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Antimicrobial Agents and Chemotherapy, February 2009, p. 688-695, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00546-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Multinormal In Vitro Distribution Model Suitable for the Distribution of Plasmodium falciparum Chemosusceptibility to Doxycycline{triangledown}

Sébastien Briolant,1,2 Meili Baragatti,1,2 Philippe Parola,1,2,3 Fabrice Simon,2,4 Adama Tall,5 Cheikh Sokhna,6 Philippe Hovette,7 Modeste Mabika Mamfoumbi,8 Jean-Louis Koeck,9 Jean Delmont,2,3,10 André Spiegel,5 Jacky Castello,7 Jean Pierre Gardair,11 Jean Francois Trape,2,6 Maryvonne Kombila,8 Philippe Minodier,12 Thierry Fusai,1,2 Christophe Rogier,1,2 and Bruno Pradines1,2,13*

Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Le Pharo, 13998 Marseille, France,1 Unité de Recherche sur les Maladies Infectieuses et Tropicales Emergentes, Unité mixte de recherche 6236, Marseille, France,2 Service des Maladies Infectieuses et Tropicales, Hôpital Nord, Assistance Publique des Hôpitaux de Marseille, Marseille, France,3 Service de Pathologies Infectieuses et Tropicales, Hôpital d'Instruction des Armées Laveran, Marseille, France,4 Service d'Epidémiologie, Institut Pasteur, Dakar, Sénégal,5 Unité de Recherche 077 de Paludologie Afrotropicale, Institut pour la Recherche et le Développement, Dakar, Sénégal,6 Centre Médical de Secours, Total Exploration et Production Congo, Pointe-Noire, République du Congo,7 Département de Parasitologie-Mycologie, Faculté de Médecine, Université des Sciences de la Santé, Libreville, Gabon,8 Service de Biologie Médicale Centre Hospitalier des Armées Bouffard, Djibouti,9 Centre de Formation et Recherche en Médecine et Santé Tropicales, Faculté de Médecine Secteur Nord,10 Département Médical International, Total, 92078 Paris la Défense, France,11 Service de Pédiatrie, Hôpital Nord, Assistance Publique des Hôpitaux de Marseille, Marseille, France,12 Centre National de Référence du Paludisme, France,13

Received 28 April 2008/ Returned for modification 20 July 2008/ Accepted 14 November 2008

The distribution and range of 50% inhibitory concentrations (IC50s) of doxycycline were determined for 747 isolates obtained between 1997 and 2006 from patients living in Senegal, Republic of the Congo, and Gabon and patients hospitalized in France for imported malaria. The statistical analysis was designed to answer the specific question of whether Plasmodium falciparum has different phenotypes of susceptibility to doxycycline. A triple normal distribution was fitted to the data using a Bayesian mixture modeling approach. The IC50 geometric mean ranged from 6.2 µM to 11.1 µM according to the geographical origin, with a mean of 9.3 µM for all 747 parasites. The values for all 747 isolates were classified into three components: component A, with an IC50 mean of 4.9 µM (±2.1 µM [standard deviation]); component B, with an IC50 mean of 7.7 µM (±1.2 µM); and component C, with an IC50 mean of 17.9 µM (±1.4 µM). According to the origin of the P. falciparum isolates, the triple normal distribution was found in each subgroup. However, the proportion of isolates predicted to belong to component B was most important in isolates from Gabon and Congo and in isolates imported from Africa (from 46 to 56%). In Senegal, 55% of the P. falciparum isolates were predicted to be classified as component C. The cutoff of reduced susceptibility to doxycycline in vitro was estimated to be 35 µM.

* Corresponding author. Mailing address: Unité de Recherche en Biologie et Epidémiologie Parasitaires, Institut de Médecine Tropicale du Service de Santé des Armées, Boulevard Charles Livon, Parc le Pharo, 13998 Marseille Armées, France. Phone: 33 4 91 15 01 10. Fax: 33 4 91 15 01 64. E-mail: bruno.pradines{at}free.fr

{triangledown} Published ahead of print on 1 December 2008.

Antimicrobial Agents and Chemotherapy, February 2009, p. 688-695, Vol. 53, No. 2
0066-4804/09/$08.00+0     doi:10.1128/AAC.00546-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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