JAC Advance Access originally published online on March 3, 2008
Journal of Antimicrobial Chemotherapy 2008 61(4):969-970; doi:10.1093/jac/dkn087
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Letters to the Editor |
Therapy for Whipple's disease—authors' response
Rheumatology Department, Radboud University Nijmegen Medical Center, Geert Grooteplein Zuid 10, PO Box 9101, 6500 HB Nijmegen, The Netherlands
* Corresponding author. Tel: +31-24-3614580; Fax: +31-24-3541433; E-mail: p.barrera{at}reuma.umcn.nl
Keywords: antibacterial agents , antibiotics , doxycycline , hydroxychloroquine , drug combinations , Tropheryma whipplei
We agree with many of the points made by Bakkali et al.1 in their letter responding to our paper ‘Therapy for Whipple’s disease’ published in JAC last year.2
In their comment, the group of Dr Raoult provides in vitro evidence for the susceptibility of Tropheryma whipplei to sulfadiazine, which is in line with the previously demonstrated susceptibility to sulfamethoxazole.3 These findings are not unexpected since both sulphonamides are competitors for the same target enzyme, dihydropteroate synthetase. In their previous review, the authors suggested using a high dose of sulfadiazine or sulfamethoxazole instead of co-trimoxazole in case of neurological involvement.4 They now choose the former drug in view of their in vitro data, the better CSF penetration and the longer half-life of sulfadiazine. Moreover, sulfamethoxazole is primarily used in combination with trimethoprim and may not be available as a single drug in many countries. Other potential considerations when using sulfadiazine are the higher risk of crystalluria and, most importantly, the risk of acquired resistance to this agent.
We fully agree with the statement that recommendations for such a rare and serious disease should be based on evidence, not only as a result of in vitro studies and genome analysis but, most importantly, from clinical trials. Unfortunately, the latter are scarce. Dr Bakkali refers to two clinical studies in progress. The trial of the European Network on T. whipplei infections, consisting of 2 weeks of induction therapy with parenteral ceftriaxone versus meropenem followed by 1 year of maintenance therapy with trimethoprim/sulfamethoxazole, was completed last year and is thus no longer in progress.5 The final analysis showed no differences in efficacy, recurrence rates or failures between both induction arms. Ceftriaxone could be preferred as induction therapy in view of its lower costs.
The second clinical study to which the authors refer encompasses doxycycline in combination with hydroxychloroquine as an alkalinizing agent, aimed at the eradication of intracellular organisms. This therapy should be combined with a sulphonamide in the case of neurological involvement, defined by the presence of neurological symptoms and/or a positive PCR assay of CSF. To date, this regimen has only been mentioned by Fenollar et al. as unpublished data from their own group, and used in four cases, only two of which had classic Whipple’s disease.4 Though promising, these preliminary data need to be expanded and compared with the results of other more classical regimens before they can be generalized.
Neurological involvement at presentation or during relapses remains one of the main concerns in Whipple’s disease and may occur without neurological symptoms and with negative PCR results.6 Doxycycline combined with hydroxychloroquine is effective against T. whipplei in vitro.4 Besides its antibiotic properties, doxycycline has other characteristics that could contribute to its efficacy.7,8 Nonetheless, both doxycycline and hydroxychloroquine have a poor penetration in CSF. In considering new recommendations for the treatment of Whipple’s disease, a standard therapeutic regimen using drugs with high penetration into the CNS should be advocated.
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1 Bakkali N, Fenollar F, Rolain JM, et al. Comment on: Therapy for Whipple’s disease. J Antimicrob Chemother (2008) 61:968–9.
2
Knaapen HK, Barrera P. Therapy for Whipple’s disease. J Antimicrob Chemother (2007) 60:457–8.
3
Boulos A, Rolain JM, Mallet MN, et al. Molecular evaluation of antibiotic susceptibility of Tropheryma whipplei in axenic medium. J Antimicrob Chemother (2005) 55:178–81.
4
Fenollar F, Puechal X, Raoult D. Whipple’s disease. N Engl J Med (2007) 356:55–66.
5 Feurle GE, Maiwald M, Marth T. Randomized, controlled trial of antimicrobial treatment in Whipple’s disease. Gastroenterology (2007) 132:A-639.
6 von Herbay A, Ditton HJ, Schuhmacher F, et al. Whipple’s disease: staging and monitoring by cytology and polymerase chain reaction analysis of cerebrospinal fluid. Gastroenterology (1997) 113:434–41.[CrossRef][Web of Science][Medline]
7 Rempe S, Hayden JM, Robbins RA, et al. Tetracyclines and pulmonary inflammation. Endocr Metab Immune Disord Drug Targets (2007) 7:232–6.[Medline]
8
Minagar A, Alexander JS, Schwendimann RN, et al. Combination therapy with interferon β-1a and doxycycline in multiple sclerosis: an open-label trial. Arch Neurol (2008) 65:199–204.
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