6 Both treatment groups exhibited similar positive rechallenge rates with an overall 11% positive rechallenge rate and no fatalities. Positive

rechallenge was associated with a lower pretreatment albumin value (3.4 g/dL versus 3.9 g/dL find more in patients with negative rechallenge; P < 0.01).6 However, the risk of positive rechallenge was unaffected by the severity of the initial DILI.6 Forty-five Turkish patients with liver injury on initial tuberculosis treatment were followed until liver injury resolved and then rechallenged with isoniazid, rifampin, ethambutol, and pyrazinamide in two different ways: simultaneous rechallenge of all four TB medications resulted in a 24% positive rechallenge rate (n = 25), whereas exclusion of pyrazinamide and dose escalation of the remaining three medications resulted in a 0% positive rechallenge rate (n = 20).7 Pyrazinamide DILI is reportedly more severe/fatal than isoniazid or rifampin,38 and its exclusion favorably affected rechallenge.7 A higher risk

of positive rechallenge was associated with hypoalbuminemia, extensive tuberculosis, and female sex.7 Possible mechanisms BIBW2992 of the predominantly hepatocellular injury observed with tuberculosis medications include the generation of a reactive metabolite of isoniazid, high daily dose of 300-1,500 mg,26 immunoallergic injury, with an HLA DQB1*0201 marker associated with liver injury (odds ratio, 1.9),39 and mitochondrial impairment. In cell cultures, isoniazid decreases mitochondrial membrane potential, releasing cytochrome C.40 Risk factors for liver injury include advanced age, female sex, alcohol use, and hypoalbuminemia.39 Therefore, tuberculosis medications induce both mitochondrial impairment and immunoallergic injury. Whereas liver injury is frequently delayed 1-4 weeks posttreatment in initial amoxicillin/clavulanate-associated

liver injury, injury appeared in only 4 days of positive rechallenge in 10 patients in a retrospective series.2 In comparison with the initial event, the severity of liver chemistry elevations was generally similar in most MRIP rechallenge events, although it was increased in one subject.2 This 41-year-old man developed hepatocellular hepatitis with initial treatment with amoxicillin/clavulanate and developed cirrhosis on subsequent rechallenge with amoxicillin/clavulanate, requiring liver transplantation.2, 4 Administered at a high daily dose of 500-3,000 mg,26 amoxicillin/clavulanate is frequently associated with cholestatic or mixed disease; only 36% of patients exhibit hepatocellular injury.41 Hypersensitivity was observed in 38% of amoxicillin/clavulanate-associated DILI in the prospective Spanish DILI Registry.