Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients.
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.
Kazanjian
P
P
Department of Internal Medicine, University of Michigan, Ann Arbor 48109-0378, USA.
Locke
A B
AB
Hossler
P A
PA
Lane
B R
BR
Bartlett
M S
MS
Smith
J W
JW
Cannon
M
M
Meshnick
S R
SR
D017088:AIDS-Related Opportunistic Infections / Q000382:microbiology / Q000517:prevention & control*; D000293:Adolescent; D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D000890:Anti-Infective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D002648:Child; D003622:Dapsone / Q000494:pharmacology / Q000627:therapeutic use*; D004094:Dihydropteroate Synthase / Q000737:chemistry / Q000235:genetics*; D004352:Drug Resistance, Microbial / Q000235:genetics; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011010:Pneumocystis / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D011020:Pneumonia, Pneumocystis / Q000382:microbiology / Q000517:prevention & control*; D016133:Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D017211:Treatment Failure; D015662:Trimethoprim, Sulfamethoxazole Drug Combination / Q000494:pharmacology / Q000627:therapeutic use*
D000890:Anti-Infective Agents; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D003622:Dapsone; D004094:Dihydropteroate Synthase