regimen ▸ Vancomycin 30—60 mg/kg/day IV q8–12h PLUS ▸ Cefotaxime 8–12 g/day IV q4–6h OR ▸Ceftriaxone 2 g IV q12h Head Trauma; Post-Neurosurgery ▸ Vancomycin 30—60 mg/kg/day IV q8–12h PLUS ▸ Ceftazidime 2 g IV q8 h OR ▸ Cefepime 2 g IV q8h OR ▸ Meropenem 2 g IV q8h

Pathogen-Based Therapy

Streptococcus pneumoniae

Penicillin MIC ≤0.06 μg/mL Preferred Regimen ▸ Penicillin G Low: 600,000–1.2 million units/day IM; High:≥ 20 million units IV q24h(=12 g) OR ▸ Ampicillin 150–200 mg/kg IV q3-4h Alternative Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) OR ▸ Chloramphenicol 0.25–1 g po IV q6h to max. of 4 g/day

Penicillin MIC ≥0.12 μg/mL Cefotaxime or Ceftriaxone MIC† <1.0 μg/mL Preferred Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) Alternative Regimen ▸ Cefepime 1–2 g IV q12h OR ▸ Meropenem 2 g IV q8h Cefotaxime or Ceftriaxone MIC† >1.0 μg/mL Preferred Regimen ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. ) AND ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine)‡ Alternative Regimen ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. ) AND ▸ Moxifloxacin 400 mg po IV q24h ɸ

Neisseria meningitidis

Neisseria meningitidis Penicillin MIC <0.1 μg/mL Preferred Regimen ▸ Penicillin G Low: 600,000–1.2 million units/day IM; High:≥ 20 million units IV q24h(=12 g) OR ▸ Ampicillin 0.25–0.5 g po q6h.150–200 mg/kg/day IV Alternative Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) OR ▸ Chloramphenicol 0.25–1 g po IV q6h to max. of 4 g/day

Neisseria meningitidis Penicillin MIC ≥0.1 μg/mL Preferred Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) Alternative Regimen ▸ Cefepime 1–2 g IV q12h OR ▸ Chloramphenicol 0.25–1 g po IV q6h to max. of 4 g/day OR ▸ FluoroquinoloneΔ OR ▸ Meropenem 2 g IV q8h

Listeria monocytogenes and Streptococcus agalactiae

Listeria Monocytogenes Preferred Regimen ▸ Ampicillin 0.25–0.5 g po q6h.150–200 mg/kg/day IV OR ▸ Penicillin G Low: 600,000–1.2 million units/day IM ;High:≥ 20 million units IV q24h(=12 g)£ Alternative Regimen ▸ Trimethoprim-sulfamethoxazole 5–20 mg/kg/day q6-12h

Streptococcus agalactiae Preferred Regimen ▸ Ampicillin 0.25–0.5 g po q6h.150–200 mg/kg/day IV OR ▸ Penicillin G Low: 600,000–1.2 million units/day IM ;High:≥ 20 million units IV q24h(=12 g)£ Alternative Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) OR ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. )

Haemophilus influenzae

Haemophilus influenzae β-lactamase negative Preferred Regimen ▸ Ampicillin 0.25–0.5 g po q6h.150–200 mg/kg/day IV Alternative Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) OR ▸ Cefepime 1–2 g IV q12h OR ▸ Chloramphenicol 0.25–1 g po IV q6h to max. of 4 g/day OR ▸ Aztreonam 1 g IV q8h–2 g IV q6h OR ▸ FluoroquinoloneΔ β-lactamase negative, ampicillin resistant Preferred Regimen ▸ Meropenem 2 g IV q8h Alternative Regimen ▸ FluoroquinoloneΔ

Haemophilus influenzae β-lactamase positive Preferred Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) Alternative Regimen ▸ Cefepime 1–2 g IV q12h OR ▸ Chloramphenicol 0.25–1 g po IV q6h to max. of 4 g/day OR ▸ Aztreonam 1 g q8h–2 g IV q6h OR ▸ FluoroquinoloneΔ

Staphylococcus aureus

Staphylococcus aureus Meticillin sensitive Preferred Regimen ▸ Nafcillin 1–2 g IV/IM q4h OR ▸ Oxacillin 1–2 g IV/IM q4h Alternative Regimen ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. ) OR ▸ linezolid 600 mg IV/PO q12h OR ▸ Daptomycin 6 mg/kg IV q24h

Staphylococcus aureus Meticillin resistant₦ Preferred Regimen ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. ) Alternative Regimen ▸ Trimethoprim-sulfamethoxazole 5–20 mg/kg/day q6-12h OR ▸ linezolid 600 mg IV/PO q12h OR ▸ Daptomycin 6 mg/kg IV q24h

Staphylococcus epidermidis and Acinetobacter baumannii^Ω

Staphylococcus epidermidis₦ Preferred Regimen ▸ Vancomycin give loading dose of 25-30 mg/kg IV then 15-20 mg/kg IV q8-12h (Target trough level is 15-20 µg/mL. For individual doses over 1 gm, infuse over 1.5-2 hrs. ) Alternative Regimen ▸ Linezolid 600 mg IV/PO q12h

Acinetobacter baumannii Preferred Regimen ▸ Meropenem 2 g IV q8h Alternative Regimen ▸ Colistin in US:2.5-5 mg/kg/day q6-12h( 6.7-13.3 mg/kg/day of colistimethate sodium (CMS),max 800 mg/day); Elsewhere: ≤60 kg, 50,000-75,000 IU/kg/day IV q8h (=4-6 mg/kg per day of CMS). >60 kg, 1-2 mill IU IV q8h (= 80-160 mg IV tid). OR ▸ Polymyxin B 15,000–25,000 units/kg/day q12hǂ

Enterobacteriaceae and Pseudomonas aeruginosa

EnterobacteriaceaeΩ Preferred Regimen ▸ Cefotaxime 1 g q8–12h to 2 g IV q4h OR ▸ Ceftriaxone 1 g IV qd (2 g IV q12h for Purulent meningitis also IM in 1% lidocaine) Alternative Regimen ▸ Aztreonam 1 g q8h–2 g IV q6h OR ▸ FluoroquinoloneΔ OR ▸ Trimethoprim-sulfamethoxazole 5–20 mg/kg/day q6-12h OR ▸ Meropenem 2 g IV q8h OR ▸ Ampicillin 150–200 mg/kg/day IV

Pseudomonas aeruginosa Preferred Regimen ▸ Ceftazidime 1–2 g IV/IM q8–12h OR ▸ Cefepime 1–2 g IV q12h£ Alternative Regimen ▸ Aztreonam 1 g q8h–2 g IV q6h OR ▸ Meropenem 2 g IV q8h OR ▸ Ciprofloxacin 500-750 mg po bid£

^† MIC = minimum inhibitory concentration.‡Addition of rifampicin can be considered if the organism is susceptible, the expected clinical or bacteriological response is delayed, or the cefotaxime/ceftriaxone MIC of the pneumococcal isolate is >4.0 μg/mL organism is susceptible, the expected clinical or bacteriological response is delayed, or the cefotaxime/ceftriaxone MIC.

^Φ No clinical data exist for use of this agent in patients with pneumococcal meningitis; recommendation is based on cerebrospinal fluid penetration and in-vitro activity against S. pneumoniae.

^£ Addition of an aminoglycoside should be considered; might need intraventricular or intrathecal administration in Gram-negative meningitis.

^ǁ Addition of rifampicin should be considered.

^Ω Choice of a specific agent should be based on in-vitro susceptibility testing.

^†† Might also need to be administered by the intraventricular or intrathecal routes.

^ǂ Might also need to be administered by the intraventricular or intrathecal routes.

^₦ Addition of rifampicin should be considered.

^Δ The fluoroquinolones gatifloxacin and moxifloxacin pene trate the CSF effectively and have greater in-vitro activity against Gram-positive bacteria than do their earlier counterparts (eg, ciprofloxacin). Findings from experi mental meningitis models suggested their efficacy in S. pneumoniae meningitis, including that caused by penicillin-resistant and cephalosporin-resistant strains. Although one controlled trial suggested the fluoroquinolone trovafl -oxacin mesilate to be as eff ective as ceftriaxone, with or without the addition of vancomycin, for paediatric bacterial meningitis, no clinical trials describe the use of gatifloxacin or moxifloxacin to treat bacterial meningitis in human beings. Trovafloxacin and gatifloxacin have been asso ciated with serious hepatic toxicity and dysglycaemia, respectively, and were with drawn from many markets. The IDSA guidelines recommend moxifloxacin as an alternative to third-generation cephalosporins plus vancomycin for meningitis caused by S. pneumoniae strains resistant to penicillin and third-generation cephalosporins, although some experts recom mend that this agent should not be used alone but rather should be combined with another drug (either vancomycin or a third-generation cephalosporin), because of the absence of clinical data supporting its use.