Meningitis medical therapy: Difference between revisions

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==References==
==References==
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Revision as of 07:17, 26 January 2014

Meningitis Main Page

Patient Information

Overview

Causes

Classification

Viral Meningitis
Bacterial Meningitis
Fungal Meningitis

Differential Diagnosis

Diagnosis

Treatment

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Cafer Zorkun, M.D., Ph.D. [3], Sheng Shi, M.D. [4]

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

  • 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).


Recommended Doses of Antimicrobial Agents via the Intraventricular Route.[3][4][5]
Antimicrobial Agent Daily Intraventricular Dose
 ▸ Vancomycin 5—20 mg
 ▸ Gentamicin 4—8 mg
 ▸ Tobramycin 5—20 mg
 ▸ Amikacin 5—50 mg
 ▸ Polymyxin B 5 mg
 ▸ Colistin 10 mg
 ▸ Quinupristin/Dalfopristin 2—5 mg
 ▸ Teicoplanin 5—40 mg
 ▸ Amphotericin B 0.1—0.5 mg/day


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.


Recommended Duration of Antimicrobial Therapy Based on Isolated Pathogen.[6]
Microorganism Duration of Therapy
 ▸ Neisseria meningitidis 7 days
 ▸ Haemophilus influenzae 7 days
 ▸ Streptococcus pneumoniae 10—14 days
 ▸ Streptococcus agalactiae 14—21 days
 ▸ Aerobic Gram-negative bacilli 21 days
 ▸ Listeria monocytogenes ≥21 days


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.[7][8][9][10][11][12] However, other studies fail to demonstrate a substantial reduction of death or neurological disability.[3][13][14][15] The occurrence of delayed cerebral thrombosis with dexamethasone therapy has been reported.[16]
  • 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.[6]
  • Dexamethasone should not be given to patients who have already received animicrobial therapy because it is unlikely to improve clinical outcome.[6]


Empiric Therapy Adapted from Lancet. 2012;380(9854):1693-702.[18] and N Engl J Med. 2010;362(2):146-54.[3]

Community-Acquired

  ▸  Newborns, Age <1 Week

  ▸  Newborns, Age 1—4 Weeks

  ▸  Infants & Children

  ▸  Adults, Age <50 Years

  ▸  Adults, Age >50 Years

  ▸  Immunocompromised

  ▸  Recurrent

Nosocomial

  ▸  Postneurosurgical Infection

  ▸  CSF Shunt Infection

  ▸  Penetrating Trauma

  ▸  Basilar Skull Fracture

Newborns, Age <1 Week
Preferred Regimen
Ampicillin 50 mg/kg IV q8h
PLUS
Cefotaxime 50 mg/kg 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 50 mg/kg 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 75 mg/kg 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 75 mg/kg IV q6h if suspecting Listeria monocytogenes.
Adults, Age <50 Years
Preferred Regimen
Vancomycin 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Vancomycin 15 mg/kg 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 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
PLUS
Ampicillin 2 g IV q4h
Alternative Regimen
Vancomycin 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Aztreonam 2 g IV q6—8h
PLUS
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)
Immunocompromised
Preferred Regimen
Vancomycin 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Cefepime 2 g IV q8h
OR
Meropenem 2 g IV q8h
PLUS
Ampicillin 2 g IV q4h
Recurrent
Preferred Regimen
Vancomycin 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Cefotaxime 2 g 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
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
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 Gram Stain-Based Therapy Adapted from Lancet. 2012;380(9854):1693-702.[18] and Clin Infect Dis. 2004;39(9):1267-84.[6]

Gram-Positive

  ▸  Gram-Positive Cocci in Chains

  ▸  Gram-Positive Cocci in Pairs

  ▸  Gram-Positive (Cocco-)Bacilli

Gram-Negative

  ▸  Gram-Negative Cocci in Pairs

  ▸  Gram-Negative Coccobacilli

  ▸  Gram-Negative Bacilli

Gram-Positive Cocci in Chains
Preferred Regimen
Vancomycin 15 mg/kg IV q8—12h (trough 15—20 μg/mL)
PLUS
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Meropenem 2 g IV q8h
OR
Moxifloxacin 400 mg IV q24h
Gram-Positive Cocci in Pairs
Preferred Regimen
Ampicillin 2 g IV q4h
OR
Penicillin G 4 MU IV q4h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Alternative Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Gram-Positive (Cocco-)Bacilli
Preferred Regimen
Ampicillin 2 g IV q4h
OR
Penicillin G 4 MU IV q4h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Alternative Regimen
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)
OR
Meropenem 2 g IV q8h
Gram-Negative Cocci in Pairs
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Penicillin G 4 MU IV q4h
OR
Ampicillin 2 g IV q4h
OR
Chloramphenicol 1—1.5 g IV q6h
OR
Moxifloxacin 400 mg IV q24h
OR
Aztreonam 2 g IV q6—8h
Gram-Negative Coccobacilli
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Chloramphenicol 1—1.5 g IV q6h
OR
Cefepime 2 g IV q8h
OR
Meropenem 2 g IV q8h
OR
Moxifloxacin 400 mg IV q24h
Gram-Negative Bacilli
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Cefepime 2 g IV q8h
OR
Meropenem 2 g IV q8h
OR
Aztreonam 2 g IV q6—8h
OR
Moxifloxacin 400 mg IV q24h
OR
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)


Pathogen-Based Therapy Adapted from Lancet. 2012;380(9854):1693-702.[18] and Clin Infect Dis. 2004;39(9):1267-84.[6]

Bacteria

  ▸  Acinetobacter baumannii

  ▸  Enterobacteriaceae

  ▸  Haemophilus influenzae

  ▸  Listeria monocytogenes

  ▸  Neisseria meningitidis

  ▸  Pseudomonas aeruginosa

  ▸  Staphylococcus aureus

  ▸  Staphylococcus epidermidis

  ▸  Streptococcus agalactiae

  ▸  Streptococcus pneumoniae

Acinetobacter baumannii
Preferred Regimen
Meropenem 2 g IV q8h
Alternative Regimen
Colistin 1.25 mg/kg IV q6—12h
OR
Polymyxin B 0.75—1.25 mg/kg IV q12h
Enterobacteriaceae
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Aztreonam 2 g IV q6—8h
OR
Moxifloxacin 400 mg IV q24h
OR
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)
OR
Meropenem 2 g IV q8h
OR
Ampicillin 2 g IV q4h
H. influenzae, β-lactamase Negative
Preferred Regimen
Ampicillin 2 g IV q4h
Alternative Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
OR
Cefepime 2 g IV q8h
OR
Chloramphenicol 1—1.5 g IV q6h
OR
Aztreonam 2 g IV q6—8h
OR
Moxifloxacin 400 mg IV q24h
H. influenzae, β-lactamase Positive
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Cefepime 2 g IV q8h
OR
Chloramphenicol 1—1.5 g IV q6h
OR
Aztreonam 2 g IV q6—8h
OR
Moxifloxacin 400 mg IV q24h
H. influenzae, β-lactamase Negative, Ampicillin Resistant
Preferred Regimen
Meropenem 2 g IV q8h
Alternative Regimen
Moxifloxacin 400 mg IV q24h
Listeria monocytogenes
Preferred Regimen
Ampicillin 2 g IV q4h
OR
Penicillin G 4 MU IV q4h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Alternative Regimen
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)
N. meningitidis, Penicillin MIC <0.1 μg/mL
Preferred Regimen
Penicillin G 4 MU IV q4h
OR
Ampicillin 2 g IV q4h
Alternative Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
OR
Chloramphenicol 1—1.5 g IV q6h
N. meningitidis, Penicillin MIC ≥0.1 μg/mL
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Cefepime 2 g IV q8h
OR
Chloramphenicol 1—1.5 g IV q6h
OR
Moxifloxacin 400 mg IV q24h
OR
Meropenem 2 g IV q8h
Pseudomonas aeruginosa
Preferred Regimen
Ceftazidime 2 g IV q8h
OR
Cefepime 2 g IV q8h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Alternative Regimen
Aztreonam 2 g IV q6—8h
OR
Meropenem 2 g IV q8h
OR
Ciprofloxacin 400 mg IV q8—12h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Staphylococcus aureus, Methicillin sensitive
Preferred Regimen
Nafcillin 1.5—2 g IV q4h
OR
Oxacillin 1.5—2 g IV q4h
Alternative Regimen
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
OR
Linezolid 600 mg IV q12h
OR
Daptomycin 6 mg/kg IV q24h
Staphylococcus aureus, Methicillin resistant
Preferred Regimen
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
PLUS
Rifampin 600 mg IV q24h
Alternative Regimen
TMP/SMZ 5 mg/kg IV q6—12h (TMP component)
OR
Linezolid 600 mg IV q12h
OR
Daptomycin 6 mg/kg IV q24h
PLUS
Rifampin 600 mg IV q24h
Staphylococcus epidermidis
Preferred Regimen
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
PLUS
Rifampin 600 mg IV q24h
Alternative Regimen
Linezolid 600 mg IV q12h
PLUS
Rifampin 600 mg IV q24h
Streptococcus agalactiae
Preferred Regimen
Ampicillin 2 g IV q4h
OR
Penicillin G 4 MU IV q4h
PLUS
Gentamicin 1.7 mg/kg IV q8h
Alternative Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
OR
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
S. pneumoniae, Penicillin MIC ≤0.06 μg/mL
Preferred Regimen
Penicillin G 4 MU IV q4h
OR
Ampicillin 2 g IV q4h
Alternative Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
OR
Chloramphenicol 1—1.5 g IV q6h
S. pneumoniae, Penicillin MIC ≥0.12 μg/mL, Cefotaxime/Ceftriaxone MIC <1.0 μg/mL
Preferred Regimen
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
Alternative Regimen
Cefepime 2 g IV q8h
OR
Meropenem 2 g IV q8h
S. pneumoniae, Penicillin MIC ≥0.12 μg/mL, Cefotaxime/Ceftriaxone MIC ≥1.0 μg/mL
Preferred Regimen
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
PLUS
Cefotaxime 2 g IV q4—6h
OR
Ceftriaxone 2 g IV q12h
PLUS
Rifampin 600 mg IV q24h
Alternative Regimen
Vancomycin 15 mg/kg IV q6h (trough 15—20 μg/mL)
PLUS
Moxifloxacin 400 mg IV q24h


References

  1. Andes, DR.; Craig, WA. (1999). "Pharmacokinetics and pharmacodynamics of antibiotics in meningitis". Infect Dis Clin North Am. 13 (3): 595–618. PMID 10470557. Unknown parameter |month= ignored (help)
  2. Nau, R.; Sörgel, F.; Eiffert, H. (2010). "Penetration of drugs through the blood-cerebrospinal fluid/blood-brain barrier for treatment of central nervous system infections". Clin Microbiol Rev. 23 (4): 858–83. doi:10.1128/CMR.00007-10. PMID 20930076. Unknown parameter |month= ignored (help)
  3. 3.0 3.1 3.2 van de Beek, D.; Drake, JM.; Tunkel, AR. (2010). "Nosocomial bacterial meningitis". N Engl J Med. 362 (2): 146–54. doi:10.1056/NEJMra0804573. PMID 20071704. Unknown parameter |month= ignored (help)
  4. Rodríguez Guardado, A.; Blanco, A.; Asensi, V.; Pérez, F.; Rial, JC.; Pintado, V.; Bustillo, E.; Lantero, M.; Tenza, E. (2008). "Multidrug-resistant Acinetobacter meningitis in neurosurgical patients with intraventricular catheters: assessment of different treatments". J Antimicrob Chemother. 61 (4): 908–13. doi:10.1093/jac/dkn018. PMID 18281693. Unknown parameter |month= ignored (help)
  5. Cruciani, M.; Navarra, A.; Di Perri, G.; Andreoni, M.; Danzi, MC.; Concia, E.; Bassetti, D. (1992). "Evaluation of intraventricular teicoplanin for the treatment of neurosurgical shunt infections". Clin Infect Dis. 15 (2): 285–9. PMID 1387805. Unknown parameter |month= ignored (help)
  6. 6.0 6.1 6.2 6.3 6.4 6.5 Tunkel AR, Hartman BJ, Kaplan SL, Kaufman BA, Roos KL, Scheld WM et al. (2004) Practice guidelines for the management of bacterial meningitis. Clin Infect Dis 39 (9):1267-84. DOI:10.1086/425368 PMID: [1]
  7. Lebel, MH.; Freij, BJ.; Syrogiannopoulos, GA.; Chrane, DF.; Hoyt, MJ.; Stewart, SM.; Kennard, BD.; Olsen, KD.; McCracken, GH. (1988). "Dexamethasone therapy for bacterial meningitis. Results of two double-blind, placebo-controlled trials". N Engl J Med. 319 (15): 964–71. doi:10.1056/NEJM198810133191502. PMID 3047581. Unknown parameter |month= ignored (help)
  8. Odio, CM.; Faingezicht, I.; Paris, M.; Nassar, M.; Baltodano, A.; Rogers, J.; Sáez-Llorens, X.; Olsen, KD.; McCracken, GH. (1991). "The beneficial effects of early dexamethasone administration in infants and children with bacterial meningitis". N Engl J Med. 324 (22): 1525–31. doi:10.1056/NEJM199105303242201. PMID 2027357. Unknown parameter |month= ignored (help)
  9. Thwaites, GE.; Nguyen, DB.; Nguyen, HD.; Hoang, TQ.; Do, TT.; Nguyen, TC.; Nguyen, QH.; Nguyen, TT.; Nguyen, NH. (2004). "Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults". N Engl J Med. 351 (17): 1741–51. doi:10.1056/NEJMoa040573. PMID 15496623. Unknown parameter |month= ignored (help)
  10. Brouwer, MC.; Heckenberg, SG.; de Gans, J.; Spanjaard, L.; Reitsma, JB.; van de Beek, D. (2010). "Nationwide implementation of adjunctive dexamethasone therapy for pneumococcal meningitis". Neurology. 75 (17): 1533–9. doi:10.1212/WNL.0b013e3181f96297. PMID 20881273. Unknown parameter |month= ignored (help)
  11. Fritz, D.; Brouwer, MC.; van de Beek, D. (2012). "Dexamethasone and long-term survival in bacterial meningitis". Neurology. 79 (22): 2177–9. doi:10.1212/WNL.0b013e31827595f7. PMID 23152589. Unknown parameter |month= ignored (help)
  12. Peltola, H.; Roine, I.; Fernández, J.; Zavala, I.; Ayala, SG.; Mata, AG.; Arbo, A.; Bologna, R.; Miño, G. (2007). "Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial". Clin Infect Dis. 45 (10): 1277–86. doi:10.1086/522534. PMID 17968821. Unknown parameter |month= ignored (help)
  13. Peltola, H.; Roine, I.; Fernández, J.; González Mata, A.; Zavala, I.; Gonzalez Ayala, S.; Arbo, A.; Bologna, R.; Goyo, J. (2010). "Hearing impairment in childhood bacterial meningitis is little relieved by dexamethasone or glycerol". Pediatrics. 125 (1): e1–8. doi:10.1542/peds.2009-0395. PMID 20008417. Unknown parameter |month= ignored (help)
  14. Nguyen, TH.; Tran, TH.; Thwaites, G.; Ly, VC.; Dinh, XS.; Ho Dang, TN.; Dang, QT.; Nguyen, DP.; Nguyen, HP. (2007). "Dexamethasone in Vietnamese adolescents and adults with bacterial meningitis". N Engl J Med. 357 (24): 2431–40. doi:10.1056/NEJMoa070852. PMID 18077808. Unknown parameter |month= ignored (help)
  15. Molyneux, EM.; Walsh, AL.; Forsyth, H.; Tembo, M.; Mwenechanya, J.; Kayira, K.; Bwanaisa, L.; Njobvu, A.; Rogerson, S. (2002). "Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial". Lancet. 360 (9328): 211–8. PMID 12133656. Unknown parameter |month= ignored (help)
  16. Schut, ES.; Brouwer, MC.; de Gans, J.; Florquin, S.; Troost, D.; van de Beek, D. (2009). "Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis". Neurology. 73 (23): 1988–95. doi:10.1212/WNL.0b013e3181c55d2e. PMID 19890068. Unknown parameter |month= ignored (help)
  17. van de Beek D, de Gans J, Tunkel AR, Wijdicks EF (2006) Community-acquired bacterial meningitis in adults. N Engl J Med 354 (1):44-53. DOI:10.1056/NEJMra052116 PMID: 16394301
  18. 18.0 18.1 18.2 van de Beek, D.; Brouwer, MC.; Thwaites, GE.; Tunkel, AR. (2012). "Advances in treatment of bacterial meningitis". Lancet. 380 (9854): 1693–702. doi:10.1016/S0140-6736(12)61186-6. PMID 23141618. Unknown parameter |month= ignored (help)