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Long-acting oily chloramphenicol for meningococcal meningitis

1998; Elsevier BV; Volume: 352; Issue: 9130 Linguagem: Inglês

10.1016/s0140-6736(05)60723-4

1474-547X

Rosamund Lewis, Fabienne Dorlencourt, Jacques Pinel,

Antibiotics Pharmacokinetics and Efficacy

The story of oily chloramphenicol is a fascinating tale of a drug developed well before the era of randomised controlled trials that, through applied field research, has found a new application in meningitis. Now, in the world of orphan drugs for tropical diseases, this drug is in danger of abandonment by the pharmaceutical industry and the medical profession. To document the history and efficacy of oily chloramphenicol, we reviewed the literature and interviewed key investigators.* Chloramphenicol in oil suspension, marketed by Roussel in 1954 as Tifomycine for typhoid fever, was proposed as a single intramuscular injection for meningococcal meningitis in 1975, at a time when increasing bacterial resistance to sulfa drugs in Africa made standard therapy useless. Oily chloramphenicol now costs US $13 per adult treatment on average, compared with $30 for 10 days of ampicillin or $100 for 5 days of ceftriaxone (excluding hospitalisation costs, injection material, and intravenous access). In two cohort studies from 1972–79 in Senegal,1Rey M Ouedraogo L Saliou P Perino L Traitement minute de la mèningite cèrèbrospinale èpidèmique par injection intramusculaire unique de chloramphènicol (suspension huileuse).Médecine et Maladies Infectieuses. 1976; 6: 120-124Crossref Scopus (10) Google Scholar Burkina Faso,1Rey M Ouedraogo L Saliou P Perino L Traitement minute de la mèningite cèrèbrospinale èpidèmique par injection intramusculaire unique de chloramphènicol (suspension huileuse).Médecine et Maladies Infectieuses. 1976; 6: 120-124Crossref Scopus (10) Google Scholar and Nigeria,2Puddicombe JB Wali SS Greenwood BM A field trial of a single intramuscular injection of long-acting chloramphenicol in the treatment of meningococcal meningitis.Trans R Soc Trop Med Hyg. 1984; 78: 399-403Summary Full Text PDF PubMed Scopus (16) Google Scholar 113 patients with confirmed meningococcal meningitis received one or two intramuscular injections of oily chloramphenicol (50–100 mg/kg dose). Sequelae-free cure rates were 90% and 93% and case-fatality ratios (CFRs) were 7·4% and 2·2%, respectively. Three randomised controlled trials compared one or two doses of intramuscular oily chloramphenicol (100 mg/kg dose) with 5 days of intramuscular penicillin (adults),3Wali SS MacFarlane JT Weir WRC et al.Single injection treatment of meningococcal meningitis. Long acting chloramphenicol.Trans R Soc Trop Med Hyg. 1979; 73: 698-701Summary Full Text PDF PubMed Scopus (40) Google Scholar 8 days of intravenous ampicillin (patients aged 2 months and older),4Pécoul B Varaine F Keita M et al.Long-acting choramphenicol versus intravenous ampicillin for treatment of bacterial meningitis.Lancet. 1991; 338: 862-866Summary PubMed Scopus (62) Google Scholar and 2 days of intramuscular ceftriaxone (children aged 2–35 months).5Varaine F, Keita M, Kaninda A-V, et al. Long-acting chloramphenicol versus ceftriaxone for treatment of bacterial meningitis in children aged 2–35 months. 8th International Congress on Infectious Diseases. Boston, USA. May 15–18, 1998 (abstr).Google Scholar Cure rates for meningococcal meningitis did not differ significantly between treatment groups. CFRs were 1·5–5·3% for chloramphenicol-treated patients. Pharmacokinetic data suggest that one injection maintains chloramphenicol concentrations inhibitory for Neisseria meningitidis in plasma and cerebrospinal fluid for 48 h.1Rey M Ouedraogo L Saliou P Perino L Traitement minute de la mèningite cèrèbrospinale èpidèmique par injection intramusculaire unique de chloramphènicol (suspension huileuse).Médecine et Maladies Infectieuses. 1976; 6: 120-124Crossref Scopus (10) Google Scholar, 3Wali SS MacFarlane JT Weir WRC et al.Single injection treatment of meningococcal meningitis. Long acting chloramphenicol.Trans R Soc Trop Med Hyg. 1979; 73: 698-701Summary Full Text PDF PubMed Scopus (40) Google Scholar No adverse effects or haematological reactions were reported. The risk of aplastic anaemia, less than 1 case per 19 000 courses of oral or intravenous chloramphenicol, is unknown for the intramuscular oily suspension. Massive epidemics of meningococcal meningitis continue to strike sub-Saharan Africa with 1–5 cases per 1000 inhabitants and neurological or auditory sequelae or death in a third of cases. The risk of death or disability in these circumstances far outweighs any theoretical risk associated with chloramphenicol. In resource-poor countries, there is an urgent need for an antibiotic that is effective, safe, cheap, stable, and easy to use in the face of high case loads of meningococcal meningitis. Oily chloramphenicol meets these criteria and, in the absence of a bacterial diagnosis, can be reserved for use during epidemics. Oily chloramphenicol is difficult to manufacture and, unfortunately, availability of a high-quality product is no longer a sure thing. Production by Roussel was stopped in 1995 and taken up by companies in Germany and India. These new products have not been tested in clinical studies and no bioequivalence data have been published. Oily chloramphenicol distributed by Médecins Sans Frontières in Cameroon in April, 1998, had to be recalled when the product was found to be defective. In 1997, Roussel transferred the original oily chloramphenicol technology and equipment to the International Dispensary Association which launched production in Malta in 1998. Let us hope this is a step in the right direction. The availability and quality of oily chloramphenicol must be ensured before this useful drug becomes a true orphan. The effectiveness, safety, and pharmacokinetics of current formulations should be documented.