PHARMACOEPIDEMIOLOGY

AND DRUG SAFETY, VOL.

5: 247-254 (1996)

ORIGINAL REPORT

Are the Adverse Drug Reactions of Amoxycillin and

Amoxycillin-Clavulanic Acid Similar?
I. MARTINEZ-MIR~,J. M. FERRER?, v. PALOP?, L. ESTANI, E. RUBIO'.?A N D F. J. MORALES-OLIVASIJ

' Deparrament de Farmacologia, Universitat de Valincia, Spain: 'Centre de Farmacovigilancia de la

Comunitat Valenciana. Conselleria de Sanitat i Consum, Spain

SUMMARY
In an attempt to assess the relative toxicity of amoxycillin and amoxycillin-clavulanic acid, we
compared the adverse drug reactions reports collected using the spontaneous reporting system of a
Regional Drug Surveillance Centre of Spain for both drugs between November 1986 and December
1992. During the 7-year period 1986-92, the 247 reports of amoxycillin-clavulanic acid represent twice
the number of reports of amoxycillin alone, and the number of reports related with sales received
concerning the association were higher than those concerning amoxycillin alone. The adverse effects
classified as severe were quantitatively and qualitatively similar for both drugs and gastrointestinal and
skin are the most common system-organ affected by both drugs. With amoxycillin-clavulanic acid
there is a higher proportion of stomatological reactions reported and a later onset of adverse drug
reactions related with oropharyngeal lesions, and the reaction of the resistance mechanism when
compared with the other organs and systems affected. The duration of the adverse drug reactions to
amoxycillin-clavulanic acid is longer than for amoxycillin alone. In conclusion: (i) the adverse drug
reactions profile of both drugs is different; (ii) the higher reporting rate for amoxycillin-clavulanic acid
may be due to more recent marketing; and (iii) amoxycillin-clavulanic acid produces proportionately
more gastrointestinal and fewer skin adverse reactions than amoxycillin alone.
KEY WORDS - amoxycillin; amoxycillin-clavulanic

acid; adverse drug reactions; profile of adverse

drug reactions

INTRODUCTION

amoxycillin-clavulanic acid are similar to those

known for amoxycillin, but at least to our
Amoxycillin-clavulanic acid was launched in the knowledge, there are no studies demonstrating this
Spanish pharmaceutical market in 1986, and in (MEDLINE from 1986 to June 1995). One of the
November 1986 a voluntary adverse reaction uses of the voluntary adverse drug reactions
reporting system within the Spanish Drug Surveil- reporting system is to assess the relative toxicities
lance Scheme was started in the Comunidad Valen- of products of the same therapeutic class, conciana (Alicante, Castellbn and Valencia). Since this structing profiles of the proportion of the total
date, the combination of amoxycillin and clavu- number of reports on a particular drug for each of
lanic acid has been increasingly used and in these the major organ-systems. The profiles for two
7 years 15 different trademarks have appeared.
drugs within the same class can be compared to
The manufacturers and the earlier published define the relative toxicity of each ~ n e . ~ - ~
studies' say that the adverse drug reactions for
In an attempt to assess the relative toxicities of
both drugs of the same therapeutic group, we
compared the adverse drug reactions reports
Addressee for correspondence: Francisco J . Morales-Olivas,
concerning
amoxycillin-clavulanic acid with those
Departament de Farmacologia, Facultat de Medicina i
related with amoxycillin alone between November
Odontologia, Avda. Blasco Ibaiiez, 15, 4601O--Valtncia,
1986 and December 1992.
Spain, tel: 34-96-3864628, fax: 34-96-3864173.
CCC 1053-8569/96/040247-08

0 1996 by John Wiley & Sons, Ltd.

Received 24 April 1994

Accepted I1 November 1995

248

I. MARTINEZ-MIR ET A L

MATERIAL AND METHODS

The reports are collected using the spontaneous
reporting system of the Regional Drug Surveillance Centre maintained by the Spanish Drug
Surveillance Scheme of the Ministerio de Sanidad y
Consumo, which participates in the WHO Collaborating Centre for International Drug Monitoring
(Uppsala).
The population under study is that of Alicante,
Castellon and Valencia, with 3.75 million inhabitants and 14,500 doctors.
The procedure involved in the reporting system
and the assessment of the data has been described
el~ewhere.~,
Briefly, in order to validate the cases,
for every adverse effect occurring in a given
patient, the purpose must be to collect the
maximum amount of information about characteristics of the patient (sex, age, medical history,
underlying diseases, etc.), treatment conditions
(suspected drug, dosage, route of administration,
indication, date of the beginning and termination
of therapy, concomitant drugs, etc.) and characteristics of the adverse event (date of onset, detailed
clinical and biological patterns, evolution, etc.).
Once the case is validated, in order to obtain an
imputability score, we employ the algorithm used
in the Spanish Drug Surveillance Scheme, which is
based on successive evaluations of five criteria,
each one of which has several degrees, which
provide grades of the causal association between
drug and adverse effect.
The reactions were classified according to the
Adverse Reaction Terminology of the
The
profile of reactions was made by calculating the
number of reports of each system-organ class of
reaction as a percentage of all the reports received
for each drug. The graphic representation of the
profile of reactions was made using a histogram.
The information on adverse drug reactions
during the life-cycle of a drug indicates that the
reporting rate during the first years is greater than
after the fifth year of marketing. To reduce this
possible bias in the data, the reporting rate as drug
reactions report/sales ratio is calculated for each
drug, using the reports of the adverse drug
reactions as numerator and the number of millions
of units sales covered by the Public Health System
as denominator data for each antibiotic. We used
the sales data for 1986 to 1989 reported by the
Ministerio de Sanidad y Consumo. lo We calculated
the reporting rate for years 1987, 1988 and 1989.
We excluded the year 1986 because amoxycillin-

0 1996 by John Wiley & Sons, Ltd.

clavulanic acid was launched in Spain in the middle

of this year and the voluntary adverse reaction
reporting system in the Comunidad Valenciana
started during November.
The statistical study of data was made using the
Student t-test. Comparison of the proportions was
made using the chi-squared test and expressed as
the odds ratio (OR).
RESULTS
Of the 5430 reports (5303 reports evaluated)
received from November 1986 to December 1992,
247 reports (4.68% of those evaluated) are
associated with amoxycillin-clavulanic acid and
124 reports (2.34% of those evaluated) with
amoxycillin alone. These values are 18.52% and
9.3% respectively of the reports of therapeutic
group J, antibiotics. Thirty reports (12.15%) in the
combination group and 32 reports (25.81%) in the
amoxycillin group have been excluded because of
insufficient information in the report or the
concurrence of other suspected drugs. The annual
numbers are given in Table 1.
A total of 114 females (52.53%), 100 males
(46.08%) and three not-known (1.38%) suffered
adverse reactions to amoxycillin-clavulanic acid.
The mean age for the group was 30.72k24.27
years (range 2 months-84 years) with the mean age
for males being 26.91 f24.83 (range 2 months-84
years; n = 99) and for females 34.22 f23.27 (range
2 months-84; n = 113). In the amoxycillin group,
49 (53.26%) were females, 42 (45.65%) males and
only one (1.09Y0) was not known. The mean age
for the group was 20.1 1 f22.53 years (range

Table 1 - Annual numbers of case reports submitted

to the Comunidad Valenciana Regional Drug Surveillance Centre
Year

Amoxycillinclavulanic acid

Amoxycillin

Overall

1986*
1987
1988
1989
1990
1991
1992

4
41
37
38
34
32
31

1
20
22
13
9
14
13

103
796
817
824
887
926
1077

Total

217

92

5430

*Only 43 days

PHARMACOEP~DEMIOLOGYAND DRUG SAFETY. VOL. 5: 247-254

(1996)

249

ADR PROFILE OF AMOXYCILLIN VS. AMOXYCILLIN-CLAVULANIC ACID

System- organ classes

Skin and apendages
M uscu lo-skele tal

Central/autonomic NS
Organ senses
Psych ia t r ic
Gast ro -in test inal
Liver and biliary
Endocrine/metabolism
Card iovas cu la r
Respiratory
H ae mato logy

Urinary
Rep roduct ive
Body as a whole
Resistance mechanism
0

10

20

30

40

50

60

70

No. adverse drug reactions/total (46)

Am oxyci 1 1 in -clavu lan ic acid

Amoxycillin
Fig. 1 - Profiles of the proportion of the total number of reports of amoxycillin-clavulanic acid and amoxycillin
for each of the major organ-system reported from November 1986 to December 1992 to the Comunidad Valenciana
Regional Drug Surveillance Centre. Note that a single report can contain several clinical manifestations

2 months-90 years; n = 90) with the mean age for

males being 16.92& 23.14 (range 4 months-90
years; n = 41) and for females 22.77 & 21.66 (range
2 months-74 years; n = 49).
The 5303 reports evaluated during this period of
time included 9879 reactions, of which 388 are for
amoxycillin-clavulanic acid and 163 for amoxycillin alone (3.93% and 1.65%, respectively).

0 1996 by John Wiley & Sons, Ltd.

Fig. 1 shows the summary of the adverse drug

reactions reported according to the organ-system
affected. Note that a single report can contain
several clinical manifestations. The results obtained show that the proportion of dermatological
reactions is significantly lower with an OR = 0.46
(95% CI 0.33-0.65) for amoxycillin-clavulanic
acid than for amoxycillin alone (106/388, 97/163,

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 5:

247-254 (1996)

250

1. MARTINEZ-MIR ET AL.

Abdominal pain
Colitis
Constipation
Diarrhoea
Dys ph ag ia
Dyspepsia
Enan thema
Enteritis
Flatulence
Gastritis
Gastroin te. haemorr
Gingivitis
Haemor roids
Hiccup
Ileus
Nausea
Stomati tis
Tongue disorder
Toot h d isco 1ou ratio n
Vomiting

10

15

20

No. adverse drug reactionsltotal (96)

Amoxycillin-clavulanic acid
Amoxycillin
Fig. 2 - Profiles of the proportion of the total number of reports of amoxycillin-clavulanic acid and amoxycillin
for digestive reactions reported from November 1986 to December 1992 to the Comunidad Valenciana Regional
Drug Surveillance Centre. Note that a single report can contain several clinical manifestations

respectively). In contrast, the proportion of

digestive reactions is significantly higher with an
OR = 2.36 (95% CI 1.58-3.57) for amoxycillinclavulanic acid (219/388 versus 39/163). The
reactions in other organs or systems are not
significantly different for either drug.
Fig. 2 shows that the adverse drug reactions that
affect the digestive system reported for both drugs
were qualitatively similar. However, amoxycillinclavulanic acid was related with oropharyngeal
0 1996 by John Wiley & Sons, Ltd.

lesions (enanthema, gingivitis, stomatitis, tongue

disorder and tooth discolouration) in a higher
proportion than amoxycillin (34/388, 3/163, respectively).
Table 2 shows the reporting rate for total
reactions and for several selected organs and
systems. Table 3 shows the time of onset and the
time of duration of the reactions for amoxycillinclavulanic acid and amoxycillin alone. The time of
onset of the reactions varied between 1 and 26 days

PHARMACOEPIDEMIOLOGY A N D DRUG SAFETY, VOL. 5:

247-254 (1996)

25 1

ADR PROFILE OF AMOXYCILLIN VS. AMOXYCILLIN-CLAVULANIC ACID

Mild 84

77 repor
Severe 2%
2 reports
Moderate 14%
13 reports

Severe 1%
3 reports
oderate 23%
49 reports

Amoxycillin-clavulanic acid

Amoxycillin

Fig. 3 - Summary of the adverse drug reactions reported according to the severity of the adverse effect using the
Spanish National Pharmacovigilance System rules from November 1986 to December 1992

and there appears to be no difference in onset time

of reactions for different systems affected. However, the amoxycillin-clavulanic acid group shows
exceptions in the case of oropharyngeal lesions and
for reactions classified as resistance mechanisms.
With respect to the duration of the reactions, this
period of time varied between 1 day and 78 days
and, as in the case of onset time, there appears to
be no difference for different systems affected.
Table 2 - Relationship between case reports and sales
during the period 1987-1989 (number of cases/106 units
sales)*
Amoxycillin- Amoxycillin
clavulanic acid
Overall reactions
Dermatological reactions
Digestive reactions

24.87
6.7
14.0

4.27
2.5
1.02

*Data of sales from Ministerio de Sanidad y Consumo.lo

However, the duration for adverse drug reactions

related with the association was significantly higher
than with amoxycillin alone. In all reports there
was a logical temporal link between the intake of
the drug and the reaction.
Fig. 3 shows the summary of the adverse drug
reactions reported according to the severity of the
adverse effect using the S anish National Pharmacovigilance System rules! There appears to be no
difference for either group of drugs. Three reports
were classified as severe for amoxycillin-clavulanic
acid: one haemolytic anaemia, one anaphylactic
shock with dyspnea and oedema of tongue and,
one larynx oedema with dyspnea, angioedema and
rash. The centre received two reports classified as
severe for patients treated with amoxycillin alone:
one anaphylactic shock, and one larynx oedema
with rash erythematous and urticaria. No other
alternative cause for the reactions was known.
Table 4 shows details of the patients experiencing adverse events in temporal association with

Table 3 - Onset and duration period for the different organs and systems affected
Onset period
(days; mean SD)*
AmoxycillinAmoxycillin
clavulanic acid
Overall
Digestive
Skin
Oropharyngeal
Resistance mechanism

2.89k3.07 (388)
2.70f2.46 (219)
2.68f2.01 (106)
4.47f2.00 (34)f
9.50f9.31 (8)f

Duration
(days; mean fSD)*
AmoxycillinAmoxycillin
clavulanic acid

3.08k2.48 (163)
3.36k2.79 (39)
3.27k2.47 (97)
2.67+ 1.25 (3)
~

4.64f7.08 (359)t
4.43k7.34 (199)
3.88f3.77 (100)
13.20+ 15.22 (30)$
8.50 +_ 2.99 (6)
~

3.1912.00 (133)
3.10f 1.86 (77)
3.27k2.47 (97)
2.67+ 1.25 (3)
_

*Number of clinical manifestations reported in brackets.

?&Testsignificant for p < 0.05 compared with amoxycillin alone.
Sr-Test significant for p < 0.05 compared with overall.

0 1996 by John Wiley & Sons, Ltd.

PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, VOL. 5: 247-254

(1996)

Tooth discolouration

Improves

Known from
anecdotal reports
Known from
anecdotal reports
Known from
anecdotal reports
Unknown

Pharyngi tis

ACA

ACA

63/M

35/F

Tonsillitis

A, amoxycillin; ACA, amoxycillin-clavulanic acid; F, female; M, male.

*Previous knowledge is applicated for a report as a whole.

41/F

Otitis media

Palpitation
Dizziness
Haemorrhoids
Unknown
Condition aggravated
Unknown
Urine discolouration
Lacrimation discolouration
Unknown
Dizziness

Sinusitis

ACA

1 I/F

4 1 ~ A

Tooth discolouration

Otitis media

ACA

Tooth discolouration

11/M

7 1 ~ ACA

Improves

Unknown

Upper respiratory
tract infection
Upper respiratory
tract infection
Tonsillitis

ACA

2IM

Improves
Improves

Unknown
Unknown

Salpingitis
Pyelonephritis

ACA
ACA

33/F
62/M

Improves

Unknown

Gastroenteritis
Epistaxis
Gastritis haemorrhagic
Vomiting
Haemorrhage rectum
Haematemesis
Haemolytic anaemia

ACA

3 1 ~

Improves

Unknown

Fixed drug eruption

ACA

17/M

Improves

Improves

Improves

Improves

Improves

Improves

information
No alternative

No alternative

No information
No information
No information

No information

No information

No information

No information

No alternative

No alternative

Weak alternative

Strong alternative

No alternative

No alternative

No information
No information

No alternative

No information

NO

No information

No information

No information

No alternative

Positive: ADR
reappeared
No information

No alternative

No information

ACA

69/F

Unknown

Strong alternative

No information

No alternative

Alternative
ethiologic
candidates

Rechallenge

Drug not ceased, No information

ADR improves
Improves
No information

Improves

Unknown

Stomatitis

ACA

33/F

Upper respiratory
tract infection
Upper respiratory
tract infection
Tonsillitis

Tonsillitis

3 1 ~ ACA

Information against
the relationship
Unknown

Previous knowledge* Dechallenge

Urinary retention
Constipation
Exanthema
Photosensitivity reaction
Exanthema
Photosensitivity reaction
Pruritus
Fixed drug eruption

Tonsillitis

3 1 ~ ACA

Adverse drug reaction

Diagnosis

Drug

Age/sex
(years)

Table 4 - Details of the patients experiencing adverse events in temporal association with the use of these medicines, but they are not published or
there are only anecdotal reports in the literature

r-.

h
Y
A

k
%

=!

h)

VI

h)

253

ADR PROFILE OF AMOXYClLLlN VS. AMOXYCILLIN-CLAVULANIC AClD

the use of these medicines, but they are not

published or there are only anecdotal reports in
the literature.
DISCUSSION
Amoxycillin and amoxycillin-clavulanic acid are
extensively documented anti-infectious agents
which are generally well-tolerated with an overall
incidence of adverse events reported of 0-28% and
6- 14%, respectively.'!"
During the 7-year period 1986-92, the 247
reports of amoxycillin-clavulanic acid represent
twice the reports of amoxycillin alone. Similarly,
there was a higher number of reports related with
sales received concerning the combination than
amoxycillin alone. This higher number of reports
for the combination than for amoxycillin alone can
be explained, as with other drugs, by Weber's
effect, the reporting is influenced by the marketing
life,4,'2 and the physician tends to report for
modern drugs.9
It is not possible to compare the absolute
number of adverse drug reactions for both drugs,
but we can compare the profiles of adverse drug
reactions for the two drugs, since both belong to
the same therapeutic class and can be compared to
define the relative toxicity of each ~ n e . And
~ - ~in
this sense, there are no reasons to report to the
Pharmacovigilance System different kinds of
adverse reactions with drugs that belong to the
same therapeutic group and that have been
prescribed for similar indications. In agreement
with Inman and Weber,13 we would like to note
that for this procedure it is not necessary to know
the denominator since we are seeking only relative
differences in proportions and not differences in the
incidence of adverse drug reactions.
In agreement with data in the literature, in both
groups, most adverse effects were mild or moderate
in severity. We have observed that the adverse
effects classified as severe were quantitatively and
qualitatively similar in both groups. In the case of
the haemolytic anaemia related with the combination, we cannot find any information in the
literature, but this reaction is well known for other
beta-lactamic antibiotics.14
Our results also show that gastrointestinal and
skin are the most common system-organs affected
for both drugs, (84% of all adverse reactions), but
the group of reports with amoxycillin alone shows
a significantly higher proportion of skin adverse

0 1996 by John Wiley & Sons, Ltd.

reactions while the proportion of adverse events

with amoxycillin-clavulanic acid is significantly
higher for gastrointestinal adverse reactions.
The most common adverse reactions with
amoxycillin-clavulanic acid reported were gastrointestinal, primarily diarrhoea, dyspepsia, nausea
and vomiting, in agreement with the clinical trials
profile.'-'' Ball and his colleagues16 indicate that
the dosage of calvulanic acid may be an important
factor influencing the frequency and severity of
digestive reactions. The higher proportion of
stomatological reactions reported with amoxycillin-clavulanic acid may be explained, at least
partially, by eliminating sensitive micro-organisms,
which may be a result of long-term therapies.
Spontaneous reporting is a passive surveillance
system and many biases can have a bearing on the
number and quality of reported cases. Only a
fraction of actual cases is revealed by spontaneous
reporting. We found little or no information in the
literature for 14 reactions induced by amoxycillinclavulanic acid and two reactions related with
amoxycillin. In this sense, it is surprising that cases
of tooth discolouration are not described in the
literature in clinical trials, however, the Australian
and the Netherlands Drug Surveillance Scheme
have described this side-effect, as has a Spanish
open study in children.17p19
Other interesting data arising from the results
shown in this study is the different onset and
duration times among the different class of sideeffects observed with both groups. The increased
onset and duration time with amoxycillin-clavulank acid may be explained by the underlying
mechanism of production of this class of reactions,
probably related to the alteration of the bacterial
flora in certain areas of the body caused by
eliminating sensitive micro-organisms. l 6
In conclusion, the analysis of data from our
voluntary reporting system permits us to conclude
that: (i) the adverse drug reactions profile for both
drugs are different; (ii) the higher reporting rate for
amoxycillin-clavulanic acid may be due to more
recent marketing; and (iii) amoxycillin-clavulanic
acid produces proportionately more gastrointestinal and fewer skin adverse reactions than
amoxycillin alone.
ACKNOWLEDGEMENTS
The authors wish to thank P. S. Derrick, for
correcting the English text.

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254

1. MARTINEZ-MIR ET AL.

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