Hepatotoxicity of antibiotics and antifungals

Clin Liver Dis 7 (2003) 381 – 399

Hepatotoxicity of antibiotics and antifungals Michael Thiim, MDa,b, Lawrence S. Friedman, MDa,b,* a

b

Harvard Medical School, 25 Shattuck Street Boston, MA 02115, USA Massachusetts General Hospital, Gastrointestinal Unit, Blake 4, 55 Fruit Street, Boston, MA 02114, USA

Antibiotic-associated hepatotoxicity is frequently asymptomatic and generally associated with only mild hepatic injury. Most episodes are not recognized and are of little clinical significance. Notable exceptions occur with the use of chronically prescribed antibiotics: nitrofurantoin for prophylaxis of urinary tract infections; minocycline for chronic acne treatment; the antituberculous drugs; and the anti-fungal agents. Many instances of antibiotic hepatotoxicity are the result of idiosyncratic reactions or re-challenge. Antibiotic-associated hepatitis is only infrequently dose related, as with high-dose tetracycline or oxacillin. Hepatic reactions to drugs including antibiotics are infrequent, in the order of a few cases per million treated patients. The difficulty in predicting the incidence of drug-induced liver disease, however, is exemplified by the impact hepatotoxicity has on drug manufacturers: hepatotoxicity is the most common cause of aftermarketing withdrawal of medications despite the rigors of preclinical testing [1]. In a recent retrospective study, antibiotics and nonsteroidal anti-inflammatory drugs were the two groups of pharmacological agents most commonly implicated in hepatotoxicity requiring medical evaluation and liver biopsy [2]. If historical patterns of increased antibiotic use and development were to continue, then increased incidences of significant hepatic reactions to antibiotics can be expected. However, because the incidence of clinically significant hepatotoxicity is low, the efficacy of routine laboratory screening is controversial and of unproven benefit. Early recognition of drug hepatotoxicity, discontinuation of the drug, and avoidance of re-exposure are the most effective methods of minimizing hepatic damage. Symptomatic hepatotoxicity from an antibiotic may occur almost immediately or after months of therapy. There are no specific medical therapies for any of the antibiotic-associated hepatotoxicities; supportive care is required at the time liver disease is severe or advanced, and liver transplantation may be * Corresponding author. Gastrointestinal Unit, Blake 4, Massachusetts General Hospital, Boston, MA 02114, USA. E-mail address: [email protected] (L.S. Friedman). 1089-3261/03/$ – see front matter D 2003 Elsevier Inc. All rights reserved. doi:10.1016/S1089-3261(03)00021-7

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indicated for irreversible liver failure. For individual drugs, there are reports of the use of corticosteroids, with essentially no clinical benefit. At this time, education of patients about the symptoms of liver disease may be the best method of identifying patients with clinically significant hepatotoxicity.

The penicillins Penicillin, ampicillin, and amoxicillin Since the introduction of penicillins into clinical practice in 1942, there have been few reports of penicillin-induced liver injury. The penicillins as a class have an excellent safety profile with regard to hepatotoxicity (Table 1). If drug-induced hepatitis occurs, it is generally necroinflammatory but asymptomatic [3]. Ampicillin is rarely associated with hepatocellular injury. A case report involving a patient in whom Stevens-Johnson syndrome developed describes chronic cholestasis, a paucity of bile ducts, and an eventual slow recovery, representing an unusual acute idiosyncratic reaction [4]. Amoxicillin is a penicillinase-susceptible semi-synthetic penicillin closely related to ampicillin, with similar antimicrobial properties. The risk for minor acute liver injury with the use of amoxicillin (not associated with clavulanic acid [see below]) has been estimated to be 3 per 100,000 prescriptions [5], and according to the Medicines Control Agency in the United Kingdom, hepatic reactions to amoxicillin are reported at a rate of 1 per 2 million prescriptions. Nafcillin, cloxacillin, dicloxacillin, floxacillin, and oxacillin Cholestasis and jaundice have been reported with all the penicillinase-resistant penicillins (see Table 1) [6 –10]. Floxacillin has been reported as a cause of prolonged intrahepatic cholestasis and vanishing bile duct syndrome [11,12]. Table 1 Hepatotoxicity of the penicillins Drug

Reported reactions

Amoxicillin Amoxicillin-clavulanate Ampicillin Carbenicillin Cloxacillin Dicloxacillin Floxacillin Nafcillin Oxacillin Penicillin Ticarcillin-clavulanate

hepatocellular, hepatic granulomasa hepatocellular, cholestatic hepatitis, VBDS, hepatic granulomasa hepatocellular, cholestatic hepatitis, VBDS, hepatic granulomasa hepatocellular cholestatic hepatitis cholestatic hepatitis, bile duct injury, VBDS, hepatic granulomasa cholestatic hepatitis, bile duct injury, VBDS, hepatic granulomasa hepatocellular hepatocellular, cholestatic hepatitis, hepatic granulomasa hepatocellular, hepatic granulomasa cholestatic hepatitis

Abbreviation: VBDS, vanishing bile duct syndrome. a Isolated case reports.

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Although mild elevations in serum aminotransferase levels are commonly seen with oxacillin, hepatotoxicity from oxacillin is considered rare and may result from either a hypersensitivity reaction or a direct toxic effect. There have been few reports of oxacillin hepatotoxicity in the past 20 years, and the reported cases have occurred in the setting of high-dose intravenous oxacillin therapy (greater than 6 g per day) [13 –15]. Risk factors for oxacillin hepatotoxicity have been suggested. In one report the rate of hepatotoxicity to high-dose (6– 12 g daily) intravenous oxacillin was 81% in persons infected with the human immunodeficiency virus (HIV) compared with 4.5% in patients not infected with HIV [16]. It has been postulated that the oxacillin metabolite hydroxylamine is inactivated by glutathione [17] and that glutathione deficiency in HIV-infected persons may predispose this population to hydroxylamine cytotoxicity [18]. Nevertheless, oxacillin has a long track record of safety with little hepatotoxicity in persons not infected with HIV. Amoxicillin-clavulanic acid (Augmentin1) Augmentin is an orally administered combination of a semi-synthetic penicillin and b-lactamase inhibitor with enhanced antimicrobial properties against beta-lactamase producing bacteria. An intravenous form is available outside the United States. Cases of amoxicillin-clavulanic acid-associated hepatitis and jaundice were first reported in 1989 (see Table 1) [19 –22]. In one of the earliest and largest series, 18 cases reported to the United States Food and Drug Administration (FDA) and to the manufacturer were reviewed. A predominantly cholestatic pattern of injury was identified in 7 cases, a mixed hepatocellularcholestatic pattern in 6 cases, a hepatocellular pattern in 4 cases, and an undefined pattern in 1 case [23]. In a recent Medline search of case reports and reviews of amoxicillin-clavulanic acid-induced adverse events [24], 153 patients with a hepatotoxic reaction were identified; 70% had a cholestatic or mixed hepatocellular-cholestatic pattern of injury, and the remainder manifested a hepatocellular pattern of injury. Mild asymptomatic increases in serum aminotransferase levels have been found in up to 23% of patients treated with amoxicillin-clavulanic acid [25]. In a retrospective cohort study, however, of computer files of patients with suspected liver injury in the United Kingdom, the incidence of reported acute liver injury during the use of amoxicillin-clavulanic acid was 1.7 per 10,000 prescriptions, and none of the cases was fatal [5]. The risk for developing acute liver injury was more than three times greater after two or more consecutive prescriptions compared with a single course of therapy, and an age greater than 65 years was associated with an increased risk for developing liver injury to a rate greater that one out of a 1000. The estimated risk for developing symptomatic hepatitis from amoxicillinclavulanic acid may, in fact, be less than 1 in 100,000 [26]. The incidence of amoxicillin-clavulanic acid-associated fatal hepatotoxicity is in the order of one in several million [27]. The low incidence of significant hepatotoxicity belies the finding that among the antimicrobials, amoxicillin-clavulanic acid may be

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responsible for the greatest incidence of symptomatic hepatotoxicity. In a report of patients with a histologic diagnosis of drug-induced liver disease over an 18-year period in London, amoxicillin-clavulanic acid was the most frequently implicated offending drug [2]. Cholestasis is a hallmark of amoxicillin-clavulanic acid-induced liver injury, and a destructive cholangiopathy with extensive inflammatory infiltration and necrosis of the intralobular bile duct wall has been described [28]. One recent report described prolonged cholestasis with ductopenia that resulted in liver failure and death [29]. A delayed onset of symptoms is seen with amoxicillin-clavulanic acid hepatotoxicity, and early recognition is difficult. Most cases present 1 to 4 weeks after cessation of therapy and some cases are delayed for more than 8 weeks [26]. Normalization of liver biochemistries usually occurs within 12 to 16 weeks and rarely more than 1 year after discontinuation of the drug. The role of metabolic idiosyncrasy in the development of hepatitis caused by amoxicillin-clavulanic acid has been explored. Immunologic hepatitis may be the result of partial hepatic metabolism of the drug with production of reactive intermediates that interact with liver proteins and thereby provide antigenic stimulation; these complexes may be recognized by the immune system and thereby lead to immunologic damage. In a Belgian study of 35 patients who met the criteria of amoxicillin-clavulanic acid hepatotoxicity established by an international consensus meeting [30], a significant association was found with human leukocyte antigen (HLA) haplotype DRB1*1501-DRB5*0101-DQB1* 0602, suggesting that an immunologic idiosyncrasy may be responsible for the toxicity and may be mediated by HLA class ll system antigens [31].

The tetracyclines Tetracycline Chlortetracycline, produced by the Streptomyces aureofaciens bacillus, was introduced in 1948, and tetracycline, which is semi-synthetically produced from chlortetracycline, was introduced in 1952 [32]. The first reports of microvesicular fatty liver and fatal hepatotoxicity were associated with the use of high-dose intravenous tetracycline in pregnant or recently postpartum women (Table 2). These reports were followed by additional cases of fatal hepatotoxicity in nonpregnant patients [33 – 35]. By 1972, 44 cases of liver failure and 37 deaths had been reported [36]. Because of hepatotoxicity with high-dose intravenous tetracycline and the availability of suitable alternatives, the sale of intravenous tetracycline (AchromycinIV1) in the United States was discontinued in 1991. Oral high-dose tetracycline therapy is also associated with liver toxicity and is believed to result from a toxic effect of the drug or a metabolite rather than an idiosyncratic reaction. In a 30-year review of tetracycline use, however, hepatotoxicity during therapy with oral tetracycline was rare, occurring with a frequency of only one in 18 million daily doses [37]. The risk for developing

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Table 2 Hepatotoxicity of quinolones, tetracyclines, and macrolides Drug

Reported reactions

Azithromycin Ciprofloxacin Clarithromycin Erythromycin Minocycline Norfloxacin Spiramycin Tetracycline Troleandomycin Trovafloxacin

Cholestatic hepatitis, fulminant hepatic failure Hepatocellular, cholestatic hepatitis, hepatic failure Cholestatic hepatitis Cholestatic hepatitis, VBDS Fatty liver, CAH, liver failure Hepatocellular, cholestatic hepatitis Cholestatic hepatitis Fatty liver, cholestatic hepatitis, fulminant hepatic failure, VBDS Cholestatic hepatitis, VBDS Cholestatic hepatitis, fulminant hepatic failure

Abbreviations: VBDS, vanishing bile duct syndrome; CAH, chronic active hepatitis.

symptomatic acute hepatitis resulting in hospitalization in the absence of preexisting liver disease has been estimated to be as low as 1.56 cases per million following a 10-day course of oral tetracycline [38]. It would therefore appear that the greatest risk for tetracycline hepatotoxicity is associated with use of high-dose tetracycline in pregnant patients. Tetracycline in high concentrations can inhibit mitochondrial b-oxidation of fatty acids, leading presumably to microvesicular steatosis [39]. The histopathology of tetracycline injury is similar to that of other conditions associated with impaired b-oxidation of fatty acids, including fatty liver of pregnancy, which may explain in part the association of tetracycline toxicity with pregnancy. Minocycline Minocycline is a semi-synthetic tetracycline widely used for extended periods in the treatment of acne vulgaris. The more convenient twice-daily dosing regimen has made it a popular alternative to tetracycline. Like tetracycline, minocycline can produce a microvesicular steatohepatitis, as described in an early report of a pregnant woman receiving high-dose intravenous minocyline therapy (see Table 2) [40]. Minocycline-induced hepatitis has been associated with the appearance of antinuclear antibodies, elevated gamma globulin levels, and morphologic findings identical to those of autoimmune hepatitis [41]. The occurrence of a systemic lupus erythematosus-like syndrome (and other rheumatologic reactions) in patients in whom hepatitis developed after treatment with minocycline also supports an autoimmune basis for the clinical syndrome [42]. Many patients who become symptomatic have been treated for many months or even years, and most cases resolve with drug withdrawal. There have been several reports of hepatic failure requiring liver transplantation and of fatal hepatotoxicity [43 –45]. There are case reports of improvement in the hepatitis with corticosteroid therapy after an initial diagnosis of autoimmune hepatitis; however, the possibility that these patients would have improved following cessation of minocycline alone cannot be excluded [40,46].

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Based on the experience with minocycline to date, periodic monitoring of liver biochemistries and autoimmune markers may be prudent in patients receiving minocycline for extended periods. The evidence suggests that most patients will recover completely with cessation of the drug.

The quinolones The quinolones are widely used in the treatment of infections caused by a variety of Gram-positive and Gram-negative organisms. Because of the broad spectrum of antimicrobial activity and the high concentrations of the drug reached in the bile, the quinolones are frequently used in the treatment of bacterial cholangitis and cholecystitis. They also are often used to treat and prevent spontaneous bacterial peritonitis. Despite the use of quinolones in patients with advanced liver disease, there have been few case reports of significant hepatotoxicity with the use of these drugs (see Table 2). There are isolated case reports of hepatocellular or cholestatic hepatitis. In a letter from Lucena and colleagues [47], 14 reported cases of hepatotoxicity caused by ciprofloxacin, norfloxacin, enoxacin, and ofloxacin up to 1998 are cited and briefly summarized. There also have been isolated cases of liver failure and death [48 – 50]. The incidence, however, of clinically significant hepatotoxicity for most quinolones seems to be low. A report describing the presence of autoantibodies to kidney and liver microsomes in six patients with quinolone-associated hepatotoxicity suggests that there may be an immune-mediated mechanism of injury [51]. Among the quinolones, one exception to the relative record of safety with regard to liver toxicity is trovafloxacin. The FDA approved trovafloxacin in 1997 and more than 300,000 monthly prescriptions were written before a public health advisory was released in 1999 concerning the risks for liver toxicity with this drug [52]. At that time, more than 100 cases of hepatotoxicity had been reported, with 14 leading to acute liver failure. Four patients required liver transplantation (one later died despite transplantation), and five patients died of liver-related illness. Trovafloxacin liver toxicity was unpredictable and occurred in some patients in as little as 2 days after initial exposure or on re-treatment. A peripheral eosinophilia was described in two cases along with centrilobular necrosis and an eosinophilic infiltration, suggesting a possible allergic reaction [53 – 55]. The FDA advisory restricting the use of trovafloxacin to hospitalized patients with life-threatening infections in whom safer alternatives are not available has effectively limited use of this drug to a few patients.

The macrolides—erythromycin, azithromycin, and clarithromycin Erythromycin was first discovered in 1952 in a soil sample from the Philippines containing a strain of the bacillus Streptomyces erythreus [32]. Several ester derivatives were then formulated to improve stability or facilitate intestinal

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absorption of the erythromycin base [56]. Within a few years of its introduction into clinical practice, there were several reports of drug-induced hepatotoxicity (see Table 2) [57,58]. Initially, erythromycin estolate was suspected as the sole derivative responsible for hepatotoxicity, but toxicity has since been documented to occur with the use of erythromycin ethylsuccinate, propionate, and stearate derivatives also [56,59 – 62]. The estolate and ethylsuccinate forms of erythromycin have been associated with reversible intrahepatic cholestatic jaundice and cholestatic hepatitis [63 – 65]. There are also reports of severe intrahepatic cholestatic jaundice, which may be associated with moderate serum aminotransferase and high alkaline phosphatase elevations. Liver biopsy may demonstrate portal inflammation with eosinophils. Peripheral eosinophilia, fever, and skin rash may be associated features, suggesting an immunoallergic mechanism of toxicity. The incidence of hepatotoxicity from erythromycin estolate and erythromycin ethylsuccinate is low and close to that seen with penicillin V, which is regarded as having a low hepatotoxicity profile [66]. It is estimated that for every one million patients treated with erythromycin for 10 days, symptomatic acute hepatitis resulting in hospitalization occurs in only 2.5 [38]. There was little suspicion of hepatotoxicity after the introduction of clarithromycin, a semi-synthetic macrolide antibiotic. Initially, there was a single case report of clarithromycin-associated cholestatic hepatitis [67]. This report, however, was followed by a brief report that found a surprisingly high frequency (36% [5 out of 14]) of reversible cholestatic hepatitis in elderly patients taking high-dose clarithromycin [68]. Case reports of reversible cholestatic hepatitis associated with azithromycin have also appeared. In two such reports, hyperbilirubinemia, eosinophilia, and oliguric acute renal failure followed a 5-day course of therapy in elderly men [69,70]. There are also two case reports of fulminant hepatic failure associated with clarithromycin [71,72]. The first such report involved a patient who had been taking less than 5 g of acetaminophen daily just before using clarithromycin [72]. The second case was that of a patient taking disulfiram who was then treated with clarithromycin [71]. Disulfiram and clarithromycin are inhibitors of cytochrome P450, and accumulation of toxic disulfiram metabolites was proposed as a possible mechanism of hepatic failure.

Nitrofurantoin Nitrofurantoin is a synthetic nitrofuran that inhibits several bacterial enzymes and is commonly used for the prophylaxis of urinary tract infections. Initial case reports and then small series of cases of nitrofurantoin-associated chronic active hepatitis established the significance of this clinical entity [73 – 77]. The association of hypergammaglobulinemia, antinuclear antibodies, and anti-smooth muscle antibodies with liver histology typical of aggressive chronic hepatitis were suggestive of autoimmune hepatitis. In the setting of nitrofurantoin exposure, however, the prognosis of this form of autoimmune hepatitis is generally good, with rapid improvement following cessation of nitrofurantoin.

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In one series, 18 of 20 patients recovered after withdrawal of nitrofurantoin; the two patients who died had continued to take the medication after developing side effects [78]. The incidence of hepatic injury caused by nitrofurantoin is low and has been estimated to be 0.0003% [79]. Initial reports of nitrofurantoin hepatotoxicity were exclusively in women, possibly because of the greater use of the drug by women than men rather than a difference in susceptibility between the sexes; the first report of toxic hepatitis in a man occurred in 1982 [80]. The female predominance seems to have been borne out in subsequent reports. The early literature suggested that nitrofurantoin hepatotoxicity generally occurred after chronic exposure to the drug, that is, after 6 weeks of continuous therapy. A recent and the largest series identified 52 cases of nitrofurantoin hepatotoxicity with most patients presenting within the first 6 weeks of beginning nitrofurantoin treatment [78]. Liver injury caused by nitrofurantoin is mainly hepatocellular, although cholestatic and mixed patterns are described, and it is presumed to be immunoallergic or the result of a metabolic idiosyncrasy. In support of an immunologic cause is an association with a lupus erythematosus-like presentation, autoantibodies against nuclear antigen and smooth muscle, and hypergammaglobulinemia. A hypersensitivity mechanism for nitrofurantoin liver injury is also supported by reports that re-challenge with the drug in a patient 17 years after the initial hepatic injury resulted in recurrent injury and that low-dose nitrofurantoin consumed in milk from a nitrofurantoin-treated cow caused hepatic injury in a hypersensitive person [81]. Clinically, a fever, rash, and eosinophilia are often seen. Liver histology variably shows acute centrilobular bridging necrosis or chronic hepatitis with or without cirrhosis [81].

Sulfamethoxazole/trimethoprim Sulfonamide is the general name given to the more than 5000 derivatives of para-aminobenzenesulfonamide. Sulfonamides were the first antimicrobial agents introduced into clinical practice in 1936, and they made a significant early contribution to the treatment of bacterial infections in humans. With the introduction of the more effective penicillins, the importance of the sulfonamides was greatly reduced. As a class, however, they have gained new relevance with the discovery of synergistic action when used in combination with trimethoprim, a diaminopyrimidine. The sulfonamides have been recognized as a cause of a probable immunoallergic form of hepatitis; rechallange has been associated with recurrent hepatitis [82]. Hepatic injury can be either cholestatic or mixed hepatocellular-cholestatic. Prolonged cholestasis with ductopenia and vanishing bile duct syndrome has been described in two reports; in one case the patient progressed to liver failure requiring liver transplantation [83,84]. There are other reports of fulminant liver failure [85,86] and granulomatous hepatitis [87]. Despite the frequency with which sulfamethoxazole/trimethoprim is prescribed, however, there are few well-

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documented examples of severe hepatotoxicity. In patients with AIDS an increased incidence of adverse reactions to sulfamethoxazole/trimethoprim has been described, although there is little in the literature to support an increased incidence of hepatotoxicity in this group of patients. Sulfadoxine-pyrimethamine (Fansidar1) is used in the treatment and prophylaxis of malaria and has been associated with hepatic granulomas and fatal hepatic necrosis [88,89].

Cephalosporins There have been few reports of hepatotoxicity with the cephalosporins, and most occurrences have been with the first-generation agents. Antibiotic-associated hypoprothrombinemia may be associated with inhibition of intestinal bacterial vitamin K production, and a profound hypoprothrombinemia has been seen with the cephalosporins moxalactam, cefoperazone, and cefamandole. The mechanism of this severe hypoprothrombinemia may involve inhibition of hepatic gamma-carboxylation of vitamin K-dependent clotting factors during posttranslational processing [90,91]. Another unusual hepatic side effect ascribed to a cephalosporin is the formation of biliary sludge from precipitation of the calcium salt of ceftriaxone [92]. This entity was first described in young children who presented with symptoms and signs of acute cholecystitis [93,94]. Ceftriaxone biliary sludge was subsequently found to occur in 25% of treated adults, as assessed by ultrasonography, although only rarely were there gallstones or symptoms of biliary colic [95]. With withdrawal of the drug, the crystals solubilize, and cholecystectomy is not required [96].

Antituberculous drugs Isoniazid In the 1980s, the incidence of tuberculosis began to rise dramatically in association with the rise in the number of inner city cases of AIDS, homelessness, and, more recently, neighborhoods of immigrants from regions of the world endemic for tuberculosis. This trend has reversed the progress that had been made in eradicating tuberculosis in the United States during the previous three decades. With the resurgence of tuberculosis, isoniazid hepatotoxicity has become increasingly important. In the 1950s, there were several case reports of hepatitis in the setting of exposure to combination antituberculous medical regimens (Table 3); it was generally believed that isoniazid monotherapy was not associated with hepatic toxicity [97 – 99]. With the increased use of isoniazid for the treatment of tuberculosis and prophylaxis of patients with a positive purified protein

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Table 3 Hepatotoxicity of antituberculous drugs Drug

Reported reactions

Ethambutol Isoniazid Para-aminosalicylic acid Pyrazinamide

Cholestatic hepatitis Hepatocellular, CAH, granulomatous hepatitis, hepatic failure Cytotoxic-zonal necrosis, chronic hepatitis Hepatocellular, massive hepatic necrosis, chronic active hepatitis, granulomatous hepatitis Hepatocellular, hyperbilirubinemia Not reported

Rifampin Streptomycin

Abbreviation: CAH, chronic active hepatitis.

derivative (PPD) skin test, the American Thoracic Society in 1967 recommended wider use of isoniazid chemoprophylaxis under the misconception that isoniazid monotherapy was rarely if ever associated with hepatic side effects [100]. First in isolated case reports and then in larger series [101,102], it soon became clear that isoniazid monotherapy may lead to hepatotoxicity. In 1974, it was reported that reversible elevations in serum aminotransferase levels to 2.5 times the upper limit of normal occurred in 12% of patients treated with isoniazid, with a greater frequency in older persons [103]. A few years later, the United States Public Health Service Cooperative Surveillance Study estimated that the risk for isoniazidassociated hepatoxicity was 20.7 per 1000 treated patients and reported 8 deaths among 174 patients with hepatitis. The risk for hepatotoxicity was three times greater in patients older than age 35 than in those younger than age 35 [104]. In 1993, in response to an isoniazid-related case of hepatic failure, the New York State Department of Health reported on an inquiry regarding isoniazidassociated hepatic failure at four liver transplant centers in New York and Pennsylvania between January 1991 and May 1993 [105]. Eight patients taking isoniazid monotherapy for prophylaxis against tuberculosis had been referred with hepatic failure; the median age of the patients was 33 years, and three were less than 20 years of age. In this report, five patients received a liver transplant, and three died while awaiting transplantation. The onset of symptoms after initiation of treatment ranged from 21 to 142 days (median 57 days), and patients continued to take the medication for 3 to 49 days (median 13 days) after the onset of symptoms of hepatitis, including fatigue, nausea, abdominal pain, and anorexia [106]. A meta-analysis of the six studies published between 1969 and 1981 on isoniazid prophylaxis found a rate of hepatotoxicity of 6 per 1000 patients [106]. These reports appear to indicate that isoniazid hepatotoxicity may occur with alarming frequency, may occur months into therapy, and may frequently be associated with liver failure. The true incidence rates of symptomatic hepatotoxicity and liver failure remain unknown, however, despite the increasing number of adverse events reported. The occurrence of hepatotoxicity has to be reconciled with the experience that in up to 20% of persons treated with isoniazid, minor asymptomatic aminotransferase elevations occur but normalize with continued treatment in most cases [107,108].

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The incidence of severe and clinically significant hepatotoxicity is likely much lower than suggested by the aforementioned reports. In a prospective study of 11,141 consecutive patients treated at an outpatient clinic, monthly interviews for symptoms and signs of hepatitis were conducted at the time the prescription was refilled, and only symptomatic patients underwent liver biochemistry testing [109]. Hepatic dysfunction was defined as a serum aspartate aminotransferase (AST) level greater than five times the upper limit of normal. Hepatotoxicity developed in only 11 patients on isoniazid, with a median interval between initiation of treatment and diagnosis of 9 weeks (range, 19 days to 5 months.) Only one patient was hospitalized, and all 11 patients with symptomatic hepatitis recovered fully. The rate of one case of symptomatic hepatitis per 1000 treated patient without any fatalities is substantially lower than estimated rates in previous reports and suggests that, with appropriate clinical observation, the current estimated frequency of hepatic failure and death is around 0.001% (2 in 202,497) [110]. The high incidence of hepatotoxicity cited in older series probably reflects inclusion of patients with less severe hepatotoxicity that can be considered clinically insignificant. Mild asymptomatic aminotransferase elevations do not require discontinuation of isoniazid so long as aminotransferase levels remain less than five times the upper limit of normal. The risk for isoniazid hepatitis is increased in patients with chronic viral hepatitis B and C and with alcohol consumption, and abstinence is advised during therapy. Isoniazid induces cytochrome P450 2E1 [111] and, when used alone or in combination with alcohol, may increase the risk for hepatotoxicity in patients taking acetaminophen [112 – 114]. Patients with isoniazid hepatitis are clinically indistinguishable from patients with other forms of hepatitis. They may be asymptomatic with mild to moderate elevations in serum aminotransferase levels or symptomatic with malaise, anorexia, nausea, vomiting, and jaundice. Whether to monitor liver biochemistries during treatment with isoniazid is controversial. Educating patients to report clinical symptoms of hepatitis with prompt laboratory evaluation and cessation of isoniazid for significant elevations may be the best safeguard against serious hepatic injury.

Rifampin and pyrazinamide Rifampin is a semi-synthetic derivative of rifamycin B, a macrocyclic antibiotic produced by Streptomyces mediterranei [32]. Rifampin may reduce the uptake of bile salts and bilirubin by hepatocytes by competing for intracellular binding proteins, thereby leading to impaired bilirubin excretion into the bile and elevated serum total bilirubin levels (see Table 3) [115]. Affected persons, however, are usually asymptomatic and rarely recognized clinically. Rifampin may be offered as monotherapy for the treatment of latent tuberculosis in patients who cannot tolerate isoniazid but is generally used as part of a combination regimen. In 2000, a short 2-month rifampin/pyrazinamide regimen

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was recommended as an alternative to isoniazid monotherapy by the American Thoracic Society and Centers for Disease Control and Prevention (CDC) [116]. By September of the same year, the first report to the CDC of fatal hepatitis associated with rifampin/pyrazinamide appeared [117], and by August 2001, a total of 23 cases of clinically significant hepatotoxic liver injury had been reported (see Table 3) [118]. Clinically significant hepatotoxic liver injury was defined as liver injury leading to hospitalization or death; five persons died of liver failure, and 16 recovered without liver transplantation. In all five patients who died, liver injury developed in the second month of therapy. New recommendations superceding the prior guidelines recommended the use of isoniazid as the preferred treatment, and caution was advised regarding the use of rifampin/pyrazinamide, particularly in the setting of known chronic liver disease or alcoholism. Pyrazinamide may be the most hepatotoxic antituberculous medication (see Table 3). The mechanism of hepatotoxicity has been considered to be dose related, although in one case report rechallenge after an initial reaction to a combination regimen led to an increase in serum aminotransferase levels to 80 times the upper limits of normal with an associated eosinophilia, suggesting a hypersensitivity reaction [119]. Hepatotoxicity caused by antituberculous medications is often difficult to sort out because the drugs generally are used in combination regimens. With the exception of streptomycin, all of the antituberculous medications have been associated with hepatotoxicity. The difficulty in assessing the risk posed by an individual drug is demonstrated in a case report in which single agents were well tolerated but toxicity occurred at the time drugs were used in combination. In one report of a patient treated for 4 days with isoniazid, rifampin, ethambutol, and pyrazinamide, abdominal pain and nausea developed in association with elevated serum AST and bilirubin levels [120]. The medications were discontinued, the liver biochemistries normalized, and isoniazid alone was resumed, with continued normal liver function. However, within 4 days of the reintroduction of rifampin, the serum AST and bilirubin levels rose dramatically, and rifampin was again discontinued with recovery of the liver biochemistries. Because of resistance, isoniazid was discontinued 4 weeks later and rifampin was reintroduced, with persistently normal liver function thereafter.

Anti-fungal agents Amphotericin B Amphotericin B has been the mainstay of systemic anti-fungal therapy since its introduction in the 1950s, and it continues to play an important role. Although amphotericin B has a significant number of associated adverse effects, hepatotoxicity is rare (Table 4). There are only a few reports of suspected amphotericin B-associated hepatotoxicity, with a reversible and predominantly hepatocellular pattern of injury [121,122].

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Table 4 Hepatotoxicity of anti-fungal agents Drug

Reported reactions

Albendazole Amphotericin B Fluconazole Griseofulvin Intraconazole Ketoconazole Mebendazole Terbinafine

Hepatocellular Rare hepatocellular, mixed hepatocellular-cholestatic Cholestatic hepatitis, hepatic failure Cholestasis Hepatocellular, cholestatic hepatitis Hepatocellular, mixed hepatocellular-cholestatic Hepatocellular Hepatocellular, mixed hepatocellular-cholestatic, hepatic failure

Terbinafine Terbinafine is an oral allyamine anti-fungal agent that is effective in the treatment of onychomycosis. With marketing aimed directly at the patient/ consumer, increased demand and use of this new agent, with possible side effects, can be expected. Hepatitis, mixed cholestasis, jaundice, and hepatic failure requiring liver transplantation have been reported (see Table 4) [123 – 127]. Also described is prolonged cholestasis, with serum alkaline phosphatase and bilirubin levels peaking up to 2 months after cessation of therapy and liver biochemistries remaining elevated for 6 months or more. Although the number of cases of terbinafine-induced hepatotoxicity remain small, some cases have been severe. In a prospective treatment trial, minor asymptomatic aminotransferase elevations were found in only 1 of 117 treated patients [128]. Azole anti-fungals—ketoconazole, fluconazole, and itraconazole Ketoconazole was introduced in 1981 as the first synthetic oral azole agent. These agents are now used widely in the treatment of systemic fungal infections. Although asymptomatic aminotransferase elevations develop in 2% to 17% of persons who use ketoconazole, symptomatic hepatic injury is rare (see Table 4) [129 –131]. Fluconazole was introduced in 1990 and itraconazole in 1992. These drugs have been associated with asymptomatic hepatitis in 1% to 7% and 1% to 5% of treated patients, respectively [132]. There are two case reports of fluconazole-associated fulminant hepatic failure, one of which occurred in a patient with AIDS [133,134].

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