Gut, 1992,33,368-371

Hepatitis associated with amoxycillin-clavulanic acidcombination report of 15 cases

D Larrey, T Vial, A Micaleff, G Babany, M Morichau-Beauchant, H Michel, J P Benhamou

AbstractFifteen cases of hepatitis related to acombination ofamoxycillin and clavulanic acidare reported. Most patients were aged 60 yearsor more and there were more men than women(sex ratio 4:1). The amoxycillin-clavulanic acidhad been given at doses ranging from 0*5 to 6 g/day (mean 2 g/day) for seven to 60 days (mean18 days). In 11 cases, the first symptomsappeared one to four weeks after stoppingtreatment. Jaundice was observed in allpatients and was frequently associated withpruritus. Serum aminotransferase activitieswere increased in all patients and were gener-ally two to 10 times the upper limit of normal.Serum alkaline phosphatase activity wasconsiderably increased, from two to seventimes the upper limit of normal. Histologicalexamination of the liver, performed in sevenpatients, showed centri- or panlobularcholestasis in all cases, associated withgranulomatous hepatitis in one. The prognosisof amoxycillin-clavulanic acid induced hepati-tis seemed to be good. None of the patientsexhibited biological or clinical features ofhepatic failure and the course of the diseasewas characterised by the resolution of jaundicewithin one to eight weeks and a completerecovery within four to 16 weeks. Taking intoaccount the number of treated subjects andreported cases, we estimated the risk ofdeveloping hepatitis with this drug combinationto be very low, probably below 1/100 000. Ourdata suggest that the risk of hepatotoxicity maybe increased in elderly men given lengthytreatment. The association of hepatitis andsigns of hypersensitivity may suggest animmunoallergic mechanism of hepatotoxicityin some patients.

Amoxycillin, a semisynthetic penicillin, hasbeen combined with clavulanic acid, an inhibitorof bacterial 3-lactamases, to decrease antimicro-bial resistance. This combination, first marketedin France in 1984, is one of the most prescribedantibiotics worldwide.' 2 In France, in each oralbrand, the ratio of amoxycillin to clavulanic acid(w/w) is 4/1. The administration of amoxycillin-clavulanic acid is associated with a moderate andasymptomatic increase in serum aminotrans-ferase activity in 23% of subjects.3 Since 1989, 32cases of acute hepatitis have been described.'2In addition, the Australian Adverse DrugReactions Advisory Committee recently noted(without individual details) the receipt of 30reports of hepatic dysfunction after amoxycillin-clavulanic acid administration.'3 In most cases,hepatitis related to amoxycillin-clavulanic acidexhibited cholestatic patterns; hepatocellular or

mixed cholestatic and hepatocellular patternshave been described less frequently.'3These data prompted a study which aimed to

assess amoxycillin-clavulanic acid hepatotoxicityin France, on the basis of cases observed inseveral hospital liver units or spontaneouslyreported to the regional centres of the FrenchSystem ofDrug Surveillance (Pharmacovigilancecentres)'4 and to the manufacturer, BeechamLaboratories.

In this report, we describe 15 cases compiledduring this collaborative study, including onecase recently published" and one case acceptedfor publication as a letter. '1 Our data confirmthat amoxycillin-clavulanic acid generally causesacute cholestatic hepatitis and show that thisdrug combination may also occasionally inducegranulomatous hepatitis. In addition, this studyshows that the risk of hepatotoxicity is low and ismainly associated with elderly men receivinglengthy treatment.

MethodsForty patients with hepatitis possibly related toamoxycillin-clavulanic acid administration wereseen in several liver units or were reported toregional centres of the national drug surveillancenetwork and Beecham Laboratories, Francebetween January 1987 and June 1990. In allcases, clinical, biological, and pathological datawere carefully reviewed.

In 25 cases the available data were consideredto be insufficient to exclude other causes ofhepatitis. In the remaining 15 patients (seeTables I and II), hepatitis was ascribed toamoxycillin-clavulanic acid administration onthe following grounds. These patients had nohistory of liver or biliary tract disease or of drugaddiction, transfusion of blood products, orsurgery within the six months preceding theonset of hepatitis. Only one patient (case 9) wasan abuser of alcohol. In all patients, IgM anti-bodies to hepatitis A virus and hepatitis B surfaceantigen were absent in serum. Serological testsfor hepatitis C virus infection were negative inthe six patients tested (patients 1, 2, 5, 7, 8, 11).Serological tests for recent infection with cyto-megalovirus in nine cases (patients 1-8, 11),herpes simplex viruses in three patients (patients1, 2, 8), and Epstein-Barr virus in six patients(patients 1, 2, 5, 7, 8, 11) were also negative in allpatients tested. Ultrasonography of the liver andbiliary tract was normal in all cases. Computedtomography of the liver and biliary tract, under-taken in five patients (patients 6, 9, 10, 11, 15)was normal, as was endoscopic retrogradecholangiography performed in eight patients(patients 1, 3, 4, 5, 6, 7, 11, 13). In all patients,there was a clear chronological relation between

Service des Maladies del'Appareil Digestif,H6pital Saint-Eloi,Montpellier, FranceD LarreyH MichelCentre dePharmacovigilance,H6pital Edouard-Herriot,Lyon, FranceT VialService d'Hepatologie,H6pital Beaujon, Clichy,FranceJ P Benhamou

Service d'Hepato-Gastroenterologie, CHRPoitiers, FranceM Morichau-BeauchantG BabanyLes LaboratoiresBeecham, FranceA MicaleffCorrespondence to:Dr D Larrey, Service desMaladies de l'AppareilDigestif, H6pital Saint-Eloi,Avenue Bertin Sans, 34059Montpellier, France.Accepted for publication23 July 1991

368

group.bmj.com on September 10, 2014 - Published by gut.bmj.comDownloaded from

evgheniHighlight

Hepatitis associated with amoxycillin-clavulanic acid combination report of15 cases

TABLE I Age, sex, and drug administration in 15 patients with amoxycillin-clavulanic acid induced hepatitisAmoxycillin-clavulanic acid administration

Interval Intervalfrom onset of from stoppingtreatment to treatment to

Duration of onset of onset of PreviousPatient Sexlage Dosage treatment Total hepatitis hepatitis administrationno (years) (glday) (days) dose (g) (days) (days) Indication Other administered drugs ofamoxicillin

1 M/48 0-5-0 75 21 13 29 8 Bronchitis asthma Theophylline, terbutaline, salbutamol Yes2 F/52 3-0 15 45 45 30 Upper respiratory Ketoprofen, metronidazole, No

tract infection netromycin, ranitidine,bethamethasone

3 M150 1-0 7 7 7 0 Sinusitis Hydroxyzine, carbocystein, framvcetin No4 M/73 6-0 24 144 42 17 Endocarditis Netromycin, clonidine, furosemide, No

digoxine, lorazepam, clobazepamS M/57 1 5 17 25 5 35 18 Bronchitis asthma Prednisolone, salbutamol, No

theophylline, beclomethasone,sodium nedocromil, ipratropiumbromide

6 M/82 2-0-3-0 15 34 38 23 Bronchitis Furosemide No7 M/79 1i5 15 22 5 35 20 Urinary tract Heptaminol, raubasine- No

infection dihydroergocristine8 M/50 15 12 18 13 1 Upper respiratory Roxithromycin Yes

tract infection9 M/75 1-0-2-0 10 30 38 18 Ocular infection Diclofenac, sucralfate, lev,odopa No10 M/82 15 -2 0 60 100 89 29 Bronchitis Prednisolone, roxithromycin Yes11 M/62 3-0 14 42 21 8 Unknown Ketoprofen, paracetamol, enoxaparine No12 M/67 2-0 10 20 22 12 Pneumonia Diltiazem, pindolol, prednisolone, No

theophylline, acetylcystein13 M/81 2-0-3-0 33 71 33 0 Pneumonia Digoxine, trinitrine, indapamine, No

nicardipine, ticlopidine, lisinopril14 F/63 15 7 10-5 29 3 Otitis Niflumic acid Yes15 M/39 Unknown 10 Unknown 28 20 Upper respiratory Prednisolone, amphotericine B, Yes

tract infection nitrazepam, serrapeptase

amoxycillin-clavulanic acid administration andthe onset of hepatitis, as well as between with-drawal of the treatment and the resolution ofliver dysfunction. The direct involvement ofother drugs in the hepatitis could be eliminatedon the basis of clinical or chronological data.

ResultsAge, sex, and drug administration as well asclinical, biological, and histological manifes-tations observed in our 15 cases are summarisedin Tables I and II.The ages of the patients with hepatitis ranged

from 39 to 82 years (mean 64 years), and therewere more men than women (12 v 3 cases; sexratio 4:1). The amoxycillin-clavulanic acid hadbeen given at doses ranging from 0-5 to 6 g/day(0 5-3 g orally; 2-6 g iv) (mean 2 g/day) with aduration of administration ranging from seven to60 days (mean 18 days). The cumulative dosevaried widely, between 7 and 144 g (mean 42 g).Hepatitis occurred seven to 89 days (mean 33days) after starting the treatment. In 11 patients,amoxycillin-clavulanic acid had already beenstopped for one to four weeks when the firstsymptoms of hepatitis were observed. In mostcases, amoxycillin-clavulanic acid was given formild or moderately severe infection of the upperrespiratory tract or for moderate bronchitis.Only three patients were receiving treatment forsevere infections: endocarditis, bronchitis, andpneumonia. Five patients had previouslyreceived amoxycillin alone, without adverseeffect.

All patients had jaundice, which was intense(serum bilirubin> 100 [tmol/l) in 12. It wasassociated with pruritus in 12, asthenia in seven,and with vomiting, nausea, hepatomegaly, andskin rash in one case each.Serum alanine and aspartate aminotransferase

activities were increased in all patients - they

ranged from two to 10 times the upper limit ofnormal in 11 cases, and were 10 to 20 times theupper limit of normal in four. Serum alkalinephosphatase activity was appreciably increased,with values ranging from two to seven times theupper limit or normal. Similarly, serum y-glutamyl transpeptidase activity exceeded 10times the upper limit of normal in eight of the 12patients tested. The 15 patients did not exhibitany clinical or biological features of hepaticfailure (data not shown in the two Tables).Hepatitis was associated with blood hyper-eosinophilia (eosinophils>400/mm') in fivepatients. Results of tests for serum antitissueantibodies were available in 10 patients. Positiveresults with low or moderate titres (

Larrey, Vial, Micaleff, Babany, Morichau-Beauchant, Michel, Benhamou

TABLE II Clinical, biological, and histological manifestations in 15 patients with amoxycillin-clavulanic acid induced hepatitisCourse of the disease

Duration ofSerum ALT AST Alk Pho GGT Serum Duration liver test

Patient Clinical bilirubin antitissue Histological ofjaundice abnormalitiesno manifestations (ismol/l) (x upper limit ofnormal) Hypereosinophilia* antibodies lesions (weeks) (weeks)

1 Jaundice, pruritus, 230 10 6 2 15 + Anti-SM: 1/50e Centrilobular 8 12vomiting Anti-Nu - cholestasis

Anti-Mit -Anti-LKM -

2 Jaundice, pruritus, 152 4 1 3 9 - Anti-Nu: 1/lOOe Centrilobular Unknown Unknownskin rash, Anti-SM - cholestasisasthenia Anti-Mit -

Anti-LKM -3 Jaundice, pruritus 243 3 2 2,5 1,5 - Anti-Nu - Cholestasis 8 Unknown

Anti-SMAnti-Mit -

4 Jaundice, pruritus, 308 2 2 2 6 + Anti-Nu: 1/160e Cholestasis 8 >12asthenia Anti-SM: 1/40e 4 12Anti-SMAnti-Mit

11 Jaundice, pruritus 438 2,5 14 2,5 13 + Anti-Mit - ND 8 >812 Jaundice 71 10 8 2 26 - ND ND 1 413 Jaundice 161 11 5 5 25 - ND ND 3 >614 Jaundice, pruritus, 57 4 2 5 ND + ND ND Unknown 400/mm3; Anti-SM=anti-smooth muscle antibodies; anti-Nu=anti-nuclear antibodies; anti-Mit=anti-mitochondrial antibodies; anti-LKM=anti liver/kidneymicrosome antibodies; +: present; -: absent; ND: not done

and to assess possible factors contributing to thisadverse reaction.Taking into account the number of cases of

hepatitis ascribed to the amoxycillin-clavulaniccombination, either reported"3 or collected inthis study, and the estimated number of treatedpatients, the prevalence of symptomatic hepatitiswas calculated to range from one to five/i 000 000treated patients in several European countriesincluding France, United Kingdom, Germanyand Belgium. Obviously, these calculated valuesdepend on the reporting rate for drug inducedadverse reactions. Nevertheless, these datasuggest that the risk of developing amoxycillin-clavulanic acid hepatitis is very low, probablybelow 1/100 000.

DiscussionAnalysis of our 15 cases confirms previousreports showing that the amoxycillin-clavulanicacid combination may induce acute hepatitis,mainly exhibiting cholestatic features, and, lessfrequently, acute cytolytic or mixed patternhepatitis.'3 One patient was affected bygranulomatous hepatitis. It is noteworthy thatthere was frequently a delay of one to four weeksbetween stopping treatment and the onset ofhepatitis in our study (Table I). A similarobservation could be made by analysing patientsreported by Reedy et al.4 Such a feature isuncommon in drug induced liver injuries andmakes diagnosis more difficult.'6 1 The prognosis

of amoxycillin-clavulanic acid induced hepatitisseems to be good. Indeed, in our patients, as wellas in previously reported cases,"O 12 there was noclinical or biological evidence of hepatic failure.Furthermore, after stopping the drug, the courseof the disease was characterised by completerecovery within four months (Table II).'2The mechanism ofamoxycillin-clavulanic acid

hepatitis is unknown. However, the frequentassociation of hepatitis with hypersensitivitymanifestations (skin rash, hypereosinophilia,presence of serum antitissue autoantibodies)and the low prevalence of liver damage suggestsan immunoallergic mechanism (Table II).4 7 8

In addition, we identified several factors thatmay contribute to hepatotoxicity of this drugcombination. Firstly, men were much morefrequently affected than women (male/femalesex ratio, 4:1 in our study). A similarpredominance of men was also seen, albeit to alesser extent (sex ratio 2:1), in other reportedcases.'"12 This difference was not related tosignificantly more frequent prescription of thedrug in men: 58% in men v 42% in women forsubjects of all ages and 50% in men and womenolder than 65 years (data provided by BeechamLaboratories). Hypothetically, this may reflectsome sexual influence in amoxycillin-clavulanicacid hepatotoxicity. Secondly, amoxycillin-clavulanic acid hepatitis seems to be influencedby age - elderly subjects being more frequentlyaffected. Nine of our 15 patients and 15 of the 31other reported cases,>"5 2 were 60 years old or

370

group.bmj.com on September 10, 2014 - Published by gut.bmj.comDownloaded from

evgheniHighlight

evgheniHighlight

Hepatitis associated with amoxycillin-clavulanic acid combination report of15 cases 371

more. In contrast, hepatitis occurs exceptionallyin children, only a single case having beenreported in patients younger than 18 years.8Thirdly, hepatotoxicity may also be timedependent. Indeed, the mean durations of treat-ment in our 15 patients (18 days) and in the 18patients reported by Reedy et al (14 days),4 wereabout twice as long as the usual length oftreatment calculated for all patients who havereceived the drug (8-4 days) (data provided byBeecham Laboratories). In addition, theproportion of subjects who were treated for morethan 15 days is 33% in our series and 24% in theother reported cases,'O 12 whereas it representsonly 1% for all treated patients (data provided byBeecham Laboratories). These findings stronglysuggest that prolonged treatment may increasethe risk of hepatotoxicity with this drugcombination. Several hypotheses may beproposed for this latter feature. Protracted treat-ment may increase the rate of immunisationagainst the drug; alternatively, it may be con-sistent with a mechanism of hepatotoxicitypartially related to formation or accumulation, orboth, of putative toxic metabolites. These pointsdeserve further investigation.

In amoxycillin-clavulanic acid hepatotoxicity,the relative contribution of each compound orthe role of the drug combination is not fullyelucidated. The direct involvement of amoxy-cillin alone is unlikely. As far as we know, thereis only one reported case of hepatitis caused bythis compound, although it has been widely usedfor more than 15 years.'8 Five of our patients hadpreviously received amoxycillin alone without illeffect (Table I). Rechallenge with amoxycillinalone performed in three patients (8and our firstcase) was not followed by a recurrence ofhepatitis, whereas rechallenge with bothcompounds in two ofthese three cases resulted inrelapse of liver injury.8 This latter observationsuggests an involvement of clavulanic acid inhepatotoxicity. This view is supported by aprevious report that clavulanic acid in associationwith another 13-lactam antibiotic, ticarcillin, mayhave been responsible for the worsening of pre-existing liver disease.'9 Whether clavulanic acidhepatotoxicity is promoted by amoxycillin is stillunknown. The potential contribution of otherdrugs to amoxycillin-clavulanic acid hepato-toxicity is also unknown.

In conclusion, these data confirm that treat-ment with amoxycillin-clavulanic acid may leadto acute hepatitis, mainly exhibiting cholestatic

features. Occasionally, granulomatous hepatitismay be observed. A time interval of one to fourweeks between stopping the treatment and thefirst manifestations is frequently present andmay hinder diagnosis. Complete recovery occurswithin 16 weeks. Hepatotoxicity caused by thisdrug combination might be mediated by animmunoallergic mechanism in some patients andseems to have a very low frequency. The risk ofhepatotoxicity may be increased in elderly menreceiving lengthy treatment.

We thank the Regional Centres of the French System of DrugSurveillance for their collaboration in the study.

1 ReadingC, ColeM. Clavulanic acid: a beta-lactamase inhibitingbeta-lactam from streptomyces clavuligerus. AntimicrobAgents Chemother 1977; 11: 852-7.

2 Labia R, Peduzzi J. Kinetics of beta-lactamase inhibition byclavulanic acid. Biochem et Biophys Acta 1978; 526: 572-9.

3 Iravani A, Richard GA. Amoxycillin-clavulanic acid versuscefaclor in the treatment of urinary tract infections and theireffects on the urogenital and rectal flora. Antimicrob AgentsChemother 1986; 29: 107-11.

4 Reddy RK, Brillant P, Schiff ER. Amoxicillin-clavulanatepotassium-associated cholestasis. Gastroenterology 1989; 96:1135-41.

5 Verhamme M, Ramboer C, Van De Bruaene P, Inderadjaja N.Cholestatic hepatitis due to an amoxycillin-clavulanic acidpreparation.J Hepatol 1989; 9: 260-4.

6 Schneider JE, Kleinman MS, Kupiec JW. Cholestatic hepatitisafter therapy with amoxycillin-clavulanate potassium. NYStateJfMed 1989; 89: 355-6.

7 Dowsett JF, Gillow T, Heagerty A, Radcliffe M, Toadi R, IsleI, et al. Amoxycillin-clavulanic acid (Augmentin) inducedintrahepatic cholestasis. Dig Dis Sci 1989; 34: 1290-3.

8 Stricker BHCh, Van Den Broek JWG, Keuning J, EberhardtW, Houben HGJ, Johnson M, et al. Cholestatic hepatitis dueto antibacterial combination of amoxycillin and clavulanicacid (Augmentin). DigDis Sci 1989; 34: 1576-80.

9 Pelletier G, Ink 0, Fabre M, Hagege H. Hepatite cholestatiqueprobablement due a I'association d'amoxicilline et d'acideclavulanique. Gastroenterol Clin Biol 1990; 14: 601-7.

10 Michielsen PP, Van Outryve MJ, Van Marck EA, De MaeyerMH, Pelckmans PA, Van Maercke YM. Amoxycillin/clavulanic acid induced cholestasis.J Hepatol 1990; 11: 392.

11 Cleau D, Jobard JM, Alves T, Gury S, Rey B, Vuillemard M,et al. Hepatite cholestatique due a I'association amoxicilline-acide clavulanique. Gastroenterol Clin Biol 1990; 14: 1007-9.

12 Smith PM, Wilton A, Routledge PA. Jaundice associated withamoxycillin - clavulanate potassium therapy. EurJ Gastro-enterol Hepatol 1991; 3: 95-6.

13 Augmentin Jaundice. Australian Adverse Drug ReactionsBulletin. November 1990.

14 Royer RJ. Pharmacovigilance. The French system. DrugSafety 1990; 5 (Suppl 1): 137-40.

15 Silvain C, Fort E, Levillain P, Labat-Labourdette J,Morichau-Beauchant M. Granulomatous hepatitis due tocombination of amoxycillin and clavulanc acid. Dig Dis Sci1991 (in press).

16 Stricker BHC, Spoelstra P. Drug-induced hepatic injury. Acomprehensive survey of the literature on adverse drug reactionsup toJ7anuary 1985. Elsevier; Amsterdam, 1985.

17 Benichou C. Criteria of drug-induced liver disorders. Reportof an Intermational consensus meeting. J Hepatol 1990; 11:272-6.

18 Trevisani F, Panicone L, Bernardi M, Mazzatti M. GasbarriniG. Beta-lactam antibiotic-induced cholestasis: synergistic ofphenobarbitone plus corticosteroid treatment. ItalJ Gastro-enterol 1988; 20: 134-6.

19 Van Der Auwera P, Legrand JC. Ticarcillin-clavulanic acidtherapy in severe infections. Drugs Exp Clin Res 1985;(Suppl 11): 805-13.

group.bmj.com on September 10, 2014 - Published by gut.bmj.comDownloaded from

evgheniHighlight

doi: 10.1136/gut.33.3.368 1992 33: 368-371Gut

D Larrey, T Vial, A Micaleff, et al.

report of 15 cases.amoxycillin-clavulanic acid combination Hepatitis associated with

http://gut.bmj.com/content/33/3/368Updated information and services can be found at:

These include:

References http://gut.bmj.com/content/33/3/368#related-urls

Article cited in:

serviceEmail alerting

in the box at the top right corner of the online article.Receive free email alerts when new articles cite this article. Sign up

CollectionsTopic

(1897 articles)Pancreas and biliary tract

Articles on similar topics can be found in the following collections

Notes

http://group.bmj.com/group/rights-licensing/permissionsTo request permissions go to:

http://journals.bmj.com/cgi/reprintformTo order reprints go to:

http://group.bmj.com/subscribe/To subscribe to BMJ go to:

group.bmj.com on September 10, 2014 - Published by gut.bmj.comDownloaded from