September 28rd, 1998

Press release

Meningococcal meningitis:

emergence of resistance to chloramphenicol

The National Reference Centre for Resistance to Antibiotics directed by Patrice Courvalin and the National Reference Centre for Meningococci directed by Jean-Yves Riou, both based at the Pasteur Institute, have recently reported the emergence of strains of Neisseria meningitidis resistant to chloramphenicol. This work was published in the New England Journal of Medicine. Chloramphenicol is the antibiotic most widely used in developing countries for treating meningococcal meningitis. The emergence of such strains is therefore worrying for countries, particularly those in sub-Saharan Africa, that periodically suffer epidemics of meningococcal infections during which the incidence of the disease may reach 500 cases per 100,000 inhabitants.

Meningococcal infections are endemic world-wide and mostly affect children less than five years old. They sometimes cause severe diseases with clinical symptoms including meningitis and fulminating septicaemia. In developed countries, 10% of cases are fatal despite appropriate antibiotic therapy. If no treatment is available, the mortality rate may rise above 50%.
The incidence differs between countries: 1 to 3 cases per 100,000 inhabitants in industrialised countries; but as high as 500 per 100,000 in China and the part of Africa known as the 'meningitis belt' (from Senegal to Ethiopia).
The causative agent is the bacterium Neisseria meningitidis, which has posed fewer problems with antibiotic resistance than many other bacterial species.
However, research teams at the Pasteur Institute have found twelve strains of Neisseria meningitidis that are highly resistant to chloramphenicol. Eleven of these strains were isolated between 1987 and 1996 from the cerebrospinal fluid of patients at the Pasteur Institute in Ho Chi Minh City, Vietnam, and one was from a child hospitalised in 1993 in France. The strains are also resistant to streptomycin and sulphonamides, antibiotics which are rarely used today. They are nevertheless sensitive to a variety of other antibiotics (penicillins, cephalosporins, tetracyclines, quinolones, and rifampicin) used both for treatment and for prevention by reducing the carriage of meningococci in the nose and throat.
Various molecular epidemiological techniques were used to study the bacterial strains, which were found to be different from one another. The cases were therefore not caused by the dissemination of a single strain. However, they all belong to the same serogroup, serogroup B, which is mostly found in Europe and North America, but has also caused epidemics in Cuba, Chile, and Brazil. There is no vaccine for serogroup B strains.
The scientists at Pasteur cloned and sequenced the gene responsible for the resistance to chloramphenicol, which turned out to be a gene already described in another species, Clostridium perfingens, the most common causative agent of gangrene. The gene was on the chromosome of the resistant Neisseria, and directs the production of an enzyme called chloramphenicol acetyltransferase, which inactivates chloramphenicol.
The source from which Neisseria meningitidis acquired this gene is unknown, but we do know that Neisseria is transformable, which means that it can easily exchange genetic material. These strains can integrate DNA from other strains into the chromosome, so genetic characteristics, in this case chloramphenicol resistance, can rapidly spread within the Neisseria species.
Neisseria strains resistant to chloramphenicol have not yet been detected elsewhere in the world or in other serogroups, but the spread of resistance is to be feared. If resistance appeared in serogroup A, the major serogroup in Africa, it would cause a serious public health problem: intramuscular chloramphenicol injection is the principal treatment for meningococcal meningitis in Africa because it is cheap and both easy to store (the antibiotic does not need to be kept cold) and easy to administer in the field (only a single injection is required). We should remember that the consequences of the west African epidemic in March 1997 were 180,000 cases reported to the WHO including 18,000 deaths, and that there have been devastating epidemics of meningococcal meningitis is 1998 in the Democratic Republic of Congo (28% mortality), Chad, Angola and Senegal.

Contact :

- Marc GALIMAND, Unité des Agents Antibactériens/ Centre National de Référence aux Antibiotiques :
Tél : 01 45 68 83 18 - e-mail : galimand@pasteur.fr

Source :

- "High-level chloramphenicol resistance in Neisseria meningitidis"
Marc GALIMAND*, Guy GERBAUD*, Martine GUIBOURDENCHE**, Jean-Yves RIOU** et Patrice COURVALIN*.
The New England Journal of Medicine, 24 septembre 1998
* Centre National de Référence pour la Résistance aux Antibiotiques - Unité des Agents Antibactériens, Institut Pasteur, Paris
** Centre National de Référence pour les Méningocoques, Institut Pasteur, Paris