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Resistance to trimethoprim-sulfamethoxazole and Tropheryma whipplei

Abstract number: P834

Fenollar F., Rolain J.M., Alric L., Papo T., Chauveheid M.P., Van de Beek D., Raoult D.

Objectives: Whipple's disease (WD) is a chronic infection caused by Tropheryma whipplei and was fatal before the advent of antibiotics. A one-year treatment of oral trimethoprim-sulfamethoxazole is commonly used. The recent advances in culture of T. whipplei has allowed for full genome sequencing and antibiotic susceptibility testing, which has demonstrated resistance of T. whipplei to trimethoprim. Several mutations in the folpP gene that encodes dihydropteroate synthase, the target of sulfonamides, has been reported by our team for one patient with clinically acquired resistance to trimethoprim-sulfamethoxazole, whereas no mutations were observed in 19 strains from patients without any evidence of clinical failure or relapse. Herein, we confirm, complete these data and propose a strategy in order to improve the management of WD.

Methods: Three new patients who experienced clinically acquired resistance to trimethoprim-sulfamethoxazole during treatment were reported as well as one patient with biological failure. Sixty-two folP sequences from DNA samples of 59 WD patients were also obtained. Primers were designed according to the two available complete genomes of T. whipplei to frame the 801-bp folP. The nucleotide and amino acid sequences obtained were compared using the CLUSTALW program.

Results: The three new patients who experienced clinically acquired resistance to trimethoprim-sulfamethoxazole during treatment, were all verified by positive PCR analysis. The patient with biological failure only showed positive PCR. From the sixty-two sequences, eight different amino acid sequence types were found. Among the detected amino acid changes, two positions (N4S and S232F) significantly predicted secondary failure (in four out of five cases). The sensitivity of the N4S substitution to predict resistance before treatment was 50%, with 98% specificity, a positive predictive value (PPV) of 75%, and a negative predictive value (NPV) of 94.4%. The sensitivity of the S234F change to predict failure before treatment was 66.7%, with a specificity of 96.4%, PPV of 50%, and a NPV of 98.2%. Besides, new mutations appeared in two out of three amino acid sequences with previous N4S or S234F changes.

Conclusion: We suggest that these mutations (N4S and S232F) should be detected at the time of the WD diagnosis by sequencing folP in order to avoid sulfamethoxazole monotherapy.

Session Details

Date: 16/05/2009
Time: 00:00-00:00
Session name: 19th European Congress of Clinical Microbiology and Infectious Diseases
Subject:
Location: Helsinki, Finland, 16 - 19 May 2009
Presentation type:
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