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BRIEF REPORT
Trovafloxacin-Induced Acute Hepatitis
M. Isabel Lucena,1 Raúl J. Andrade,2 Luis Rodrigo,3 Javier Salmerón,4
Arancha Alvarez,3 M. J. Lopez-Garrido,4 Raquel Camargo,2 and Ramiro
Alcantára2
From 1Servicio de Farmacología Clínica y 2Unidad de Hepatología,
Hospital Universitario, Facultad de Medicina, Málaga; 3Sevicio de
Gatroenterología, Hospital Central de Asturias, Oviedo; and 4Servicio
de Gastroenterología, Hospital Clinico S. Cecilio, Granada, Spain
Reprints or correspondence: M. Isabel Lucena, Servicio de Farmacología
Clínica, Facultad de Medicina, Campus Universitario de Teatinos s/n,
29071 Málaga, Spain (lucena@uma.es).
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Trovafloxacin, a new trifluoronaphthyridone derivative related to
fluoroquinolone antimicrobial drugs, appears to be more effective than
available quinolones. As a class, the most common adverse effects
involve the CNS and gastrointestinal tract [1]. Liver enzyme
abnormalities have been noted in 2%3% of patients, and liver toxicity
is reported infrequently [2]. Since use of this drug in the United
States was authorized in December 1997, 152 cases of serious hepatic
events probably related to trovafloxacin have been reported to the US
Food and Drug Administration (140 cases) and to the European Agency
for the Evaluation of Medicinal Products (12 cases as of July 1998).
Because the frequency of serious adverse reactions to trovafloxacin
was well out of proportion to that seen in other drugs in this class,
the manufacturer withdrew trovafloxacin from the European markets on
15 June 1999. The drug remains available in the United States for very
restricted indications [3]. We report 3 patients who had acute
hepatitis after taking trovafloxacin.
A 68-year-old man (patient 1) was treated with trovafloxacin (200
mg/d) for 7 days because of a respiratory infection. At the time of
initiation, his liver test values were normal. He had been taking
pentoxifylline for peripheral vascular disorder. One week after the
end of antibiotic therapy, he presented because of a 3-kg weight loss,
rash, pruritus, and dark urine, and was admitted to the hospital.
Physical examination findings were normal except for jaundice. Serum
chemistry indicated acute liver injury (table 1), and serology ruled
out viral causes. Screening for autoantibodies was negative, and
findings of an abdominal ultrasonographic examination were normal. A
liver biopsy specimen showed predominantly centrozonal necrosis and
inflammatory eosinophilic infiltrates. Laboratory findings at 45 days
were normal.
Table 1. Serum concentrations at time of presentation with
trovafloxacin-induced acute hepatitis.
A 33-year-old man (patient 2) was treated with trovafloxacin (200
mg/d) for 7 days because of a flulike syndrome. Ten days after
treatment ended, he noticed fever and dark urine. He was prescribed
roxithromycin, paracetamol, and carbocisteine. On admission 5 days
later, he was febrile (40°C) and jaundiced. Laboratory results
indicated hepatocellular injury without evidence of viral causes
(table 1). Screening for autoantibodies was negative. Findings of
endoscopic retrograde cholangiography were normal. A liver biopsy
showed marked centrozonal necrosis. Results of liver tests became
normal during the subsequent 2 months.
A 58-year-old man (patient 3) started therapy with trovafloxacin (200
mg/d for 21 days) for lobar pneumonia. He was also given codeine for
cough, prednisone (30 mg/d), and ranitidine (150 mg/d) for 10 days.
Fourteen days after starting therapy, he complained of asthenia and
anorexia. Four days after treatment ended he presented because of
fever and dark urine. He reported intake of alcohol (30 g/d). Physical
examination showed no jaundice or signs of chronic liver disease.
Serum chemistry indicated acute liver injury (table 1). Serology ruled
out viral causes, and a screening for autoantibodies was negative.
Laboratory findings were normal at 45 days.
We believe that these are the first published reports of acute
hepatitis due to trovafloxacin. In each case, other causes of liver
injury were ruled out. Withdrawal of the drug was followed by
abatement of liver dysfunction. The histologic picture was similar in
biopsy specimens for both patients (patients 1 and 2) from whom a
specimen was obtained, and it was consistent with drug-induced hepatic
injury. It is noteworthy that there was a delay of 410 days between
the end of treatment and the onset of hepatitis; such a delay may
hinder the diagnosis of iatrogenic liver injury. The association of
hepatitis with hypersensitivity manifestations and the presence of
eosinophils in the liver biopsy specimen suggest an immunoallergic
mechanism.
Temafloxacin, another fluoroquinolone with the same core structure as
trovafloxacin, was withdrawn worldwide in 1992 after the detection of
severe hemolysis, associated in more than one-half of the cases with
renal failure and hepatic dysfunction [4]. Both drugs share a unique
difluorinated side chain that is not found in the other quinolones and
that renders these drugs highly lipophilic. It is surprising that, in
light of these structural similarities, no special attention has been
given to the approval and postmarketing surveillance of trovafloxacin.
References
1. Garey KW, Amsden GW. Trovafloxacin: an overview. Pharmacotherapy
1999; 19:2134. First citation in article | PubMed
2. Lucena MI, Andrade RJ, Sanchez-Martinez H, Perez-Serrano JM,
Gomez-Outes A. Norfloxacin-induced cholestatic jaundice. Am J
Gastroenterol 1998; 93:230911. First citation in article | PubMed
3. European Agency for the Evaluation of Medicinal Products. Public
statement on trovafloxacin/alatrofloxacin: recommendation to suspend
the marketing authorisation in the European Union. London, 15 June
1999. First citation in article
4. Blum MD, Graham DJ. Temafloxacin syndrome: review of 95 cases. Clin
Infect Dis 1994; 18:94650. First citation in article | PubMed
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