© 2002 by the Infectious Diseases Society of America. All rights reserved.

1058-4838/2001/3312-0024$03.00

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BRIEF REPORT

Possible Levofloxacin-Induced Acute Hepatocellular Injury in a Patient with Chronic Obstructive Lung Disease

Anita Karim,1 Shahid Ahmed,1 Leonard J. Rossoff,1 Rina K. Siddiqui,2 and Harry N. Steinberg1

1Department of Medicine, Long Island Jewish Medical Center, New Hyde Park, Long Island Campus of the Albert Einstein College of Medicine, Bronx, and 2Department of Pathology, St. Luke'sRoosevelt Hospital, New York, New York

Received 13 June 2001; revised 27 August 2001; electronically published 9 November 2001.

Levofloxacin is one of the most commonly prescribed antibiotics for both inpatient and outpatient care of respiratory tract infection. It is generally well tolerated, and it has an excellent safety profile. We report a case of severe acute liver toxicity that apparently complicated intravenous administration of levofloxacin, which resolved after discontinuation of the drug.

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Reprints or correspondence: Dr. Leonard J. Rossoff, Div. of Pulmonary and Critical Care Medicine, Long Island Jewish Medical Center, Long Island Campus of the Albert Einstein College of Medicine, Rm. C-20, 270-05 76th Ave., New Hyde Park, NY 11040 (anitakarim00@yahoo.com).

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Levofloxacin is a fluoroquinolone antibiotic that is widely used for the treatment of respiratory, urinary, and soft-tissue infections. We describe a case of reversible hepatotoxicity associated with the administration of levofloxacin.

Case report. A 74-year-old woman with severe emphysema and chronic atrial fibrillation was admitted to the hospital with a lower respiratory tract infection and without radiographic evidence of infiltrates. Two years before admission, she underwent right upper lobectomy for epidermoid carcinoma without evidence of recurrence. Physical examination of the patient revealed the following values: blood pressure, 105/60 mm Hg; respiratory rate, 30 beats/min; temperature, 37.3°C; pulse, 100 beats/min; and oxygen saturation, 92% on 2 liters of oxygen. Respiratory examination was remarkable for significant hyperinflation and decreased breath sounds bilaterally. A diagnosis of acute bronchitis was made, and the patient began receiving iv methylprednisolone, 60 mg per day, and levofloxacin, 500 mg per day. The other medications that the patient was receiving were digoxin, warfarin, inhaled albuterol, and ipratropium bromide. She denied use of alcohol, herbal products, or any over-the-counter medications.

Laboratory evaluation revealed a WBC count of 14.1 × 109 cells/L, a hemoglobin level of 14.3 g/dL, and a platelet count of 163 × 109 platelets/L. Serum chemistry evaluation revealed a bicarbonate level of 31 mM, blood urea nitrogen level of 20 mg/dL, and a creatinine level of 1.1 mg/dL. A liver function test performed at the time of admission to the hospital revealed the following values; aspartate aminotransferase, 32 U/L (normal range, 1047 U/L), alanine aminotransferase, 40 U/L (normal range, 952 U/L); total bilirubin, 0.4 mg/dL (normal range, 0.21.3 mg/dL); and alkaline phosphatase, 82 U/L (normal range, 25115 U/L). Two days after administration of levofloxacin was initiated, the serum transaminase levels increased precipitously, eventually reaching the following peak values: aspartate aminotransferase, 4962 U/L; alanine aminotransferase, 7071 U/L; total bilirubin, 2.5 mg/dL; and alkaline phosphatase, 90 U/L (table 1). Prothrombin time increased from 15 s to 37 s, and the international normalization ratio increased from 3 to 9.3, with an activated partial prothrombin time of 40 s. There was no clinical evidence of bleeding, jaundice, ascites, or organomegaly, and the patient did not have a rash, peripheral eosinophilia, or other manifestations of an allergic reaction. The patient was transferred to our tertiary care hospital for further treatment.

Table 1. The results of liver function tests after administration of levofloxacin.

Several hours after the patient was transferred, she developed acute respiratory distress that required that she undergo intubation and mechanical ventilation. Arterial blood gas analysis on a fraction of inspired oxygen of 50% revealed the following values: pH, 7.09; partial pressure of carbon dioxide, 106 mm Hg; partial pressure of oxygen, 191 mm Hg; alveolar-arterial oxygen gradient, 33; bicarbonate level, 32 mM; and oxygen saturation, 99%. Serum chemistry evaluation demonstrated an anion gap of 10 mM; however, a lactic acid level was not determined. The patient's blood pressure remained stable, and she never lost consciousness. A chest radiograph did not reveal infiltration. Therapy with levofloxacin and warfarin was discontinued, and within 1 week, a significant reduction in the serum transaminase levels was noted and prothrombin times returned to normal. The results of serologic testing for viral hepatitis (A, B, and C) were negative, and the findings of ultrasonography of the liver and biliary tract were normal. Initial weaning efforts were not successful, and the patient underwent tracheostomy. Her clinical course was subsequently complicated by nosocomial pneumonia, sepsis, and upper gastrointestinal bleeding. The patient eventually developed multiorgan failure and died. Autopsy was declined by the patient's family.

Discussion. Liver toxicity may result from the administration of a number of chemical and pharmacological agents, and the spectrum of injury can resemble any form of liver disease. The factors that determine individual vulnerability to liver toxicity may include genetic predisposition, age, nutritional status, systemic disease, and concomitant exposure to other hepatotoxic agents. Acute liver toxicity is often classified as a cytotoxic or cholestatic injury. Only a few medications, such as acetaminophen and salicylates, are intrinsically hepatotoxic, causing liver injury in a dose-dependent and predictable manner. The majority of drug-induced liver injuries are idiosyncratic reactions and occur in an unpredictable manner. The idiosyncratic reaction could be either metabolic or a hypersensitivity reaction, and it may occur at any time during exposure to a drug [1, 2].

Antimicrobial agents have been implicated as a potential cause of liver injury. During the past 2 decades, fluoroquinolones have become a dominant class of antimicrobial agents, and, among them, levofloxacin has emerged as a first-line therapy for community-acquired pneumonia [3]. It has an excellent safety profile, with 2%9.9% of study subjects having experienced adverse events in various clinical trials. Nausea (in 1%3% of subjects) and diarrhea (in 1%2%) are the most frequently reported reactions [4]. As a group, fluoroquinolones have been associated with liver toxicity, usually in the form of transient elevation of transaminase levels; cholestatic jaundice and hepatitis have been less common, and hepatic failure has been rare. The clinical use of trovafloxacin has been restricted because of multiple reports of fulminant hepatic failure [3, 4]. The medical literature, however, reveals only a few cases of fluoroquinolone-induced liver toxicity [5, 6]. Data from clinical trials have revealed a very low frequency (0.3%) of abnormal liver function test values associated with the use of levofloxacin, none of which necessitated the discontinuation of therapy [7].

In the present report, we describe a case of acute reversible hepatocellular injury after the administration of levofloxacin. To our knowledge, severe hepatic toxicity associated with levofloxacin use has not been previously reported in the English-language literature. Although hepatotoxicity has been described as a rare complication of the use of coumarin anticoagulants, the presence of a temporal relationship between the liver injury and levofloxacin administration, and a rapid reduction in liver enzyme levels after discontinuation of the drug, strongly implicated levofloxacin as a potential cause of hepatocellular injury [8, 9]. Furthermore, an increase in liver enzyme levels before respiratory failure and the exclusion of other causes or factors, such as negative results of serologic tests for hepatitis, absence of hypotension, or use of other hepatotoxic agents, further support levofloxacin hepatotoxicity in our case. The mechanism that caused transient elevation of serum transaminase levels and acute hepatocellular injury owing to levofloxacin administration is not known. Levofloxacin is the levorotatory isomer of ofloxacin; it undergoes limited metabolism and is primarily excreted unchanged in urine. The absence of allergic manifestations in our patient suggests an idiosyncratic reaction. Coadministration of warfarin with levofloxacin in healthy volunteers has not revealed significant interaction, and any potential role of warfarin as a factor contributing to hepatocellular injury in our patient is unknown [10]. It is unclear whether a prolonged half-life of levofloxacin in the presence of renal impairment may have potentiated its toxicity.

In conclusion, levofloxacin is commonly used and has an excellent safety profile, which may result in a low index of suspicion of drug-induced hepatic dysfunction. Clinicians should be aware of the possibility of severe hepatic injury associated with fluoroquinolones, in general, and with levofloxacin, specifically. Liver enzyme abnormalities should be addressed seriously, because discontinuation of the drug appears to result in rapid improvement. It is unclear whether there is need for routine monitoring of hepatic function in view of the apparent rarity of this adverse effect.

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