OVERVIEW

CASE REPORT

CASE REPORTS SUBMITTED TO LIVERTOX

Clinical cases of drug-induced liver injury that have been submitted to LiverTox ("Submit a Case Report") are available for review. Most of these reference cases are from the Drug-Induced Liver Injury Network, but others are from users of LiverTox who have submitted data from an actual clinical case. All cases have been reviewed and cleared of personal identifiers and a brief comment added by the LiverTox editors. Click on the following link to view the submitted case reports that have been made publically available.

Submitted Cases on Clarithromycin

PRODUCT INFORMATION

CHEMICAL FORMULA AND STRUCTURE

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DRUG	CAS REGISTRY NUMBER	MOLECULAR FORMULA	STRUCTURE
Clarithromycin	81103-11-9	C38-H69-N-O13

ANNOTATED BIBLIOGRAPHY

References updated: 10 August 2017

• Moseley RH. Macrolide antibiotics. Hepatotoxicity of antimicrobials and antifungal agents. In, Kaplowitz N, DeLeve LD, eds. Drug-induced Liver Disease. 3rd ed. Amsterdam: Elsevier, 2013, pp. 466-7.

  (Expert review of macrolide antibiotic induced liver injury mentions that clarithromycin has been implicated in cases of cholestatic hepatitis, particularly in elderly patients on high doses).
• MacDougall C, Chambers HF. Macrolides and ketolides. In, Brunton LL, Chabner BA, Knollman BC, eds. Goodman & Gilman’s the pharmacological basis of therapeutics. 12th ed. New York: McGraw-Hill, 2011, pp. 1529-34. (Textbook of pharmacology and therapeutic.

  s).
• Wallace RJ Jr, Brown BA, Griffith DE. Drug intolerance to high-dose clarithromycin among elderly patients. Diagn Microbiol Infect Dis 1993; 16: 215-21. [PubMed: 8477575]

  (Elevations of Alk P and GGT occurred in 5 of 14 elderly patients receiving clarithromycin in high doses [2 g/day] after 1 to 6 weeks of therapy, resolving slowly; no jaundice and few symptoms).
• Yew WW, Chau CH, Lee J, Leung CW. Cholestatic hepatitis in a patient who received clarithromycin therapy for a Mycobacterium chelonae lung infection. Clin Infect Dis 1994; 18: 1025-6. [PubMed: 8086541]

  (62 year old man with atypical mycobacterial disease received high doses of clarithromycin [2 g/day] and developed rising Alk P [110 to 447 U/L], bilirubin [0.5 to 2.2 mg/dL] and ALT [18 to 46 U/L] during 2 months of therapy, resolving slowly once drug was stopped).
• Brown BA, Wallace RJ Jr, Griffith DE, Girard W. Clarithromycin-induced hepatotoxicity. Clin Infect Dis 1995; 20: 1073-4. [PubMed: 7795060]

  (Letter in response to Yew et al. pointing out similarity of details in case to those from their study [Wallace 1993] and adding two further cases of marked Alk P and GGT elevations during high dose clarithromycin therapy, particularly in elderly and frail patients, resolving slowly over 1 to >3 months; not seen with lower doses).
• Cadranel JF, Bachmeyer C, Pras V, Bouraya D, Pourvillain S, Biour M, Mougeot-Martin M. [Acute symptomatic cytolytic hepatitis probably related to clarithromycin] Gastroenterol Clin Biol 1996; 20: 1034-5. French. [PubMed: 9119179]

  (41 year old woman developed acute abdominal pain after 3 days of clarithromycin therapy [bilirubin 0.7 mg/dL, ALT 10 times ULN, Alk P normal], resolving with a month of stopping).
• Shaheen N, Grimm IS. Fulminant hepatic failure associated with clarithromycin. Am J Gastroenterol 1996; 91: 394-5. [PubMed: 8607519]

  (25 year old man developed jaundice and abdominal pain after 9 days of clarithromycin [bilirubin 12.6 rising to 32 mg/dL, ALT 4790 U/L, Alk P 225 U/L], with subsequent signs of liver failure leading to transplant 11 days after admission; patient died postoperatively).
• Sousa C, Correia J, Santos J, Silvestre F, Bernardo A. [Cholestatic hepatitis probably induced by clarithromycin] Gastroenterol Clin Biol 1997; 21: 632-3. French. [PubMed: 9587506]

  (74 year old man developed jaundice after 7th day of 10-day course of clarithromycin [bilirubin 25.1 mg/dL, ALT 498 U/L, Alk P 3148 U/L], resolving fully within 3 months of stopping: Case 1).
• Vial T, Biour M, Descotes J, Trepo C. Antibiotic-associated hepatitis: update from 1990. Ann Pharmacother 1997; 31: 204-20. [PubMed: 9034423]

  (Extensive review including discussion of 3 macrolides [erythromycin, clarithromycin and azithromycin], ALT elevations occurred in 0.4-1.2% of patients treated, but similar rates found in placebo controls; rare instances of cholestatic hepatitis have been reported with all three).
• Baylor P, Williams K. Interstitial nephritis, thrombocytopenia, hepatitis, and elevated serum amylase levels in a patient receiving clarithromycin therapy. Clin Infect Dis 1999; 29: 1350-1. [PubMed: 10525003]

  (77 year old man developed acute interstitial nephritis and thrombocytopenia with mild increases in AST and CPK without jaundice after 5 days of clarithromycin therapy, but also 5 days after a 7 day course of trimethoprim/ sulfamethoxazole; all abnormalities subsequently resolved).
• Fox JC, Szyjkowski RS, Sanderson SO, Levine RA. Progressive cholestatic liver disease associated with clarithromycin treatment. J Clin Pharmacol 2002; 42: 676-80. [PubMed: 12043957]

  (59 year old woman developed jaundice a few days after stopping a 3 day course of clarithromycin [bilirubin 17 mg/dL, ALT 428 U/L, Alk P 2831 U/L], eventually leading to liver and renal failure and death 3 weeks later).
• Masiá M, Gutiérrez F, Jimeno A, Navarro A, Borrás J, Matarredona J, Martín-Hidalgo A. Fulminant hepatitis and fatal toxic epidermal necrolysis (Lyell disease) coincident with clarithromycin administration in an alcoholic patient receiving disulfiram therapy. Arch Intern Med 2002; 162: 474-6. [PubMed: 11863483]

  (47 year old man developed severe rash 1 month after starting disulfiram and 1 week after starting clarithromycin [bilirubin 15.3 mg/dL, ALT 2603 U/L, Alk P 240 U/L], with subsequent liver failure and death; authors hypothesized that there were drug interactions with combined inhibition of CYP 3A4 and 2E1 by the 2 agents).
• Christopher K, Hyatt PA, Horkan C, Yodice PC. Clarithromycin use preceding fulminant hepatic failure. Am J Gastroenterol 2002; 97: 489-90. [PubMed: 11866297]

  (40 year old woman developed nausea, abdominal pain and fever at the end of a 7 day course of clarithromycin, with subsequent jaundice and hepatic failure [bilirubin 33.4 mg/dL, ALT 1974 U/L, Alk P 1095 U/L, protime 21 seconds], dying 13 days after presentation).
• Tietz A, Heim MH, Eriksson U, Marsch S, Teracciano L, Krähenbühl S. Fulminant liver failure associated with clarithromycin. Ann Pharmacother 2003; 37: 57-60. [PubMed: 12503933]

  (58 year old woman with heart disease developed jaundice after 4 days of clarithromycin treatment [bilirubin 4.6 mg/dL, ALT 13,853 U/L, Alk P 258 U/L, prothrombin index 10%], recovering within 2 weeks; possibly due to ischemic hepatitis).
• Sopena N, Martínez-Vázquez C, Rodríguez-Suárez JR, Segura F, Valencia A, Sabrià M. Comparative study of the efficacy and tolerance of azithromycin versus clarithromycin in the treatment of community-acquired pneumonia in adults. J Chemother 2004; 16: 102-3. [PubMed: 15078008]

  (Comparison of 3 day azithromycin vs 10-14 day clarithromycin course in 70 adult patients with pneumonia showing similar efficacy [>90%] and frequency of side effects [26.5% vs 25%], with no mention of hepatic injury).
• Peters TS. Do preclinical testing strategies help predict human hepatotoxic potentials? Toxicol Pathol 2005; 33: 146-54. [PubMed: 15805066]

  (FDA scientist review of discrepancies between preclinical testing and toxicity identified when agent becomes generally available; clarithromycin is used as an example).
• Björnsson E, Olsson R. Suspected drug-induced liver fatalities reported to the WHO database. Dig Liver Dis 2006; 38: 33-8. [PubMed: 16054882]

  (Among 4690 reports of drug induced liver injury with fatal outcome reported to WHO, clarithromycin was among the top 20 agents implicated [51 cases]).
• Giannattasio A, D'Ambrosi M, Volpicelli M, Iorio R. Steroid therapy for a case of severe drug-induced cholestasis. Ann Pharmacother 2006; 40: 1196-9. [PubMed: 16720710]

  (Adolescent girl developed jaundice 1 week after 15 day course of clarithromycin and nimesulide [ALT 69 U/L, GGT normal and bilirubin 10.6 mg/dL]; prolonged jaundice led to use of prednisone [starting at 1 mg/kg/day] with rapid improvement, stopped after 12 weeks, ultimately complete recovery).
• Chalasani N, Fontana RJ, Bonkovsky HL, Watkins PB, Davern T, Serrano J, Yang H, Rochon J; Drug Induced Liver Injury Network (DILIN). Causes, clinical features, and outcomes from a prospective study of drug-induced liver injury in the United States. Gastroenterology 2008; 135: 1924-34. [PMC free article: PMC3654244] [PubMed: 18955056]

  (Among 300 cases of drug induced liver disease in the US collected from 2004 to 2008, 5 cases were attributed to telithromycin and 3 to azithromycin as single agents, but none to erythromycin or clarithromycin).
• Leitner JM, Graninger W, Thalhammer F. Hepatotoxicity of antibacterials: pathomechanisms and clinical data. Infection 2010; 38: 3-11. [PubMed: 20107858]

  (Review; the macrolide antibiotics may cause cholestatic hepatitis at an estimated rate of 3.6 for erythromycin, 3.8 for clarithromycin, and 5.5 cases per 100,000 prescriptions for telithromycin, compared to 10 for sulfonamides and 2000 per 100,000 for isoniazid).
• Caramaschi P, Mahamid H, Bambara LM, Biasi D. Liver impairment after concomitant administration of bosentan and clarithromycin in systemic sclerosis. Joint Bone Spine 2010; 77: 81-2. [PubMed: 20022782]

  (Two cases, 47 and 69 year old women with systemic sclerosis were treated with bosentan without difficulty, but developed ALT elevations [peak 503 and 94 U/L, Alk P 263 and 293 U/L] without jaundice within 5-7 days of starting clarithromycin, which resolved with stopping both or either, attributed to drug-drug interactions).
• Ferrajolo C, Capuano A, Verhamme KM, Schuemie M, Rossi F, Stricker BH, Sturkenboom MC. Drug-induced hepatic injury in children: a case/non-case study of suspected adverse drug reactions in VigiBase. Br J Clin Pharmacol 2010; 70: 721-8. [PMC free article: PMC2997312] [PubMed: 21039766]

  (Worldwide pharmacovigilance database containing 9036 hepatic adverse drug reactions in children includes 63 cases attributed to azithromycin, 60 to erythromycin and 35 to clarithromycin).
• Reuben A, Koch DG, Lee WM; Acute Liver Failure Study Group. Drug-induced acute liver failure: results of a U.S. multicenter, prospective study. Hepatology 2010; 52: 2065-76. (Among 1198 patients with acute liver failure enrolled in a US prospective study between 1998 and 2007, 133 were attributed to drug induced liver injury, of which 31 were due to antibiotics, one of which was attributed to clarithromycin). [PMC free article: PMC3992250] [PubMed: 20949552]
• Hydzik P, Gawlikowski T, Groszek B. [Drug-induced erythrodermia complicated by multiorgan failure--case report]. Przegl Lek 2011; 68: 503-5. Polish. [PubMed: 22010450]

  (23 year old young woman developed toxic epidermal necrolysis with liver, lung and renal injury two weeks after starting a course of clarithromycin, ibuprofen and acetaminophen [bilirubin 10.7 mg/dL, ALT 915 U/L, GGT 252 U/L, INR 1.7], with ultimate complete resolution).
• Kwon H, Lee SH, Kim SE, Lee JH, Jee YK, Kang HR, Park BJ, Park JW, Hong CS. Spontaneously reported hepatic adverse drug events in Korea: multicenter study. J Korean Med Sci 2012; 27: 268-73. [PMC free article: PMC3286773] [PubMed: 22379337]

  (Summary of 2 years of adverse event reporting in Korea; of 9360 reports, 567 were liver related, including 6 [1.1%] attributed to macrolide antibiotics).
• Maggi P, Solarino B, Cassano P, Tattoli L, Leone A, Maselli E, Angarano G. Fatal fulminant hepatitis following administration of clarithromycin in a patient chronically treated with antipsycotic drugs. Immunopharmacol Immunotoxicol. 2013; 35: 191-4. [PubMed: 22804484]

  (23 year old man developed nausea, diarrhea and fever within 3 days of starting a 5 day course of clarithromycin, with subsequent jaundice [bilirubin 9.6 mg/dL, ALT 4065 U/L] followed by hepatic failure, coagulopathy, intracerebral hemorrhage and death).
• Ferrajolo C, Verhamme KM, Trifirò G, 't Jong GW, Giaquinto C, Picelli G, Oteri A, et al. Idiopathic acute liver injury in paediatric outpatients: incidence and signal detection in two European countries. Drug Saf 2013; 36: 1007-16. [PubMed: 23591830]

  (Analysis of 3 large, electronic healthcare databases identified 785 cases of acute liver injury of unknown cause, 110 of which occurred in relationship to a prescription, the highest relative risk [RR] being associated with clarithromycin [RR=25.9], amoxicillin/ clavulanate [RR=18.6] and amoxicillin [RR=6.0]).
• Björnsson ES, Bergmann OM, Björnsson HK, Kvaran RB, Olafsson S. Incidence, presentation and outcomes in patients with drug-induced liver injury in the general population of Iceland. Gastroenterology 2013; 114: 1419-25. [PubMed: 23419359]

  (In a population based study of drug induced liver injury from Iceland, 96 cases were identified over a 2 year period, none of which were attributed to clarithromycin or other macrolide antibiotics).
• Hernández N, Bessone F, Sánchez A, di Pace M, Brahm J, Zapata R, A Chirino R, et al. Profile of idiosyncratic drug induced liver injury in Latin America. An analysis of published reports. Ann Hepatol 2014; 13: 231-9. [PubMed: 24552865]

  (Systematic review of literature of drug induced liver injury in Latin American countries published from 1996 to 2012 identified 176 cases, one of which was attributed to clarithromycin [acute liver failure], but none were attributed to other macrolide antibiotics).
• Ferrajolo C, Coloma PM, Verhamme KM, Schuemie MJ, de Bie S, Gini R, Herings R, et al.; EU-ADR consortium. Signal detection of potentially drug-induced acute liver injury in children using a multi-country healthcare database network. Drug Saf 2014; 37: 99-108. [PubMed: 24446276]

  (Analyses of large spontaneous reporting databases from 3 European countries between 1995 and 2010 identified 125 drugs with at least one exposed case of unexplained acute liver injury in children, 20 of which had a statistically significant association, including clarithromycin [5 cases] and erythromycin [4 cases]).
• Kaye JA, Castellsague J, Bui CL, Calingaert B, McQuay LJ, Riera-Guardia N, Saltus CW, et al. Risk of acute liver injury associated with the use of moxifloxacin and other oral antimicrobials: a retrospective, population-based cohort study. Pharmacotherapy 2014; 34: 336-49. [PMC free article: PMC4260122] [PubMed: 24865821]

  (In a nested case control analysis of a health care network database of persons between 2001 and 2009, 8 selected antibiotics were assessed for association with risk of hospitalization for liver injury, adjusted relative risks being significantly elevated for levofloxacin [3.2], moxifloxacin [2.3], doxycycline [2.5], amoxicllin/clavulanate [2.5] and amoxicillin [2.3], but not for clarithromycin [1.8], telithromycin [1.7] or cefuroxime [0.9]).
• Chalasani N, Bonkovsky HL, Fontana R, Lee W, Stolz A, Talwalkar J, Reddy KR, et al.; United States Drug Induced Liver Injury Network. Features and outcomes of 899 patients with drug-induced liver injury: The DILIN Prospective Study. Gastroenterology 2015; 148: 1340-52.e7. [PMC free article: PMC4446235] [PubMed: 25754159]

  (Among 899 cases of drug induced liver injury enrolled in a US prospective study between 2004 and 2013, 323 [36%] were attributed to antibiotics including 29 [3.2%] due to marolides of which 18 were linked to azithromycin, 2 to clarithromycin, 2 erythromycin and 7 telithromycin).
• Ferrajolo C, Verhamme KM, Trifirò G, 't Jong GW, Picelli G, Giaquinto C, Mazzaglia G, et al. Antibiotic-induced liver injury in paediatric outpatients: a case-control study in primary care databases. Drug Saf 2017; 40: 305-15. [PMC free article: PMC5362651] [PubMed: 28025733]

  (In a health care database of 429,772 children in Italy and the Netherlands followed between 2008 and 2010, 938 cases of liver injury of uncertain cause were identified, the rate being higher in those with current use of antibiotics [12% vs 3.6%] for an adjusted odds rate ratio [aOR] of 3.2; specific antibiotics most commonly implicated were fluoroquinolones [19.0], cephalosporins [4.5], macrolides [3.5] and penicillins [2.6], and specific aOR for clarithromycin of 5.6 [12 cases]).
• Bonkovsky HL, Kleiner DE, Gu J, Odin JA, Russo MW, Navarro VM, Fontana RJ, et al.; U.S. Drug Induced Liver Injury Network Investigators. Clinical presentations and outcomes of bile duct loss caused by drugs and herbal and dietary supplements. Hepatology 2017; 65: 1267-77. [PMC free article: PMC5360519] [PubMed: 27981596]

  (Among 363 patients with drug induced liver injury who underwent liver biopsy, 26 [7%] had bile duct loss, including 2 cases attributed to azithromycin, but none to clarithromycin or other macrolides).