title: Dihydropteroate synthase mutations in Pneumocystis pneumonia: impact of applying different definitions of prophylaxis, mortality endpoints and mutant in a single cohort.
abstract: Pneumocystis jirovecii dihydropteroate synthase (DHPS) gene mutations are well-reported. Although sulfa prophylaxis generally is associated with DHPS mutant infection, whether mutant infection is associated with poorer clinical outcomes is less clear. The differing definitions of sulfa prophylaxis and the different mortality endpoints used in these studies may be one explanation for the conflicting study results. Applying different definitions of prophylaxis, mortality endpoints and DHPS mutant to 301 HIV-infected patients with Pneumocystis pneumonia, we demonstrate that prophylaxis, irrespective of definition, increased the risk of infection with pure mutant (any prophylaxis: AOR 4.00, 95% CI: 1.83-8.76, P < 0.001) but not mixed genotypes (any prophylaxis: AOR 0.78, 95% CI: 0.26-2.36, P = 0.65). However, infection with mutant DHPS, irrespective of definition, was not associated with increased mortality (all-cause or PCP death) at the three time-intervals examined (all P > 0.05). Future studies should standardize key variables associated with DHPS mutant infection as well as examine DHPS mutant subtypes (pure mutant vs. mixed infections) - perhaps even individual DHPS mutant genotypes - so that data can be pooled to better address this issue.
authors.affiliation: San Francisco General Hospital, Division of Pulmonary & Critical Care Medicine, University of California, San Francisco, California 94110, USA. christina.yoon@ucsf.edu
authors.forename: Christina
authors.initials: C
authors.lastname: Yoon
authors.forename: Anuradha
authors.initials: A
authors.lastname: Subramanian
authors.forename: Amy
authors.initials: A
authors.lastname: Chi
authors.forename: Kristina
authors.initials: K
authors.lastname: Crothers
authors.forename: Steven R
authors.initials: SR
authors.lastname: Meshnick
authors.forename: Steve M
authors.initials: SM
authors.lastname: Taylor
authors.forename: Charles B
authors.initials: CB
authors.lastname: Beard
authors.forename: Leah G
authors.initials: LG
authors.lastname: Jarlsberg
authors.forename: Gena G
authors.initials: GG
authors.lastname: Lawrence
authors.forename: Melissa
authors.initials: M
authors.lastname: Avery
authors.forename: Alexandra
authors.initials: A
authors.lastname: Swartzman
authors.forename: Serena
authors.initials: S
authors.lastname: Fong
authors.forename: Brenna
authors.initials: B
authors.lastname: Roth
authors.forename: Laurence
authors.initials: L
authors.lastname: Huang
mesh_terms: D000328:Adult; D000935:Antifungal Agents / Q000627:therapeutic use; D018890:Chemoprevention / Q000379:methods; D004094:Dihydropteroate Synthase / Q000235:genetics*; D025141:Drug Resistance, Fungal; D005260:Female; D015658:HIV Infections / Q000150:complications*; D006801:Humans; D008297:Male; D008875:Middle Aged; D050505:Mutant Proteins / Q000235:genetics; D009154:Mutation; D045363:Pneumocystis carinii / Q000201:enzymology* / Q000235:genetics*; D011020:Pneumonia, Pneumocystis / Q000382:microbiology* / Q000517:prevention & control
chemical_list: D000935:Antifungal Agents; D050505:Mutant Proteins; D004094:Dihydropteroate Synthase