Effect of dexamethasone on therapy of experimental penicillin- and cephalosporin-resistant pneumococcal meningitis

Abstract

Treatment of pneumococcal meningitis has become problematic because of the emergence of penicillin-and cephalosporin-resistant strains and because of the concern that dexamethasone therapy might reduce penetration of antibiotics into the cerebrospinal fluid (CSF). We addressed these issues with our rabbit meningitis model by studying two pneumococcal isolates that were resistant to penicillin and ceftriaxone and susceptible to vancomycin and rifampin. Ceftriaxone, vancomycin, and rifampin were given alone or in combination, with or without coadministration of dexamethasone. Treatment was started 12 to 14 h after intracisternal inoculation of i104 CFU of one of the organisms. Rifampin concentrations in serum and CSF were similar, regardless of whether dexamethasone was given, whereas those of ceftriaxone were somewhat lower at each time point in animals given dexamethasone. The penetration of vancomycin into CSF was consistently and substantially reduced with dexamethasone treatment, which resulted in a delay in CSF sterilization not observed in non-dexamethasone-treated animals. When rifampin was used with ceftriaxone for treatment of meningitis caused by the more resistant strain, bacteriologic cure occurred promptly, with or without dexamethasone therapy. In areas with high rates of occurrence of resistant pneumococcal strains, we believe initial empiric therapy of bacterial meningitis should include two antibiotics: ceftriaxone and either rifampin or vancomycin. When dexamethasone is used, the combination of ceftriaxone and rifampin is preferred for therapy.Dexamethasone has been shown to improve the long-term outcome in infants and children with bacterial meningitis, especially meningitis caused by Haemophilus influenzae type b (19,20,27,28). Its role in the management of Streptococcus pneumoniae meningitis is uncertain, although a retrospective study of 97 infants and children (18) and a prospective trial in 106 older patients (15) with pneumococcal meningitis suggested a satisfactory effect. With routine use of conjugate Haemophilus vaccines in many countries, meningitis caused by this organism has virtually disappeared (1,4,6,23,26,29), leaving the pneumococcus and meningococcus as the principal causes of meningitis in these areas.Attention has recently focused on management of pneumococcal meningitis because of the emergence of penicillin-and cephalosporin-resistant strains (7,8,10,11 (214) 648-2961. showed synergistic killing of resistant pneumococci in the rabbit meningitis model (12), and this regimen has been suggested for routine initial therapy of bacterial meningitis until results of culture and susceptibility studies are available.Because of concerns about the highly variable concentrations of vancomycin in cerebrospinal fluid (CSF) after parenteral administration (22,34) and about possible reduced penetration of vancomycin into CSF when dexamethasone is concomitantly given, the present study was undertaken. The impact of dexamethasone therapy on the decrease of clearance of resistant pneum...

Penetration of Drugs through the Blood-Cerebrospinal Fluid/Blood-Brain Barrier for Treatment of Central Nervous System Infections

“…For patients with inflamed meninges, bactericidal CSF concentrations of vancomycin against susceptible pathogens are reached during high intravenous doses (2). Adjunctive dexamethasone therapy as recommended for community-acquired bacterial meningitis in patients reduced CSF vancomycin concentrations substantially, resulting in a delay in CSF sterilization in a rabbit model of experimental meningitis (188). Based on these data, those authors concluded that when dexamethasone is used as an adjunctive therapy for bacterial meningitis in areas with high rates of occurrence of penicillinresistant pneumococci, the combination of rifampin and ceftriaxone should be preferred instead of vancomycin and ceftriaxone (188) (see below).…”

“…When rifampin was used with ceftriaxone for the treatment of experimental meningitis caused by penicillin-resistant S. pneumoniae in rabbits, bacteriologic cure occurred promptly, with or without dexamethasone therapy (188). Although clinical data on the efficacy of rifampin in patients with S. pneumoniae meningitis are scarce, some authors recommended that in areas with high rates of occurrence of penicillin-resistant pneumococcal strains, the combination of ceftriaxone plus rifampin instead of vancomycin should be preferred, or rifampin, vancomycin, and ceftriaxone should be administered together when adjunctive dexamethasone is used (188,243).…”

Steroid Therapy for Bacterial Meningitis

“…The effect of dexamethasone therapy on the activity of the cephalosporins and vancomycin and their penetration into the CSF of these patients is required before definitive recommendations can be made. Data derived from studies of experimental pneumococcal meningitis clearly indicate that dexamethasone reduces the CSF penetration of ceftriaxone and vanco-mycin sufficiently to alter the clearance of resistant organisms from CSF cultures [30]. Penetration of rifampin into the CSF appears to be unaffected by concomitant dexamethasone therapy.…”

Adjunctive Therapy in Children with Bacterial Meningitis

“…In the rabbit model, vancomycin levels in CSF were reduced in the presence of dexamethasone and this was associated with a delay in CSF sterilization of penicillin-susceptible or penicillin-and cephalosporin-resistant isolates. 39,40 Relatively little is known about the pharmacology of vancomycin entrance into CSF in patients also receiving dexamethasone. In one study from Spain, 11 adults received vancomycin along with dexamethasone (0.25 mg/kg q 6 hours x 4 days) for pneumococcal meningitis.…”