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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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Levofloxacin

Last Update: March 10, 2020.

OVERVIEW

Introduction

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.

Background

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, severe hypersensitivity reactions, Stevens Johnson syndrome, angioedema and photosensitivity.

Hepatotoxicity

In short term studies, levofloxacin has been associated with minor elevations in serum ALT and AST levels in 2% to 5% of patients. The abnormalities were usually asymptomatic and transient and rarely require dose modification. With its wide scale use, levofloxacin has been implicated in in at least 50 instances of clinically apparent liver injury mostly in isolated case reports. The clinical presentation and course are 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 or mixed 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. While liver injury from levofloxacin is rare, the fluoroquinolones collectively are among the most frequent causes of clinically apparent liver injury including fatal cases and cases of chronic liver injury and bile duct paucity.

Likelihood score: A (well established cause of clinically apparent 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

The severity of levofloxacin liver injury 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 resolution of clinical symptoms and signs is usually rapid (4 to 8 weeks). There are no known effective therapies for levofloxacin or other fluoroquinolone associated liver injury. Features of hypersensitivity, such as fever and rash may respond rapidly to corticosteroids, but the dose and duration of such treatment should be limited and carefully monitored. Recurrence of features of hypersensitivity and liver injury on rechallenge is common and should be avoided. Cross reactivity of the hepatic injury between different fluoroquinolones has been demonstrated in rare instances and, based upon the similarity of clinical patterns of injury and latency, should be suspected. Thus, patients should be advised to avoid further exposure to levofloxacin as well as other fluoroquinolones.

Drug Class: Antiinfective Agents

Other Drugs in the Subclass, Fluoroquinolones: Ciprofloxacin, Delafloxacin, Gemifloxacin, Moxifloxacin, Norfloxacin, Ofloxacin

CASE REPORT

Case 1. Acute hepatocellular injury due to levofloxacin therapy.(1)

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.

Key Points

Medication:Levofloxacin, 500 mg intravenously daily for 5 days
Pattern:Hepatocellular (ALT elevations with normal Alk P)
Severity:3+ (jaundice and hospitalization)
Latency:5 days
Recovery:Incomplete before death due to complications of underlying illness
Other medications:Digoxin, coumadin, inhaled albuterol and ipratropium

Laboratory Values

Time After
Starting		Time After
Stopping		ALT
(U/L)		Alk P
(U/L)		Bilirubin
(mg/dL)		Other
1 day40820.4Protime 15 sec.
3 days128890.5
5 days07071731.9Protime 37 sec.
7 days2 days3736702.5
8 days3 days2336811.7
9 days4 days1659851.2
10 days5 days749851.2
16 days11 days75900.8
Normal Values <53 <115 <1.2

Comment

This patient developed dramatic serum aminotransferase elevations within days of starting levofloxacin, compatible with the short latency period and abrupt onset of hepatic injury that is typical of liver injury from the fluoroquinolones. In this instance, another possible diagnosis was acute heart failure and ischemic hepatitis, but no mention was made in the brief report of hypotension or hypoxemia. Serum LDH levels would have been 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.

PRODUCT INFORMATION

REPRESENTATIVE TRADE NAMES

Levofloxacin – Generic, Levaquin®

DRUG CLASS

Antiinfective Agents

COMPLETE LABELING

Product labeling at DailyMed, National Library of Medicine, NIH

CHEMICAL FORMULA AND STRUCTURE

DRUGCAS REGISTRY NOMOLECULAR FORMULASTRUCTURE
Levofloxacin 100986-85-4 C18-H20-F-N3-O4 image 135015357 in the ncbi pubchem database

CITED REFERENCE

1.
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: 11712098]

ANNOTATED BIBLIOGRAPHY

References updated: 10 March 2020

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    (Among 363 patients with drug induced liver injury who underwent liver biopsy, 26 [7%] had bile duct loss of whom 94% developed evidence of chronic liver injury suggestive of vanishing bile duct syndrome, 2 of which were due to fluoroquinolones, 1 to moxifloxacin and 1 levofloxacin).
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    (Among 124 patients with cirrhosis and ascites given prophylaxis with daily norfloxacin [400 mg] or weekly oral ciprofloxacin [750 mg], subsequent rates of bacterial peritonitis were similar [7% vs 5%] as were rates of liver transplantation and death).
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    (Table comparing 4 fluoroquinolones [cipro-, levo-, dela- and moxifloxacin] mentions that ALT and AST elevations are a class adverse event).
  • Mavros MN, Theochari NA, Kyriakidou M, Economopoulos KP, Sava JA, Falagas ME. Fluoroquinolone-based versus β-lactam-based regimens for complicated intra-abdominal infections: a meta-analysis of randomised controlled trials. Int J Antimicrob Agents. 2019;53:746–54. [PubMed: 30639629]
    (Systematic review of controlled trials of fluoroquinolones versus βlactam-based antibiotic regimens found similar rates of efficacy and adverse events, no discussion of ALT elevations or liver related toxicities).
  • Kuula LSM, Viljemaa KM, Backman JT, Blom M. Fluoroquinolone-related adverse events resulting in health service use and costs: A systematic review. PLoS One. 2019;14:e0216029. [PMC free article: PMC6485715] [PubMed: 31026286]
    (Systematic review of observational studies on safety of fluoroquinolones concluded that due to lack of published literature, health service and costs could not be evaluated).

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