Isabelle Suárez1, Lisa Roderus1, Edeltraud van Gumpel1,2, Norma Jung1, Clara Lehmann1,3, Gerd Fätkenheuer1,3, Pia Hartmann1,3, Georg Plum4, Jan Rybniker5,6,7. 1. Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. 2. Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne, Germany. 3. German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany. 4. Institute for Medical Microbiology, Immunology and Hygiene, University Hospital of Cologne, Cologne, Germany. 5. Department I of Internal Medicine, University Hospital of Cologne, Kerpener Str. 62, 50937, Cologne, Germany. jan.rybniker@uk-koeln.de. 6. German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany. jan.rybniker@uk-koeln.de. 7. Center for Molecular Medicine Cologne, University of Cologne, 50931, Cologne, Germany. jan.rybniker@uk-koeln.de.
Abstract
BACKGROUND: Pneumocystis pneumonia (PCP) is an opportunistic and potentially life-threatening infection of immunocompromised individuals. A combination of trimethoprim-sulfamethoxazole is widely used for prophylaxis and treatment of PCP. Polymorphisms in the drug targets, the dihydropteroate synthase (DHPS) or the dihydrofolate reductase (DHFR) are presumably a reason for treatment failure. METHODS: We retrospectively examined the prevalence of DHPS and DHFR mutations in Pneumocystis jirovecii isolates obtained from HIV-infected and non-HIV-infected PCP patients. DHFR and DHPS genes were amplified using semi-nested PCR followed by sequencing. Obtained data were correlated with clinical findings. RESULTS: Sequencing of the DHPS gene was achieved in 81 out of 128 isolates (63%), the DHFR-gene was successfully sequenced in 96 isolates (75%). The vast majority of DHFR and DHPS sequences were either wild-type or showed synonymous single nucleotide polymorphisms. Only one sample contained a double mutation at DHPS codon 55 and codon 57 which was associated with treatment failure in some studies. No linkage of treatment failure to a DHFR or DHPS genotype was observed. In our cohort, 35 of 95 Patients (37%) were HIV-positive and 60 (63%) were HIV-negative. The overall mortality rate was 24% with a much higher rate among non-HIV patients. CONCLUSION: DHPS and DHFR mutations exist but are infrequent in our cohort. The contribution of gene polymorphisms to treatment failure needs further research. In immunocompromised HIV-negative patients PCP is associated with high mortality rates. Prophylactic treatment is warranted in this patient subset.
BACKGROUND:Pneumocystis pneumonia (PCP) is an opportunistic and potentially life-threatening infection of immunocompromised individuals. A combination of trimethoprim-sulfamethoxazole is widely used for prophylaxis and treatment of PCP. Polymorphisms in the drug targets, the dihydropteroate synthase (DHPS) or the dihydrofolate reductase (DHFR) are presumably a reason for treatment failure. METHODS: We retrospectively examined the prevalence of DHPS and DHFR mutations in Pneumocystis jirovecii isolates obtained from HIV-infected and non-HIV-infected PCPpatients. DHFR and DHPS genes were amplified using semi-nested PCR followed by sequencing. Obtained data were correlated with clinical findings. RESULTS: Sequencing of the DHPS gene was achieved in 81 out of 128 isolates (63%), the DHFR-gene was successfully sequenced in 96 isolates (75%). The vast majority of DHFR and DHPS sequences were either wild-type or showed synonymous single nucleotide polymorphisms. Only one sample contained a double mutation at DHPS codon 55 and codon 57 which was associated with treatment failure in some studies. No linkage of treatment failure to a DHFR or DHPS genotype was observed. In our cohort, 35 of 95 Patients (37%) were HIV-positive and 60 (63%) were HIV-negative. The overall mortality rate was 24% with a much higher rate among non-HIV patients. CONCLUSION:DHPS and DHFR mutations exist but are infrequent in our cohort. The contribution of gene polymorphisms to treatment failure needs further research. In immunocompromised HIV-negative patients PCP is associated with high mortality rates. Prophylactic treatment is warranted in this patient subset.
Authors: T R Navin; C B Beard; L Huang; C del Rio; S Lee; N J Pieniazek; J L Carter; T Le; A Hightower; D Rimland Journal: Lancet Date: 2001-08-18 Impact factor: 79.321
Authors: T Glück; H F Geerdes-Fenge; R H Straub; M Raffenberg; B Lang; H Lode; J Schölmerich Journal: Infection Date: 2000 Jul-Aug Impact factor: 3.553
Authors: A K Tyagi; B R Mirdha; K Luthra; R Guleria; A Mohan; U B Singh; J C Samantaray; L Dar; V K Iyer; V Sreenivas Journal: Med Mycol Date: 2010-08-18 Impact factor: 4.076
Authors: J A Kovacs; J W Hiemenz; A M Macher; D Stover; H W Murray; J Shelhamer; H C Lane; C Urmacher; C Honig; D L Longo Journal: Ann Intern Med Date: 1984-05 Impact factor: 25.391
Authors: P Nickel; M Schürmann; H Albrecht; R Schindler; K Budde; T Westhoff; J Millward; N Suttorp; P Reinke; D Schürmann Journal: Infection Date: 2014-08-29 Impact factor: 3.553
Authors: Sang Min Lee; Yong Kyun Cho; Yon Mi Sung; Dong Hae Chung; Sung Hwan Jeong; Jeong-Woong Park; Sang Pyo Lee Journal: Korean J Parasitol Date: 2015-06-30 Impact factor: 1.341
Authors: Amir Arastehfar; Toni Gabaldón; Rocio Garcia-Rubio; Jeffrey D Jenks; Martin Hoenigl; Helmut J F Salzer; Macit Ilkit; Cornelia Lass-Flörl; David S Perlin Journal: Antibiotics (Basel) Date: 2020-12-08
Authors: Thomas R Rogers; Paul E Verweij; Mariana Castanheira; Eric Dannaoui; P Lewis White; Maiken Cavling Arendrup Journal: J Antimicrob Chemother Date: 2022-07-28 Impact factor: 5.758