The study was conceived as an observational, retrospective analysis of spontaneous reporting systems (SRSs) combined with microbiological data on antibiotic resistance.
We used a descriptive approach based on unsolicited publicly accessible reports submitted to both international and national SRSs to extract pharmacovigilance data, whereas microbiological data were obtained using publicly available reports provided by the European Centre for Disease Prevention and Control (ECDC). This mixed approach combining two different real-world datasets would allow to (a) identify previously unknown safety issues, (b) provide a public health perspective to ADRs and (c) test the potential relationship between safety issues and antimicrobial resistance.
Three different SRSs (FDA Adverse Event Reporting System [FAERS] Database, AIFA Database and Yellow Card Scheme) were queried in order to retrieve reports of ADRs for newer and older agents used in KPC treatment, namely colistin, meropenem, tigecycline, gentamicin and ceftazidime/avibactam.
Although the consultation of national SRSs may be insufficient to detect rare events with respect to larger international database, especially in the post-marketing monitoring of newer antibiotics, their use allows to compare results among several countries . Furthermore, the use of national databases provides the actual local picture of the risk, closely associated with the real drug consumption, while avoiding a potential “dilution” phenomenon of reporting pattern that may occur in international databases analysis.
The three SRSs differ as regards data availability, catchment area and date of beginning of ADR collection.
The FAERS database collects worldwide adverse events (US and serious non-US reports) spontaneously submitted by drug companies, healthcare professionals and consumers , and offers public access to data from 1968 through the recent public dashboard. The Italian pharmacovigilance database is directly managed by AIFA and contains ADRs collected in Italy from 2002 . Finally, the Yellow Card Scheme is the UK system for collecting information on suspected ADRs to medicines and vaccines . It is maintained by the Medicines and Healthcare Products Regulatory Agency (MHRA) and offers public access to raw data starting from 1964.
Since 2009 the European Centre for Disease Prevention and Control (ECDC) provides annual surveillance reports on antimicrobial resistance, including KPC-Kp, for 30 European countries, including all 28 EU Member States in addition to Norway and Iceland. The results presented in ECDC reports are based on antimicrobial resistance data from invasive isolates (blood and cerebrospinal fluid) collected in European microbiology laboratories and reported to European Antimicrobial Resistance Surveillance Network . The inclusion of isolates obtained only from sterile sites allows to evaluate serious infections characterized by undisputable clinical relevance and requiring a given antibiotic treatment. In order to perform a comparison between countries with different prevalence of KPC isolates and to investigate ADR/resistance relationship, we considered data from Italy (high prevalence of KPC-Kp) and UK (low prevalence of KPC-kp). For both countries, the absolute number of KPC isolates and the proportion of these among the total Kp isolates per year were retrieved from 2009 to 2017.
First, a descriptive analysis including demographic data (age and sex), number of total and serious ADRs, overall number of drug-System Organ Class (SOC) pairs, frequencies of ADRs in terms of SOC and Preferred Term (PT) levels, and frequency of KPC isolates was performed. For every selected agent, serious ADRs were extracted from each SRS in terms of SOC and PT levels, as codified through the standardized Medical Dictionary for Regulatory Activities (MedDRA) terminology. A serious ADR was defined as “An adverse reaction which results in death, is life-threatening, requires in-patient hospitalization, or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly/birth defect” .
Second, a quantitative-qualitative comparison between the absolute number of total and serious ADRs per year for each selected drug reported from 2009 to 2018 (after KPC outbreak) with respect to the previous 10 years (from 1999 to 2008) was performed. Comparisons were calculated for each of the three different SRSs. Because Italian Medicines Agency (AIFA) Database collected ADRs only from 2002, the historical control was performed on the previous 7 years (from 2002 to 2008) instead of 10 years.
Tigecycline was approved by Food and Drug Administration (FDA) in 2005 and by European Medicines Agency (EMA) in 2006, so the comparison of ADRs pre-post KPC outbreak took into account 4 years (from 2005 to 2008) for FAERS, and 3 years (from 2006 to 2008) for AIFA Database and Yellow Card Scheme.
Qualitative evaluation compared ADR frequencies at SOC and PT levels between the different SRSs, in order to describe safety profile of newer and older agents used for KPC management.
Finally, the existence of a possible relationship between the number of KPC-Kp isolates and the total and serious number of ADR reports after KPC outbreak (from 2009 to 2017) was investigated (pharmacovigilance-microbiological approach). Analysis was performed for both Italy and UK, in order to compare European countries with opposite epidemiological situation in terms of microbiological resistance.
Continuous data were expressed as mean ± standard deviation (SD) and the Student’s t test was used for comparison. Categorical variables were expressed as count or percentages, and the Chi-square test or the Fisher’s exact test were used as appropriate.
In order to make a reliable comparison, we have normalized data calculating the mean number of reports per year for the different antibiotics in each SRS. In this way, we obtained data expressing an equal amount and directly comparable using the Student’s t test for unpaired data. Similar statistical analyses were performed in order to compare the tigecycline data.
The correlation between the absolute number of total and serious ADRs reports per year for selected agents (x-axis) and the absolute number of KPC isolates per year (y-axis) was assessed by a scatter plot for both Italy and UK. A regression line between the KPC and ADRs prevalence was drawn and the Pearson’s r value was calculated. A p value of < 0.05 was considered significant.