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The UK joint specialist societies guideline on the diagnosis and management of acute meningitis and meningococcal sepsis in immunocompetent adults

  • Author Footnotes
    x On behalf of the British Infection Association.
    F. McGill
    Correspondence
    Corresponding author. Institute of Infection and Global Health, Ronald Ross Building, University of Liverpool, 8 West Derby Street, Liverpool, L69 7BE, UK. Tel.: +44 0151 795 9606.
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, UK

    Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK

    Leeds Teaching Hospitals NHS Trust, UK
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    x On behalf of the British Infection Association.
    R.S. Heyderman
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Division of Infection & Immunity, University College London, UK
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  • Author Footnotes
    y On behalf of the Association of British Neurologists.
    B.D. Michael
    Footnotes
    y On behalf of the Association of British Neurologists.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    Walton Centre NHS Foundation Trust, Liverpool, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    S. Defres
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK

    NHS Tayside, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    N.J. Beeching
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, UK

    Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK

    Liverpool School of Tropical Medicine, UK
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  • Author Footnotes
    ab On behalf of Public Health England.
    R. Borrow
    Footnotes
    ab On behalf of Public Health England.
    Affiliations
    Vaccine Evaluation Unit, Public Health England, Manchester, UK
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  • Author Footnotes
    ac On behalf of the Meningitis Research Foundation.
    L. Glennie
    Footnotes
    ac On behalf of the Meningitis Research Foundation.
    Affiliations
    Meningitis Research Foundation, Bristol, UK
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  • Author Footnotes
    aa On behalf of the Society for Acute Medicine.
    O. Gaillemin
    Footnotes
    aa On behalf of the Society for Acute Medicine.
    Affiliations
    Salford Royal NHS Foundation Trust, UK
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  • Author Footnotes
    z On behalf of the Intensive Care Society.
    D. Wyncoll
    Footnotes
    z On behalf of the Intensive Care Society.
    Affiliations
    Guy's and St Thomas' NHS Foundation Trust, UK
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  • Author Footnotes
    ab On behalf of Public Health England.
    E. Kaczmarski
    Footnotes
    ab On behalf of Public Health England.
    Affiliations
    Public Health England, UK
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  • Author Footnotes
    ac On behalf of the Meningitis Research Foundation.
    S. Nadel
    Footnotes
    ac On behalf of the Meningitis Research Foundation.
    Affiliations
    St Mary's Hospital, London, UK

    Imperial College, London, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    G. Thwaites
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Nuffield Department of Medicine, Oxford University, UK

    Oxford University Clinical Research Unit, Ho Chi Minh City, Viet Nam
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  • Author Footnotes
    x On behalf of the British Infection Association.
    J. Cohen
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Brighton and Sussex Medical School, Brighton, UK
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  • Author Footnotes
    y On behalf of the Association of British Neurologists.
    N.W.S. Davies
    Footnotes
    y On behalf of the Association of British Neurologists.
    Affiliations
    Chelsea and Westminster Hospital NHS Foundation Trust, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    A. Miller
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    North Cumbria University Hospitals NHS Trust, UK
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  • Author Footnotes
    z On behalf of the Intensive Care Society.
    A. Rhodes
    Footnotes
    z On behalf of the Intensive Care Society.
    Affiliations
    St Georges University Hospitals NHS Foundation Trust, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    R.C. Read
    Footnotes
    x On behalf of the British Infection Association.
    Affiliations
    Clinical and Experimental Sciences Unit, University of Southampton, UK

    University Hospital Southampton NHS Foundation Trust, UK
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  • Author Footnotes
    y On behalf of the Association of British Neurologists.
    T. Solomon
    Footnotes
    y On behalf of the Association of British Neurologists.
    Affiliations
    Institute of Infection and Global Health, University of Liverpool, UK

    National Institute for Health Research Health Protection Research Unit on Emerging and Zoonotic Infections, UK

    Royal Liverpool and Broadgreen University Hospitals NHS Trust, UK

    Walton Centre NHS Foundation Trust, Liverpool, UK
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  • Author Footnotes
    x On behalf of the British Infection Association.
    y On behalf of the Association of British Neurologists.
    z On behalf of the Intensive Care Society.
    aa On behalf of the Society for Acute Medicine.
    ab On behalf of Public Health England.
    ac On behalf of the Meningitis Research Foundation.
Open AccessPublished:February 01, 2016DOI:https://doi.org/10.1016/j.jinf.2016.01.007

      Highlights

      • Up-to-date recommendations for managing adults with meningitis and meningococcal sepsis in the UK.
      • Includes viral meningitis
      • Includes audit tool
      • Includes algorithm

      Summary

      Bacterial meningitis and meningococcal sepsis are rare conditions with high case fatality rates. Early recognition and prompt treatment saves lives. In 1999 the British Infection Society produced a consensus statement for the management of immunocompetent adults with meningitis and meningococcal sepsis.
      Since 1999 there have been many changes. We therefore set out to produce revised guidelines which provide a standardised evidence-based approach to the management of acute community acquired meningitis and meningococcal sepsis in adults.
      A working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, public health experts and patient group representatives was formed. Key questions were identified and the literature reviewed. All recommendations were graded and agreed upon by the working party. The guidelines, which for the first time include viral meningitis, are written in accordance with the AGREE 2 tool and recommendations graded according to the GRADE system.
      Main changes from the original statement include the indications for pre-hospital antibiotics, timing of the lumbar puncture and the indications for neuroimaging. The list of investigations has been updated and more emphasis is placed on molecular diagnosis. Approaches to both antibiotic and steroid therapy have been revised. Several recommendations have been given regarding the follow-up of patients.

      Keywords

      Introduction

      Although bacterial meningitis and meningococcal sepsis are rare in adults and the average UK NHS district general hospital will see ten or fewer laboratory confirmed cases per year, they continue to carry a high morbidity and mortality. Delays in diagnosis and treatment can have disastrous consequences so prompt recognition and treatment are essential. The British Infection Society (the predecessor of the British Infection Association) published a consensus statement on the management of meningitis and meningococcal sepsis in adults in 1999.
      • Begg N.
      • Cartwright K.A.V.
      • Cohen J.
      • Kaczmarski E.B.
      • Innes J.A.
      • Leen C.L.S.
      • et al.
      Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults.
      This was followed by a management algorithm in 2003, which was produced and distributed by the Meningitis Research Foundation.
      • Heyderman R.S.
      • Lambert H.P.
      • O'Sullivan I.
      • Stuart J.M.
      • Taylor B.L.
      • Wall R.A.
      • et al.
      Early management of suspected bacterial meningitis and meningococcal septicaemia in adults.
      Since then, the epidemiology has changed, especially following changes in immunisation programmes, and there are new diagnostics and further data available regarding adjunctive treatments. In addition, global increases in the prevalence of antibiotic resistant bacteria underlines the importance of good antimicrobial stewardship. The partner organisations for these updated guidelines formed a working party consisting of infectious diseases physicians, neurologists, acute physicians, intensivists, microbiologists, paediatricians, public health experts and patient group representatives to review the literature published since 1999 and update the recommendations in light of any new evidence. The working party included representatives of the original authors from the 1999 consensus statement. The working party aimed to create user-friendly, comprehensive guidelines primarily for hospital-based clinicians in the UK with auditable outcomes. In addition to the published manuscript there is also an updated algorithm to aid emergency management. Key changes are highlighted in Box 1. These guidelines may also be useful to clinicians from other countries or settings, although there are other international guidelines available (Box 2).
      Key Changes since consensus document in 1999.
      • Updated epidemiology
      • Change in recommendations regarding pre-hospital antibiotics
      • Clear guidance on when to perform a CT scan
      • Recommended durations of antibiotics and adjunctive treatment including the removal of activated protein C.
      • Updated recommendations on empirical antibiotics
      • Recommendations regarding outpatient treatment
      • Updated guidance on prophylaxis for contacts
      • Infection control advice
      • The addition of a section on viral meningitis
      • Audit tool
      Guidelines which may be of use in other settings.

      Definitions

      Some definitions are given in Table 1.
      Table 1Definitions.
      MeningismSymptoms of headache, neck stiffness and photophobia often associated with meningitis
      MeningitisInflammation of the meninges

      Strictly a pathological diagnosis

      Elevated cerebrospinal fluid white cell count and protein are normally used as indicators of inflammation

      Meningeal enhancement may be seen on contrast enhanced CT or MRI
      SepsisPresence of infection with systemic manifestations such as:
      • Fever or hypothermia
      • Tachycardia
      • Tachypnoea
      • Altered mental state
      (see the surviving sepsis guidelines for a full list of potential manifestations of sepsis
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      )
      Severe sepsisAcute organ dysfunction secondary to documented or suspected sepsis
      Septic shockSevere sepsis plus hypotension not reversed with fluid resuscitation
      Meningococcal sepsisEvidence of sepsis with or without a characteristic petechial/purpuric skin rash and hypoperfusion. Neisseria meningitidis may be identified from blood, CSF or skin lesions (culture or PCR).
      Invasive meningococcal disease (IMD)Invasion of any normally sterile site by Neisseria meningitidis including meningitis and bacteraemia
      EncephalitisInflammation of the brain parenchyma

      Strictly a pathological diagnosis

      Elevated cerebrospinal fluid white cell count and protein normally used to indicate inflammation

      Parenchymal inflammation may be seen on MRI
      MeningoencephalitisInflammation of the meninges and adjoining brain parenchyma
      Aseptic MeningitisSymptoms of meningism and raised numbers of cells in the CSF with a sterile bacterial culture.

      Epidemiology

      Estimates of the incidence of bacterial meningitis and meningococcal sepsis in the UK are derived from several sources of information including clinical and laboratory statutory notifications, Hospital Episode Statistics and the Office of National Statistics. Although meningitis is a notifiable disease in the UK and in other countries, it is widely believed to be underreported.
      • Gjini A.
      • Stuart J.M.
      • George R.C.
      • Nichols T.
      • Heyderman R.S.
      capture-recapture analysis and pneumococcal meningitis estimates in England.
      • Brabazon E.D.
      • O'Farrell A.
      • Murray C.A.
      • Finnegan P.
      Trends in viral meningitis hospitalisations and notifications in the North Eastern Health Board (1997–2001): a cause for concern?.
      Several studies have shown reductions in the frequency of bacterial meningitis and meningococcal sepsis in recent years, although these largely reflect changes seen in children. Disease in adults has remained stable or increased.
      • Thigpen M.C.
      • Whitney C.G.
      • Messonnier N.E.
      • Zell E.R.
      • Lynfield R.
      • Hadler J.L.
      • et al.
      Bacterial meningitis in the United States, 1998–2007.
      • Gjini A.B.
      • Stuart J.M.
      • Lawlor D.A.
      • Cartwright K.
      • Christensen H.
      • Ramsay M.
      • et al.
      Changing epidemiology of bacterial meningitis among adults in England and Wales 1991–2002.
      A recent study in England and Wales showed an increase in the incidence of meningitis in adults between 2004 and 2011, with an increase of 3% per year in patients over 65 years of age. The incidence in adults was estimated to be 1.05 cases per 100,000 population (between 2004 and 2011) with the highest incidence in the 45–64 age group (1.21 per 100,000).
      • Okike I.O.
      • Ribeiro S.
      • Ramsay M.
      • Heath P.T.
      • Sharland M.
      • Ladhani S.N.
      Trends in bacterial, mycobacterial and fungal meningitis in England and Wales 2004-11: an observational study.
      The mortality rate of community acquired bacterial meningitis is high, approximately 20% for all causes and up to 30% in pneumococcal meningitis, increasing with age.
      • Chadwick D.
      • Lever A.
      The impact of new diagnostic methodologies in the management of meningitis in adults at a teaching hospital.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      The number of cases of invasive meningococcal disease (including meningitis and meningococcal sepsis) has declined over the last decade in the UK, following the introduction of the group C vaccine and the natural variation of meningococci. Meningococcal disease has a bimodal distribution with one peak in children less than 5 years of age and a second peak in the adolescent/early adult age group.
      Public Health England
      Meningococcal disease: laboratory confirmed cases in England and Wales.
      • Harrison L.H.
      • Pass M.A.
      • Mendelsohn A.B.
      • Egri M.
      • Rosenstein N.E.
      • Bustamante A.
      • et al.
      Invasive meningococcal disease in adolescents and young adults.
      • Barquet N.
      • Domingo P.
      • Cayla J.A.
      • Gonzalez J.
      • Rodrigo C.
      • Fernandez-Viladrich P.
      • et al.
      Meningococcal disease in a large urban population (Barcelona, 1987–1992): predictors of dismal prognosis. Barcelona Meningococcal Disease Surveillance Group.
      Amongst adults, the incidence of meningococcal disease is highest in younger adults, between the ages of 16–25.
      • Okike I.O.
      • Ribeiro S.
      • Ramsay M.
      • Heath P.T.
      • Sharland M.
      • Ladhani S.N.
      Trends in bacterial, mycobacterial and fungal meningitis in England and Wales 2004-11: an observational study.
      • Bijlsma M.W.
      • Bekker V.
      • Brouwer M.
      • Spanjaard L.
      • van de Beek D.
      • van der Ende A.
      Epidemiology of invasive meningococcal disease in the NEtherlands, 1960–2012:an analysis of national surveillance data.
      Other bacteria that cause meningitis in adults include Listeria monocytogenes (most commonly in older adults and the immunocompromised), Streptococcus pyogenes, Enterococcus species, Group B streptococcus, non-type B Haemophilus influenzae and other gram negative bacteria such as Klebsiella, Pseudomonas and Enterobacter.
      • Okike I.O.
      • Ribeiro S.
      • Ramsay M.
      • Heath P.T.
      • Sharland M.
      • Ladhani S.N.
      Trends in bacterial, mycobacterial and fungal meningitis in England and Wales 2004-11: an observational study.
      Mycobacterium tuberculosis should also be considered in those with appropriate risk factors, even in patients with an acute presentation.
      The likelihood of any specific aetiology depends on a range of factors, see Table 2 for some key considerations and risk factors. In many cases (34%–74%), no pathogen is identified.
      • Delerme S.
      • Castro S.
      • Viallon A.
      • Boutoille D.
      • Bendahou M.
      • Riou B.
      • et al.
      Meningitis in elderly patients.
      • Michael B.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.
      • Bonington A.
      • et al.
      Acute central nervous system infections in adults—a retrospective cohort study in the NHS North West region.
      • Harrell T.
      • Hammes J.S.
      Meningitis admitted to a military hospital: a retrospective case series.
      • de Ory F.
      • Avellon A.
      • Echevarria J.E.
      • Sanchez-seco M.P.
      • Trallero G.
      • Cabrerizo M.
      • et al.
      Viral infections of the Central nervous system in Spain: a prospective study.
      • Kupila L.
      • Vuorinen T.
      • Vainionpaa R.
      • Hukkanen V.
      • Marttila R.J.
      • Kotilainen P.
      Etiology or aseptic meningitis and encephalitis in an adult population.
      • Nowak D.A.
      • Boehmer R.
      • Fuchs H.H.
      A retrospective clinical, laboratory and outcome analysis in 43 cases of acute aseptic meningitis.
      Table 2Key aetiological considerations for specific demographic groups.
      Young adultsViral meningitis more common than bacterial, especially in women in their 20s–40s.

      Second peak of meningococcal disease in late teens/early 20s
      Older adultsPneumococcal disease more common in over 50s Listeria commoner in over 60s but remains rare.
      Skull fracture/CSF leakPneumococcal meningitis and a risk factor for recurrent meningitis
      Previous lymphocytic meningitisHSV-2 is the commonest cause of recurrent lymphocytic meningitis
      RashMeningococcal meningitis more likely to present with a rash than pneumococcal meningitis
      Co-existing upper respiratory tract infection e.g. otitis media, sinusitisPneumococcal meningitis is often associated with an upper respiratory tract infection
      HIV PositiveCryptococcal meningitis – commonest in those with a CD4 count <100 × 106 but should be considered in anyone with a CD4 count of <200 × 106 or <14%.

      TB meningitis an important consideration at all CD4 counts

      Pneumococcal meningitis also increased
      Other immunocompromisedAsplenic individuals are at increased risk from all encapsulated bacteria e.g. Streptococcus pneumoniae, Neisseria meningitidis and Haemophilus influenzae.

      Complement deficiency increases risk of meningococcal disease.

      Risk factors for listeria meningitis include relative immunocompromise from alcohol dependency, diabetes and malignancy as well as overt immunocompromised from illness or medication.
      Travel historyAn appropriate travel history may determine other rarer causes including Toscana Virus (Mediterranean), Tick Borne Encephalitis Virus (Central and Eastern Europe), other meningococcal (meningitis belt in Africa), West Nile Virus (USA), Lyme disease (appropriate exposure in Europe or USA) and parasitic meningitis (such as Naegleri fowleri – abundant globally occurring following visits to warm, fresh or brackish water, or trypanosomiasis – South America or parts of Africa).

      Aims and scope of the guidelines

      These guidelines cover the management of adults with suspected and confirmed acute meningitis and meningococcal sepsis, from pre-hospital care to post-discharge support, including clinical features, investigations, treatment, follow-up and prevention. As previously the guidelines focus on bacterial meningitis and meningococcal sepsis but now also include a section on viral meningitis which is increasing in relative importance. Meningitis in immunocompromised individuals, post-surgical/iatrogenic meningitis and tuberculous meningitis are beyond the scope of these guidelines and not considered further. Guidelines on the management of tuberculous meningitis
      • Thwaites G.
      • Fisher M.
      • Hemingway C.
      • Scott G.
      • Solomon T.
      • Innes J.
      British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous system in adults and children.
      and the management of bacterial meningitis and sepsis in children are available elsewhere.
      Guideline Development Group

      Methods

      A literature search was performed in Medline for all English language articles from the years 1999–2014 to identify all publications since the first British Infection Society guidelines were published using the key words ‘meningitis’ AND ‘symptoms’; ‘signs’; ‘management’; ‘diagnosis’; ‘investigation’; ‘lumbar puncture’; ‘cerebrospinal fluid’; ‘computed tomography (CT)’; ‘magnetic resonance imaging (MRI)’; ‘treatment’; ‘antiviral’; ‘antibiotic’; ‘steroids/dexamethasone’; ‘prevention’; ‘risk factors’ and ’immunocompromise’ separately and in combination with the following MESH terms: (Viral, meningococcal, pneumococcal, Haemophilus, bacterial). This yielded a total of 5027 citations. The working party identified the main questions that we wanted to address (see Box 3); titles and abstracts were reviewed by one author (FM) to eliminate articles that were not relevant to these questions. This left 621 articles which were then reviewed in full by 3 members of the writing group (BDM, FM, SD) to remove any further articles that were felt not to be helpful in answering the questions identified; mostly these were case reports or studies relevant to specific populations only. This resulted in 284 potentially relevant articles that were made available to the whole working party. All authors could also add to this core list of publications other articles, for example those published before 1999; this included many referenced in the original consensus statement.
      • Begg N.
      • Cartwright K.A.V.
      • Cohen J.
      • Kaczmarski E.B.
      • Innes J.A.
      • Leen C.L.S.
      • et al.
      Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults.
      A further literature search was done (by BDM and FM) prior to publication to identify any further relevant articles that had been published in the interim.
      Key questions.
      • What are the indications for hospital admission?
      • What should the pre-hospital management be?
      • What are the clinical signs to look for including early recognition?
      • What is the initial assessment and immediate action?
      • Are prognostic or diagnostic scores of any value?
      • What are the contraindication to LP?
      • What are the indications for imaging?
      • What investigations should be requested?
        • Microbiological
        • Biochemical
        • Haematological
        • Others (including travel related)
      • When should an HIV test be offered?
      • What treatment should be given?
        • Empirical
        • Directed
        • Adjunctive
      • What is the role of steroids?
      • What is the role of glycerol?
      • When should you refer to specialists/intensive care?
      • What is the role for fluid management, inotropes and indications for ventilation?
      • What should the intensive care management be?
      • What preventative measures should/can be taken? (including notification and primary and secondary prevention)
      • What are the appropriate infection control measures?
      • Who should be screened for predisposing factors?
      • What should follow up look like? (including the role of support services)
      • How should viral meningitis be investigated and treated?
      • What are the auditable measures? (to include an audit tool)
      • When should this guideline be reviewed?
      Using this final list of articles each section was written by a primary author and reviewed by others from the working party before being reviewed by the whole working party. When a final draft was agreed upon by the working party it was then sent for a first consultation to the boards and councils of all the partner organisations and then a second consultation to all the members of the partner organisations.
      A single document was assimilated in accordance with the principles of the AGREE 2 (appraisal of guideline research and evaluation) tool,
      • Brouwers M.
      • Kho M.E.
      • Browman G.P.
      • Burgers J.S.
      • Cluzeau F.
      • Feder G.
      • et al.
      AGREE II: advancing guideline development, reporting and evaluation in healthcare.
      and we used the GRADE approach to grade the strength of evidence (see Table 3).
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Where recommendations are not based on published evidence but were agreed on by the working party, they are graded as “authors' recommendation” or “AR”.
      Table 3GRADE rating system for the strength of the guidelines recommendations and the quality of the evidence.
      • Guyatt G.H.
      • Oxman A.D.
      • Vist G.E.
      • Kunz R.
      • Falck-Ytter Y.
      • Alonso-Coello P.
      • et al.
      GRADE: an emerging consensus on rating quality of evidence and strength of recommendations.
      Strength of the recommendationQuality of the evidence
      1 Strongly recommendedA High quality – RCT, meta-analysis
      2 Weakly recommendedB Moderate quality – downgraded RCT or an upgraded observational study
      C Low quality – Observational study

      D Very low quality – downgraded observational study.
      a: Factors that may influence the grading of quality of evidence
      Factors that might decrease the quality of evidenceFactors that might increase the quality of evidence
      Study LimitationsLarge magnitude of effect
      Inconsistency of resultsPlausible confounding, which would reduce a demonstrated effect
      Indirectness of evidenceDose-response gradient
      Imprecision
      Publication bias
      b. Factors that determine the strength of a recommendation
      Balance between desirable and undesirable effects
      Quality of evidence
      Values and preferences
      Costs of the intervention
      RCT = Randomised controlled trial.

      Presentation

      Pre-hospital management

      What are the indications for hospital admission and what are the clinical signs to look for?

      Recommendations

      • 1.
        All patients where meningitis and/or meningococcal sepsis is suspected in the community should be referred to hospital for further evaluation and consideration of a lumbar puncture (1C)
      • 2.
        Rapid admission to hospital, via an emergency ambulance, should be arranged so that, where possible, the patient arrives within an hour of being assessed in the community (AR)
      • 3.
        Presence or absence of headache, altered mental status, neck stiffness, fever, rash (of any description), seizures and any signs of shock (e.g. hypotension, poor capillary refill time) should be documented (1C)
      • 4.
        Kernig's sign and Brudzinski's sign should not be relied upon for diagnosis (2B)

      Rationale

      The diagnosis of meningitis and meningococcal sepsis may seem relatively straightforward in patients with classical features of fever, headache, neck stiffness and altered mental status in the case of meningitis or fever, purpuric rash and shock in meningococcal sepsis but in many patients some of these signs will be absent.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      • Attia J.
      • Hatala R.
      • Cook D.J.
      • Wong J.G.
      Does this adult patient have acute meningitis?.
      • Wiberg K.
      • Birnbaum A.
      • Gradon J.
      Causes and presentation of meningitis in a Baltimore Community Hospital 1997–2006.
      The problem for general practitioners and acute physicians is to identify, from the large number of patients who present with symptoms consistent with meningitis or meningococcal sepsis, the small minority of patients who do in fact have these conditions and require urgent investigation and management.

      Clinical features of meningitis

      Urgent hospital referral is mandatory in adults in whom meningitis or meningococcal sepsis is suspected in view of the possibility of rapid deterioration. The individual common clinical signs such as fever, vomiting, headache and neck stiffness occur frequently in primary care and taken independently are poor discriminators for meningitis.
      • Granier S.
      • Owen P.
      • Pill R.
      • Jacobson L.
      Recognising meningococcal disease in primry care: qualitative study of how general practitioners process clinical and contextual information.
      Combinations of symptoms and signs may be more useful at identifying serious disease. Although bacterial meningitis is of greater concern, clinical features alone cannot distinguish between viral and bacterial disease and in specific populations, such as the elderly or immunocompromised, the clinical presentation may be different. For example, the elderly are more likely to have an altered conscious level than their younger counterparts and less likely to have neck stiffness or fever.
      • Magazzini S.
      • Nazerian P.
      • Vanni S.
      • Paladini B.
      • Pepe G.
      • Casanova B.
      • et al.
      Clinical picture of meningitis in the adult patient and its relationship with age.
      • Domingo P.
      • Pomar V.
      • de Benito N.
      • Coll P.
      The specturm of acute bacterial meningitis in elderly patients.
      • Shah K.
      • Richard K.
      • Edlow J.A.
      Utility of Lumbar puncture in the Afebrile Vs Febrile elderly patient with altered mental status: a pilot study.
      Age can also be an indicator of the likely causative agent. Listeria or pneumococcal disease is more common in older people, viral meningitis commonly occurs in adults in their 20s–40s and meningococcal infection in adolescents and young adults.
      • Thigpen M.C.
      • Whitney C.G.
      • Messonnier N.E.
      • Zell E.R.
      • Lynfield R.
      • Hadler J.L.
      • et al.
      Bacterial meningitis in the United States, 1998–2007.
      • Delerme S.
      • Castro S.
      • Viallon A.
      • Boutoille D.
      • Bendahou M.
      • Riou B.
      • et al.
      Meningitis in elderly patients.
      • Magazzini S.
      • Nazerian P.
      • Vanni S.
      • Paladini B.
      • Pepe G.
      • Casanova B.
      • et al.
      Clinical picture of meningitis in the adult patient and its relationship with age.
      In the largest single published study on bacterial meningitis in adults Van de Beek and colleagues describe the clinical and laboratory features in 696 episodes of bacterial meningitis.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      The ‘classic triad’ of neck stiffness, fever and altered consciousness was present in less than 50% of cases.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      Other studies have shown similar findings.
      • Attia J.
      • Hatala R.
      • Cook D.J.
      • Wong J.G.
      Does this adult patient have acute meningitis?.
      • Stockdale A.J.
      • Weekes M.P.
      • Aliyu S.H.
      An audit of acute bacterial meningitis in a large teaching hospital 2005–10.
      • Durand M.L.
      • Calderwood S.B.
      • Weber D.J.
      • Miller S.I.
      • Southwick F.S.
      • Caviness Jr., V.S.
      • et al.
      Acute bacterial meningitis in adults: a review of 493 episodes.
      Patients with pneumococcal disease are more likely to have seizures, focal neurological symptoms and a reduced conscious level (as determined by the Glasgow Coma Scale (GCS)). When a rash was present in the context of meningitis, the causative organism was Neisseria meningitidis in 92% of cases (the rash was petechial in 89% of these). However, 37% of cases of meningococcal meningitis patients did not have a rash. Kernig's and Brudzinski's signs are not helpful in the clinical diagnosis of suspected meningitis; they have been reported to have high specificity (up to 95%) but the sensitivity can be as low as 5%.
      • Attia J.
      • Hatala R.
      • Cook D.J.
      • Wong J.G.
      Does this adult patient have acute meningitis?.
      • Thomas K.E.
      • Hasbun R.
      • Jekel J.
      • Quagliarello V.J.
      The diagnostic accuracy of Kernig's sign, Brudzinski's sign, and nuchal rigidity an adults with suspected meningitis.
      • Brouwer M.C.
      • Thwaites G.
      • Tunkel A.R.
      • van de Beek D.
      Dilemmas in the diagnosis of acute community-acquired bacterial meningitis.
      • Uchihara T.
      • Tsukagoshi H.
      Jolt accentuation of headache: the most sensitive sign of CSF pleocytosis.
      • Waghdhare S.
      • Kalantri A.
      • Joshi R.
      • Kalantri S.
      Accuracy of physical signs for detecting meningitis: a hospital-based diagnostic accuracy study.
      As the clinical features are often not clear cut, concern from either the referring doctor or a relative should always be taken seriously.
      • Van den Bruel A.
      • Aertgeerts B.
      • Brutninckx R.
      • Aerts M.
      • Buntinx F.
      Signs and symptoms for diagnosis of serious infections in children: a prospective study in primary care.
      In addition to the above, a history of travel, the presence of a source of infection such as otitis media or sinusitis, or contact with another person with meningitis or sepsis should be ascertained.

      Additional features of meningococcal sepsis and shock

      Meningitis is the commonest presentation of meningococcal disease, occurring in about 60% of patients. 10–20% of patients may have evidence of shock or fulminant sepsis with or without meningitis and up to 30% of patients may have mild disease with just fever and a rash with no evidence of either meningitis or shock.
      • Stephens D.S.
      • Greenwood B.
      • Brandtzaeg P.
      Epidemic meningitis, meningococcaemia and Neisseria meningitidis.
      Meningococcal sepsis can present with hypotension, altered mental state and rash; typically this is purpuric or petechial in nature but it may take other forms including a maculopapular rash. Patients with meningococcal sepsis can deteriorate rapidly, and shock ensues; they must be monitored frequently even if they initially look well.
      Shock in meningococcal sepsis results from a combination of hypovolaemia (caused by capillary leak syndrome), myocardial dysfunction, altered vasomotor tone and in some instances, adrenal insufficiency.
      • Oragui E.E.
      • Nadel S.
      • Kyd P.
      • Levin M.
      Increased excretion of urinary glycosaminoglycans in meningococcal septicemia and their relationship to proteinuria.
      • Boucek M.M.
      • Boerth R.C.
      • Artman M.
      • Graham T.P.
      • Boucek R.J.
      Myocardial dysfunction in children with acute meningococcaemia.
      The clinical features of shock arise because perfusion of the vital organs (such as the brain and heart) is maintained at the expense of perfusion of the skin, kidneys and gut. In the early phases of shock these processes compensate for hypovolaemia and maintain central circulating blood volume, blood pressure and cardiac output. As a result, patients with meningococcal sepsis often present with cold peripheries and prolonged capillary refill time as well as oliguria. In the most severe cases, ischaemia of the skin or even whole limbs may occur, particularly if there is thrombosis in areas of vascular stasis. In addition, many patients with septic shock will develop renal dysfunction, often leading to acute kidney injury.
      • Harrison L.H.
      • Pass M.A.
      • Mendelsohn A.B.
      • Egri M.
      • Rosenstein N.E.
      • Bustamante A.
      • et al.
      Invasive meningococcal disease in adolescents and young adults.
      The pathophysiology is fully reviewed by Pathan and colleagues.
      • Pathan N.
      • Faust S.N.
      • Levin M.
      Pathophysiology of meningococcal meningitis and septicaemia.
      Despite severe shock, in healthy young people and adolescents preservation of brain perfusion and function is often maintained until relatively late, so that the young person's relatively alert state may make nursing and medical staff under-estimate the degree of cardiovascular collapse. Eventually cerebral dysfunction indicates loss of cerebral vascular homeostasis and reduced brain perfusion.
      The onset of hypotension signifies a failure of the compensatory mechanisms. It should be remembered that shock in young people is not always accompanied by the presence of arterial hypotension (cryptic shock), but may be indicated by the presence of a high blood lactate level (>4 mmol/L). Risk factors for a fatal outcome in meningococcal sepsis are shown in Box 4.
      Risk factors for a fatal outcome in meningococcal disease.
      Tabled 1
      Rapidly progressing rash
      Coma
      Hypotension and shock
      Lactate >4 mmol/L
      Low/normal peripheral white blood cell count
      Low acute phase reactants
      Low platelets
      Coagulopathy
      Absence of meningitis
      The Surviving Sepsis guidelines also provide additional guidance on the management of patients with suspected sepsis.
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      Should antibiotics be given prior to admission?

      Recommendations

      • 5.
        Antibiotics should be given to patients in the community in whom there are signs of meningococcal disease e.g. a rash in combination with signs of meningism or severe sepsis (1D)
      • 6.
        Antibiotics should be given to patients in the community in whom there are signs of severe sepsis e.g. hypotension, poor capillary refill time, altered mental state (1D)
      • 7.
        Antibiotics should be given to patients in the community, with suspected meningitis, who will have a delay of more than one hour in getting to hospital (2D)
      • 8.
        If antibiotics are given in the community they should be in the form of Benzylpenicillin 1200 mg IM or IV, or a third generation cephalosporin such as Cefotaxime (2 g) or Ceftriaxone (2 g) IM or IV (1C)
      • 9.
        In the case of known anaphylaxis to penicillins or cephalosporins, antibiotics should not be given until admission to hospital (AR)
      • 10.
        The administration of parenteral antibiotics should not delay transfer to hospital (1D)

      Rationale

      The aim of pre-hospital antibiotics is to reduce the mortality associated with delays in antibiotic therapy.
      • Miner J.R.
      • Heegaard W.
      • Mapes A.
      • Biros M.
      Presentation, time to antibiotics, and mortality of patients with bacterial meningitis at an urban county medical center.
      • Proulx N.
      • Frechette D.
      • Toye B.
      • Chan J.
      • Kravcik S.
      Delays in the administration of antibiotics are associated with mortality from acute bacterial meningitis.
      • Auburtin M.
      • Wolff M.
      • Charpentier J.
      • Varon E.
      • Tulzo Y.L.
      • Girault C.
      • et al.
      Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study.
      • Koster-Rasmussen R.
      • Korshin A.
      • Meyer C.N.
      Antibiotic treatment delay and outcome in acute bacterial meningitis.
      However there are some drawbacks to this approach; these include the risk of allergic reaction to the antibiotic and the need to consider concurrent steroid administration to reduce complications associated with pneumococcal meningitis. In addition, antibiotic treatment before lumbar puncture (LP) can alter the initial diagnostic investigations, reducing the likelihood of identifying bacteria from cerebrospinal fluid (CSF) culture, and may lead to the misdiagnosis of bacterial meningitis as viral.
      • Wylie P.A.I.
      • Stevens D.
      • Drake W.D.
      • Stuart J.
      • Cartwright K.
      Epidemiology and clinical management of meningococcal disease in west Gloucestershire: retrospective population absed study.
      • Michael B.
      • Menezes B.
      • Cunniffe J.
      • Miller A.
      • Kneen R.
      • Francis G.
      • et al.
      Effect of delayed lumbar punctures on the diagnosis of acute bacterial meningitis in adults.
      Molecular diagnostics such as the polymerase chain reaction (PCR), can detect pathogens up to 9 days after antibiotics have been given
      • Bryant P.A.
      • Li H.Y.
      • Zaia A.
      • Griffith J.
      • Hogg G.
      • Curtis N.
      • et al.
      Prospective study of a real-time PCR that is highly sensitive, specific, and clinically useful for diagnosis of meningococcal disease in children.
      • Bronska E.
      • Kalmusova J.
      • Dzupova O.
      • Maresova V.
      • Kriz P.
      • Benes J.
      Dynamics of PCR-based diagnosis in patients with invasive meningococcal disease.
      but they do not give antibiotic susceptibilities which remain vital.
      Two systematic reviews investigating pre-hospital antibiotics in meningococcal meningitis have been carried out in recent years.
      • Sudarsanam T.D.
      • Rupali P.
      • Tharyan P.
      • Abraham O.C.
      • Thomas K.
      Pre-admission antibiotics for suspected cases of meningococcal disease.
      • Hahne S.J.
      • Charlett A.
      • Purcell B.
      • Samuelsson S.
      • Camaroni I.
      • Ehrhard I.
      • et al.
      Effectiveness of antibiotics given before admission in reducing mortality from meningococcal disease: systematic review.
      One
      • Sudarsanam T.D.
      • Rupali P.
      • Tharyan P.
      • Abraham O.C.
      • Thomas K.
      Pre-admission antibiotics for suspected cases of meningococcal disease.
      only identified a single trial, based during an epidemic in Niger, that met their inclusion criteria of randomised (or quasi randomised) controlled trials comparing antibiotics with placebo/no intervention.
      • Nathan N.
      • Borel T.
      • Djibo A.
      • Evans D.
      • Djibo S.
      • Corty J.F.
      • et al.
      Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study.
      The other identified 14 studies, all of which were observational. The studies used oral or parenteral antibiotics and five stratified by disease severity. Overall these systematic reviews do not provide evidence for or against the use of pre-hospital antibiotics and it is unlikely further randomised controlled trials will be undertaken. However, given the evidence that in general early antibiotics reduce mortality, it would seem prudent that they are used as soon as possible in patients with a strong suspicion of bacterial meningitis, especially if there are signs indicative of a worse outcome,
      • Aronin S.I.
      • Peduzzi P.
      • Quagliarello V.J.
      Community acquired bacterial meningitis risk stratification for adverse clinical outcome and effect of antibiotic timing.
      or where there may be a delay in hospital admission. Pre-hospital antibiotics should also be given if the patient is thought to have meningococcal disease in view of the potential for rapid catastrophic deterioration. If antibiotics are given in the community this must not delay hospital admission. As benzylpenicillin, cefotaxime and ceftriaxone have good CSF penetration in inflamed meninges and can be given via the intramuscular route as well as intravenously they are good options for use in the community. If there is known anaphylaxis to these beta-lactam antibiotics, treatment should be delayed until admission to hospital when appropriate antibiotics can be given.

      Immediate action within the first hour of arriving at hospital

      What should the initial hospital assessment and immediate action be?

      Recommendations

      • 11.
        Stabilisation of the patient's airway, breathing and circulation should be an immediate priority (AR).
      • 12.
        A decision regarding the need for senior review and/or intensive care admission should be made within the first hour (AR).
      • 13.
        The patient's conscious level should be documented using the Glasgow coma scale (2C).
      • 14.
        Blood cultures should be taken as soon as possible and within 1 h of arrival at hospital (AR)
      • 15.
        In patients with suspected meningitis (with no signs of shock or severe sepsis)
        • LP should be performed within 1 h of arrival at hospital provided that it is safe to do so (1D)
        • treatment should be commenced immediately after the LP has been performed, and within the first hour (1B)
        • If the LP cannot be performed within 1 h treatment should be commenced immediately after blood cultures have been taken and LP performed as soon as possible after that (1B)
      • 16.
        In patients with predominantly sepsis or a rapidly evolving rash:
        • Antibiotics should be given immediately after blood cultures have been taken (AR)
        • Fluid resuscitation should be commenced immediately with an initial bolus of 500 ml of crystalloid (1B)
        • The Surviving sepsis guidelines should be followed (AR)
        • LP should not be performed at this time (1D)
      • 17.
        All clinicians managing such patients should have postgraduate training on the initial management of acute bacterial meningitis and meningococcal sepsis [AR]
      • 18.
        Patients with meningitis and meningococcal sepsis should be cared for with the input of an infection specialist such as a microbiologist or a physician with training in infectious diseases and/or microbiology [AR].

      Rationale

      The priority for patients admitted with suspected meningitis is to a) stabilise their airway, breathing and circulation, b) begin appropriate investigations, and c) instigate prompt treatment. These three things should largely happen concurrently. All patients should be reviewed by a senior clinician. The Royal College of Physicians recommend consultant review for all acute medical patients within 14 h of admission. Most patients with suspected meningitis or meningococcal sepsis should be seen much earlier than this. The need for urgent review should be assessed early using the National Early Warning Score.
      • Royal College of Physicians
      National early warning score (NEWS): standardising the assessment of acute illness severity in the NHS.
      An aggregate score of 5/6 (or a score of 3 in any single physiological parameter) should prompt an urgent review by a clinician competent to assess acutely ill patients; a score of 7 or more should prompt an urgent assessment by a team with critical care competencies. Clinicians should, however, not be falsely reassured if the early warning score is lower than these parameters, because patients with meningitis, and meningococcal sepsis in particular, can deteriorate rapidly. In addition the presence or absence of a rash and the use of pre-admission antibiotics should be recorded for all patients. The GCS should be recorded both for its prognostic value, and to allow changes to be monitored. A GCS of ≤8 is associated with a poor outcome.
      • Merkelbach S.
      • Rohn S.
      • Konig J.
      • Muller M.
      Usefulness of clinical scores to predict outcome in bacterial meningitis.
      The GCS also helps with decisions about whether it is safe to perform a LP (see Box 5). Blood cultures should be taken as soon as possible and certainly within 1 h of presentation, prior to the prompt administration of antibiotics.
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      Indications for neuroimaging before lumbar puncture (LP) in suspected meningitis*.
      Tabled 1
      • Focal neurological signs
      • Presence of papilloedema**
      • Continuous or uncontrolled seizures
      • GCS12***
      *to exclude significant brain swelling and shift that may predispose to cerebral herniation post LP.
      **inability to view the fundus is not a contraindication to LP, especially in patients who have had a short duration of symptoms.
      *** LP without prior neuroimaging may be safe at levels below this.

      Patients with suspected meningitis (without shock or any signs of meningococcal sepsis)

      Ideally the LP should also be performed before starting antibiotics in order to allow the best chance of a definitive diagnosis. This may require the equipment, facilities and personnel to carry out LPs to be available within the emergency department. The need for a rapid LP has to be weighed against the desire to start antimicrobial treatment urgently.
      • Grindborg O.
      • Naucler P.
      • Sjolin J.
      • Glimaker M.
      Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians.
      Even if treatment has been initiated, a LP should still be performed as soon as possible, preferably within 4 h of commencing antibiotics, to help identify the cause of meningitis. The culture rate can drop off rapidly after that time and it can become difficult to identify the causative bacteria in cases of bacterial meningitis.
      • Grindborg O.
      • Naucler P.
      • Sjolin J.
      • Glimaker M.
      Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians.
      Intravenous antibiotics should be given promptly in hospital as there is evidence that delays increase mortality.
      • Proulx N.
      • Frechette D.
      • Toye B.
      • Chan J.
      • Kravcik S.
      Delays in the administration of antibiotics are associated with mortality from acute bacterial meningitis.
      • Auburtin M.
      • Wolff M.
      • Charpentier J.
      • Varon E.
      • Tulzo Y.L.
      • Girault C.
      • et al.
      Detrimental role of delayed antibiotic administration and penicillin-nonsusceptible strains in adult intensive care unit patients with pneumococcal meningitis: the PNEUMOREA prospective multicenter study.
      • Koster-Rasmussen R.
      • Korshin A.
      • Meyer C.N.
      Antibiotic treatment delay and outcome in acute bacterial meningitis.

      Patients with suspected meningococcal sepsis, suspected meningitis with shock or a rapidly evolving rash

      In patients with suspected meningococcal sepsis, or meningitis with shock, the priority is circulatory stabilization although there is conflicting evidence surrounding the amount and type of fluid to be used. In shocked patients fluid resuscitation should be given carefully in boluses of 500 ml monitoring the patient for fluid overload with an initial fluid bolus of 500 ml of crystalloid given rapidly (over 5–10 min). Shock may be rapidly reversed by this initial fluid bolus, but repeated review is necessary. In such critically ill patients careful fluid resuscitation should continue, aiming to achieve the therapeutic endpoints for surviving sepsis shown in Box 6.
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      Vasopressors may be necessary if shock does not respond to initial fluid challenges but this should be instituted in a critical care setting. In keeping with international guidance on the management of sepsis, if there are any signs of severe sepsis or septic shock antibiotics should be given immediately and certainly within the first hour.
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      Initial therapeutic endpoints in the resuscitation of septic shock
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.
      Tabled 1
      Capillary refill time less than 2 s

      Normal blood pressure for age (in adults > 65 mmHg mean BP)

      Normal pulses with no differential between peripheral and central pulses

      Warm extremities

      Urine output >0.5 ml/kg/hour (A urinary catheter is required)

      Normal mental status

      Central venous pressure 8–12 mmHg

      Lactate < 2 mmol/L
      Bacterial meningitis and meningococcal sepsis are rare medical emergencies. Therefore, it is essential that all doctors who may encounter a case are adequately trained. In addition specialists in the management of infectious diseases should be consulted early as there is some observational evidence that patient outcomes are improved if they are managed by a specialist.
      • Grindborg O.
      • Naucler P.
      • Sjolin J.
      • Glimaker M.
      Adult bacterial meningitis-a quality registry study: earlier treatment and favourable outcome if initial management by infectious diseases physicians.

      Lumbar punctures and imaging

      Which patients with suspected meningitis should have a lumbar puncture (LP)?

      Recommendations

      • 1.
        Patients should not have neuroimaging before their LP unless there is a clinical indication suggestive of brain shift (see Box 5) (1D)
      • 2.
        If prior neuroimaging is indicated an LP should be performed as soon as possible after the neuroimaging unless:
        • a.
          neuroimaging reveals significant brain shift (1D)
        • b.
          An alternative diagnosis is established (AR)
        • c.
          The patient's clinical condition precludes an LP by having continued seizures, rapidly deteriorating GCS or cardiac/respiratory compromise (AR)
      • 3.
        Regardless of neuroimaging considerations LP should be delayed/avoided in the following situations (AR):
        • a
          Respiratory or cardiac compromise
        • b.
          Signs of severe sepsis or a rapidly evolving rash
        • c.
          Infection at the site of the LP
        • d.
          A coagulopathy
      When should a lumbar puncture be performed in patients who are on anticoagulants?

      Recommendations

      • 4.
        If a neurological infection is suspected on admission prophylactic subcutaneous low molecular weight heparin (LMWH) should not be started until 4 h after the LP is performed (AR)
      • 5.
        In patients already on prophylactic LMWH the LP should not be performed until 12 h after the dose (AR)
      • 6.
        Prophylactic LMWH should be delayed until 4 h after a LP (AR)
      • 7.
        Patients on therapeutic LMWH should not have an LP until 24 h after a dose (AR)
      • 8.
        Therapeutic intravenous unfractionated heparin can be restarted 1 h after an LP (2C)
      • 9.
        In patients on warfarin LP should not be performed until INR is ≤1.4 (2D)
      • 10.
        Patients on aspirin and other non-steroidal anti-inflammatories do not need to have their LP delayed (1C)
      • 11.
        In patients on clopidogrel an LP should be delayed for 7 days or until a platelet transfusion or desmopressin (DDAVP) is given – these should be discussed with a haematologist and the risk benefit ratio of performing a LP discussed (AR)
      • 12.
        Expert advice, from a haematologist, must be sought for those patients on newer anticoagulants such as apixaban, dabigatran etexilate and rivaroxaban (AR)
      • 13.
        In patients with known thrombocytopenia LP should not be performed at platelet counts of <40 × 109/L or with a rapidly falling platelet count (1D)
      • 14.
        LP should not be delayed for the results of blood tests unless there is a high clinical suspicion of a bleeding diathesis (AR)
      • 15.
        In situations where a LP is not possible immediately, this should be reviewed at 12 h and regularly thereafter (AR)

      Should diagnostic scoring systems be used?

      • 16.
        Diagnostic scoring systems are not recommended (1D).

      Rationale

      A LP is an essential investigation in the management of patients with suspected meningitis. In the majority of patients this can be performed without prior neuroimaging, though this has been a controversial area.
      • Kneen R.
      • Solomon T.
      • Appleton R.
      The role of lumbar puncture in children with suspected central nervous system infection.
      • Joffe A.R.
      Lumbar puncture and brain herniation in acute bacterial meningitis: a review.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      • Glimaker M.
      • Johansson B.
      • Bell M.
      • Ericsson M.
      • Blackberg J.
      • Brink M.
      • et al.
      Early Lumbar Puncture in adult bacterial meningitis - rationale for revised guidelines.
      Performing a CT scan before the LP is associated with delays in antibiotics, which in turn can lead to an increase in mortality.
      • Michael B.
      • Sidhu M.
      • Stoeter D.
      • Roberts M.
      • Beeching N.
      • Bonington A.
      • et al.
      Acute central nervous system infections in adults—a retrospective cohort study in the NHS North West region.
      • Proulx N.
      • Frechette D.
      • Toye B.
      • Chan J.
      • Kravcik S.
      Delays in the administration of antibiotics are associated with mortality from acute bacterial meningitis.
      A CT scan should only be performed if there are clinical signs suggestive of a shift of brain compartments. This is because there is a theoretical risk that a lumbar puncture, by lowering the pressure, might make such shift worse, resulting in a brain herniation syndrome. If there are signs suggestive of brain shift, the CT scan may identify any space occupying lesions, brain swelling or shift, although these may occur in the context of a normal brain CT.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      The CT scan does not detect raised intracranial pressure. The clinical features indicative of a possible shift of brain compartments include focal neurological signs and a reduced GCS (Box 5). The exact level of GCS at which a CT scan is indicated is debated.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      Guideline Development Group
      • Kneen R.
      • Solomon T.
      • Appleton R.
      The role of lumbar puncture in children with suspected central nervous system infection.
      • Joffe A.R.
      Lumbar puncture and brain herniation in acute bacterial meningitis: a review.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      • Addy D.
      When not to do a lumbar puncture.
      • van Crevel H.
      • Hijdra A.
      • de Gans J.
      Lumbar puncture and the risk of herniation: when should we first perform CT?.
      A range of values has been suggested ranging from a GCS of <8 to <13.
      • Chaudhuri A.
      • Martinez-Martin P.
      • Kennedy P.G.
      • Seaton A.R.
      • Portegies P.
      • Bojar M.
      • et al.
      EFNS guideline on the management of community acquired bacterial meningitis: report of an EFNS Task Force on acute bacterial meningitis in older children and adults.
      • Solomon T.
      • Michael B.D.
      • Smith P.E.
      • Sanderson F.
      • Davies N.W.S.
      • Hart I.
      • et al.
      National ABN/BIA guideline for the management of encephalitis for adults.
      Some guidelines just state ‘abnormal level of consciousness’,
      • Tunkel A.R.
      • Hartman B.J.
      • Kaplan S.L.
      • Kaufman B.A.
      • Roos K.L.
      • Scheld M.
      • et al.
      Practice guidelines for the management of bacterial meningitis.
      meaning obtunded/not alert or unresponsive.
      • Hasbun R.
      • Abrahams J.
      • Jekel J.
      • Quagliarello V.J.
      Computed tomography of the head before lumbar puncture in adults with suspected meningitis.
      We recommend that an LP can be performed without prior neuroimaging if the GCS is >12 and may be safer at lower levels. Those with a GCS12 will require a brain scan but should first be assessed by a critical care physician and intubation may be considered.
      Of note, in 2009, the Swedish guidelines for the management of meningitis changed their recommendations and removed altered conscious level as an indication for CT before LP. A subsequent study compared the management of approximately 400 patients before and 300 after the change in guidelines; it showed that after the change, antimicrobial treatment was started on average 1.2 h earlier, and the mortality was lower, (6.9% vs 11.7%) with a lower risk of sequelae (38% vs 49%).
      • Glimåker M.
      • Johansson B.
      • Grindborg Ö.
      • Bottai M.
      • Lindquist L.
      • Sjölin J.
      Adult bacterial meningitis: earlier treatment and improved outcome following guideline revision promoting prompt lumbar puncture.
      Whilst there may have been other changes implemented during this time period that led to the improved outcomes it does support the fact that patients do not suffer excess harm or mortality when an LP is performed without a CT scan.
      Some authorities also suggest ‘immunocompromise’ as a reason to perform a CT scan before an LP. Whilst we recognise that immunocompromised patients may be more at risk of intracranial mass lesions we find no evidence that they would be at any increased risk of cerebral herniation if they presented without the clinical signs indicated in Box 5.
      If neurological imaging is performed and no contraindication is found the LP should be performed as soon as possible afterwards (unless an alternative diagnosis has been made in the interim).

      Lumbar puncture and clotting abnormalities

      Subdural haematoma is a potential complication of an LP; although the exact incidence of post-LP haematomas is unknown the risk is increased if the LP is performed in patients with abnormal clotting. However, there is little objective evidence on which to guide safe clotting parameters for LP in patients with neurological infections. In line with the UK Department of Health's recommendations on venothromboembolic disease
      • National Institute for Health and Care Excellence
      Venous thromboembolism: reducing the risk. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital.
      we recommend for patients already on prophylactic LMWH the LP should not be performed until 12 h after the last dose. If patients have not commenced on LMWH the LP should be performed as soon as possible and prophylactic LMWH can be started 4 h afterwards. The duration of action of LMWH will be longer in patients with severe renal impairment and coagulation parameters such as the APTTr, may need to be checked in such cases.
      • National Institute for Health and Care Excellence
      Venous thromboembolism: reducing the risk. Reducing the risk of venous thromboembolism (deep vein thrombosis and pulmonary embolism) in patients admitted to hospital.
      • Horlocker T.T.
      • Wedel D.J.
      • Rowlingson J.C.
      • Enneking F.K.
      • Kopp S.L.
      • Benzon H.T.
      • et al.
      Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American society of regional anesthesia and pain medicine evidence-based guidelines (Third edition).
      For patients who are on higher doses of LMWH an LP should not be performed within 24 h of therapeutic LMWH.
      • Layton K.F.
      • Kallmes D.F.
      • Horlocker T.T.
      Recommendations for anticoagulated patients undergoing image-guided spinal procedures.
      There have been large observational studies evaluating unfractionated heparin and spinal or epidural anaesthesia. In these studies the risk of spinal haematomas was negligible in patients in whom the heparin was given after at least 60 min.
      • Rao T.L.K.
      • El Etr A.A.
      Anticoagulation following placement of epidural and subarachnoid catheters: an evaluation of neurologic sequelae.
      • Ruff R.L.
      • Dougherty J.H.
      Complications of lumbar puncture followed by anticoagulation.
      Extrapolating from this we recommend that unfractionated heparin can be restarted 1 h after an LP.
      In patients on warfarin the risks of reversing the warfarin will need to be weighed against the benefits of performing an LP. An LP should not be routinely performed at an INR of ≥1.5.
      • Horlocker T.T.
      Regional anaesthesia in the patient receiving antithrombotic and antiplatelet therapy.
      • Association of Anaesthetists of Great Britain and Ireland
      • Obstetric Anaesthetists'Association
      • Regional Anaesthesia UK
      Regional anaesthesia and patients with abnormalities of coagulation.
      Therapy with aspirin or non-steroidal anti-inflammatory medications alone does not increase the risk of spinal haematoma after LP
      • Horlocker T.T.
      • Wedel D.J.
      • Schroeder D.R.
      • Rose S.H.
      • Elliott B.A.
      • McGregor D.G.
      • et al.
      Preoperative antiplatelet therapy does not increase the risk of spinal hematoma associated with regional anesthesia.
      and LP does not need to be delayed in patients who are taking these drugs. Clopidogrel inhibits platelet aggregation for the whole lifespan of the platelet which is between 7 and 10 days.
      • Patel I.J.
      • Davidson J.C.
      • Nikolic B.
      • Salazar G.M.
      • Schwartzberg M.S.
      • Walker G.
      • et al.
      Consensus guidelines for periprocedural managment of coagulation status and hemostasis risk in percutaneous image-guided interventions.
      If the benefits of performing the LP are deemed to outweigh the risks, in consultation with a haematologist, a platelet transfusion can be given 6–8 h after the last dose of clopidogrel) prior to LP. Patients receiving the newer oral anticoagulants such as apixaban, dabigatran etexilate and rivaroxaban should be discussed with a haematologist. Trials are ongoing regarding specific reversal agents for these drugs and a monoclonal antibody fragment, specifically aimed at dabigatran, has recently been approved by the European Medicines Agency.
      • Pollack C.V.
      • Reilly P.A.
      • Eikelboom J.
      • Glund S.
      • Verhamme P.
      • Bernstein R.A.
      • et al.
      Idarucizumab for dabigatran reversal.
      There may be a role for reversal agents prior to LP in the future but these cases should be discussed with a specialist.
      The evidence regarding a platelet count at which it is safe to perform a LP mostly comes from patients with haematological malignancies, obstetric patients and patients requiring regional anaesthesia. The risk of the procedure must be balanced against the benefits of having a definitive diagnosis. A recent review of the literature by van Veen has suggested that a platelet count of >40 × 109/L is safe and that even lower counts may be acceptable, depending on the individual case.
      • van Veen J.J.
      • Nokes T.J.
      • Makris M.
      The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals.
      In addition to the absolute platelet count both the trend and the cause of thrombocytopenia must be taken into consideration: a rapidly falling platelet count is likely to be a higher risk than a stable thrombocytopenia; similarly, thrombocytopenia secondary to chronic idiopathic thrombocytopenic purpura probably carries a lower risk than thrombocytopenia due to DIC. The majority of the studies (five of seven) identified in van Veen's review were in paediatrics, and all were in patients with cancer and not infection. In the patients who developed complications after LP this was almost always in the presence of another risk factor such as rapidly falling platelet count, other coagulopathy or traumatic LP. Unless there is a strong suspicion that the patient will have a clotting abnormality the LP should not be delayed to await the results of blood tests.
      If there is any reason to delay the LP initially this decision should be reviewed regularly and consideration given to performing the procedure later if the diagnosis has not been confirmed by other means.
      A low pressure type headache is a much more common complication following LP and can occur in up to a third of patients.
      • van Oosterhout W.P.
      • van der Plas A.A.
      • van Zwet E.W.
      • Zielman R.
      • Ferrari M.D.
      • Terwindt G.M.
      Postdural puncture headache in migraineurs and nonheadache subjects: a prospective study.
      Some methods and myths associated with the prevention of a post LP headache are shown in Box 7.
      Methods to reduce headache post lumbar puncture.
      Tabled 1
      Definition and aetiology

      Headache following a lumbar puncture (LP) typically has a low-pressure phenotype; i.e. worse upright and better lying flat. It is usually caused by a dural tear sustained at the time of LP and does not relate to the volume of cerebrospinal fluid (CSF) taken. In most cases it is self-limiting although a few patients may require a blood patch for persistent headache, and rarely the low pressure may be associated with the development of subdural haematomas.

      Practices associated with reduced risk of post-LP headache
      • 1.
        Finer gauge needles
        • Tourtellotte W.W.
        • Henderson W.G.
        • Tucker R.P.
        • Gilland L.O.F.
        • Walker J.E.
        • Kokman E.
        A randomized, double-blind clinical trial comparing the 22 versus 26 gauge needle in the production of the post-lumbar puncture syndrome in normal individuals.
        • Carson D.
        • Serpell M.
        Choosing the best needle for diagnostic lumbar puncture.
      • 2.
        Risk of headache decreases with smaller gauge needles, but this needs to be balanced with the length of time the procedure will take with a very fine needle. Practically a 22G needle is probably the smallest that can be used.
      • 3.
        Non-traumatic (less traumatic) needles
        • Carson D.
        • Serpell M.
        Choosing the best needle for diagnostic lumbar puncture.
        • Thomas S.R.
        • Jamieson D.R.
        • Muir K.
        Randomised controlled trial of atraumatic versus standard needles for diagnostic lumbar puncture.
        • Paraesthesia rate and failure rate may be higher with these needles
      • 4.
        Orientation of the bevel of the needle in a transverse plane (perpendicular to the longitudinal axis)
        • Norris M.C.
        • Leighton B.L.
        • DeSimone C.A.
        Needle bevel direction and headache after inadvertent dural puncture.
        • Richman J.M.
        • Joe E.M.
        • Cohen S.R.
        • Rowlingson A.J.
        • Michaels R.K.
        • Jeffries M.A.
        • et al.
        Bevel direction and postdural puncture headache.
        • This is probably less important if an atraumatic needle is being used.
      • 5.
        Replacement of the stylet before withdrawing the needle
        • Strupp M.
        • Brandt T.
        • Muller A.
        Incidence of postlumbar puncture syndrome reduced by reinserting the stylet: a randomized prospective study of 600 patients.
      • 6.
        Experience of performing LPs and number of attempts at LP
        • MacArthur C.
        • Lewis M.
        • Know E.G.
        Accidental dural puncture in obstetric patients and long term symptoms.
        • Fewer attempts at dural puncture is thought to be associated with a decreased incidence of headache after lumbar puncture.
      Practices NOT proven to reduce risk of post LP headache
      • 1.
        Reducing the volume of CSF taken
        • Kuntz K.M.
        • Kokmen E.
        • Stevens J.C.
        • Miller P.
        • Offord K.P.
        • Ho M.M.
        Post-lumbar puncture headaches: experience in 501 consecutive procedures.
        • There is no evidence that the amount of CSF removed influences the incidence of post LP headache
      • 2.
        Bed rest
        • Sung R.K.
        • Hyun S.C.
        • Mi J.Y.
        • Jung H.H.
        • Kwang J.C.
        • Sun J.C.
        No effect of recumbency duration on the occurrence of post-lumbar puncture headache with a 22G cutting needle.

        Carbaat PAT, Crevel HV. Lumbar puncture headache: controlled study on the preventive effect of 24 hours' bed rest. Lancet 318(8256):1133–1135. 2049

        • Patients are often advised to lie recumbent for a period of time after an LP but there is no evidence that this reduces the risk of headache.
      • 3.
        Hydration
        • Dieterich M.
        • Brandt T.
        Incidence of post-lumbar puncture headache is independent of daily fluid intake.
        • There has only been one study looking at fluid post LP as a preventative strategy and it showed no difference between those who took 1.5 L and those who had 3 L post LP.
      • 4.
        Caffeine
        • There have been some experiments looking at IV caffeine to treat post LP headache but there is no evidence that either oral or IV caffeine can prevent the headache.

      Diagnostic scoring systems

      Several scoring systems have been developed to try and help clinicians differentiate bacterial meningitis from other forms of meningitis, especially viral, based mostly on the initial CSF findings.
      • Nigrovic L.E.
      • Malley R.
      • Kuppermann N.
      Meta-analysis of bacterial meningitis score validation studies.
      • Bonsu B.K.
      • Harper M.B.
      Differentiating acute bacterial meningitis from acute viral meningitis among children with cerebrospinal fluid pleocytosis. A multivariable regression model.
      • Spanos A.
      • Harrell F.E.
      • Durack D.T.
      Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations.
      • Brivet F.G.
      • Ducuing S.
      • Jacobs F.
      • Chary I.
      • Pompier R.
      • Prat D.
      • et al.
      Accuracy of Clinical Presentation for differentiating bacterial from viral meningitis in adults: a multivariate approach.
      • Tokuda Y.
      • Koizumi M.
      • Dtein G.
      • Birrer R.B.
      Identifying low-risk patient for bacterial meningitis in adult patients with acute meningitis.
      • Chavanet P.
      • Schaller C.
      • Levy C.
      • Flores-Cordero J.
      • Arens M.
      • Piroth L.
      • et al.
      Performance of a predictive rule to distinguish bacterial and viral meningitis.
      • Hoen B.
      • Viel J.F.
      • Paquot C.
      • Gerard A.
      • Canton P.
      Multivariate approach to differential diagnosis of acute meningitis.
      • Thwaites G.E.
      • Chau T.T.H.
      • Stepniewska K.
      • Phu N.H.
      • Chuong L.V.
      • Sinh D.X.
      • et al.
      Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features.
      • Hasbun R.
      • Bijlsma M.
      • Brouwer M.C.
      • Khoury N.
      • Hadi C.M.
      • van der Ende A.
      • et al.
      Risk score for identifying adults with csf pleocytosis and negative csf gram stain at low risk for an urgent treatable cause.
      This is because CSF culture results can take some time, and an early indicator, based on initial CSF results, would allow unnecessary antibiotics to be stopped and patients deemed to have viral meningitis to be discharged. In addition to requiring CSF data, many rely on plasma glucose, which is often not performed; while others require complex calculations which are impractical in a busy acute medical setting. Most have been developed in paediatric settings, only been tested retrospectively and have not been externally validated although there has been a recent score developed prospectively for adults
      • Hasbun R.
      • Bijlsma M.
      • Brouwer M.C.
      • Khoury N.
      • Hadi C.M.
      • van der Ende A.
      • et al.
      Risk score for identifying adults with csf pleocytosis and negative csf gram stain at low risk for an urgent treatable cause.
      ). No clinical predictor tool has been widely translated to use in routine clinical practice and we do not recommend their use.

      Investigations

      Laboratory investigations help establish the aetiology of meningitis and sepsis, especially differentiating between viral and bacterial causes, identify antibiotic resistant organisms, assist with prognosis and guide public health management including infection control, immunisation for the patient and contacts, and antibiotic prophylaxis (Fig. 1).
      What investigations should be performed for suspected meningitis or meningococcal sepsis?

      Recommendations

      • 1.
        In all patients with suspected meningitis and/or meningococcal sepsis blood should be sent for:
        • a.
          Culture (prior to antibiotics wherever possible) (1C).
        • b.
          If antibiotics have been given in the community blood cultures should be taken as soon as possible on arrival in hospital (within the first hour) (1C)
        • c.
          Pneumococcal and meningococcal PCR (EDTA sample) (1C)
        • d.
          Storage, to enable serological testing if a cause is not identified (a convalescent serum sample should also be sent 4–6 weeks later – discuss with microbiologist) [1C]
        • e.
          Glucose measurement (1C)
        • f.
          Lactate measurement (1C)
        • g.
          Procalcitonin (if available) (2C)
        • h.
          Full blood count, urea, creatinine, electrolytes, liver function tests and clotting screen
      • 2.
        In all patients in whom a LP is performed the following should be documented/requested: [1C]
        • a.
          CSF opening pressure (unless the LP is performed in the sitting position).
        • b.
          CSF glucose with concurrent plasma glucose
        • c.
          CSF protein
        • d.
          CSF lactate (if prior antibiotics have not been given) (2B)
        • e.
          CSF for microscopy, culture and sensitivities
      • 3.
        CSF PCR for pneumococci and meningococci should be performed in all cases of suspected bacterial meningitis[1C]
      • 4.
        CSF should be stored for later tests if initial investigations do not yield a pathogen [1C]
      • 5.
        A swab of the posterior nasopharyngeal wall should be obtained as soon as possible, and sent for meningococcal culture, in all cases of suspected meningococcal meningitis/sepsis [1C]
      • 6.
        Any significant bacterial isolates (including meningococci identified from the nasopharynx) should be sent to the relevant national reference laboratory for serotyping [1C]

      Rationale

      Blood tests

      Blood cultures should be taken in all cases of suspected bacterial meningitis or meningococcal sepsis. Ideally this should be before any antibiotics are given, when the yield can be as high as 74%. If a patient received antibiotics before hospital admission, blood cultures should be taken as soon as possible after arrival in hospital. Non-culture diagnostics approaches to pathogen identification, such as PCR, are becoming increasingly important. PCR of peripheral blood increases the laboratory confirmation rate in meningococcal disease substantially, especially as it will remain positive for several days after antibiotics have been initiated.
      • Newcombe J.
      • Cartwright K.
      • Palmer W.H.
      • McFadden J.
      PCR of peripheral blood for diagnosis of meningococcal disease.
      There are fewer data on the sensitivity and specificity of blood PCR in patients with pneumococcal meningitis, though a small paediatric study showed it to be useful,
      • Azzari C.
      • Moriondo M.
      • Indolfi G.
      • Massai C.
      • Becciolini L.
      • de Martino M.
      • et al.
      Molecular detection methods and serotyping performed directly on clinical samples improve diagnostic sensitivity and reveal increased incidence of invasive disease by Streptococcus pneumoniae in Italian children.
      and a multiplex PCR was highly sensitive in another study.
      • Tzanakaki G.
      • Tsopanomichalou M.
      • Kesanopoulos K.
      • Matzourani R.
      • Sioumala M.
      • Tabaki A.
      • et al.
      Simultaneous single-tube PCR assay for the detection of Neisseria meningitidis, Haemophilus influenzae type b and Streptococcus pneumoniae.
      There is a concern that in children PCR of blood for pneumococci can be positive without evidence of invasive disease, presumably because of asymptomatic carriage,
      • Dagan R.
      • Shriker O.
      • Hazan I.
      • Leibovitz E.
      • Greenberg D.
      • Schlaeffer F.
      • et al.
      Prospective study to determine clinical relevance of detection of pneumococcal DNA in sera of children by PCR.
      the same has not been shown in adults. However, in adults with features of bacterial meningitis a positive PCR in the blood can be a useful adjunct for diagnosing the aetiological cause.
      Serological assays may also play a role in the diagnosis of meningitis caused by mumps, syphilis or Lyme disease for example. If no pathogen is identified on first line testing, an acute serum sample should be taken and stored and a convalescent sample taken at 4–6 weeks. These tests should be discussed with local infection specialists.
      Glucose must be taken at the same time as the LP in order to allow interpretation of the CSF glucose. Lactate measurement is useful in the management of anyone with suspected sepsis and if raised can provide useful guidance for resuscitation (Box 6).
      Serum procalcitonin can be helpful for the differentiation of bacterial and viral infections. It has a sensitivity of 95% and a specificity of 100% (PPV – 97–100%; NPV – 93.9–100%) for distinguishing bacterial meningitis from viral in adults.
      • Viallon A.
      • Zeni F.
      • Lambert C.
      • Pozzetto B.
      • Tardy B.
      • Venet C.
      • et al.
      High sensitivity and specificity of serum procalcitonin levels in adults with bacterial meningitis.
      • Morales Casado M.I.
      • Moreno Alonso F.
      • Juarez Belaunde A.L.
      • Heredero Galvez E.
      • Talavera Encinas O.
      • Julian-Jimenea A.
      Ability of procalcitonin to predict bacterial meningitis in the emergency department.
      Its routine use is limited by its availability and cost although a recent meta-analysis has suggested it might be cost effective in the paediatric setting.
      • Bell J.M.
      • Shields M.D.
      • Agus A.
      • Dunlop K.
      • Bourke T.
      • Kee F.
      • et al.
      Clinical and cost-effectiveness of procalcitonin test for prodromal meningococcal disease-a meta-analysis.
      A recent technology assessment by the UK National Institute of Health and Care Excellence (NICE) has found that whilst procalcitonin assays show promise there is currently insufficient evidence to recommend routine adoption into the NHS. However, it should be noted that they did not consider any studies looking at meningitis. They also accepted that some centres do use procalcitonin to guide management – these centres were encouraged to take part in relevant data collection and research. As a result we continue to recommend the use of procalcitonin if it is available.
      • National Institute of Health and Care Excellence
      Procalcitonin testing for diagnosing and monitoring sepsis.

      CSF

      Initial CSF analysis of cells protein and glucose helps determine the likely cause of meningitis; subsequent microscopy and culture can confirm the aetiology and antibiotic susceptibilities. The use of pre-prepared LP packs, with all the necessary sampling tubes may increase the diagnostic yield.
      • Michael B.D.
      • Powell G.
      • Curtis S.
      • Bailey L.
      • Almond S.
      • McGill F.
      • et al.
      Improving the diagnosis of central nervous system infections in adults through introduction of a simple lumbar puncture pack.
      Often inappropriately small volumes of CSF are taken limiting the number of investigations that can be performed. As CSF is produced at a rate of approximately 22 ml/h (similar to urine) amounts of at least 15 ml can be safely removed from adults.
      • Huang T.
      • Chung H.
      • Chen M.
      • Giiang L.
      • Chin S.
      • Chen C.Y.
      • et al.
      Supratentorial cerebrospinal fluid production rate in healthy adults: quantification with two-dimensional cine phase contrast MR imaging with high temporal and spatial resolution.
      • Rubin R.C.
      • Henderson E.S.
      • Ommaya A.K.
      • Walker M.D.
      • Rall D.P.
      The production of cerebrospinal fluid in man and its modifications by acetazolamide.
      CSF opening pressure should always be measured when doing a lumbar puncture (unless it is done in the sitting position, when it will be artificially raised because of the positioning). The opening pressure is normally elevated above 20 cm CSF in bacterial meningitis, and is often higher.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.

      CSF cell count

      In acute bacterial meningitis there is classically a polymorphonuclear pleocytosis in the CSF (see Table 4) but there are always exceptions to the rule. There can be minimal, even no white cells, especially early on in the course of the illness; in one study 10% of patients had fewer than 100 cells per mm3.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      • Onorato I.M.
      • Wormser G.P.
      • Nicholas P.
      'Normal' CSF in bacterial meningitis.
      • Kelly C.
      • Sohal A.
      • Michael B.D.
      • Riordan A.
      • Solomon T.
      • Kneen R.
      Suboptimal management of central nervous system infections in children: a multi-centre retrospective study.
      There may be a predominance of lymphocytes in some cases of bacterial meningitis e.g. listeria or partially treated bacterial meningitis.
      • Arevalo C.E.
      • Barnes P.F.
      • Duda M.
      • Leedom J.M.
      Cerebrospinal fluid cell counts and chemistries in bacterial meningitis.
      A predominance of neutrophils may also be seen in early viral meningitis,
      • Negrini B.
      • Kelleher K.J.
      • Wald E.
      Cerebrospinal fluid findings in aseptic versus bacterial meningitis.
      especially enteroviral disease, although such patients are unlikely to have a total CSF white cell count of over 2000 cells per mm3.
      • Spanos A.
      • Harrell F.E.
      • Durack D.T.
      Differential diagnosis of acute meningitis. An analysis of the predictive value of initial observations.
      Table 4Classical CSF Features of the different causes of meningitis.
      NormalBacterialViralTuberculousFungal
      Opening Pressure (cm CSF)12–20RaisedNormal/mildly raisedRaisedRaised
      AppearanceClearTurbid, cloudy, purulentClearClear or cloudyClear or cloudy
      CSF WCC (cells/uL)<5Raised (typically >100)
      Occasionally the CSF WCC may be normal (especially in immunodeficiency or tuberculous meningitis).
      Raised (typically 5–1000)
      Occasionally the CSF WCC may be normal (especially in immunodeficiency or tuberculous meningitis).
      Raised (typically 5–500)
      Occasionally the CSF WCC may be normal (especially in immunodeficiency or tuberculous meningitis).
      Raised (typically 5–500)
      Occasionally the CSF WCC may be normal (especially in immunodeficiency or tuberculous meningitis).
      Predominant cell typen/aNeutrophils
      May be lymphocytic if antibiotics given before lumbar puncture (partially treated bacterial meningitis), or with certain bacteria e.g. Listeria monocytogenes.
      Lymphocytes
      May be neutrophilic in enteroviral meningitis (especially early in disease).
      Lymphocytes
      May be neutrophils early on in the course of disease.
      Lymphocytes
      CSF protein (g/L)<0.4RaisedMildly raisedMarkedly raisedRaised
      CSF glucose (mmol)2.6–4.5Very lowNormal/slightly lowVery lowLow
      CSF/plasma glucose ratio>0.66Very lowNormal/slightly lowVery lowLow
      CSF – cerebrospinal fluid; WCC – white cell count.
      Local laboratory ranges for biochemical tests should be consulted and may vary from these quoted here.
      A traumatic lumbar puncture will affect the results by falsely elevating the white cells due to excessive red cells. A common correction factor used is 1:1000.
      a Occasionally the CSF WCC may be normal (especially in immunodeficiency or tuberculous meningitis).
      b May be lymphocytic if antibiotics given before lumbar puncture (partially treated bacterial meningitis), or with certain bacteria e.g. Listeria monocytogenes.
      c May be neutrophilic in enteroviral meningitis (especially early in disease).
      d May be neutrophils early on in the course of disease.

      CSF biochemistry

      The CSF glucose, protein and lactate are all useful for differentiating viral, bacterial and other causes of meningitis. The values can give valuable pointers to the likely aetiology but are not usually definitive because of overlap between the different diseases. Bacterial meningitis tends to have a higher CSF protein than viral meningitis and one study found that a patient is unlikely to have bacterial disease if the CSF protein is less than 0.6 g/L.
      • White K.
      • Ostrowski K.
      • Maloney S.
      • Norton R.
      The Utility of cerebrospinal fluid parameters in the early microbiological assessment of meningitis.
      The CSF glucose is lowered in bacterial meningitis; however the concentration also varies according to the plasma glucose and so the CSF:plasma glucose ratio should be used. Normally CSF glucose is about two thirds of the plasma glucose. In bacterial meningitis the ratio is usually significantly lower than this, a CSF:plasma glucose ratio cut off of 0.36 for diagnosing bacterial meningitis has a high sensitivity and specificity (93%).
      • Tamune H.
      • Takeya H.
      • Suzuki W.
      • Tagashira Y.
      • Kuki T.
      • Honda H.
      • et al.
      Cerebrospinal fluid/blood glucose ratio as an indicator for bacterial meningitis.
      Unfortunately plasma glucose is often not performed in clinical practice, and so the CSF glucose must be interpreted in isolation. One report suggest a CSF glucose of above 2.6 mmol/L is unlikely to be associated with bacterial meningitis.
      • Leen W.G.
      • Willemsen M.A.
      • Wevers R.A.
      • Verbeen M.M.
      Cerebrospinal fluid glucose and lactate: age -specific reference values and implications for clinical practice.
      No CSF parameters give an absolute indication of cause, and any CSF results must be interpreted in the context of the clinical presentation.
      CSF lactate has a high sensitivity and specificity (93% and 96% respectively) in distinguishing between bacterial and viral meningitis if antibiotics had not been given beforehand. A CSF lactate cut off of 35 mg/dl has been suggested to have the best sensitivity for distinguishing between bacterial and viral meningitis. If patients have received antibiotics the sensitivity drops to less than 50%.
      • Sakushima K.
      • Hayashino Y.
      • Kawaguchi T.
      • Jackson J.L.
      • Fukuhara S.
      Diagnostic accuracy of cerebrospinal fluid lactate for differentiating bacterial meningitis from aseptic meningitis: a meta-analysis.
      The high negative predictive value makes it a useful test, if done prior to commencing antibiotics, to rule out bacterial meningitis and reassurance to stop or withhold antibiotics.

      CSF gram stain and culture

      Gram stain of the CSF is a rapid method for detecting bacteria with a sensitivity of between 50 and 99% (dependent on organism and prior antibiotics) and a specificity of 97–100%.
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial meningitis.
      Cytospin centrifugation of CSF can increase the yield.
      • Shanholtzer C.J.
      • Schaper P.J.
      • Peterson L.R.
      Concentrated gram stain smears prepared with a cytospin centrifuge.
      The gold standard for the diagnosis of bacterial meningitis is CSF culture. Depending on whether prior antibiotics have not been given, and depending on the infecting organism, it is diagnostic in 70–85% of cases of bacterial meningitis.
      • Bohr V.
      • Rasmussen N.
      • Hansen B.
      • Kjersem H.
      • Jessen O.
      • Johnsen N.
      • et al.
      875 cases of bacterial meningitis: diagnostic procedures and the impact of preadmission antibiotic therapy. Part III of a three-part series.
      CSF sterilization may occur within the first 2 h of administration of antibiotics for meningococci and within 4 h for pneumococci.
      • Kanegaye J.T.
      • Soliemanzadeh P.
      • Bradley J.S.
      Lumbar puncture in pediatric bacterial meningitis: defining the time interval for recovery of cerebrospinal fluid pathogens after parenteral antibiotic pretreatment.
      However, even if rendered culture negative, CSF analysis may be helpful up to 48 h after commencing parenteral antibiotics.

      CSF PCR

      CSF PCR can rapidly identify the causative organism in meningitis and is especially useful if antibiotics have been given prior to LP. PCR has a sensitivity of 87–100% and specificity of 98–100%
      • Poppert S.
      • Essig A.
      • Stoehr B.
      • Steingruber A.
      • Wirths B.
      • Juretschko S.
      • et al.
      Rapid diagnosis of bacterial meningitis by real-time PCR and fluorescence in situ hybridization.
      • Richardson D.C.
      • Louie L.
      • Louie M.
      • Simor A.E.
      Evaluation of a rapid PCR assay for diagnosis of meningococcal meningitis.
      • Singhi S.G.
      • Mohankumar D.
      • Singhi P.D.
      • Sapru S.
      • Ganguly N.K.
      Evaluation of ploymerase chain reaction (PCR) for diagnosing Haemophilus influenzae b meningitis.
      • Balganesh M.
      • Lalitha M.K.
      • Nathaniel R.
      Rapid diagnosis of acute pyogenic meningitis by a combined PCR dot-blot assay.
      . If an organism cannot be identified by pathogen specific PCR, then PCR for 16S ribosomal RNA, which is present in almost all bacteria may be used, although it has lower specificity.
      • Srinivasan L.
      • Pisapia R.
      • Shah S.
      • Halpern C.
      • Harris M.
      Can broad-range 16S ribosomal ribonucleic acid gene polymerase chain reactions improve the diagnosis of bacterial meningitis? a systematic review and meta analysis.
      Multiplex PCR and other platforms that can detect multiple pathogens at the same time are increasingly being trialled and can reduce time and increase sensitivity.
      • Hsu C.C.
      • Tokarz R.
      • Briese T.
      • Tsai H.C.
      • Quan P.L.
      • Lipkin W.I.
      Use of staged molecular analysis to determine causes of unexplained central nervous system infections.
      • Wang Y.
      • Guo G.
      • Wang H.
      • Yang X.
      • Shao F.
      • Yang C.
      • et al.
      Comparative study of bacteriological culture and real-time fluorescence quantitative PCR (RT-PCR) and multiplex PCR-based reverse line blot (mPCR/RLB) hybridization assay in the diagnosis of bacterial neonatal meningitis.
      • Rhein J.
      • Bahr N.C.
      • Hemmert A.C.
      • Cloud J.L.
      • Bellamkonda S.
      • Oswald C.
      • et al.
      Diagnostic performance of a multiplex PCR assay for meningitis in an HIV-infected population in Uganda.
      We would recommend that each diagnostic laboratory evaluate any tests prior to use.

      Latex agglutination tests

      The bacteria commonly causing meningitis carry specific polysaccharide surface antigens that can be detected by agglutination tests on the CSF. They have largely been surpassed by the use PCR and are not recommended except in large outbreak situations where rapid PCR is not available.
      Some CSF should also be stored in order to be used for further investigations if necessary.

      Nasopharyngeal isolates

      Meningococci can be isolated from the nasopharynx in up to 50% of patients with meningococcal disease. If patients have started antibiotics nasal swabs may still be positive when blood and CSF cultures are negative, although these data predates the widespread use of empirical cephalosporins.
      • Cartwright K.
      • Reilly S.
      • White D.
      • Stuart J.
      Early treatment with parenteral penicillin in meningococcal disease.
      Given that many patients are diagnosed by PCR alone (in the blood and/or CSF), without a cultured isolate, nasopharyngeal swabs should be taken to attempt to grow an organism which is important for surveillance and determination of vaccine coverage. Such isolates are almost always identical to those from their blood or CSF (when culture of these samples has been successful)
      • Cartwright K.
      • Jones D.M.
      Value of throat swabs from index cases of meningococcal meningitis.
      • Sippel J.E.
      • Girgis N.I.
      Throat culture from patients with meningococcal meningitis.
      but the possibility of asymptomatic and irrelevant carriage should be considered – especially if the clinical picture is not compatible with acute meningococcal meningitis. All significant isolates (from any site) should be referred to the relevant reference laboratory.
      Streptococcus pneumoniae is also carried asymptomatically in the nose but there are often multiple strains and it is not clear that the strain in the nose is definitely related to that which causes meningitis, hence nasal swabbing is not recommended for pneumococcal disease.

      Treatment

      What antibiotic treatment should be given empirically? (Table 5 and Fig. 2)
      Table 5Empirical antibiotic choices.
      Preferred choiceAlternative
      Adults <60 years of age
      Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci are prevalent (if unsure, check with local infectious diseases/microbiology expertise).
      Cefotaxime 2 g 6 hourly

      OR

      Ceftriaxone 2 g 12 hourly
      Chloramphenicol 25 mg/kg 6 hourly
      Adults ≥60 years of age
      Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci are prevalent (if unsure, check with local infectious diseases/microbiology expertise).
      Cefotaxime 2 g 6 hourly

      OR

      Ceftriaxone 2 g 12 hourly

      AND

      Amoxicillin 2 g 4 hourly
      Chloramphenicol 25 mg/kg 6 hourly

      AND

      Co-trimoxazole 10–20 mg/kg (of the trimethoprim component) in four divided doses
      a Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci are prevalent (if unsure, check with local infectious diseases/microbiology expertise).
      Figure thumbnail gr2
      Figure 2Algorithm for the empirical treatment of suspected meningitis.

      Recommendations

      • 1.
        All patients with suspected meningitis or meningococcal sepsis should be given 2 g ceftriaxone intravenously (IV) every 12-h or 2 g cefotaxime IV every 6-h [1B]
      • 2.
        If the patient has, within the last 6 months, been to a country where penicillin resistant pneumococci are prevalent, IV vancomycin 15–20 mg/kg should be added 12-hourly (or 600 mg rifampicin 12-hourly IV or orally) [1C]
      • 3.
        Those aged 60 or over should receive 2 g IV ampicillin/amoxicillin 4-hourly in addition to a cephalosporin [1B].
      • 4.
        Immunocompromised patients (including diabetics and those with a history of alcohol misuse) should receive 2 g IV ampicillin/amoxicillin 4-hourly in addition to a cephalosporin [1B].
      • 5.
        If there is a clear history of anaphylaxis to penicillins or cephalosporins give IV chloramphenicol 25 mg/kg 6-hourly [1C]

      Rationale

      The choice of antibiotics in patients with bacterial meningitis is a three stage process, with initial empirical decisions based on clinical suspicion, modified once CSF Gram stain is available, and then again if CSF culture results are positive. Antimicrobial penetration into the CSF is dependent on lipid solubility, molecular size, capillary and choroid plexus efflux pumps, protein binding, and the degree of inflammation of the meninges.
      • Andes D.R.
      • Craig W.A.
      Pharmacokinetics and pharmacodynamics of antibiotics in meningitis.
      Although there is little high quality trial evidence to guide the antibiotics used in suspected meningitis and meningococcal sepsis the choice of empirical antibiotic is based largely on known pharmacokinetics, the likely infecting organism and known or suspected antimicrobial resistance patterns. Third generation cephalosporins
      • Prasad K.
      • Kumar A.
      • Singhal T.
      • Gupta P.K.
      Third generation cephalosporins versus conventional antibiotics for treating acute bacterial meningitis.
      have known bactericidal activity for both pneumococci and meningococci and penetrate inflamed meninges; as such they are the empirical antibiotic of choice in most settings where resistance rates are low.
      Rates of pneumococcal resistance to penicillin in the UK are low, but a travel history may indicate that a patient with meningitis has recently been in a country with high rates of pneumococcal resistance (Box 8). If a patient has visited such a country in the last 6 months, then vancomycin or rifampicin should be added to the empirical antibiotics. Up to date European and worldwide data on resistance can be found via the European Centre for Disease Prevention and Control website or the World Health Organisation (http://bit.ly/1Kosckx and http://bit.ly/1rOb3cx). Although meningococci with reduced susceptibility to penicillin have been reported, patients infected by these strains do respond to the high doses of penicillin or cephalosporins usually given in meningitis. Overt meningococcal resistance to penicillin is extremely rare.
      • Bijlsma M.W.
      • Bekker V.
      • Brouwer M.
      • Spanjaard L.
      • van de Beek D.
      • van der Ende A.
      Epidemiology of invasive meningococcal disease in the NEtherlands, 1960–2012:an analysis of national surveillance data.
      Selected countries with penicillin resistance (refer to
      • van de Beek D.
      • Brouwer Matthijs C.
      • Thwaites G.
      • Tunkel A.R.
      Advances in treatment of bacterial meningitis.
      for a complete list).
      Tabled 1
      Canada

      China

      Croatia

      Greece

      Italy

      Mexico

      Pakistan

      Poland

      Spain

      Turkey

      USA
      Listeria meningitis occurs in people who are immunocompromised, have chronic illnesses such as alcohol dependency, diabetes, and malignancy, or are elderly.
      • Gerner-Smidt P.
      • Ethelberg S.
      • Schiellerup P.
      • Christensen J.J.
      • Engberg J.
      • Fussing V.
      • et al.
      Invasive listeriosis in Denmark 1994–2003: a review of 299 cases with special emphasis on risk factors for mortality.
      It responds poorly to cephalosporin treatment, and so amoxicillin should be added. The age at which it should be added is debated. Although in some guidelines a cut-off of 50 years has been advocated,
      • Begg N.
      • Cartwright K.A.V.
      • Cohen J.
      • Kaczmarski E.B.
      • Innes J.A.
      • Leen C.L.S.
      • et al.
      Consensus statement on diagnosis, investigation, treatment and prevention of acute bacterial meningitis in immunocompetent adults.
      • Tunkel A.R.
      • Hartman B.J.
      • Kaplan S.L.
      • Kaufman B.A.
      • Roos K.L.
      • Scheld M.
      • et al.
      Practice guidelines for the management of bacterial meningitis.
      a review of the literature has shown that Listeria meningitis or invasive Listeriosis in the immunocompetent adult was rare if under 60.
      • Koopmans M.M.
      • Brouwer M.
      • Bijlsma M.W.
      • Bovenkerk S.
      • Keijzers W.
      • van der Ende A.
      • et al.
      Listeria monocytogenes sequence type 6 and increased rate of unfavorable outcome in meningitis: epidemiologic cohort study.
      • Pórdardóttir Á.
      • Erlendsdóttir H.
      • Sigurdardóttir B.
      • Hardardottir H.
      • Reynisson I.K.
      • Gottfredsson M.
      • et al.
      Bacterial meningitis in adults in Iceland, 1995–2010.
      • Roed C.
      • Neess Engsig F.
      • Omland L.H.
      • Skinhoj P.
      • Obel N.
      Long-term mortality in patients diagnosed with Listeria monocytogenes menignitis: a Danish nationwide cohort study.
      • Amaya-Villar R.
      • García-Cabrera E.
      • Sulleiro-Igual E.
      • Fernández-Viladrich P.
      • Fontanals-Aymerich D.
      • Catalán-Alonso P.
      • et al.
      Three-year multicenter surveillance of community-acquired listeria monocytogenes meningitis in adults.
      • Gillespie I.A.
      • McLauchlin J.
      • Little C.L.
      • Penman C.
      • Mook P.
      • Grant K.
      • et al.
      Disease presentation in relation to infection Foci for non-pregnancy-associated human listeriosis in England and Wales, 2001 to 2007.
      • Schuchat A.
      • Robinson K.
      • Wenger J.D.
      • Harrison L.H.
      • Farley M.
      • Reingold A.L.
      • et al.
      Bacterial meningitis in the United States in 1995.
      • Brouwer M.C.
      • van de Beek D.
      • Heckenberg S.G.B.
      • Spanjaard L.
      • de Gans J.
      Community-acquired Listeria monocytogenes meningitis in adults.
      • Doorduyn Y.
      • de Jager C.M.
      • van der Zwaluw W.K.
      • Wannet W.J.B.
      • van der Ende A.
      • Spanjaard L.
      • et al.
      Invasive Listeria monocytogenes infections in the Netherlands, 1995–2003.
      Although reactions to penicillin are commonly reported by patients, a careful history should be taken as there is often little evidence for a true allergy. Alternative antibiotics should be given only when there is a clear history of anaphylaxis to penicillins or cephalosporins and the history of any alleged allergic reactions should be investigated carefully.
      What definitive antimicrobial treatment should be given once microbiology results are available? (Table 6)
      Table 6Definitive antibiotic treatment.
      AetiologyAntibiotic (s)DoseAlternative antibiotic choicesDoseDuration
      Treatment durations may need to be extended if patient is not responding.
      Neisseria meningitidisCefotaxime

      OR

      Ceftriaxone
      2 g 6 hourly/2 g 12 hourlyChloramphenicol (if anaphylaxis) OR Benzylpenicillin25 mg/kg 6 hourly

      2.4 g 4 hourly
      5 days
      Streptococcus pneumoniae (sensitivities unknown or penicillin resistant, cephalosporin sensitive)Cefotaxime
      Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci is prevalent (if unsure, check with local infectious diseases/microbiology expertise.


      OR

      Ceftriaxone
      Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci is prevalent (if unsure, check with local infectious diseases/microbiology expertise.
      2 g 6 hourly

      2 g 12 hourly
      Chloramphenicol25 mg/kg 6 hourly10 days (if stable)

      Up to 14 days if taking longer to respond
      Streptococcus pneumoniae (penicillin sensitive, MIC0.06)Benzylpenicillin

      OR

      Cefotaxime

      OR

      Ceftriaxone
      If low risk of Clostridium difficile infection and/or requiring outpatient therapy.
      2.4 g 4 hourly

      2 g 6 hourly/2 g 12 hourly
      Chloramphenicol25 mg/kg 6 hourly10 days (if stable)

      Up to 14 days if taking longer to respond
      Streptococcus pneumoniae (penicillin and cephalosporin non-susceptible, penicillin MIC>0.06 or cefotaxime/ceftriaxone MIC>0.5)Cefotaxime

      OR

      Ceftriaxone

      AND

      Vancomycin
      Serum vancomycin trough concentrations of 15–20 ug/ml should be aimed for.


      OR

      Rifampicin
      2 g 6 hourly

      2 g 12 hourly

      15–20 mg/kg 12 hourly (adjusting according to serum trough levels)

      600 mg bd
      Chloramphenicol25 mg/kg 6 hourly14 days
      Listeria monocytogenesAmoxicillin2 g 4 hourlyCo-trimoxazole10–20 mg/kg (of the trimethoprim component) in 4 divided doses21 days
      Haemophilus influenzaeCefotaxime

      OR

      Ceftriaxone
      2 g 6 hourly

      2 g 12 hourly
      Moxifloxacin400 mg od10 days
      a Add in IV Vancomycin 15–20 mg/kg bd or Rifampicin 600 mg bd if penicillin resistance is suspected e.g. patient has recently arrived from a country where penicillin resistant pneumococci is prevalent (if unsure, check with local infectious diseases/microbiology expertise.
      b Treatment durations may need to be extended if patient is not responding.
      c If low risk of Clostridium difficile infection and/or requiring outpatient therapy.
      d Serum vancomycin trough concentrations of 15–20 ug/ml should be aimed for.

      Recommendations

      Patients with meningitis:

      Treatment following CSF Gram stain result
      • 6.
        If Gram-positive diplococci (likely Streptococcus pneumoniae) are visible on Gram stain of CSF:
        • Continue 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly (AR)
        • If the patient comes from a country where penicillin resistance is common add vancomycin 15–20 mg/kg IV 12-hourly (rifampicin 600 mg IV/orally 12-hourly can be given as an alternative and should be used in patients with renal failure) until antimicrobial resistance information is available (AR)
      • 7.
        If Gram-negative diplococci (likely N. meningitidis) are visible on Gram stain of CSF:
        • Continue 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly (AR)
      • 8.
        If Gram-positive bacilli suggestive of Listeria monocytogenes are visible on Gram stain of CSF:
        • Add ampicillin/amoxicillin 2 g 4-hourly IV (if not started empirically) (AR).
        • Continue with 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly until culture confirmed (AR).
      • 9.
        If Gram negative rods are visible on Gram stain:
        • Continue 2 g ceftriaxone IV 12-hourly or 2 g cefotaxime IV 6-hourly and seek specialist advice regarding local antimicrobial resistance patterns (AR)
        • If there is a high suspicion that an extended spectrum beta lactamase (ESBL) organism might be present IV Meropenem 2 g 8 hourly should be given (AR)
      Treatment following positive culture or PCR result (from blood or CSF):

      Pneumococcal meningitis

      • 10.
        If Streptococcus pneumoniae is identified:
        • Continue with 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly (AR)
        • If the pneumococcus is penicillin sensitive (MIC0.06 mg/L) any of the following options would be suitable: IV benzylpenicillin 2.4 g 4 hourly, 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly (AR)
        • If the pneumococcus is penicillin resistant (MIC>0.06) but cephalosporin sensitive then cefotaxime or ceftriaxone should be continued (AR)
        • If the pneumococcus is both penicillin and cephalosporin resistant, continue using 2 g ceftriaxone IV 12-hourly or 2 g cefotaxime IV 6-hourly plus vancomycin 15–20 mg/kg IV 12-hourly plus 600 mg rifampicin IV/orally 12-hourly (AR).
      • 11.
        For patients with confirmed pneumococcal meningitis who have recovered by day 10 treatment should be stopped (1C).
      • 12.
        For patients with confirmed pneumococcal meningitis who have not recovered by day 10, 14 days treatment should be given (1C)
      • 13.
        For patients with penicillin or cephalosporin resistant pneumococcal meningitis, treatment should be continued for 14 days (1C)

      Meningococcal meningitis

      • 14.
        If N. meningitidis is identified:
        • Continue 2 g ceftriaxone IV 12 hourly or 2 g cefotaxime IV 6-hourly (AR)
        • 2.4 g benzylpenicillin IV 4-hourly may be given as an alternative (AR)
        • If the patient is not treated with ceftriaxone, a single dose of 500 mg ciprofloxacin orally should also be given (1C)
      • 15.
        For patients with confirmed meningococcal meningitis who have recovered by day 5 treatment can be stopped (1C)

      Other bacteria

      • 16.
        If Listeria monocytogenes is identified:
        • Give 2 g ampicillin/amoxicillin IV 4-hourly (stop Ceftriaxone/Cefotaxime) and continue for at least 21 days (AR)
        • Co-trimoxazole 10–20 mg/kg in four divided doses(of the trimethoprim component) or chloramphenicol 25 mg/kg 6 hourly are alternatives in cases of anaphylaxis to beta lactams (AR).
      • 17.
        If H. influenzae is identified:
        • Continue 2 g ceftriaxone IV 12-hourly or 2 g cefotaxime IV 6-hourly for 10 days (1D)
      • 18.
        If a member of the Enterobacteriaceae is isolated from blood or CSF:
        • Continue 2 g ceftriaxone IV 12-hourly or 2 g cefotaxime IV 6-hourly and seek specialist advice regarding local antimicrobial resistance patterns (AR)
        • If there is a high suspicion that an extended spectrum beta lactamase (ESBL) organism might be present IV Meropenem 2 g 8 hourly should be given (AR)
        • Treatment should continue for 21 days (AR)
      • 19.
        In patients with no identified pathogen who have recovered by day 10 treatment can be discontinued (AR)

      Patients with probable/confirmed meningococcal sepsis (no lumbar puncture):

      • 20.
        Patients with confirmed meningococcal sepsis:
        • Continue 2 g IV ceftriaxone every 12 h or 2 g cefotaxime IV 6-hourly (AR)
        • 2.4 g benzylpenicillin IV 4-hourly may be given as an alternative (AR)
        • For patients who have recovered by day 5, treatment can be discontinued (1C).
      • 21.
        For patients with a typical petechial/purpuric meningococcal rash but no identified pathogen who have been treated as above, and recovered by day 5, treatment can be stopped (1C).
      • 22.
        In patients with confirmed or probable meningococcal sepsis who have not been treated with ceftriaxone, a single dose of 500 mg ciprofloxacin orally should also be given (1C)

      All patients

      • 23.
        Outpatient intravenous therapy should be considered in patients who are clinically well (AR)

      Rationale

      Definitive antibiotic choices are based on the organism identified (or likely organism) and its antimicrobial susceptibilities. As cephalosporins are recommended for empirical treatment, we recommend their continued use for patients found to have meningococcal or pneumococcal disease, although we recognise that some centres will prefer to narrow the spectrum and use benzylpenicillin for patients with a susceptible organism. Previously gentamicin has been advocated for its synergistic activities in listeria meningitis but its use is not supported by recent studies.
      • Amaya-Villar R.
      • García-Cabrera E.
      • Sulleiro-Igual E.
      • Fernández-Viladrich P.
      • Fontanals-Aymerich D.
      • Catalán-Alonso P.
      • et al.
      Three-year multicenter surveillance of community-acquired listeria monocytogenes meningitis in adults.
      • Mitjà O.
      • Pigrau C.
      • Ruiz I.
      • Vidal X.
      • Almirante B.
      • Planes A.-M.
      • et al.
      Predictors of mortality and impact of aminoglycosides on outcome in listeriosis in a retrospective cohort study.
      Vancomycin is recommended for penicillin resistance but it should never be used alone as there are doubts about its penetration into adult CSF, especially if dexamethasone has also been given.
      • Cabellos C.
      • Martinez-Lacasa J.
      • Martos A.
      • Tubau F.
      • Fernández A.
      • Viladrich P.F.
      • et al.
      Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis.
      A trough vancomycin level of 15–20 mg/L should be aimed for. It is widely accepted that this trough range should be aimed for in serious infection. Most of the evidence is in patients with staphylococcal infection and in patients with bacteraemia or pneumonia, but has been extrapolated to other infections.
      • American Society of Health Pharmacists
      • Infectious Diseases Society of America, Society of Infectious Diseases Pharmacists
      Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-system Pharmacists, the Infectious Diseases Society of America, and the society of infectious diseases pharmacists.
      Some experts also recommend repeating the lumbar puncture after 48–72 h of therapy in patients who have a penicillin and cephalosporin resistant pneumococcus. This should be discussed with an infection specialist on a case by case basis.
      No beta-lactams other than ceftriaxone have been shown to reliably eradicate meningococcal carriage in the oropharynx. Therefore a single dose of Ciprofloxacin should be given to eliminate throat carriage to all patients in whom meningococcal disease is confirmed or strongly suspected, who have been treated with an antibiotic other than ceftriaxone (including those treated with cefotaxime). If ciprofloxacin is contraindicated rifampicin 600 mg twice daily for two days can be given as an alternative.
      Meningitis caused by gram negative bacilli is rare, although incidence may be increasing.
      • Okike I.O.
      • Ribeiro S.
      • Ramsay M.
      • Heath P.T.
      • Sharland M.
      • Ladhani S.N.
      Trends in bacterial, mycobacterial and fungal meningitis in England and Wales 2004-11: an observational study.
      • Castelblanco R.L.
      • Lee M.
      • Hasbun R.
      Epidemiology of bacterial meningitis in the USA from 1997 to 2010: a population-based observational study.
      In addition multidrug resistance such as extended spectrum beta lactamases (ESBLs) enterobacteriaciae is increasing. ESBL should be considered in patients who have Gram negative bacilli in the CSF or on blood culture and have recently returned from a country or area of high prevalence, or who have an ESBL cultured from other sites e.g. urine.

      Duration of treatment

      There is little evidence to guide the duration of treatment in adults. The recommendations here have been extrapolated from the paediatric literature. The duration of antibiotic therapy depends upon which pathogen is identified. The management of epidemic meningococcal meningitis in Africa with a single dose of ceftriaxone has been evaluated
      • Nathan N.
      • Borel T.
      • Djibo A.
      • Evans D.
      • Djibo S.
      • Corty J.F.
      • et al.
      Ceftriaxone as effective as long-acting chloramphenicol in short-course treatment of meningococcal meningitis during epidemics: a randomised non-inferiority study.
      and compared well with earlier studies of single doses of combined penicillins or depot chloramphenicol.
      • Puddicombe J.B.
      • Wali S.S.
      • Greenwood B.M.
      A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis.
      Short courses of penicillin (3 days) have been advocated for treatment of uncomplicated adult meningococcal meningitis in New Zealand but have not been evaluated in controlled, prospective studies.
      • Briggs S.
      • Ellis-Pegler R.
      • Roberts S.
      • Thomas M.
      • Woodhouse A.
      Short course intravenous benzylpenicillin treatment of adults with meningococcal disease.
      A meta-analysis found no difference between short (4–7 days) versus long (7–14 days) courses of antibiotics for all causes of bacterial meningitis.
      • Karageorgopoulos D.E.
      • Valkimadi P.E.
      • Kapaskelis A.
      • Rafailidis P.I.
      • Falagas M.E.
      Short versus long duration of antibiotic therapy for bacterial meningitis: a meta analysis of randomised controlled trials in children.
      However, no trials in adults were identified for inclusion. In a subsequent double-blind randomised equivalence study conducted in Bangladesh, Egypt, Malawi, Pakistan, and Vietnam, it was concluded that antibiotics can be safely discontinued in children who are stable by day 5 of ceftriaxone treatment.
      • Molyneux E.
      • Nizami S.Q.
      • Saha S.
      • Huu K.T.
      • Azam M.
      • Bhutta Z.A.
      • et al.
      5 versus 10 days of treatment with ceftriaxone for bacterial meningitis in children: a double-blind randomised equivalence study.
      We recommended that if the patient is judged clinically to have recovered by 10 days for pneumococcal disease and 5 days for meningococcal disease the antibiotics can be stopped. In addition, if no pathogen has been found antibiotics can be stopped after 10 days if the patient has clinically recovered.

      Alternative antibiotic therapy approaches

      Alternative antibiotics may be useful in cases of allergy, or increased antimicrobial resistance. Carbapenems have a broad range of activity against Gram-positive and Gram-negative bacteria. Controlled trials in children and a small number of adults, suggest that meropenem has similar efficacy to cefotaxime or ceftriaxone in the treatment of bacterial meningitis
      • Odio C.M.
      • Puig J.R.
      • Feris J.M.
      • Khan W.N.
      • Rodriguez W.J.
      • McCracken Jr., G.H.
      • et al.
      Prospective, randomized, investigator-blinded study of the efficacy and safety of meropenem vs. cefotaxime therapy in bacterial meningitis in children. Meropenem Meningitis Study Group.
      and may be useful in the future. Gatifloxacin and moxifloxacin penetrate the CSF well and experimental models support their potential role in the treatment of penicillin and cephalosporin-resistant meningitis,
      • Giamarellos-Bourboulis E.J.
      • Douzinas E.
      • Tsaganos T.
      • Pagoulatou A.
      • Livaditi O.
      • Vafiadou M.
      • et al.
      Cerebrospinal fluid of patients administered moxifloxacin modulates the secretion of cytokines from human monocytes.
      • Lutsar I.
      • Friedland I.R.
      • Wubbel L.
      • McCoig C.C.
      • Jafri H.S.
      • Ng W.
      • et al.
      Pharmacodynamics of gatifloxacin in cerebrospinal fluid in experimental cephalosporin-resistant pneumococcal meningitis.
      however there is concern regarding the rapid emergence of resistance with fluoroquinolone treatment.
      • Mehta G.
      • Goyal R.
      Emerging fluoroquinolone resistance in Neisseria meningitidis in India: cause for concern.
      Intraventricular antimicrobial agents have been shown to be of use in nosocomial meningitis associated with extra ventricular drains,
      • Pfausler Bettina
      • Spiss Heinrich
      • Beer Ronny
      • Kampfl Andreas
      • Engelhardt Klaus
      • Schober Maria
      • et al.
      Treatment of staphylococcal ventriculitis associated with external cerebrospinal fluid drains: a prospective randomized trial of intravenous compared with intraventricular vancomycin therapy.
      but are not indicated in the management of adult community acquired bacterial meningitis. There is some evidence from animal models of pneumococcal meningitis that compared with ceftriaxone, antibiotics such as daptomycin and rifampicin sterilise the CSF more rapidly, modulate CSF inflammation, and protect against cortical injury.
      • Egermann U.
      • Stanga Z.
      • Ramin A.
      • Acosta F.
      • Stucki A.
      • Gerber P.
      • et al.
      Combination of daptomycin plus ceftriaxone is more active than vancomycin plus ceftriaxone in experimental meningitis after addition of dexamethasone.
      • Vivas M.
      • Force E.
      • Garrigós C.
      • Tubau F.
      • Platteel A.C.M.
      • Ariza J.
      • et al.
      Experimental study of the efficacy of daptomycin for the treatment of cephalosporin-resistant pneumococcal meningitis.
      However, until there are human trials to support the use of these antibiotics they cannot be recommended as an alternative to cephalosporins.

      Outpatient antibiotic therapy

      Outpatient antibiotic therapy (OPAT) is increasingly being used for many different infections including meningitis.
      • Barr D.A.
      • Semple L.
      • Seaton R.A.
      Outpatient parenteral antimicrobial therapy (OPAT) in a teaching hospital-based practice: a retrospective cohort study describing experience and evolution over 10 years.
      • Tice A.D.
      • Strait K.
      • Ramey R.
      • Hoaglund P.A.
      Outpatient parenteral antimicrobial therapy for Central nervous system infections.
      • Waler J.A.
      • Rathore M.H.
      Outpatient management of pediatric bacterial meningitis.
      • Allison G.M.
      • Muldoon E.G.
      • Kent D.M.
      • Paulus J.K.
      • Ruthazer R.
      • Ren A.
      • et al.
      Prediction model for 30-Day hospital readmissions among patients discharged receiving outpatient parenteral antibiotic therapy.
      Outpatient therapy has cost savings by freeing up hospital beds and there may be psychological benefits for the patient treated in their own home.
      • Vinen J.D.
      Intravenous antibiotic treatment outside the hospital: safety and health economic aspects.
      • Poretz D.M.
      • Woolard D.
      • Eron L.J.
      • Goldenberg R.I.
      • Rising J.
      • Sparks S.
      Outpatient use of ceftriaxone: a cost-benefit analysis.
      Some indications for when OPAT may be appropriate and what regimens might be considered are given in Box 9.
      Outpatient therapy (OPAT) of meningitis and meningococcal disease.
      Tabled 1
      7a. Indications where outpatient therapy may be appropriate
      • The decision to commence OPAT must be made by a physician familiar with OPAT and should be carried out by a specialist OPAT team and include regular review of cases by a physician
      • The patient should:
        • be afebrile and clinically improving
        • have received ≥5 days of inpatient therapy and monitoring (?shorter)
        • have reliable intravenous access
        • be able to access medical advice/care from the OPAT team or delegated individuals 24 h a day
        • have no other acute medical needs other than the need for parenteral antimicrobials
      • The patient and family/carer must be willing to participate in OPAT
      7b. Regimes that could be used in the community
      • Ceftriaxone 2 g bd IV (4 g od IV can be used after the first 24 h of therapy)
      • Ceftriaxone 2 g bd IV and Rifampicin 600 mg bd PO for penicillin resistant pneumococci
      There is concern regarding once daily cephalosporins in meningitis and the risk of having sub-therapeutic levels. Animal studies have shown that once daily ceftriaxone achieves similar CSF sterilisation rates as twice daily after the first 24 h
      • Lutsar I.
      • Ahmed A.
      • Friedland I.R.
      • Trujillo M.
      • Wubbel L.
      • Olsen K.
      • et al.
      Pharmacodynamics and bactericidal activity of ceftriaxone therapy in experimental cephalosporin-resistant pneumococcal meningitis.
      and a small clinical study, with no comparator arm, showed once daily ceftriaxone achieved effective CSF concentrations and sterilised the CSF within 24–48 h.
      • Dankner W.M.
      • Connor J.D.
      • Sawyer M.
      • Stranbe R.
      • Specter S.A.
      Treatment of bacterial meningitis with once daily ceftriaxone therapy.
      In the first 24 h cephalosporins should be given twice a day to achieve rapid CSF sterilisation, thereafter they can be given once daily to patients who have recovered sufficiently to be considered for OPAT.
      Which adjunctive treatment should be given?

      Recommendations

      For patients with suspected meningitis:
      • 24.
        10 mg dexamethasone IV 6 hourly should be started on admission, either shortly before or simultaneously with antibiotics [1A].
      • 25.
        If antibiotics have already been commenced 10 mg IV dexamethasone every 6 h should still be initiated, up until 12 h after the first dose of antibiotics (AR).
      • 26.
        If pneumococcal meningitis is confirmed, or thought probable based on clinical, epidemiological and CSF parameters, dexamethasone should be continued for 4 days [1C].
      • 27.
        If another cause of meningitis is confirmed, or thought probable, the dexamethasone should be stopped (1C).
      • 28.
        Glycerol is not recommended as adjuvant therapy for community acquired bacterial meningitis in adults [1B].
      • 29.
        Therapeutic hypothermia is not recommended for adults with bacterial meningitis [1B]

      Rationale

      Over 10% of adults with bacterial meningitis die, even when appropriate antibiotics are started promptly, and it is likely that major further improvements in outcome will not come from changes in antibiotic therapy but from manipulation of the host responses to infection or with the development of alternatives to antibiotics, such as engineered liposomes – still in early animal trials.
      • Henry B.D.
      • Neill D.R.
      • Becker K.A.
      • Gore S.
      • Bricio-Moreno L.
      • Ziobro R.
      • et al.
      Engineered liposomes sequester bacterial exotoxins and protect from severe invasive infections in mice.

      The role of corticosteroids in community acquired bacterial meningitis

      Corticosteroids have many potential anti-inflammatory effects in bacterial meningitis including decreasing the amount of cytokines released, for example, through inhibiting the transcription of mRNA for TNF-α and IL-1
      • Beutler B.
      • Krochin N.
      • Milsark I.W.
      • Luedke C.
      • Cerami A.
      Control of cachectin (Tumor necrosis factor) synthesis: mechanisms of endotoxin resistance.
      • Lee S.W.
      • Tsou A.P.
      • Chan H.
      • Thomas J.
      • Petrie K.
      • Eugui E.M.
      • et al.
      Glucocorticoids selectively inhibit the transcription of the interleukin 1 beta gene and decrease the stability of interleukin 1 beta mRNA.
      • Täuber M.G.
      • Shibl A.M.
      • Hackbarth C.J.
      • Larrick J.W.
      • Sande M.A.
      Antibiotic therapy, endotoxin concentration in cerebrospinal fluid, and brain edema in experimental Escherichia coli meningitis in rabbits.
      • Tuomanen E.
      • Hengstler B.
      • Rich R.
      • Bray M.A.
      • Zak O.
      • Tomasz A.
      Nonsteroidal anti-inflammatory agents in the therapy for experimental pneumococcal meningitis.
      • Mustafa M.M.
      • Ramilo O.
      • Saez-llorens X.
      • Mertsola J.
      • McCracken Jr., G.H.
      Role of tumor necrosis factor alpha (cachectin) in experimental and clinical bacterial meningitis.
      and inhibition of the production of prostaglandins and platelet activating factor.
      • Kadurugamuwa J.L.
      • Hengstler B.
      • Bray M.A.
      • Zak O.
      Inhibition of complement-factor-5a-induced inflammatory reactions by prostaglandin E2 in experimental meningitis.
      Methylprednisolone decreases meningeal inflammation in a rabbit model of pneumococcal meningitis,
      • Nolan C.M.
      • McAllister C.K.
      • Walters E.
      • Beaty H.N.
      Experimental pneumococcal meningitis. IV. The effect of methyl prednisolone on meningeal inflammation.
      decreases CSF outflow resistance
      • Scheld W.M.
      • Dacey R.G.
      • Winn H.R.
      • Welsh J.E.
      • Jane J.A.
      • Sande M.A.
      Cerebrospinal fluid outflow resistance in rabbits with experimental meningitis, altererations with penicillin and methylprednisolone.
      and reduces cerebral oedema.
      • Tauber M.G.
      • Khayam-Bachi H.
      • Sande M.A.
      Effects of ampicillin and corticosteroids on brain water content, cerebrospinal fluid pressure and cerebrospinal fluid lactate levels in experimental pneumococcal meningitis.
      Dexamethasone plus ceftriaxone when given in a rabbit model of H. influenzae meningitis resulted in significantly reduced CSF TNF-α concentration and a reduced CSF white cell count.
      • Mustafa M.M.
      • Ramilo O.
      • Saez-llorens X.
      • Mertsola J.
      • McCracken Jr., G.H.
      Role of tumor necrosis factor alpha (cachectin) in experimental and clinical bacterial meningitis.
      In these animal models the improvement in outcome only occurred when dexamethasone was given before or with the antibiotics.
      • Mustafa M.M.
      • Ramilo O.
      • Saez-llorens X.
      • Mertsola J.
      • McCracken Jr., G.H.
      Role of tumor necrosis factor alpha (cachectin) in experimental and clinical bacterial meningitis.
      On the other hand corticosteroids may be associated with side effects. In experimental models the administration of corticosteroids reduced the penetration of antibiotics into the CSF,
      • Cabellos C.
      • Martinez-Lacasa J.
      • Martos A.
      • Tubau F.
      • Fernández A.
      • Viladrich P.F.
      • et al.
      Influence of dexamethasone on efficacy of ceftriaxone and vancomycin therapy in experimental pneumococcal meningitis.
      although this has not been born out in small studies conducted in humans.
      • Buke A.C.
      • Cavusoglu C.
      • Karasulu E.
      • Karakartal G.
      Does dexamethasone affect ceftriazone penetration into cerebrospinal fluid in adult bacterial meningitis.
      • Ricard J.-D.
      • Wolff M.
      • Lacherade J.-C.
      • Mourvillier B.
      • Hidri N.
      • Barnaud G.
      • et al.
      Levels of vancomycin in cerebrospinal fluid of adult patients receiving adjunctive corticosteroids to treat pneumococcal meningitis: a prospective multicenter observational study.
      • Gaillard J.L.
      • Abadie V.
      • Cheron G.
      • Lacaille F.
      • Mahut B.
      • Silly C.
      • et al.
      Concentrations of ceftriaxone in cerebrospinal fluid of children with meningitis receiving dexamethasone therapy.
      Animal studies also suggest that corticosteroids can aggravate the cognitive deficits that may occur after bacterial meningitis.
      • Leib S.L.
      • Heimgartner C.
      • Bifrare Y.-D.
      • Loeffler J.M.
      • Tauber M.G.
      Dexamethasone aggravates Hippocampal apoptosis and learning deficiency in pneumococcal meningitis in infant rats.
      Trials of corticosteroids in man have shown conflicting results regarding overall benefit. Controlled trials in children showed some benefit in reducing deafness and neurological deficit, largely in meningitis caused by H. influenzae. Dexamethasone, given before or with the first dose of antibiotics in adults, improved outcome, particularly in those with pneumococcal meningitis, in a Dutch trial.
      • de Gans J.
      • van de Beek D.
      European dexamethasone in Adulthood bacterial meningitis study investigators. Dexamethasone in adults with bacterial meningitis.
      In contrast, 20 years of experience in Croatia and randomised controlled trials of adult meningitis in Malawi and Vietnam did not show any benefits overall.
      • Peterković V.
      • Trkulja V.
      • Kutleša M.
      • Krajinović V.
      • Lepur D.
      Dexamethasone for adult community-acquired bacterial meningitis: 20 years of experience in daily practice.
      • Mai N.
      • Chau T.
      • Thwaites G.
      • Chuong L.V.
      • Sinh D.
      • Nghia H.
      • et al.
      Dexamethason in Vietnamese adolescents and adults with bacterial meningitis.
      • Scarborough M.
      • Gordon S.
      • Whitty C.
      • French N.
      • Njalale Y.
      • Chitani A.
      • et al.
      Corticosteroids for bacterial meningitis in adults in sub Saharan Africa.
      Two systematic reviews and one meta-analysis (including four studies from 1999 to 2007) suggested that adjunctive corticosteroids are beneficial in adults with bacterial meningitis in high-income countries.
      • Brouwer M.C.
      • McIntyre P.
      • van de Beek D.
      Corticosteroids for acute bacterial meningitis.
      • Borchorst S.
      • MØLler K.
      The role of dexamethasone in the treatment of bacterial meningitis – a systematic review.
      • Assiri A.M.
      • Alasmari F.A.
      • Zimmerman V.A.
      • Baddour L.M.
      • Erwin P.J.
      • Tleyjeh I.M.
      Corticosteroid administration and outcome of adolescents and adults with acute bacterial meningitis: a meta-analysis.
      However, a subsequent meta-analysis of individual patient data from trials amongst children and adults in resource-rich and poor settings showed no benefit.
      • van de Beek D.
      • Farrar J.J.
      • de Gans J.
      • Mai N.T.H.
      • Molyneux E.M.
      • Peltola H.
      • et al.
      Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data.
      This analysis is confounded, however, by considerable heterogeneity between the trials analysed.
      The most recent Cochrane review concluded there was a small reduction in mortality for patients with pneumococcal meningitis who received corticosteroid therapy, but not other causes. There was also a reduction in hearing loss and short term neurological sequelae for all causes.
      • Brouwer M.C.
      • McIntyre P.
      • van de Beek D.
      Corticosteroids for acute bacterial meningitis.
      Data from this review and a meta-analysis of individual patient data showed no difference in outcome when comparing corticosteroids that were given before or after antibiotics,
      • van de Beek D.
      • Farrar J.J.
      • de Gans J.
      • Mai N.T.H.
      • Molyneux E.M.
      • Peltola H.
      • et al.
      Adjunctive dexamethasone in bacterial meningitis: a meta-analysis of individual patient data.
      there was even a slight improvement in hearing loss in the studies that gave steroids post antibiotics.
      • Brouwer M.C.
      • McIntyre P.
      • van de Beek D.
      Corticosteroids for acute bacterial meningitis.
      The data so far do not show any increase in adverse events, such as increased cognitive deficits or gastrointestinal bleeding.
      • Brouwer M.C.
      • McIntyre P.
      • van de Beek D.
      Corticosteroids for acute bacterial meningitis.
      • Hoogman M.
      • van de Beek D.
      • Weisfelt M.
      • de Gans J.
      • Schmand B.
      Cognitive outcome in adults after bacterial meningitis.
      • Weisfelt M.
      • Hoogman M.
      • van de Beek D.
      • de Gans J.
      • Dreschler W.A.
      • Schmand B.A.
      Dexamethasone and long term outcome in adults with bacterial meningitis.
      A potential rare complication of dexamethasone therapy in pneumococcal meningitis is delayed cerebral thrombosis
      • Schut E.S.
      • Brouwer M.C.
      • de Gans J.
      • Florquin S.
      • Troost D.
      • van de Beek D.
      Delayed cerebral thrombosis after initial good recovery from pneumococcal meningitis.
      • Lucas M.
      • Brouwer M.
      • van de Beek D.
      Delayed cerebral thrombosis in bacterial meningitis: a prospective cohort study.
      although a causal relationship between this complication and dexamethasone has not yet been established.
      Given that there is no evidence for harm in giving corticosteroids, and that some groups do appear to benefit, we recommend that for adults in whom bacterial meningitis is suspected, dexamethasone be given before, or up to 12 h after, antibiotics are started. Steroids should be then stopped, if a cause, other than Streptococcus pneumoniae is identified. If no cause is found and pneumococcal meningitis remains most likely based on clinical, epidemiological and CSF parameters, the steroids should be continued for 4 days.
      Whilst high dose steroids are used in meningitis to reduce brain inflammation and oedema, low dose hydrocortisone is occasionally used in septic shock to restore haemodynamic stability. Recommendations on when hydrocortisone would be appropriate in septic shock can be found below and in the surviving sepsis guidelines.
      • Dellinger R.P.
      • Levy M.M.
      • Rhodes A.
      • Annane D.
      • Gerlach H.
      • Opal S.M.
      • et al.
      Surviving sepsis campaign: international guidelines for management of severe sepsis and septic shock: 2012.

      Adjunctive therapy with glycerol in community acquired bacterial meningitis

      Glycerol is a hyperosmolar agent that has been used to decrease intracranial pressure in a number of brain conditions. A randomised clinical trial in Finland suggested that glycerol might protect against sequelae in children with bacterial meningitis.
      • Kilpi T.
      • Pettola H.
      • Jauhianen T.
      • Kallio M.J.
      Oral glycerol and intravenous dexamethasone in preventing neurologic and audiologic sequelae of childhood bacterial meningitis. The Finnish Study Group.
      However, a subsequent South American trial showed no significant benefit of adjuvant intravenous dexamethasone, oral glycerol, or both on death or deafness but there was a reduction in neurological sequelae in both the glycerol alone group and those who received dexamethasone and glycerol.
      • Peltola H.
      • Roine I.
      • Fernández J.
      • Zavala I.
      • Ayala S.G.
      • Mata A.G.
      • et al.
      Adjuvant glycerol and/or dexamethasone to improve the outcomes of childhood bacterial meningitis: a prospective, randomized, double-blind, placebo-controlled trial.
      Later randomised trials in Malawi found an increase in mortality in adults treated with glycerol and no benefit in children.
      • Ajdukiewicz K.M.B.
      • Cartwright K.
      • Scarborough M.
      • Mwambene J.B.
      • Goodson P.
      • Molyneux M.E.
      • et al.
      Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial.
      • Molyneux E.M.
      • Kawaza K.
      • Phiri A.
      • Chimalizeni Y.
      • Mankhambo L.
      • Schwalbe E.
      • et al.
      Glycerol and acetaminophen as adjuvant therapy did not affect the outcome of bacterial meningitis in Malawian children.

      Other therapeutic approaches

      Animal models and individual patient data suggested a potential benefit of induced hypothermia in bacterial meningitis.
      • Irazuzta J.E.
      • Pretzlaff R.
      • Rowin M.
      • Milam K.
      • Zemlan F.P.
      • Zingarelli B.
      Hypothermia as an adjunctive treatment for severe bacterial meningitis.
      • Lepur D.
      • Kutlesa M.
      • Barsic B.
      Induced hypothermia in adult community-acquired bacterial meningitis - more than just a possibility?.
      However a recent randomised controlled trial was stopped prematurely because of excess mortality in the hypothermia arm.
      • Mourvillier B.
      • Tubach F.
      • van de Beek D.
      • Garot D.
      • Pichon N.
      • Georges H.
      • et al.
      Induced hypothermia in severe bacterial meningitis. A randomised clinical trial.

      Critical care

      Which patients with suspected or confirmed meningitis should be referred for critical care?

      Recommendations

      • 1.
        Intensive care teams should be involved early in patients with rapidly evolving rash, evidence of limb ischaemia, cardiovascular instability, acid/base disturbance, hypoxia, respiratory compromise, frequent seizures or altered mental state (1B).
      • 2.
        The following patients should be transferred to critical care (1B):
        • a.
          Those with a rapidly evolving rash
        • b.
          Those with a GCS of 12 or less (or a drop of >2 points)
        • c.
          Those requiring monitoring or specific organ support
        • d.
          Those with uncontrolled seizures
      • 3.
        Intubation should be strongly considered in those with a GCS of less than 12 (AR)
      • 4.
        Patients with evidence of severe sepsis should be managed in a critical care setting in accordance with the surviving sepsis guidelines (AR).

      Rationale

      Given the predisposition of patients with bacterial meningitis and meningococcal sepsis to deteriorate quickly, and the high mortality rate, critical care input should be sought early in patients with risk factors for a poor outcome, especially a reduced GCS, haemodynamic instability, persistent seizures, and hypoxia.
      • Flores-Cordero J.M.
      • Amaya-Villar R.
      • Rincon-Ferrari M.D.
      • Leal-Noval S.R.
      • Garnacho-Montero J.
      • Llanos-Rodriguez A.C.
      • et al.
      Acute community acquired bacterial meningitis in adults admitted to the intensive care unit: clinical manifestations, management and prognostic factors.
      Patients with meningococcal sepsis are typically young adults, who tend to maintain their blood pressure until late in disease, and then deteriorate rapidly. Patients should be examined for other signs of cardiac instability and impaired perfusion for example delayed capillary refill time, and dusky or cold extremities.
      What other critical care management issues are important?

      Recommendations

      • 5.
        Patients should be kept euvolaemic to maintain normal haemodynamic parameters (2C)
      • 6.
        Fluid restriction in an attempt to reduce cerebral oedema is not recommended (2C)
      • 7.
        When intravenous fluid therapy is required, crystalloids are the initial fluid of choice (1B)
      • 8.
        Albumin should be considered in patients who have persistent hypotensive shock in spite of corrective measures (1C)
      • 9.
        Patients with suspected or proven raised intracranial pressure should receive basic measures to control this and maintain cerebral perfusion pressure (1C)
      • 10.
        Routine use of ICP monitoring is not recommended (AR)
      • 11.
        Hydrocortisone (200 mg od) should also be considered in patients with persisting hypotensive shock (2C)
      • 12.
        A mean arterial pressure (MAP) of >/= 65 mmHg is recommended; although this may need to be individualised (1B)
      • 13.
        Use norepinephrine as opposed to epinephrine or vasopressin as the initial vasopressor for hypotension after euvolaemia is restored (1B)
      • 14.
        Suspected or proven seizures should be treated early (1C).
      • 15.
        Patients with suspected or proven status epilepticus (including non-convulsive/subtle motor status), such as those with fluctuating GCS off sedation or subtle abnormal movements, should have electroencephalogram monitoring (AR)

      Evidence

      Adult patients with bacterial meningitis and meningococcal sepsis have differing needs for intravenous fluid therapy. Some patients, such as those with primarily meningitis and little evidence of sepsis, are relatively euvolaemic, whereas others have profound or occult shock requiring early restoration of circulating volume. Over-vigorous administration of intravenous fluids in patients with meningitis may risk exacerbation of cerebral oedema, but paediatric meningitis studies have shown that fluid restriction may also contribute to a worse outcome.
      • Singhi S.C.
      • Singhi P.D.
      • Srinivas B.
      • Narakesri H.P.
      • Ganguli N.K.
      • Sialy R.
      • et al.
      Fluid restriction does not improve the outcome of acute meningitis.
      • Maconochie I.
      • Baumer H.
      • Stewart M.E.
      Fluid therapy for acute bacterial meningitis.
      Consequently, the management of meningitis should target the maintenance of a normal circulating volume avoiding both under and over-hydration and the associated adverse outcomes.
      In patients with meningitis, control of raised intracranial pressure is also essential to prevent mortality although it is still not clear how best to achieve this and there is not sufficient evidence to support the routine use of ICP monitoring.
      • Durand M.L.
      • Calderwood S.B.
      • Weber D.J.
      • Miller S.I.
      • Southwick F.S.
      • Caviness Jr., V.S.
      • et al.
      Acute bacterial meningitis in adults: a review of 493 episodes.
      • Edberg M.
      • Furebring M.
      • SjÖLin J.
      • Enblad P.
      Neurointensive care of patients with severe community-acquired meningitis.
      Measures such as achievement of normal to elevated MAP, control of venous pressure, head elevation, avoidance of hyperthermia and hyponatraemia and maintenance of normocarbia and normoglycaemia may be considered.
      • Lindvall P.
      • Ahlm C.
      • Ericsson M.
      • Gothefors L.
      • Naredi S.
      • Koskinen L.-O.D.
      Reducing intracranial pressure may increase survival among patients with bacterial meningitis.
      Seizures have been reported to occur in 15% of patients with acute bacterial meningitis and are associated with a worse outcome,
      • van de Beek D.
      • de Gans J.
      • Spanjaard L.
      • Weisfelt M.
      • Reitsma J.B.
      • Vermeulen M.
      Clinical features and prognostic factors in adults with bacterial men