Review
Alternatives to antibiotics—a pipeline portfolio review

https://doi.org/10.1016/S1473-3099(15)00466-1Get rights and content

Summary

Antibiotics have saved countless lives and enabled the development of modern medicine over the past 70 years. However, it is clear that the success of antibiotics might only have been temporary and we now expect a long-term and perhaps never-ending challenge to find new therapies to combat antibiotic-resistant bacteria. A broader approach to address bacterial infection is needed. In this Review, we discuss alternatives to antibiotics, which we defined as non-compound approaches (products other than classic antibacterial agents) that target bacteria or any approaches that target the host. The most advanced approaches are antibodies, probiotics, and vaccines in phase 2 and phase 3 trials. This first wave of alternatives to antibiotics will probably best serve as adjunctive or preventive therapies, which suggests that conventional antibiotics are still needed. Funding of more than £1·5 billion is needed over 10 years to test and develop these alternatives to antibiotics. Investment needs to be partnered with translational expertise and targeted to support the validation of these approaches in phase 2 trials, which would be a catalyst for active engagement and investment by the pharmaceutical and biotechnology industry. Only a sustained, concerted, and coordinated international effort will provide the solutions needed for the future.

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

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

References (142)

  • DJ Payne et al.

    Drugs for bad bugs: confronting the challenges of antibacterial discovery

    Nat Rev Drug Discov

    (2007)
  • R Tommasi et al.

    ESKAPEing the labyrinth of antibacterial discovery

    Nat Rev Drug Discov

    (2015)
  • EE Gill et al.

    Antibiotic adjuvants: diverse strategies for controlling drug-resistant pathogens

    Chem Biol Drug Des

    (2015)
  • S Palliyil et al.

    High-sensitivity monoclonal antibodies specific for homoserine lactones protect mice from lethal Pseudomonas aeruginosa infections

    Appl Environ Microbiol

    (2014)
  • M Starkey et al.

    Identification of anti-virulence compounds that disrupt quorum-sensing regulated acute and persistent pathogenicity

    PLoS Pathog

    (2014)
  • L Hua et al.

    Assessment of an anti-alpha-toxin monoclonal antibody for prevention and treatment of Staphylococcus aureus-induced pneumonia

    Antimicrob Agents Chemother

    (2014)
  • Q Lu et al.

    Pharmacokinetics and safety of panobacumab: specific adjunctive immunotherapy in critical patients with nosocomial Pseudomonas aeruginosa O11 pneumonia

    J Antimicrob Chemother

    (2011)
  • T Secher et al.

    The anti-Pseudomonas aeruginosa antibody panobacumab is efficacious on acute pneumonia in neutropenic mice and has additive effects with meropenem

    PLoS One

    (2013)
  • A DiGiandomenico et al.

    A multifunctional bispecific antibody protects against Pseudomonas aeruginosa

    Sci Transl Med

    (2014)
  • V Szijártó et al.

    Bactericidal monoclonal antibodies specific to the lipopolysaccharide O antigen from multidrug-resistant Escherichia coli clone ST131-O25b:H4 elicit protection in mice

    Antimicrob Agents Chemother

    (2015)
  • Guidelines for the evaluation of probiotics in food. Report of a Joint FAO/WHO working group on drafting guidelines for the evaluation of probiotics in food. April 30–May 1, 2002

  • J Villena et al.

    Modulation of intestinal TLR4-inflammatory signaling pathways by probiotic microorganisms: lessons learned from Lactobacillus jensenii TL2937

    Front Immunol

    (2014)
  • JZ Goldenberg et al.

    Probiotics for the prevention of Clostridium difficile associated diarrhea in adults and children

    Cochrane Database Syst Rev

    (2013)
  • L Bo et al.

    Probiotics for preventing ventilator-associated pneumonia

    Cochrane Database Syst Rev

    (2014)
  • R Schuch et al.

    Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia

    J Infect Dis

    (2014)
  • H Yang et al.

    Engineered bacteriophage lysins as novel anti-infectives

    Front Microbiol

    (2014)
  • Y Briers et al.

    Engineered endolysin-based “artilysins” to combat multidrug-resistant gram-negative pathogens

    MBio

    (2014)
  • MJ Lai et al.

    Antibacterial activity of Acinetobacter baumannii phage AB2 endolysin (LysAB2) against both gram-positive and gram-negative bacteria

    Appl Microbiol Biotechnol

    (2011)
  • M Pastagia et al.

    Lysins: the arrival of pathogen-directed anti-infectives

    J Med Microbiol

    (2013)
  • R Lood et al.

    Novel phage lysin capable of killing the multidrug resistant Gram-negative bacterium Acinetobacter baumannii in a mouse bacteremia model

    Antimicrob Agents Chemother

    (2015)
  • R Schuch et al.

    Combination therapy with lysin CF-301 and antibiotic is superior to antibiotic alone for treating methicillin-resistant Staphylococcus aureus-induced murine bacteremia

    J Infect Dis

    (2014)
  • SY Jun et al.

    Preclinical safety evaluation of intravenously administered SAL200 containing the recombinant phage endolysin SAL-1 as a pharmaceutical ingredient

    Antimicrob Agents Chemother

    (2014)
  • ST Abedon et al.

    Phage treatment of human infections

    Bacteriophage

    (2011)
  • HW Smith et al.

    Successful treatment of experimental Escherichia coli infections in mice using phage: its general superiority over antibiotics

    J Gen Microbiol

    (1982)
  • HW Smith et al.

    Effectiveness of phages in treating experimental Escherichia coli diarrhoea in calves, piglets and lambs

    J Gen Microbiol

    (1983)
  • AD Morgan et al.

    Effects of antagonistic coevolution on parasite-mediated host coexistence

    J Evol Biol

    (2009)
  • A Wright et al.

    A controlled clinical trial of a therapeutic bacteriophage preparation in chronic otitis due to antibiotic-resistant Pseudomonas aeruginosa; a preliminary report of efficacy

    Clin Otolaryngol

    (2009)
  • H Fairhead

    SASP gene delivery: a novel antibacterial approach

    Drug News Perspect

    (2009)
  • Cass J, Cullen S, Castillo AL, Wilkinson A, Fairhead H. SASPject: a novel antibacterial technology targeting MDR...
  • Cass J, Castillo AL, Cullen S, et al. SASPject: Microbiological characterisation of a novel therapeutic targeting MDR...
  • TK Lu et al.

    Dispersing biofilms with engineered enzymatic bacteriophage

    Proc Natl Acad Sci USA

    (2007)
  • REW Hancock et al.

    Modulating immunity as a therapy for bacterial infections

    Nat Rev Microbiol

    (2012)
  • R Raqib et al.

    Improved outcome in shigellosis associated with butyrate induction of an endogenous peptide antibiotic

    Proc Natl Acad Sci USA

    (2006)
  • P Sarker et al.

    Ciprofloxacin affects host cells by suppressing expression of the endogenous antimicrobial peptides cathelicidins and beta-defensin-3 in colon epithelia

    Antibiotics

    (2014)
  • P Bergman et al.

    Vitamin D3 supplementation in patients with frequent respiratory tract infections: a randomised and double-blind intervention study

    BMJ Open

    (2012)
  • A Mily et al.

    Oral intake of phenylbutyrate with or without vitamin D3 upregulates the cathelicidin LL-37 in human macrophages: a dose finding study for treatment of tuberculosis

    BMC Pulm Med

    (2013)
  • Cited by (0)

    View full text