Dihydropteroate synthase gene mutations in Pneumocystis and sulfa resistance

Pneumocystis pneumonia (PCP) remains a major cause of illness and death in HIV-infected persons. Sulfa drugs, trimethoprim-sulfamethoxazole (TMP-SMX) and dapsone are mainstays of PCP treatment and prophylaxis. While prophylaxis has reduced the incidence of PCP, its use has raised concerns about development of resistant organisms. The inability to culture human Pneumocystis, Pneumocystis jirovecii, in a standardized culture system prevents routine susceptibility testing and detection of drug resistance. In other microorganisms, sulfa drug resistance has resulted from specific point mutations in the dihydropteroate synthase (DHPS) gene. Similar mutations have been observed in P. jirovecii. Studies have consistently demonstrated a significant association between the use of sulfa drugs for PCP prophylaxis and DHPS gene mutations. Whether these mutations confer resistance to TMP-SMX or dapsone plus trimethoprim for PCP treatment remains unclear. We review studies of DHPS mutations in P. jirovecii and summarize the evidence for resistance to sulfamethoxazole and dapsone

Association between a Specific Pneumocystis jiroveci Dihydropteroate Synthase Mutation and Failure of Pyrimethamine/Sulfadoxine Prophylaxis in Human Immunodeficiency Virus-Positive and -Negative Patients

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 (n=14) had a strain harboring DHPS with an amino acid change at position 57 (Pro→Ser). This mutation was only present in 20 (14%) of 144 patients not receiving prophylaxis (P<.001). Hospitalization in a specific hospital was an independent risk factor for having P. jiroveci harboring the same DHPS mutation, which indirectly supports that interhuman transmission may affect the dissemination of the mutant strain

Interhuman Transmission as a Potential Key Parameter for Geographical Variation in the Prevalence of Pneumocystis jirovecii Dihydropteroate Synthase Mutations

Background. Pneumocystis jirovecii dihydropteroate synthase (DHPS) mutations are associated with failure of prophylaxis with sulfa drugs. This retrospective study sought to better understand the geographical variation in the prevalence of these mutations. Methods. DHPS polymorphisms in 394 clinical specimens from immunosuppressed patients who received a diagnosis of P. jirovecii pneumonia and who were hospitalized in 3 European cities were examined using polymerase chain reaction (PCR) single-strand conformation polymorphism. Demographic and clinical characteristics were obtained from patients' medical charts. Results. Of the 394 patients, 79 (20%) were infected with a P. jirovecii strain harboring one or both of the previously reported DHPS mutations. The prevalence of DHPS mutations was significantly higher in Lyon than in Switzerland (33.0% vs 7.5%; P<.001). The proportion of patients with no evidence of sulfa exposure who harbored a mutant P. jirovecii DHPS genotype was significantly higher in Lyon than in Switzerland (29.7% vs 3.0%; P<.001). During the study period in Lyon, in contrast to the Swiss hospitals, measures to prevent dissemination of P. jirovecii from patients with P. jirovecii pneumonia were generally not implemented, and most patients received suboptimal prophylaxis, the failure of which was strictly associated with mutated P. jirovecii. Thus, nosocomial interhuman transmission of mutated strains directly or indirectly from other individuals in whom selection of mutants occurred may explain the high proportion of mutations without sulfa exposure in Lyon. Conclusions. Interhuman transmission of P. jirovecii, rather than selection pressure by sulfa prophylaxis, may play a predominant role in the geographical variation in the prevalence in the P. jirovecii DHPS mutation

Cutaneous Fusarium infection in a renal transplant recipient: a case report

<p>Abstract</p> <p>Introduction</p> <p>Fungal infections in the immunocompromised host are fairly common. Of the mycoses, <it>Fusarium </it>species are an emerging threat. <it>Fusarium </it>infections have been reported in solid organ transplants, with three reports of the infection in patients who had received renal transplants. To the best of our knowledge, this is the first case of an isolated cutaneous lesion as the only form of infection.</p> <p>Case presentation</p> <p>We report the case of a 45-year-old South Indian man who presented with localized cutaneous <it>Fusarium </it>infection following a renal transplant.</p> <p>Conclusion</p> <p>In an immunocompromised patient, even an innocuous lesion needs to be addressed with the initiation of prompt treatment.</p

Association between a specific Pneumocystis jiroveci dihydropteroate synthase mutation and failure of pyrimethamine/sulfadoxine prophylaxis in human immunodeficiency virus-positive and -negative patients

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 (n=14) had a strain harboring DHPS with an amino acid change at position 57 (Pro--&gt;Ser). This mutation was only present in 20 (14%) of 144 patients not receiving prophylaxis (P&lt;.001). Hospitalization in a specific hospital was an independent risk factor for having P. jiroveci harboring the same DHPS mutation, which indirectly supports that interhuman transmission may affect the dissemination of the mutant strains

Molecular Evidence of Pneumocystis Transmission in Pediatric Transplant Unit

We describe an outbreak of Pneumocystis jirovecii pneumonia in a pediatric renal transplant unit, likely attributable to patient-to-patient transmission. Single-strand conformation polymorphism molecular typing showed that 3 affected patients had acquired the same 2 strains of Pneumocystis, which suggests interhuman infection. An infant with mitochondriopathy was the probable index patient

Hypothetical Pneumocystis jirovecii Transmission from Immunocompetent Carriers to Infant

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Molecular Evidence of Interhuman Transmission of Pneumocystis Pneumonia among Renal Transplant Recipients Hospitalized with HIV-Infected Patients

Molecular evidence indicates that P. jirovecii may be nosocomially transmitted to severely immunosuppressed patients

Pneumocystis jirovecii Transmission from Immunocompetent Carriers to Infant

We report a case of Pneumocystis jirovecii transmission from colonized grandparents to their infant granddaughter. Genotyping of P. jirovecii showed the same genotypes in samples from the infant and her grandparents. These findings support P. jirovecii transmission from immunocompetent carrier adults to a susceptible child

Detection of Pneumocystis DNA in samples from patients suspected of bacterial pneumonia- a case-control study

BACKGROUND: Pneumocystis jiroveci (formerly known as P. carinii f.sp. hominis) is an opportunistic fungus that causes Pneumocystis pneumonia (PCP) in immunocompromised individuals. Pneumocystis jiroveci can be detected by polymerase chain reaction (PCR). To investigate the clinical importance of a positive Pneumocystis-PCR among HIV-uninfected patients suspected of bacterial pneumonia, a retrospective matched case-control study was conducted. METHODS: Respiratory samples from 367 patients suspected of bacterial pneumonia were analysed by PCR amplification of Pneumocystis jiroveci. To compare clinical factors associated with carriage of P. jiroveci, a case-control study was done. For each PCR-positive case, four PCR-negative controls, randomly chosen from the PCR-negative patients, were matched on sex and date of birth. RESULTS: Pneumocystis-DNA was detected in 16 (4.4%) of patients. The median age for PCR-positive patients was higher than PCR-negative patients (74 vs. 62 years, p = 0.011). PCR-positive cases had a higher rate of chronic or severe concomitant illness (15 (94%)) than controls (32 (50%)) (p = 0.004). Twelve (75%) of the 16 PCR positive patients had received corticosteroids, compared to 8 (13%) of the 64 PCR-negative controls (p < 0.001). Detection of Pneumocystis-DNA was associated with a worse prognosis: seven (44%) of patients with positive PCR died within one month compared to nine (14%) of the controls (p = 0.01). None of the nine PCR-positive patients who survived had developed PCP at one year of follow-up. CONCLUSIONS: Our data suggest that carriage of Pneumocystis jiroveci is associated with old age, concurrent disease and steroid treatment. PCR detection of P. jiroveci has low specificity for diagnosing PCP among patients without established immunodeficiency. Whether overt infection is involved in the poorer prognosis or merely reflects sub-clinical carriage is not clear. Further studies of P. jiroveci in patients receiving systemic treatment with corticosteroids are warranted