title: Glycerol adjuvant therapy in adults with bacterial meningitis in a high HIV seroprevalence setting in Malawi: a double-blind, randomised controlled trial.
abstract: BACKGROUND
  Southern Africa has a high incidence of bacterial meningitis in adults, often associated with HIV co-infection. Mortality exceeds 50%, even with appropriate antibiotic therapy, and is not improved with corticosteroids. Glycerol adjuvant therapy reduces long-term morbidity in bacterial meningitis in children, and its use is being promoted. We aimed to assess the effectiveness of glycerol as an adjuvant therapy for adults with bacterial meningitis in Africa.
  
  
  METHODS
  The study was done in two phases. First, in an open-label dose-finding study, 45 adult patients with symptoms, signs, and cerebrospinal fluid findings consistent with bacterial meningitis received either 50 mL, 75 mL, or 100 mL of glycerol four times a day for 4 days. We then did a randomised, double-blind, placebo-controlled trial of oral glycerol in adults with bacterial meningitis. Patients with clinical and cerebrospinal fluid findings suggestive of bacterial meningitis were randomly assigned in blocks of 12 by use of a random number list produced by an independent statistician to receive either glycerol or an equivalent volume of sugar solution. Glycerol and placebo were indistinguishable by colour or taste. The primary outcome was mortality at 40 days, with secondary outcomes including disability and mortality restricted to pneumococcal disease. All patients were analysed for the primary outcome excluding those who were lost to follow-up. This trial is registered at controlled-trials.com, number ISRCTN70121840.
  
  
  RESULTS
  75 mL glycerol four times a day was the highest tolerated dose, and was used for the main study. 265 patients were assigned treatment: 137 glycerol and 128 placebo. The trial was stopped early on the advice of the data and safety monitoring board after a planned interim analysis. By day 40, 61 (49%) of 125 patients in the placebo group and 86 (63%) of 136 in the glycerol group had died (adjusted odds ratio 2.4, 95% CI 1.3-4.2, p=0.003). There was no benefit from glycerol for death and disability by day 40, and glycerol did not improve death and disability by day 40 or death at day 40 in patients with proven bacterial disease or pneumococcal disease. Two serious adverse events occurred that were possibly due to the study drug.
  
  
  CONCLUSIONS
  Oral glycerol therapy cannot be recommended as an adjuvant therapy in adults with bacterial meningitis in resource-poor settings with a high HIV prevalence.
  
  
  BACKGROUND
  Meningitis Research Foundation.
authors.affiliation: Department of Medicine, College of Medicine, Chichiri, Blantyre, Malawi. katherineaz@doctors.org.uk
authors.forename: Katherine Mb
authors.initials: KM
authors.lastname: Ajdukiewicz
authors.forename: Katharine E
authors.initials: KE
authors.lastname: Cartwright
authors.forename: Matthew
authors.initials: M
authors.lastname: Scarborough
authors.forename: James B
authors.initials: JB
authors.lastname: Mwambene
authors.forename: Patrick
authors.initials: P
authors.lastname: Goodson
authors.forename: Malcolm E
authors.initials: ME
authors.lastname: Molyneux
authors.forename: Eduard E
authors.initials: EE
authors.lastname: Zijlstra
authors.forename: Neil
authors.initials: N
authors.lastname: French
authors.forename: Christopher Jm
authors.initials: CJ
authors.lastname: Whitty
authors.forename: David G
authors.initials: DG
authors.lastname: Lalloo
mesh_terms: D000277:Adjuvants, Pharmaceutic / Q000008:administration & dosage*; D000328:Adult; D000900:Anti-Bacterial Agents / Q000008:administration & dosage*; D004311:Double-Blind Method; D004359:Drug Therapy, Combination / Q000379:methods; D005260:Female; D005990:Glycerol / Q000008:administration & dosage*; D015658:HIV Infections / Q000453:epidemiology*; D015528:HIV Seroprevalence; D006801:Humans; D008295:Malawi; D008297:Male; D016920:Meningitis, Bacterial / Q000150:complications / Q000188:drug therapy* / Q000401:mortality; D010919:Placebos / Q000008:administration & dosage; D016896:Treatment Outcome
chemical_list: D000277:Adjuvants, Pharmaceutic; D000900:Anti-Bacterial Agents; D010919:Placebos; D005990:Glycerol