Levofloxacin is a third generation fluoroquinolone that is widely used in the treatment of mild-to-moderate respiratory and urinary tract infections due to sensitive organisms. Levofloxacin has been linked to rare instances of clinically apparent hepatic injury marked by a short latency period and a hepatocellular pattern of enzyme elevations, similar to what has been described with ciprofloxacin.
Levofloxacin (lee" voe flox' a sin) is the L-enantiomer of ofloxacin and is considered a third generation fluoroquinolone. Like other fluoroquinolones, levofloxacin is active against a wide range of aerobic gram-positive and gram-negative organisms. The fluoroquinolones are believed to act by inhibition of type II DNA toposiomerases (gyrases) that are required for synthesis of bacterial mRNAs (transcription) and DNA replication. They demonstrate little inhibition of human, host enzymes and have had an excellent safety record. Levofloxacin was approved for use in the United States in 1996 and remains in wide use. Levofloxacin is used for mild-to-moderate infections, the typical indications including sinusitis, bronchitis, community acquired pneumonia, skin infections, urinary tract infections, pyelonephritis, prostatitis, plague and anthrax. Levofloxacin is available in generically and under the commercial name Levaquin as tablets of 250, 500 and 750 mg, the usual dose being 250 to 750 mg once daily depending upon the indication and severity of the infection. Intravenous formulations are available for moderate-to-severe infections, the usual IV dosages being 500 mg daily. Oral therapy is typically continued for 7 to 14 days, but both shorter and longer courses have been used. Levofloxacin, like other fluoroquinolones, is generally well tolerated, but common side effects can include
gastrointestinal disturbances, headaches, skin rash and allergic reactions. Rare but more severe side effects include QT prolongation, seizures, hallucinations, tendon rupture, hypersensitivity reactions, angioedema and photosensitivity.
In short term studies, levofloxacin has been associated with minor elevations in serum ALT and AST levels in approximately 5% of patients. The abnormalities are usually asymptomatic and transient are rarely require dose modification. Despite its wide scale use, levofloxacin has been implicated only rarely in cases of clinically apparent liver injury and in isolated case reports. The clinical presentation and course is typical of the hepatotoxicity of other fluoroquinolones, and the injury is likely a class effect. The latency to onset is usually short (1 to 3 weeks) and the onset is often abrupt with a hepatocellular pattern of injury, jaundice and, in some instances, hepatic failure. Cholestatic hepatitis can also occur. Immunoallergic features such as fever, rash and eosinophilia are common, but not particularly prominent. Autoantibodies are rare. The liver injury is usually self-limited, but several cases of acute liver failure have been linked to fluoroquinolones as well as instances of prolonged jaundice, cholestasis and vanishing bile duct syndrome. Levofloxacin, like ciprofloxacin, has also been implicated hypersensitivity reactions including rare cases of Stevens Johnson syndrome and toxic epidermal necrolysis, which may be accompanied by liver injury.
Mechanism of Injury
The rapid onset and severe course of levofloxacin associated liver injury suggests hypersensitivity, although allergic manifestations are not always present and are generally mild and transient.
Outcome and Management
Severity ranges from mild and transient serum enzyme elevations to self-limited hepatocellular injury, cholestatic hepatitis, to acute liver failure. In milder cases, complete recovery is expected after stopping the drug and recovery is usually rapid (4 to 8 weeks). Recurrence on rechallenge is common. Cross reactivity of the hepatic injury between different fluoroquinolones has been demonstrated in rare instances and is suspected, based upon the similarity of clinical patterns of injury and latency. Thus, patients should be advised to avoid further exposure to levofloxacin as well as other fluoroquinolones.
Drug Class: Antiinfective Agents, Fluoroquinolones
Case 1. Acute hepatocellular injury due to levofloxacin therapy.
[Modified from: Karim A, Ahmed S, Rossoff LJ, Siddiqui RK, Steinberg HN. Possible levofloxacin-induced acute hepatocellular injury in a patient with chronic obstructive lung disease. Clin Infect Dis 2001; 33: 2088-90. PubMed Citation]
A 74 year old woman with emphysema and chronic atrial fibrillation was admitted for therapy of suspected acute bronchitis and treated with intravenous methylprednisolone (60 mg/day) and levofloxacin (500 mg/day). Serum aminotransferases were normal on admission, but became abnormal after 3 days of therapy and were markedly elevated by 5 days (Table). She became mildly icteric, but recovered rapidly once levofloxacin was discontinued. There was no rash or eosinophilia. Tests for hepatitis A, B and C were negative and ultrasonography of the liver and biliary tract was normal. She had no history of alcohol use and there was no apparent episode of acute heart failure or shock. While she appeared to be recovering from the hepatic injury, she developed progressive pulmonary failure, pneumonia and died of sepsis, gastrointestinal bleedings and multiorgan failure several weeks later.
|| Levofloxacin, 500 mg intravenously daily for 5 days
|Pattern:|| Hepatocellular (ALT elevations with normal Alk P)|
||3+ (jaundice and hospitalization)
|| 5 days
|Recovery:||Incomplete before death due to complications of underlying illness|
|Other medications:|| Digoxin, coumadin, inhaled albuterol and ipratropium|
|Time After Starting
||Time After Stopping
||Alk P (U/L)
||Protime 15 sec.
||Protime 37 sec.
This patient developed dramatic serum aminotransferase elevations within days of starting levofloxacin, compatible with the short latency period to onset of hepatic injury with the fluoroquinolones. Another possible diagnosis was acute heart failure, but no mention is made in the brief report of hypotension or hypoxemia. Serum LDH levels would be helpful in making this distinction. The patient did not develop rash, fever or eosinophilia with the hepatic injury, but she was receiving high doses of methylprednisolone which may have blunted these manifestations of hypersensitivity (as well as the severity of the liver injury itself). While recovering from the hepatic injury, the patient developed further pulmonary complications and died of multiorgan failure. Thus, while apparently self-limited, the hepatic injury may have contributed to her further complications of her chronic obstructive pulmonary disease.
REPRESENTATIVE TRADE NAMES
Levofloxacin – Generic, Levaquin®
Product labeling at DailyMed, National Library of Medicine, NIH
||CAS REGISTRY NO
References updated: 24 February 2014
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Karim A, Ahmed S, Rossoff LJ, Siddiqui RK, Steinberg HN. Possible levofloxacin-induced acute hepatocellular injury in a patient with chronic obstructive lung disease. Clin Infect Dis 2001; 33: 2088-90. PubMed Citation (74 year old woman developed serum enzyme elevations within 2 days and jaundice after 5 days of iv levofloxacin [bilirubin 2.5 mg/dL, ALT 4962 U/L, Alk P 90 U/L], with rapid improvement upon stopping; however, patient subsequently died of sepsis and multiple organ failure: Case 1).
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