Gatifloxacin-Associated Acute Hepatitis


from Pharmacotherapy
Neil E. Henann, Pharm.D., and Michael F. Zambie, M.D., from the College of Pharmacy, University of Louisiana at Monroe, and St. Francis Medical Center, Monroe, Louisiana (Dr. Henann); and the Allergy and Asthma Clinic, Monroe, Louisiana, and Louisiana State University Medical Center, Shreveport, Louisiana (Dr. Zambie).


Abstract and Introduction
Abstract
Gatifloxacin, a fluoroquinolone with extended gram-positive activity, has become extensively used in both the community and hospital environments. Unfortunately, concerns have been raised about the use of certain fluoroquinolones because of adverse drug reactions. A 44-year-old woman developed acute hepatitis while receiving gatifloxacin for chronic sinusitis. After 5 days of receiving antibiotics, the patient developed nausea, lethargy, and abdominal pain, all of which progressed over the next few days. Liver function tests were elevated, with bilirubin peaking at 9.4 mg/dl. The patient also became jaundiced. A percutaneous liver biopsy showed acute hepatitis with eosinophilic infiltrates consistent with drug-induced hepatitis. All other drugs and disease processes were ruled out as likely causes of the patient's hepatitis. Clinicians should be alerted to the possibility that hepatitis may occur with gatifloxacin administration.

Introduction
Gatifloxacin (Tequin; Bristol-Myers Squibb Co., Princeton, NJ), an 8-methoxy-fluoroquinolone approved in December 1999, has been used in treating community-acquired pneumonia, acute sinusitis, acute exacerbations of chronic bronchitis, genitourinary tract infections, and skin and soft tissue infections. Its antimicrobial spectrum is similar to that of levofloxacin and moxifloxacin. All of these agents have greater gram-positive activity than older fluoroquinolones and gram-negative activity and efficacy against atypical pathogens.[1] Their safety profiles generally are considered favorable; however, specific agents in this class have been associated with significant adverse effects.
Temafloxacin, associated with immune-mediated hemolytic anemia accompanied by renal dysfunction, was withdrawn voluntarily in 1992. Grepafloxacin, due to a small number of cardiac arrhythmias related to QT-interval prolongation, voluntarily was withdrawn in 1999. Sparfloxacin causes a significant occurrence of skin reactions. Hypersensitivity reactions such as rash, urticaria, pruritus, and angioedema have occurred in up to 6.6% of patients receiving this agent. Moderate-to-severe phototoxicity has occurred in 2-7.9% of patients exposed to direct or indirect sunlight or to artificial ultraviolet light during or after treatment.[2] Trovafloxacin has been associated with severe liver abnormalities including symptomatic hepatitis, jaundice, and liver failure resulting in hepatic necrosis with eosinophilic infiltration,[3] liver transplantation, and death. The Food and Drug Administration (FDA) has reported more than 100 cases of hepatotoxicity associated with trovafloxacin; 14 cases involved acute liver failure, 4 patients required transplantation, and 5 patients died of liver disease. An FDA-issued black box warning describes the liver injury associated with trovafloxacin and provides recommendations for its use. Trovafloxacin should be reserved for patients with serious, life- or limb-threatening infections.[4] The chemical structures of both trovafloxacin and temafloxacin contain the 2,4-difluorophenyl group, which is hypothesized to cause hepatotoxicity.

As gatifloxacin's chemical structure does not contain the 2,4-difluorophenyl group, and less than 1% of the drug is metabolized in the liver, the risk for hepatotoxicity is probably low.[1] In a review of the literature and premarketing clinical trials, the agent has not been associated with significant alterations in liver function.[1] Hepatotoxicity and other adverse events related to gatifloxacin were evaluated in 15 clinical trials with a total enrollment of 6198 patients.[5] Alterations in liver function, defined as elevations of aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase, and bilirubin levels greater than 5 times the upper limit of normal, were reviewed. The results showed that the frequency of clinically significant elevations was less than or equal to 0.1% for AST, ALT, and alkaline phosphatase, and less than 0.4% for bilirubin. The authors concluded that gatifloxacin was not associated with hepatotoxicity.

The requirement that liver function tests must be greater than 5 times the upper limit of normal to be considered a clinically relevant alteration probably results in a significant number of patients with mild-to-moderate elevations who are missed. Liver injury is present when ALT, alkaline phosphatase, and bilirubin are increased to more than 2 times the upper limit of normal.[6] Furthermore, the Council for International Organizations of Medical Sciences defines liver injury as an increase of over 2 times the upper limit of the normal range for ALT or conjugated bilirubin, or a combined increase in AST, alkaline phosphatase, and total bilirubin, provided one of them is above 2 times normal.[7]

Data concerning adverse events related to gatifloxacin were obtained through the Freedom of Information Department at the FDA. The Adverse Event Reporting System in the Office of Postmarketing Drug Risk Assessment is a database of adverse events reported by health care professionals and others through the MedWatch program. Although the FDA does not assign causality, a suspect drug is reported. Accumulated case reports cannot be used to calculate frequency of estimates of drug risk.

Twenty-seven cases were reported by the FDA in which gatifloxacin was noted as the primary suspect in causing hepatotoxicity. Thirteen of them involved patients who were less than 50 years old. Six of these patients were jaundiced and five died, although the deaths were not necessarily attributed to gatifloxacin. In 11 other cases in which gatifloxacin was listed as the primary suspect for causing death, hepatotoxicity was listed as the principle reported reaction.

Bristol-Myers Squibb has indicated that one report of gatifloxacin-associated hepatotoxicity does exist (DR Blue, personal communication, April 2001).

We report a patient who developed acute hepatitis while receiving gatifloxacin for chronic sinusitis. To our knowledge, no reports describing this adverse drug reaction from this antibiotic have been published.

Case Report
A 44-year-old Caucasian woman with a history of chronic sinusitis was prescribed clarithromycin 500 mg every 12 hours. After taking the two doses of the agent, the patient experienced diarrhea and the drug was discontinued. Levofloxacin 500 mg/day was started and continued for 10 days with no clinical improvement. After 3 days without antibiotics, the patient was prescribed amoxicillin-clavulanate 875/125 mg twice/day for 35 days, also with little clinical improvement. A sinus computed tomography scan revealed persistent infection.
The patient was then started on gatifloxacin 400 mg once/day. On day 5 she developed nausea and epigastric pain, with subsequent progression of intermittent nausea and vomiting. She stopped taking the antibiotic on day 7. After three more days of persistent pain, lethargy, and nausea, the patient was hospitalized for evaluation. Her concurrent drugs were AlleRx (a combination of methscopolamine 2.5 mg plus pseudoephedrine 120 mg [AlleRx AM], and methscopolamine 2.5 mg plus chlorpheniramine 8 mg [AlleRx PM]), as well as a homeopathic remedy of colloidal silver.

On admission the patient's transaminase levels were elevated, and an ultrasound demonstrated mild cholelithiasis. Results from an endoscopic retrograde cholangiopancreatography were unremarkable, with no evidence of biliary obstruction or intrahepatic duct abnormality. An ultrasound of the gall bladder, liver, and pancreas revealed no abnormal findings. Hepatitis B surface antigen and antibody, hepatitis B core antibody, and hepatitis A antibody-IgM were all negative. Antinuclear antibody, anti-smooth muscle antibody, and anti-liver-kidney microsomal antibody also were negative. The patient remained significantly weak and fatigued with right upper quadrant pain and subsequently developed jaundice. Table 1 shows the results of liver function tests during the patient's hospitalization.

The patient was discharged but was then readmitted because of increasing malaise and abdominal pain. Liver function tests revealed bilirubin peaking at 9.4 mg/dl. No confusion, peripheral edema, or increasing abdominal girth were noted. The patient's jaundice and conjunctival icterus continued to worsen. She was placed on intravenous fluids and a clear liquid diet.

Computed tomography of the abdomen ruled out inferior vena cava hepatic vein abnormality as well as duct enlargement. A percutaneous liver biopsy demonstrated acute hepatitis with eosinophilic infiltrates consistent with drug-induced hepatitis. The patient remained weak with some peripheral pruritis. Repeat transaminase levels declined slightly, with a small improvement in bilirubin values. The patient was tolerating an oral diet reasonably well and was discharged. Liver function test results indicated little change 3 days after discharge, but significant declines were noted on follow-up evaluations. Her fatigue and pruritis also improved significantly during this time but still persisted for approximately 5 weeks after discharge.

Discussion
Fluoroquinolones are used extensively in institutional settings because of their excellent spectrum of activity for hospital-acquired infections, favorable pharmacokinetic characteristics, and, for most agents in the group, good safety profiles. With the advent of new fluoroquinolones with improved gram-positive activity and atypical coverage, this group has experienced a significant increase in use for the community environment. Published guidelines from the Infectious Diseases Society of America recommend a fluoroquinolone as empiric therapy for outpatients and general medical ward patients with community-acquired pneumonia.[8] The American Thoracic Society included an antipneumococcal fluoroquinolone in its recommendation for treating community-acquired pneumonia in outpatients with cardiopulmonary disease and/or modifying factors, as well as patients not in the intensive care unit, with or without risk factors.[9]
Our patient presented with no chronic illnesses other than the sinusitis for which the antibiotic was prescribed. Her hepatic and renal functions were normal. No previous hepatic disease or alcohol or drug use predisposed the patient to developing hepatitis. After 5 days of gatifloxacin, the patient developed acute hepatitis with subsequent symptomatic jaundice. Other causes of hepatitis, including viral, autoimmune, and functional disorders, were ruled out. A biopsy revealed acute hepatitis with eosinophilic infiltrates consistent with drug-induced hepatitis. A complete blood count also demonstrated eosinophilia (eosinophils 7%).

Drugs received before this event were evaluated as possible causes of the hepatitis. Amoxicillin-clavulanate is associated with cholestatic liver injury. Evidence of liver injury usually occurs within 2 weeks of beginning the drug, although it may appear later.[10] In our patient, the onset of the reaction occurred after 43 days of beginning amoxicillin-clavulanate. More important, the patient had taken this drug on at least seven occasions with no adverse effects.

The patient also had taken levofloxacin on several occasions with no adverse effects. She had taken AlleRx (a combination of methscopol-amine, pseudoephedrine, and chlorpheniramine) before being hospitalized, but she had taken pseudoephedrine and chlorpheniramine many times without mishap. The three drugs in the combination product have been available for decades and have not been associated with hepatitis. According to the manufacturer (Adams Laboratories, Inc.), no cases of drug-induced hepatitis that may be associated with AlleRx have been reported (DJ Keyser, personal communication, March 2001).

The patient used a homeopathic remedy of colloidal silver during the month preceding this adverse event. Silver toxicity, or argyria, appears as a blue-gray discoloration of the skin, mucous membranes, and conjunctiva, cornea, or lens. Hepatic damage has been implicated with administration of soluble silver salts to animals. The minimal oral dosage necessary to cause systemic argyria is estimated to be 25-30 g over 6 months.[11] The patient had taken a total of eight doses during the month, with each 5-ml dose containing 5 parts/million of colloidal silver. The total colloidal silver dose was calculated to be 0.2 mg. This is significantly below the exposure associated with any toxicity.

The time frame in which the adverse effect occurred in our patient is consistent with gatifloxacin administration. Another fluoro-quinolone demonstrated a similar presentation.[12] Norfloxacin was implicated as causing acute hepatitis 7 days after starting the drug. Liver biopsy showed focal necrosis. Ofloxacin also has been incriminated in a case of hepatocellular injury.[13] Based on the onset and resolution of the adverse effect in our patient, its causality is described as suggestive.[7] Two methods[14, 15] for estimating the probability of adverse effects were applied to this case, and the association of gatifloxacin was determined to be probable.

Although the frequency of drug-induced hepatitis with gatifloxacin is probably uncommon and is not as high as that with trovafloxacin, clinicians should be alerted to the possibility that this adverse effect may occur with the drug.