Pneumocystis cariniiDihydropteroate Synthase but Not Dihydrofolate Reductase Gene Mutations Correlate with Prior Trimethoprim‐Sulfamethoxazole or Dapsone Use

Recent studies of the human Pneumocystis carinii dihydropteroate synthase (DHPS) gene suggest that P. carinii is developing resistance to sulfamethoxazole (SMX) and dapsone.To explore whether P. carinii is also developing resistance to trimethoprim (TMP), the human P. carinii dihydrofolate reductase (DHFR) gene was cloned, DHFR and DHPS genes in 37 P. carinii isolates from 35 patients were sequenced, and the relationship between TMP-SMX or dapsone use and gene mutations was analyzed.The DHFR gene sequences were identical in all isolates except 1 with a synonymous substitution.In contrast, the DHPS gene sequences showed mutations in 16 of the 37 isolates; prior sulfa/sulfone prophylaxis was associated with the presence of these mutations ().In addition to suggesting that there is less selective P !.001pressure on DHFR than on DHPS, this study reinforces the hypothesis that mutations in the DHPS gene are likely involved in the development of sulfa resistance in P. carinii.The combination of trimethoprim (TMP) and sulfamethoxazole (SMX) serves as the first-line therapeutic and prophylactic regimen for pneumonia caused by Pneumocystis carinii, which remains a major opportunistic agent in patients infected with human immunodeficiency virus (HIV) and in other immunocompromised patients.This combination inhibits 2 key enzymes in folate metabolism.Dapsone is another commonly used prophylactic agent, and, like SMX, it targets the enzyme dihydropteroate synthase (DHPS), which catalyzes the condensation of para-aminobenzoic acid with 7,8-dihydropterin-pyrophosphate (DHPPP), forming 7,8-dihydropteroate.TMP acts on dihydrofolate reductase (DHFR), which catalyzes the reduction of dihydrofolate to tetrahydrofolate and is dependent on the reduced form of nicotinamide adenine dinucleotide phosphate.The widespread use of DHFR and DHPS inhibitors in antimicrobial chemotherapy has resulted in the emergence of antifolate drug resistance in numerous bacteria and some protozoa [1-10], raising concerns that similar resistance would develop