Trimethoprim-Sulfamethoxazole for Skin and Soft Tissue Infections—Let Us Not Forget the Risks

Abstract

In the emergency department (ED), treatment of skin infections with trimethoprim-sulfamethoxazole has markedly increased1Pallin D.J. Egan D.J. Pelletier A.J. et al.Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant.Staphylococcus aureus. Ann Emerg Med. 2008; 51: 291-298Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar and trimethoprim-sulfamethoxazole–related adverse events have become more frequent.2Goldman J.L. Jackson M.A. Herigon J.C. et al.Trends in adverse reactions to trimethoprim-sulfamethoxazole.Pediatrics. 2013; 131: e103-e108Crossref PubMed Scopus (17) Google Scholar We report a case of severe hyperkalemia associated with trimethoprim-sulfamethoxazole prescribed for a possible wound infection, highlighting the need for ED providers to recognize and mitigate the risks associated with this antibiotic.CaseAn 83-year-old woman with chronic cardiopulmonary disease and diabetes mellitus presented for evaluation of a 2- to 3-cm wound on her lower extremity. The assessment was a “laceration which may have early signs of cellulitis.” The treatment plan included local wound care, elevation, and trimethoprim-sulfamethoxazole 160 mg/800 mg orally twice daily for 10 days. Notable concomitant medications included lisinopril, spironolactone, and furosemide. Laboratory values 5 weeks before included a serum potassium level of 5.2 mEq/L and creatinine level of 1.1 mg/dL (clearance ≈28 mL/minute).Nine days later, routine laboratory monitoring revealed a serum potassium level of 7.5 mEq/L and creatinine level of 1.7 mg/dL, necessitating admission to the ICU. The elevated potassium and creatinine rapidly normalized with medical therapy and discontinuation of trimethoprim-sulfamethoxazole, lisinopril, and spironolactone.Since the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), trimethoprim-sulfamethoxazole has become the most frequently prescribed antibiotic for skin infections.1Pallin D.J. Egan D.J. Pelletier A.J. et al.Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant.Staphylococcus aureus. Ann Emerg Med. 2008; 51: 291-298Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Hyperkalemia is a well-known adverse effect of trimethoprim-sulfamethoxazole, with risk factors including older age, higher trimethoprim-sulfamethoxazole doses, renal insufficiency, and concomitant use of medications that increase serum potassium levels such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics.4Antoniou T. Gomes T. Juurlink D.N. et al.Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study.Arch Intern Med. 2010; 170: 1045-1049Crossref PubMed Scopus (92) Google Scholar, 5Antoniou T. Gomes T. Mamdani M.M. et al.Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.BMJ. 2011; 343: d5228Crossref PubMed Scopus (51) Google ScholarTrimethoprim-sulfamethoxazole is associated with numerous other potential drug interactions. Among these, trimethoprim-sulfamethoxazole potentiates the effect of warfarin, leading to an elevation in the international normalized ratio. Trimethoprim-sulfamethoxazole also interacts with sulfonylureas (increased hypoglycemic effect) and increases serum concentrations of digoxin and phenytoin. Drug interactions should therefore always be considered before trimethoprim-sulfamethoxazole is prescribed.The majority of patients treated with trimethoprim-sulfamethoxazole experience a transient decrease in creatinine clearance; the resultant increase in serum creatinine level is not usually indicative of reduced glomerular filtration. However, acute kidney injury is a recognized complication of trimethoprim-sulfamethoxazole. Most cases of acute kidney injury are caused by acute interstitial nephritis and are usually reversible on discontinuation of trimethoprim-sulfamethoxazole.6Fraser T.N. Avellaneda A.A. Graviss E.A. et al.Acute kidney injury associated with trimethoprim/sulfamethoxazole.J Antimicrob Chemother. 2012; 67: 1271-1277Crossref PubMed Scopus (71) Google ScholarIn the case described herein, trimethoprim-sulfamethoxazole was a suboptimal choice in light of the patient's numerous risk factors for hyperkalemia, including advanced age, use of lisinopril and spironolactone, renal insufficiency, and a recent elevated potassium level. The relatively long duration (10 days) of trimethoprim-sulfamethoxazole may have been a contributing factor. Such prolonged treatment courses are frequently prescribed3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar despite that a treatment duration as short as 5 days is supported by national guidelines.7Liu C. Bayer A. Cosgrove S.E. et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.Clin Infect Dis. 2011; 52: 285-292Crossref PubMed Scopus (1253) Google ScholarThe use of combination therapy with trimethoprim-sulfamethoxazole and a β-lactam in the treatment of skin infections has become common in the era of community-associated MRSA.3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This presumably reflects the desire to adequately cover both MRSA and β-hemolytic streptococci. However, a recent trial of outpatients with cellulitis demonstrated that trimethoprim-sulfamethoxazole plus cephalexin did not improve outcomes compared with cephalexin alone, suggesting combination therapy may not be warranted.8Pallin D.J. Binder W.D. Allen M.B. et al.Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial.Clin Infect Dis. 2013; 56: 1754-1762Crossref PubMed Scopus (100) Google ScholarIn summary, increasing use of trimethoprim-sulfamethoxazole for skin infections has led to an increase in adverse events. To prevent complications of trimethoprim-sulfamethoxazole, ED providers must recognize risk factors and potential drug interactions and use alternative agents when appropriate, prescribe shorter courses of therapy, and avoid unnecessary combination therapy. In the emergency department (ED), treatment of skin infections with trimethoprim-sulfamethoxazole has markedly increased1Pallin D.J. Egan D.J. Pelletier A.J. et al.Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant.Staphylococcus aureus. Ann Emerg Med. 2008; 51: 291-298Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar and trimethoprim-sulfamethoxazole–related adverse events have become more frequent.2Goldman J.L. Jackson M.A. Herigon J.C. et al.Trends in adverse reactions to trimethoprim-sulfamethoxazole.Pediatrics. 2013; 131: e103-e108Crossref PubMed Scopus (17) Google Scholar We report a case of severe hyperkalemia associated with trimethoprim-sulfamethoxazole prescribed for a possible wound infection, highlighting the need for ED providers to recognize and mitigate the risks associated with this antibiotic. CaseAn 83-year-old woman with chronic cardiopulmonary disease and diabetes mellitus presented for evaluation of a 2- to 3-cm wound on her lower extremity. The assessment was a “laceration which may have early signs of cellulitis.” The treatment plan included local wound care, elevation, and trimethoprim-sulfamethoxazole 160 mg/800 mg orally twice daily for 10 days. Notable concomitant medications included lisinopril, spironolactone, and furosemide. Laboratory values 5 weeks before included a serum potassium level of 5.2 mEq/L and creatinine level of 1.1 mg/dL (clearance ≈28 mL/minute).Nine days later, routine laboratory monitoring revealed a serum potassium level of 7.5 mEq/L and creatinine level of 1.7 mg/dL, necessitating admission to the ICU. The elevated potassium and creatinine rapidly normalized with medical therapy and discontinuation of trimethoprim-sulfamethoxazole, lisinopril, and spironolactone.Since the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), trimethoprim-sulfamethoxazole has become the most frequently prescribed antibiotic for skin infections.1Pallin D.J. Egan D.J. Pelletier A.J. et al.Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant.Staphylococcus aureus. Ann Emerg Med. 2008; 51: 291-298Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Hyperkalemia is a well-known adverse effect of trimethoprim-sulfamethoxazole, with risk factors including older age, higher trimethoprim-sulfamethoxazole doses, renal insufficiency, and concomitant use of medications that increase serum potassium levels such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics.4Antoniou T. Gomes T. Juurlink D.N. et al.Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study.Arch Intern Med. 2010; 170: 1045-1049Crossref PubMed Scopus (92) Google Scholar, 5Antoniou T. Gomes T. Mamdani M.M. et al.Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.BMJ. 2011; 343: d5228Crossref PubMed Scopus (51) Google ScholarTrimethoprim-sulfamethoxazole is associated with numerous other potential drug interactions. Among these, trimethoprim-sulfamethoxazole potentiates the effect of warfarin, leading to an elevation in the international normalized ratio. Trimethoprim-sulfamethoxazole also interacts with sulfonylureas (increased hypoglycemic effect) and increases serum concentrations of digoxin and phenytoin. Drug interactions should therefore always be considered before trimethoprim-sulfamethoxazole is prescribed.The majority of patients treated with trimethoprim-sulfamethoxazole experience a transient decrease in creatinine clearance; the resultant increase in serum creatinine level is not usually indicative of reduced glomerular filtration. However, acute kidney injury is a recognized complication of trimethoprim-sulfamethoxazole. Most cases of acute kidney injury are caused by acute interstitial nephritis and are usually reversible on discontinuation of trimethoprim-sulfamethoxazole.6Fraser T.N. Avellaneda A.A. Graviss E.A. et al.Acute kidney injury associated with trimethoprim/sulfamethoxazole.J Antimicrob Chemother. 2012; 67: 1271-1277Crossref PubMed Scopus (71) Google ScholarIn the case described herein, trimethoprim-sulfamethoxazole was a suboptimal choice in light of the patient's numerous risk factors for hyperkalemia, including advanced age, use of lisinopril and spironolactone, renal insufficiency, and a recent elevated potassium level. The relatively long duration (10 days) of trimethoprim-sulfamethoxazole may have been a contributing factor. Such prolonged treatment courses are frequently prescribed3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar despite that a treatment duration as short as 5 days is supported by national guidelines.7Liu C. Bayer A. Cosgrove S.E. et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.Clin Infect Dis. 2011; 52: 285-292Crossref PubMed Scopus (1253) Google ScholarThe use of combination therapy with trimethoprim-sulfamethoxazole and a β-lactam in the treatment of skin infections has become common in the era of community-associated MRSA.3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This presumably reflects the desire to adequately cover both MRSA and β-hemolytic streptococci. However, a recent trial of outpatients with cellulitis demonstrated that trimethoprim-sulfamethoxazole plus cephalexin did not improve outcomes compared with cephalexin alone, suggesting combination therapy may not be warranted.8Pallin D.J. Binder W.D. Allen M.B. et al.Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial.Clin Infect Dis. 2013; 56: 1754-1762Crossref PubMed Scopus (100) Google ScholarIn summary, increasing use of trimethoprim-sulfamethoxazole for skin infections has led to an increase in adverse events. To prevent complications of trimethoprim-sulfamethoxazole, ED providers must recognize risk factors and potential drug interactions and use alternative agents when appropriate, prescribe shorter courses of therapy, and avoid unnecessary combination therapy. An 83-year-old woman with chronic cardiopulmonary disease and diabetes mellitus presented for evaluation of a 2- to 3-cm wound on her lower extremity. The assessment was a “laceration which may have early signs of cellulitis.” The treatment plan included local wound care, elevation, and trimethoprim-sulfamethoxazole 160 mg/800 mg orally twice daily for 10 days. Notable concomitant medications included lisinopril, spironolactone, and furosemide. Laboratory values 5 weeks before included a serum potassium level of 5.2 mEq/L and creatinine level of 1.1 mg/dL (clearance ≈28 mL/minute). Nine days later, routine laboratory monitoring revealed a serum potassium level of 7.5 mEq/L and creatinine level of 1.7 mg/dL, necessitating admission to the ICU. The elevated potassium and creatinine rapidly normalized with medical therapy and discontinuation of trimethoprim-sulfamethoxazole, lisinopril, and spironolactone. Since the emergence of community-associated methicillin-resistant Staphylococcus aureus (MRSA), trimethoprim-sulfamethoxazole has become the most frequently prescribed antibiotic for skin infections.1Pallin D.J. Egan D.J. Pelletier A.J. et al.Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant.Staphylococcus aureus. Ann Emerg Med. 2008; 51: 291-298Abstract Full Text Full Text PDF PubMed Scopus (362) Google Scholar, 3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar Hyperkalemia is a well-known adverse effect of trimethoprim-sulfamethoxazole, with risk factors including older age, higher trimethoprim-sulfamethoxazole doses, renal insufficiency, and concomitant use of medications that increase serum potassium levels such as angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and potassium-sparing diuretics.4Antoniou T. Gomes T. Juurlink D.N. et al.Trimethoprim-sulfamethoxazole-induced hyperkalemia in patients receiving inhibitors of the renin-angiotensin system: a population-based study.Arch Intern Med. 2010; 170: 1045-1049Crossref PubMed Scopus (92) Google Scholar, 5Antoniou T. Gomes T. Mamdani M.M. et al.Trimethoprim-sulfamethoxazole induced hyperkalaemia in elderly patients receiving spironolactone: nested case-control study.BMJ. 2011; 343: d5228Crossref PubMed Scopus (51) Google Scholar Trimethoprim-sulfamethoxazole is associated with numerous other potential drug interactions. Among these, trimethoprim-sulfamethoxazole potentiates the effect of warfarin, leading to an elevation in the international normalized ratio. Trimethoprim-sulfamethoxazole also interacts with sulfonylureas (increased hypoglycemic effect) and increases serum concentrations of digoxin and phenytoin. Drug interactions should therefore always be considered before trimethoprim-sulfamethoxazole is prescribed. The majority of patients treated with trimethoprim-sulfamethoxazole experience a transient decrease in creatinine clearance; the resultant increase in serum creatinine level is not usually indicative of reduced glomerular filtration. However, acute kidney injury is a recognized complication of trimethoprim-sulfamethoxazole. Most cases of acute kidney injury are caused by acute interstitial nephritis and are usually reversible on discontinuation of trimethoprim-sulfamethoxazole.6Fraser T.N. Avellaneda A.A. Graviss E.A. et al.Acute kidney injury associated with trimethoprim/sulfamethoxazole.J Antimicrob Chemother. 2012; 67: 1271-1277Crossref PubMed Scopus (71) Google Scholar In the case described herein, trimethoprim-sulfamethoxazole was a suboptimal choice in light of the patient's numerous risk factors for hyperkalemia, including advanced age, use of lisinopril and spironolactone, renal insufficiency, and a recent elevated potassium level. The relatively long duration (10 days) of trimethoprim-sulfamethoxazole may have been a contributing factor. Such prolonged treatment courses are frequently prescribed3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar despite that a treatment duration as short as 5 days is supported by national guidelines.7Liu C. Bayer A. Cosgrove S.E. et al.Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children: executive summary.Clin Infect Dis. 2011; 52: 285-292Crossref PubMed Scopus (1253) Google Scholar The use of combination therapy with trimethoprim-sulfamethoxazole and a β-lactam in the treatment of skin infections has become common in the era of community-associated MRSA.3Hurley H.J. Knepper B.C. Price C.S. et al.Avoidable antibiotic exposure for uncomplicated skin and soft tissue infections in the ambulatory care setting.Am J Med. 2013; 126: 1099-1106Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar This presumably reflects the desire to adequately cover both MRSA and β-hemolytic streptococci. However, a recent trial of outpatients with cellulitis demonstrated that trimethoprim-sulfamethoxazole plus cephalexin did not improve outcomes compared with cephalexin alone, suggesting combination therapy may not be warranted.8Pallin D.J. Binder W.D. Allen M.B. et al.Clinical trial: comparative effectiveness of cephalexin plus trimethoprim-sulfamethoxazole versus cephalexin alone for treatment of uncomplicated cellulitis: a randomized controlled trial.Clin Infect Dis. 2013; 56: 1754-1762Crossref PubMed Scopus (100) Google Scholar In summary, increasing use of trimethoprim-sulfamethoxazole for skin infections has led to an increase in adverse events. To prevent complications of trimethoprim-sulfamethoxazole, ED providers must recognize risk factors and potential drug interactions and use alternative agents when appropriate, prescribe shorter courses of therapy, and avoid unnecessary combination therapy.