Expert Opinion on Drug Safety

ISSN: 1474-0338 (Print) 1744-764X (Online) Journal homepage: http://www.tandfonline.com/loi/ieds20

Amoxicillin and amoxicillin plus clavulanate: a

safety review

Francesco Salvo MD, Angelina De Sarro, Achille Patrizio Caputi & Giovanni
Polimeni

To cite this article: Francesco Salvo MD, Angelina De Sarro, Achille Patrizio Caputi & Giovanni
Polimeni (2009) Amoxicillin and amoxicillin plus clavulanate: a safety review, Expert Opinion on
Drug Safety, 8:1, 111-118, DOI: 10.1517/14740330802527984

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 Drug Safety Evaluation

Amoxicillin and amoxicillin plus

clavulanate: a safety review
Francesco Salvo, Angelina De Sarro, Achille Patrizio Caputi &
Giovanni Polimeni
1. Introduction University of Messina, Department of Clinical and Experimental Medicine and Pharmacology,
2. Pharmacological properties Section of Pharmacology, Messina, Italy
3. Safety
Despite the considerable number of newer antibacterials made available
4. Conclusions
over the past decades, amoxicillin, alone or in combination with clavulanic
5. Expert opinion acid, still accounts among the most widely used antibacterial agents.
Although they are often considered twin drugs, they are different both in
terms of antibacterial activities and of safety profile. It is well documented
that the clavulanate component may cause adverse reactions by itself,
thus exposing patients to further, and sometimes undue, risks. Although
amoxicillin/clavulanate should be considered as an alternative agent only
for the treatment of resistant bacteria, evidence shows that it is often used
also when a narrow-spectrum antibiotic would have been just as effective.
This prescription habit may have serious consequences in terms of patients
safety, as well as in terms of the development of bacterial resistance.

Keywords: adverse drug reactions, amoxicillin, clavulanic acid, -lactams

Expert Opin. Drug Saf. (2009) 8(1):111-118

1. Introduction

Infections still represent a common cause of morbidity and mortality worldwide,

with acute respiratory tract infections (RTIs) accounting among the most prominent
reasons for hospital admissions and increased economic burdens for national
health systems [1]. Despite the considerable number of newer antibacterials
made available over the past decades, -lactam antibiotics are still the most used
antibacterials all over the world. The first -lactams were licensed in the 1950s
(penicillin G and V) and presented substantial inconveniences, most notably a
limited range of activity, a short half-life, and the administration route had to be
parenteral. The development of a semisynthetic pathway for their production in
the 1960s led to the creation of newer penicillins, with significant improvements
in their range of activity. Namely, ampicillin and amoxicillin (AMX) were the two
most striking innovations, effective not only in the treatment of upper and lower
RTIs but also for urinary tract, soft-tissue and skin infections.
AMX, in particular, is a moderate-spectrum, semisynthetic -lactam active
against a wide range of Gram-positive and a limited range of Gram-negative
organisms [2]. It was marketed in 1972, and still remains the most commonly
utilised drug in this class because its oral absorption is better when compared
with other -lactam antibiotics [3].
Unfortunately, during the past decades, an increasing number of bacteria have
become resistant to antibiotics, making bacterial resistance one of the worlds most
pressing public health problems. -Lactamase production is one of the most common
mechanisms of bacterial resistance; these enzymes, that cleave the -lactam ring,
can be produced by several Gram-positive organisms (including Staphylococci spp.),
Gram-negative organisms (Escherichia coli, Neisseria gonorrhoeae, Haemophilus influenzae,
Moraxella catarrhalis, Pseudomonas and Klebsiella spp.), and anaerobic organisms
(Bacteroides spp.) [4,5]. To overcome this problem, in the 1970s, a new area of

10.1517/14740330802527984 2009 Informa UK Ltd ISSN 1474-0338 111

All rights reserved: reproduction in whole or in part not permitted
Amoxicillin and amoxicillin plus clavulanate
research was focused on identifying compounds able to
inhibit -lactamase, and in 1972 clavulanic acid (CA) was
identified. CA is structurally related to penicillins; it prevents
inactivation of antibiotics, thus increasing their effectiveness
when combined [6]. The association of amoxicillin/clavulanate
(AMC) was first marketed in 1981, and it is the only
penicillin combined with a -lactamase inhibitor available in
oral formulation [7].
This review examines data available in literature for AMX
and AMC to highlight differences in their safety profile.
2. Pharmacological properties
2.1 Mechanism of action
-Lactams interfere with the synthesis of peptidoglycan,
an important component of Gram-positive bacterial cell
walls. The final transpeptidation step in the synthesis of the
peptidoglycan layer is facilitated by transpeptidases (penicillin-
binding proteins). The -lactam nucleus permanently binds to
the penicillin-binding proteins, preventing the final crosslinking
(transpeptidation) between the linear peptidoglycan polymer
chains and disrupting cell wall structure [3].
CA binds irreversibly with -lactamase, preventing it from
inactivating -lactam antibiotics [8]. Consequently, when
combined, it broadens the range of activity of AMX to include
AMX sensitive and -lactamase-producing bacterial strains [8,9].
This property has become increasingly important for respiratory
pathogens, most notably H. influenzae and M. catarrhalis, to
acquire the capacity to produce -lactamase [10,11].
2.2 Available formulations and dosage regimens
AMX and AMC are available in a range of formulation and
dosage combinations for parenteral and peroral delivery [12].
Over the years, several formulations of AMC have been
developed and the ratio of AMX to CA has been varied to
reflect new prescribing guidelines for the treatment of more
severe infections or those caused by resistant microorganisms.
The following ratios of AMX:CA combinations are available
on the market for oral use: 2:1 (250/125 mg), 4:1 (125/31.25,
250/62.5 or 500/125 mg) and 7:1 (200/28.5, 400/57 or
875/125 mg). In addition, a new high-dose formulation
(600/43 mg, 14:1 ratio) has been approved in the US for
twice-daily administration [12].
2.3 Pharmacokinetic
Both AMX and CA are well absorbed in the gastrointestinal
(GI) tract after administration of oral suspension or tablet
formulations. However, differences in the extent of AMX
absorption in various regions of the GI tract have been observed,
with major absorption in the upper small intestine and poor
colonic absorption [13-16]. The oral bioavailability of AMX is
about 70 90% and maximum serum concentrations occur
in 60 90 min after administration [17]. CA shows more
variable oral bioavailability (60.0 23.1% on average, with
a range between 31.4 and 98.8%) [18].
112 Expert Opin. Drug Saf. (2009) 8(1)
Although AMX is excreted unchanged in the urine in
6 h after administration (50 80%), CA undergoes more
extensive liver metabolism, possibly by hydrolysis followed
by decarboxylation, with only 20 60% of unchanged drug
being excreted in the urine in 6 h after administration [19-21].
The mean elimination half-lifes of AMX and CA are
1 h each. Both drugs are well distributed into body
tissues and extracellular fluids, with low binding to plasma
proteins (18 25%) [13].
2.4 Clinical use
Because AMX is well absorbed after oral administration, it is
extensively used in out-patient settings, primarily in the treat-
ment of community-acquired RTIs; furthermore, together with
penicillin V, it is the first-choice antibiotic for the treatment of
Streptococcus pyogenes infections [10,22,23]. It is also combined
with other medications for Helicobacter pylori eradication [24].
AMC is suggested for the treatment of suspected or
documented Gram-negative infections caused by -lactamase-
producing strains of H. influenzae, N. gonorrhoeae, E. coli,
M. catarrhalis and Proteus, Klebsiella and Bacteroides species.
It is also a first-choice antibiotic in clinical situations in which
there is increased development of -lactamase-producing
organisms, as for the treatment of otitis media, sinusitis,
bronchitis, urinary tract infections and skin and soft tissue
infections [25]. AMC has no clinical utility against Pseudomonas
or methicillin-resistant Staphylococcus aureus, owing to its
negligible in vitro activity. Moreover, it is important to underline
that the Streptococcus pneumoniae mechanism of resistance is
not owing to -lactamase production, and, therefore, AMC
does not add efficacy to the use of AMX alone.
3. Safety
AMX and AMC are well tolerated; the most frequently
reported adverse events for both are GI disturbances, including
diarrhoea, nausea and vomiting, although published studies
indicate some differences on their safety profiles [26-28].
3.1 Gastrointestinal tolerability
AMX and AMC have been associated to mild/moderate GI
side effects, such as nausea, vomiting, cramping (prevalence
3 6%), or diarrhoea (4 15%) [29].
The good oral absorption of AMX makes it better tolerated
at the GI level compared with other -lactams. For instance,
because AMX is more completely absorbed than ampicillin,
a smaller amount of AMX remains in the intestinal tract,
thus provoking less diarrhoea than ampicillin [26]. Evidence
available from both clinical trials and postmarketing studies
indicates a higher frequency of GI events, including transient
diarrhoea, vomiting and nausea, linked to AMC than to
AMX use [27-28]; the frequency of these events seem to be
related to the dosage of CA [13]. Moreover, five clinical trials
reviewed by Bax showed a small reduction in the frequency
of diarrhoea when b.i.d. AMC dosage (875/125 mg) was

compared to the t.i.d. regimen (500/125 mg) [30]. Although
it is still a matter of debate, AMC-induced diarrhoea could
be explained by its greater resistance to -lactamases compared
with AMX, which may result in a higher concentration of
the antibiotic in the intestine and a consequent stronger
modification of the normal GI microflora. Colonic bacteria
metabolise carbohydrates as an energy source, producing
lactic acid and short-chain fatty acids, the latter being readily
absorbed by the colon [31]. Loss of these bacteria owing to
antibiotic treatment increases the amount of carbohydrate in
the colonic lumen, leading to osmotic diarrhoea [32]. Finally,
a double-blind crossover study showed that oral AMC
is associated with the occurrence of small intestinal motor
disturbances, possibly related to a direct influence of the CA
on GI motility [33].
3.2 Liver tolerability
Among antibiotics, AMC is the one most frequently associated
with liver injury (Table 1), as well as the most frequently
prescribed drug leading to hospitalisation for drug-induced
liver disease [34-39]. AMC-related liver injury was first reported
in 1988, and since then > 200 cases have appeared in
literature [40,41]. Although transient elevation of serum
transaminases is not uncommon after AMC-therapy, hepatic
injuries are rare, with an incidence ranging from 1 to
1.7 per 10,000 users [35,42]. Other studies estimated a much
lower risk, with an overall rate of < 1 in 100,000 persons
exposed [43]. The difference in incidence rates may be owing
to several factors, including the type of study, degree of liver
injury, age of study population and so on.
Some evidence suggests a direct responsibility of the CA
component in the adverse hepatic events attributed to AMC.
In fact, AMX alone provided a sixfold lower incidence of
liver injury than for AMC in two different studies [35,42].
Moreover, despite its longer use, only four published
case-reports of AMX-induced liver injury are available [44-47].
Furthermore, some published case-reports describe patients
who had experienced liver injury with AMC but did not
have any hepatic event after switching to AMX, although
other reports described positive rechallenge in patients with
AMC-induced hepatotoxicity [48-50]. Further confirmation is
derived from reports of liver damage that occurred in patients
treated with combination of CA with tircacillin [51].
AMC-liver injury typically occurs as cholestatic hepatitis;
hepatocellular or mixed cholestatic and hepatocellular
patterns may also occur [35,52,53]. The onset is generally
delayed from several days up to weeks after starting the
therapy (8.9 days after the first administration on average,
range 1 48 days), but might also occur up to 8 weeks after
its cessation [45,49-56]. Such a feature is uncommon in drug-
induced liver injuries and makes diagnosis more difficult.
Interestingly, it has been reported that hepatocellular damage
is more frequent in patients < 55, and after shorter treatments;
conversely, older patients, who have also had prolonged
AMC therapy, develop cholestatic/mixed type damage [56].
Expert Opin. Drug Saf. (2009) 8(1)
Salvo, De Sarro, Caputi & Polimeni
A slower drug elimination related to advanced age and
its concomitant retention in the body would, in turn, allow
a prolonged exposure of the bile duct cells to the drug
metabolite through canalicular excretion, which may trigger
an immune response against haptenised duct cell proteins
and a periductular inflammatory reaction [57]. Overall,
advanced age and male gender seem two recognised risk
factors for AMC-induced liver injury [49,50,53]. The combi-
nation of advanced age and long-term therapy ( 10 days)
resulted in the greatest absolute risk of developing acute
liver injury during AMC therapy (> 1/1000 users) [42,43].
Nevertheless, Thomson et al. did not find a significant
correlation between the duration of the therapy and
hepatitis [57]. Furthermore, a population-based case-control
study did not confirm a relation with age, sex or long-term
use, although suggesting a dose-dependent mechanism [35].
AMC-induced hepatitis is normally reversible after drug
withdrawal, with a wide variability in the duration of symptoms
(1 8 weeks) [43,58-60]. However, a prospective case-series
involving 69 patients estimated an unfavourable outcome
(death, liver transplantation or persistent liver damage)
in 7% of AMC-related hepatotoxicity [56]. Moreover, an
analysis from a Spanish hepatotoxicity registry showed that
AMC was the first causative drug of chronic liver injury;
it is noteworthy that chronicity was more common with
cholestatic reactions than with hepatocellular or mixed [61].
Although the mechanism of AMC-related hepatitis
remains unclear, its frequent association with hypersensitivity
manifestations (such as skin rash or hypereosinophilia)
suggests an immunoallergic mechanism, possibly related to
selected human leukocyte antigen (HLA) haplotypes [62].
In particular, HLA-DRB1*15 and -DQB1*06 alleles seem
to be involved in the development of a cholestatic/mixed
pattern in drug-induced liver injury; on the other hand, DRB1*07
and DQB1*02 alleles seem to be protective [63]. These findings
support the general notion of the allergic-based mechanism
of cholestatic/mixed hepatotoxicity. More recently, the combined
deficiency of alleles M1 and T1 in glutathione S-transferase
genes have been found to play a role in susceptibility to
AMC-induced liver injury [64].
3.3 Allergic reactions
Allergic reactions to -lactams occur in 0.7 8% of treated
patients [65]. These effects have for long time been related to
the sensitising effect of the benzylpenicilloyl moiety, which
is formed when the -lactam ring is cleft [66]. However, the
contribution made by the chemical structure of the AMX
side chain is gaining importance as a part of the epitope
responsible for the specificity of the response [67]. The
contribution of CA to IgE-mediated reactions seems to be
modest, because this molecule has proven to be by itself
poorly immunogenic and allergenic [68]. This hypothesis is
also supported by two large postmarketing studies, showing
a similar reporting rate for both AMX and AMC, in spite of
the wider use of the latter [69,70]. Conversely, two spontaneous
113
Amoxicillin and amoxicillin plus clavulanate
Table 1. Adjusted odds ratio for acute liver disorder and
current use of antibiotic.
Antibiotics Adjusted odds ratio (95% CI)
Amoxicillin/clavulanic acid 94.8 (27.8 323)
Flucloxacillin 15.3 (2.9 80.7)
Tetraciclines 6.2 (2.4 15.8)
Clarithromycin 6.1 (0.8 45.9)
Erythromycin 5.3 (1.4 45.9)
Trimethoprim 2.9 (0.6 14.1)
Amoxicillin 1.7 (0.6 4.8)
Adapted from De Abajo et al. [35].
reporting studies have found consistent differences, concluding
that AMX causes more skin reactions than AMC [27,28]. One
of them showed that, despite the higher frequency of
AMX-induced cutaneous reactions (82 versus 76% of spon-
taneous reports), AMC was more frequently involved in
non-IgE-mediated hypersensitivity reactions, and in particular
StevenJohnson Syndrome (SJS) (reporting odds ratio
2.6 versus 0.64) [28]. This apparently controversial evidence
could be explained by the two different mechanisms involved.
In particular, although the higher frequency of AMX-related
skin reactions is mainly caused by hypersensitivity reactions
to the penicillin ring component, an immunologic idiosyncrasy
involving HLA-class-II antigens has been supposed for
AMC. This hypothesis originates from the observation that
in some reports CA-induced hepatitis occurred together with
cutaneous adverse reactions, and in particular one patient
developed fatal SJS after severe hepatotoxicity [43,52,71].
3.4 Safety in special population
3.4.1 Children
Most frequently reported AMC-induced adverse events in
children were mild GI disturbances (< 5%); as for adults,
diarrhoea is largely attributed to the CA component [69].
The incidence of diarrhoea is significantly lower for b.i.d.
than with t.i.d. regimen (6.7 9.6 versus 10.3 26.7%,
respectively) [72]. Moreover, a study on out-patient children
showed a statistically significant increased risk of antibiotic-
associated diarrhoea related to AMC use compared with
all other antibiotics combined (RR2.43 CI 95%:1.40 4.21;
p = 0.003). The relative risk rose to 3.5 (1.89 6.46) in
children aged < 2 years [73].
No serious adverse events and a low total incidence of
events (3.6%) were reported during postmarketing surveillance
of 3048 children aged 14 years with acute otitis media who
received AMC 300 450 mg/day in three divided doses [72].
3.4.2 Elderly people
With the exception of AMC-hepatotoxicity, available data do
not indicate an increased risk of developing adverse reactions
114 Expert Opin. Drug Saf. (2009) 8(1)
due to AMX or AMC treatment with the increase of
age [49,58]. Nevertheless, because the two drugs are substantially
excreted by the kidney, the risk may be greater in elderly
patients, who are more likely to have impaired renal function.
The common use of combinations of several medications in
the elderly may also pose patients a higher risk of drugdrug
interactions between either AMX or AMC and other drugs.
Albeit, the risk of clinically relevant interactions is low; three
case-reports suggested a possible relation between the decrease
in vitamin K-producing flora of the intestine induced by AMC
and the occurrence of bleeding complications in patients treated
with warfarin [74-76].
3.4.3 Pregnant women
Penicillins as a class are generally considered safe for use
in pregnancy; although both AMX and AMC cross the
placenta to enter the foetal circulation and amniotic fluid,
their use in pregnant women for the treatment of various
infections has not, until now, produced recognised congenital
malformations [77-79]. Furthermore, an expert review of pub-
lished data on AMX use during pregnancy concluded that
therapeutic doses are unlikely to pose a substantial teratogenic
risk [80]. There are, however, no adequate studies showing its
safety when administered to pregnant women. The FDA now
classifies both AMX and AMC in the B category (no adverse
effects in well-controlled studies of human pregnancies with
adverse effects seen in animal pregnancies or no adverse effects
in animal pregnancies without well-controlled human pregnancy
data available) [81]. Finally, both drugs are considered as
usually compatible with breastfeeding [82].
4. Conclusions
The relative toxicity of AMX and AMC showed some
significant differences. Liver toxicity is strongly related to AMC
treatment, whereas AMX is only marginally implicated. The
involvement of the CA component, which is significantly
metabolised through the liver, has been confirmed by several
case-reports and postmarketing studies. There is still a debate
concerning the mechanism involved in such adverse reactions;
the most frequently evoked is an immunologic idiosyncrasy
against the CA component. These immunogenic properties
also explain, at least partially, the higher frequency in SJS
occurrence with AMC, despite the overall higher number of
cutaneous adverse reactions related to AMX. Finally, AMC
is more frequently involved in GI disturbances than AMX,
probably owing to the CA dosage.
5. Expert opinion
There is a growing body of evidence showing that AMX and
AMC have different safety profiles, with an overall higher
risk for AMC than AMX. In particular, the presence of CA
may pose for a significant number of treated patients at an
increased risk of liver toxicity and serious cutaneous reactions

with clinically relevant consequences. It may be argued
that the increased risk for AMC is counteracted by its
broader range of antibacterial activity, which allows treatment
of a wider range of pathogens, including -lactamase-
producing strains. Nevertheless, because AMX and AMC
are used indifferently for the same indications in clinical
practice, this advantage is often neutralised; moreover, AMC
use has been reported to induce the selection of strains
producing penicillinase, thus leading to an increased risk of
clinical resistance [83,84]. Generally speaking, during the past
2 decades, concern has grown about substantial overuse of
broad-spectrum antibiotics including not only AMC but also
quinolones, second- and third-generation cephalosporins,
and second-generation macrolides [85-88].
There is evidence showing the lack of clinically meaningful
differences in treatment rates between broad- and narrow-
spectrum agents curing acute RTIs [89]. As an example,
because many patients with sinusitis improve spontaneously,
it has been suggested that narrow-spectrum antibiotics (such as
AMX) should be prescribed as first-choices only for very
sick patients or for those with a high complications risk.
AMC and second- and third-generation cephalosporins should
be considered as alternative agents only for the treatment of
resistant infections [90,91]. Moreover, despite the absence of
consistent supporting data and the risk of promoting drug
resistance, some infections are routinely treated with antibiotics
even for self-limited illnesses or for those with a predominantly
viral aetiology, such as common colds and acute bronchitis [92-94].
Overall, it has been estimated that 55% of all antibiotic
prescriptions for RTIs are unnecessary [95,96]. This attitude is
unsafe for these patients who are exposed to unjustified
risks. It is also critical for the antibiotic itself, which will
progressively lose efficacy when used against the strain
selected from previous overloaded use.
Choosing the most appropriate antibiotic is difficult,
especially in primary care. A variety of factors can affect
prescribing behaviour, including the severity of illness,
the likelihood of a resistant organism, physician training
and local patterns of practice, cost of treatment or
formulary restrictions.
The only way to protect these antibiotics, and consequently
their efficacy, is to invert the prescription trend. To achieve
Expert Opin. Drug Saf. (2009) 8(1)
Salvo, De Sarro, Caputi & Polimeni
this goal, several strategies could be adopted to modify
physicians attitude to prescribing:
Promote targeted educational intervention strategies
towards general physicians, aimed at implementing guide-
lines for optimising antibiotic prescribing in primary care.
There are several examples of successful, tailored interventions
in this field, with significant and enduring reductions in
prescribing broad-spectrum antibiotics, in favour of those
with a narrow spectrum [97,98].
Involve consumer associations and patients in public education
programmes to reduce any inappropriate antibiotic demand
and, as a consequence, improper physician prescribing.
Particular emphasis should be directed towards the risk of
developing resistant strains owing to the widespread and
inappropriate use of broad-spectrum antibiotics. It is also
important to underline the opportunity to reduce the
economic burdens on national health systems, without
influencing patients proper infection management.
The growing use of software to support general physicians
prescription writing is now a reality. Build-up tools to support
the correct choice of antibiotics may reduce the level of
making inappropriate prescriptions. Such tools may also help
to improve prescribers counselling before antibiotic treatment.
For instance, an automated electronic reminder may activate
every time a prescription of AMC is made, to remind pre-
scribers that a period of observation without immediate use
of antibiotics may be a valid option for certain conditions,
and that the drug should be used cautiously in patients with
cholestatic jaundice/hepatic dysfunction, using an alternative
antibiotic whenever it is possible.
Acknowledgements
The authors would like to thank Professor Mathieu Molimard
for his fruitful suggestions, and Professor Philip Cowey for
help in manuscript preparation.
Declaration of interest
The authors state no conflict of interest and have received
no payment in preparation of this manuscript.
115
Amoxicillin and amoxicillin plus clavulanate
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Affiliation
Francesco Salvo1 MD, Angelina De Sarro1,
Achille Patrizio Caputi1,2 & Giovanni Polimeni2
Author for correspondence
1University of Messina,
Department of Clinical and Experimental
Medicine and Pharmacology,
Section of Pharmacology,
Messina, Italy
Tel: +0039 090 2213878;
Fax: +0039 090 2213300;
E-mail: fsalvo@unime.it
2Istituto di Ricovero e Cura a Carattere
Scientifico (IRCCS) Centro Neurolesi
Bonino-Pulejo,
Messina, Italy