Effects of mutations in Pneumocystis carinii dihydropteroate synthase gene on outcome of AIDS-associated P carinii pneumonia

Epidemiology and clinical relevanceofPneumocystis jiroveciiFrenkel, 1976 dihydropteroate synthase gene mutations

“…A potential association of point mutations at P. jirovecii DHPS codons 55 and 57 with sulpha or sulphone resistance has already been reported by several authors. These sequence variations are located at one of the active sites of the enzyme and are similar to point mutations that lead to sulpha drugs resistance in other organisms (Lopez et al, 1987;Brooks et al, 1994;Kazanjian et al, 1998;Triglia et al, 1998;Vedantam et al, 1998;Helweg-Larsen et al, 1999;Armstrong et al, 2000;Huang et al, 2004). For this reason, mutations at codons 55 and 57 are the most studied sequence variations in the P. jirovecii DHPS locus.…”

“…Several point mutations have been identified in patients receiving anti-P. jirovecii prophylaxis with TMP-SMZ or dapsone, suggesting that point mutations in DHPS gene may be a consequence of exposure to sulpha drugs and that the widespread use of TMP-SMZ may be exerting a selective pressure of P. jirovecii genotypes circulating among humans (Lane et al, 1997;Ma et al, 1999;Huang et al, 2000). Other studies have associated the occurrence of specific mutations in the P. jirovecii DHPS gene with the failure of sulpha or sulphone prophylaxis and with the outcome HIV-associated PcP, which suggests the emergence of sulpha or sulphone-resistant strains of P. jirovecii (Kazanjian et al, 1998;Mei et al, 1998;Helweg-Larsen et al, 1999;Kazanjian et al, 2000;Takahashi et al, 2000;Visconti et al, 2001;Crothers et al, 2005). Therefore, several P. jirovecii DHPS point mutations have been studied and are suspected of association with TMP-SMZ resistance.…”

“…In total, these studies span a period between 1976 and 2007, involving patients and respective clinical data from United States of America (USA) and several countries in Europe. Eleven of those studies have demonstrated a significant association between the use of sulpha or sulphone agents for PcP prophylaxis in HIV-infected patients and the presence of DHPS mutations (Kazanjian et al, 1998;Ma et al, 1999;Helweg-Larsen et al, 1999;Santos et al, 1999;Kazanjian et al, 2000;Huang et al, 2000;Visconti et al, 2001;Ma et al, 2002;Miller et al, 2003;Nahimana et al, 2003;Zingale et al, 2003) (Table II). However, these studies used different PcP prophylaxis and exposure to sulpha drugs definitions, which limits the possibility of comparing results and detailing the analysis.…”

Sulfa Resistance and Dihydropteroate Synthase Mutants in RecurrentPneumocystis cariniiPneumonia

“…Dapsone is a sulfone drug, also frequently used, that targets DHPS. Widespread use of sulfa and sulfone drugs to prevent and treat PCP in recent years has correlated with an increase of the prevalence of mutations in the gene coding for DHPS ( 2 , 3 ). The most frequent DHPS mutations occur at nucleotide positions 165 and 171, which lead to an amino acid change at positions 55 (Thr to Ala) and 57 (Pro to Ser).…”

“…Similar mutations in other microbial pathogens confer sulfa resistance ( 4 , 5 ). In P. carinii, DHPS mutations are associated with failure of sulfa or sulfone prophylaxis ( 1 , 6 ) and decreased survival of the patient at 3 months after PCP ( 2 ). However, patients harboring P. carinii types with DHPS mutations are most often successfully treated with high-dose co-trimoxazole ( 6 ).…”