meningitis%20-%20acute,%20bacterial
MENINGITIS - ACUTE, BACTERIAL

Acute meningitis is the infection of the subarachnoid space and cerebrospinal fluid by bacteria that may cause local and systemic inflammatory response.
There is the classic triad of symptoms of fever, neck stiffness and altered level of consciousness.
Other symptoms include chills, myalgia, photophobia, severe headache, focal neurologic symptoms, nausea, vomiting, seizures and some patients may present with rash.

 

Principles of Therapy

  • Initial antibiotic therapy of purulent meningitis should be based on results of Gram stain or rapid bacterial antigen tests
  • If lumbar puncture is delayed longer than 90-120 minutes or no etiologic agent can be identified, empiric therapy should be instituted
  • Delay of antimicrobial therapy may be associated with adverse clinical outcomes especially if the patient has advanced to a high stage of prognostic severity
  • Antimicrobial entry into the cerebrospinal fluid (CSF) decreases as inflammation subsides and permeability across the blood brain barrier decreases
    • Therefore, maximal parenteral doses of antibiotics should be continued throughout the course of therapy to maintain adequate cerebrospinal fluid concentrations

Pharmacotherapy

Empiric Therapy for Patients with a Presumptive Cerebrospinal Fluid (CSF) Gram Stain

  • Prompt initiation of therapy should be the standard of care
  • Empiric antibiotic therapy should be directed to the most likely pathogens on the basis of the patient’s age and underlying health status
    • In general, antibiotics should be directed against N meningitidis, S aureus, and S pneumoniae
  • Below is a list of the likely pathogens of acute bacterial meningitis in different groups of patients, depending on age/predisposing factors:
Empiric Antibiotic Therapy for Patients with a Presumptive CSF Gram Stain
Predisposing Factor of Patient Likely Causative Pathogen Recommended Antibiotics
Age <1 month Streptococcus agalactiae (Group B streptococcus, GBS), Escherichia coli, Listeria monocytogenes Ampicillin +
(Cefotaxime or aminoglycoside)
Age 1-23 months Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, S agalactiae, E coli Vancomycin +
(Cefotaxime or Ceftriaxone)* or
Vancomycin + Ampicillin + Chloramphenicol
Age 2-50 years S pneumoniae, N meningitidis Vancomycin + Ampicillin +
(Cefotaxime or Ceftriaxone)*
Age >50 years S pneumoniae, N meningitidis, L monocytogenes, aerobic Gram-negative bacilli Vancomycin + Ampicillin +
(Cefotaxime or Ceftriaxone)*
Impaired cellular immunity S pneumoniae, N meningitidis, L monocytogenes, aerobic Gram-negative bacilli including Pseudomonas aeruginosa Ampicillin + Vancomycin +
(Meropenem or Cefepime)
Penetrating head trauma, neurosurgery, or CSF shunt Staphylococcus aureus, coagulase-negative staphylococci (S epidermidis), aerobic Gram-negative bacilli including P aeruginosa, Propionibacterium acnes in CSF shunt Vancomycin +
(Cefepime, Ceftazidime, Ceftriaxone, or Meropenem)
Basilar skull fracture S pneumoniae, H influenzae, group A beta-hemolytic streptococci Vancomycin +
(Cefotaxime or Ceftriaxone)
Modify treatment regimen for optimal therapy once culture & susceptibility results are in
* In patients suspected of having pneumococcal meningitis, consider adding Rifampicin if Dexamethasone is also given.
Addition of Ampicillin may be considered in patients highly suspicious of L monocytogenes infection.
 
 
 
 
 
 
 
 

Considerations for Patients with Diagnostic Gram Stain Results

  • A presumptive diagnosis may be made based on the results of the CSF Gram stain
  • Modify treatment regimen for optimal therapy once culture and susceptibility results are available

S pneumoniae

  • If culture is available, perform minimum inhibitory concentration (MIC) determination for S pneumoniae

H influenzae

  • Testing for beta-lactamase production of H influenzae may also aid in tailoring the antibiotic regimen
    • 3rd and 4th generation cephalosporins, carbapenems, or Aztreonam may be used for beta-lactamase producing organisms

Antibiotic Therapy

Aminoglycosides
  • Exhibit synergistic activity with cell wall antibiotics eg penicillins, cephalosporins, monobactams and carbapenems
  • Accumulation of CSF lactate in CSF during bacterial meningitis results in a decreased CSF pH, which may inhibit the bactericidal activity of this group of drugs
  • Have inadequate penetration into the cerebrospinal fluid, may have to be given intrathecally
  • Consider adding Gentamicin to Ampicillin or Penicillin G in proven L monocytogenes meningitis
Aztreonam
  • May be used for meningitis due to aerobic Gram-negative bacilli
  • Treatment option for patients with contraindications to beta-lactam antimicrobial agents or Meropenem
Cephalosporins
  • Broad-spectrum cephalosporins used in meningitis include the 3rd generation cephalosporins eg Cefotaxime, Ceftriaxone and 4th generation cephalosporins eg Cefepime
  • Cefotaxime or Ceftriaxone
    • Very active against streptococci and are usually effective against Penicillin-resistant strains but clinical failures have been reported
    • Drug of choice for patients with meningitis due to enteric Gram-negative bacilli
    • 3rd generation cephalosporin eg Cefotaxime or Ceftriaxone may be used for N meningitidis with reduced susceptibility to Penicillin or as an alternative drug for S agalactiae
  • Cefepime
    • Has been shown to be safe and therapeutically equivalent to Cefotaxime in the treatment of meningitis in infants and children
    • Has in vitro activity similar to that of Cefotaxime and Ceftriaxone against H influenzae, N meningitidis, and S pneumoniae and greater in vitro activity against Enterobacter sp and P aeruginosa
  • Ceftazidime
    • Usually reserved for P aeruginosa (combine with aminoglycoside)
Chloramphenicol
  • Bacteriostatic antibiotic
  • H influenzae, S pneumoniae and N meningitidis are highly susceptible
  • Co-administration with a bacteriostatic agent, eg an aminoglycoside, may result in antagonism
  • Has important toxic effects especially on the bone marrow (eg aplastic anemia)
    • Because of this, it is no longer the drug of choice for any specific infection
Co-trimoxazole [Sulfamethoxazole (SMZ) and Trimethoprim (TM)]
  • An alternative drug for a patient with L monocytogenes meningitis and Penicillin allergy
Penicillins
  • Ampicillin or Penicillin
    • Ampicillin and Penicillin G are the drugs of choice for N meningitidis and L monocytogenes meningitis
    • These recommendations may change as the trends of antimicrobial susceptibility of meningococci change
  • Ampicillin
    • Ampicillin combined with an aminoglycoside is the standard therapy for S agalactiae and L monocytogenes meningitis
    • The drug combination is synergistic and effective against Penicillin-tolerant strains
  • Penicillin G
    • The drug of choice for susceptible isolates of S pneumoniae & Propionibacterium acnes infection
  • Antistaphylococcal Penicillins
    • Nafcillin or Oxacillin should be used to treat Methicillin-susceptible S aureus meningitis
Meropenem
  • May be used for meningitis caused by Penicillin-resistant S pneumoniae or by aerobic Gram-negative bacilli including aeruginosa
    • Pneumococcal strains that are highly resistant to penicillins and cephalosporins may also be resistant to Meropenem
  • First-line therapy for infections caused by Ceftazidime-resistant Gram-negative bacilli eg extended spectrum beta-lactamase-producing organisms, Acinetobacter spp 
  • Has been shown to have clinical and microbiologic outcomes similar to Cefotaxime and Ceftriaxone and may be considered as an alternative to these agents
  • Has less seizure proclivity than Imipenem
Quinolones
  • Ciprofloxacin has been used successfully in some patients with Gram-negative meningitis
  • Moxifloxacin may be considered for patients with contraindications to Penicillin therapy
  • Combination with a 3rd-generation cephalosporin or Vancomycin is recommended
Rifampicin
  • May be added to Vancomycin in the treatment of the following:
    • Meningitis caused by Penicillin-resistant S pneumoniae when the organism is demonstrated to be susceptible and the expected clinical or bacteriologic response is delayed
    • Meningitis due to coagulase-negative staphylococci or Methicillin-resistant Staphylococcus aureus (MRSA) when patient fails to improve with Vancomycin alone
    • Cerebrospinal fluid shunt infections caused by Staphylococci, especially when shunt cannot be removed
Vancomycin
  • Empiric therapy in an area of high prevalence of Penicillin-resistant S pneumoniae should consist of a combination of Vancomycin plus a 3rd generation cephalosporin
    • Vancomycin should never be used alone in the treatment of pneumococcal meningitis
  • Recommended for meningitis caused by Methicillin-resistant Staphylococcus aureus or coagulase-negative staphylococci and is considered an alternative drug for patients with Penicillin allergy and Methicillin-susceptible Staphylococcus aureus (MSSA) meningitis
  • Concomitant administration of Dexamethasone results in decreased brain inflammation and poor entry of Vancomycin into the CSF
  • Consider intrathecal administration in patients not responding to IV administration
Duration of Antibiotic Therapy
  • Duration of therapy has been based more on tradition than on scientific evidence
    • 7-10 days for H influenzae
    • 7 days for N meningitidis
    • 10-14 days for S pneumoniae
    • 14-21 days for Group B streptococci (eg S agalactiae)
    • 21 days for aerobic Gram-negative bacilli (in the neonate, duration is 2 weeks beyond 1st sterile cerebrospinal fluid culture or for 3 weeks whichever is longer)
    • ≥21 days for L monocytogenes
  • Some patients may require longer courses of antibiotic therapy; therefore, treatment must always be individualized
  • IV administration of antibiotic is recommended for the duration of treatment to ensure adequate cerebrospinal fluid concentrations of specific antimicrobial agents are achieved

Pathogen Specific Therapy

  • If culture results are positive, tailor treatment regimen based on the results
  • If test is available, perform minimum inhibitory concentration (MIC) determination for Streptococcus pneumoniae
  • Alternative regimens may be used in case of allergy to the recommended drug
Organism Recommended Antibiotics Alternative Antibiotics
S pneumoniae
Cephalosporin-resistant (MIC >2 mcg/mL)
Vancomycin + (Cefotaxime or Ceftriaxone) or Vancomycin + Rifampicin or Rifampicin + (Cefotaxime or Ceftriaxone)  Vancomycin + Moxifloxacin
Linezolid
S pneumoniae
Penicillin-susceptible (MIC <0.1 mcg/mL)
Penicillin or Amoxicillin or Ampicillin Cefotaxime, Ceftriaxone or Chloramphenicol
S pneumoniae
Penicillin-resistant (MIC >0.1 mcg/mL), third generation cephalosporin-susceptible (MIC <2 mcg/mL)
Cefotaxime or Ceftriaxone Cefepime or Meropenem or Moxifloxacin
N meningitidis
Penicillin-susceptible (MIC <0.1 mcg/mL)
Penicillin or Amoxicillin or Ampicillin Cefotaxime, Ceftriaxone or Chloramphenicol
N meningitidis
Penicillin-resistant (MIC ≥0.1 mcg/mL)
Cefotaxime or Ceftriaxone
Cefepime, Ciprofloxacin, Chloramphenicol or Meropenem
E coli or other
Enterobacteriaceae‡
3rd generation cephalosporin
(consider adding aminoglycoside) 
Ampicillin, Aztreonam, Co-trimoxazole, Meropenem, Trimethoprim-sulfamethoxazole or Ciprofloxacin
Streptococcus agalactiae
Ampicillin or Penicillin G
(consider adding aminoglycoside)
Cefotaxime or Ceftriaxone
L monocytogenes
Amoxicillin or Ampicillin or Penicillin G
(consider adding aminoglycoside)
Co-trimoxazole or Meropenem or Moxifloxacin or Linezolid
Pseudomonas aeruginosa‡
Cefepime or Ceftazidime or Meropenem
(consider adding aminoglycoside) 
Aztreonam or Ciprofloxacin
(consider adding aminoglycoside)
H influenzae
beta-lactamase negative
Amoxicillin or Ampicillin  Cefotaxime, Ceftriaxone, Chloramphenicol or quinolone 
H influenzae
beta-lactamase positive
3rd generation cephalosporin (Cefotaxime or Ceftriaxone)
Cefepime, Aztreonam, Chloramphenicol or quinolone
H influenzae
beta-lactamase negative Ampicillin resistant
 Cefotaxime or Ceftriaxone + Meropenem  Ciprofloxacin
Staphylococcus aureus
Methicillin-sensitive 
Flucloxacillin or Nafcillin or Oxacillin
Vancomycin, Linezolid, Daptomycin, Rifampicin*, Fosfomycin*
Staphylococcus aureus
Methicillin-resistant
Vancomycin◇
Daptomycin, Trimethoprim-sulfamethoxazole, or Linezolid, Rifampicin*, Fosfomycin* 
Propionibacterium acnes Penicillin G Cefotaxime, Ceftriaxone,Vancomycin, Daptomycin, or Linezolid
* Must not be used in monotherapy
‡ Base antimicrobial choice on in vitro susceptibility test results
◇Consider adding Rifampicin

Adjunctive Therapy
  • Adjunctive therapy includes anti-inflammatory therapy, agents to reduce the intracranial pressure (ICP) and anticonvulsants
Anti-inflammatory Therapy
Dexamethasone
  • Action: Significantly reduces synthesis of proinflammatory cytokines, attenuates subarachnoid space inflammatory response and ameliorates meningeal inflammatory indices
  • Should be started by IV route 10-20 minutes before or at the same time as the first dose of antibiotic
    • Benefit is uncertain when dexamethasone is administered ≥1 hour after the 1st antibiotic dose
  • Use in children
    • Dexamethasone is recommended in previously well and non-immunocompromised infants and children with clinically suspected bacterial meningitis caused by H influenzae and S pneumoniae (eg early focal neurologic signs are present)
  • Use in adults
    • Adjunctive Dexamethasone is recommended in previously well and non-immunocompromised adults with clinically suspected or known pneumococcal meningitis
    • Dexamethasone should be continued only if the CSF Gram stain shows Gram-positive cocci in pairs, chains or scattered singly or if blood or CSF cultures are positive for S pneumoniae
  • Precautions
    • By decreasing brain inflammation, Dexamethasone may reduce the penetration of antibiotic into the CSF, particularly Vancomycin, and this may result in delayed sterilization of the CSF
    • Patients who are given Dexamethasone must be closely monitored for evidence of gastrointestinal (GI) blood loss; addition of histamine-2 antagonists is recommended to decrease the risk of gastrointestinal bleeding
  • Dosage
    • Adults: 10 mg IV 6 hourly x 4 days
    • Infants and children: 0.15 mg/kg/dose IV 6 hourly x 4 days
Agents to Decrease Intracranial Pressure (ICP)
  • The following agents (except Dexamethasone) have not been studied in clinical trials in patients with meningitis
Dexamethasone
  • As above
Mannitol
  • Action: Mannitol is a hyperosmolar agent that makes the intravascular space hyperosmolar to the brain and permits movement of water from brain tissue into the intravascular compartment
  • Dosage: 1-1.5 g/kg IV given over 15 minutes; may repeat once
High-dose Barbiturates
  • Eg Phenobarbital 
  • Barbiturates may be considered in patients with continued elevated ICP after other measures have failed
  • Action: Decreases cerebral metabolic demands and cerebral blood flow
Antihypertensive Agents
  • May be considered for decreasing ICP
  • Use with caution as rapid lowering of blood pressure may cause compromise in intracranial perfusion and cause brain injury
Anticonvulsants
  • Eg Diazepam, Lorazepam
  • Administer if patient has seizures

Non-Pharmacological Therapy

Elevated Intracranial Pressure (ICP)
  • Patients with signs of increased intracranial pressure (eg changes in level of consciousness, nonreactive or poorly reactive pupils, ocular movement disorders) and who are comatose or are stuporous may benefit from intracranial pressure monitoring
  • ICP >20 mmHg should be treated
  • Consider treating ICP >15 mmHg to avoid larger elevations that can lead to cerebral herniation and brain stem injury
Maneuvers to Decrease Elevated Intracranial Pressure (ICP)
  • Elevation of head of the bed to maximize venous drainage with minimum compromise of cerebral perfusion
  • Hyperventilation to cause cerebral vasoconstriction and reduction in cerebral blood volume
    • Be cautious with this maneuver as it may exacerbate focal cerebral ischemia
  • An intraventricular shunt with cerebrospinal fluid (CSF) drainage may be needed when there is evidence of hydrocephalus
    • The need to perform this procedure depends on patient’s level of consciousness and degree of ventricular dilatation as seen on brain imaging
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