Focussing on resistance to front-line drugs is the most effective way to combat the antimicrobial resistance crisis

Abstract

In medical, scientific and political arenas relating to antimicrobial resistance (AMR) 20there is currently an intense focus on multi-drug resistant pathogens that render last-21 line antimicrobial treatments ineffective [1][2][3] . We question the current emphasis of 22 attention on resistance to last-line antimicrobials, arguing that tackling resistance to 23 front-line antimicrobials has a greater public health benefit. Using AMR monitoring 24 data on 25 drug-pathogen combinations from across Europe 4 , here we show that the 25 presence of front-line pathogen resistance initiates a cascade of resistance selection that 26 ultimately leads to pathogen resistance to last-line antimicrobials. We then interrogate, 27 by modelling the dynamics of resistance evolution, whether 3 key interventions in the 28 strategic response to AMR are more effectively targeted at front-line or last-line 29 treatment. We show that interventions that make front-line therapy more effective by 30 use of antimicrobial adjuvants or front-line resistance diagnostics or by introduction of 31 a novel, front-line antimicrobial all lead to a larger reduction in mortality and 32 morbidity than the same interventions implemented in last-line therapy. Mass use of a 33 newly discovered antimicrobial in front-line infection management to maximise its 34 public health benefit is contrary to current policy 5 but may provide valuable incentives 35 for drug developers. We demonstrate that funding, publications, and attention to those 36 publications do not reflect the importance of front-line antimicrobials and are 37 disproportionately devoted to last-line antimicrobials that account for less than 10% of 38 antimicrobial prescriptions 6,7,8 . While studying resistance to last-line drugs is 39 undoubtedly important, our work relays a strong message to public health agencies, 40 funding bodies, and researchers that allocating resources to front-line infections can be 41 a more effective way to combat the antimicrobial resistance crisis. 42 43 Antimicrobial resistance (AMR) is predicted over time to significantly increase rates of 44 morbidity, mortality, and healthcare expenditure, as well as adversely affect medical 45 advances in all clinical specialties 9 . The medical and scientific communities have reacted 46 with a broad multi-disciplinary approach including antimicrobial stewardship programmes 10 , 47 AMR diagnostic development 11,12 , microbiology of resistance 13,14 and development of 48 antimicrobial adjuvants and alternatives to antimicrobials 15 . Multi-faceted attempts are being 49 made to incentivise and promote new antimicrobial drug development 16,17 . However, the vast 50 scale of investment required to combat the antimicrobial resistance crisis was recently 51 estimated to be somewhere between the Large Hadron Collider project (£6 billion) and the 52 International Space Station ($96 billion) 18 . 53 54In this context of limited resources interventions must be targeted to maximise reductions in 55 morbidity and mortality, which is the...

Exploring the Pharmacokinetics of Phenoxymethylpenicillin (Penicillin-V) in Adults: A Healthy Volunteer Study

“…Concern surrounding antimicrobial resistance means that there is an urgent need to prolong and maximize the effectiveness of current front-line, Access-classified antimicrobials [ 10 ]. An important and often neglected aspect of antimicrobial optimization is ensuring that an appropriate dose is delivered for each individual patient.…”

“…With the rise in antimicrobial resistance and its threat to human health, there is a need to optimize the use of narrow-spectrum, front-line antimicrobials to prolong their efficacy, reduce collateral impact, and safeguard broader-spectrum agents [ 10 ]. This has been reflected by the World Health Organization’s Access, Watch, and Reserve (AwARe) index, which classifies penicillin-V within its Access group [ 11 ].…”

Long-Term Temporal Stability of the Resistome in Sewage from Copenhagen

“…Sewage-based AMR data therefore represent a different measure of AMR obtained using a different sampling frame and is, as such, complementary to the current surveillance based on clinical isolates. The surveillance of larger healthy populations and including surveillance of the most common genes might also have some benefits, since it was recently suggested that resistance to front-line drugs is more important than resistance to last-resort antimicrobials ( 7 ).…”

Longitudinal effects of antibiotics and fecal transplant on lemur gut microbiota structure, associations, and resistomes

“…Here, we find that lemurs are not exempt from these phenomena and, for captive animals especially, ABR could pose a severe threat to animal health 88,89 . Methods to mitigate the development and spread of ABR among animal populations, including perhaps via fecal transfaunation, may prove to be a critical facet of combatting the resistance crisis 86,90 .…”