Acute Eosinophilic Hepatitis from Trovafloxacin

Chen, Henry J.L.; Bloch, Kurt J.; MacLean, James A.

doi:10.1056/nejm200002033420517

Cited by 72 publications

(17 citation statements)

References 6 publications

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“…Elevated IL-4 and eosinophil infiltration have been reported in a wide variety of human liver diseases, including chronic hepatitis C (57-59), drug-induced liver disease (60,61), primary biliary cirrhosis (62,63), and liver transplantation (64). It is very likely that activation of IL-4/STAT6 and the consequent infiltration of eosinophils are also involved in a variety of human liver diseases.…”

Section: Discussionmentioning

confidence: 99%

Crucial Role of IL-4/STAT6 in T Cell-Mediated Hepatitis: Up-Regulating Eotaxins and IL-5 and Recruiting Leukocytes

Jaruga

Hong

Sun

et al. 2003

The Journal of Immunology

137

143

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T cell-mediated immune responses are implicated in the pathogenesis of a variety of liver disorders; however, the underlying mechanism remains obscure. Con A injection is a widely accepted mouse model to study T cell-mediated liver injury, in which STAT6 is rapidly activated. Disruption of the IL-4 and STAT6 gene by way of genetic knockout abolishes Con A-mediated liver injury without affecting IFN-γ/STAT1, IL-6/STAT3, or TNF-α/NF-κB signaling or affecting NKT cell activation. Infiltration of neutrophils and eosinophils in Con A-induced hepatitis is markedly suppressed in IL-4 −/− and STAT6−/− mice compared with wild-type mice. IL-4 treatment induces expression of eotaxins in hepatocytes and sinusoidal endothelial cells isolated from wild-type mice but not from STAT6−/− mice. Con A injection induces expression of eotaxins in the liver and elevates serum levels of IL-5 and eotaxins; such induction is markedly attenuated in IL-4−/− and STAT6−/− mice. Finally, eotaxin blockade attenuates Con A-induced liver injury and leukocyte infiltration. Taken together, these findings suggest that IL-4/STAT6 plays a critical role in Con A-induced hepatitis, via enhancing expression of eotaxins in hepatocytes and sinusoidal endothelial cells, and induces IL-5 expression, thereby facilitating recruitment of eosinophils and neutrophils into the liver and resulting in hepatitis.

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Section: Discussionmentioning

confidence: 99%

Crucial Role of IL-4/STAT6 in T Cell-Mediated Hepatitis: Up-Regulating Eotaxins and IL-5 and Recruiting Leukocytes

Jaruga

Hong

Sun

et al. 2003

The Journal of Immunology

137

143

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“…55,56,88,89 Reports of significant levofloxacin-associated hepatotoxicity are extremely rare. 90 More severe adverse effects (AEs) were reported with trovafloxacin (a fluoronaphthyridone) during PMS, with treatment leading to liver failure, 91 the necessity for transplantation, 91 and a small number of deaths 91 ; these AEs may have been related to a hypersensitivity reaction and perhaps associated with neoantigen formation induced by the 1-[2,4]-difluorophenyl side chain. 55,92 These findings led to the suspension/withdrawal of trovafloxacin in June 1999.…”

Section: Hepatitis and Liver Failurementioning

confidence: 99%

Efficacy and safety of levofloxacin in the context of other contemporary fluoroquinolones: a review

Ball

2003

Current Therapeutic Research

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Background: In recent years, fluoroquinolone research has focused on achieving several goals, including (1) enhanced potency against gram-positive cocci, notably Streptococcus pneumoniae, and anaerobes, while (2) maintaining potency against gram-negative pathogens, (3) optimizing pharmacokinetics and pharmacodynamics (PK/PD), and (4) minimizing potential adverse drug reactions through recognition and avoidance of structural configurations that have characterized earlier, reactive compounds.Objective: This review examines the efficacy and safety of fluoroquinolones and the specific clinical evidence regarding levofloxacin.Methods: Using published literature collected over time by the author, a review was conducted, focusing on the efficacy and safety profile of levofloxacin and other fluoroquinolones.Results: The newer fluoroquinolones have fulfilled many of the research goals described above. Levofloxacin has improved anti-gram-positive potency, PK/PD properties, a proven clinical trial record (particularly for communityacquired pneumonia [CAP]), and an excellent safety profile-in the context of the treatment of Ͼ250 million patients worldwide in the past decade. It is licensed for management of drug-resistant S pneumoniae infections in the United States and has gained widespread formulary acceptance and guideline inclusion. Studies assessing levofloxacin for CAP therapy show significant advantages over standard therapy, such as trends toward reduced IV therapy and length of hospitalization, reduced mortality, and significant associated cost reduction. In addition, levofloxacin has proved highly effective in acute exacerbations of

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“…In this regard, it is interesting that human clinical studies of TVX hepatotoxicity revealed the presence of inflammatory cells in liver biopsies (Chen et al, 2000). In rats and mice, nontoxic doses of TVX and bacterial lipopolysaccharide (LPS) synergized to cause acute liver injury (Waring et al, 2006;Shaw et al, 2007).…”

mentioning

confidence: 99%

Tumor Necrosis Factorα Is a Proximal Mediator of Synergistic Hepatotoxicity from Trovafloxacin/Lipopolysaccharide Coexposure

Shaw

Ganey

Roth

2008

J Pharmacol Exp Ther

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The use of trovafloxacin (TVX), a fluoroquinolone antibiotic, was severely restricted because of an association of TVX therapy with idiosyncratic hepatotoxicity in patients. The mechanisms underlying idiosyncratic toxicity are unknown; however, one hypothesis is that an inflammatory stress can render an individual sensitive to the drug. Previously, we reported that treatment of mice with TVX and lipopolysaccharide (LPS) induced tumor necrosis factor (TNF) ␣-dependent liver injury, whereas TVX or LPS treatment alone was nontoxic. The goal of this study was to elucidate the role of TNF␣ in TVX/LPS-induced liver injury. TNF receptor (TNFR) 1 p55 Ϫ/Ϫ and TNFR2 (p75 Ϫ/Ϫ ) mice were protected from hepatotoxicity caused by TVX/LPS coexposure, suggesting that TVX/LPS-induced liver injury requires both TNF receptors. TNF␣ inhibition using etanercept significantly reduced the TVX/LPS-induced increases in the plasma concentrations of several cytokines around the time of onset of liver injury. However, despite the reduction in chemokines, etanercept treatment did not affect the TVX/LPSinduced hepatic accumulation of neutrophils. In addition, etanercept treatment attenuated TVX/LPS induction of plasminogen activator inhibitor-1, and this was associated with a reduction in hepatic fibrin deposition. Mice treated with TVX and a nontoxic dose of TNF␣ also developed liver injury. In summary, TNF␣ acts through p55 and p75 receptors to precipitate an innocuous inflammatory cascade. TVX enhances this cascade, converting it into one that results in hepatocellular injury.

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Acute Eosinophilic Hepatitis from Trovafloxacin

Cited by 72 publications

References 6 publications

Crucial Role of IL-4/STAT6 in T Cell-Mediated Hepatitis: Up-Regulating Eotaxins and IL-5 and Recruiting Leukocytes

Crucial Role of IL-4/STAT6 in T Cell-Mediated Hepatitis: Up-Regulating Eotaxins and IL-5 and Recruiting Leukocytes

Efficacy and safety of levofloxacin in the context of other contemporary fluoroquinolones: a review

Tumor Necrosis Factorα Is a Proximal Mediator of Synergistic Hepatotoxicity from Trovafloxacin/Lipopolysaccharide Coexposure

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