Infections, Bacterial Clinical Trial
Official title:
WEUKBRE5555: IMI PROTECT (Work Package 2): The Risk of Acute Liver Injury Associated With the Use of Antibiotics
The studies described in this protocol are all performed within the framework of PROTECT
(Pharmacoepidemiological Research on Outcomes of Therapeutics by a European ConsorTium)
Workpackage 2 (WP2) and Workgroup 1. The primary aim of these studies is to develop, test
and disseminate methodological standards for the design, conduct and analysis of
Pharmacoepidemiological (PE) studies applicable to different safety issues and using
different data sources. To achieve this, results from PE studies on 5 key adverse events
(AEs) performed in different databases will be evaluated. Therefore, emphasis will be on the
methodological aspects of the studies in this protocol and not on the clinical consequences
of the association under investigation. The standards to develop will contribute to
decreasing the discrepancies in results from different studies in the future and increase
the usefulness and reliability of these studies for benefit-risk assessment in the EU.
We propose to assess the association between antibiotics use and idiopathic acute liver
injury with different study designs (descriptive, cohort, nested case-control and case
crossover) across different primary care databases and to compare the results between
databases, across designs to evaluate the impact of design/database/population differences
on the outcome of the studied association.
Specific aims (in each database):
1. To describe characteristics, clinical features, and risk factors for acute liver injury
in patients exposed and unexposed to antibiotics.
2. To estimate the overall risk of acute liver injury associated with antibiotics exposure
(users and non-users) in each database
3. To estimate the risk of acute liver injury associated with various antibiotics classes
4. To estimate the risk of acute liver injury associated with specific individual
antibiotics
5. To assess the effect of dose and duration of use for specific individual antibiotics.
6. To compare the results of a case-control study with the results of a retrospective
cohort study and self-controlled case series study in the different databases
The proposed studies will be collected in populations from the following databases: The
General Practice Research Database [GPRD] (UK), Health Improvement Network [THIN] (UK),
BIFAP [Base de datos Informatizada para estudios Farmacoepidemiologicos en Atencion
Primaria] (Spain)- the Bavarian Claims Database (Germany), Mondriaan (Netherlands), and the
National Databases of Denmark.
Acute liver injury is one of the most important safety concerns, being the leading cause for
drug withdrawal from the market on safety grounds. For most suspected hepatotoxic drugs the
only existing information comes from spontaneous reports, lacking appropriate risk
quantification through formal epidemiological studies. A few population-based studies
examining the risk of acute and clinically relevant liver injury among users of various
drugs have been published, reporting an elevated risk of liver injury in users of
antibiotics. As acute liver injury is often idiosyncratic and because its diagnostic
criteria used in epidemiological studies have been variable, the reported range of
incidences of acute liver injury caused by antibiotics is broad. In the United Kingdom (UK),
case-control studies investigating the effect of antibiotics on acute liver injury have
generated odds ratios ranging from 94.8 for the combination of amoxicillin/clavulanic acid
to 6.2 for tetracyclines. Age, sex, alcohol intake, concomitant medication and comorbidities
have been proposed as risk factors for antibiotic induced liver injury and may have
influenced the quantification of risk estimates. In the present protocol, we propose to
further quantify the risk of acute liver injury associated with antibiotics in the general
population using different study designs and in different primary care databases, and to
compare the results to evaluate the impact of design and population differences on the
outcome of the study association.
Acute liver injury or hepatotoxicity in this study implies chemical, drug driven liver
damage which can be classified based on clinical presentation and laboratory features
ranging from asymptomatic mild biochemical abnormalities to acute liver failure. The most
common classification used for drug induced liver injury (DILI) is according to laboratory
abnormalities (hepatocellular, cholestatic or mixed) and according to mechanism of toxicity
(direct, immune-mediated, idiosyncratic, or mitochondrial toxicity). Being idiosyncratic in
most cases, reactions often cannot be reproduced experimentally in laboratory animals. The
relationship between the dose and the occurrence or severity of the reaction is not
constant, and the latent period between drug exposure and sensitivity reaction is rather
variable. The infrequency of DILI, though with significant impact, and complicated case
ascertainment in pharmacoepidemiological studies has led to wide ranges of reported
incidence rates. A recent study, using data from the GPRD database, reported crude incidence
rates of liver injury caused by any type of drug ranging from 1 to 18 per 100,000
prescriptions. The Drug-Induced Liver Injury Network (DILIN), a US based collaboration
between academic and health institutions to study the aetiology and prevention of DILI,
found antibiotics to be the largest class of agents to cause drug-induced liver injury. UK
based estimates of incidence rates of antibiotic induced liver injury range from 2.5 to 8.6
per 100,000 users.
Antibiotics are a type of antimicrobial used to treat infections and are amongst the twenty
most prescribed drugs in England, with approximately 38.7 million prescriptions dispensed in
2009. The most frequently prescribed type of antibiotics is penicillins, a group of
bactericidal antibiotics that interfere with bacterial cell wall synthesis. Other
bactericidal antibiotics include cephalosporins and aminoglycosides. Antibiotics with
bacteriostatic mechanisms of action, inhibiting the growth or proliferation of bacterial
cells, include tetracyclines, macrolides, sulphonamides and quinolones. Most types of
antibiotics have been associated with drug-induced liver injury.
Liver injury accounts for 10% of all adverse reactions to drugs and is the most frequent
reason for withdrawal of medications from the market. This study would provide a valuable
contribution to our current knowledge as drug induced liver injury is the most common cause
of acute liver failure and antibiotics are the largest drug class of agents, with the
highest exposure prevalence, to cause acute liver injury.
;
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