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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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Trimethoprim-Sulfamethoxazole

, MD.

Author Information and Affiliations

Last Update: January 15, 2026.

OVERVIEW

Introduction

Sulfamethoxazole with trimethoprim is an oral, fixed dose combination of antibiotics that is widely used in short term courses for mild-to-moderate bacterial infections and chronically as prophylaxis against opportunistic infections. Like other sulfonamide-containing medications, this combination is a well-known, although rare cause of clinically apparent acute liver injury which can be severe and even fatal.

Background

Trimethoprim-sulfamethoxazole (TMP-SMZ) is an oral, fixed dose combination of two antibiotics, a sulfonamide and a methoprim. This combination is widely used as therapy of acute infections due to susceptible bacteria as well as chronically for prevention of opportunistic infections with Pneumocystis jirovecii (formerly carinii) in immune deficient individuals. The two agents are synergistic in inhibition of folate synthesis – the sulfamethoxazole (sul" fa meth ox' a zole) inhibiting production of dihydrofolate from para-aminobenzoic acid, and the trimethoprim (trye meth' oh prim) inhibiting the next step in the pathway from dihydrofolate to tetrahydrofolate. TMP-SMZ was approved for use as a combination antibiotic in the United States in 1973 and is still in wide use, more than 4 million prescriptions being filled yearly. TMP-SMZ is recommended for use in adults and children for urinary tract infections, bronchitis, sinusitis, and otitis media and for prophylaxis against opportunistic infections due to parasites and pneumocystitis jirovecii. TMP-SMZ is available in multiple generic and trade formulations in tablets containing 80 or 160 mg of trimethoprim and 200, 400, or 800 mg of sulfamethoxazole. Trade names include Bactrim, Cotrim, and Septra. TMP-SMZ 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.

Trimethoprim is also available separately and is used as an antibiotic for uncomplicated urinary tract infections. Trimethoprim is a synthetic antifolate that acts on a late step in the pathway of folate synthesis. Trimethoprim has activity against many aerobic gram-negative organisms such as Escherichia coli, Kiebsiella pneumoniae, Proteus mirabilis and Enterobacter species. Resistance is common. Trimethoprim was approved for use in the United States in 1980, but is used much less frequently that TMP-SMZ. Trimethoprim is available in several generic forms in tablets of 100 mg and the usual oral adult dose regimen is 100 mg twice daily for 10 days. Trimethoprim is generally well tolerated; side effects can include nausea, abdominal upset, rash and pruritus.

Hepatotoxicity

TMP-SMZ is a well-known cause of acute drug-induced liver injury and typically has features suggestive of hypersensitivity much like other sulfonamides. In most recent case series from the United States and Europe, TMP-SMZ ranked among the top 5 causes of drug-induced idiosyncratic liver injury. The estimated incidence of liver injury after TMP-SMZ use ranges from 1 per 2,000 to 1 per 5,000 treated patients. The typical latency to onset is 2 to 8 weeks. Cases with shorter latencies are likely due to re-challenge after minor or forgotten toxicity with the previous exposures. At least half of cases are accompanied by signs and symptoms of hypersensitivity such as fever, rash, facial edema, lymphadenopathy, and peripheral eosinophilia (Case 1). Liver injury can be an accompanying finding in patients with DRESS syndrome, or more rarely, Stevens Johnson syndrome (SJS) or toxic epidermal necrosis (TEN). The most frequent pattern of initial enzyme elevations is mixed, but markedly cholestatic and markedly hepatocellular patterns occur. For unknown reasons, injury in children and young adults is more often hepatocellular, while cholestatic cases occur more frequently in the elderly. The course of the liver injury may be short-lived with rapid recovery or complicated and prolonged. Cases with cholestatic TMP-SMZ related liver injury are often prolonged and some are accompanied by varying degrees of bile duct injury and loss leading to vanishing bile duct syndrome and chronic cholestasis which, if severe, can lead to biliary cirrhosis, chronic liver failure, and death or need for liver transplantation. However, most cases of vanishing bile duct syndrome usually improve spontaneously over time, with gradual resolution of jaundice and symptoms, leaving minor alkaline phosphatase and GGT elevations that may persist for years.

As with other sulfonamides, TMP-SMZ can also cause acute hepatocellular injury that ranges in severity from mild (Case #2) to severe and can lead to acute liver failure and death (Case #3). Hepatocellular injury with jaundice is associated with a high mortality rate, and in large case series, TMP-SMZ ranks within the top 10 causes of drug induced, idiosyncratic fulminant hepatic failure. However, most hepatocellular injury cases resolve rapidly upon stopping the drug, usually within 2 to 4 weeks. TMP-SMZ can also cause mild to moderate elevations in ALT levels without jaundice and symptoms. TMP-SMZ liver injury with prominent symptoms or signs of hypersensitivity may be accompanied by hepatic granulomas on liver biopsy.

Clearly TMP-SMZ related liver injury presents in a wide spectrum of clinical phenotypes. Perhaps most characteristic is the sudden development of fever and rash followed a few days later by jaundice within a few weeks of starting the medication. Latencies longer than 8 weeks are rare even with chronic prophylactic use of TMP-SMZ.

Trimethoprim by itself is also capable of causing idiosyncratic, clinically apparent acute liver injury. The injury usually arises after 2 to 12 weeks of therapy and the typical pattern of serum enzyme elevations is mixed or cholestatic. Immunoallergic features are not common, which separates the typical hepatotoxicity of trimethoprim from that of sulfamethoxazole, the sulfonamide component of TMP-SMZ. In several instances, patients who have developed clinically apparent liver injury due to TMP-SMZ, have re-developed symptoms and laboratory abnormalities when treated with trimethoprim alone. Retreatment of patients after recovery with TMP-SMZ or with another sulfonamide should not be done, as several severe and fulminant cases of recurrence have been described after re-challenge.

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

Mechanism of Injury

The clinical pattern of injury with TMP-SMZ suggests a drug-allergy or hypersensitivity mechanism, perhaps through its metabolism to a toxic, reactive or antigenic metabolite. Adverse hypersensitivity-like reactions to TMP-SMZ are particularly common in HIV-infected individuals, toxicity requiring discontinuation developing in up to 75% of patients, with hepatic enzyme abnormalities in 20%. TMP-SMZ liver injury may be more frequent in persons of African ancestry in whom the HLA-B*35:01 allele appears to be a risk factor. In studies from the United States, African Americans appear to have a higher rate of immunoallergic forms of drug-induced liver injury and are at higher risk for liver injury from sulfonamides, allopurinol, phenytoin, carbamazepine, and lamotrigine than Americans of European ancestry.

Outcome and Management

TMP-SMZ induced liver injury varies greatly in severity, from mild, anicteric and self-limited liver enzyme elevations, to acute symptomatic hepatitis, to a prolonged cholestatic syndrome, and to acute liver failure. Most cases are self-limited and resolve rapidly with discontinuation of drug, with full recovery within 2 to 8 weeks. Severe cholestatic injury may be prolonged and rare cases of chronic liver injury with vanishing bile duct syndrome have been reported. The hepatic injury may be part of a systemic hypersensitivity reaction and categorized as DRESS syndrome. 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. Trimethoprim by itself can also cause acute liver injury and some patients have re-developed injury when switched from TMP-SMZ to trimethoprim alone. However, in most instances, the sulfonamide component of TMP-SMZ is the culprit. Prednisone has been used with variable success but may be helpful and speed clinical improvement in the allergic features of TMP-SMZ injury (rash, fever, eosinophilia), but has not been shown to ameliorate or shorten the degree of hepatic injury. Corticosteroids do not appear to benefit sulfonamide-induced cholestatic injury without allergic or hypersensitivity manifestations and demonstrate no evidence of benefit for the vanishing bile duct syndrome.

Drug Class: Antiinfective Agents, Sulfonamides

CASE REPORTS

Case 1. Cholestatic hepatitis due to TMP-SMZ.(1)

A 47 year old woman was treated with antihistamines and a 7 day course “double strength” trimethoprim-sulfamethoxazole (160 mg/800 mg: TMP-SMZ) for an upper respiratory tract infection. During the final days of treatment, she began to feel unwell and, despite stopping the medication, developed worsening fatigue, nausea and pruritus followed by dark urine, jaundice and right upper quadrant pain. Blood tests showed liver test abnormalities (Table) and she was hospitalized. She had severe itching but no rash or fever. Her liver was tender to palpation, and she was jaundiced. She had no history of liver disease, did not drink alcohol and had no risk factors for viral hepatitis. Her only medications were calcium and multivitamins. She had taken TMP/SMZ at least once in the past and was allergic to penicillin (rash). Tests for hepatitis A, B and C and for autoantibodies were negative. An abdominal ultrasound was normal. Blood counts showed mild eosinophilia. Her jaundice and symptoms rapidly improved and itching and liver test abnormalities resolved within a few weeks.

Key Points

Medication:Trimethoprim (160 mg)-sulfamethoxazole (800 mg)
Pattern:Cholestatic (R=0.6)
Severity:3+ (jaundiced, hospitalization)
Latency:One week
Recovery:Two weeks
Other medications:Multivitamins, calcium

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
6 days0773387.2TMP-SMZ Stopped
9 days2 days54301
10 days3 days5428110.2Hospitalized
11 days4 days472613.4Ultrasound normal
12 days5 days462522.3
18 days11 days341512.4Asymptomatic
6 months6 months14840.6
Normal Values <45 <130 <1.2

Comment

This patient developed a cholestatic hepatitis with minimal ALT elevations within a week of starting TMP-SMZ. She had a history of taking this medication in the past, but without apparent problems or hypersensitivity reactions. The liver injury was moderately severe but resolved rapidly beginning within 4 days of stopping the medication. Signs of hypersensitivity were mild, but the precipitous onset, peripheral eosinophilia, and rapid recovery fit the pattern of immunoallergic hepatitis due to sulfonamides.

Case 2. Hypersensitivity reaction and ALT elevations without jaundice attributed to TMP-SMZ.(1)

A 33 year old woman was treated with a 21 day course of trimethoprim-sulfamethoxazole (TMP-SMZ) (80 mg/400 mg) for sinusitis. One day after stopping therapy she developed a macular rash, fever, right upper quadrant abdominal pain and nausea. Three days later she was seen in an emergency room, found to have fever, rash and systemic symptoms, and was hospitalized (Table). She had elevations in ALT and alkaline phosphatase, but serum bilirubin levels remained in the normal range. She had no history of liver disease, high risk behaviors, or exposures to viral hepatitis. She drank little alcohol (1 to 2 drinks per week) and took no other medication except for multivitamins and an occasional ibuprofen. Blood counts were normal except for mild eosinophilia (7%). Tests for hepatitis A, B and C were negative as were autoantibodies. Ultrasound of the liver was normal without gallstones. Her fever and rash resolved and she was discharged with a diagnosis of sulfonamide hypersensitivity reaction. Liver tests fell into the normal range within 4 weeks on onset of symptoms.

Key Points

Medication:Trimethoprim (80 mg)-sulfamethoxazole (400 mg) (TMP-SMZ)
Pattern:Hepatocellular (R=14)
Severity:1+ (anicteric)
Latency:Three weeks
Recovery:Four weeks
Other medications:Multivitamins, ibuprofen

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
25 days4 days9811950.5Hospitalization
26 days5 days8052130.8Normal ultrasound
27 days6 days6233161.1Discharged
5 weeks12 days1563860.6Asymptomatic
6 weeks3 weeks491680.4
9 weeks5 weeks34770.4
Normal Values <45 <130 <1.2

Comment

This patient had a typical, but mild immunoallergic hepatitis with fever, rash, constitutional symptoms, eosinophilia, and ALT elevations, appearing within 3 weeks of starting TMP-SMZ and resolving rapidly once it was stopped. Despite the height to the ALT elevations, the liver injury was mild, minimally symptomatic, and not associated with jaundice or hepatic synthetic dysfunction. Some degree of ALT or alkaline phosphatase elevations is common in patients who have hypersensitivity reactions to sulfonamides and might be missed if blood testing is not done. This case might also qualify for the diagnosis of DRESS syndrome. The patient should be warned against future exposure to sulfonamides; with second exposures, the liver injury can become more acute and more severe.

Case 3. Acute liver failure due to TMP-SMZ.(1)

A 49 year old man developed jaundice within days of stopping a one week course of oral trimethoprim-sulfamethoxazole (TMP-SMZ: 160/800 mg twice daily) which was given for a superficial cellulitis. He subsequently developed worsening anorexia, fatigue, dyspepsia, and pruritus with a generalized body rash, but no fever or chills. He had a history of cocaine use, but denied injection drug use or other risk factors for viral hepatitis. He drank alcohol sparingly and had no history of liver disease or drug allergies. His other medications included ranitidine which he had taken for years for gastroesophageal reflux and ibuprofen which he took intermittently for headaches and body pain. Physical examination showed deep jaundice and a macular papular rash over the trunk. Laboratory tests showed marked elevations in serum bilirubin (29.5 mg/dL) and aminotransferase levels (ALT 2229 U/L, AST 2684 U/L), with minimal increase in alkaline phosphatase (188 U/L). Serum albumin was low (2.3 g/dL) and prothrombin time was mildly elevated (INR 1.2). Tests for acute hepatitis A, B and C (including HCV RNA) were negative. Smooth muscle antibody was present in low titer (1:80), but antinuclear antibody was not detected. Abdominal ultrasound revealed a contracted gallbladder, but no evidence of biliary obstruction. Abdominal CT scan showed a small gallstone but no dilatation of the extra- or intra-hepatic bile ducts. Liver biopsy demonstrated submassive necrosis and collapse with prominent inflammation and eosinophils, suggestive of severe drug induced liver injury. He was treated with corticosteroids, but without improvement in his liver tests. Because of deepening jaundice and progressive hepatic failure, he was referred for liver transplantation, but was not accepted as a candidate because of recent drug use. He subsequently developed complications of liver failure and died three months after initial presentation.

Key Points

Medication:Trimethoprim (160 mg)-sulfamethoxazole (800 mg)(TMP-SMZ)
Pattern:Hepatocellular (R=~34)
Severity:5+ (acute liver failure and death)
Latency:3-4 weeks
Recovery:Incomplete
Other medications:Ranitidine, ibuprofen chronically

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
5 weeks3 weeks222918829.5Admission
6 weeks4 weeks224016628.7Imaging tests
7 weeks5 weeks116421122.1Liver biopsy
8 weeks6 weeks85529727.9INR 1.4
4 months3 monthsDied of hepatic failure
Normal Values <45 <130 <1.2

Comment

Sulfonamides can cause acute liver failure and are usually listed in the top 10 cases of fatal drug induced liver injury in large case series. Cases of sulfonamide hepatotoxicity presenting with acute liver failure typically have a hepatocellular pattern of serum enzyme elevations with marked increases in serum aminotransferase levels. Corticosteroids are often used, particularly if immunoallergic features (rash, fever, eosinophilia) are present, but it is not clear whether they are beneficial and alter the course and outcome of the liver injury.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Trimethoprim-Sulfamethoxazole – Generic, Bactrim®, Septra®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Trimethoprim-Sulfamethoxazole 8064-90-2 C14-H18-N4-O3.
C10-H11-N3-O3-S		 image 134990779 in the ncbi pubchem database

CITED REFERENCES

1.
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]

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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    (80 year old man developed jaundice [bilirubin 10 mg/dL, ALT 135 U/L, Alk P 245 U/L] 10 days after a 10 day course of TMP-SMZ progressing to hepatic failure; massive hepatic necrosis on autopsy).
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    (16 year old boy developed rash and fever 7 weeks after starting TMP-SMZ [bilirubin 9.4 mg/dL, ALT 294 U/L, Alk P 880 U/L, 13% eosinophils], no mention of recovery).
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    (Review of indications, efficacy and safety of TMP-SMZ).
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    (61 year old man with cholestatic hepatitis with minimal ALT and Alk P elevations after 10 days of TMP-SMZ, resolving in 2 months).
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    (70 year old woman with severe cholestatic hepatitis with vague previous history of exposure to TMP-SMZ and prolonged exacerbation with restarting treatment before full recovery).
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    (52 year old woman developed jaundice within 7 days of starting TMP-SMZ [bilirubin 11.2 mg/dL, ALT 78 U/L, Alk P 210 U/L], recovery within 2 months of stopping).
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    (55 year old man developed fever and jaundice 1 week after stopping a 2 week course of TMP-SMZ [bilirubin 7.1 mg/dL, AST 86 U/L, Alk P 1341 U/L], resolving within 6 weeks of onset).
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    (70 year old man, with a history of rash after taking TMP-SMZ, developed rash followed by jaundice after 2 doses of TMP/SMZ with progressive acute liver failure [bilirubin 32 rising to 44 mg/dL, AST 2390 U/L, Alk P 270 U/L] and death, autopsy showing massive necrosis).
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    (53 year old woman developed fever and arthralgias followed by jaundice 3 days after 10 day course of sulfamethoxazole with mixed enzyme pattern and recovery in ~6 weeks, recurrence with retreatment – twice)
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    (Follow up of 40,000 patients admitted to 25 Boston hospitals from 1966-80, 1,121 received TMP-SMZ, and 91 [8%] had an adverse reaction, usually gastrointestinal upset [3.7%], skin rash [3.3%], fever [0.2%], no reports of liver injury or jaundice).
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    (Review of world’s literature on TMP-SMZ adverse drug reactions; common side effects are gastrointestinal upset and skin rash; liver injury is rare ~2% of reported adverse events).
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    (5 year old girl developed rash, fever and jaundice one week after starting TMP-SMZ [bilirubin 6.5 mg/dL, ALT 44 U/L, Alk P 776 U/L], recovery within 2 weeks).
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    (54 year old man developed jaundice within 1 week of starting TMP-SMZ [bilirubin 5.0 mg/dL, ALT 255 U/L, GGT 198 U/L], resolving in 4 weeks with positive inadvertent rechallenge with 3 day latency).
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    (67 year old developed rash, fever and nausea within 1 week of starting TMP-SMZ, but continued drug for 4 weeks when he was found to be jaundiced with bilirubin 9.8 mg/dL, AST 150 U/L, Alk P 332 U/L).
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    (49 year old woman developed TMP-SMZ induced cholestatic hepatitis with latency of 3 weeks and resolution in 8 weeks, developed similar pattern after five days of TMP alone).
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    (65 year old man developed jaundice 4 weeks after starting TMP-SMZ therapy [bilirubin 4.5 mg/dL, AST 114 U/L, Alk P > 500 U/L], resolving within 3 months of stopping).
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    (26 year old man developed acute liver failure and pancreatitis 5 days after starting TMP-SMZ while also taking 4.5 grams of acetaminophen daily, which may have contributed to the liver injury).
  • Kumar VV, Mahesh BV, Raju VK, Devi KR. Trimethoprim induced intrahepatic cholestasis. Indian Pediatr 1989; 26: 181-3. [PubMed: 2753538]
    (10 year old boy developed jaundice 10 days after starting TMP-SMZ [bilirubin 8.0 mg/dL, AST 80, Alk P 5 times ULN] with rapid resolution; 3 months later a course of TMP alone led to jaundice within 1 week with similar pattern of serum enzyme elevations).
  • Muñoz SJ, Martinez-Hernandez A, Maddrey WC. Intrahepatic cholestasis and phospholipidosis associated with the use of trimethoprim-sulfamethoxazole. Hepatology 1990; 12: 342-7. [PubMed: 2167870]
    (60 year old woman developed jaundice 4 days after starting TMP-SMZ [bilirubin 20.5 mg/dL, Alk P 502 U/L, AST 188 U/L], not resolving until 6 months after stopping).
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    (Review of pharmacology, efficacy and safety of TMP-SMZ).
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  • Kowdley KV, Keeffe EB, Fawaz KA. Prolonged cholestasis due to trimethoprim sulfamethoxazole. Gastroenterology 1992; 102: 2148-50. [PubMed: 1587437]
    (Two women, ages 43 and 48 years, developed prolonged cholestasis after exposure to TMP-SMZ with latency to onset of rash of 4 days, but 2-3 weeks to onset of jaundice [bilirubin 3.6 and 27.1 mg/dL, ALT 422 and 63 U/L, Alk P 229 and 306 U/L], requiring 12 and 18 months to recover).
  • Friis H, Andreasen PB. Drug-induced hepatic injury: an analysis of 1100 cases reported to the Danish Committee on Adverse Drug Reactions between 1978 and 1987. J Intern Med 1992; 232: 133-8. [PubMed: 1506809]
    (Adverse drug reaction reports in Denmark from 1978 to 1987; 62 cases [5%] were attributed to either TMP-SMZ or SMZ alone).
  • Malnick SD, Atali M, Israeli E, Abend Y, Geltner D. Trimethoprim/sulfamethoxazole-induced rash, fever, abnormal liver function tests, leukopenia, and thrombocytopenia. Ann Pharmacother 1993; 27: 1139-40. [PubMed: 8219452]
    (54 year old woman developed rash, fever and cytopenia with minimal ALT elevations 5 days after starting TMP-SMZ).
  • Carr A, Tindall B, Penny R, Cooper DA. Patterns of multiple-drug hypersensitivities in HIV-infected patients. AIDS 1993; 7: 1532-3. [PubMed: 8280426]
    (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]).
  • Carson JL, Strom BL, Duff A, et al. Acute liver disease associated with erythromycins, sulfonamides, and tetracyclines. Ann Intern Med 1993; 119(7 Pt 1): 576-83. [PubMed: 8363168]
    (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).
  • Altraif I, Lilly L, Wanless IR, Heathcote J. Cholestatic liver disease with ductopenia (vanishing bile duct syndrome) after administration of clindamycin and trimethoprim-sulfamethoxazole. Am J Gastroenterol 1994; 89: 1230-4. [PubMed: 8053440]
    (Two case reports; 30 year old man developed TMP-SMZ induced allergic hepatitis with jaundice evolving into a prolonged cholestatic syndrome with ductopenia).
  • Pickert CB, Belsha CW, Kearns GL. Multi-organ disease secondary to sulfonamide toxicity. Pediatrics 1994; 94: 237-9. [PubMed: 8036081]
    (13 year old boy developed rash during 3 week course of TMP-SMZ followed 10 days later by fever and pharyngitis with eosinophilia [25%], AST 252 U/L, GGT 210 U/L and renal failure with slow recovery).
  • Lindgren A, Olsson R. Liver reactions from trimethoprim. J Intern Med 1994; 236: 281-4. [PubMed: 8077884]
    (Summary of Swedish adverse drug reaction reports of 21 cases of liver injury due to TMP alone; latency 5 to 24 days, all recovered, similar onset as to TMP-SMZ, but no details given).
  • Jick H, Derby LE. A large population-based follow-up study of trimethoprim-sulfamethoxazole, trimethoprim, and cephalexin for uncommon serious drug toxicity. Pharmacotherapy 1995; 15: 428-32. [PubMed: 7479194]
    (Boston database on 232,390 patients given TMP-SMZ and 266,951 given TMP alone; rates of hepatic events similar with both drugs: 3.8-5.2/100,000 exposed persons).
  • Simma B, Meister B, Deutsch J, et al. Fulminant hepatic failure in a child as a potential adverse effect of trimethoprim-sulphamethoxazole. Eur J Pediatr 1995; 154: 530-3. [PubMed: 7556317]
    (5 year old given TMP-SMZ and then amoxicillin-clavulanate and two weeks later developed jaundice [bilirubin 20.5 mg/dL, ALT 546 U/L, Alk P 538 U/L], progressing to liver failure and need for emergency transplantation).
  • 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).
  • García Rodríguez LA, Ruigómez A, Jick H. A review of epidemiologic research on drug-induced acute liver injury using the general practice research data base in the United Kingdom. Pharmacotherapy 1997; 17: 721-8. [PubMed: 9250549]
    (Review of studies of drug induced liver injury from the UK general practice database identified 23 cases of liver injury from TMP-SMZ among 232,390 users giving an incidence rate of 3.2 per 100,000 prescriptions, a rate similar to comparable antibiotics).
  • Rieder MJ, King SM, Read S. Adverse reactions to trimethoprim-sulfamethoxazole among children with human immunodeficiency virus infection. Pediatr Infect Dis J 1997; 16: 1028-31. [PubMed: 9384334]
    (Single center survey; 40% of 25 children with HIV treated with TMP-SMZ developed short latency onset allergic reactions, none hepatic).
  • Ilario MJ, Ruiz JE, Axiotis CA. Acute fulminant hepatic failure in a woman treated with phenytoin and trimethoprim-sulfamethoxazole. Arch Pathol Lab Med 2000; 124: 1800-3. [PubMed: 11100060]
    (60 year old woman developed acute liver failure while receiving both phenytoin and TMP-SMZ).
  • Windecker R, Steffen J, Cascorbi I, Thürmann PA. Co-trimoxazole-induced liver and renal failure. Case report. Eur J Clin Pharmacol 2000; 56: 191-3. [PubMed: 10877016]
    (48 year old man developed jaundice [bilirubin 10.2 mg/dL, ALT 723 U/L, Alk P 413 U/L], with bone marrow and renal failure 6 days after 10 day course of TMP-SMZ, ultimately recovering within 6 months).
  • Mainra RR, Card SE. Trimethoprim-sulfamethoxazole-associated hepatotoxicity - part of a hypersensitivity syndrome. Can J Clin Pharmacol 2003; 10: 175-8. [PubMed: 14712321]
    (24 year old woman developed fever, eosinophilia and jaundice while taking multiple herbal medications and after a brief course of TMP-SMZ [bilirubin 10.0 mg/dL, ALT 2479 U/L, Alk P 472 U/L], severe course but ultimate recovery).
  • Zaman F, Ye G, Abreo KD, Latif S, Zibari GB. Successful orthotopic liver transplantation after trimethoprim-sulfamethoxazole associated fulminant liver failure. Clin Transplant 2003; 17: 461-4. [PubMed: 14703931]
    (23 year old man developed liver injury arising within 7 days of starting TMP-SMZ [bilirubin rising from 0.8 to 6.9 to 10.3 mg/dL, ALT 1706 U/L], evolving rapidly into acute liver failure and need for transplant).
  • Karpman E, Kurzrock EA. Adverse reactions of nitrofurantoin, trimethoprim and sulfamethoxazole in children. J Urol 2004; 172: 448-53. [PubMed: 15247700]
    (Review article on side effects of antibiotics used in pediatric urologic practice).
  • Slatore CG, Tilles SA. Sulfonamide hypersensitivity. Immunol Allergy Clin North Am 2004; 24: 477-90, vii. PMID: 15242722 [PubMed: 15242722]
    (Review of mechanisms of hypersensitivity to sulfonamides).
  • Russo MW, Galanko JA, Shrestha R, Fried MW, Watkins P. Liver transplantation for acute liver failure from drug-induced liver injury in the United States. Liver Transpl 2004; 10: 1018-23. [PubMed: 15390328]
    (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]).
  • Andrade RJ, Lucena MI, Fernández MC, Pelaez G, Pachkoria K, Garcia-Ruiz E, Garcia-Munoz B, et al.; Spanish Group for the Study of Drug-Induced Liver Disease. Drug-induced liver injury: an analysis of 461 incidences submitted to the Spanish registry over a 10-year period. Gastroenterology 2005; 129: 512-21. [PubMed: 16083708]
    (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]).
  • Garcia Rodriguez LA, Ruigomez A, Jick H. Fulminant drug-induced hepatic failure leading to death or liver transplantation in Sweden. Scand J Gastroenterol 2005; 40: 1095-1101. [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]).
  • Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. [PubMed: 16054882]
    (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]).
  • Kouklakis G, Mpoumponaris A, Zezos P, Moschos J, Koulaouzidis A, Nakos A, Pehlivanidis A, et al. Cholestatic hepatitis with severe systemic reactions induced by trimethoprim-sulfamethoxazole. Ann Hepatol 2007; 6: 63-5. [PubMed: 17297432]
    (30 year old man developed fever and rash 2 weeks after stopping a 15 day course of TMP-SMZ [bilirubin 2.9 mg/dL, ALT 456 U/L, Alk P 223 U/L], resolving within 3 months of onset).
  • Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]
    (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).
  • Crowell CS, Melin-Aldana H, Tan TQ. Fever, rash, and hepatic dysfunction in a 3-year-old child: a case report. Clin Pediatr (Phila) 2008; 47: 517-20. [PubMed: 18509155]
    (3 year old boy with rash, fever, cough and 19% atypical lymphocytes was thought to have Kawasaki disease or mononucleosis, but later found to have received TMP-SMZ 1 week before onset [bilirubin 1.6 mg/dL, ALT 354 U/L, Alk P 351 U/L], rapid response to corticosteroids).
  • Hanses F, Zierhut S, Schölmerich J, Salzberger B, Wrede CE. Severe and long lasting cholestasis after high-dose co-trimoxazole treatment for Pneumocystis pneumonia in HIV-infected patients-a report of two cases. Int J Infect Dis 2009; 13: e467-9. [PubMed: 19299179]
    (Two patients with HIV infection and pneumocystis pneumonia developed elevations in Alk P and bilirubin while on TMP-SMZ, but both also had CMV infection and multiple complications, and abnormalities persisted long term).
  • Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]
    (Worldwide pharmacovigilance database contained 9036 hepatic adverse drug reactions in children, TMP-SMZ accounting for 48 cases [0.5%] for an adjusted odds ratio of 1.3).
  • Devarbhavi H, Dierkhising R, Kremers WK, Sandeep MS, Karanth D, Adarsh CK. Single-center experience with drug-induced liver injury from India: causes, outcome, prognosis, and predictors of mortality. Am J Gastroenterol 2010; 105: 2396-404. [PubMed: 20648003]
    (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].
  • García-Aparicio J, Herrero-Herrero JI. [Toxic hepatitis following sequential treatment with cotrimoxazol, levofloxacin, doxycycline and sertraline in a patient with a respiratory infection]. Farm Hosp 2010; 34: 152-4. Spanish. PMID: 20471573 [PubMed: 20471573]
    (65 year old woman developed jaundice shortly after having received TMP-SMZ as well as doxycycline and levofloxacin for a urinary tract infection [bilirubin 3.5 rising to 14.2 mg/dL, ALT 937 U/L, Alk P 373 U/L], resolving within 3 months of onset).
  • Bell TL, Foster JN, Townsend ML. Trimethoprim-sulfamethoxazole-induced hepatotoxicity in a pediatric patient. Pharmacotherapy 2010; 30: 539. [PubMed: 20412003]
    (9 year old boy developed fever and abdominal pain without rash 14 days after starting a course of TMP-SMZ [bilirubin 0.6 mg/dL, ALT 624 U/L, Alk P 153 U/L, 9% eosinophils], resolving within a week of stopping).
  • Chisholm-Burns MA, Patanwala AE, Spivey CA. Aseptic meningitis, hemolytic anemia, hepatitis, and orthostatic hypotension in a patient treated with trimethoprim-sulfamethoxazole. Am J Health Syst Pharm 2010; 67: 123-7. [PubMed: 20065266]
    (37 year old man developed fever and rash 8 days after starting TMP-SMZ [bilirubin 2.3 mg/dL, ALT 1290 U/L, Alk P not given], with hemolytic anemia, resolving in 2 weeks).
  • Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. [PMC free article: PMC3992250] [PubMed: 20949552]
    (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 from TMP-SMZ and 3 sulfasalazine).
  • 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).
  • Bollaert M, Jeulin H, Waton J, Gastin I, Tréchot P, Rabaud C, Schmutz JL, et al. [Six cases of spring DRESS]. Ann Dermatol Venereol 2012; 139: 15-22. French. PMID: 22225738 [PubMed: 22225738]
    (Description of 6 cases of DRESS syndrome arising during a single one month period, all with reactivation of herpes virus infections [EBV, HHV-6, HHV-7 or CMV] and due to different medications, including amoxicillin, allopurinol, carbamazepine, trimethoprim-sulfamethoxazole and multiple antibiotics).
  • Descamps V. [Drug reaction with eosinophilia and systemic symptoms (DRESS)]. Rev Prat 2012; 62: 1347-52. French. PMID: 23424909 [PubMed: 23424909]
    (Review of clinical features of DRESS syndrome in French).
  • Sembera S, Lammert C, Talwalkar JA, Sanderson SO, Poterucha JJ, Hay JE, Wiesner RH, Gores GJ, Rosen CB, Heimbach JK, Charlton MR. Frequency, clinical presentation, and outcomes of drug-induced liver injury after liver transplantation. Liver Transpl 2012; 18: 803-10. [PMC free article: PMC3396746] [PubMed: 22389256]
    (Among 29 cases of suspected drug induced liver injury occurring in patients after liver transplantation, 11 [38%] were attributed to TMP-SMZ the mostly commonly implicated agent).
  • Cangemi DJ, Donovan ST, Johnson MM. 62-year-old man with painless jaundice and hyponatremia. Mayo Clin Proc 2013; 88: e49-53. [PubMed: 23726406]
    (62 year old man developed jaundice shortly after 4 day course of TMP-SMZ for cellulitis [bilirubin 25.8 mg/dL, ALT 425 U/L, Alk P 1515 U/L], resolving within 3 months of onset).
  • Ng CT, Tan CK, Oh CC, Chang JP. Successful extracorporeal liver dialysis for the treatment of trimethoprim-sulfamethoxazole-induced fulminant hepatic failure. Singapore Med J 2013; 54: e113-6. [PubMed: 23716163]
    (17 year old man developed fever and rash 28 days after starting TMP-SMZ for acne [bilirubin 3.0 rising to 19.2 mg/dL, ALT 1660 U/L, Alk P 227 U/L, eosinophils 670/μL], progressing to hepatic failure, but ultimate recovery without liver transplantation within 2 months of onset).
  • Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 144: 1419-25. [PubMed: 23419359]
    (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).
  • Yang JJ, Huang CH, Liu CE, Tang HJ, Yang CJ, Lee YC, Lee KY, Tsai MS, et al. Multicenter study of trimethoprim/sulfamethoxazole-related hepatotoxicity: incidence and associated factors among HIV-infected patients treated for Pneumocystis jirovecii pneumonia. PLoS One 2014; 9: e106141. [PMC free article: PMC4153565] [PubMed: 25184238]
    (Among 284 HIV infected patients treated with SMZ-TMP for P. jirovecii pneumonia, 152 [53%] developed liver test abnormalities which was attributed to SMP/TMP in 47 [17%] of whom 3 [1%] developed jaundice, but none died of liver failure).
  • Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]
    (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 dapsone or 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 [3.5%] ranking 4th in frequency).
  • 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;112:1382-1388.. [PMC free article: PMC5667647] [PubMed: 28762375]
    (Among 1182 patients enrolled in a prospective study of drug-induced liver injury in the United States between 2004 and 2016, the most frequently implicated agent among Blacks was TMP-SMZ [7.6%] while it ranked 5th among Whites [3.6%] among whom Amoxicillin-Clavulanate was most frequently implicated [13.4%] which ranked 4th among Blacks [4.1%].
  • Slim R, Asmar N, Yaghi C, Honein K, Sayegh R, Chelala D. Trimethoprim-sulfamethoxazole-induced hepatotoxicity in a renal transplant patient. Indian J Nephrol. 2017;27:482-483.. [PMC free article: PMC5704419] [PubMed: 29217891]
    (38 year old Indian male underwent renal transplantation and was started on TMP/SMZ for prophylaxis against Pneumocystis pneumonia and was found to have abnormal liver tests without symptoms or jaundice 9 days later [bilirubin normal, ALT 375 U/L, GGT 571 U/L] which resolved rapidly resolved once TMP/SMZ was stopped].
  • Kathi PR, Tama M, Ehrinpreis M, Mutchnick M, Westerhoff M, Mowers J, Fontana RJ. Vanishing bile duct syndrome arising in a patient with HIV infection sequentially treated with trimethoprim/sulfamethoxazole and dapsone. Clin J Gastroenterol. 2020;13:276-280.. [PubMed: 31317370]
    (58 year old African American man with HIV infection developed pruritus within 2 days and jaundice by 8 days of starting TMP-SMZ [bilirubin 11.9 mg/dL, ALT 1519 U/L, Alk P 1345 U/L] which resolved slowly after stopping but recurred 9 months later within 7 days of starting dapsone [bilirubin 16.9 mg/dL, ALT 282 U/L, Alk P 1353 U/L] which did not improve upon stopping, resulting in persistent jaundice, intractable pruritus, and liver biopsy showing vanishing bile duct syndrome resulting in hepatic failure and death 2 years later).
  • Siddique AS, Siddique O, Einstein M, Urtasun-Sotil E, Ligato S. Drug and herbal/dietary supplements-induced liver injury: A tertiary care center experience. World J Hepatol. 2020;12:207-219.. [PMC free article: PMC7280859] [PubMed: 32547688]
    (Among 38 patients with suspected drug induced liver injury who presented at a single US referral center between 2013 and 2017, one was attributed to TMP-SMZ [bilirubin 10.9 mg/dL, ALT 152 U/L, Alk P 198 U/L] with macrovesicular steatosis and cholestasis on liver biopsy).
  • Sharma B, Antoine M, Shah M, John S. Idiosyncratic drug-induced liver injury secondary to trimethoprim-sulfamethoxazole. Am J Ther. 2020;27:e664-e667.. [PubMed: 31425162]
    (44 year old woman developed nausea and abdominal pain 4 days after starting TMP-SMZ for a urinary tract infection, with rash and fever [bilirubin 0.8 rising to 2.2 mg/dL, ALT 563 rising to 6916 U/L, Alk P 100 rising to 164 U/L] with improvement on stopping TMP/SMZ and administration of N-acetyl cysteine).
  • Li YJ, Phillips EJ, Dellinger A, Nicoletti P, Schutte R, Li D, Ostrov DA, et al; Drug-induced Liver Injury Network. Human Leukocyte Antigen B*14:01 and B*35:01 are associated with trimethoprim-sulfamethoxazole induced liver injury. Hepatology. 2021;73:268-281.. [PMC free article: PMC7544638] [PubMed: 32270503]
    (Among 71 patients with liver injury attributed to use of TMP-SMZ, HLA testing showed an association with HLA-B*14:01 found among 5 of 51 European Americans (AF 0.049 vs 0.009) but not African Americans among whom 5 of 10 had B*35:01 [AF 0.25 vs 0.09])
  • van Asperdt JAA, De Moor RA. Aseptic meningitis, hepatitis and cholestasis induced by trimethoprim/sulfamethoxazole: a case report. BMC Pediatr. 2021;21:345.. [PMC free article: PMC8365906] [PubMed: 34399711]
    (2.5 year old girl was hospitalized for meningitis 2 weeks after starting TMP-SMZ for otitis and developed jaundice 4 days later [bilirubin 4.4 rising to 5.8 mg/dL, ALT 358 U/L, GGT ~450 U/L] with clinical resolution and near normal values 34 days after stopping).
  • Huang YS, Tseng SY, Chang TE, Perng CL, Huang YH. Sulfamethoxazole-trimethoprim-induced liver injury and genetic polymorphisms of NAT2 and CYP2C9 in Taiwan. Pharmacogenet Genomics. 2021;31:200-206.. [PubMed: 34149005]
    (Among 158 Han Chinese patients seen at Taipei Veterans General Hospital between 2003 and 2010 with suspected TMP-SMZ hepatotoxicity, slow NAT2 acetylation status was more frequent in patients than in 145 controls who tolerated therapy [42% vs 26%], with no clear association with age, latency, or clinical features.
  • Hindosh N, Kotala R, Nguyen K, Pintor A. Trimethoprim-sulfamethoxazole-induced drug reaction with eosinophilia and systemic symptoms (DRESS) complicated by acute liver failure. Cureus. 2022;14:e30852.. [PMC free article: PMC9705226] [PubMed: 36457619]
    (57 year old Asian American man developed fatigue, fever, and rash 2 weeks after finishing of a 2 week course of TMP-SMZ [bilirubin 20.5 mg/dL, ALT 376 U/L, Alk P 1476 U/L, INR 1.2, eosinophils 29%, and platelet count of 1,000/μL], improving after intravenous methylprednisolone but with slow recovery]
  • 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 93 cases of TMP- SMZ induced liver injury enrolled in a prospective U.S. database between 2004 and 2020, the median age was 46 years, 52% were female, 76% white and 17% black, 82% were jaundiced with mean bilirubin of 4.3 mg/dL, ALT of 388 U/L, and Alk P of 258 U/L], 40% were severe and 4% fatal or transplanted within 6 months; the proportion of patients with cholestatic injury increased with age while the proportion with hepatocellular injury decreased; a weak association with HLA-B*14:01 was found in Whites (carrier rate 16%] and with HLA-B*35:01 in Blacks).
  • Sircar S, Rayan M, Okonoboh P. TMP-SMX induced type 4 hypersensitivity with multi-organ involvement. ID Cases. 2023;34:e01917.. [PMC free article: PMC10638065] [PubMed: 37954169]
    (61 year old man developed fever, rash, and confusion 2 weeks after stopping a one-week course of TMP-SMZ [bilirubin 0.6 mg/dL, ALT 79 rising to 214 U/L, Alk P not given, INR 1.1, creatinine 2.8 mg/dL, platelets 13,000/μL] responding to supportive care and blood test results improving on discharge 5 days later).
  • Kato H, Hagihara M, Asai N, Mikamo H, Iwamoto T. Evaluation of effectiveness, hyperkalaemia, and hepatotoxicity of trimethoprim-sulphamethoxazole prophylaxis for Pneumocystis jirovecii pneumonia in paediatric patients: A single-centre retrospective study. Int J Antimicrob Agents. 2024;63:107151.. [PubMed: 38508538]
    (Among 215 children with HIV infection seen at a single Japanese referral center between 2018 and 2023, who were given prophylaxis against Pneumocystis jirovecii pneumonia with TMP-SMZ, no child developed pneumocystis pneumonia but 34 [16%] developed hepatotoxicity, but no information given about severity, jaundice, hospitalizations, or outcomes).
  • Torgersen J, Mezochow AK, Newcomb CW, Carbonari DM, Hennessy S, Rentsch CT, Park LS, et al. Severe acute liver injury after hepatotoxic medication initiation in real-world data. JAMA Intern Med. 2024;184:943-952.. [PMC free article: PMC11197444] [PubMed: 38913369]
    (Analysis of the US Veterans Administration electronic health records between 1999 and 2021 identified 1739 hospitalizations for acute liver injury suspected to be due to medications including 32 attributed to SMZ for an estimated incidence rate of 1 per 1960 patients exposed).
  • 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).
  • Chen VL, Rockey DC, Bjornsson ES, Barnhart H, Hoofnagle JH; Drug-Induced Liver Injury Network Investigators. Incidence of idiosyncratic drug-induced liver Injury caused by prescription drugs. Drug Saf. 2025;48:151-160. 39317916. [PMC free article: PMC11785493] [PubMed: 39317916]
    (Analysis of 1284 cases of drug-induced liver injury enrolled in a U.S. prospective study, identified 75 cases [6%] attributed to TMP-SMZ making it the second most frequently implicated drug, occurring at a rate estimated at 1 per 4,900 persons treated).
  • Lammert C, Teal E, Ghabril M, Chalasani N. Incidence of possible drug-induced liver injury due to commonly implicated agents in the United States. Clin Gastroenterol Hepatol. 2025;23:1061-1062.e1. 39447947. [PubMed: 39447947]
    (Analysis of a health database of 16 Indiana University Health hospitals between 2017 and 2022, identified 54 cases of drug-induced liver injury to commonly implicated agents such as azithromycin [15 cases], amoxicillin-clavulanate [8], levofloxacin [7], and ciprofloxacin [6); but none were attributed to TMP-SMZ, despite 10,161 persons exposed).
  • Björnsson RA, Sigurdsson SS, Arnarson DT, Logason E, Björnsson ES. The frequency of drug-induced liver injury due to antibiotics among hospitalised patients. Drug Saf. 2025;48:795-804.. [PubMed: 40072769]
    (Among 2292 patients treated with the 14 most used antibiotics while hospitalized in a single Icelandic referral center between 2012-2023, 52 developed evidence of drug-induced liver injury including 3 attributed to TMP/SMZ for an estimated rate of one per 1096 patients exposed).
  • Rahnama-Moghadam S, Arora N, Vuppalanchi R, Li YJ, Gu J, Barnhart H, Phillips E, Chalasani N; Drug Induced Liver Injury Network. DRESS syndrome in patients with drug-induced liver injury: characteristics and high-risk factors. Am J Gastroenterol. 2025 Jun 12:10. Epub ahead of print.. [PMC free article: PMC12715855] [PubMed: 40504263]
    (Among 2121 patients with suspected drug-induced liver injury enrolled in a prospective US registry between 2004 and 2023, 105 were attributed to TMP-SMZ including 20 [19%] with drug-reaction with eosinophilia and systemic symptoms [DRESS] and another 23 [22%] with rash without DRESS).
  • Hishinuma M, Hasegawa M, Minatoguchi S, Umeda R, Koide S, Hayashi H, Yuzawa Y, et al. A case of vanishing bile duct syndrome caused by a treatment regimen including avacopan for microscopic polyangiitis. Intern Med. 2025 Sep 11. Epub ahead of print.. [PubMed: 40930823]
    (81 year old man with vasculitis developed jaundice 42 days after starting rituximab, prednisolone, avacopan, and prophylaxis with TMP-SMZ [bilirubin 3.1 rising to 35 mg/dL, ALT 274 U/L, Alk P 402 U/L] with progressive cholestasis and liver biopsy showing vanishing bile duct syndrome, which was attributed to avacopan and which led to liver failure and death within 3 months of onset).
    Bannoud M, Hong L, Ibelaidene M, Acosta M, Mehdizadeh C. Acute liver injury with cholestatic pattern: an adverse effect of trimethoprim-sulfamethoxazole. Cureus. 2025;17:e92749. PMID: 41122585.
    (52 year old woman developed jaundice 12 days after starting an 11-day course of TMP-SMZ, metronidazole, and phenazopyridine [bilirubin 7.8 mg/dL, ALT 123 U/L, Alk P 903 U/L] with rapid and spontaneous recovery upon stopping).

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