title: High Prevalence of Pneumocystis jirovecii Dihydropteroate Synthase Gene Mutations in Patients with a First Episode of Pneumocystis Pneumonia in Santiago, Chile, and Clinical Response to Trimethoprim-Sulfamethoxazole Therapy.
abstract: Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Carolina A
authors.initials: CA
authors.lastname: Ponce
authors.affiliation: University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
authors.forename: Magali
authors.identifier: 0000-0002-6732-6772
authors.initials: M
authors.lastname: Chabé
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Claudio
authors.initials: C
authors.lastname: George
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Cárdenas
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Luisa
authors.initials: L
authors.lastname: Durán
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Julia
authors.initials: J
authors.lastname: Guerrero
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
authors.forename: Rebeca
authors.initials: R
authors.lastname: Bustamante
authors.affiliation: Unidade de Parasitología Médica, Grupo de Protozoários Oportunistas/VIH e Outros Protozoarios, Global Health and Tropical Medicine, Instituto de Higiene e Medicina Tropical, Universidade NOVA de Lisboa, Lisbon, Portugal.
authors.forename: Olga
authors.initials: O
authors.lastname: Matos
authors.affiliation: Division of Pulmonary and Critical Care Medicine, and HIV, Infectious Diseases, and Global Medicine Division, Department of Medicine, San Francisco General Hospital, University of California, San Francisco, California, USA.
authors.forename: Laurence
authors.initials: L
authors.lastname: Huang
authors.affiliation: Research Department of Infection and Population Health, Institute of Epidemiology and Healthcare, University College London, London, United Kingdom.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Miller
authors.affiliation: Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile svargas@med.uchile.cl.
authors.forename: Sergio L
authors.identifier: 0000-0002-9299-6428
authors.initials: SL
authors.lastname: Vargas
mesh_terms: D017088:AIDS-Related Opportunistic Infections / Q000188:drug therapy / Q000382:microbiology; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000077336:Caspofungin; D002677:Chile / Q000453:epidemiology; D003622:Dapsone / Q000627:therapeutic use; D004094:Dihydropteroate Synthase / Q000235:genetics*; D054714:Echinocandins / Q000627:therapeutic use; D005260:Female; D006801:Humans; D055666:Lipopeptides / Q000627:therapeutic use; D008297:Male; D008875:Middle Aged; D009154:Mutation; D045363:Pneumocystis carinii / Q000187:drug effects / Q000235:genetics*; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy* / Q000453:epidemiology / Q000382:microbiology; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D054714:Echinocandins; D055666:Lipopeptides; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D003622:Dapsone; D004094:Dihydropteroate Synthase; D000077336:Caspofungin
keywords: DHPS; Pneumocystis jirovecii; dihydropteroate synthase; sulfa drugs; sulfa resistance; sulfamethoxazole trimethoprim