Ponce Carolina A, Chabé Magali, George Claudio, Cárdenas Alejandra, Durán Luisa, Guerrero Julia, Bustamante Rebeca, Matos Olga, Huang Laurence, Miller Robert F, Vargas Sergio L
Programa de Microbiología y Micología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
University Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019-UMR 8204-CIIL-Centre d'Infection et d'Immunité de Lille, Lille, France.
Antimicrob Agents Chemother. 2017 Jan 24;61(2). doi: 10.1128/AAC.01290-16. Print 2017 Feb.
Mutations in the dihydropteroate synthase (DHPS) gene of Pneumocystis jirovecii are associated with the failure of sulfa prophylaxis. They can develop by selection in patients receiving sulfa drugs or be acquired via person-to-person transmission. DHPS mutations raise concern about the decreasing efficacy of sulfa drugs, the main available therapeutic tool for Pneumocystis pneumonia (PCP). The prevalence of Pneumocystis DHPS mutations was examined in Pneumocystis isolates from 56 sulfa-prophylaxis-naive adults with a first episode of PCP from 2002 to 2010 in Santiago, Chile. Their clinical history was reviewed to analyze the effect of these mutations on response to trimethoprim-sulfamethoxazole (TMP-SMX) therapy and outcome. Mutant genotypes occurred in 22 (48%) of 46 HIV-infected patients and in 5 (50%) of 10 HIV-uninfected patients. Compared to patients with a wild-type genotype, those with mutant genotypes were more likely to experience sulfa treatment-limiting adverse reactions and to have a twice-longer duration of mechanical ventilation if mechanically ventilated. Specific genotypes did not associate with death, which occurred in none of the HIV-infected patients and in 50% of the non-HIV-infected patients. Chile has a high prevalence of DHPS mutations, which were presumably acquired through interhuman transmission because patients were not on sulfa prophylaxis. These results contrast with the low prevalence observed in other Latin American countries with similar usage of sulfa drugs, suggesting that additional sources of resistant genotypes may be possible. The twice-longer duration of mechanical ventilation in patients with mutant DHPS genotypes suggests a decreased efficacy of TMP-SMX and warrants collaborative studies to assess the relevance of DHPS mutations and further research to increase therapeutic options for PCP.
耶氏肺孢子菌二氢蝶酸合酶（DHPS）基因突变与磺胺预防治疗失败相关。这些突变可在接受磺胺类药物治疗的患者中通过选择产生，或通过人际传播获得。DHPS基因突变引发了人们对磺胺类药物疗效下降的担忧，磺胺类药物是目前治疗肺孢子菌肺炎（PCP）的主要可用治疗手段。2002年至2010年期间，在智利圣地亚哥，对56例首次发生PCP且未接受过磺胺预防治疗的成人患者的肺孢子菌分离株进行了耶氏肺孢子菌DHPS基因突变的患病率检测。回顾了他们的临床病史，以分析这些突变对甲氧苄啶-磺胺甲恶唑（TMP-SMX）治疗反应和结局的影响。46例HIV感染患者中有22例（48%）出现突变基因型，10例未感染HIV的患者中有5例（50%）出现突变基因型。与野生型基因型患者相比，突变基因型患者更有可能出现限制磺胺治疗的不良反应，并且如果接受机械通气，机械通气时间会延长两倍。特定基因型与死亡无关，在HIV感染患者中无一例死亡，在未感染HIV的患者中有50%死亡。智利DHPS基因突变的患病率很高，推测是通过人际传播获得的，因为患者未接受磺胺预防治疗。这些结果与其他磺胺类药物使用情况相似的拉丁美洲国家观察到的低患病率形成对比，表明可能存在其他耐药基因型来源。DHPS基因突变型患者机械通气时间延长两倍表明TMP-SMX疗效降低，有必要开展合作研究以评估DHPS基因突变的相关性，并进一步开展研究以增加PCP的治疗选择。
