Despite the fact that the spread of antibiotic-resistant bacteria poses a substantial threat to morbidity and mortality worldwide, pharmaceutical research and development has failed to meet the clinical need for new antibiotics.1, 2 In particular, the need for investments in research and development of new anti-tuberculosis drugs has been highlighted by WHO for several years3 with dedicated and prioritised programmes.4, 5 As for other antibiotic-resistant bacteria, in the past 20 years, only two new antibiotic classes (lipopeptides and oxazolidinones) have been developed and approved by international drug agencies (US Food and Drug Administration and European Medicines Agency)—both of which provide coverage against Gram-positive bacteria.6 The quinolones, discovered in 1962, was the last novel drug class identified to be active against Gram-negative bacteria. Of the 44 new antibiotics in the pipeline for clinical intravenous use, only 15 show some activity against Gram-negative bacteria and only five (all modified agents of known antibiotic classes) have progressed to phase 3 testing.7
The decreased interest in antibiotic research and development of pharmaceutical companies in the past few decades is probably related to difficulties in clinical development and scientific, regulatory, and economic issues. The discovery of new antibiotic classes that are highly active, have acceptable pharmacokinetic properties, and are reasonably safe is complex. Clinical antibiotic trials evaluating the efficacy of new antibiotics can be difficult and expensive, especially when targeting multidrug-resistant Gram-negative bacteria, because of the near absence of rapid diagnostic tests to facilitate patient recruitment, and Mycobacterium tuberculosis, because of the complex combination therapy and prolonged patients' follow-up. When widely used, modified agents of old drug classes might face the challenge of rapid development of antibiotic resistance, and could run the risk of co-selecting resistance through use of new molecules.8, 9
Research in context
Evidence before the study
We searched PubMed and Google scholar for publications from Jan 1, 1960, to July 1, 2017, that aimed to develop a priority list of human infectious diseases due to antibiotic-resistant bacteria, and reported the method and criteria used to determine priorities. The search terms included (“priority AND list AND infections” OR “priority list AND resistance” OR “research and development AND priority AND bacteria”) and (“antibiotic AND priority AND infections OR bacteria”). Reference lists of retrieved studies were also screened for relevant publications. No restriction on publication type or language was applied. Seven publications were reviewed; one report dealt with risk of spread of infectious diseases during mass gathering, and three considered antibiotic resistance an emerging issue, but the prioritisation of pathogens was assessed together for resistant and susceptible strains. In 2011, the Public Health Agency of Sweden prioritised pathogens according to national public health relevance; using a Delphi process, five experts scored the pathogens on ten variables. Two antibiotic-resistant bacteria were evaluated: meticillin-resistant Staphylococcus aureus and extended-spectrum β-lactamase-producing Enterobacteriaceae. Only two publications focused on antibiotic-resistant bacteria. To define the national need for monitoring and prevention activities, the 2013 priority list from the US Centers for Disease Control and Prevention prioritised antibiotic-resistant bacteria and drug-resistant Candida spp, according to expert opinion, into three levels of threat (urgent, serious, and concerning). In 2015, using multicriteria analysis and expert review, the Public Health Agency of Canada prioritised antibiotic-resistant bacteria to assess the magnitude of national antimicrobial resistance and the state of surveillance.
Added value of this study
All previous priority lists focused on single-country data, and none focused on research and development needs for new antibiotics. The WHO priority list is the first international, global effort to prioritise research and development of new antibiotics according to bacterial drug resistance. The list combines evidence in ten criteria and expert opinion via a multicriteria decision analysis method, and will be regularly updated.
Implications of the available evidence
We recommend pharmaceutical companies and research centres working on the research and development of new antibiotics include multidrug-resistant and extensively resistant Gram-negative bacteria and bacteria common in the community—eg, antibiotic-resistant Mycobacterium tuberculosis, Salmonella spp, Campylobacter spp, Neisseria gonorrhoeae, and Helicobacter pylori—in their long-term plans. The priority list is a new tool to be included in a global, multifaceted strategy to increase awareness of antibiotic resistance and favourably affect patient outcome.
The stimulation of antibiotic research and development has a pivotal role in the development of strategies to address the global threat of antibiotic-resistant bacteria.10, 11 In support of the Global Action Plan for Antimicrobial Resistance,12 WHO—in collaboration with the Drugs for Neglected Diseases initiative—launched the Global Antibiotic Research and Development Partnership to develop new antibiotic treatments addressing antimicrobial resistance, and to promote the responsible use of these treatments for optimal conservation.13 The US Biomedical Advanced Research and Development Authority's Broad Spectrum Antimicrobial and Combating Antibiotic Resistant Bacteria Biopharmaceutical Accelerator programmes (co-sponsored by the Wellcome Trust), and the Innovative Medicine Initiative's New Drugs for Bad Bugs programme are new models of collaboration between pharmaceutical companies and academia that promote innovation in the research and development of new antibiotics.14, 15, 16, 17 In parallel, regulatory agencies, such as the US Food and Drug Administration and the European Medicines Agency, are actively working on the simplification of the approval pathway for antibiotics for selected unmet medical needs.
In 2016, in the wake of the increasing global awareness of the need for new antibiotics, WHO's member states mandated that WHO create a priority list of antibiotic-resistant bacteria to direct research and development of new and effective drugs. The mandate also followed recommendations of the 2016 UN report of a high-level panel on the global response to health crises, which emphasised the threat posed to humanity from a number of under-researched antibiotic-resistant bacteria that urgently require enhanced and focused research and development investments.18 The major goal of the WHO priority list is to prioritise funding and facilitate global coordination of research and development strategies for the discovery of new active agents against bacteria with acquired resistance to antibiotics that are also responsible for acute infections and multidrug-resistant tuberculosis. The list is aimed at pharmaceutical companies likely to invest in the research and development of new antibiotics, and at universities, public research institutions, and public–private partnerships that are becoming increasingly involved in antibiotic research and development.
