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 Last Updated: 24 February 2014
Zimmerman HJ. Quinolones. In, Zimmerman HJ. Hepatotoxicity: the adverse effects of drugs and other chemicals on the liver. 2nd ed. Philadelphia: Lippincott, 1999. p 603. (Expert review of hepatotoxicity published in 1999; mentions that cinoxacin, nalidixic acid, ciprofloxacin, norfloxacin, enoxacin, and ofloxacin are associated with minor serum enzyme elevations during therapy and with rare instances of clinically apparent liver injury; levofloxacin is not discussed).
Moseley RH. Fluoroquinolones. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced liver disease. 3rd Edition. Amsterdam: Elsevier, 2013. p. 468-9. (Review of hepatotoxicity of fluoroquinolones; mentions that hepatocellular and cholestatic forms of injury have been reported due to the quinolones including cases of ductopenia, acute liver failure and death).
Petri WA Jr. The quinolones. Sulfonamides, trimethoprim-sulfamethoxazole, quinolones, and agents for urinary tract infections. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1470-4. (Textbook of pharmacology and therapeutics).
Kahn JB. Latest industry information on the safety profile of levofloxacin in the United States. Chemotherapy 2001; 47 (Suppl 3): 32-7; discussion 44-8. PubMed Citation (Industry summary of postmarketing reporting on adverse side effects of levofloxacin; after 130 million prescriptions, estimated rate of hepatitis and hepatic failure was less than 1 per million prescriptions).
Spahr L, Rubbia-Brandt L, Marinescu O, Armenian B, Hadengue A. Acute fatal hepatitis related to levofloxacin. J Hepatol 2001; 35: 308-9. PubMed Citation (99 year old man developed jaundice 8 days after starting oral levofloxacin [bilirubin 18.9 mg/dL, ALT 4440 U/L, Alk P 157 U/L, prothrombin time 57 seconds], with rapid progression to coma and death 6 days after presentation).
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).
Digwood-Lettieri S, Reilly KJ, Haith LR Jr, Patton ML, Guilday RJ, Cawley MJ,
Ackerman BH. Levofloxacin-induced toxic epidermal necrolysis in an elderly patient. Pharmacotherapy 2002; 22: 789-93. PubMed Citation (78 year old woman developed rash 2 days after finishing a 10 day course of levofloxacin, with blistering and mucosal sloughing involving 73% of body surface area and stormy course but recovery; no mention of liver test results).
Heluwaert F, Roblin X, Duffournet V, Capony P, Martin D, Roblin X. [Hepatitis related to amoxicillin or levofloxacin: a case report]. Rev Med Interne 2003; 24: 841-3. French. PubMed Citation (31 year old woman developed jaundice a few days after a 5 day course of oral levofloxacin [bilirubin 8.1, ALT 9.6 times ULN, Alk P 1.9 times ULN], with persistence of jaundice and pruritus for 1 month, but resolution within 2 months).
Schwalm JD, Lee CH. Acute hepatitis associated with oral levofloxacin therapy in a hemodialysis patient. CMAJ 2003; 168: 847-8. PubMed Citation (73 year old man diabetes, coronary artery disease and renal failure was found to be jaundiced and confused 3 weeks after starting oral levofloxacin [bilirubin 4.1 mg/dL, ALT 857 U/L, Alk P 423 U/L, INR 2.4], improving rapidly upon stopping levofloxacin, but dying 2 weeks later from postoperative complications after bilateral above knee amputations).
Coban S, Ceydilek B, Ekiz F, Erden E, Soykan I. Levofloxacin-induced acute fulminant hepatic failure in a patient with chronic hepatitis B infection. Ann Pharmacother 2005; 39: 1737-40. PubMed Citation (55 year old woman, who was known to be an HBsAg carrier, developed jaundice and fatigue 2 days after finishing a 2 week course of oral levofloxacin [bilirubin 32.3 mg/dL, ALT 401 U/L, Alk P 147 U/L, prothrombin time 29.7 seconds], developing hepatic failure and dying 3 months later, becoming HBsAg negative with injury but remaining IgM anti-HBc negative).
Carrascosa MF, Lucena MI, Andrade RJ, Caviedes JRS, et al. Fatal acute hepatitis after sequential treatment with levofloxacin, doxycycline, and naproxen in a patient presenting with acute Mycoplasma pneumoniae infection. Clin Ther 2009; 31: 1014-19. PubMed Citation (63 year old man developed jaundice 6 days after stopping a 4 day course of levofloxacin and at the end of a 6 day course of doxycycline [bilirubin 4.0 mg/dL, ALT 1577 U/L, Alk P 189 U/L], progressing to hepatic failure and death 17 days later).
Orman ES, Conjeevaram HS, Vuppalanchi R, Freston JW, Rochon J, Kleiner DE, Hayashi PH; DILIN Research Group. Clinical and histopathologic features of fluoroquinolone-induced liver injury. Clin Gastroenterol Hepatol 2011; 9: 517-523. PubMed Citation (Among 679 cases of drug induced liver injury presenting between 2004 and 2010 at 8 US medical centers, 12 [1.8%] were attributed to fluoroquinolones including 6 cipro-, 4 moxi-, 1 levo-, and 1 gati-floxacin; average time to onset 4 days [range 1-39], with both hepatocellular and cholestatic enzyme patterns, seven with rash or fever, mortality limited to those with hepatocellular injury and jaundice; levofloxacin case was 23 year old woman who developed mixed serum enzyme elevations [peak bilirubin 0.8 mg/dL, ALT 199 U/L, Alk P 170 U/L] 1 day after starting drug).
Figueira-Coelho J, Pereira O, Picado B, Mendonça P, Neves-Costa J, Neta J. Acute hepatitis associated with the use of levofloxacin. Clin Ther 2010; 32: 1733-7. PubMed Citation (77 year old man with chronic bronchitis developed liver test elevations within 7 days of starting levofloxacin [peak bilirubin 0.7 mg/dL, ALT 912 U/L, Alk P 119 U/L], improving upon stopping and resolving completely within 3 months).
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. PubMed Citation (65 year old woman received TMP/SMZ for 5 days, followed by levofloxacin for 6 days and then doxycycline for 10 days with sertraline for the whole period, developing fatigue and pruritus 15 days after stopping antibiotics [bilirubin 3.5 rising to 14.2 mg/dL, ALT 937 U/L, Alk P 373 U/L], resolving with stopping all medications and prednisone therapy).
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. PubMed
Citation (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, of which 1 was attributed to
ciprofloxacin but none to other fluoroquinolones including levofloxacin).
Titos-Arcos JC, Hallal H, Robles M, Andrade RJ. [Acute cholestatic hepatitis associated with levofloxacin.]. Gastroenterol Hepatol 2011; 34: 369-370. Spanish. PubMed Citation (51 year old woman developed serum enzyme elevations within 5 days of starting oral levofloxacin and iv ceftriaxone [bilirubin normal, ALT 41 U/L, Alk P 1327 U/L], resolving within a month of stopping both antibiotics).
Coelho J, Gonçalves C, Leitão S, Marques Dos Santos R, Nascimento Costa J.
[Levofloxacin hepatotoxicity. Higher risk in diabetics?]. Acta Med Port 2011; 24 Suppl 3: 729-34. Portuguese. PubMed Citation (Two cases of levofloxaxin hepatotoxicity in elderly patients [81 and 87 years old] with type 2 diabetes, with onset of symptoms or jaundice within 3 weeks of starting [bilirubin 2.2 and 7.8 mg/dL, ALT 85 and 352 U/L, Alk P 1129 and 908 U/L], both with recovery after stopping).
Levofloxacin revisited. Med Lett Drugs Ther 2011; 53: 55. PubMed Citation (Short review of the safety of levofloxacin stressing the adverse effects of tenodon rupture, hypersensitivity reactions, Stevens Johnson syndrome and toxic epidermal necrolysis).
Fernández Arenas O, López Lunar E, Gutiérrez García M, Hidalgo Correas FJ,
García Díaz B. [Levofloxacin-related Stevens-Johnson syndrome]. Farm Hosp 2012; 36: 53-5. Spanish.PubMed Citation (84 year old woman developed rash within a day of starting levofloxacin that was continued for 4 days, and followed a week later by extensive rash with mucosal involvement and complicated course, no mention of hepatic injury).
Paterson JM, Mamdani MM, Manno M, Juurlink DN; Canadian Drug Safety and
Effectiveness Research Network. Fluoroquinolone therapy and idiosyncratic acute
liver injury: a population-based study. CMAJ 2012; 184: 1565-70. PubMed Citation (In a population based study using Canadian health care databases, the risk of admission to hospital for acute liver injury was increased for persons who received a prescription for moxifloxacin or levofloxacin relative to clarithromycin, but not for ciprofloxacin).
Hayashi PH, Chalasani NP.
Liver injury in the elderly due to fluoroquinolones: should these drugs be
avoided? CMAJ 2012; 184: 1555-6. PubMed Citation (Editorial in response to Paterson  stressing the low
absolute risk of liver injury from the fluoroquinolones [4-9 per 100,000
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; 114: 1419-25. PubMed Citation (In a population
based study of drug induced liver injury from Iceland, 96 cases were identified
over a 2 year period, none of which were attributed to levofloxacin or other
Naveen KN, Pai VV, Rai V, Athanikar SB. Retrospective analysis of Steven
Johnson syndrome and toxic epidermal necrolysis over a period of 5 years from
northern Karnataka, India. Indian J Pharmacol 2013; 45: 80-2. PubMed Citation (Among 22 patients seen at a single referral hospital in India between 2002-2007 with Stevens Johnson syndrome or toxic epidermal necrolysis, 11 were due to anticonvulsants and 7 to antibiotics, including 1 attributed to levofloxacin).
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