Can We Track Antimicrobial Resistance Using Pharmacovigilance Intelligence? Habarugira, JMV; Figueras, AS
Can we track Antimicrobial Resistance using Pharmacovigilance intelligence? Habarugira, JMV; Figueras, AS
ICREID 2019, Addis Ababa, 14 March 2019 Disclosure
• Employee of the European and Developing Countries Clinical Trials Partnership (EDCTP), The Netherlands • Researcher at the Autonomous University of Barcelona, Spain Outline • Rationale &Objectives • Methodology • Findings • Results exploitation and further plans • Conclusion Rationale & Objectives
• Pharmacovigilance (PV) experts argue that antimicrobial resistance (AMR) is an overlooked adverse event which should be reported as part of events around drug ineffectiveness (Uppsala Report No.74, Jan 2017)
Overall Objective • To investigate the potential role of Adverse Drug Reactions (ADRs) reporting tools in the track of Antimicrobial Resistance (AMR) cases
Specific objectives ▪ Are Pharmacovigilance databases using terms specific to resistance? ▪ Can existing reporting codes be repurposed for AMR monitoring? Methodology
Defining the Drugs of interest • The AWaRe list
Finding the ADRs of interest
•a VigiBase search for “drug-event” pairs was conducted, targeting reports of any adverse drug reaction or “event” referring to, or suggesting pathogen resistance after administration of an antimicrobial (drug)”.
Linking the reporting Terms to existing codes • Terms used to report resistance-related ADRs were reviewed and matched with coded terms in the MedDRA dictionary (version 21.1).
Inventory of Key AMR-relevant PTs with MedDRA codes The AWaRe (Access, Watch, Reserve) List Access Watch Reserve • Amoxicillin • Anti-pseudomonal penicillins with beta- • Amoxicillin and clavulanic acid lactamase inhibitor (eg. piperacillin and • Aztreonam • Ampicillin tazobactam) • Cephalosporins, 4th • Benzathine benzylpenicillin • Carbapenems or penems (eg. generation (eg. • Benzylpenicillin faropenem, imipenem and cilastatin, cefepime) • Cefalexin or cefazolin meropenem) • Cephalosporins, fifth • Chloramphenicol • Cephalosporins, third generation (with generation (eg. • Clindamycin or without beta-lactamase inhibitor; eg. ceftaroline) • Cloxacillin cefixime, cefotaxime, ceftazidime, • Doxycyline ceftriaxone) • Daptomycin • Gentamicin or amikacin • Glycopeptides (eg. teicoplanin, • Metronidazole vancomycin) • Fosfomycin (intravenous) • Nitrofurantoin • Macrolides (eg. azithromycin, • Oxazolidinones (eg. • Phenoxymethylpenicillin clarithromycin, erythromycin) linezolid) • Procaine benzylpenicillin • Quinolones and fluoroquinolones (eg. • Polymyxins (eg. colistin, • Spectinomycin ciprofloxacin, levofloxacin, moxifloxacin, polymyxin B) • Sulfamethoxazole and trimethoprim norfloxacin) • Azithromycin • Tigecycline • Cefixime • Cefotaxime • Ceftriaxone Classified in • Ciprofloxacin • Clarithromycin Access and • Piperacillin and tazobactam Watch • Meropenem • Vancomycin Data Source and Collection Vigibase
VigiBase contains over 10 million adverse drug reactions (ADRs) reports from 134 countries participating in the WHO Programme for International Drug Monitoring MedDRA structure From System Organ Classes (SOCs) to Preferred Terms (PTs) Findings 17 Preferred Terms (PTs) identified Findings PTs linked with corresponding MedDRA codes Findings
AWaRe classification Access Access and Watch Watch Reserve Sample antimicrobials Amoxicillin Cefalotin Ciprofloxacin Clarithromycin levofloxacin Daptomycin
Number of ADRs in VigiBase 102794 2550 88748 40246 77330 5706 Pathogen resistance 153 143 140 115 116 82 Drug Ineffective 588 2 791 538 621 167 Treatment Failure 25 49 26 39 99 Drug resistance 12 1 112 41 89 95 Drug effect decreased 10 32 10 33 3 Drug effect incomplete 9 12 6 10 3 Off label use 52 204 49 126 102 Decreased activity 4 40 57 Drug ineffective for unapproved 3 29 4 61 indication Therapeutic product ineffective 1 3 1 3 Product use in unapproved 16 44 11 35 43 indication Therapeutic response decreased 2 63 53 46 5 Medication error 119 94 20 Drug prescribing error 3 40 33 49 Multiple-drug resistance 17 Therapy non-responder 53 10 96 21 Contraindicated product 22 administered Signals on AMR-related ADRs 6 drugs, 17 PTs
Amoxicillin, cefalotin, ciprofloxacin, clarithromycin, levofloxacin, Daptomycin
Pathogen resistance Drug Ineffective Treatment Failure Drug resistance Drug effect decreased Drug effect incomplete Off label use Decreased activity Drug ineffective for unapproved indication Therapeutic product ineffective Product use in unapproved indication Therapeutic response decreased Medication error Drug prescribing error Multiple-drug resistance Therapy non-responder Contraindicated product administered non-AMR related Signals on AMR-related ADRs A close look at Amoxicillin
amoxicillin Pathogen resistance Drug Ineffective Treatment Failure Drug resistance Drug effect decreased Drug effect incomplete Off label use Decreased activity Drug ineffective for unapproved indication Therapeutic product ineffective Product use in unapproved indication Therapeutic response decreased Medication error Drug prescribing error Multiple-drug resistance Therapy non-responder Contraindicated product administered Signals for key ADRs for 6 antimicrobials Example – proportion “off label use” of Daptomycin A relatively new drug on the “Reserve” list, low proportion of total ADRs (yearly average) but high proportion of “off-label” and “pathogen resistance” cases
Off label
Drug Ineffective
Pathogen resistance
ADRs
0% 20% 40% 60% 80% 100% Yearly Average amoxicillin cefalotin ciprofloxacin clarithromycin levofloxacin Daptomycin Findings Underreporting from the African region
Geographical distribution, % of ADRs per continent
120
100
80
60
40
20
0
Africa Americas Asia Europe Oceania Findings Or more raised questions • What is the impact of Public Health Emergencies (PHEs) on the rational use of Reserve antimicrobials? • Ebola as an ADR following cefixime administration or cefixime administered in Ebola units?
• Drug=cefixime • ADRs n=8796 • Infections and Infestations n= 930 • 1 of 930 recorded as “Ebola Disease” Results exploitation and further plans Building and Piloting the “AMR Tracker” (App OR Site?)
Pharmacy, hospital, Pharmacovigilance community dispensing center center Conclusions
• Yes we can use PV intelligence to track AMR • Improving online-based or App-based ADRs reporting tools • Tackling under reporting in general • In particular -Targeting antimicrobials for: – specific signals of resistance or – possible triggers of resistance – collecting geo-tagged real-time data Thank you