Bacterial meningitis continues to be a significant cause of mortality and morbidity world-wide. Empirical antimicrobial therapy must be started promptly in patients with bacterial meningitis. Penetration of the antibiotic across the blood–brain barrier and into the CSF (i.e. Cerebrospinal fluid) is the most important factor. The empirical antimicrobial therapy administered depends on the age of the patient, his/her vaccination coverage, risk factors and the prevalence of resistant bacteria in the area. In this review, empirical antimicrobial regimens and the use of adjunctive therapy with dexamethasone are discussed.
Eradication of the infecting organism from the CSF depends on antibiotics. Bactericidal antibiotics should be administered intravenously at the highest clinically validated doses to patients with suspected bacterial meningitis . Several retrospective and prospective studies have shown that delay in antibiotic treatment is associated with adverse outcomes . In patients with suspected bacterial meningitis for which immediate lumbar puncture is delayed pending brain imaging or the presence of disseminated intravascular coagulation, blood cultures must be obtained and antimicrobial treatment should be initiated immediately.
Empirical antimicrobial therapy
The selection of empirical antimicrobial regimens is designed to cover the probable pathogens, based on the age of the patient and specific risk factors (Table 1), with modifications if the CSF Gram stain is diagnostic. The ability of an antimicrobial agent to penetrate the blood–brain barrier (BBB) is the most important factor that determines whether efficient bacterial killing happens in the CSF [3, 4]. The environment of the CSF is unique, and antimicrobial agents are generally not metabolized significantly in the CSF. Therefore their concentration largely depends on their penetration and elimination through the BBB. In inflamed meninges, inflammatory cytokines act to damage and separate the tight junctions and increase the number of pinocytotic vesicles in the endothelial cells of the BBB, which enhances drug entry into the CSF . BBB penetration is affected by the lipophilic properties, molecular weight, ionization (the CSF has a low pH with bacterial meningitis) and protein-binding ability of the drugs, inflammation of the meninges, and efflux transporters . Lipophilic agents (i.e. fluoroquinolones and rifampicin) penetrate relatively well into the CSF even if the meninges are not inflamed, whereas hydrophilic agents (i.e. β-lactams and vancomycin) have a decreased penetration into the CSF in the absence of meningeal inflammation.
Antibacterial killing activity in the CSF also depends on the bacterial burden at the start of treatment. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration are established in laboratories using a bacterial inoculum size of 104–105 organisms/mL. However, some patients with bacterial meningitis (e.g. caused by group B streptococcus and Streptococcus pneumoniae), who have many Gram stain-positive organisms in the CSF, are likely to yield 107–108 organisms/mL, and MIC values can be 100–1000 times higher than would normally be expected. Therefore, careful monitoring of the response to antimicrobial treatment is necessary in patients with bacterial meningitis who have a high bacterial burden on the basis of the initial CSF Gram stain.
An important factor in the choice of empirical antimicrobial agents is the emergence of antimicrobial-resistant organisms, including S. pneumoniae that is resistant to penicillin and third-generation cephalosporins, and Gram-negative bacilli that are resistant to many β-lactam drugs. For example, the prevalence of S. pneumoniae strains that are relatively resistant to penicillin (MIC 0.1–1.0 μg/mL) or highly resistant to penicillin (MIC greater than 1.0 μg/mL) is increasing, and many of the penicillin-resistant pneumococci have reduced susceptibility to third-generation cephalosporins (i.e. cefotaxime and ceftriaxone) . Treatment failures in bacterial meningitis as a result of multiresistant organisms have been reported . Therefore, empirical treatment for patients with bacterial meningitis in areas where resistant S. pneumoniae strains are prevalent must include the addition of vancomycin (Table 1). However, penetration of vancomycin into the CSF can be reduced in the absence of meningeal inflammation and also in patients who receive adjunctive dexamethasone treatment .
Treatment of patients at risk of infection with Listeria monocytogenes must include a synergistic regimen containing ampicillin and an aminoglycoside (e.g. gentamicin), whereas a regimen for Gram-negative bacilli with a high likelihood of resistance (e.g. nosocomial meningitis) should also include an aminoglycoside (e.g. amikacin). However, the penetration of intravenously given aminoglycosides into the CSF remains variable or poor even in the presence of meningeal inflammation, and thus cannot be used as monotherapy for bacterial meningitis.
Antimicrobial susceptibility patterns must be established for all organisms isolated from the CSF. For example, although penicillins are the treatment of choice for meningococcal meningitis there have been recent reports of an increased incidence of resistant strains in Spain . Therefore, third-generation chephalosporins should be used initially and treatment changed to penicillin once penicillin susceptibility is confirmed.
The use of newer antimicrobials has been reported from animal studies as well as from case reports and case series of patients infected with resistant organisms. Meropenem is less neurotoxic and has a lower risk of inducing seizures compared with imipenem. Recent clinical trials in both children and adults have indicated that meropenem is clinically and microbiologically comparable with cefotaxime and ceftriaxone . Teicoplanin has been used alone in the experimental treatment of pneumococcal meningitis and meningitis caused by methicillin-resistant Staphylococcus aureus (MRSA). Fluoroquinolones have excellent in vitro activity against many of the meningeal pathogens, and good penetration in CSF. Recent studies have demonstrated that moxifloxacin and levofloxacin are efficacious when used to treat patients with meningitis caused by resistant organisms . Daptomycin is a lipopeptide with potent bactericidal activity against multidrug-resistant Gram-positive organisms, but there is limited experience of its use in bacterial meningitis . Finally, linezolid has been used successfully in patients with resistant pneumococcus, vancomycin-resistant enterococcus and MRSA . However, the use of these new drugs should be limited to patients with multidrug-resistant organisms and only based on CSF culture results.
Neurological sequelae are common in survivors of meningitis, and include hearing loss, cognitive impairment and developmental delay. Hearing loss happens in 22–30% of survivors of pneumococcal meningitis, compared with 1–8% after meningococcal meningitis . The beneficial effect of adjunctive dexamethasone treatment is evident in children and adults with bacterial meningitis, mainly pneumococcal. Dexamethasone should be given shortly before or when antibiotics are first given. Rifampin should be added for patients treated with vancomycin.
In a 2007 Cochrane review, adjunctive treatment with dexamethasone was associated with lower mortality rates, and lower rates of severe hearing loss and long-term neurological sequelae . However, recently the benefit of adjunctive dexamethasone has been questioned, as new meta-analyzes have indicated that although its use reduces hearing loss there is no observed reduction in death or severe neurological sequelae [9, 10]. Currently, corticosteroids are used as an adjunctive treatment in bacterial meningitis.
Table 1: Empirical antimicrobial regimens for the treatment of bacterial meningitis by age
|Age||Probable pathogen||Antimicrobial regimen|
|<1 month||Group B streptococci, E. coli, L. monocytogenes||Ampicillin plus gentamicin or ampicillin plus cefotaxime|
|1–3 months||S. pneumoniae, N. meningitides, Group B streptococci, E. coli, L. monocytogenes||Ampicillin plus cefotaxime or ceftriaxone. Add vancomycin if a Gram+ strain for resistant pneumonia|
|3–23 months||S. pneumoniae, N. meningitides, E. coli, H. influenzae||Cefotaxime or ceftriaxone plus vancomycin|
|2–50 years||S. pneumoniae, N. meningitides||Cefotaxime or ceftriaxone plus vancomycin|
|>50 years||S. pneumoniae, N. meningitides, L. monocytogenes||Cefotaxime or ceftriaxone plus ampicillin plus vancomycin|
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Papaevangelou Vana, Associate Professor of Pediatrics, Second Department of Pediatrics, National and Kapodistrian University of Athens