The Review benefited from expert summaries and non-confidential information on approaches and projects provided by its members and comprehensive scientific literature and database searching, which was used to identify approaches, projects, companies, and publications to inform the group. All projects in progress identified that were within scope were included in the portfolio review. Historic projects informed the review, but were not included in the portfolio analysis. Preclinical and clinical
ReviewAlternatives to antibiotics—a pipeline portfolio review
Introduction
Given the rise of antibacterial resistance and the challenges of conventional antibacterial agent discovery and development that have led to a very small pipeline of new therapies, it would be prudent to consider the potential of non-conventional approaches.1, 2 This Review—written by 24 scientists from academia and industry, commissioned by the Wellcome Trust, and jointly funded by the Department of Health (England)—considers the prospects for alternatives to antibiotics. Although there have been technical reviews of individual alternative approaches,3 this Review seeks to define the present state of alternatives to antibiotics at the portfolio level, prioritise approaches, and provide evidence-based expectations of their delivery to inform funding decisions and policy in this crucial area of health care.
Alternatives to antibiotics were defined by us as non-compound approaches (ie, products other than classic antibacterial agents) that target bacteria or approaches that target the host. Thus, an antibody targeting a virulence factor or quorum sensing would be included, but a compound targeting these processes would not.4, 5 Biological drugs or compounds targeting the host were included. This Review focuses on therapies that could be developed to treat systemic or invasive infections rather than superficial infections and is therefore restricted to therapies that are administered orally, by inhalation, or by injection. External topical administration is beyond the scope of this Review. The primary objective is to identify and review prospective therapeutic replacements for antibiotics. Alternatives that could be used in combination with conventional antibiotics and prophylactic approaches are also considered.
In this Review, we discuss feasibility of informative clinical trials, magnitude of medical potential, likelihood and consequences of resistance, level of current research activity, likely timeline to registration, and activities that might enable validation and progression. The review process involved the preparation of a 50-page document summarising 19 current alternatives to antibiotics within the scope of the review, a meeting to discuss and prioritise approaches, and collective preparation of a report for the funders, which is summarised in this Review. This process allowed us to compile and share broad and well informed views on the state of the art for alternatives to antibiotics with a wider community.
Section snippets
Portfolio of alternative approaches
We identified 19 alternatives-to-antibiotics approaches for consideration and recognised that the list might be incomplete (table 1 and panel). Projects were not reviewed in sufficient detail to make individual funding recommendations. Technical feasibility and clinical potential of the approaches were considered for all projects, but the commercial attractiveness, potential return on investment, or potential for reimbursement of specific projects were not analysed. Given the wide range of
Alternatives to antibiotics portfolio analysis
To enable an evidence-based review of the current state of development and likelihood of success of the prioritised alternative approaches, detailed internet searches and knowledge of the members of our group were used to define the breadth (number of projects and targets) and depth (phase of development) of the alternatives-to-antibiotics portfolio. Company websites and news releases were used to identify projects that were in progress as of January–March, 2015 (table 2). Because companies
What will the portfolio cost?
Named projects were budgeted to 2025 using industry standard costs for clinical development phases to estimate funding needs (table 2). Although some organisations might aim to deliver with smaller budgets, standard costs are based on real projects, are more suggestive of reality, and remove bias.
The funds for the current phase of the project are assumed to be in place and confirmed. The risk-adjusted funds needed for registration were calculated by addition of the cost of subsequent stages of
Challenges of development and use of alternatives to antibiotics
The innovators in this space (largely academics and biotechnology companies) often do not have industry-level development and clinical skills. Increased funding should, therefore, be partnered with investment in translational skills development. Alternatives-to-antibiotics programmes could benefit from greater access to expertise in pharmacokinetics and pharmacodynamics, formulation, toxicology, and manufacturing. Provision of adequate funding for multidisciplinary teams and costs associated
Future outlook
The objective of this Review was to find out which alternatives to antibiotics are most likely to deliver new therapies of clinical use. Our group found that academic researchers and the pharmaceutical industry have successfully generated a diverse portfolio of potential alternatives-to-antibiotics projects from preclinical optimisation to phase 3 studies and prioritised ten approaches for more detailed review. Results from studies of these approaches are still emerging and these approaches
Search strategy and selection criteria
References (142)
- et al.
Probiotics for infectious diseases: more drugs, less dietary supplementation
Int J Antimicrob Agents
(2012) - et al.
Phenylbutyrate induces cathelicidin expression via the vitamin D receptor: linkage to inflammatory and growth factor cytokines pathways
Mol Immunol
(2015) - et al.
Effect of pneumococcal Haemophilus influenzae protein D conjugate vaccine (PHiD-CV10) on outpatient antimicrobial purchases: a double-blind, cluster randomised phase 3–4 trial
Lancet Infect Dis
(2014) - et al.
Changes in Streptococcus pneumoniae serotypes causing invasive disease with non-universal vaccination coverage of the seven-valent conjugate vaccine
Clin Microbiol Infect
(2008) - et al.
Azithromycin synergizes with cationic antimicrobial peptides to exert bactericidal and therapeutic activity against highly multidrug-resistant gram-negative bacterial pathogens
EBioMedicine
(2015) - et al.
Bacterial biofilm development as a multicellular adaptation: antibiotic resistance and new therapeutic strategies
Curr Opin Microbiol
(2013) - et al.
Complexities of targeting innate immunity to treat infection
Trends Immunol
(2007) - et al.
Artificial activation of toxin-antitoxin systems as an antibacterial strategy
Trends Microbiol
(2012) - et al.
Simplified captopril analogues as NDM-1 inhibitors
Bioorg Med Chem Lett
(2014) - et al.
Efficacies of calcium-EDTA in combination with imipenem in a murine model of sepsis caused by Escherichia coli with NDM-1 β-lactamase
J Infect Chemother
(2013)