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LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012-.

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LiverTox®: Clinical and Research Information on Drug-Induced Liver Injury [Internet].

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Sulfadiazine

, MD.

Author Information and Affiliations

Last Update: January 15, 2026.

OVERVIEW

Introduction

Sulfadiazine is a sulfonamide antibacterial agent used in the therapy of mild-to-moderate infections due to sensitive organisms. Sulfadiazine, like other sulfonamides, is a well known cause of clinically apparent, idiosyncratic liver injury.

Background

Sulfadiazine (sul" fa dye' a zeen) is an orally administered sulfonamide antibiotic that acts by inhibition of folic acid synthesis, which is required for bacterial replication and growth. Different forms of sulfonamides have been used in clinical medicine since the 1930s. Sulfadiazine was approved for use in the United States in 1973. Current indications are many and include urinary tract infections and otitis media due to sensitive organisms. Sulfadiazine is also used as prophylaxis against rheumatic fever and meningococcal meningitis. It is used in combination with pyrimethamine for prevention and treatment of toxoplasmosis and is also effective in nocardiosis, chancroid, and trachoma. It is used as adjunctive therapy for chloroquine-resistant malaria and several forms of bacterial meningitis. Sulfadiazine is now infrequently used for common infections, other agents with safer profiles and wider antibiotic activity are generally preferred. Sulfadiazine is available in multiple generic forms in tablets of 500 mg. For urinary tract infections, the usual dose is 2 to 4 grams daily in 3 to 6 divided doses. Topical forms of sulfadiazine are available and used frequently for prophylaxis and treatment of burns and major wounds. Sulfadiazine is usually well tolerated but has many reported adverse side effects including fatigue, weakness, insomnia, dizziness, headache, nausea, diarrhea, and rash. Rare but potential severe adverse events include hypersensitivity reactions, drug rashes, Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), Stevens-Johnson syndrome, toxic epidermal necrolysis, aplastic anemia, agranulocytosis, thrombocytopenia, anaphylaxis, shock, Clostridioides difficile associated diarrhea, and embryo-fetal toxicity.

Hepatotoxicity

Sulfadiazine, like other sulfonamides, causes a characteristic idiosyncratic liver injury which has features of drug-allergy or hypersensitivity. The typical onset is sudden development of fever and rash followed by jaundice within a few days or weeks of starting the medication. The pattern of injury is typically mixed, although fatal cases are often hepatocellular and prolonged cholestatic cases have also been described. Eosinophilia or atypical lymphocytosis are also common and the clinical pattern can be considered a part of DRESS syndrome (drug rash with eosinophilia and systemic symptoms). Cases of Stevens Johnson syndrome due to sulfadiazine have also been described. Sulfonamides such as sulfadiazine have been linked to many cases of acute liver failure and as a class, the sulfonamides still rank in the top 5 to 10 causes of drug induced, idiosyncratic fulminant hepatic failure. However, most cases of sulfonamide induced liver injury resolve rapidly, usually within 2 to 4 weeks unless cholestasis is severe. Onset of injury is more rapid with rechallenge and can appear within a day or reexposure. Patients with hepatic injury due to sulfadiazine may have a history of previous exposure to the drug without injury. Sulfonamides such as sulfadiazine can also cause mild and transient ALT elevations that do not progress to jaundice or more severe liver injury either alone or as a part of a generalized hypersensitivity reaction. Sulfonamides have also been linked to hepatic granulomas.

Likelihood score: A (probable cause of clinically apparent acute liver injury)

Mechanism of Injury

The clinical pattern of injury with sulfadiazine suggests a drug-allergy or hypersensitivity mechanism, perhaps through its metabolism to a toxic, reactive or antigenic metabolite.

Outcome and Management

Sulfadiazine induced liver injury ranges in severity from anicteric and asymptomatic liver enzyme elevations, to symptomatic hepatitis with jaundice to severe acute hepatic failure. Sulfadiazine hepatotoxicity can result in acute liver failure, but most cases resolve rapidly with discontinuation of drug and full recovery is expected within 2 to 8 weeks. Severe cholestatic injury may be prolonged, and rare cases of chronic liver injury with vanishing bile duct syndrome due to sulfadiazine have been reported. The hepatic injury due to sulfonamides is usually a part of systemic hypersensitivity reaction. Rechallenge should not be done, and patients should be told that they are allergic to sulfonamides (“sulfa-drugs”) and not receive other drugs in this class. Prednisone has been used with variable success, but may be particularly helpful in patients with prominent allergic features with systemic features and fever, rash, lymphadenopathy and eosinophilia or atypical lymphocytosis.

References to the safety and potential hepatotoxicity of sulfadiazine are given in the Overview on Sulfonamides.

Drug Class: Antiinfective Agents, Sulfonamides

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Sulfadiazine – Generic, Microsulfon®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Sulfadiazine 68-35-9 C10-H10-N4-O2-S image 134971211 in the ncbi pubchem database

ANNOTATED BIBLIOGRAPHY

References updated: 15 January 2026

Abbreviations: TMP-SMZ, trimethoprim and sulfamethoxazole; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens Johnson syndrome; TEN, toxic epidermal necrolysis; iv, intravenous; HLA, human leukocyte antigen.

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    (Expert review of the sulfonamides and sulfones published in 1999; sulfonamides are thought to cause clinically apparent liver injury in 0.5-1.0% of recipients generally with a sudden onset within 14 days of starting, often with immunoallergic features and a hepatocellular or mixed pattern of injury; mortality may be as high as 10%).
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    (Survey of a Health Management Organization admissions over 5 years identified only 12 cases of drug induced liver injury, 1 due to sulfonamides [1:6400 exposures] and one to TMP-SMZ [1:12,706 exposures]).
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    (Adverse drug reaction reports in Denmark from 1978 to 1987; 62 cases [5%] were attributed to either TMP-SMZ or SMZ alone).
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    (Survey of 108 AIDs patients for history of allergic reactions to antibiotics, 39% reported allergy to sulfonamides, often cross reactive, but not always [dapsone vs TMP-SMZ]).
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    (In Medicaid records between 1980-87, 107 patients were hospitalized for acute hepatitis of unknown cause, 8 had received TMP-SMZ, estimated risk from sulfonamides was <1 per 100,000 prescriptions).
  • George DK, Crawford DH. Antibacterial-induced hepatotoxicity. Incidence, prevention and management. Drug Saf 1996; 15: 79-85. [PubMed: 8862966]
    (Review of hepatotoxicity from antibiotics including sulfonamides indicating that transient increases in aminotransferase levels occur in 10% of patients, but that clinical liver injury is rare, in one study <1,100,000 prescriptions).
  • Pillans PI. Drug associated hepatic reactions in New Zealand: 21 years’ experience. N Z Med J 1996; 109: 315-9. [PubMed: 8816722]
    (Adverse drug reaction reports identified 943 liver injuries over 21 years in New Zealand; TMP-SMZ accounted for 29 (ranking 9th), 1 case being fatal).
  • Cribb AE, Pohl LR, Spielberg SP, Leeder JS. Patients with delayed-onset sulfonamide hypersensitivity reactions have antibodies recognizing endoplasmic reticulum luminal proteins. J Pharmacol Exp Ther 1997; 282: 1064-71. [PubMed: 9262376]
    (Comprehensive review of the major and minor side effects of sulfonamides including discussion of mechanisms).
  • Sgro C, Clinard F, Ouazir K, Chanay H, Allard C, Guilleminet C, Lenoir C, et al. Incidence of drug-induced hepatic injuries: a French population-based study. Hepatology 2002; 36: 451-5. [PubMed: 12143055]
    (All adverse drug reactions from French region from 1997-2000 found 34 cases of liver injury, 40 drugs involved, 2 possibly due to sulfasalazine).
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    (Review of mechanisms of hypersensitivity to sulfonamides).
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    (Among ~50,000 liver transplants done in the US between 1990 and 2002, 270 [0.5%] were done for drug induced acute liver failure, 3 of which were attributed to sulfasalazine and 1 to TMP-SMZ).
  • Björnsson E, Jerlstad P, Bergqvist A, Olsson R. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-101. [PubMed: 16165719]
    (Among 103 cases of fulminant drug induced liver injury reported to a Swedish registry between 1966 and 2002, 6 cases were attributed to TMP-SMZ, 3 to sulfonamides and 1 to sulfasalazine [~10% overall]).
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    (Reports to a Spanish network between 1994-2004, included 461 cases of drug induced liver disease; sulfonamides were not mentioned in the top 19 causes [drugs with 5 or more cases]).
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    (Among 103 cases of fulminant drug induced liver injury reported to a Swedish registry between 1966 and 2002, 6 cases were attributed to TMP-SMZ, 3 to sulfonamides and 1 to sulfasalazine [~10% overall]).
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    (Survey of drug induced liver fatalities reported to WHO database between 1968-2003 revealed 4690 reports – 89% from the US; 21 drugs were associated with more than 50 cases each, including TMP-SMZ [ranking 10th]).
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    (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 9 were due to TMP-SMZ, which ranked 4th as a cause).
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    (313 cases of drug induced liver injury were seen over a 12 year period at a large hospital in Bangalore, India; dapsone accounted for 17 cases [5.4%] of which 2 were fatal, and TMP-SMZ accounted for 7 cases [2.2%], but none were fatal).
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    (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury including 12 due to sulfonamides [9%], 9 due to SMZ/TMP, and 3 due to sulfasalazine).
    Molleston JP, Fontana RJ, Lopez MJ, Kleiner DE, Gu J, Chalasani N; for the Drug-Induced Liver Injury Network. Characteristics of idiosyncratic drug-induced liver injury in children: results from the DILIN Prospective Study. J Pediatr Gastroenterol Nutr 2011; 53: 182-189. PMID: 25188760.
    (Among 30 children with drug induced liver injury enrolled in a prospective US database between 2004 and 2008, 15 were due to antibiotics including 1 from sulfamethoxazole).
  • Devarbhavi H, Karanth D, Prasanna KS, Adarsh CK, Patil M. Drug-Induced liver injury with hypersensitivity features has a better outcome: a single-center experience of 39 children and adolescents. Hepatology 2011; 54: 1344-50. [PubMed: 21735470]
    (Between 1997 and 2010, 450 cases of drug induced liver injury were seen at a single center in India, including 45 cases in children [9%], among whom the most common causes were antituberculosis drugs [n=22, 50% mortality], anticonvulsants [phenytoin 10, carbamazepine 6], and dapsone 4; others included 1 case each due to TMP-SMZ, ciprofloxacin, amoxicillin and Ayuryedic agents).
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    (Review of clinical features of DRESS syndrome in French).
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    (In a population-based study of drug induced liver injury from Iceland, 96 cases were identified over a 2-year period, including 2 that were attributed to TMP-SMZ).
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    (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, including 39 attributed to antimicrobial agents, but none to TMP-SMZ).
  • Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]
    (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 31 cases were attributed to TMP-SMZ and 2 cases to dapsone).
  • Chalasani N, Reddy KRK, Fontana RJ, Barnhart H, Gu J, Hayashi PH, Ahmad J, et al. Idiosyncratic drug induced liver injury in African-Americans is associated with greater morbidity and mortality compared to Caucasians. Am J Gastroenterol 2017; 112: 1382-8. [PMC free article: PMC5667647] [PubMed: 28762375]
    (Among 985 patients enrolled in a US prospective database of drug induced liver injury between 2004 and 2016, SMZ-TMP was the most implicated medication among 144 African Americans [7.6%], but ranked fifth among 841 Caucasians [3.6%] behind amoxicillin-clavulanate, nitrofurantoin, anabolic steroids and isoniazid).
  • Ferrajolo C, Verhamme KM, Trifirò G, 't Jong GW, Picelli G, Giaquinto C, Mazzaglia G, et al. Antibiotic-induced liver injury in paediatric outpatients: a case-control study in primary care databases. Drug Saf 2017; 40: 305-15. [PMC free article: PMC5362651] [PubMed: 28025733]
    (In a case control study from a large population-based database from Europe, sulfonamides were being used in 0.5% of children with new-onset, unexplained acute liver injury compared to 0.1% of controls yielding an adjusted odds ratio of 24.2).
  • Casoy J, Nascimento H, Silva LMP, Fernández-Zamora Y, Muccioli C, Dias JRO, Nóbrega MJ, et al. Effectiveness of treatments for ocular toxoplasmosis. Ocul Immunol Inflamm. 2020;28:249-255.. [PubMed: 30806556]
    (Among 451 Brazilian patients with ocular toxoplasmosis treated between 2013 and 2017 with either SMZ-TMP or sulfadiazine and pyrimethamine or both, successful outcomes occurred in 97% while adverse events were reported in 10% which included maculopapular rash in 4%, ALT or AST elevations in 0.4%, and Stevens Johnson syndrome in 1 patient [0.2%], no details provided).
  • Fontana RJ, Kleiner DE, Chalasani N, Bonkovsky H, Gu J, Barnhart H, Li YJ, et al. The impact of patient age and corticosteroids in patients with sulfonamide hepatotoxicity. Am J Gastroenterol. 2023;118:1566-1575.. [PMC free article: PMC10511659] [PubMed: 36848311]
    (Among 105 cases of sulfonamide-induced liver injury enrolled in a prospective U.S. database between 2004 and 2020, 93 were attributed to TNP-SMZ, 9 to sulfasalazine, 2 to dapsone, and only 1 to sulfadiazine).
  • Casado FC, Samper AD. Sulfonamide allergy and alternative treatments in ocular toxoplasmosis. Rom J Ophthalmol. 2025;69:147-157. [PMC free article: PMC12277979] [PubMed: 40698108]
    (The first line therapy of ocular toxoplasmosis is either TMP-SMZ or pyrimethamine-sulfadiazine but for the 3% to 8% of patients who are allergic to sulfonamides, alternatives include clindamycin or azithromycin both of which are similarly effective).
  • West W 3rd, Buller KT, McArthur M, Wright B, Bodnar M, Marek JC, Smith DJ, et al. a retrospective review of silver sulfadiazine use in patients with sulfa-allergic burns at a regional burn center. Cureus. 2025;17:e84360. [PMC free article: PMC12174480] [PubMed: 40535410]
    (Among 71 patients cared for in a referral burn center who gave a history of sulfa allergy but were nevertheless treated with topical silver sulfadiazine for burn management, none suffered an allergic local or systemic reaction).
  • Bessone F, Hernandez N, Medina-Caliz I, García-Cortés M, Schinoni MI, Mendizabal M, Chiodi D, et al. Drug-induced liver injury in Latin America: 10-year experience of the Latin American DILI (LATINDILI) Network. Clin Gastroenterol Hepatol. 2025;23:89-102.. [PubMed: 38992407]
    (Among 483 cases of drug-induced liver injury enrolled in a prospective Latin American database, only 3 were attributed to TMP-SMZ, 3 to sulfadiazine, 2 to dapsone, and one to sulfasalazine).
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