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Potentiated Sulfonamide Antibiotics

Potentiated Sulfonamide Antibiotics

Lauren A. Trepanier , DVM, PhD, DACVIM, DACVCP, University of Wisconsin–Madison

Pharmacology & Medications

|May 2016|Peer Reviewed

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Overview

  • Potentiated sulfonamides are broad-spectrum antibacterial and antiprotozoal agents that inhibit bacterial folate synthesis and have been used for more than 50 years.
  • Because of associated adverse events, these drugs are predominantly used in veterinary medicine to treat resistant infections of the skin, urinary tract, or respiratory tree.

Toxicities

Dose Dependent

  • Keratoconjunctivitis sicca (KCS)  
    • Occurs in ≈15% of dogs1
    • May be reversible with early drug discontinuation2
  • Folate deficiency
    • Nonregenerative anemia, often normocytic and normochromic, with prolonged administration3
  • Drug-induced hypothyroidism
    • Antimicrobial sulfonamides reversibly inhibit thyroid peroxidase.4  
    • May interfere with thyroid hormone synthesis with prolonged high-dose administration (6 weeks) in dogs5
    • Clinical hypothyroidism can develop with chronic use.6

Idiosyncratic

  • Acute idiosyncratic toxicities (eg, drug hypersensitivity reactions) typically develop between 5 days and 4 weeks of treatment (median onset, 12 days).7
    • Clinical signs may be noted immediately after a 7- to 10-day course of sulfonamide antibiotic treatment.7
    • Signs can be seen earlier than 5 days in dogs previously exposed to potentiated sulfonamides.
  • Idiosyncratic sulfonamide reactions in dogs appear to be immune-mediated and caused by a reactive metabolite of the sulfonamide antibiotic that binds to tissue proteins and acts as a hapten.8
  • Incidence is unclear.
  • Clinical signs can include
    • Fever7
    • Blood dyscrasias7-9  
      • Regenerative immune-mediated thrombocytopenia
      • Immune-mediated hemolytic anemia
      • Transient neutropenia
    • Skin eruptions10
      • Range in severity from erythema and pruritus to toxic epidermal necrolysis
    • Acute hepatopathy
      • Often moderate-to-severe increases in ALT levels can occur in patients with acute parenchymal damage7
      • May also present with or progress to cholestatic changes (author’s observations)
    • Polyarthropathy11-17
      • Clinically resembles Lyme disease or primary immune- mediated polyarthropathy
        • Involves distal joints (eg, elbow, stifle, carpal, tarsal)
        • Nonseptic polyarthritis, with synovial fluid containing a predominance of nontoxic neutrophils without the presence of organisms
      • Improvement is seen 1 to 3 days after discontinuation of sulfonamide antibiotics, with or without glucocorticoid administration.
      • Doberman pinschers are overrepresented.11,12,18,19
        • Additional signs of lymphadenopathy, retinitis, protein-losing nephropathy, leukopenia, and modest thrombocytopenia may be seen.11
    • Proteinuria
      • May be severe but is rapidly reversible with drug discontinuation20

Client education is the most important monitoring tool, as idiosyncratic toxicities can develop acutely between routine rechecks.

Monitoring

  • Weekly baseline Schirmer tear test if treatment will extend beyond 10 days
    • Instruct owners to monitor daily for mucoid ocular discharge, redness, or blepharospasm.
  • Monitor for clinical signs of hypothyroidism if prolonged treatment (6 weeks or longer) is needed.
  • For administration longer than 3 weeks, consider monitoring CBC every 1 to 2 weeks and checking serum folate if new anemia is noted.
  • Instruct owners to monitor for signs of drug hypersensitivity, including
    • Pallor, petechiae, or fever
    • New or worsening skin lesions
    • Jaundice, GI upset, or dark urine
    • Shifting leg lameness
  • Client education is the most important monitoring tool, as idiosyncratic toxicities can develop acutely between routine rechecks.

Management of Adverse Events

  • At first signs of KCS, discontinue drug and treat patient with topical immunomodulator (eg, cyclosporine, tacrolimus) and artificial tears.
    • Sulfonamide-induced KCS is often reversible with early drug discontinuation.
  • Nonregenerative anemia associated with chronic use can be prevented by coadministration of folinic (but not folic) acid.
  • Because idiosyncratic toxicities do not respond to dose reduction, discontinue sulfonamide antibiotic at first sign of a potential adverse event.
    • Evaluate patient as soon as possible.
    • Include careful examination for ocular lesions, petechiae, jaundice, skin eruptions, joint effusion, hematuria, melena, and oral or mucocutaneous ulcerations.
    • Screen with CBC, serum chemistry profile, and urinalysis.
    • Consider treating with glutathione precursor (eg, oral S-adenosylmethionine [SAMe], IV N-acetylcysteine) to help decrease haptenization of the reactive sulfonamide metabolite.
    • If response to drug discontinuation and glutathione precursors is poor after 24 to 48 hours, consider short course of immunosuppressive glucocorticoids.
  • Although dogs with thrombocytopenia or hepatopathies have a more guarded outcome, even those with severe clinical manifestations can survive with good clinical support.7

All potentiated sulfonamide antibiotics commercially available in the United States have been implicated in cases of sulfonamide hypersensitivity.

Reexposure Risk

  • All potentiated sulfonamide antibiotics commercially available in the United States have been implicated in cases of sulfonamide hypersensitivity.
    • Trimethoprim–sulfadiazine
    • Ormetoprim–sulfadimethoxine  
    • Trimethoprim–sulfamethoxazole (human generic formulations)
  • There is no evidence of cross-reactivity with other sulfonamide-containing drugs that have different underlying structures (eg, acetazolamide, furosemide, glipizide, hydrochlorothiazide).21,22  
    • Drug hypersensitivity to sulfonamide antibiotics is mediated by a different part of the molecule (ie, an arylamine ring) and not by the sulfonamide moiety.
    • No evidence supports avoidance of nonantibiotic sulfonamides in dogs with a history of idiosyncratic toxicity to potentiated sulfonamide antibiotics.21,22

ALT = alanine aminotransferase, KCS = keratoconjunctivitis sicca, SAMe = S-adenosylmethionine

References and Author Information

For global readers, a calculator to convert laboratory values, dosages, and other measurements to SI units can be found here.

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