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Principles of Therapy
General Principles of Antibiotic Therapy
An initial empiric antibiotic therapy should be initiated as soon as
bacterial meningitis is suspected, within 1 hour of arrival in the hospital, and
after performing lumbar puncture and taking blood samples for blood cultures. This
may be based on the likely pathogen depending on the patient's age and
predisposing factors or on CSF test results (eg CSF findings, Gram stain). An
intravenous administration of antibiotics is recommended for the duration of
treatment to ensure that adequate CSF concentrations of specific antimicrobial
agents are achieved. A delay in antimicrobial therapy may be associated with
adverse clinical outcomes especially if the patient has advanced to a high
stage of prognostic severity. The antimicrobial entry into the CSF decreases as
inflammation subsides and permeability across the BBB decreases; therefore,
maximal parenteral doses of antibiotics should be continued throughout the
course of therapy to maintain adequate CSF concentration.
Meningitis - Acute, Bacterial_Management 1Pharmacological therapy
ANTIBIOTIC THERAPY
Empiric Therapy for Patients with a Presumptive Cerebrospinal
Fluid Gram Stain
A presumptive diagnosis may be made based on the results of the CSF
Gram stain. A prompt initiation of therapy should be the standard of care.
Modify the treatment regimen for optimal therapy once culture and
susceptibility results are available.
Streptococcus pneumoniae
Once culture is available, perform minimum inhibitory concentration
(MIC) determination for S pneumoniae.
Hemophilus influenzae
Testing for beta-lactamase production of H influenzae may also
aid in tailoring the antibiotic regimen. Third- and fourth-generation
cephalosporins, carbapenems or Aztreonam may be used for beta-lactamase
producing organisms.
Antibiotic Therapy
Aminoglycosides
Aminoglycosides exhibit synergistic activity with cell wall antibiotics
(eg penicillins, cephalosporins, monobactams, carbapenems). An 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. If these have
inadequate penetration into the CSF, these may have to be given intrathecally.
Consider adding Gentamicin to Ampicillin or Penicillin G in proven L
monocytogenes meningitis.
Aztreonam
Aztreonam may be used for meningitis due to aerobic Gram-negative
bacilli. This is a treatment option for patients with contraindications to
beta-lactam antimicrobial agents or Meropenem.
Cephalosporins
Broad-spectrum cephalosporins are used in meningitis and include the
third-generation cephalosporins (eg Cefotaxime, Ceftriaxone) and
fourth-generation cephalosporins (eg Cefepime).
Cefotaxime or Ceftriaxone
Cefotaxime or Ceftriaxone are very active against streptococci and are
usually effective against Penicillin-resistant strains but clinical failures have
been reported. These are the drugs of choice for patients with meningitis due
to enteric Gram-negative bacilli. Third-generation cephalosporin (eg
Cefotaxime, Ceftriaxone) may be used for N meningitidis with reduced susceptibility
to Penicillin or as an alternative drug for S agalactiae.
Cefepime
Cefepime has been shown to be safe and is therapeutically equivalent to
Cefotaxime in the treatment of meningitis in infants and children. This 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
Ceftazidime is usually reserved for P aeruginosa when combined with
aminoglycoside.
Chloramphenicol
Chloramphenicol is a bacteriostatic antibiotic where H influenzae, S
pneumoniae and N meningitidis are highly susceptible. Co-administration
with another bacteriostatic agent such as an aminoglycoside, may result in
antagonism. This is no longer the drug of choice for any specific infection due
to its toxic effects, especially on the bone marrow (eg aplastic anemia).
Co-trimoxazole (Sulfamethoxazole [SMZ] and Trimethoprim [TM])
Co-trimoxazole is an alternative drug for a patient with L
monocytogenes meningitis and Penicillin allergy.
Penicillins
Ampicillin or Penicillin
Ampicillin or Penicillin 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. This drug combination is
synergistic and effective against Penicillin-tolerant strains.
Penicillin G
Penicillin G is the drug of choice for susceptible isolates of S
pneumoniae and Propionibacterium acnes infection.
Antistaphylococcal Penicillins
Nafcillin or Oxacillin should be used to treat Methicillin-susceptible S
aureus meningitis.
Meningitis - Acute, Bacterial_Management 2Meropenem
Meropenem is the first-line therapy for infections caused by Ceftazidime-resistant Gram-negative bacilli (eg extended spectrum beta-lactamase-producing organisms, Acinetobacter spp). This has been shown to have clinical and microbiologic outcomes similar to Cefotaxime and Ceftriaxone and may be considered as an alternative to these agents. This may be used for meningitis caused by Penicillin-resistant S pneumoniae or by aerobic Gram-negative bacilli including P aeruginosa. Pneumococcal strains that are highly resistant to penicillins and cephalosporins may also be resistant to Meropenem. Meropenem 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 third-generation cephalosporin or Vancomycin is recommended.
Rifampicin
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 S aureus (MRSA) when the patient fails to improve with Vancomycin alone; and CSF shunt infections caused by staphylococci, especially when the shunt cannot be removed.
Vancomycin
The empiric therapy in an area of high prevalence of Penicillin-resistant S pneumoniae should consist of a combination of Vancomycin plus a third-generation cephalosporin. Vancomycin should never be used alone in the treatment of pneumococcal meningitis. This is recommended for meningitis caused by MRSA or coagulase-negative staphylococci and is considered an alternative drug for patients with Penicillin allergy and Methicillin-susceptible S aureus (MSSA) meningitis. A 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
The duration of antibiotic therapy has been based more on tradition than on scientific evidence. For H influenzae: 7-10 days; N meningitidis: 7days; S pneumoniae: 7-10 days; Group B streptococci (eg S agalactiae): 14-21 days; Aerobic Gram-negative bacilli: 21 days; and for L monocytogenes: ≥21 days. Some patients may require longer courses of antibiotic therapy; therefore, treatment must always be individualized. In cases of complicated meningitis (eg subdural empyema, ventriculitis, brain abscess, suppurative venous sinus thrombosis), longer courses of antibiotic therapy may also be required.
ADJUNCTIVE THERAPY
Adjunctive therapy includes anti-inflammatory therapy, agents to reduce the intracranial pressure, and anticonvulsants.
Anti-inflammatory Therapy
Dexamethasone
Dexamethasone significantly reduces synthesis of proinflammatory cytokines, attenuates subarachnoid space inflammatory response and ameliorates meningeal inflammatory indices. This should be started by IV route at 10 mg 6 hourly for 10-20 minutes before or at the same time as the first dose of antibiotic for 4 days. The benefit is uncertain when Dexamethasone is administered ≥1 hour after the first antibiotic dose. 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. The precautions for its use are as follows: By decreasing brain inflammation, Dexamethasone may reduce the penetration of antibiotics into the CSF, particularly Vancomycin, and this may result in delayed sterilization of the CSF; and patients who are given Dexamethasone must be closely monitored for evidence of gastrointestinal blood loss. An addition of histamine-2 antagonists is recommended to decrease the risk of gastrointestinal bleeding.
Agents to Decrease Intracranial Pressure
The following agents (except Dexamethasone) have not been studied in clinical trials in patients with meningitis.
Dexamethasone
Please see the discussion above in Anti-inflammatory Therapy.
Mannitol
Meningitis - Acute, Bacterial_Management 3Mannitol 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. The dosage is 1-1.5 g/kg IV given over 15 minutes and may be repeated once.
Barbiturates
Example drug: Phenobarbital
A high-dose of barbiturates decreases cerebral metabolic demands and cerebral blood flow. This may be considered in patients with persistently elevated ICP after other measures have failed.
Antihypertensive Agents
Antihypertensive agents may be considered for decreasing intracranial pressure. Use with caution, as rapid lowering of blood pressure may cause compromise in intracranial perfusion and cause brain injury.
Anticonvulsants
Example drugs: Diazepam, Lorazepam, Phenytoin
Administer anticonvulsants if the patient has seizures. Diazepam or Lorazepam may be given for immediate treatment of seizures at the following dosages: Diazepam at 10-20 mg rectally and Lorazepam at 0.1 mg/kg/dose IV. Phenytoin may be given to reduce likelihood of recurrence at 15-18 mg/kg loading dose.
Nonpharmacological
Maneuvers to Decrease Elevated Intracranial Pressure (ICP)
Patients
with signs of increased intracranial pressure (eg changes in level of
consciousness, non-reactive or poorly reactive pupils, ocular movement
disorders) and who are comatose or stuporous may benefit from ICP monitoring.
Consider treating ICP of >15 mmHg to avoid larger elevations that can lead
to cerebral herniation and brain stem injury. Treat an ICP of >20 mmHg.
Elevation
of the head of the bed (30-45°) should be done to maximize venous drainage with
minimum compromise of cerebral perfusion. Hyperventilation can 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 CSF drainage may be needed when there is evidence of hydrocephalus.
The need to perform this procedure depends on the patient’s level of
consciousness and degree of ventricular dilatation as seen on brain imaging.
Supportive Measures
Supervise
Patient Closely
Monitor
the patient’s vital signs and neurologic status regularly. Shock may develop in
a patient with meningitis. Patients with a depressed sensorium and/or seizures
may need intubation for airway protection or assisted ventilation. Maintain
adequate nutrition and hydration. Due to a patient’s altered level of
consciousness, tube feeding may be necessary.
Other
Supportive Measures
Keep the patient’s surroundings quiet and semi-dark.
Prevention
Precautions
The use of masks, gloves and gowns prevents the spread of disease, as
meningitis is a droplet infection.
Vaccination
Completion
of the recommended schedule of vaccination is an effective way of protecting
individuals from certain types of bacterial meningitis (eg meningococcus [N
meningitidis], pneumococcus [S pneumoniae], Hib). Pneumococcal
vaccine is recommended in patients who had an episode of bacterial meningitis and
CSF leakage to reduce recurrences. Adults ≥19 years old with CSF leak should
receive PCV13 followed by PPSV23 at least 8 weeks after PCV13. The pediatric
dose depends on the child’s immunization history. In patients with CSF leakage,
additional vaccination with Hib and N meningitidis is recommended.
Meningitis - Acute, Bacterial_Management 4Meningococcal serogroup A, C, W and Y conjugate vaccine is recommended by the Advisory Committee on Immunization Practices (ACIP) of the Centers for Disease Control and Prevention (CDC) to be given to persons at increased risk for meningococcal disease such as patients aged ≥2 months, adolescents aged 11-12 years old with booster dose at age 16, while serogroup B meningococcal vaccine is recommended for patients aged ≥10 with increased risk for meningococcal disease and to adolescents and young adults aged 16-18 years. Vaccination against meningococcal serogroup A, C, W, Y and B is also recommended for persons with increased risk for meningococcal disease which includes those with certain medical conditions (eg complement component deficiency, functional or anatomic asplenia [including sickle cell disease], HIV), taking complement inhibitors, traveling to or residing in countries where meningococcal disease is common, and occupation or setting wherein there is exposure to causal pathogen (eg microbiologist, military recruit, community outbreak).
The Hib conjugate vaccine is recommended by the CDC to be given to all children starting at 2 months of age, patients with asplenia, sickle cell disease, HIV infection, antibody and complement deficiency syndromes and cancer requiring certain treatments (eg chemotherapy, radiation therapy, bone marrow transplant).
Recommendations for vaccination may vary between countries. Please refer to the local guidelines.
Post-exposure Chemoprophylaxis
Determine the need for chemoprophylaxis of the patient’s contacts. Prophylaxis of meningitis of the patient’s contacts using antimicrobial agents may be appropriate for certain types of bacterial meningitis. Administered as soon as possible after exposure, ideally <24 hours after identification of an index patient. Chemoprophylaxis eradicates nasopharyngeal colonization, thereby preventing transmission.
Hemophilus influenzae
Recommended agents: Rifampicin, Ciprofloxacin, Ceftriaxone
These agents eradicate nasopharyngeal colonization, thereby preventing transmission to young, susceptible contacts along with stopping the development of invasive disease in those already colonized. These are recommended for all household contacts with at least one unvaccinated or incompletely vaccinated child <48 months, or an immunocompromised child of any age.
Neisseria meningitidis
Recommended agents: Rifampicin, Ciprofloxacin, Ceftriaxone
These agents are recommended for all household and other contacts of patients, including day care center members and anyone directly exposed to the patient’s oral secretions and for healthcare workers whose mouth or nose has been directly exposed to respiratory secretions or droplets from a patient with meningococcal meningitis during the acute phase of illness and before completion of antibiotics for 24 hours. These are not recommended for school, work or transportation contacts. Azithromycin may be used as an alternative agent in case of sustained Ciprofloxacin-resistant strains of N meningitidis.
Streptococcus agalactiae
Recommended agents: Ampicillin, Penicillin G
All pregnant patients should be screened at 35-37 weeks of gestation for anogenital colonization with group B streptococci. Maternal group B streptococci carriers should receive chemoprophylaxis if they have ≥1 of the following risk factors: Preterm labor at 37 weeks of gestation, fever (>38°C) during labor or after membranes have been ruptured 18 hours or more during any gestation, and previous delivery of a sibling with invasive group B streptococcal disease. Clindamycin or Erythromycin may also be used as alternative agents.