Azithromycin is a semisynthetic macrolide antibiotic which is commonly used for a wide variety of mild-to-moderate bacterial infections. Azithromycin has been linked to rare instances of acute liver injury.


Azithromycin (ay zith" roe mye' sin) is a semisynthetic macrolide antibiotic used widely to treat mild-to-moderate bacterial infections caused by sensitive agents. Azithromycin, like other macrolide antibiotics such as erythromycin and clarithromycin, is bacteriostatic against many gram positive bacteria including many strains of streptococci, staphylococci, clostridia, corynebacteria, listeria, haemophilus sp., moxicella, and Neisseria meningitidis. Azithromycin is more active than erythromycin against several gram negative bacteria as well as Mycoplasma pneumonia, Helicobacter pylori, Toxoplasma gondii, cryptosporidia and several atypical mycobacteria. Macrolide antibiotics act by inhibiting protein synthesis of bacteria by binding to the 50S ribosomal element. Resistance occurs by several mechanisms. Azithromycin was approved for use in the United States in 1994 and currently it is the most commonly prescribed antibiotic in America. Typical indications are community acquired pneumonia, acute exacerbations of chronic bronchitis, sinusitis, pelvic inflammatory disease, urethritis and other infections caused by susceptible bacteria. Azithromycin is also used to treat disseminated mycobacterium avium complex infections. Azithromycin is available as tablets of 250 and 500 mg and as solutions and powders for suspension generically and under the name Zithromax. Azithromycin is typically given in once daily doses for 5 to 7 days. Chronic use of azithromycin is used to treat atypical mycobacterial infections and as prophylaxis against common bacterial infections in highly susceptible persons (with cystic fibrosis, chronic granulomatous disease, or bronchiectasis). Parenteral azithromycin is typically given in doses of 500 mg iv daily for the first few days of therapy in moderate-to-severe infections. Azithromycin is generally well tolerated, but side effects can include nausea, abdominal pain, diarrhea, dyspepsia, headache, dizziness, angioedema and rash. Severe adverse reactions include infantile pyloric stenosis, Clostridia difficile diarrhea, QTc prolongation, hepatotoxicity and severe hypersensitivity reactions including Stevens Johnson syndrome and toxic epidermal necrolysis.


Like other macrolide antibiotics, azithromycin has been linked to a low rate of acute, transient and asymptomatic elevation in serum aminotransferases which occurs in 1% to 2% of patients treated for short periods, and a somewhat higher proportion of patients given azithromycin long term.

Azithromycin can also rarely cause clinically apparent liver injury. Because azithromycin has become so commonly used, it has also become one of the more common causes of drug induced liver injury. The typical liver injury caused by azithromycin resembles that described with other macrolides and is a self-limited, cholestatic hepatitis, arising within 1 to 3 weeks of starting treatment (Case 1). It occasionally arises after azithromycin is stopped and can occur even after a short, 2 or 3 day course. Typical symptoms are fatigue, jaundice, abdominal pain and pruritus. Fever and eosinophilia may also be present, but immunoallergic features are usually not prominent. This form of liver injury from azithromycin is usually benign, but in some instances is associated with prolonged jaundice and persistence of liver test abnormalities for 6 months or more. Liver histology in these cases generally demonstrates bile duct loss, which if severe, can result in vanishing bile duct syndrome and chronic cholestatic liver failure, ultimately requiring liver transplantation. Other instances of bile duct loss and prolonged cholestatic hepatitis ultimately resolve, but may be marked by persistent serum alkaline phosphatase elevations of uncertain clinical significance.

Azithromycin can also cause hepatocellular injury with symptoms and jaundice. In these cases, the latency is typically short and may be 1 to 3 days only (Case 2). Serum aminotransferase levels are markedly elevated and alkaline phosphatase values are usually less than twice the upper limit of normal, although they may rise to higher levels with time. The hepatocellular forms of liver injury from azithromycin can be severe and lead to acute liver failure and death or need for emergency liver transplantation. However, in most cases, recovery occurs within 4 to 8 weeks.

Azithromycin has also been associated with severe cutaneous reactions such as erythema multiforme, drug reaction with eosinophilia and systemic signs (DRESS) syndrome, Stevens Johnson syndrome (SJS) and toxic epidermal necrosis (TEN). These severe cutaneous reactions are often associated with some degree of liver injury and may be accompanied by clinically apparent injury with jaundice, usually with a cholestatic pattern. However, the severe cutaneous reactions usually overshadow the liver injury.

In cell culture, azithromycin exhibits some degree of antiviral activity and was shown to inhibit the Severe Acute Respiratory Syndrome, coronavirus type 2 (SARS-CoV-2), the cause of the pandemic of severe COVID-19 pneumonia that arose in 2019 and led to more than 3 million deaths worldwide. In view of the antiviral activity as well as antiinflammatory actions of azithromycin, it was repurposed as a potential therapy of COVID-19. Despite early promising reports, subsequent randomized controlled trials found that it had no benefit in either prevention of infection or amelioration of the course of COVID-19 illness. An emergency use authorization granted to azithromycin as therapy of COVID-19 in early 2020 was later withdrawn.

Likelihood score: A (well known but rare cause of clinically apparent liver injury).


Azithromycin hepatotoxicity is typically associated histologically with a cholestatic hepatitis similar to what is described with erythromycin induced liver injury. Scattered bile casts are found in canaliculi with modest parenchymal inflammation and necrosis. Portal tracts often have more pronounced inflammation characterized by mononuclear cells and eosinophils. The cholestasis can be profound and prolonged, and azithromycin is a well known cause of vanishing bile duct syndrome. Less common is hepatocellular injury, a pattern seen most commonly with reexposure, with a short latency to onset and biopsy taken early in the course of injury.

CHOLESTATIC HEPATITIS with Bile Plugs and Scant Parenchymal Inflammation


Mechanism of Liver Injury

The cause of the idiosyncratic liver injury due to azithromycin is unknown, but the rapidity of onset suggests hypersensitivity as a cause.

Outcome and Management

The minor serum aminotransferase elevations that appear during therapy with azithromycin are usually benign, asymptomatic and resolve rapidly whether or not azithromycin is stopped. The acute hepatic injury with jaundice, however, can be prolonged and troublesome and lead to loss of intrahepatic bile ducts and vanishing bile duct syndrome. The injury and jaundice may arise after azithromycin is stopped, but appearance of jaundice in someone on azithromycin should lead to its prompt discontinuation. Rare instances of acute liver failure and fatality from azithromycin induced liver disease have been reported. Persons with preexisting, underlying chronic liver disease may be more susceptible to severe outcomes. There is likely to be cross reactivity in hepatic injury with other macrolide antibiotics, but this has not been well documented.

Drug Class: Antiinfective Agents, Macrolide Antibiotics


Case 1. Cholestatic hepatitis after azithromycin.(1)

A 69 year old man with community acquired pneumonia was treated with azithromycin (500 mg daily) for 3 days and developed dark urine and jaundice 3 days later. Laboratory tests showed marked elevations in alkaline phosphatase and bilirubin with modest increases in ALT and AST levels (Table). He tested negative for markers of hepatitis A, B and C infection, and liver ultrasound was normal. He was given ceftriaxone for his unresolved bronchopneumonia and recovered within the next few weeks.

Key Points

Laboratory Values


This was an early case report of azithromycin hepatotoxicity and clearly demonstrated its typical clinical pattern of abrupt onset of illness within a week of starting the medication—and actually a few days after stopping it. The cholestatic pattern of liver enzymes and jaundice are typical (but not invariable) of azithromycin hepatotoxicity. There was no mention of signs of hypersensitivity such as fever, rash, arthralgias or eosinophilia, although the concurrent pneumonia may have confounded the clinical picture. Recovery was reasonably rapid, but the benign outcome may have been because azithromycin was given for 3 days only. This patient should be advised against future exposure to azithromycin, but there is little information about his risks of liver injury with other macrolide antibiotics (such as erythromycin or clarithromycin).

Case 2. Hepatocellular liver injury due to azithromycin.(2)

A 69 year old woman developed weakness, anorexia, nausea, diarrhea, pruritus and jaundice 4 days after starting oral azithromycin (1000 mg initially, then 500 mg daily) for suspected acute bronchitis. She had no history of liver disease, did not drink alcohol and had no risk factors for viral hepatitis. Her past medical history included hypertension, dyslipidemia, a 50 pack year history of cigarette smoking, chronic obstructive pulmonary disease, hypothyroidism and depression for which she was taking lisinopril, simvastatin, aspirin, loratadine, albuterol by inhaler, levothyroxine and fluoxetine. She was also increasingly symptomatic from her acute pulmonary infection. Physical examination revealed jaundice but no fever, rash or organomegaly. She was dyspneic and had basilar inspiratory crackles and signs of consolidation. Laboratory tests showed bilirubin of 2.0 (direct 0.9) mg/dL, ALT 1065 U/L, AST 2001 U/L, Alk P 125 U/L and INR of 2.3 (Table). Tests for acute hepatitis A, B and C (including HCV RNA) were negative. ANA was negative, but smooth muscle antibody was reactive. A chest CT showed bibasilar pulmonary consolidations. She was admitted to the hospital, azithromycin was held and levofloxacin started. The following day she had a respiratory arrest, but was successfully resustained and placed on mechanical ventilation. Ultrasound of the abdomen showed no evidence of biliary obstruction although there was biliary sludge and gallbladder wall thickening. Over the first week of admission her serum enzymes remained high and serum bilirubin climbed to 18.5 mg/dL. However, her pulmonary status improved, she was successfully extubated and was eventually discharged on her previous medications without antibiotics and with improving serum enzymes. When seen in the outpatient clinic 2 and 5 months later, her liver tests were normal.

Key Points

Laboratory Values


The rapidity of onset of injury after starting azithromycin suggests previous exposure either to azithromycin specifically or to another macrolide. The initial injury was distinctly hepatocellular, with ALT levels 20 fold elevated and alkaline phosphatase at the upper limit of the normal range. The clinical course was complicated by a fairly severe pneumonitis in the setting of chronic obstructive pulmonary disease that led to a respiratory arrest, which may have accounted for the second rise in ALT levels and worsening of jaundice for 7 to 10 days after stopping the implicated antibiotic. Several of the other medications she was taking have a potential to cause acute liver injury, but all were restarted without recurrence. Thus, while atypical in some regards, the timing and course of the liver injury make azithromycin the most likely cause.



Azithromycin — Generic, Zithromax®


Antiinfective Agents


Product labeling at DailyMed, National Library of Medicine, NIH


Azithromycin is a macrolide antibiotic and semisynthetic derivative of erythromycin with a methyl-substituted nitrogen atom in the large lactone ring. It is orally bioavailable, has a prolonged half-life (allowing for once daily administration), and exhibits excellent tissue penetration and distribution.


Longo G, Valenti C, Gandini G, Ferrara L, Bertesi M, Emilia G. Azithromycin-induced intrahepatic cholestasis. Am J Med. 1997;102:217–8. [PubMed: 9217574]
Lockwood AM, Cole S, Rabinovich M. Azithromycin-induced liver injury. Am J Health Syst Pharm. 2010;67:810–4. [PubMed: 20479103]


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    (In Brazil between March and August 2020, a total of 631 adverse event reports in 402 patients with COVID-19 were received between March and August 2020, of which 56 cases [9%] were hepatic including 28 attributed to hydroxychloroquine [2 fatal], 4 azithromycin [1 fatal], and 2 chloroquine [2 fatal]).
  • RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial. Lancet. 2021;397(10274):605–12. [PMC free article: PMC7884931] [PubMed: 33545096]
    (Among 2582 hospitalized patients with COVID-19 pneumonia randomized to receive azithromycin [500 mg daily for 10 days] vs 5181 given usual care, the mortality rate in the two groups was identical [22%] and duration of hospitalization similar [10 vs 11 days]; only one serious adverse event was reported due to azithromycin: a self-limited case of pseudomembranous colitis).
  • PRINCIPLE Trial Collaborative Group. Azithromycin for community treatment of suspected COVID-19 in people at increased risk of an adverse clinical course in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. Lancet. 2021;397(10279):1063–74. [PMC free article: PMC7972318] [PubMed: 33676597]
    (In an adaptive UK based study with a randomized trial of azithromycin [500 mg daily for 3 days] or usual care in patients with suspected COVID-19 who were above the age of 65 years [or above the age of 50 with comorbidities], the rates of recovery by 28 days were similar [80% vs 77%] and there were no deaths and few adverse events that could be related to drug).