Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients

Kazanjian, Powel; Locke, Amy; Hossler, Paul A.; Lane, Brian R.; Bartlett, Marilyn S.; Smith, James W.; Cannon, Mark; Meshnick, Steven R.

doi:10.1097/00002030-199808000-00009

Cited by 200 publications

(213 citation statements)

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“…Prior exposure to sulfonamide drugs has been identified as a predictor of mutant genotypes (reviewed in Totet et al, 2004). In addition the city in which a patient resides has also been identified as an independent risk factor (Huang et al, 2000;Kazanjian et al, 2000), a factor that supports the hypothesis that P. jirovecii is transmitted from infected treated patients to susceptible untreated patients, either directly or through a common envi-ronmental source. Totet and colleagues identified P. jirovecii genotypes at the DHPS locus in immunocomptetent infants with primary infection and immunosuppressed adults with PCP (Totet et al, 2004).…”

Section: Transmission Of Possible Resistant P Jirovecii Organisms Inmentioning

confidence: 99%

NosocomialPneumocystis jiroveciiinfections

et al. 2008

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Summary :Airborne transmission of Pneumocystis sp. from host to host has been demonstrated in rodent models and several observations suggest that interindividual transmission occurs in humans. Moreover, it is accepted that the Pneumocystis organisms infecting each mammalian species are host specific and that the hypothesis of an animal reservoir for Pneumocystis jirovecii (P. jirovecii), the human-specific Pneumocystis species, can be excluded. An exosaprophytic form of the fungus cannot be strictly ruled out. However, these data point toward the potential for the specific host to serve as its own reservoir and for Pneumocystis infection in humans as an anthroponosis with humans as a reservoir for P. jirovecii. This review highlights the main data on host-to-host transmission of Pneumocystis in rodent models and in humans by the airborne route and provides a rationale for considering the occurrence of nosocomial infections and measures for their prevention KEY WORDS : Pneumocystis jirovecii, nosocomial infections, genotyping.

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Section: Transmission Of Possible Resistant P Jirovecii Organisms Inmentioning

confidence: 99%

NosocomialPneumocystis jiroveciiinfections

et al. 2008

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“…Other drugs including dapsone, atovaquone and pentamidine are alternatives to TMP/SMX, but they are either more toxic or less active against P. jirovecii (Hughes et al, 1993;Hughes, 1998;Kovacs et al, 2001a;Sattler et al, 1988;Vasconcelles et al, 2000). Unfortunately, recent studies have identified mutations in the gene encoding DHPS suggesting the emergence of resistance in P. jirovecii to sulfa drugs (dapsone and SMX) (Helweg-Larsen et al, 1999;Kazanjian et al, 2000;Ma et al, 1999;Navin et al, 2001). Development of new drugs to treat or prevent PCP thus remains an important priority for research.…”

Section: Introductionmentioning

confidence: 99%

Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine

Vestereng

Kovacs

2004

Microbiology

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Because thymidine metabolism is a potential target for therapy of Pneumocystis pneumonia, it was investigated whether Pneumocystis organisms have a salvage pathway for thymidine by administering 5-bromo-29-deoxyuridine (BrdU) to mice and rats with Pneumocystis pneumonia. Although BrdU incorporation was detected in host cells, no incorporation was seen in Pneumocystis organisms infecting either rats or mice. This suggests that Pneumocystis organisms do not have a salvage pathway for thymidine, and that inhibitors of de novo synthesis, such as thymidylate synthase inhibitors, may be effective drugs for treating Pneumocystis pneumonia. INTRODUCTIONPneumocystis jirovecii is an atypical fungus that infects patients suffering from a variety of immunosuppressive diseases, such as AIDS and cancer (Kovacs et al., 2001a;Roblot et al., 2002). Although there has been a decrease in morbidity among AIDS patients due to the availability of potent anti-retroviral regimens, Pneumocystis pneumonia (PCP) continues to be the most common life-threatening opportunistic infection among HIV-infected patients. Therapy with the combination of trimethoprim and sulfamethoxazole (TMP/SMX) is the preferred approach for primary prophylaxis in susceptible patients (i.e. for AIDS patients with CD4 + count levels <200 mm 23 ) as well as for treatment of active PCP (Kovacs & Masur, 2000;Phair et al., 1990). These drugs target the enzymes dihydrofolate reductase and dihydropteroate synthase (DHPS), respectively. Other drugs including dapsone, atovaquone and pentamidine are alternatives to TMP/SMX, but they are either more toxic or less active against P. jirovecii (Hughes Hughes, 1998;Kovacs et al., 2001a;Sattler et al., 1988; Vasconcelles et al., 2000). Unfortunately, recent studies have identified mutations in the gene encoding DHPS suggesting the emergence of resistance in P. jirovecii to sulfa drugs (dapsone and SMX) (Helweg-Larsen et al., 1999;Kazanjian et al., 2000;Ma et al., 1999;Navin et al., 2001). Development of new drugs to treat or prevent PCP thus remains an important priority for research.P. jirovecii is closely related to Pneumocystis species that infect rats (Pneumocystis carinii) and mice (P. carinii f. sp. muris). A better understanding of the metabolic pathways of Pneumocystis species may lead to the identification of novel therapeutic targets. Thymidine metabolism has been partially characterized in Pneumocystis: thymidylate synthase has been identified, isolated, cloned and crystallized (Anderson et al., 2000; Edman et al., 1989;Kovacs et al., 1990;Santi et al., 1991). Thus, Pneumocystis organisms possess de novo synthetic pathways for thymidine, a target of chemotherapy in other infections. Therapies that target de novo thymidylate synthesis can potentially be bypassed using thymidine salvage pathways. To see if Pneumocystis organisms possessed a salvage pathway for thymidine, 5-bromo-29-deoxyuridine (BrdU) was administered for 14 days to Pneumocystis-infected rats and mice. BrdU is a thymidine analogue which can be incorpora...

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“…[ [11][12][13] Terbinafine is an allylamine agent which appears to act by preventing fungal ergosterol biosynthesis via specific and selective inhibition of fungal sequalene epoxidase. [3,4] It is orally and topically active especially on dermatophyte, filamentous, dimorphic and dematiaceous fungi, and some yeast species.…”

Section: Discussionmentioning

confidence: 99%

Evaluation Of Terbinafine Activity On Pneumocystis Carinii At The Rat Model

Artan¹,

Koç²,

Öztürk³

2009

TUTFD

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© Trakya Üniversitesi T p Fakültesi Dergisi. AVES Yay nc l k taraf ndan bas lm t r. Her hakk sakl d r. © Medical Journal of Trakya University. Published by AVES Publishing. All rights reserved. Evaluation of Terbinafine Activity onObjective: The purpose of this study was to test the hypothesis thThis study was planned to investigate the antipneumocystis activity of terbinafine in a rat model. Material and Methods: Rats were obtained from the Hakan Çetinsaya Experimental and Clinical ResearchInstitutions, Erciyes University, Kayseri, Turkey. Terbinafine administered orally in doses of 40, 80, 120 and 160 mg/kg/day after nine weeks of immunosuppression with dexamethasone to facilitate the development of acute Pneumocystis carinii penumoniae (PCP).Results: Untreated animals showed P. carinii infection levels with a mean (±standard deviation) log number of cysts per gram of lung tissue of 4.6±1.6 at the end of the experiment. Terbinafine administered at a dose of 160 mg/kg/day significantly reduced the log number of cysts per gram to 2.2±1.5. The therapeutic efficacy of terbinafine administered at 160 mg/kg/day (log 2.2±1.5 cysts/lung) was similar to that obtained with trimethoprim-sulfamethoxazole (TMP-SMX), 50/250 mg/kg/ day (p<0.001). A reduction in the number of cysts was also observed in infected animals treated with 80, and 120 mg of terbinafine/kg/day, although the results were not statistically significant (p>0.05). Conclusion:In our model, the efficacy of terbinafine in PCP has been found to be dose dependent.Key words: Pneumocystis carinii; rat; terbinafine.Amaç: Bu çal ma rat modelinde terbinafinin antiPneumocystis aktivitesini belirlemek için planlanm t r. Gereç ve Yöntemler: Ratlar Erciyes ÜniversitesiDeneysel ve Klinik Ara t rma Merkezin'den sa lanm t r. Dokuz hafta boyunca akut Pneumocystis carinii pnömo-nisi (PCP) olu turmak üzere, deksamethazon ile immün-süpresyon yap lan ratlara oral olarak 40, 80, 120 ve 160 mg/kg/gün terbinafin verildi.Bulgular: Çal man n sonunda tedavi almayan grupda PCP enfeksiyon düzeyi ortalama (±standart sapma) akci er dokusu gram ndaki kist say s log 4.6±1.6 idi. Terbinafin 160mg/kg/gün uygulanan grupta gramdaki kist say s nda önemli dü ü gözlendi log 2.2±1.5. Terbinafin 160mg/kg/gün uygulanan tedavi etkinli i, trimetoprim-sulfametoksazol (TMP-SMX), 50/250 mg/ kg/gün uygulamas ile benzer sonuç verdi (p<0.001).Terbinafin 80 ve 120 mg/kg/gün uygulamalar nda da kist say s nda dü ü görülmekle birlikte bu de erler istatistiksel olarak anlaml de ildi (p>0.05).Sonuç: Bizim modelimizde terbinafinin PCP etkinli i doza ba l bulundu.Anahtar sözcükler: Pneumocystis carinii; rat modeli; terbinafin.

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Pneumocystis carinii mutations associated with sulfa and sulfone prophylaxis failures in AIDS patients

Cited by 200 publications

References 18 publications

NosocomialPneumocystis jiroveciiinfections

NosocomialPneumocystis jiroveciiinfections

Inability of Pneumocystis organisms to incorporate bromodeoxyuridine suggests the absence of a salvage pathway for thymidine

Evaluation Of Terbinafine Activity On Pneumocystis Carinii At The Rat Model

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