Potentiated Sulfonamide Antibiotics

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.<sup4  sup>  

  • 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 dyscrasias^7-9  

    • 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)

  • Polyarthropathy^11-17

    • 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

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

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).<sup21,22  sup>  

  • 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