BACKGROUND: Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDS patients do occur, but no evidence for drug resistance has yet been presented. OBJECTIVE: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent. METHODS: Portions of the gene for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfone target, from 27 patients (20 of whom had AIDS) diagnosed with PCP between 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were receiving sulfa or sulfone drugs as prophylaxis for PCP. RESULTS: Mutations were found at only two amino-acid positions and were significantly more common in patients who received sulfa/sulfone prophylaxis. Mutations were observed in five (71%) out of seven isolates from AIDS patients receiving sulfa/sulfone as prophylaxis compared with only two (15%) out of 13 specimens from AIDS patients who did not (P = 0.022). No mutations were seen in isolates from seven non-HIV-infected patients, none of whom were on prophylaxis. Mutations were only observed in specimens obtained in 1995-1997. CONCLUSIONS: Mutations in two amino-acid positions were significantly more common in AIDS patients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. carinii DHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients.
BACKGROUND: Failures of prophylaxis against Pneumocystis carinii pneumonia (PCP) in AIDSpatients do occur, but no evidence for drug resistance has yet been presented. OBJECTIVE: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of prophylaxis using a sulfa-containing agent. METHODS: Portions of the gene for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfone target, from 27 patients (20 of whom had AIDS) diagnosed with PCP between 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were receiving sulfa or sulfone drugs as prophylaxis for PCP. RESULTS: Mutations were found at only two amino-acid positions and were significantly more common in patients who received sulfa/sulfone prophylaxis. Mutations were observed in five (71%) out of seven isolates from AIDSpatients receiving sulfa/sulfone as prophylaxis compared with only two (15%) out of 13 specimens from AIDSpatients who did not (P = 0.022). No mutations were seen in isolates from seven non-HIV-infectedpatients, none of whom were on prophylaxis. Mutations were only observed in specimens obtained in 1995-1997. CONCLUSIONS: Mutations in two amino-acid positions were significantly more common in AIDSpatients with PCP who failed sulfa/sulfone prophylaxis. These amino acids appeared to be directly involved in both substrate and sulfa binding, based on homology to the Escherichia coliDHPS crystal structure. Thus, the results were consistent with the possibility that mutations in the P. cariniiDHPS are responsible for some of the failures of sulfa/sulfone prophylaxis in AIDSpatients.
Authors: Melanie T Cushion; Peter D Walzer; Alan Ashbaugh; Sandra Rebholz; Ronald Brubaker; Jean Jacques Vanden Eynde; Annie Mayence; Tien L Huang Journal: Antimicrob Agents Chemother Date: 2006-07 Impact factor: 5.191
Authors: T Takahashi; N Hosoya; T Endo; T Nakamura; H Sakashita; K Kimura; K Ohnishi; Y Nakamura; A Iwamoto Journal: J Clin Microbiol Date: 2000-09 Impact factor: 5.948
Authors: C B Beard; J L Carter; S P Keely; L Huang; N J Pieniazek; I N Moura; J M Roberts; A W Hightower; M S Bens; A R Freeman; S Lee; J R Stringer; J S Duchin; C del Rio; D Rimland; R P Baughman; D A Levy; V J Dietz; P Simon; T R Navin Journal: Emerg Infect Dis Date: 2000 May-Jun Impact factor: 6.883
Authors: Christina Yoon; Anuradha Subramanian; Amy Chi; Kristina Crothers; Steven R Meshnick; Steve M Taylor; Charles B Beard; Leah G Jarlsberg; Gena G Lawrence; Melissa Avery; Alexandra Swartzman; Serena Fong; Brenna Roth; Laurence Huang Journal: Med Mycol Date: 2013-03-08 Impact factor: 4.076
Authors: E Calderón; C de la Horra; F J Medrano; A López-Suárez; M A Montes-Cano; N Respaldiza; J Elvira-González; J Martín-Juan; A Bascuñana; J M Varela Journal: Eur J Clin Microbiol Infect Dis Date: 2004-06-03 Impact factor: 3.267