Sulfamethoxazole-trimethoprim (SMX-TMP)


Both components of cotrimoxazole act as antifolate drugs by inhibiting the biosynthesis of tetrahydrofolic acid.
Cotrimoxazole is widely used in AIDS patients with Pneumocystis carinii pneumonia.
 
Incidence
General population: 3 to 5%.
 
AIDS patients treated with high-dose cotrimoxazole: 44 to 83%.
 
Severe, life threatening idiosyncratic toxicity: 1/10000.
 
Risk factors (uncertain)
Degree of immunodeficiency (CD4+<200/mm3).
 
Duration and dose of therapy.
 
Coexisting viral infection.
 
Slow acetylator phenotype.
 
Atopic diathesis.
 
Clinical manifestations
Differentiate:
 
Pharmacologic toxicity: blood dyscrasias associated with folate deficiency, renal tubular acidosis, nausea and vomiting, headache and neurological disturbances, hypoglycemia, goitrogenic effects.
 
Intrinsic toxicity: renal toxicity, methaemoglobinaemia, keratoconjunctivitis sicca.
 
Idiosyncratic or hypersensitivity toxicity:
 
1 Sulfonamide allergy (rare).

Anaphylactic shock.

Bronchospasm.

Urticaria, rash.
 
2 Sulfonamide hypersensitivity reactions (AIDS).

Occurring 7-12 days after starting treatment.
 
Cutaneous rash: erythematous, maculopapular, pruritis, most prominent on the body and upper limbs.
 
Fever.
 
Anicteric hepatitis.
 
Acute interstitial pneumonitis.
 
Aseptic meningitis, myocarditis, serum sickness, uveitis, eosinophilia, leukocytosis.
 
Other cutaneous manifestations: erythema nodosum, erythema multiforme, lupus erythematosus, toxic epidermal necrolysis.
 
Diagnostic methods (in immediate type I reactions)
Cutaneous testing
 
Skin-prick tests with SMX-poly-L-tyrosine up to 1 mg/ ml.
 
Intradermal skin-tests with SMX-poly-L-tyrosine 0.03 mg/ ml.
 
27% positive in 44 patients with histories of allergic reaction to sulfamethoxazole. Inhibition of skin-test reactivity with a monovalent inhibitor.
 
Specific IgE anti -SMX (RAST and RAST inhibition).
 
Mechanisms
1° IgE-mediated hypersensitivity (rare).
 
positive skin-tests, specific IgE.
 
The major determinant is N4-sulfonamidyl group
 
2° Sulfonamide hypersensitivity reactions in AIDS patients.
 
SMX is either acetylated or hydroxylated at the N4 position to form: N4 acetyl SMX (45-70%) and N4 hydroxyl SMX (2-5%): SMX-HA.
 
The SMX-HA metabolic is believed to be critical in the pathogenesis of many of the SMX adverse effects.
 
SMX is oxidized to SMX-HA by the cytochrome P450 and by myeloperoxidase-dependent oxidation in neutrophils and macrophages/ monocytes.
 
SMX-HA auto-oxidizes to the more reactive nitroso metabolites with production of superoxide anion radicals.
 
Nitroso-SMX reacts with glutathione to form an unstable semimercaptal which is reduced back to SMX-HA in the presence of excess glutathione.
 
Slow acetylator phenotype is associated with a susceptibility to sulfonamide hypersensitivity reactions.
 
Glutathione protects against the toxicity of SMX-HA to isolated peripheral blood mononuclear cells by preventing its oxidation to nitroso SMX.
 
The nitroso SMX which covalently binds to proteins is the ultimate toxic metabolite.
 
This binding is inhibited by acetylation, reaction with glutathione or reduction back to SMX-HA and SMX.
 
In summary, high incidence of hypersensitivity reactions to sulfonamides in AIDS patients is probably multifactorial: high-dose regimens, altered immunological responses, altered pathways of drug metabolism.
 
There is no correlation between presence of anti-SMX-antibodies (IgG) and occurrence of adverse reaction, except thrombocytopenia.
 
Management
Cross-sensitivity between SMX-TMP and sulfadiazine is frequent.
 
There is no evident cross-reactivity between sulfonamide antimicrobials and sulfamide diuretics (furosemide, chlorothiazide, acetazolamide) ; hypoglycemics (tolbutanol, chlorpropanol) or antihypertensives (diazoxide).
 
Faced with hypersensitivity reaction to cotrimoxazole in AIDS patients, there are 3 possibilities:
  1. Treatment throughout the duration of hypersensitivity.

    The rash (general exanthema, pruritic or non-pruritic, fever) may be treatedsymptomatically with antihistamines and may resolve.
     
  2. Re-challenge

    A history of cutaneous rash is not a contra-indication to retreatment, since only 20 to 66% cutaneous reactions occur on re-challenge.
     
  3. Desensitization.

    Numerous studies, involving no more than 45 patients differed greatly with regard to the inclusion criteria, duration of the protocol, dose progression and success rate (33 to 96%). For example:

    Hours

    Dose of SMX-TMP (mg)

    D19 AM

    4-0.8

    11 AM

    8-1.6

    1 PM

    20-4

    5 PM

    40-8

    D29 AM

    80-16

    3 PM

    160-32

    9 PM

    200-40

    D39 AM

    400-80

Risk factor of desensitization failure: female sex.
 
Life-threatening reactions may occur during desensitization.

References

  1. Caumes E, Guermonprez G, Lecomte C, Katlama C, Bricaire F, "Efficacy and safety of desensitization with sulfamethoxazole and trimethoprim in 48 previously hypersensitive patients infected with human immunodeficiency virus", Arch. Dermatol., 1997 ; 133 (4): 465-9
  2. Cribb A.E, Lee B.L, Trepanier L.A, Spielberg S.P, "Adverse reactions to sulfonamide and sulfonamide-trimethoprim antimicrobials: clinical syndromes and pathogenesis", Adverse Drug. React. Toxicol. Rev., 1996 ; 15 (1): 9-50
  3. Carr A, Cooper D.A, "Pathogenesis and management of HIV-associated drug hypersensitivity", AIDS. Clin. Rev., 1995 - 96: 65-97
  4. Meekins C.V, Sullivan T.J, Gruchalla R.S, "Immunochemical analysis of su lfonamide drug allergy: identification of sulfamethoxazole-substituted human serum proteins", J. Allergy. Clin. Immunol, 1994 ; 94 (6.1): 1017-24
  5. Gruchalla R.S, Sullivan T.J, "Detection of human IgE to sulfamethoxazole by skin-testing with sulfamethoxazoyl-poly-L-tyrosine", J. Allergy. Clin. Immunol., 1991 ; 88 (5): 784-92

As in all diagnostic testing, the diagnosis is made by the physican based on both test results and the patient history.