PNEUMOCYSTIS-CARINII MUTATIONS ASSOCIATED WITH SULFA AND SULFONE PROPHYLAXIS FAILURES IN AIDS PATIENTS

Background: Failures of prophylaxis against Pneumocystis carinii pneum onia (PCP) in AIDS patients do occur, but no evidence for drug resista nce has yet been presented. Objective: To determine whether mutations in the sulfa and sulfone drug target are associated with failure of pr ophylaxis using a sulfa-containing agent. Methods: Portions of the gen e for P. carinii dihydropteroate synthase (DHPS), the sulfa and sulfon e target, from 27 patients (20 of whom had AIDS) diagnosed with PCP be tween 1976 and 1997 were amplified using polymerase chain reaction and sequenced. Seven of the 27 patients (all of whom had AIDS) were recei ving sulfa or sulfone drugs as prophylaxis for PCP. Results: Mutations were found at only two amino-acid positions and were significantly mo re common in patients who received sulfa/sulfone prophylaxis. Mutation s were observed in five (71%) out of seven isolates from AIDS patients receiving sulfa/sulfone as prophylaxis compared with only two (15%) o ut of 13 specimens from AIDS patients who did not (P = 0.022). No muta tions were seen in isolates from seven non-HIV-infected patients, none of whom were on prophylaxis. Mutations were only observed in specimen s obtained in 1995-1997. Conclusions: Mutations in two amino-acid posi tions were significantly more common in AIDS patients with PCP who fai led sulfa/sulfone prophylaxis. These amino acids appeared to be direct ly involved in both substrate and sulfa binding, based on homology to the Escherichia coli DHPS crystal structure. Thus, the results were co nsistent with the possibility that mutations in the P. carinii DHPS ar e responsible for some of the failures of sulfa/sulfone prophylaxis in AIDS patients. (C) 1998 Lippincott-Raven Publishers.