Determinants of the Clinical Expression of Amoxicillin-Clavulanate Hepatotoxicity: A Prospective Series From Spain
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LIVER DISEASE
Determinants of the Clinical Expression of Amoxicillin-
Clavulanate Hepatotoxicity:
A Prospective Series From Spain
M. Isabel Lucena,1 Raúl J. Andrade,2 M. Carmen Fernández,3 Ketevan Pachkoria,1 Gloria Pelaez,3 José A. Durán,4
Macarena Villar,4 Luis Rodrigo,5 Manuel Romero-Gomez,6 Ramón Planas,7 Anabel Barriocanal,7 Joan Costa,7
Carlos Guarner,8 Sonia Blanco,9 José M. Navarro,10 Fernando Pons,11 Agustin Castiella,12 and Susana Avila,13 on behalf
of the Spanish Group for the Study of Drug-Induced Liver Disease (Grupo de Estudio para las Hepatopatı́as Asociadas a
Medicamentos (GEHAM))
Amoxicillin-clavulanate (AC) hepatotoxicity has been reported to exhibit a higher predom-
inance of cholestatic types of damage, especially in males. However, the determinants of its
clinical expression are unknown. This study prospectively evaluated the profile of AC hep-
atotoxicity. Data on all cases of hepatotoxicity reported to the Spanish Registry attributed to
AC and assessed as definite or probable on the Council for International Organizations of
Medical Sciences (CIOMS) scale were collated and compared to published case series. Hep-
atotoxicity related to amoxicillin-clavulanate was identified in 69 patients (36 males; mean
age 56 years) representing 14% of all cases of hepatotoxicity submitted to the Registry. There
was an overall sex distribution and the predominant pattern of lesion was hepatocellular
(36%) which occurred at a shorter duration of treatment (P < .03). Mean time lapse between
therapy initiation and jaundice onset was 16 days. Late onset of symptoms following end of
treatment occurred in half the cases. Multiple logistic regression analysis identified advanc-
ing age as the factor associated with the development of cholestatic/mixed type of injury
(odds ratio for an age interval for 1 year: 1.045 [95% CI ⴝ 1.013-1.078; P ⴝ .005). An
unfavorable outcome was seen in 7% of patients. In conclusion, age is the most important
determinant in the biochemical expression of AC hepatotoxicity; younger age is associated
with cytolytic damage and shorter treatment duration, whereas cholestatic/mixed type of
damage is related to older age and prolonged AC therapy. (HEPATOLOGY 2006;44:850-856.)
Abbreviations: AC, amoxicillin-clavulanate; GEHAM, Grupo de Estudio para las Hepatopatı́as Asociadas a Medicamentos; CIOMS, Council for International
Organizations of Medical Sciences; NHS, National Health System; ALT, alanine aminotransferase; AP, alkaline phosphatase; ULN, upper limit of normal; SPSS,
statistical package for social sciences; HLA, human leukocyte antigen; FIS, fondo investigaciones sanitarias.
From the 1Servicio de Farmacologı́a Clı́nica and 2Unidad de Hepatologı́a, Grupo de Estudio para las Hepatopatı́as Asociadas a Medicamentos, Coordinating Centre,
Hospital Universitario Virgen de la Victoria, Facultad de Medicina, Campus Universitario de Teatinos s/n, Málaga, Spain; 3Servicio Aparato Digestivo, Hospital
Torrecárdenas, Almeria, Spain; 4Servicio Aparato Digestivo, Hospital Virgen de la Macarena, Sevilla, Spain; 5Servicio Aparato Digestivo, Hospital Central de Asturias,
Oviedo, Spain; 6Servicio Aparato Digestivo, Hospital Valme, Sevilla, Spain; 7Servicio Aparato Digestivo y Farmacologı́a Clı́nica, Hospital Germans Trias i Pujol,
Barcelona, Spain; 8Servicio Aparato Digestivo, Hospital Sant Pau, Barcelona, Spain; 9Servicio Aparato Digestivo, Hospital Basurto, Vizcaya, Spain; 10Servicio Aparato
Digestivo, Hospital Costa del Sol, Málaga, Spain; 11Servicio Aparato Digestivo, Hospital Marqués de Valdecilla, Santander, Spain; 12Servicio Aparato Digestivo, Hospital
Ntra Sra de Aranzazu, San Sebastián, Spain; 13Servicio Aparato Digestivo, Hospital General de Lugo, Lugo, Spain.
Received May 18, 2006; accepted June 17, 2006.
Supported, in part, by research grants from the Agencia Española del Medicamento and FIS 04-1688 and FIS 04-1759. The funding source had no involvement in the
study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the paper for publication.
Address reprint requests to: M. Isabel Lucena, M.D., Ph.D., Servicio de Farmacologı́a Clı́nica, Departamento de Farmacologı́a Facultad de Medicina, Boulevard Louis
Pasteur 32, Campus de Teatinos s/n, 29071 Málaga, Spain. E-mail: lucena@uma.es; fax: (34) 952 131568.
Copyright © 2006 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.21324
Potential conflict of interest: No co-author has any involvement that could be construed as a conflict of interest.
850HEPATOLOGY, Vol. 44, No. 4, 2006 LUCENA ET AL. 851
A
moxicillin-clavulanate (AC) has become one of Victoria University Hospital of Malaga, Spain. With the
the most widely prescribed antibiotics1 and, al- collaboration of several Liver Units from hospitals within
though the penicillin variants are considered rela- the National Health System (NHS) in various parts of
tively safe, adverse reactions such as those in the Spain, 69 cases of acute liver injury associated with the use
gastrointestinal tract can occur more frequently with this of AC were collated between November 1995 and Octo-
combination.2 Several reports incriminate AC in the de- ber 2005. The same structured assessment protocol was
velopment of cholestatic hepatitis.3-7 Yet despite the po- used in all cases.9 A prospective registry was set up and
tentially serious adverse reactions, the sales of this coordinated by two authors of this manuscript (MIL and
antibiotic combination have increased steadily to become RJA). We assessed all the cases of AC in the registry to
the leading antibiotics prescribed in Spain and other Eu- review their clinical features and outcomes. Some of these
ropean countries.8 A recent multicentered Spanish study9 cases have been reported elsewhere.17,18
showed that AC was the most common drug involved in A clinical history was obtained from each patient. De-
drug-induced liver injury and was the single most fre- tails included antecedents of liver or biliary tract disease,
quently prescribed drug leading to hospitalization for drug addiction and/or alcohol abuse, transfusion of blood
drug-induced liver disease. Other studies, using different products, surgery within the 6 months preceding the on-
methodologies, also found a strong association between set of hepatitis, prescription drugs, and over-the-counter
the AC combination and acute liver injury.10,11 In 1996, medications. Duration of therapy with AC, time to symp-
using the UK-based General Practice Research Database, toms onset, time lapse between cessation of therapy and
the incidence of acute hepatitis related to AC was esti- jaundice onset, and clinical features with special emphasis
mated as 1.7 per 10,000 prescriptions, a 6-fold higher on evidence of hypersensitivity were noted, as was the
incidence than for amoxicillin alone (0.3 per 10,000 pre- clinical and laboratory course of the reaction once the
scriptions) despite its more widespread use.12 Similarly, in drug was withdrawn.
a recent retrospective analysis in the United Kingdom of Serological markers of acute hepatitis viral infection
800 patients presenting with jaundice, AC and fluclox- were evaluated in all patients, as was serum ceruloplasmin
acillin (not registered for use in Spain) ranked as the main where appropriate. Screening for autoimmune liver dis-
drugs responsible for pharmacologically induced cases of orders was conducted systematically. Ultrasonography of
liver disease.13 More than 200 cases of liver damage re- the liver and billiary tract was performed in all cases. Ad-
lated to AC use have been collated in a recent review of the ditional imaging tests (magnetic resonance and/or endo-
literature by Gresser.14 scopic cholangiography) were performed in dubious cases
The type of liver damage most frequently associated to exclude biliary obstruction.
with AC has been cholestasis with signs of hypersensitiv- The patterns of liver injury and the chronological rela-
ity.5-7,12 The hepatocellular and mixed patterns of injury tionship between the drug and the onset of hepatitis were
have been described less frequently,14 but the determi- defined according to the criteria of the International Con-
nants of these clinical expressions are unknown. Some sensus Meeting for Drug-induced Liver Injury.19 The pat-
studies5,12,14 suggested that older age, longer duration of tern of liver damage was defined as hepatocellular when
therapy and male gender are predisposing risk factors, R ⬎ 5 [R is the ratio of ALT/AP activity, expressed as a
whereas other studies10,11 contradict these findings. The multiple of the upper limit of normality (ULN)], choles-
general consensus is that complete clinical recovery is the tatic when R ⬍ 2, and mixed when R ⬎ 2 but ⬍ 5. The
norm and that hepatotoxicity associated with AC use is liver function tests used in the classification of liver dam-
mild but which, in some instances, could follow a more age were those from the first blood test available following
severe, or protracted, course.15,16 liver injury. Liver damage was established according to
In this study, we analyzed the clinical profile of the liver biopsy results, when available.
largest cohort to-date of well-characterized patients of AC The direct involvement of other drugs in hepatic injury
hepatotoxicity and sought factors that could explain its was assessed on the basis of clinical features or time course
clinical presentation. We performed a comparative anal- of disease. Case ascertainment was initially that of the
ysis to provide a perspective for our Spanish data in rela- attending physician and, subsequently, evaluated at the
tion to other large published studies from different Coordinating Centre where causality was determined by
countries. applying the CIOMS scale.20 Only the cases assigned as
“definite” or “highly probable” have been included in this
Patients and Methods report.
The study protocol was approved by the local ethics An age ⱖ55 years was taken as a cutoff for analysis in
committee of the Coordinating Centre at the Virgen de la keeping with the CIOMS scale stratification of age as a852 LUCENA ET AL. HEPATOLOGY, October 2006
Table 1. Demographic and Clinical Parameters of Amoxicillin-Clavulanate Hepatotoxicity Cases in the Spanish Registry
Compared to Other Published Large Patient Series in Other Countries
Spain (Current Study) Belgium6 USA4 France5 England‡ (n ⴝ 22)†
Variables (n ⴝ 69) (n ⴝ 35) (n ⴝ 18)* (n ⴝ 15) Mean (range)
Age (range); years 56 (16–87) 66 (18–88)§ 59 (33–80) 64 (39–82) 59 (43–91)
Males; n (%) 36 (52%) 24 (69%) 12 (67%) 13 (87%) 10 (45%)
Treatment duration; days (95%CI) 12 (10–14) 14 (11–16) 13 (8–18) 18 (11–26)** 7 (3–21)
Onset from therapy initiation; days (95%CI) 16 (13–20)¶ 28 (22–33) 37 (14–59) 34 (23–44) 17 (3–48)
Onset from therapy cessation; days (range) 15 (2–55)(n ⫽ 34) 18 (13–24)(n ⫽ 28) – 14 (8–20)(n ⫽ 13) 21(n ⫽ 6)
Hepatocellular damage 25 (36%)†† 4 (11%) 4 (24%) 2 (13%) 1 (6%)
Cholestatic damage 22 (31%) 23 (66%)†† 7 (41%) 11 (74%)†† 8 (47 %)
Mixed damage 23 (33%) 8 (23%) 6 (35%) 2 (13%) 8 (47%)
NOTE. *1 case of 18 was not categorized according to pattern of liver injury; † 5 cases of 22 were not categorized according to pattern of liver injury; ‡No individual
data of patients were provided, therefore this study was not used for comparison purposes. However, mean values and range when available and are included in the
table; Kruskal-Wallis test §P ⬍ .024; ¶P ⬍ .0001; **ANOVA test (P ⬍ .018; ††Chi-square test P ⬍ .05).
risk factor. Cases were classified as hypersensitivity in na- Results
ture if they presented with any of the classical clinical or
Between November 1995 and October 2005, of the
laboratory features of allergy (fever, rash, serum eosino-
486 cases of idiopathic liver injury submitted to the Co-
philia, cytopenia, or detectable titers of autoantibodies)
ordinating Centre, 69 cases (14%) were classified as hav-
and/or there was accompanying suggestive pathological
ing hepatotoxicity attributable to AC use. Using the
findings (eosinophil-rich inflammatory infiltrate and/or
CIOMS diagnostic scale, these patients were classified as
granuloma formation). In the remaining cases, the mech-
“definite” in 55 (80%) cases and “probable” in 14. There
anism was presumed to be metabolic idiosyncrasy.
were 36 men (52%), the overall mean age was 56 years,
Outcomes were assessed by clinical analytical imaging
and hepatocellular damage predominated (36%) (Table
tests and histological methods, when available. Cases were
1).
defined as “resolved” when liver test values returned to
Overall, there was a similar gender distribution. The
within the laboratory reference range within 3 months for indication for AC treatment was respiratory infection (35
hepatocellular pattern of damage, or 6 months for chole- cases; 51%), followed by urinary infection (9 cases; 13%),
static/mixed pattern of injury; or “chronic” when liver test and ear-nose-throat infections (7 cases; 10%). The mean
values remained altered. daily dose administered was 2017 mg (range: 500 mg to
For statistical comparisons, we retrieved individual 3000 mg) orally, and 2 cases intravenously (daily dose
data (when available) from the larger studies published on 3000 and 4500 mg). The AC formulation ratio was 4:1
AC-induced hepatotoxicity. We compared our data with (500/125 mg) in 42 cases and 7:1 (875/125 mg) in 12
that of the American study by Reddy et al.,4 the French cases. The mean duration of treatment was 12 days (rang-
study by Larrey et al.,5 and the Belgian study by Haute- ing from 1 to 37 days). Symptoms of liver disease oc-
keete et al.6 In the UK study performed by O’Donohue et curred within a mean of 16 days (ranging from 1 to 71
al.,7 individual data had not been provided and therefore days) after the initiation of treatment. In 31 patients,
was not suitable for the present comparisons. However, there was a clear time-course relationship between AC
mean values and ranges were included when available. administration and the onset of liver injury, as well as
Data were analyzed with the SPSS software for Win- between withdrawal of treatment and the resolution of
dows (version 12.0). Bivariate associations were measured liver dysfunction. The exception was 1 patient who died
using the Student t test for continuous variables and the and 5 patients who developed chronic disease. In 34 pa-
2 test for categorical items. Analysis of variance tients, hepatotoxicity was late onset and the mean time
(ANOVA) was used for comparisons of groups. Nonpara- lapse from cessation of therapy to onset of jaundice was 15
metric analyses were performed where variables did not days (Table 1). Other drugs taken concurrently by 6 pa-
follow a normal distribution. All P values of less than .05 tients were diclofenac (2 cases, the pattern of damage was
were considered statistically significant. Variables relevant cholestatic), ibuprofen (2 cases, one hepatocellular and
to the development of cholestatic/mixed type of injury the other cholestatic), and erythromycin and ketorolac
were included in a multiple logistic regression model. Cal- trometamol (1 case of mixed damage each).
ibration of the model was assessed using the Hosmer and Jaundice was the most frequent manifestation at the
Lemeshow 2 statistics (P ⬍ .05). time the case was first identified (56 cases; 81%), and 46HEPATOLOGY, Vol. 44, No. 4, 2006 LUCENA ET AL. 853
Table 2. Demographic, Clinical, and Laboratory Parameters of the 69 Cases of Liver Injury Due to Amoxicillin-Clavulanate
Use, and Segregated According to Type of Liver Damage
Type of damage
Variables Hepatocellular (n ⴝ 25) Cholestatic (n ⴝ 21) Mixed (n ⴝ 23)
Mean age; years (range) 45 (16–83) 67 (44–87)* 58 (17–82)
Men; n (%) 15 (60%) 10 (48%) 11 (48%)
Jaundice; n (%) 16 (64%) 20 (95%) † 20 (87%)
Hospital admission 16 (64%) 14 (67%) 16 (70%)
Hypersensitivity; n (%) 9 (36%) 8 (38%) 9 (39%)
Daily dose; mg (95%CI) 1869 (1609–2129) 2095 (1890–2300) 2086 (1880–2293)
Treatment duration; days (95%CI) 9 (7–12) 13 (9–16) 14 (9–19)
Onset from therapy initiation: days (95%CI) 15 (9–21) 14 (4–19) 21 (13–30)
Onset from therapy cessation; days (range) 20 (2–55) n ⫽ 10 9 (2–34) n ⫽ 11 16 (2–50) n ⫽ 14
Total bilirubin (mg/dL) 6.9 (0.4–32.6) 11.7 (0.6–36.9) 9.5 (0.4–31.7)
ALT (⫻ ULN) 26.9 (2.7–68.2)* 4.1 (1.1–8.4) 7.4 (1.8–16.9)
AP (⫻ ULN) 1.4 (0.1–3.81) 4.5 (1.1–13.8)* 2.2 (0.8–5.6)
79 (44–114) 80 (47–113) 72 (46–98)
Recovery, days (95%CI) n ⫽ 17 n ⫽ 17 n ⫽ 21
Liver transplantation, n (%) 1 (4%) 0 0
Death; n (5) 0 0 1 (4%)
Chronicity, n (%) 1 (4%) 3 (14%) 0
Rechallenge, n (%) 2 (8%) 0 1 (4%)
Abbreviations: ALT, alanine aminotransferase; AP, alkaline phosphatase; AST, aspartate aminotransferase Values are expressed as multiples of the upper limit of
normal (ULN). The ALT and AST values are those at presentation, whereas bilirubin values are at peak expression. Hypersensitivity refers to the presence of fever, rash,
and/or eosinophilia; *, ANOVA test, (P ⬍ .0001); †, Chi-square test, (P ⬍ .018).
patients (67%) required hospitalization. All patients were agnosis in 11 (69 %) patients. Centrilobular cholestasis
negative for viral hepatitis (cytomegalovirus; Epstein-Barr was the diagnosis in 3 cases; 1 patient presented with bile
virus; hepatitis A, B, and C viruses). Ultrasonographic duct proliferation and intense fibrosis. This patient even-
examination revealed no abnormalities of the liver or the tually developed liver cirrhosis. In patients with histolog-
intrahepatic bile ducts in any of the patients. None of the ical diagnosis of hepatocellular necrosis, 2 had focal
patients had had a previous history of hepatitis, blood necrosis and 1 had chronic hepatitis. Eosinophils were
transfusions, or recent acute hypotension. A history of found in biopsy specimens from 3 patients.
moderate alcohol consumption (mean 47 g/day; range: Comparison of Demographic Characteristics and
6-177 g/day) was noted in 15 patients. Clinical and Laboratory Features According to Type
Indicators of hypersensitivity were present in 38% of of Damage. The findings are summarized in Table 2.
the patients. Underlying liver disease was evident in 3 Patients with cholestatic pattern were significantly older
patients (4%). A positive (inadvertent) rechallenge oc- than patients with other patterns of liver damage (P ⬍
curred in 3 (4%) patients, 1 of whom developed liver
.0001). Conversely, patients with the hepatocellular type
cirrhosis and underwent liver transplantation.18 This was
damage had the highest mean serum alanine aminotrans-
a young patient (44 years) that did not have any other risk
ferase (ALT) values (P ⬍ .001). It is noteworthy that
factors for chronic liver disease. Presumably, re-exposure
chronicity was more common with cholestatic reactions
to the offending drug was critical for the evolution to liver
cirrhosis. than hepatic ones.
In the 55 patients in whom we were able to continue a Demographic Characteristics, Clinical and Labo-
follow-up for an extended period, liver test values re- ratory Features in Patients Younger or Older Than 55
turned to within the laboratory reference range within a Years of Age. Patients aged ⱖ55 years accounted for
mean of 77 days (range: 10-300 days). The overall out- 65% of the overall population presenting with jaundice
come was death in 1 patient and liver transplantation in (93%; P ⬍ .001). They had the highest mean plasma
another (2.9%). The only fatal case had compensated bilirubin values, in keeping with the largest number of
liver cirrhosis. In a mean follow-up of 8.5 months, 4 pa- cases with a cholestatic/mixed damage presentation (P ⬍
tients (5.8%) fulfilled the criteria of chronic outcome .003). Overall, cholestatic presentation was only 40% of
with persistent alterations in liver test values. those patients classified as over 55 years, but when con-
Liver histology was available in 16 patients. Cholestasis sidering patients aged ⱖ70 years, 10 of 16 patients (63%)
with hepatitis was the most common histopathologic di- had cholestatic reactions (P ⬍ .002).854 LUCENA ET AL. HEPATOLOGY, October 2006
Table 3. Comparison of Demographic Characteristics and Clinical and Laboratory Findings in Patients Above and Below the
Age of 55 Years and Segregated With Respect to Amoxicillin-Clavulanate Hepatotoxicity
Variables 55 years (n ⴝ 45) P value
Men, n (%) 14 (64%) 21 (47%) 0.148
Daily dose; mg (⫾SD) 2075 ⫾ 595 2000 ⫾ 485 0.56
Treatment duration; days (⫾SD) 8.8 ⫾ 5 12.7 ⫾ 9 0.03
Onset from treatment cessation; days (⫾SD) 18 ⫾ 14 17 ⫾ 16 0.902
Symptom resolution; days (⫾SD) 56 ⫾ 31 86 ⫾ 70 0.032
Hypersensitivity features; n (%) 7 (32%) 18 (40%) 0.354
Total billirubin (mg/dL) 5.5 11.4 0.006
ALT (⫻ ULN) 19.5 9.9 0.038
AP (⫻ ULN) 2.4 3.1 0.282
Jaundice 13 (59%) 42 (93%) 0.001
Hospital Admission 13 (59%) 33 (73%) 0.503
Hepatocellular damage 14 (64%) 10 (22%) 0.003
Cholestatic damage 3 (13%) 18 (40%) 0.003
Mixed damage 5 (23%) 17 (38%) 0.003
Chronic damage, n (%) 1 (5%) 3 (7%) 0.12
Duration of treatment was shorter in patients younger not differ significantly in relation to other case series
than 55 years of age (8.8 days; P ⬍ .03), exhibiting, pre- (2 ⫽ .06) (Table 1). Patients in the Belgian study were
dominantly, hepatocellular damage (P ⬍ .003) (Table 3). the oldest (66 years; P ⬍ .024) and treatment duration
In a multiple logistic regression model, older age was the was the longest in the French study (18 days; P ⬍ .018).
variable associated with the development of cholestatic/ The Spanish patient population had the shortest mean
mixed type of injury induced by AC [OR for an age in- time interval between initiation of therapy and onset of
terval for 1 year: 1.045 (95% CI: 1.013-1.078); P ⫽ jaundice (16 days; P ⬍ .0001). The mean time lapse
.005]. Patients with hepatotoxicity during treatment did between cessation of therapy and onset of jaundice was
not differ in laboratory findings and outcome from those similar between the studies. In the Spanish and Belgian
with a late onset. studies, approximately half the patients had late-onset dis-
Influence of Time-to-Hepatic Reaction on the Pat- ease, while in the French and English series the percent-
tern of Liver Damage. The time lapse from start of AC ages were much higher (87% and 95%, respectively).
therapy to the onset of hepatitis, and segregated according Liver injury was predominantly cholestatic in the French
to type of liver damage, is represented in Fig. 1. Cases of (74%), Belgian (66%), and U.S. (41%; P ⬍ .05) studies,
cholestatic and hepatocellular damage peaked at 1-2 as classified according to the International Consensus Cri-
weeks from start of treatment. Appearance of a second teria.19
peak at around 4-5 weeks was less meaningful whereas the
numbers of patients with mixed liver injury became more
evident after 3-4 weeks.
Discussion
Demographic and Clinical Parameters of Amoxi- This study contains clinical and epidemiological fea-
cillin-Clavulanate Hepatotoxicity in the Spanish Case tures of hepatotoxicity induced by AC derived from one
Registry Compared to Published Data Frrom Other of the largest cohorts of patients ever collated prospec-
Countries. The segregation with respect to gender did tively, and follows the same structured report format from
Fig. 1. Distribution of the 69 patients with
amoxicillin-clavulanate-induced hepatotoxicity
segregated according to time lapse between
treatment initiation and the onset of hepatitis,
and type of liver damage.HEPATOLOGY, Vol. 44, No. 4, 2006 LUCENA ET AL. 855
several hospitals. It suggests that AC might be the most was observed in our study in half the cases, and the time
common cause of unpredictable hepatotoxicity in adults lapse ranged from a few days up to 7.8 weeks. This late
in Spain, accounting for 14% of all cases recorded in the onset has been recognized for AC and is a feature shared
registry. Our results show that age is the most important by very few drugs.23,24 Contrary to previous studies,4,5 our
determinant in the biochemical expression of AC hepato- findings do not support the view that male gender acts as
toxicity, cholestatic/mixed injury being related to older risk factor in the development of AC hepatitis.
age, whereas younger age is associated with a cytolytic Assigning causality when more than one drug could be
damage. The pattern of age-associated damage has been the culprit, and when treatments are started simulta-
highlighted recently in the analysis of a cohort of patients neously, remains a major challenge. The complicity of a
with hepatotoxicity which considered all drugs collec- single agent can rarely be determined unequivocally. In all
tively.9 Thomson et al.10 also suggested increasing age as a but 6 of the cases we report, AC was the only hepatotoxin
risk factor for jaundice resulting from AC treatment. identified. Of these 6 patients, 2 received diclofenac and
Indeed, patients younger than 55 years of age exhibited developed cholestatic damage. Diclofenac-associated
predominantly hepatocellular damage which occurred at hepatitis is a rare complication that occurs mainly as hep-
a significantly shorter AC exposure. Interestingly, our atocellular damage in females.25 In 2 cases, an involve-
data also indicate that the appearance of hepatic injury ment of ibuprofen, which has been implicated in hepatitis
may follow a distinct periodicity from onset of AC ther- of various types, could not be discarded unequivocally,
apy. Hepatocellular damage appears to predominate at 1 whereas in another case, the potential for erythromycin to
week, cholestatic liver injury occurs mostly at 2-3 weeks, be implicated in causing hepatitis (usually cholestatic) was
and the mixed liver injury proportionally predominates acknowledged.26
after 3 weeks. In the French and Belgian series there was a Although AC is widely prescribed and is administered to
predominance of the cholestatic/mixed type of damage. all age groups, the clinical and biological characteristics of the
The French case series5 had a longer treatment period, the associated hepatotoxicities have been described in relation
Belgian6 had the oldest set of patients, and all the other mainly to adult populations. A potential limitation on the
countries4-7 had a longer interval between commence- interpretation of the data is that pediatric populations have
ment of treatment and onset of jaundice, compared to our been clearly underrepresented. The case-control study11 that
Spanish study. All together, these factors may explain the showed AC to have had the strongest association of acute and
higher proportion of patients with cholestatic/mixed pre- clinically relevant liver injury (adjusted OR: 94.8 [95% CI:
sentation associated with AC combination therapy. Fur- 27.8-323]), was conducted using the UK-based General
thermore, in a retrospective cohort study conducted in Practice Research Database as the source of information.
the United Kingdom, Garcia Rodriguez et al.12 found This database includes children of all ages but the youngest
that the greatest absolute risk of acute liver injury associ- patient in the study was 17 years old, similar to the popula-
ated with the AC combination was among elderly patients tion ages of our data. As such, the speculation could be that a
who were receiving long-term therapy, and of note was pediatric patient population might be less susceptible to de-
that the type of liver injury in this cohort was cholestatic veloping hepatotoxicity related to the AC combination. The
in three quarters of the cases. need for, and a proposal to establish, a multidisciplinary net-
Explanations for the age-related pattern of liver damage work to monitor drug-induced pediatric liver disease has
induced by AC remain speculative. We may hypothesize that been highlighted.27
a slower drug elimination related to advanced age and its Our data indicate that the probability of an unfavor-
concomitant retention in the body would, in turn, allow a able outcome (death, liver transplant, and persistent liver
prolonged exposure of the bile duct cells to the drug metab- damage) is 7%. A severe outcome (death/transplant) oc-
olite through canalicular excretion, which might trigger an curred in 2.9% of the patients, numbers that are similar in
immune response against haptenized duct cell proteins and a other series.14,28 This brings into question the generally-
periductular inflammatory reaction.21 Recent data show an held opinion that the clinical outcome of hepatotoxicity
association between cholestatic/mixed injury and human induced by AC is invariably toward recovery.
leukocyte antigen (HLA) class II antigens (DRB1*15 and In summary, age is the most important determinant in
DQB1*06 alleles).22 This supports the concept that most the biochemical expression of AC hepatotoxicity; younger
cases of hepatotoxicity with cholestatic/mixed expression of age is associated with cytolitic damage and shorter treat-
damage are probably allergy based. ment duration while cholestatic/mixed type of damage is
A characteristic of the hepatotoxicity induced by AC is related to older age and a prolonged AC therapy. These
the variation in time lapse between the cessation of ther- features could be helpful in the initial clinical evaluation
apy and the onset of jaundice. Late onset after treatment of a patient exposed to AC and presenting with hepatitis.856 LUCENA ET AL. HEPATOLOGY, October 2006
Acknowledgment: We are grateful to D. Ramón 6. Hautekeete ML, Horsmans Y, Van Waeyenberge C, Demanet C, Henrion
J, Verbist L, et al. HLA association of amoxicillin-clavulanate-induced
Hidalgo of the Servicio Central de Informática de la Uni-
hepatitis. Gastroenterology 1999;117:1181-1186.
versidad de Málaga for his invaluable help in the statistical 7. O’Donohue J, Oien KA, Donaldson P, Underhill J, Clare M, MacSween
analyses. RN, et al. Co-amoxiclav jaundice: Clinical and histological features and
HLA class II association. Gut 2000;47:717-720.
8. Goossens H, Ferech M, Vander Stichele R, Elseviers M, ESAC Project
APPENDIX Group. Outpatient antibiotic use in Europe and association with resis-
tance: A cross-national database study. Lancet 2005;365:579-587.
9. Andrade RJ, Lucena MI, Fernandez MC, Pelaez G, Pachkoria K, Garcia-
GEHAM Principal Investigators and Their Affiliations Ruiz E, et al. Drug-induced liver injury: an analysis of 461 incidences
Investigator Institution submitted to the Spanish registry over a 10-year period. Gastroenterology
2005;129:512-521.
R. J. Andrade, M. I. Lucena, B. Garcı́a- Hospital Universitario Virgen de la
10. Thomson JA, Fairley CK, Ugoni AM, Forbes AB, Purcell PM, Desmond
Ruiz, R. Camargo, E. Garcı́a-Ruiz, M. Victoria, Málaga (Co-ordinating
PV, et al. Risk factors for the development of amoxycillin-clavulanic acid
Garcı́a-Cortés, K. Pachkoria, Y. Borraz. Centre)
associated jaundice. Med J Aust 1995;162:638-640.
M. C. Fernández, G. Peláez, M. Casado, Hospital Torrecárdenas, Almerı́a
11. de Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA. Acute and
J. L. Vega, M. González-Sánchez, F.
clinically relevant drug-induced liver injury: A population based case-con-
Suárez.
trol study. Br J Clin Pharmacol 2004;58:71-80.
J. A. Durán, M. Jiménez-Sáez, M. Hospital Virgen Macarena, Sevilla
12. Garcia Rodriguez LA, Stricker BH, Zimmerman HJ. Risk of acute liver
Fernández, A. Ruiz, J. Alanis-López, M.
injury associated with the combination of amoxicillin and clavulanic acid.
Villar
Arch Intern Med 1996;156:1327-1332.
M. Romero, C. Trabadela Hospital Universitario Virgen de
13. O⬘Brien CS, Despott EJ, Hussaini SH, Dalton HR. A high incidence of
Valme, Sevilla
drug-induced community jaundice in the UK: Flucloxacillin and co-amoxi-
L. Rodrigo-Sáez Hospital Central de Asturias,
clav are the main culprits [Abstract]. J Hepatol 2005;44(Suppl 4):P23.
Oviedo
14. Gresser U. Amoxicillin-clavulanic acid therapy may be associated with severe
J. M. Pérez-Moreno, M. Puertas Hospital de Puerto Real, Cádiz
side effects—review of the literature. Eur J Med Res 2001;6:139-149.
J. Salmerón, M. A. López-Garrido, A. Hospital Universitario San Cecilio,
15. Ryley NG, Fleming KA, Chapman RW. Focal destructive cholangiopathy
Caballero, A. Gila Granada
associated with amoxycillin/clavulanic acid (Augmentin). J Hepatol 1995;
R. Planas, A. Soler, J. Costa, A. Hospital Germans Trias i Puyol,
23:278-282.
Barriocanal Barcelona
16. Richardet JP, Mallat A, Zafrani ES, Blazquez M, Bognel JC, Campillo B.
R. Martı́n-Vivaldi, F. Nogueras Hospital Universitario Virgen de
Prolonged cholestasis with ductopenia after administration of amoxicillin/
las Nieves, Granada
clavulanic acid. Dig Dis Sci 1999;44:1997-2000.
J. M. Navarro Hospital Costa del Sol, Málaga
17. Andrade RJ, Lucena MI, Fernandez MC, Vega JL, Camargo R. Hepato-
H. Sánchez-Martinez Hospital La Inmaculada, Huércal-
toxicity in patients with cirrhosis, an often unrecognized problem: Lessons
Overa, Almerı́a
from a fatal case related to amoxicillin/clavulanic acid. Dig Dis Sci 2001;
A. Piñar Hospital Virgen del Rocı́o, Sevilla
46:1416-1419.
M. Ramos, T. Ferrer Hospital Juan Ramón Jiménez,
18. Jordan T, Gonzalez M, Casado M, Suarez JF, Pulido F, Guerrero E, et al.
Huelva
Amoxicillin-clavulanic acid induced hepatotoxicity with progression to
C. Sánchez-Robles Hospital General Básico de Vélez,
cirrhosis. Gastroenterol Hepatol 2002;25:240-243.
Málaga
19. Benichou C. Report of an international consensus meeting. Criteria of
F. Pons, R. Taheri Hospital Marqués de Valdecilla,
drug-induced liver disorders. J Hepatol 1990;11:272-276.
Santander
20. Lucena MI, Camargo R, Andrade RJ, Perez-Sanchez CJ, Sanchez De La
C. Guarner, D. Monfort H. Sant Pau, Barcelona
Cuesta F. Comparison of two clinical scales for causality assessment in
M. Jiménez-Perez Hospital Carlos Haya, Málaga
hepatotoxicity. HEPATOLOGY 2001;33:123-130.
M. Garcı́a-Bengoechea Hospital Nuestra Sra. de
21. Kaplowitz N. Idiosyncratic drug hepatotoxicity. Nat Rev Drug Discov
Aranzazu, San Sebastián
2005;4:489-499.
A. Castiella Hospital de Mendaro, Guipuzcuoa
22. Andrade RJ, Lucena MI, Alonso A, Garcia-Cortes M, Garcia-Ruiz E, Benitez
S. Blanco Hospital Basurto, Vizcaya
R, et al. HLA class II genotype influences the type of liver injury in drug-
S. Avila Hospital General de Lugo, Lugo
induced idiosyncratic liver disease. HEPATOLOGY 2004;39:1603-1612.
M. Bruguera Hospital Clinic, Barcelona
23. Lucena MI, Andrade RJ, Rodrigo L, Salmeron J, Alvarez A, Lopez-Garrido
MJ, et al. Trovafloxacin-induced acute hepatitis. Clin Infect Dis 2000;30:
400-401.
References 24. Perez Moreno JM, Saldana Gonzalez FJ, Puertas Montenegro M, Baez
1. Cars O, Molstad S, Melander A. Variation in antibiotic use in the Euro- Perea J. Cholestatic hepatitis caused by midecamycin. Gastroenterol Hepa-
pean Union. Lancet 2001;357:1851-1853. tol 1996;19:459-461.
2. Martinez-Mir I, Ferrer JM, Palop V, Estan L, Rubio E, Morales-Olivas FJ. 25. Banks AT, Zimmerman HJ, Ishak KG, Harter JG. Diclofenac-associated
Are the adverse drug reactions of amoxycillin and amoxycillin-clavulanic hepatotoxicity: Analysis of 180 cases reported to the Food and Drug Ad-
acid similar? Pharmacoepidemiol Drug Saf 1996;5:247-254. ministration as adverse reactions. HEPATOLOGY 1995;22:820-827.
3. van den Broek JW, Buennemeyer BL, Stricker BH. Cholestatic hepatitis 26. Horsmans Y, Geubel AP. Amoxycillin-calvulanic acid-erythromycin cross-
caused by a combination of amoxicillin and clavulanic acid (Augmentin). liver toxicity: A case report. J Hepatol 1994;21:911-912.
Ned Tijdschr Geneeskd 1988;132:1495-1497. 27. Peire MA, Lucena MI, Ruiz-Extremera A, Jara P, Romero-Gonzalez J,
4. Reddy KR, Brillant P, Schiff ER. Amoxicillin-clavulanate potassium-asso- Andrade RJ. Toxicidad hepatica por fármacos. Donde estamos y hacia
ciated cholestasis. Gastroenterology 1989;96:1135-1141. donde caminamos. An Esp Pediatr 2002;56:434-442.
5. Larrey D, Vial T, Pauwels A, Castot A, Biour M, David M, et al. Hepatitis 28. Australian Adverse Drug Reactions Advisory Committee. Drug-induced
associated with amoxycillin-clavulanic acid combination report of 15 cases. liver disease: Antibiotics of continuing concern. Australian Adverse Drug
Gut 1992;33:368-371. Reactions Bulletin 1996;15:1-4.You can also read
