by author ESCMID Online Lecture Library Steroids in acute bacterial meningitis

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1 Steroids in acute bacterial meningitis Javier Garau, MD, PhD University of Barcelona Spain ESCMID Summer School, Porto, July 2009

2 Dexamethasone treatment in childhood bacterial meningitis in Malawi: a randomised controlled trial. Double-blind, placebo controlled trial; 598 children with pyogenic meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi. Neurological, developmental, and hearing assessments at 1 and 6 months after discharge. Primary outcome: overall death. Secondary outcomes: sequelae, in-hospital deaths, and death after discharge. Analysis was done by intention to treat. FINDINGS: Of the 598 children, 307 (51%) were assigned to DXM and 295 (49%) to placebo. 338 (40%) had Streptococcus pneumoniae, 170 (28%) Haemophilus influenzae type b, 66 (11%) Neisseria meningitidis, and 29 (5%) Salmonella spp. The number of overall deaths was the same in the two treatment groups (RR 1.00 [95% CI ], p=0.93). At final outcome, sequelae were identified in 84 (28%) of children on steroids and in 81 (28%) on placebo (RR 0.99 [95% CI ], p=0.97). INTERPRETATION: Steroids are not an effective adjuvant treatment in children with acute bacterial meningitis in developing countries. Molyneux EM et al. Lancet 2002;360:211-8

3 IDSA Recommendations for use of adjuntive dexamethasone (DXM) in meningitis. Children At present, insufficient data to make a recommendation on the use of DXM in neonates with bacterial meningitis. Despite some variability in result of published trials, we believe the available evidence supports the use of adjunctive DXM in infants and children with H. influenzae type b meningitis (A-I). DXM should be given prior to, or at least concomitant with, the first antimicrobial dose, at 0.15 mg/kg every 6 h for 2 4 days. In infants and children with pneumococcal meningitis, there is controversy concerning DXM (C-II). IDSA Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis 2004; 39:

4 Glycerol and/or Dexamethasone in Childhood Bacterial Meningitis: A Randomized, Double-Blind, Placebo-Controlled Trial Glycerol, a naturally occurring trivalent alcohol, an essential compound of the human cell membrane, a hyperosmolar agent, and an osmotic diuretic, long used in neurosurgery, neurology, and ophthalmology to reduce raised tissue pressure The first systematic trial was performed in Finland during the period Glycerol appeared to reduce profound hearing loss and persistent neurological abnormalities as efficaciously as dexamethasone, but the series was too small for definitive conclusions. Prospective, randomized, double-blind trial comparing adjuvant dexamethasone or glycerol with placebo in children aged from 2 months through 16 years in Latin America. Primary end points were death, severe neurological sequelae, or deafness, with the first 2 end points forming a composite end point. Peltola H et al, Clin Infect Dis 2007; 45:

5 IV ceftriaxone, mg/kg/once daily for 7 10 days. DXM, 0.15 mg/kg/q6h, for 48 h, the first dose 15 min prior to administration of ceftriaxone (if possible). Oral 85% glycerol, given for 48 h, 1.5 g (1.5 ml)/kg/q6h. The first dose 15 min prior to ceftriaxone No fluid restriction was used Peltola H et al, Clin Infect Dis 2007; 45:

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7 a Determined by x2 test between 4 groups (for heterogeneity). b Severe neurological sequelae included blindness (7 patients), quadriplegia (8), hydrocephalus requiring a shunt (4), or severe psychomotor retardation (26), with each child counted only once. c Hearing threshold of 80 db for the better ear.

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10 No adjuvant therapy significantly affected death or deafness. In contrast, glycerol and dexamethasone plus glycerol reduced severe neurological sequelae, compared with placebo; the ORs were 0.31 (95% CI, ; P<.010) and 0.39 (95% CI, ; P<.033), respectively. For neurological sequelae and death, the ORs were 0.44 (95% CI, ; P<.003) and 0.55 (95% CI, ; P<.027), respectively. Dexamethasone therapy prevented deafness in patients with H. influenzae type b meningitis only if patients were divided grossly into dexamethasone recipients and nonrecipients and if timing between dexamethasone and ceftriaxone administration was not taken into account (OR, 0.27; 95% CI, ; P<.014). Peltola H et al, Clin Infect Dis 2007; 45:

11 ACUTE BACTERIAL MENINGITIS ADULTS

12 DEXAMETHASONE IN ADULTS WITH BACTERIAL MENINGITIS Prospective, randomized, double-blind trial of adjuvant treatment with DXM as compared with placebo in acute bacterial meningitis. DXM (10 mg/q6h/4 days) and placebo administered minutes before or with the first dose of antibiotic (Amoxicillin, 2 G/q4h) and given q6h x 4 days. The primary outcome measure was the score of The Glasgow Outcome Scale at eight weeks De Gans, J, et al, NEJM 2002;347:

13 OUTCOMES EIGHT WEEKS AFTER ADMISSION, ACCORDING TO CULTURE RESULTS Jean de Gans et al, NEJM 2002

14 OUTCOMES EIGHT WEEKS AFTER ADMISSION, ACCORDING TO CULTURE RESULTS Jean de Gans et al, NEJM 2002

15 OUTCOMES EIGHT WEEKS AFTER ADMISSION, ACCORDING TO CULTURE RESULTS Jean de Gans et al, NEJM 2002

16 OUTCOMES EIGHT WEEKS AFTER ADMISSION, ACCORDING TO CULTURE RESULTS Jean de Gans et al, NEJM 2002

17 OUTCOMES EIGHT WEEKS AFTER ADMISSION, ACCORDING TO CULTURE RESULTS Jean de Gans et al, NEJM 2002

18 * * * RR 0,48 CI95%, Jean de Gans et al, NEJM 2002

19 IDSA Recommendations for use of adjuntive dexamethasone (DXM) in meningitis Adjunctive DXM should be initiated in all adult patients with suspected pneumococcal meningitis. DXM should only be continued if the CSF Gram stain reveals grampositive diplococci,or if blood or CSF cultures are positive for S. pneumoniae. DXM should not be given to adult patients who have already received antimicrobial therapy, because administration of DXM in this circumstance is unlikely to improve patient outcome (A-I). The data are inadequate to recommend adjunctive DXM to adults with meningitis caused by other bacterial pathogens, although some authorities would initiate dexamethasone in all adults. In patients with suspected pneumococcal meningitis who receive adjunctive DXM,addition of rifampin to the empirical combination of vancomycin plus a third-generation cephalosporin may be reasonable pending culture results and in vitro susceptibility testing (B-III). IDSA Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis 2004; 39:

20 DEXA METHASONE IN ADULT BACTERIAL MENINGITIS Recent experience

21 Dexamethasone in Vietnamese Adolescents and Adults with Bacterial Meningitis Randomized, double-blind, placebo-controlled trial of dexamethasone in 435 patients over the age of 14 years who had suspected bacterial meningitis. Results An ITT analysis of all the patients showed that DXM was not associated with a significant reduction in the risk of death at 1 month (RR, 0.79; 95% CI, 0.45 to 1.39) or the risk of death or disability at 6 months (OR, 0.74; 95% CI, 0.47 to 1.17). In patients with confirmed bacterial meningitis, however, there was a significant reduction in the risk of death at 1 month (RR, 0.43; 95% CI, 0.20 to 0.94) and in the risk of death or disability at 6 months (OR, 0.56; 95% CI, 0.32 to 0.98). Conclusions Dexamethasone does not improve the outcome in all adolescents and adults with suspected bacterial meningitis A beneficial effect is confined to patients with microbiologically proven disease, including those who have received prior treatment with antibiotics. Nguyen THM et al,n Engl J Med 2007;357:

22 Nguyen THM et al,n Engl J Med 2007;357:

23 Corticosteroids for Bacterial Meningitis in Adults in Sub-Saharan Africa In sub-saharan Africa, bacterial meningitis is common and is associated with a high mortality. Adjuvant therapy with corticosteroids reduces mortality among adults in the developed world, but it has not been adequately tested in developing countries or in the context of advanced HIV infection Randomized, double-blind, placebo-controlled trial of DXM (16 mg twice daily for 4 days) and an open-label trial of IM vs. IV ceftriaxone (2 g twice daily for 10 days) in adults with an admission diagnosis of bacterial meningitis in Blantyre, Malawi Scarborough M et al. N Engl J Med 2007;357:

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25 Scarborough M et al N Engl J Med 2007;357:

26 DXM IN MENINGITIS CONCLUSIONS Overall, corticosteroids significantly reduce mortality, severe hearing loss and neurological sequelae. In adults with community-acquired bacterial meningitis, corticosteroid therapy should be administered in conjunction with the first antibiotic dose. In children, data support the use of adjunctive corticosteroids in children in high-income countries. No beneficial effect of corticosteroids found for children in low-income countries (Cochrane Database Syst Rev Jan 24;(1):CD004405) In children, GLY seriously challenges the position of DXM as adjuvant medication. Severe neurological sequelae are relieved by GLY, whereas no current medication prevents hearing impairment. The same can be said of adults with similar baseline characteristics. Patient selection on the basis of host and pathogen genotype may improve the outcome.

27 Levels of Vancomycin in CSF of Adult Patients Receiving Adjunctive Corticosteroids to Treat Pneumococcal Meningitis Observational open multicenter study, adult patients admitted to ICU because of suspected pneumococcal meningitis IV cefotaxime (200 mg per kg of body weight per day), vancomycin (administered as continuous infusion of 60 mg per kg of body weight per day after a loading dose of 15 mg per kg of body weight) Adjunctive therapy with dexamethasone (10 mg/q6h). Vancomycin levels in CSF were measured on day 2 or day 3 of therapy and were correlated with protein levels in CSF and vancomycin levels in serum (determined at the same time as levels in CSF). Ricard JD et al, Clin Infect Dis 2007;44:250-5

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29 Correlation between levels of vancomycin in serum and CSF in patients with meningitis. The bold arrow indicates the patient who was eventually determined to have meningitis due to Neisseria meningitidis. Ricard JD et al, Clin Infect Dis 2007:44:250-5

30 Correlation between the concentration of protein in CSF and the ratio of vancomycin concentration in CSF to vancomycin concentration in serum. Positive correlation confirms that meningeal permeability, partly induced by meningeal inflammation, affects the rate of vancomycin penetration into the CSF. The bold arrow indicates the patient with severe hypoproteinemia

31 Mean levels of VAN in CSF, compared with mean levels of VAN in serum, in experimental and clinical studies. There was a strong positive correlation between serum and CSF levels of VAN. Open circles, clinical studies that used dexamethasone, including our study (arrow); open squares, experimental studies with dexamethasone; solid circles, clinical studies in which treatment did not include use of dexamethasone; solid squares, experimental studies without dexamethasone.

32 DEXAMETHASONE AND VANCOMYCIN Adjunctive therapy (10 mg every 6 h) for two days. Appropriate concentrations of vancomycin in CSF may be obtained even when concomitant steroids are used. Dexamethasone can, therefore, be used without fear of impeding vancomycin penetration into the CSF of patients with pneumococcal meningitis, provided that vancomycin dosage is adequate Ricard JD et al, Clin Infect Dis 2007

33 Management algorithm for adults with suspected bacterial meningitis. Stat indicates that the intervention should be done emergently. e Dexamethasone and antimicrobial therapy should be administered immediately after CSF is obtained. IDSA Guidelines for the Management of Bacterial Meningitis. Clin Infect Dis 2004; 39:

34 Kaplan Meier Survival curve of 187 patients with S.pneumoniae meningitis in Denmark according to the focus of the infection. Otogenic focus vs. pneumonic focus, sinusitic focus, other foci, and no primary infection focus: Log rank test: P = , 0.008,<0.0001, and 0.03, respectively. Other foci vs. no primary infection focus: P = 0.01.

35 PNEUMOCOCCAL MENINGITIS EMPIRICAL ANTIBIOTIC TREATMENT Prevalence of penicillin resistance - No invasive strains with Cefotaxime MIC >1 mg/l reported: Cefotaxime, 200 mg/kg/day, - Invasive strains with cefotaxime MIC > 1 mg/l: Cefotaxime, 300 mg/kg/day PLUS Vancomycin* *Continuous infusion of 60 mg/kg/day after a loading dose of 15 mg/kg Mean levels of vancomycin in serum and CSF, 25.2 and 7.2 mg/l, respectively (Ricard JD et al, Clin Infect Dis 2007)

36 PNEUMOCOCCAL MENINGITIS DIRECTED THERAPY - If pen MIC < 0.1 mg/l Penicillin G, U/24h - If pen MIC 0.1 to 4 mg/l (CEF MIC, 0,1-1 (2?) Cefotaxime, mg/kg/day Ceftriaxone, 4 grams/day - Allergic to penicillin Vancomycin + rifampin - Cefotaxime MIC > 2 mg/l As above

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38 Fernández-Viladrich P et al, AAC 1996

39 Evaluation of ceftriaxone, vancomycin and rifampicin alone and combined in an experimental model of meningitis CSF bacterial counts at 0 h and bacterial killing rates at 6, 24 and 26 h after antimicrobial therapy in experimental pneumococcal meningitis caused by the highly cephalosporin-resistant ATCC strain Ribes S et al, JAC 2005: 56,

40 Evaluation of ceftriaxone, vancomycin and rifampicin alone and combined in an experimental model of meningitis caused by highly cephalosporin-resistant Streptococcus pneumoniae ATCC Ribes, S et al, JAC 2005