title: Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance.
abstract: Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone.
authors.affiliation: University of California San Francisco, USA. lhuang@php.ucsf.edu
authors.forename: Laurence
authors.initials: L
authors.lastname: Huang
authors.forename: Kristina
authors.initials: K
authors.lastname: Crothers
authors.forename: Chiara
authors.initials: C
authors.lastname: Atzori
authors.forename: Thomas
authors.initials: T
authors.lastname: Benfield
authors.forename: Robert
authors.initials: R
authors.lastname: Miller
authors.forename: Meja
authors.initials: M
authors.lastname: Rabodonirina
authors.forename: Jannik
authors.initials: J
authors.lastname: Helweg-Larsen
mesh_terms: D000890:Anti-Infective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D003622:Dapsone / Q000494:pharmacology; D004094:Dihydropteroate Synthase / Q000235:genetics* / Q000378:metabolism; D025141:Drug Resistance, Fungal / Q000235:genetics*; D015870:Gene Expression; D006801:Humans; D009154:Mutation; D045363:Pneumocystis carinii / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D011020:Pneumonia, Pneumocystis / Q000188:drug therapy / Q000401:mortality; D012307:Risk Factors; D013420:Sulfamethoxazole / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology* / Q000627:therapeutic use; D014295:Trimethoprim / Q000494:pharmacology
chemical_list: D000890:Anti-Infective Agents; D013450:Sulfones; D003622:Dapsone; D014295:Trimethoprim; D004094:Dihydropteroate Synthase; D013420:Sulfamethoxazole