Evaluation of sulfonamide detoxification pathways in haematologic malignancy patients prior to intermittent trimethoprim-sulfamethoxazole prophylaxis

Authors

  • Mahmoud Abouraya,

    1. Department of Medical Sciences, School of Veterinary Medicine
    Search for more papers by this author
  • James C. Sacco,

    1. Department of Medical Sciences, School of Veterinary Medicine
    Search for more papers by this author
  • Brad S. Kahl,

    1. Department of Medicine, School of Medicine and Public Health, University of Wisconsin-Madison, Madison, WI, USA
    Search for more papers by this author
  • Lauren A. Trepanier

    Corresponding author
    1. Department of Medical Sciences, School of Veterinary Medicine
      Dr Lauren A. Trepanier, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-1102, USA. Tel.: +608 265 9022 Fax: +608 265 8020 E-mail: latrepanier@vetmed.wisc.edu
    Search for more papers by this author

Dr Lauren A. Trepanier, School of Veterinary Medicine, University of Wisconsin-Madison, 2015 Linden Drive, Madison, WI 53706-1102, USA. Tel.: +608 265 9022 Fax: +608 265 8020 E-mail: latrepanier@vetmed.wisc.edu

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT

• Previously, it was reported that patients with haematologic malignancies on daily trimethoprim-sulfamethoxazole prophylaxis appeared to have a higher risk of sulfonamide hypersensitivity compared with the general population. However, the mechanisms for this apparent higher risk have not been explored.

WHAT THIS STUDY ADDS

• This paper provides the first prospective evaluation of antioxidant and reduction detoxification pathways in patients with haematologic malignancies prior to sulfonamide prophylaxis.

• It also provides the first prospective evaluation of sulfonamide hypersensitivity, including the development of drug-specific T cells, in patients started on intermittent trimethoprim-sulfamethoxazole prophylaxis.

• Our findings suggest that defects in the reduction of sulfonamide metabolites are not common in patients with haematologic malignancies, and further, that the incidence of skin rash and the development of drug-specific T cells appears to be low in patients on intermittent, rather than daily, sulfonamide prophylaxis.

AIMS Patients with haematologic malignancies have a reportedly high incidence of sulfamethoxazole (SMX) hypersensitivity. The objective of this study was to determine whether deficiencies in sulfonamide detoxification pathways, to include glutathione (GSH) and ascorbate (AA), and cytochrome b5 (b5) and cytochrome b5 reductase (b5R), were prevalent in these patients. A secondary pilot objective was to determine whether the incidence of drug hypersensitivity following intermittent trimethoprim-SMX (TMP-SMX) prophylaxis approached that reported for high dose daily regimens.

METHODS Forty adult patients with haematologic malignancies (HM) and 35 healthy adults were studied; an additional 13 HM patients taking ascorbate supplements (HM-AA) were also evaluated. Twenty-two of 40 HM patients were prescribed and were compliant with TMP-SMX 960 mg three to four times weekly.

RESULTS There were no significant differences between HM and healthy groups in plasma AA (median 37.2 µmvs. 33.9 µm) or red blood cell GSH (1.9 mmvs. 1.8 mm). However, plasma AA was correlated significantly with leucocyte b5/b5R reduction (r= 0.39, P= 0.002). Deficient b5/b5R activities were not found in HM patients. In fact, patients with chronic lymphocytic leukaemia or myeloma had significantly higher median activities (80.7 µmol mg–1 min−1) than controls (18.9 µmol mg–1 min−1, P= 0.008). After 3–4 weeks of treatment, no patients developed SMX-specific T cells and only one patient developed rash.

CONCLUSIONS Deficiencies of blood antioxidants and b5/b5R reduction were not found in this population with haematologic malignancies, and the development of skin rash and drug-specific T cells appeared to be uncommon with intermittent TMP-SMX prophylaxis.

Ancillary