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 eythromycin 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 anitbiotic 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 brochiectasis). 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.
Like other macrolide antibiotics, azithromycin has been linked to two forms of hepatotoxicity. The first is an acute, transient and asymptomatic elevation in serum aminotransferases which occurs in 1-2% 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 liver injury caused by azithromycin resembles that described with other macrolides and is typically cholestatic, 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. The initial pattern of liver enzyme elevations can be hepatocellular (Case 2), but the subsequent course is usually cholestatic and can be prolonged. In most cases, recovery occurs within 4 to 8 weeks of stopping the medication, but striking examples of prolonged jaundice and vanishing bile duct syndrome have been reported after azithromycin use.
Mechanism of Liver Injury:
The idiosyncratic liver injury 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. Rare instances of acute liver failure and fatality from azithromycin-induced liver disease have been reported. There is likely to be cross-reactivity in hepatic injury with other macrolide antibiotics but this has not been documented.
Case 1. Cholestatic hepatitis after azithromycin.
[Modified from: Longo G, Valenti C, Gandini G, Ferrara L, Bertesi M, Emilia G. Azithromycin-induced intrahepatic cholestasis. Am J Med 1997; 102: 217-8. PubMed Citation]
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.
|Medication:||Azithromycin (500 mg daily for 3 days)|
|Pattern:|| Cholestatic (R=0.4)|
||3+ (Jaundice and hospitalization)
|Recovery:||Complete within one month|
|Other medications:|| None mentioned|
|Time After Starting
||Time After Stopping
||Alk P* (U/L)
|Dark urine and jaundice 3 days after stopping azithromycin
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.
[Modified from: Lockwood AM, Cole S, Rabinovich M. Azithromycin-induced liver injury. Am J Health Syst Pharm 2010; 67: 810-4. PubMed Citation.]
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 lisiniopril, 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 anitbody 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.
||Azithromycin (500-1000 mg daily orally for 4 days)
|| Hepatocellular (R=20)
||4+ (Jaundice, hospitalization, prolonged INR)
||Complete within two months
|| Chronically: lisinopril, simvastatin, aspirin, albuterol, loratadine, levothyroxine, fluoxetine
|Days After Starting
||Days After Stopping
||Alk P (U/L)
|Fatigue, weakness, nausea and jaundice 4 days after starting azithromycin
||Admission, INR 2.3
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.
Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from
the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared
of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.
REPRESENTATIVE TRADE NAMES
FDA pProduct labeling at DailyMed, National Library of Medicine, NIH
Zithromax® (azithromycin) – Product Labeling, Pfizer Labs, May 2006.
||CAS REGISTRY NUMBER
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.
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