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Philippe M Hauser - One of the best experts on this subject based on the ideXlab platform.
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Pneumocystis Jiroveci dihydropteroate synthase polymorphisms confer resistance to sulfadoxine and sulfanilamide in saccharomyces cerevisiae
Antimicrobial Agents and Chemotherapy, 2004Co-Authors: I Meneau, Jacques Bille, Dominique Sanglard, Philippe M HauserAbstract:Failure of anti-Pneumocystis Jiroveci prophylaxis with sulfa drugs is associated with mutations within the putative active site of the fungal dihydropteroate synthase (DHPS), an enzyme encoded by the multidomain FAS gene. This enzyme is involved in the essential biosynthesis of folic acid. The most frequent polymorphisms are two mutations leading to two amino acid changes (55Trp-Arg-57Pro to 55Ala-Arg-57Ser), observed as a single or double mutation in the same P. Jiroveci isolate. In the absence of a culture method for P. Jiroveci, we studied potential resistance to sulfa drugs conferred by these polymorphisms by using Saccharomyces cerevisiae as a model. Single or double mutations identical to those observed in the DHPS domain of the P. Jiroveci FAS gene were introduced by in vitro site-directed mutagenesis into alleles of the S. cerevisiae FOL1 gene, which is the orthologue of the P. Jiroveci FAS gene. The mutated alleles were integrated at the genomic locus in S. cerevisiae and expressed by functional complementation in a strain with a disrupted FOL1 allele. The single mutation 55Trp to 55Ala conferred resistance to sulfanilamide, whereas the single mutation 57Pro to 57Ser conferred resistance to both sulfanilamide and sulfadoxine. Both single mutations also separately conferred hypersensitivity to sulfamethoxazole and dapsone. The resistance to sulfadoxine is consistent with epidemiological data on P. Jiroveci. The double mutation 55Trp-Arg-57Pro to 55Ala-Arg-57Ser conferred on S. cerevisiae a requirement for p-aminobenzoate, suggesting reduced affinity of DHPS for this substrate. This characteristic is commonly observed in mutated DHPS enzymes conferring sulfa drug resistance from other organisms. However, the double mutation conferred hypersensitivity to sulfamethoxazole, which is not in agreement with epidemiological data on P. Jiroveci. Taken together, our results suggest that the DHPS polymorphisms observed in P. Jiroveci confer sulfa drug resistance on this pathogen.
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association between a specific Pneumocystis Jiroveci dihydropteroate synthase mutation and failure of pyrimethamine sulfadoxine prophylaxis in human immunodeficiency virus positive and negative patients
The Journal of Infectious Diseases, 2003Co-Authors: Aimable Nahimana, Meja Rabodonirina, Giorgio Zanetti, Isabelle Meneau, Patrick Francioli, Jacques Bille, Philippe M HauserAbstract:To investigate the possible association between different prophylactic sulfa drugs and the genotype of the Pneumocystis Jiroveci dihydropteroate synthase (DHPS) gene, we examined DHPS polymorphisms in clinical specimens from 158 immunosuppressed patients (38 HIV-negative and 120 HIV-positive), using polymerase chain reaction–single-strand conformation polymorphism. Fifty-seven (36.1%) of 158 patients were infected with a mutant DHPS genotype. All patients who developed P. Jiroveci pneumonia (PcP) while receiving pyrimethamine/sulfadoxine (PM/SD) prophylaxis ( ) had a strain harboring DHPS with an amino acid n p 14 change at position 57 (ProrSer). This mutation was only present in 20 (14%) of 144 patients not receiving prophylaxis ( ). Hospitalization in a specific hospital was an independent risk factor for having P. P ! .001 Jiroveci harboring the same DHPS mutation, which indirectly supports that interhuman transmission may affect the dissemination of the mutant strains.
Ann E Wakefield - One of the best experts on this subject based on the ideXlab platform.
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genotypes of Pneumocystis Jiroveci isolates obtained in harare zimbabwe and london united kingdom
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: R F Miller, Austin R Lindley, Helen E Ambrose, Adam S Malin, Ann E WakefieldAbstract:Isolates of Pneumocystis Jiroveci from sulfa-exposed and nonexposed patients from London, United Kingdom, and Harare, Zimbabwe, were genotyped. At the dihydropteroate synthase (DHPS) locus, there was evidence of selection pressure from sulfa drug exposure, and reversal of DHPS genotype ratios occurred when selection pressure was absent or was removed.
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asymptomatic carriage of Pneumocystis Jiroveci in subjects undergoing bronchoscopy a prospective study
Thorax, 2003Co-Authors: Nick A Maskell, R F Miller, Ann E Wakefield, Austin R Lindley, D J Waine, Justin Pepperell, Rjo DaviesAbstract:Background: The opportunistic fungus Pneumocystis Jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, Pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P Jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P Jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy. Methods: A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P Jiroveci. Polymerase chain reaction for detection of P Jiroveci specific DNA was also performed. Results: Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P Jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P Jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P Jiroveci DNA. In contrast, P Jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher's exact test). Conclusions: P Jiroveci colonisation, as determined by detection of P Jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.
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limited asymptomatic carriage of Pneumocystis Jiroveci in human immunodeficiency virus infected patients
The Journal of Infectious Diseases, 2003Co-Authors: Ann E Wakefield, Austin R Lindley, Helen E Ambrose, Cecilemarie Denis, R F MillerAbstract:Forty-seven bronchoalveolar lavage fluid samples from 16 human immunodeficiency virus (HIV)-infected patients were used to test the latency model of Pneumocystis infection in the human host. Identification of DNA sequence polymorphisms at 4 independent loci were used to genotype Pneumocystis Jiroveci from the 35 samples that contained detectable P. Jiroveci DNA. Eighteen of those 35 samples came from patients who did not have Pneumocystis pneumonia (PCP) and had confirmed alternative diagnoses. Seven patients had asymptomatic carriage of P. Jiroveci over periods of less than or equal to9.5 months after an episode of PCP, and in all 7 cases, a change in genotype from that in the original episode of PCP was observed. The absence of P. Jiroveci DNA in one-fourth of the 47 samples and the observed changes in genotype during asymptomatic carriage do not support the latency model of infection. Asymptomatic carriage in HIV-infected patients may play a role in transmission of P. Jiroveci and may even supply a reservoir for future infections.
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a new name Pneumocystis Jiroveci for Pneumocystis from humans
Emerging Infectious Diseases, 2002Co-Authors: James R Stringer, R F Miller, Charles B Beard, Ann E WakefieldAbstract:The disease known as Pneumocystis carinii pneumonia (PCP) is a major cause of illness and death in persons with impaired immune systems. While the genus Pneumocystis has been known to science for nearly a century, understanding of its members remained rudimentary until DNA analysis showed its extensive diversity. Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. In recognition of its genetic and functional distinctness, the organism that causes human PCP is now named Pneumocystis Jiroveci Frenkel 1999. Changing the organism's name does not preclude the use of the acronym PCP because it can be read "Pneumocystis pneumonia." DNA sequence variation exists among samples of P. Jiroveci, a feature that allows reexamination of the relationships between host and pathogen. Instead of lifelong latency, transient colonization may be the rule.
R F Miller - One of the best experts on this subject based on the ideXlab platform.
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genotypes of Pneumocystis Jiroveci isolates obtained in harare zimbabwe and london united kingdom
Antimicrobial Agents and Chemotherapy, 2003Co-Authors: R F Miller, Austin R Lindley, Helen E Ambrose, Adam S Malin, Ann E WakefieldAbstract:Isolates of Pneumocystis Jiroveci from sulfa-exposed and nonexposed patients from London, United Kingdom, and Harare, Zimbabwe, were genotyped. At the dihydropteroate synthase (DHPS) locus, there was evidence of selection pressure from sulfa drug exposure, and reversal of DHPS genotype ratios occurred when selection pressure was absent or was removed.
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asymptomatic carriage of Pneumocystis Jiroveci in subjects undergoing bronchoscopy a prospective study
Thorax, 2003Co-Authors: Nick A Maskell, R F Miller, Ann E Wakefield, Austin R Lindley, D J Waine, Justin Pepperell, Rjo DaviesAbstract:Background: The opportunistic fungus Pneumocystis Jiroveci is a common cause of respiratory infection in immunocompromised patients. By contrast, Pneumocystis pneumonia (PCP) occurs only rarely in immunocompetent individuals. Asymptomatic colonisation with P Jiroveci has recently been described in patients who are either minimally immunosuppressed or who have underlying lung disorders such as bronchiectasis. We sought to determine the prevalence of asymptomatic colonisation by P Jiroveci in a cohort of adult patients undergoing diagnostic bronchoscopy. Methods: A prospective observational cohort study was performed in patients who required bronchoscopy and bronchoalveolar lavage (BAL) as part of their routine clinical assessment. All the samples underwent standard microbiological analysis and a Grocott methenamine silver stain was performed where clinically indicated to detect the presence of P Jiroveci. Polymerase chain reaction for detection of P Jiroveci specific DNA was also performed. Results: Ninety three consecutive BAL fluid samples were analysed, 17 (18%) of which contained P Jiroveci DNA. Of the potential predictors examined, only glucocorticoid use was significantly associated with detectable P Jiroveci DNA. Eighteen patients were receiving oral glucocorticoids (equivalent to >20 mg/day prednisolone) at the time of bronchoscopy, of whom eight (44%) had detectable P Jiroveci DNA. In contrast, P Jiroveci was detected in only nine of 75 patients (12%) who were not receiving glucocorticoids (difference between proportions 32%, 95% CI 8 to 57; p=0.004, two tailed Fisher's exact test). Conclusions: P Jiroveci colonisation, as determined by detection of P Jiroveci DNA in BAL fluid, is common in HIV negative patients with primary respiratory disorders undergoing bronchoscopy and BAL. The higher prevalence in patients receiving corticosteroids suggests that oral glucocorticoid therapy is an independent risk factor for colonisation. In contrast, underlying lung cancer or COPD did not appear to be risk factors.
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limited asymptomatic carriage of Pneumocystis Jiroveci in human immunodeficiency virus infected patients
The Journal of Infectious Diseases, 2003Co-Authors: Ann E Wakefield, Austin R Lindley, Helen E Ambrose, Cecilemarie Denis, R F MillerAbstract:Forty-seven bronchoalveolar lavage fluid samples from 16 human immunodeficiency virus (HIV)-infected patients were used to test the latency model of Pneumocystis infection in the human host. Identification of DNA sequence polymorphisms at 4 independent loci were used to genotype Pneumocystis Jiroveci from the 35 samples that contained detectable P. Jiroveci DNA. Eighteen of those 35 samples came from patients who did not have Pneumocystis pneumonia (PCP) and had confirmed alternative diagnoses. Seven patients had asymptomatic carriage of P. Jiroveci over periods of less than or equal to9.5 months after an episode of PCP, and in all 7 cases, a change in genotype from that in the original episode of PCP was observed. The absence of P. Jiroveci DNA in one-fourth of the 47 samples and the observed changes in genotype during asymptomatic carriage do not support the latency model of infection. Asymptomatic carriage in HIV-infected patients may play a role in transmission of P. Jiroveci and may even supply a reservoir for future infections.
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a new name Pneumocystis Jiroveci for Pneumocystis from humans
Emerging Infectious Diseases, 2002Co-Authors: James R Stringer, R F Miller, Charles B Beard, Ann E WakefieldAbstract:The disease known as Pneumocystis carinii pneumonia (PCP) is a major cause of illness and death in persons with impaired immune systems. While the genus Pneumocystis has been known to science for nearly a century, understanding of its members remained rudimentary until DNA analysis showed its extensive diversity. Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. In recognition of its genetic and functional distinctness, the organism that causes human PCP is now named Pneumocystis Jiroveci Frenkel 1999. Changing the organism's name does not preclude the use of the acronym PCP because it can be read "Pneumocystis pneumonia." DNA sequence variation exists among samples of P. Jiroveci, a feature that allows reexamination of the relationships between host and pathogen. Instead of lifelong latency, transient colonization may be the rule.
J. M. Varela - One of the best experts on this subject based on the ideXlab platform.
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systemic inflammation in patients with chronic obstructive pulmonary disease who are colonized with Pneumocystis Jiroveci
Clinical Infectious Diseases, 2007Co-Authors: Enrique J Calderon, F. J. Medrano, N. Respaldiza, J. M. Varela, Laura Rivero, Ruben Morilla, M A Montescano, Vicente Friaza, F Munozlobato, C. De La HorraAbstract:In chronic obstructive pulmonary disease, high levels of airway and systemic inflammatory markers are associated with a faster decrease in lung function. Our study shows that patients colonized by Pneumocystis Jiroveci have higher proinflammatory cytokine levels than do noncolonized patients. This suggests that Pneumocystis may play a role in disease progression.
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Pneumocystis Jiroveci isolates with dihydropteroate synthase mutations in patients with chronic bronchitis
European Journal of Clinical Microbiology and Infectious Diseases, 2004Co-Authors: E. Calderón, C. De La Horra, F. J. Medrano, A. López-suárez, M. A. Montes-cano, N. Respaldiza, J. Elvira-gonzález, J. Martín-juan, A. Bascuñana, J. M. VarelaAbstract:Since mutations in the dihydropteroate synthase (DHPS) gene possibly associated with sulfonamide resistance have been reported in patients with Pneumocystis Jiroveci (previously carinii ) pneumonia, and since P. Jiroveci colonization has been recently demonstrated in patients with chronic pulmonary diseases, the present study aimed to investigate the possible occurrence of P. Jiroveci DHPS mutations in patients with chronic bronchitis. P. Jiroveci colonization was detected in 15 of 37 non-selected patients with chronic bronchitis by amplifying the large subunit of the mitochondrial gene of the ribosomal RNA using nested PCR. DHPS mutations were demonstrated using touchdown PCR and restriction enzyme analysis in two of eight patients with chronic bronchitis and in two of six patients from the same region who had AIDS-associated Pneumocystis pneumonia. In all cases, mutations were observed in subjects with no prior exposure to sulfonamides. These data could have important implications for public health, since (i) P. Jiroveci colonization could speed the progression of chronic bronchitis, and (ii) these patients, who are customary sputum producers, could represent a reservoir for sulfonamide-resistant strains with the potential ability to transmit them to immunocompromised hosts susceptible to Pneumocystis pneumonia.
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Pneumocystis Jiroveci genotypes in the spanish population
Clinical Infectious Diseases, 2004Co-Authors: M Montes A Cano, C. De La Horra, F. J. Medrano, N. Respaldiza, J. M. Varela, Jose Martinjuan, R Torronteras, Enrique J CalderonAbstract:This study describes the genotype distribution of Pneumocystis Jiroveci in 79 respiratory samples obtained from 15 patients with acquired immunodeficiency syndrome (AIDS) with P. Jiroveci pneumonia and 64 human immunodeficiency virus-negative subjects with different chronic pulmonary diseases. The genotyping was based in analysis of 2 independent genetic loci: the mitochondrial large subunit ribosomal RNA (mt LSU rRNA) fragment (assessed by direct sequencing) and the gene for dihydropteroate synthase (DHPS; assessed by restriction fragment-length polymorphism). The mt LSU rRNA analysis revealed the presence of 3 different polymorphisms for both populations. The major genotype, 85C/248C, was found to be significantly higher in patients with AIDS and P. Jiroveci pneumonia than in patients with pulmonary disease. The rate of genotypes 85A/248C and 85T/248C was similar in both groups. The analysis of DHPS genotypes assesses the prevalence of its 4 possible genotypes, with 35.5% of genotypes related to sulfa resistance. The data suggest a common source of infection between both groups.
C. De La Horra - One of the best experts on this subject based on the ideXlab platform.
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systemic inflammation in patients with chronic obstructive pulmonary disease who are colonized with Pneumocystis Jiroveci
Clinical Infectious Diseases, 2007Co-Authors: Enrique J Calderon, F. J. Medrano, N. Respaldiza, J. M. Varela, Laura Rivero, Ruben Morilla, M A Montescano, Vicente Friaza, F Munozlobato, C. De La HorraAbstract:In chronic obstructive pulmonary disease, high levels of airway and systemic inflammatory markers are associated with a faster decrease in lung function. Our study shows that patients colonized by Pneumocystis Jiroveci have higher proinflammatory cytokine levels than do noncolonized patients. This suggests that Pneumocystis may play a role in disease progression.
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Pneumocystis Jiroveci isolates with dihydropteroate synthase mutations in patients with chronic bronchitis
European Journal of Clinical Microbiology and Infectious Diseases, 2004Co-Authors: E. Calderón, C. De La Horra, F. J. Medrano, A. López-suárez, M. A. Montes-cano, N. Respaldiza, J. Elvira-gonzález, J. Martín-juan, A. Bascuñana, J. M. VarelaAbstract:Since mutations in the dihydropteroate synthase (DHPS) gene possibly associated with sulfonamide resistance have been reported in patients with Pneumocystis Jiroveci (previously carinii ) pneumonia, and since P. Jiroveci colonization has been recently demonstrated in patients with chronic pulmonary diseases, the present study aimed to investigate the possible occurrence of P. Jiroveci DHPS mutations in patients with chronic bronchitis. P. Jiroveci colonization was detected in 15 of 37 non-selected patients with chronic bronchitis by amplifying the large subunit of the mitochondrial gene of the ribosomal RNA using nested PCR. DHPS mutations were demonstrated using touchdown PCR and restriction enzyme analysis in two of eight patients with chronic bronchitis and in two of six patients from the same region who had AIDS-associated Pneumocystis pneumonia. In all cases, mutations were observed in subjects with no prior exposure to sulfonamides. These data could have important implications for public health, since (i) P. Jiroveci colonization could speed the progression of chronic bronchitis, and (ii) these patients, who are customary sputum producers, could represent a reservoir for sulfonamide-resistant strains with the potential ability to transmit them to immunocompromised hosts susceptible to Pneumocystis pneumonia.
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Pneumocystis Jiroveci genotypes in the spanish population
Clinical Infectious Diseases, 2004Co-Authors: M Montes A Cano, C. De La Horra, F. J. Medrano, N. Respaldiza, J. M. Varela, Jose Martinjuan, R Torronteras, Enrique J CalderonAbstract:This study describes the genotype distribution of Pneumocystis Jiroveci in 79 respiratory samples obtained from 15 patients with acquired immunodeficiency syndrome (AIDS) with P. Jiroveci pneumonia and 64 human immunodeficiency virus-negative subjects with different chronic pulmonary diseases. The genotyping was based in analysis of 2 independent genetic loci: the mitochondrial large subunit ribosomal RNA (mt LSU rRNA) fragment (assessed by direct sequencing) and the gene for dihydropteroate synthase (DHPS; assessed by restriction fragment-length polymorphism). The mt LSU rRNA analysis revealed the presence of 3 different polymorphisms for both populations. The major genotype, 85C/248C, was found to be significantly higher in patients with AIDS and P. Jiroveci pneumonia than in patients with pulmonary disease. The rate of genotypes 85A/248C and 85T/248C was similar in both groups. The analysis of DHPS genotypes assesses the prevalence of its 4 possible genotypes, with 35.5% of genotypes related to sulfa resistance. The data suggest a common source of infection between both groups.