JAC Advance Access originally published online on February 5, 2008
Journal of Antimicrobial Chemotherapy 2008 61(4):968-969; doi:10.1093/jac/dkn035
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Letters to the Editor |
Comment on: Therapy for Whipple's disease
Université de la Méditerranée, Unité des Rickettsies, CNRS-IRD UMR 6020, Faculté de Médecine et de Pharmacie, 27 Bd Jean Moulin, 13385 Marseille cedex 05, France
* Corresponding author. Tel: +33-491324375; Fax: +33-491387772; E-mail: jm.rolain{at}medecine.univ-mrs.fr
Keywords: Tropheryma whipplei , MICs , failure
Sir,
We read with much interest the article by Knaapen and Barrera1 recently published in JAC on Whipple's disease treatment. It is fascinating as it shows, in this intriguing and rare disease, how successive deductive opinions finally came to be considered as established facts. There are no comparative studies on therapy of Whipple's disease and, until recently, treatment recommendation was empirical, based on anecdotal reports of failures or relapses.2 We believe that this is confusing.
Relapse rates depend on the length of treatment and follow-up. As tetracyclines have been used for many years before co-trimoxazole in the treatment of Whipple's disease, there are more reports on failures with the tetracyclines than with co-trimoxazole.2 There is no published evidence of the superiority of any regimen in terms of relapse rate during 5 years post-treatment follow-up.
The situation is also confusing for primary treatment failure. Whipple's disease can exacerbate when treated, as during leprosy with lepromatous reaction or as in immune reconstitution. These immediate ‘failures’ are not antibiotic failures and when they are excluded, the only difference in failure rates between treatment regimens in the single published comparative study (tetracycline versus co-trimoxazole)2 is observed in patients with initial neurological manifestations. In these patients, doxycycline is poorly effective. In addition, treatment with co-trimoxazole is associated with failures caused by acquired resistance3 and, in our clinical experience, has a frequency of 
3%.2
We should base our recommendations on objective information such as in vitro data, genome analysis and clinical trials. Antibiotic susceptibility testing in vitro demonstrated that doxycycline alone was bacteriostatic rather than bactericidal, against Tropheryma whipplei, although the addition of hydroxychloroquine makes doxycycline bactericidal. T. whipplei is intrinsically resistant to trimethoprim (the gene coding for the target enzyme of this compound is missing in the genome of T. whipplei),4,5 and it has been confirmed in vitro that trimethoprim is ineffective.5 Thus, only the sulphonamide component of co-trimoxazole is active against T. whipplei, and there is no objective reason to prescribe co-trimoxazole instead of a sulphonamide compound alone.
The antibiotic susceptibility of T. whipplei to sulfadiazine has never been evaluated in vitro. We therefore determined the MICs of sulfadiazine for T. whipplei Twist and Neuro 20 strains using quantitative real-time PCR with methods as previously described.5 Experiments were conducted in 24-well plates. Cultures were centrifuged at 7500 rpm for 10 min. Pellets were resuspended to 1/100 in axenic medium. Antibiotics were diluted in culture medium at the concentrations of 0.25, 0.5, 1 and 2 mg/L. Antibiotic-free wells served as growth controls and experiments were performed in triplicate. During the experiments, cultures were harvested at day 0, day 14 and day 21 and frozen at –20°C, until DNA extraction for quantitative PCR assays. The MICs were determined by the measurement of the number of DNA copies by real-time quantitative PCR assay, compared with the number of DNA copies at day 0 of the experiment. MICs were defined as the minimal antibiotic concentrations allowing complete inhibition of bacterial growth. This was determined by measuring DNA copies using quantitative PCR assay when compared with a growth control at the beginning of the experiment. The MICs for the two strains of T. whipplei ranged from 0.5 to 1 mg/L for sulfadiazine versus 0.5 mg/L for sulfamethoxazole (Figure 1 shows an example of MIC determination for sulfadiazine and the Twist strain). Therefore, sulfadiazine is as effective as sulfamethoxazole in vitro.5
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In view of these new in vitro data, we believe that it is time to change from co-trimoxazole to sulfadiazine. Currently, two clinical studies are in progress to evaluate treatment strategies using either a combination of doxycycline (2 x 100 mg/day) with hydroxychloroquine (600 mg/day) associated with a sulphonamide in the case of neurological involvement (i.e. a positive PCR in CSF and/or neurological symptoms),6 or induction therapy with parenteral ceftriaxone, or a carbapenem for 14 days followed by 1 year of treatment with oral co-trimoxazole.2 We suggest only using a sulphonamide if the patient has neurological symptoms or a positive T. whipplei PCR assay on CSF.6 In our experience, preliminary results with this regimen are encouraging.6 Because sulfadiazine has better penetration into CSF, a longer plasma and CSF half-life, and higher plasma concentrations compared with sulfamethoxazole, this compound may be valuable in the treatment of Whipple's disease when a sulphonamide is required.
In conclusion, with advances in knowledge of T. whipplei, the diagnosis of Whipple's disease will be easier and more accurate than previously found. The evidence used to form past recommendations has been impaired by the lack of information on, for example, inclusion criteria and follow-up methods.
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This work was supported by a grant from the fifth Framework Program of the European Commission (QL G1-CT-2002-01049).
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TopFundingTransparency declarationsReferences |
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None to declare.
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Acknowledgements |
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We thank Paul Newton for reviewing the manuscript prior to submission.
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TopFundingTransparency declarationsReferences |
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1 Knaapen HKA, Barrera P. Therapy for Whipple's disease. J Antimicrob Chemother (2007) 60:457–8.
2 Schneider T, Moos V, Loddenkemper C, et al. 100th anniversary of Whipple's disease: new aspects on pathogenesis and treatment of this enigmatic multisystemic infection. Lancet Infect Dis (2008) in press.
3 Levy M, Poyart C, Lamarque D, et al. Whipple's disease: acquired resistance to trimethoprim–sulfamethoxazole. Am J Gastroenterol (2000) 95:2390–1.[Web of Science][Medline]
4 Cannon R. Whipple's disease, genomics, and drug therapy. Lancet (2003) 361:1916.[Web of Science][Medline]
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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.
6 Fenollar F, Puechal X, Raoult D. Whipple's disease. N Engl J Med (2007) 256:55–66.
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  H. K. A. Knaapen and P. Barrera Therapy for Whipple's disease--authors' response J. Antimicrob. Chemother., April 1, 2008; 61(4): 969 - 970. [Full Text] [PDF]
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