Kelly J. Airey, Internal Medicine Resident

University of Nebraska Medical Center, Nebraska-Western Iowa Veteran's Administration Health Care,

Elizabeth Koller

Send letter to journal:

Re: Acute hepatitis associated with levaquin in a patient with renal insufficiency taking amiodarone

We note with interest the report by Schwalm and Lee (April 1 issue)(1), of acute hepatitis in a hemodialysis patient taking oral levofloxacin. We observed an acute rise in hepatobiliary enzymes after therapy with levofloxacin, resolution with discontinuation, and recurrence with rechallenge with another drug in the same class (ciprofloxacin).

Our patient was a 63-year-old African American male with mitral valve disease, coronary artery disease, chronic renal insufficiency, and lung cancer discovered at the time of cardiac surgery which resulted in abortion of the cardiac procedure. Post-operatively, he developed atrial fibrillation which was managed with amiodarone, 200 mg/day, and warfarin. He had no known underlying liver disease and did not use alcohol or over- the-counter medications. Other medications included furosemide, metolazone, simvastatin, iron sulfate, and inhaled triamcinolone. Six weeks post-operative, he developed orchitis, which was treated with levofloxacin, 250 mg/day. Hepatobiliary enzyme tests were unremarkable before initiation of levofloxacin with AST 44 U/L (15-46), ALT 49 U/L (11 – 66), alkaline phosphatase 118 U/L (38 – 126), and total bilirubin <1.7 mmol/L (1.7 – 2.2 ). His course was complicated by profuse epistaxis requiring hospitalization ten days after levofloxacin therapy institution. The protime was 47.35 sec (26.3-35.6) and INR 8.9 . The physical exam was negative for fever, rigors, icterus, hepatomegaly, or bony tenderness. He was mildly tender over the liver and in the epigastric region. Routine laboratory testing revealed an AST 360 U/L, ALT 468 U/L, alkaline phosphatase 1350 U/L, bilirubin 3.4 mmol/L and creatinine 371 mmol/L (62-133; baseline for patient 168 mmol/L). A hepatitis panel (hepatitis A IgM, hepatitis B surface antigen, hepatitis C antibody) was negative. Ultrasound revealed no biliary tract obstruction or evidence of liver disease. Hepatobiliary scanning was negative for cholecystitis. The oral levofloxacin was continued for two more days after admission and then discontinued along with the amiodarone. Thirty-six hours after discontinuation, hepatobiliary enzymes peaked: AST 270 U/L, ALT 346 U/L, and alkaline phosphatase 1053 U/L. Within three days of discontinuation, the level decreased dramatically: AST 40 U/L, ALT 145 U/L, alkaline phosphatase 577 U/L, and bilirubin 8.5 mmol/L. Oral ciprofloxacin, 500 mg bid was initiated. The following morning, his hepatobiliary enzymes were again elevated: AST 207 U/L, ALT 244 U/L, and alkaline phosphatase 933 U/L. The ciprofloxacin was discontinued. The following day his AST was 215 UI/l, ALT 274 U/L, alkaline phosphatase 1073 U/L, and bilirubin 2.8 mmol/L. Two weeks after discontinuation of the ciprofloxacin, the AST was 21 U/L, ALT 35 U/L, alkaline phosphatase 289 U/L, and bilirubin of 10.2 mmol/L.

The patient appears to have incurred two adverse events in conjunction with fluoroquinolone use. The first of these, the coagulopathy when used with warfarin, is relatively well established (2). The second, an increase in hepatobiliary enzymes, is less well established, but has been demonstrated with other drugs in the same class, such as trovofloxacin (3). Although amiodarone can exhibit delayed hepatotoxicity with accumulation of the drug, hepatotoxicity is usually heralded by a rise in ALT months after initiation of therapy unless the reaction is idiosyncratic and presents within the first four weeks (4). The initial rise in hepatobiliary enzymes in this patient occurred within days of initiation of levofloxacin and re-challenge with a second fluoroquinolone. Similar to the patient reported by Schwalm and Lee (1), our patient had acute-on-chronic renal dysfunction. Creatinine values were 212 mmol/L, with a pre-renal picture at the time of levofloxacin initiation, and a peak of 371 mmol/L with the appearance of epistaxis and a decrease to 177 mmol/L within four days with rehydration therapy and discontinuation of levofloxacin. Although nephrotoxicity and allergic nephritis have been linked to levofloxacin (5,6), it is unclear whether the drug was the precipitating factor for the reduced renal clearance in this patient. The altered renal clearance, however, could have further increased the potential for hepatotoxicity. Nonetheless, markedly decreased renal clearance was not required for a subsequent increase in hepatobiliary enzymes with fluoroquinolone rechallenge. The creatinine was 124 mmol/L at the time hepatobiliary enzymes began to rise. Once again, physicians should be alert to the possibility of fluoroquinolone associated hepatotoxicity. Co-morbidities such as renal failure may increase the potential for toxicity.

Kelly Airey M.D. Elizabeth Koller M.D. University of Nebraska Medical Center Nebraska-Western Iowa Veterans Administration Health Care Center Omaha, NE

The authors are with the Department of Internal Medicine, University of Nebraska Medical Center, Omaha, Nebraska.

Competing interests: none

Contributors: Dr. Airey is responsible for patient management, literature search and design. Dr. Koller is responsible for article conception and critical review of the manuscript for intellectual concept. Both authors approved of the final version.

References

1. Schwalm J, Lee C. Acute hepatitis associated with oral levofloxacin therapy in a hemodialysis patient. CMAJ 2003;168(7):847-848

2. Jones CB, Fugate SE. Levofloxacin and warfarin interaction. Ann Pharmoacother 2002 Oct:36(10):1554-7

3. Cunha BA. Antibiotic side effects. Med Clin North Am 2001 Jan;85:149-85

4. Pollak PT, You YD. Monitoring of hepatic function during amiodarone Therapy. Am Journal Cardiology Mar:1(5):613-16

5. Famularo G, De Simone C. Nephrotoxicity and purpura associated with levofloxacin. Ann Pharmacother 2002 Sep;36(9):1380-2

6. Physician’s Desk Reference, Medical Economics. Mortivale, NJ, Levaquin ®, Ortho-McNeill, 2003: 2466-2471