Pediatric Bacterial Meningitis - Antibiotic Therapy

Pediatric Bacterial Meningitis Treatment

Antibiotic Therapy

Neonates

In neonates with bacterial meningitis, antibiotics should be administered as soon as venous access is established (see Tables 1 and 2 below). Traditionally, initial antimicrobial treatment consists of ampicillin plus an aminoglycoside (ampicillin plus cefotaxime is 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 plus ceftazidime, amikacin, or meropenem.

Table 1. Antibiotic Dosages for Neonatal Bacterial Meningitis, Adjusted by Weight and Age (Open Table in a new window)

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

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

Aminoglycosides (eg, gentamicin, tobramycin, and 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, such as cefotaxime and ceftriaxone, achieve good CSF levels and have emerged as effective agents against gram-negative infections. 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; therefore, they should not be used alone for initial treatment. A combination of ampicillin and a third-generation cephalosporin is required.

If the offending pathogen is proved to be an ampicillin-susceptible bacterium with a low minimum inhibitory concentration (MIC) for ampicillin, ampicillin may be continued alone. Cefotaxime and ceftriaxone also provide good activity against most penicillin-resistant strains of 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 GBS and susceptible enterococci. Routine intrathecal administration of aminoglycosides offers no additional benefit in this setting.

Infections involving S aureus, anaerobes, or P aeruginosamay require other antimicrobials, such as oxacillin, methicillin, vancomycin, or a combination of ceftazidime with an aminoglycoside. Use of antimicrobial agents should be determined by their CSF penetration and safety.

The duration of antibiotic therapy is dictated by the pathogen responsible for the meningitis and the patient’s clinical course. In most cases, 14-21 days of treatment is adequate for GBS infection. With gram-negative bacillary meningitis, however, it may take longer to sterilize the CSF, and 3-4 weeks of treatment is usually necessary.

If no clinical improvement is noted or the meningitis is determined to be caused by resistant S pneumoniae strains or gram-negative enteric bacilli, repeat lumbar puncture is indicated. 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 if CSF sterilization is not demonstrated or clinical response is not apparent.

Infants and children

Prompt administration of antibiotics to a patient with suspected bacterial meningitis is essential (see Table 3 below). Initial antibiotic selection should provide coverage for the 3 most common pathogens: S pneumoniae, N meningitidis, and H influenzae. All antibiotics should be administered IV to achieve adequate serum and CSF levels. An intraosseous route is acceptable if venous access is not an option.

Table 3. Dosages and Dosing Intervals for Intravenous Antimicrobials in Infants and Children With Bacterial Meningitis (Open Table in a new window)

According to the 2004 Infectious Diseases Society of America (IDSA) practice guidelines for bacterial meningitis, vancomycin plus either ceftriaxone or cefotaxime is recommended for those with suspected bacterial meningitis, with targeted therapy based on the susceptibilities of isolated pathogens.[3] This combination provides adequate coverage for most penicillin-resistant pneumococci and beta-lactamase–resistant Hib. Ceftazidime has poor activity against pneumococci and should not be substituted for cefotaxime or ceftriaxone.

Because vancomycin penetrates the central nervous system (CNS) poorly, a higher dosage (60 mg/kg/day) is recommended when this agent 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, sterilization of the CSF may not be achieved promptly, and a high dosage of cefotaxime (300 mg/kg/day) plus vancomycin (60 mg/kg/day) 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 bactericidal activity against the pathogen. Carbapenem treatment is another valid option for cephalosporin-resistant carbapenem-susceptible isolates. Meropenem is preferred to imipenem because of the risk of seizures associated with the latter.

The roles of other classes of antibiotics, such as the oxazolidinones (eg, linezolid), in the treatment of bacterial meningitis in infants and children remain to be determined. Fluoroquinolones may be an option for patients in whom either other antibacterials cannot be used or previous therapy has failed, but they should be used with caution because resistance may develop during treatment.

When there is a history of significant hypersensitivity to beta-lactam antibiotics (ie, penicillins and cephalosporins), the choice of alternative agent varies with the cause of the meningitis. Vancomycin and rifampin should be considered for S pneumoniae. Chloramphenicol can also be used if the MIC is 4 µg/mL or less. It 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 proved helpful for predicting relapses or recrudescence of meningitis. Hib isolates can persist in the nasopharyngeal secretions even after successful treatment of meningitis. For this reason, rifampin 20 mg/kg must be given 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 are usually eradicated from the nasopharynx after successful treatment of meningitis.

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

Duration of antimicrobial therapy

The IDSA 2004 guidelines for management of bacterial meningitis provide the following recommendations for the duration of antibiotic therapy, 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 (GBS) - 14-21 days
• Aerobic gram-negative bacilli - 21 days or 2 weeks beyond the 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.[25] Five open-label trials were included, involving children aged 3 weeks to 16 years. No differences between short-course (4-7 days) and long-course (7-14 days) treatment with IV ceftriaxone were demonstrated with respect to end-of-therapy clinical success, long-term neurologic complications, long-term hearing impairment, total adverse events, and secondary nosocomial infections.

However, the American Academy of Pediatrics (AAP) does not endorse courses of therapy shorter than 5-7 days for meningococcus, 10 days for H influenzae, and 14 days for S pneumoniae.[4] Although the available evidence is limited, some studies show no difference between short-course and long-course antibiotic regimens for treatment of bacterial meningitis in children.[26]

A double-blind, placebo-controlled, randomized, multicountry equivalence study compared 5-day and 10-day ceftriaxone regimens for treatment of purulent meningitis in children (aged 2 months to 12 years).[14] The investigators concluded that antibiotic treatment of purulent meningitis caused by Hib, N meningitidis, or S pneumoniae could be safely discontinued in children who are stable by day 5. However, this should not be considered the standard of care.