Sulfa Use, Dihydropteroate Synthase Mutations, and<i>Pneumocystis jirovecii</i>Pneumonia

Stein, Cheryl R.; Poole, Charles; Kazanjian, Powel; Meshnick, Steven R.

doi:10.3201/eid1010.040362

Cited by 54 publications

(26 citation statements)

References 33 publications

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“…This proportion stands in contrast to the lower frequencies reported from the African continent and other countries outside the industrialized world (8,12,23,25,30,34,40,46,48). The risk that P. jirovecii will develop mutations in the DHPS gene is higher for patients with PCP receiving sulfa drug prophylaxis than for those not receiving it (5,15,16,22,26,32,38). A general assumption is that the frequency of occurrence of mutations in the DHPS gene in developing countries is low due to the less extensive use of sulfa drug prophylaxis against PCP.…”

Section: Discussioncontrasting

confidence: 47%

“…Sulfonamides inhibit the enzyme dihydropteroate synthase (DHPS), an essential component of the folate synthesis pathway (36). In P. jirovecii, two nonsynonymous point mutations in the fas gene, which encodes the DHPS enzyme, are associated with prior exposure to sulfa drugs (5,15,16,22,26,32), and concerns have been raised about the possible emergence of resistance to sulfa drugs (38). These mutations, at nucleotide positions 165 and 171, cause the amino acid substitutions Thr55Ala and Pro57Ser in the DHPS protein, respectively.…”

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confidence: 99%

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High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

et al. 2010

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Pneumocystis jirovecii pneumonia (PCP) is an important cause of morbidity and mortality in immunocompromised patients. Sulfa-containing drugs are used for the treatment and prophylaxis of PCP. Mutations in the P. jirovecii fas gene, which encodes dihydropteroate synthase (DHPS), are associated with prior exposure to sulfa drugs, and their appearance suggests the emergence of variants with reduced sulfa susceptibility. The present study examined the prevalence of DHPS mutations in P. jirovecii strains isolated from South African patients with PCP. P. jirovecii infection was investigated by immunofluorescence microscopy and quantitative real-time PCR with respiratory specimens from 712 patients (93% of whom were >15 years of age) with suspected PCP consecutively received for the detection of P. jirovecii over 1 year. PCR amplification and sequencing of the DHPS fas gene was attempted with DNA from the P. jirovecii-positive samples. P. jirovecii infection was confirmed by immunofluorescence microscopy in 168/712 (24%) of the patients. Carriage of the fungus was revealed by real-time PCR in 17% of the patients with negative microscopy results. The P. jirovecii fas gene was successfully amplified from specimens from 151 patients and sequenced. Mutations resulting in the Thr55Ala and/or Pro57Ser amino acid substitution were detected in P. jirovecii strains from 85/151 (56%) patients. The high frequency of PCP episodes with P. jirovecii harboring DHPS mutations in South Africa indicates that populations of this fungus are evolving under the considerable selective pressure exerted by sulfa-containing antibiotics. These results, similar to previous observations of sulfa drug resistance in bacterial populations, underscore the importance of the rational use of sulfa medications either prophylactically against PCP or for the treatment of other infections.

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Section: Discussioncontrasting

confidence: 47%

mentioning

confidence: 99%

High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

et al. 2010

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“…Patients who have PcP despite the use of TMP-SMX prophylaxis, are usually successfully treated with TMP-SMX. In this way, the presence of mutations in the DHPS gene of P. jirovecii has been associated with resistance to sulfa drugs, although the clinical outcome is uncertain (Crothers et al 2005;Huang et al, 2004;Stein et al, 2004). Drug related toxicities from TMP-SMX are greater than that from therapy with other anti-Pneumocystis agents.…”

Section: Trimethoprim-sulfamethoxazole (Tmp-smx)mentioning

confidence: 98%

“…Such mutations were shown to be associated with the use of TMP-SMX or dapsone (two DHPS inhibitors), the duration of sulfa or dapsone prophylaxis and with geographic areas in which sulfamethoxazole or dapsone were commonly used for PcP prophylaxis Kazanjian et al, 2000). However, results of studies searching specifically to establish an association between the presence of P. jirovecii DHPS mutations and clinical outcomes, such as treatment failure or death, are contradictory (Alvarez-Martinez et al, 2008, Helweg-Larsen et al, 1999Huang et al, 2004, www.intechopen.com Stein et al, 2004;van Hal et al, 2009). Outstandingly, most PcP patients carrying P. jirovecii isolates with DHPS mutations responded well to TMP-SMX treatment and survived probably because these mutations may confer a low-level of resistance to sulfa-drugs that is overcome by high drug concentration achieved in lung tissues by sulfamethoxazole (Calderon et al, 2004;Huang et al, 2004).…”

Section: Molecular Detection Of Pneumocystismentioning

confidence: 99%

Pneumocystis jirovecii Pneumonia in AIDS Patients

Varela¹,

Medrano²,

Dei‐Cas³

et al. 2011

Microbes, Viruses and Parasites in AIDS Process

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“…TMP-SMX interrupts folate syntheses in Pneumocystis organisms and is also the most common regimen for treatment of PcP. Unfortunately, TMP-SMX-resistant Pneumocystis organisms have emerged due to mutations in the dihydropteroate synthase gene (2)(3)(4), and some PcP patients may fail TMP-SMX therapy (3).…”

mentioning

confidence: 99%

Pneumocystis Mediates Overexpression of Antizyme Inhibitor Resulting in Increased Polyamine Levels and Apoptosis in Alveolar Macrophages

Liao

Lasbury

Wang

et al. 2009

Journal of Biological Chemistry

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Pneumocystis pneumonia (PcP) is the most common opportunistic disease in immunocompromised patients. Alveolar macrophages are responsible for the clearance of Pneumocystis organisms; however, they undergo a high rate of apoptosis during PcP due to increased intracellular polyamine levels. In this study, the sources of polyamines and mechanisms of polyamine increase and polyamine-induced apoptosis were investigated. The level of ornithine decarboxylase (ODC) was elevated in alveolar macrophages, and the number of alveolar macrophages that took up exogenous polyamines was increased 20-fold during PcP. Monocytes, B lymphocytes, and CD8؉ T lymphocytes that were recruited into the lung during PcP expressed high levels of ornithine decarboxylase, suggesting that these cells are sources of polyamines. Both protein and mRNA levels of antizyme inhibitor (AZI) were increased in alveolar macrophages during PcP. This AZI overexpression correlated with increased polyamine uptake by alveolar macrophages, because AZI expression knockdown decreased the polyamine uptake ability of these cells. AZI expression knockdown also decreased the apoptosis rate of alveolar macrophages. Pneumocystis organisms and zymosan A were found to induce AZI overexpression in alveolar macrophages, suggesting that ␤-glucan, which is the major component of the Pneumocystis cell wall, induces AZI overexpression. The levels of mRNA, protein, and activity of polyamine oxidase were increased in alveolar macrophages during PcP, indicating that the H 2 O 2 generated during polyamine catabolism caused alveolar macrophages to undergo apoptosis. Taken together, results of this study indicate that Pneumocystis organisms induce AZI overexpression in alveolar macrophages, leading to increased polyamine synthesis and uptake and apoptosis rate of these cells.Pneumocystis is an opportunistic pathogen; it causes Pneumocystis pneumonia (PcP) 3 in immunocompromised individuals, especially in patients with AIDS. Advanced PcP is characterized by infiltration of inflammatory cells in the lung, thickened alveolar septa, and foamy exudates that fill the alveoli. Although host inflammatory responses are important in the defense against Pneumocystis infection, they may also cause lung injury leading to impaired gas exchange and respiratory failure. CD4ϩ T lymphocytes are crucial in the defense against Pneumocystis infection, because a severe decrease in the number of CD4ϩ T lymphocytes predisposes patients to the infection (1). Therefore, prophylaxis with a combination of trimethoprim and sulfamethoxazole (TMP-SMX) is usually given to patients with fewer than 200 CD4ϩ T lymphocytes per microliter in the blood. TMP-SMX interrupts folate syntheses in Pneumocystis organisms and is also the most common regimen for treatment of PcP. Unfortunately, TMP-SMX-resistant Pneumocystis organisms have emerged due to mutations in the dihydropteroate synthase gene (2-4), and some PcP patients may fail TMP-SMX therapy (3).The alveolar macrophage is the major cell type responsible for the clear...

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Sulfa Use, Dihydropteroate Synthase Mutations, andPneumocystis jiroveciiPneumonia

Abstract: Meta-analysis shows increased risk for DHPS mutations in patients exposed to sulfa prophylaxis for PCP, but clinical relevance of mutations is not known.

Cited by 54 publications

References 33 publications

High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

High Prevalence of Dihydropteroate Synthase Mutations in Pneumocystis jirovecii Isolated from Patients with Pneumocystis Pneumonia in South Africa

Pneumocystis jirovecii Pneumonia in AIDS Patients

Pneumocystis Mediates Overexpression of Antizyme Inhibitor Resulting in Increased Polyamine Levels and Apoptosis in Alveolar Macrophages

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