Possible Roxithromycin-Induced Fulminant Hepatic Failure
Possible Roxithromycin-Induced Fulminant Hepatic Failure
A pediatric formulation of roxithromycin is a relatively new addition to the antibiotic market in Australia. A previously healthy 5-year-old boy with no significant medical history was treated with roxithromycin 50 mg twice/day for cough, fever, and anorexia. After completing a 5-day course of the agent, he developed a nonpruritic, nonurticarial, erythematous, maculopapular, generalized rash and occasional vomiting. Three days later his symptoms included jaundice, dark urine, and pale stools. Laboratory results revealed acute hepatitis, and the patient was admitted to the hospital. His hepatic function continued to deteriorate, so the boy was transferred to a tertiary pediatric hospital. His condition continued to worsen, and 6 days after transfer, he underwent liver transplantation. Clinicians should be aware of potential hepatic complications associated with the use of roxithromycin.
It is not possible to evaluate accurately the frequency or prevalence of drug-associated hepatotoxicity. Nonetheless, there is significant morbidity and even mortality associated with drug-induced liver injury. Data from the United States suggest that drug-induced liver disease accounts for 2-5% of hospital admissions for jaundice and 10-20% of cases involving fulminant liver failure. Studies of adverse drug reaction reports in the United Kingdom and Denmark show that hepatic reactions account for 3-6% of all reports and are fatal in 5-7% of these cases. The drugs most commonly implicated in hepatotoxicity are halothane, antibiotics such as erythromycin and trimethoprim-sulfamethoxazole, phenothiazines, nonsteroidal antiinflammatory agents, and oral contraceptives.
Two mechanisms for drug-induced hepatotoxicity are described in the literature: intrinsic hepatotoxicity (direct toxic type) and idiosyncratic hepatotoxicity. Intrinsic hepatotoxins destroy the hepatocyte, usually by direct physiochemical methods such as peroxidation or denaturation of cell membranes. Intrinsic hepatotoxicity occurs with predictable regularity in individuals exposed to the offending agent. The response is dose dependent, and the time to development of liver injury is usually short (often several hours), although clinical manifestations may be delayed for 24-48 hours.
In contrast, idiosyncratic drug-induced hepatotoxicity is usually unpredictable, and the response is not dose dependent. The time at which hepatotoxicity develops is also unpredictable, as hepatotoxicity may occur any time during or shortly after exposure to the drug. Extrahepatic manifestations of hypersensitivity such as rash, arthralgia, fevers, leukocytosis, and eosinophilia occur in approximately 25% of patients with idiosyncratic hepatotoxic drug reactions. Their occurrence, along with the unpredictability of idiosyncratic hepatotoxicity, lead to the hypothesis that this category of drug reactions is immunologically mediated. More recent evidence suggests that idiosyncratic reactions may result from differences in patients' metabolic reactivity to specific agents. These differences in the pharmacokinetics of toxic metabolite generation are what appear to make a patient susceptible to developing an idiosyncratic reaction.
A pediatric formulation of roxithromycin is a relatively new addition to the antibiotic market in Australia. A previously healthy 5-year-old boy with no significant medical history was treated with roxithromycin 50 mg twice/day for cough, fever, and anorexia. After completing a 5-day course of the agent, he developed a nonpruritic, nonurticarial, erythematous, maculopapular, generalized rash and occasional vomiting. Three days later his symptoms included jaundice, dark urine, and pale stools. Laboratory results revealed acute hepatitis, and the patient was admitted to the hospital. His hepatic function continued to deteriorate, so the boy was transferred to a tertiary pediatric hospital. His condition continued to worsen, and 6 days after transfer, he underwent liver transplantation. Clinicians should be aware of potential hepatic complications associated with the use of roxithromycin.
It is not possible to evaluate accurately the frequency or prevalence of drug-associated hepatotoxicity. Nonetheless, there is significant morbidity and even mortality associated with drug-induced liver injury. Data from the United States suggest that drug-induced liver disease accounts for 2-5% of hospital admissions for jaundice and 10-20% of cases involving fulminant liver failure. Studies of adverse drug reaction reports in the United Kingdom and Denmark show that hepatic reactions account for 3-6% of all reports and are fatal in 5-7% of these cases. The drugs most commonly implicated in hepatotoxicity are halothane, antibiotics such as erythromycin and trimethoprim-sulfamethoxazole, phenothiazines, nonsteroidal antiinflammatory agents, and oral contraceptives.
Two mechanisms for drug-induced hepatotoxicity are described in the literature: intrinsic hepatotoxicity (direct toxic type) and idiosyncratic hepatotoxicity. Intrinsic hepatotoxins destroy the hepatocyte, usually by direct physiochemical methods such as peroxidation or denaturation of cell membranes. Intrinsic hepatotoxicity occurs with predictable regularity in individuals exposed to the offending agent. The response is dose dependent, and the time to development of liver injury is usually short (often several hours), although clinical manifestations may be delayed for 24-48 hours.
In contrast, idiosyncratic drug-induced hepatotoxicity is usually unpredictable, and the response is not dose dependent. The time at which hepatotoxicity develops is also unpredictable, as hepatotoxicity may occur any time during or shortly after exposure to the drug. Extrahepatic manifestations of hypersensitivity such as rash, arthralgia, fevers, leukocytosis, and eosinophilia occur in approximately 25% of patients with idiosyncratic hepatotoxic drug reactions. Their occurrence, along with the unpredictability of idiosyncratic hepatotoxicity, lead to the hypothesis that this category of drug reactions is immunologically mediated. More recent evidence suggests that idiosyncratic reactions may result from differences in patients' metabolic reactivity to specific agents. These differences in the pharmacokinetics of toxic metabolite generation are what appear to make a patient susceptible to developing an idiosyncratic reaction.
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