P. Kazanjian et al., PNEUMOCYSTIS-CARINII MUTATIONS ASSOCIATED WITH SULFA AND SULFONE PROPHYLAXIS FAILURES IN AIDS PATIENTS, AIDS, 12(8), 1998, pp. 873-878
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.