Pediatric Bacterial Meningitis Medication

Antimicrobial therapy for neonates

Antibiotics should be administered as soon as venous access is established in patients with bacterial meningitis. Traditionally, initial antimicrobial treatment consists of ampicillin and an aminoglycoside combination (ampicillin and cefotaxime also appropriate). If S pneumoniae is suspected, vancomycin should be added. Initial empiric therapy for late-onset disease in preterm infants should include an antistaphylococcal agent and ceftazidime, amikacin, or meropenem. See Tables 1-2.

Ampicillin provides good coverage for gram-positive cocci, including group B streptococci, enterococci, L monocytogenes, some strains of E coli, and H influenzae type b. Ampicillin also achieves adequate levels in cerebrospinal fluid (CSF).

Aminoglycosides (eg, gentamicin, tobramycin, amikacin) have good activity against most gram-negative bacilli, including P aeruginosa and S marcescens. However, aminoglycosides achieve only marginal levels in both CSF and ventricular fluid, even when the meninges are inflamed.

Several third-generation cephalosporins achieve good CSF levels and have emerged as effective agents against gram-negative infections. There has been considerable experience with cefotaxime and ceftriaxone. Ceftriaxone competes with bilirubin for binding of albumin, and therapeutic levels of ceftriaxone decrease the reserve albumin concentration in newborn serum by 39%; thus, ceftriaxone may increase the risk of bilirubin encephalopathy, especially in high-risk newborns. Ceftriaxone also causes sludging of bile. None of the cephalosporins have any activity against L monocytogenes and enterococci and, therefore, should not be used as a single agent for initial treatment. A combination of ampicillin and a third-generation cephalosporin is required.

If the offending pathogen is proven to be an ampicillin-susceptible bacterium with a low minimum inhibitory concentration (MIC) for ampicillin, then ampicillin may be continued alone. Cefotaxime and ceftriaxone also provide good activity against most penicillin-resistant S pneumoniae. Both vancomycin and cefotaxime should be administered in patients with S pneumoniae meningitis before antibiotic susceptibility results are available.

Among the aminoglycosides, gentamicin and tobramycin have been used extensively in combination with ampicillin. Despite concerns about the adequacy of their CSF levels, these agents have proven effective when combined with a beta-lactam antibiotic for the treatment of meningitis caused by organisms such as group B streptococci and susceptible enterococci. Routine intrathecal administration of aminoglycosides offers no additional benefit in this capacity.

Infections involving S aureus, anaerobes, or P aeruginosa may require other antimicrobials, such as oxacillin, methicillin, vancomycin, or a combination of ceftazidime with aminoglycoside. CSF penetration and safety of antimicrobial agents should determine usage.

Etiologic agent and clinical course dictate duration of treatment; however, a 10-day to 21-day treatment is usually adequate for group B streptococcal infection. It may take longer to sterilize the CSF with gram-negative bacillary meningitis, and 3-4 weeks of treatment is usually necessary.

Indications for repeat lumbar puncture include lack of clinical improvement or meningitis caused by resistant S pneumoniae strains or by gram-negative enteric bacilli. In neonates with gram-negative bacillary meningitis, examination of CSF during treatment is necessary to verify that cultures are sterile. Reexamination of CSF for chemistries and culture should be performed 48-72 hours after treatment initiation; further specimens are obtained based upon demonstrating lack of sterilization or lack of apparent clinical response.

Table 1. Antibiotic Dosages for Neonatal Bacterial Meningitis to be Adjusted by Weight and Age Dosage (mg/kg/dose or U/kg/dose for Highest Dose Within Dosage Range) and Intervals of Administration (Open Table in a new window)

Table 2. Antibiotics for Neonatal Bacterial Meningitis That Need to be Dosed According to Serum levels (Open Table in a new window)

Antimicrobial therapy for infants and children

Prompt administration of antibiotics to a patient with suspected bacterial meningitis is essential (see Table 3). Initial antibiotic selection should provide coverage for all 3 common pathogens: S pneumoniae, N meningitidis, and H influenzae.

As per the 2004 Infectious Diseases Society of America (IDSA) practice guidelines for bacterial meningitis, the combination of vancomycin and either ceftriaxone or cefotaxime is recommended for those with suspected bacterial meningitis, with targeted therapy based upon susceptibilities of isolated pathogens.^[4] This combination provides adequate coverage for most penicillin-resistant pneumococci and beta-lactamase resistant H influenzae type b. Of note, ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone.

Because vancomycin poorly penetrates the CNS, a higher dose of 60 mg/kg/d is recommended when vancomycin is used to treat CNS infections. Cefotaxime or ceftriaxone is adequate if pneumococci are susceptible to cefotaxime. However, if S pneumoniae isolates have a higher MIC for cefotaxime and fall in the intermediate resistance group, there have been concerns regarding prompt sterilization of the CSF, and a high dose of cefotaxime (300 mg/kg/d) with vancomycin (60 mg/kg/d) may be preferred. In the rare event that a pneumococcal isolate has high resistance to cefotaxime or ceftriaxone, vancomycin alone may not be adequate for prompt sterilization of the CSF, and rifampin should be added to the regimen to provide 4- to 8-fold CSF cidal activity against the pathogen.

Carbapenem treatment is another valid option for cephalosporin-resistant carbapenem-susceptible isolates. Meropenem is preferred over imipenem because of the risk of seizures with the latter antibiotic. The role of other new classes of antibiotics, such as the oxazolidinones (linezolid), remains an area of investigation. Fluoroquinolones may be an option for patients who either cannot use other antibacterials or have failed previous therapy, but they should be used with caution as resistance may develop during treatment.

Administer all antibiotics intravenously to achieve adequate serum and CSF levels. An intraosseous route is acceptable if venous access is not an option. In patients with a history of significant hypersensitivity to beta-lactam antimicrobial agents (penicillins and cephalosporins) the choice of alternative agent varies with the etiology of meningitis. Vancomycin and rifampin should be considered for S pneumoniae. Chloramphenicol can also be used if minimum bactericidal concentration is ≤4 µg/mL. Chloramphenicol is recommended for patients with meningococcal meningitis who have significant hypersensitivity to beta-lactam antimicrobial agents.

Examination of the CSF at the end of treatment has not proven helpful in predicting relapses or recrudescence of meningitis. H influenzae type b isolates can persist in the nasopharyngeal secretions, even after a successful treatment of meningitis. For this reason, the patient must be given rifampin 20 mg/kg once daily for 4 days if high-risk children are at home or at a childcare center (unless the medication was ceftriaxone). N meningitidis and S pneumoniae usually are eradicated from the nasopharynx after successful treatment of meningitis.

Phlebitis at the intravenous site and antibiotic fever are the most common of several causes of secondary fever in patients with meningitis. Thoroughly evaluate any patient with fever.

Table 3. Dose Guidelines of Intravenous Antimicrobials in Infants and Children With Bacterial Meningitis (Open Table in a new window)

Duration of antimicrobial therapy

The IDSA 2004 guidelines for management of bacterial meningitis provide the following information on length of therapy with antibiotics with the caveat that "the guidelines are not standardized and that duration of therapy may need to be individualized on the basis of the patient's clinical response:"

• N meningitidis - 7 days
• H influenzae - 7 days
• S pneumoniae - 10-14 days
• S agalactiae - 14-21 days
• Aerobic gram-negative bacilli - 21 days or 2 weeks beyond first sterile culture (whichever is longer)
• L monocytogenes - 21 days or longer

A meta-analysis of randomized controlled trials evaluated the efficacy and safety of short-course antibiotic therapy for bacterial meningitis.^[5] Five open-label trials involving children (aged 3 wk to 16 y) were included. No difference was demonstrated in end-of-therapy clinical success, long-term neurological complications, long-term hearing impairment, total adverse events, and secondary nosocomial infections between short-course (4-7 d) and long-course (7-14 d) treatment with intravenous ceftriaxone. However, the American Academy of Pediatrics does not endorse a shorter course of therapy than 5-7 days for meningococcus, 10 days for H influenzae, and 14 days for S pneumoniae.^[6] Although the available evidence is limited, some studies show no difference between short-course and long-course antibiotics for bacterial meningitis in children.^[7]

A double-blind, placebo-controlled, randomized, multicountry, equivalence study evaluated treatment of purulent meningitis in children in developing countries aged 2 months to 12 years with 5 versus 10 days of treatment with ceftriaxone. The results found that antibiotic treatment of purulent meningitis caused by H influenzae type b, N meningitidis, or S pneumoniae can be safely discontinued in children who are stable by day 5. However, this should not be considered the standard of care.^[8]

Dexamethasone administration

Experimental studies have revealed a correlation between outcome and the severity of the inflammatory process in the subarachnoid space.^[9] Animal models of bacterial meningitis have shown decreased inflammation, reduction in cerebral edema and intracranial pressure, and lessening brain damage with use of dexamethasone.

Better understanding of the mechanisms of inflammation in meningitis led to controlled double-blind clinical trials. In these trials, the beneficial effects of adjunctive dexamethasone were demonstrated in infants and children with H influenzae type b meningitis. Follow-up examination demonstrated a significant decrease in the incidence of neurologic and audiologic sequelae, with evidence of clinical benefit being greatest for overall hearing impairment. As a result, the IDSA guidelines recommend the use of adjunctive dexamethasone in cases of H influenzae type b meningitis to be initiated 10-20 minutes prior to or at least concomitant with the first antimicrobial dose at 0.15 mg/kg q6h for 2-4 days.

A prospective double-blind placebo-controlled multicenter trial in adults with bacterial meningitis showed benefits (lower percentage of unfavorable outcomes including death) in the subgroup of patients with pneumococcal meningitis but not others. Although, data from pediatric patients so far does not demonstrate a clear clinical benefit with dexamethasone use in patients with S pneumoniae meningitis, a Cochrane review recommended consideration of the use of corticosteroids in children (non-neonates) with bacterial meningitis in high-income countries.^[9] However, given the lack of clear benefit favoring dexamethasone use in this setting and the concerns about decreased antibiotic penetration in the CSF with its use, decision to use this agent is considered on a case-by-case basis after weighing the potential risks and benefits. Likewise, data are insufficient to recommend adjunctive steroids in neonates with bacterial meningitis.