Pharmacological Research, Vol. 46, No.

5, 2002
doi:10.1016/S1043-6618(02)00210-4, available online at http://www.idealibrary.com on

ADVERSE DRUG REACTIONS TO ANTIBIOTICS OBSERVED IN TWO

PULMONOLOGY DIVISIONS OF CATANZARO, ITALY: A SIX-YEAR
RETROSPECTIVE STUDY
L. GALLELLI a , G. FERRERI a , M. COLOSIMO a , D. PIRRITANO a , L. GUADAGNINO a ,
G. PELAIA b , R. MASELLI b and G. B. DE SARRO a,∗
a Chair of Pharmacology, Department of Experimental and Clinical Medicine, University “Magna

Graecia” of Catanzaro, Regional Pharmacovigilance Center, “Mater Domini” University Hospital,

Via T. Campanella, 88100 Catanzaro, Italy, b Chair of Respiratory Diseases, Department of
Experimental and Clinical Medicine, University “Magna Graecia” of Catanzaro,
“Mater Domini” University Hospital, Via T. Campanella, 88100 Catanzaro, Italy

Accepted 7 August 2002

We retrospectively analysed adverse drug reactions (ADRs) associated with antibiotic therapy and
reported over a 6-year period, from January 1995 to December 2000, in clinical notes of two Pul-
monology Units of “Mater Domini” University Hospital and “Pugliese-Ciaccio” Hospital, both lo-
cated in Catanzaro, Italy.
Antibiotics were responsible for 92 (44.9%) out of 205 episodes of ADRs. In particular, 22 episodes
(23.9%) were observed after penicillin G administration, 19 episodes (20.7%) following ceftazidime
and cefotaxime administration, 16 episodes (17.4%) after therapy with ampicillin, and 35 reac-
tions (38%) were further reported during treatments with other antibiotics. We determined that the
drug–ADR relationship was certain in 63% of the reports; withdrawal of the suspected drug led to re-
covery in 95% of cases. In conclusion, this retrospective evaluation demonstrated that antibiotics are
a common cause of ADRs in hospitalised patients and, therefore, drug surveillance can successfully
identify targeted adverse events.
© 2002 Elsevier Science Ltd. All rights reserved.

Key wo rds: antibiotics, adverse drug reactions, clinical records, pulmonology, hospitalised patients.

INTRODUCTION Antibiotics are some of the major contributors to drug

Pharmacovigilance or post-marketing surveillance aims
to identify and quantify the risks associated with the use
of drugs [1], thus contributing to better understand the
most important characteristics of adverse drug reactions
(ADRs) and the pathogenic mechanisms involved. Indeed,
ADRs represent a common clinical problem and can be
responsible for an increased number and/or duration of
hospitalisations [2,3]. An ADR is associated with a sig-
nificantly prolonged length of stay, increased economic
burden, morbidity, and an almost 2-fold increased risk of
death [4]. Any drug can cause ADRs, which may range
from mild skin rashes (hives) to a life-threatening allergic
reaction.
∗ Corresponding
author. Cattedra di Farmacologia, Dipartimento di
Medicina Sperimentale e Clinica, Policlinico Universitario “Mater
Domini”, Via T. Campanella, 88100 Catanzaro, Italy.
E-mail: desarro@unicz.it
hypersensitivity and represent the most frequently used
drugs in hospital practice [5,6]. Although spontaneous re-
porting is, among the several different methods that can be
used to detect ADRs, the only surveillance system capa-
ble of routinely monitoring these events [7], it alone can-
not provide sufficient guarantee that a particular adverse
event is a true ADR. Therefore, this approach has to be
integrated with other procedures using retrospective data
based on clinical trials and medical reports, in order to de-
fine ADRs which are either not time-related or associated
with chronic drug administration [8].
These retrospective analysis carried out to investigate
ADRs in hospital populations could be very useful to im-
prove the health care system with regard to both financial
aspects and cost–benefit evaluations. A better health care
can be achieved by applying this knowledge to the indi-
vidual patient, thus trying to avoid possible troubles. The
magnitude of these problems implies the need of investing
sufficient resources in order to implement programs aimed
to identify, assess, and manage ADRs [9]. The purpose

1043-6618/02/$ – see front matter © 2002 Elsevier Science Ltd. All rights reserved.
396
of our research was to evaluate, by analysing the clinical
features as well as the frequency of ADRs, the involve-
ment of antibiotics in such reactions occurring during
hospitalisation.
METHODS
This study was carried out in two pulmonology divisions
of Catanzaro, Italy, located at “Mater Domini” University
Hospital and “Pugliese-Ciaccio” Hospital, respectively.
We retrospectively analysed the medical records referring
to patients who were hospitalised between 1 January 1995
and 31 December 2000. The clinical records of patients
receiving antibiotics were reviewed and the following data
were obtained: sex and age of the patient, previous history
of drug allergy and therapy duration, possible ADRs and
drug classes involved.
Definition of ADRs
An ADR was defined as an untoward clinical manifes-
tation consequent to and caused by the administration of a
particular drug [10] or interacting drugs, excluding inten-
tional overdose, substance abuse and therapeutic failure
[11–13]. The clinical manifestation may be an abnormal
sign, symptom or laboratory test, or a cluster of abnormal
signs, symptoms and tests [14]. ADRs were considered
as serious when: (1) fatal; (2) life-threatening; (3) perma-
nently/significantly disabling; (4) required or prolonged
hospitalisation; (5) required intervention to prevent per-
manent impairment or damage. Only suspected ADRs de-
finable as certain, probable or possible, were included in
the analysis of antibiotic-associated adverse reactions.
Types of ADRs
ADRs may be subdivided into two major types:
- Type A reactions are the most common ADRs and in-
clude nonintentional overdosing, side effects, and drug
interactions which can occur when the patient is taking
two or more medications simultaneously. This type of
ADRs is usually predictable but sometimes unavoid-
able.
- Type B reactions are usually not predictable and include
allergic reactions to drugs, intolerance to a specific drug
or an uncommon reaction to a given drug such as skin
rashes, liver or kidney damage, anaemia, decrease in the
white blood cell count, and nerve injury with possible
visual or hearing impairment. These reactions typically
develop in a very small number of people, who may
complain of drug allergy or hypersensitivity because of
genetic differences in drug metabolism or in their body
response to drugs.
Causality of ADRs
In order to assess the likelihood that ADRs were deter-
mined by antibiotics, a causality rating was assigned to
each antibiotic using the validate Kramer’s algorithm [10]
Pharmacological Research, Vol. 46, No. 5, 2002
Table I
The six axes and total score in Kramer’s algorithm for ADRs
(amended from Hutchinson et al. [25])
Axis Scoring of evidence for reaction
Favours Uncertain Against
Historya +1 0 −1
No alternative illnessesb +2 0 −1
Timing of eventsc +1 0 −2
Drug levels +1 0 −1
Dechallenged +1 0 −1
Rechallengee +1 0 −1
Total score f +7 0 −7
a Previous experience of ADR. b No other factor related to
underlying disease, as well as no other drug-unrelated aetiology may
explain the presence of the clinical manifestation in the patient. c Time
elapsed between drug administration and ADR manifestation; ADR
onset immediately follows drug administration. d ADR either
attenuates or disappears after drug reduction or interruption,
respectively. e ADR reappearance after drug re-administration; not
done in any of the patients analysed in this observational study. f Less
than 0 ADR, unlikely; 0–3, possible; 4 and 5, probable; 6 and 7,
definite.
with Hutchinson’s questionnaire [15]. The diagnostic cri-
teria in Kramer’s algorithm are divided into six axes, with
a scoring system incorporated into each axis. The cumu-
lative score corresponds to the probability that the clinical
manifestation represents an ADR (Table I). We compared
the score obtained for a suspected ADR caused by a drug
interaction with the scores obtained for the clinical man-
ifestation caused by the single drugs. When a candidate
single drug had a higher score, that drug rather than the
interaction was held responsible for the ADR.
Therefore, we defined four distinct classes with regard
to ADRs causality: (a) Certain: temporal or spatial corre-
lation confirmed by dechallenge and rechallenge and/or
laboratory test; (b) Probable: temporal or spatial correla-
tion confirmed by dechallenge and not induced by disease,
and/or recovery on withdrawal of the drug if no other drug
was withdrawn and no therapy given; (c) Possible: a pos-
sible alternative explanation exists when a strict tempo-
ral relationship is not clear, and/or a recovery occurs after
therapy prescription in addition to drug withdrawal, and/or
more than one drug is suspected; (d) Unclear causality:
the clinical event could be consistently attributed to either
the underlying disease or to other drug-unrelated causes.
Records were screened as positive and then reviewed by
clinicians, who identified any adverse event and completed
a detailed Hutchinson’s questionnaire.
Patient characteristics
Patient age and sex, hospitalisation cause, and the num-
ber of prescriptions and ADRs were considered. Patients
were subdivided into six age groups: infants, children and
adolescents (0–15 years); young adults (16–30 years),
adults (31–45 years), older adults (46–60 years), el-
derly adults (61–75 years), and very elderly adults (over
75 years).
Pharmacological Research, Vol. 46, No. 5, 2002 397

Table II
ADRs frequency in all patients treated with drugs and in patients treated with antibiotics

Age (years) Total number of patients Total ADRs Total number of patients ADRs induced by
treated with antibiotics antibiotics
N % N % N % N %

0–15 153 3.3 3 1.5 59 1.8 1 1.1

16–30 361 7.8 11 5.4 164 5 16 17.4
31–45 597 13 18 8.8 263 8.1 13 14.1
46–60 1019 22.1 45 21.9 723 22.2 20 21.7
61–75 1652 35.8 89 43.4 1386 42.6 31 33.7
>75 830 18 39 19 659 20.3 11 12
Total 4612 100 205 100 3254 100 92 100

Table III
Patient demographics

Characteristics Non-ADRs ADRs induced by other treatments ADRs induced by antibiotics

Man (%) 54.8 56.2 53.2

Woman (%) 45.2 43.8 46.8
Hospitalisation cause Bronchitis (25%), pneumonia (20%), Bronchitis (20%), pneumonia (18%), Bronchitis (15%), pneumonia (32%),
COPD (20%), asthma (18%), fibrosis asthma (27%), COPD (10%), fibrosis asthma (2%), COPD (5%), fibrosis
(5%), lung cancer (5%), other (13%), lung cancer (10%), other (15%), lung cancer (30%), other
diseases (7%) diseases (2%) diseases (1%)
Number of prescriptions 1–2 drugs: 66% 1–2 drugs: 22% 1–2 drugs: 20%
3–4 drugs: 23% 3–4 drugs: 40% 3–4 drugs: 43%
>4 drugs: 11% >4 drugs: 38% >4 drugs: 37%

Statistical analysis by antibiotics vs total number of patients treated with an-

Data were statistically analysed using a computerised
system. Comparisons between groups were made us-
ing the Student’s t-test for continuous variables, and
χ 2 -statistics for noncontinuous data. Logistic regression
was also performed to examine the relationship between
patient age and ADRs induced by antibiotic treatment.
Differences were considered statistically significant when
P values were <0.05. We carried out statistical analysis
using the SPSS statistical software.
RESULTS
During the study period, 4612 clinical records and 18 464
prescriptions were analysed. According to the definition
of ADRs and Kramer’s causality algorithm, we reported
that within 205 suspects of ADRs (1.11% of total prescrip-
tions), 92 were induced by antibiotics (44.9%). Patients
with ADRs induced by antibiotics and by other drugs, did
not show any significant difference in the sex ratio (man
53.2% and woman 46.8%; man 56.2% and woman 43.8%,
respectively).
The percentage of patients with a reported ADR var-
ied among the six age groups. In fact, older patients
were more likely to suffer an ADR in comparison with
all drug-treated patients, as well as with respect to
antibiotic-treated patients (P < 0.0001 for total ADRs vs
total number of patients; P = 0.0160 for ADRs induced
tibiotics) (Table II). Patients who showed a documented
ADR had more concurrent chronic medical diagnoses
such as pulmonary fibrosis or lung cancer, with respect to
those who did not develop ADRs (P < 0.001) (Table III).
The most frequently reported side effects were cu-
taneous (70.5%), gastrointestinal (7.6%) and cardio-
vascular (7.6%) disturbances (Table IV). Most of the
side effects involved penicillins and cephalosporines
(Table V). Moreover, 63% of the reports were classi-
fied as certain, 29% as probable and 8% as possible.
With regard to the study population, 12% of side effects
were classified as serious ARDs (Table VI). Among the
non-serious side effects (88%), 32.2% were severe and
67.8% mild (data not shown). Withdrawal of the suspected
drug led to a full recovery from 95% of ADRs (data not
shown).
DISCUSSION
An ADR is any response that is unintended and undesired,
and that occurs at commonly used doses. The reaction
may be idiosyncratic or pharmacologically predictable.
Cumulative side effects of medications taken concurrently
increase the risk of adverse reactions.
Antibiotics are the most widely used drugs in hospi-
talised patients. Due to limitations of spontaneous report-
ing, pharmaco-epidemiological studies may be the only
398 Pharmacological Research, Vol. 46, No. 5, 2002

Table IV
Antibiotics involved in ADRs
Antibiotics Doses Route and times ADR
N %

Penicillin G 1 000 000 U i.m. b.i.d. 22 23.9

Ampicillin 1g i.v. b.i.d. 16 17.4
Cefotaxime 1g i.v. b.i.d. 10 10.9
Ceftazidime 1g i.v. b.i.d. 9 9.8
Piperacillin 1g i.v. b.i.d. 6 6.6
Amoxicillin 1g i.v. b.i.d. 5 5.5
Ciprofloxacin 400 mg i.v. b.i.d. 5 5.5
Methylprednisolone + cefotaxime 1 mg kg−1 + 1 g i.v. b.i.d. 2 2.1
Rifampin 1.5 g i.v. b.i.d. 2 2.1
Ceftizoxime 1g i.v. b.i.d. 2 2.1
Ceftriaxone 2g i.v. d.i.e. 2 2.1
Clarithromycin 500 mg o.s. b.i.d. 2 2.1
Ampicillin + sulbactam + methylprednisolone 3 g + 1 mg kg−1 i.v. b.i.d. 1 1.1
Ampicillin + sulbactam 3g i.v. b.i.d. 1 1.1
Ampicillin + sulbactam + bromexine 3 g + 8mg i.v. b.i.d. 1 1.1
Ampicillin + doxycycline 500 + 100 mg o.s. b.i.d. 1 1.1
Erythromycin 500 mg o.s. b.i.d. 1 1.1
Trimethoprim + sulfamethoxypyridazine 100 mg o.s. b.i.d. 1 1.1
Ofloxacin 300 mg o.s. b.i.d. 1 1.1
Imipenem 500 mg i.v. b.i.d. 1 1.1
Sulbactam 1g i.v. b.i.d. 1 1.1

Table V
Descriptions of ADRs as reported in medical records

ADRs Other treatments (N = 113) Antibiotics (N = 92)

Descriptive classes % %
Skin and appendages Rash (28), hives (14), itching (11) Rash (43), hives (18), itching (9.5)
Gastroenteric system Nausea/vomiting (7.2), diarrhoea (5.2) Nausea/vomiting (4.2), diarrhoea (3.4)
Cardiovascular system Hypotension (8.3%), tachycardia (3.2) Tachycardia (5.1), hypotension (2.5)
Nervous system Dizziness (0.9), forgetfulness (0.8), lethargy (0.7), Dizziness (1.1), forgetfulness (1), lethargy (0.8),
headache (0.3) headache (0.4)
Respiratory system Cough (6.2), dyspnoea (1.7) Dyspnoea (1.5), cough (0.7)
Connective tissue 2.7 1.1
Haematologic system Thrombocytopenia (2.3), leukopenia (1.2), anaemia (0.9) Leukopenia (0.7), trombocitopenia (1.5), anaemia (1.1)
Neuromuscular system Muscular pain (2.7) Muscular pain (2.2)
Mucous membranes Oedema (2.7) Oedema (2.2)
Total 100 100

Table VI
Serious ADRs induced by antibiotics

Drug Doses Route and times ADR (N)

Penicillin G 1 000 000 U i.m. b.i.d. Serious angina (2)

Cefotaxime 1g i.v. b.i.d. Serious angina (1); lipothymia (1); leukopenia (1)
Amoxicillin 1g i.v. b.i.d. Psoriasis (1)
Ampicillin 1g i.v. b.i.d. Arrhythmia (1)
Ceftizoxime 1g i.v. b.i.d. Extrasystoles (1)
Ampicillin + sulbactam + 3 g + 1 mg kg−1 i.v. b.i.d. Bronchoconstriction (1)
methylprednisolone
Ceftazidime 1g i.v. b.i.d. Stevens–Johnson syndrome (1); dyspnoea +
tachycardia (1)

source of information about the benefit–risk profile of
medications received by hospitalised patients [16].
In the present study, we reviewed ADRs induced by
antibiotic agents in hospitalised patients in order to deter-
mine the prevalence and the clinical expression of these
reactions, as well as to evaluate which antibiotics are
mainly involved in such events. The characteristics of
hospitalised patients and drug administration records
were reviewed to determine whether adverse reactions
occurred.
Pharmacological Research, Vol. 46, No. 5, 2002
Our retrospective analysis demonstrated that 3% of
patients who received an antibiotic during hospitalisa-
tion, developed an ADR; antibiotics caused more than
44.5% of the ADRs detected in hospitalised patients, and
there was no significant difference between male and
female. These data are quite consistent with those of a
previous study made by Lemozit et al. [17] who showed
that antimicrobial drugs were involved in 31 and 22.1%
of the ADRs recorded in hospitals and private medicine
practice, respectively. The relatively high percentage of
ADRs to antibiotics detected by us could depend on the
wide use of these agents for the treatment of infectious
exacerbations of chronic pulmonary diseases. Moreover,
by using the Kramer’s algorithm [10,15] and statistical
comparisons we detected the highest percentage of ADRs
within the group of patients with an age ranging from 61
to 75 years. Such a percentage is similar to the results
of previous studies performed using an algorithm in hos-
pitalised patients [18,19]. Furthermore, our observations
are consistent with recent studies showing that the inci-
dence of ADRs in the elderly is estimated to be two to
three times higher than in young adults [20]. This high
percentage is probably underestimated, in fact in many
older adults is difficult to recognise an ADR because it
can mimic some features of their age-related disease.
In fact, medications can induce dizziness, forgetfulness,
drowsiness and lethargy and these effects should not be
confused with “ageing” effects. In agreement with litera-
ture data, according to our study the potential adverse drug
interactions were, therefore, more common in elderly
patients, and this could be explained by the higher num-
ber of concurrent medications rather than by age-based
factors [21].
In our retrospective evaluation, penicillin G resulted to
be the most frequently involved antibiotic in both types
A and B ADRs (23.9% of cases). Previous study, showed
that penicillin-induced type B reactions such as anaphy-
laxis is responsible for the majority of all drug-elicited
anaphylactic deaths in the United States. Patients with a
history of a previous reaction have a 6-fold higher risk
of experiencing a further reaction on subsequent expo-
sure, compared with those without a previous history [22].
The most important risk factors for drug hypersensitivity
are related to the chemical properties of drugs and to the
age of patients. This observation is consistent with the nat-
ural history of drug allergies, and it is noteworthy to point
out that hypersensitivity reactions to penicillin depend on
the presence of preformed antibodies [23]. The likelihood
of a prior exposure to penicillins increases with age, and
therefore, older patients develop an allergic ADR more
easily than young people.
Moreover, our results indicate that another important
risk factor for the development of type A ADRs is rep-
resented by the number of drugs associated in prescribed
therapies. In fact, in agreement with other literature data
[13,14], our observations have confirmed that the use of
multiple drugs is more related to ADRs than the presence
of concomitant diseases.
399
The organ/system distribution of ADRs was similar
within patients developing ADRs to antibiotics or to other
treatments. Indeed, more than 85 and 76% of ADRs in-
duced by antibiotics and other treatments, respectively,
affected skin and the gastroenteric and cardiovascular
systems. With respect to other treatments, skin was the
body district most involved in ADRs induced by antibi-
otics. It has been reported that cutaneous adverse effects
occur in 2–3% of hospitalised patients, and the use of
several common drugs is associated with a greater than
1% incidence of skin reactions. It is noteworthy that ap-
proximately 3% of all disabling injuries occurring in hos-
pitalised patients are attributable to cutaneous reactions
[24,25], and in agreement with these data we observed
that the most important ADRs affected skin. In addition,
using a MEDLINE database research, Bigby showed that
skin is an important target of ADR manifestations [26];
likewise, Chosidow pointed out that antibiotics must be
considered high risk drugs for skin reactions [27].
In agreement with the results of other reports [28],
most ADRs detected in our study were type A reactions,
and in particular they were dose-related. Many of these
were well-known reactions resulting from either primary
or secondary pharmacological actions of the prescribed
drugs, such as gastrointestinal effects, tachycardia or
leukopenia.
Another feature of ADRs refers to their “seriousness”,
and we demonstrated that 12% of the reported ADRs could
be classified as “serious”. Such a finding may indeed de-
pend on the frequent occurrence, in hospitalised patients,
of several concomitant diseases which require numerous
medications as part of their daily treatments. Therefore,
hospital practice seems to predispose to a higher incidence
of adverse effects and interactions related to antibiotic
agents, thus possibly being associated with an increased
risk of experiencing severe ADRs. In our retrospective
analysis, psoriasis was recognised as a serious ADR in-
duced by amoxicillin, and this event could be related to
low CYP2C activity. In fact, recent paper show that any
drugs metabolised by CYP2C can induce severe psoriasis
related to decreased CYP activity [29]. In contrast, the se-
rious angina induced by penicillin G may depend on both
A and B types of ADRs, possibly related to patient charac-
teristics, prescribed drugs, and body response to drugs. In
fact, patients who complained of angina after penicillin G
treatment were elderly subjects receiving associations of
more than four drugs. Therefore, angina onset could have
been favoured by an age-related low hepatic cytochrome
P450 activity, combined with the cardiovascular effects
attributable to interactions among several different drugs
[30].
However, is important to underline that there are sev-
eral limitations to our study. The most important limita-
tion is represent under-reporting of suspect ADRs. In fact,
doctors seem unaware of the need to report well-known
serious reactions and need more guidance on what to re-
port. Under-reporting, may also occur because doctors are
under the misconception that they need to be absolutely
400
confident in the cause–effect relation between drug and
presumed adverse reaction before reporting it.
In conclusion, our results indicate that antibiotics rep-
resent a common cause of ADRs in hospitalised patients,
and that drug surveillance can successfully identify tar-
geted adverse events. Moreover, these findings highlight
the importance of retrospective analysis for all types of
ADR-related research studies.
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