We are running out of antibiotics. One reason for why antibiotic resistant bacteria are attracting so much attention right now is that we have reached a point where there are hardly any treatment alternatives left for some bacterial infections.
Resistant infections occurred also in the early days of antibiotic use, but a steady flow of new antibiotics provided alternative treatments. It was possible to simply switch treatment once resistance against a specific antibiotic became a major problem. But then the antibiotics stopped coming. The latest discovery of a new antibiotic class that has reached the market was back in 1987. Since then there has been a lack of innovation in the field, and today there are few novel antibiotic classes in the drug pipeline. The consequences are seen worldwide as more and more bacterial infections are becoming hard to treat once again. Especially worrisome is the lack of antibiotics against Gram-negative bacteria. Figure 1 shows when the different major antibiotic classes were discovered.
Why so few antibiotics in development?
Here are some of the reasons:
- Scientific difficulties: It is extremely difficult to develop an antibiotic drug. First, it needs to get to the right place in the body at a high enough concentration without being toxic to the patient. Then, it also has to enter and stay in the bacterial cell, which has proven very problematic. Efforts to screen large existing libraries of small molecules have failed to find new antibiotics.
- Financial and regulatory hurdles: It is very expensive and often takes ten years or more to develop an antibiotic. Each new formulation needs to go through rigorous testing for activity and patient safety, and only a minority will actually make it through the whole drug-development process. Resistance development can be fast and may hamper usability, which could result in low profits for the developing company. In addition, novel antibiotics would have to be used sparingly to avoid resistance development. Companies have pointed out regulatory requirements to be unclear, which have led to uncertainty of the likelihood of approval of new drugs
- Lack of know-how: Poor financial incentives in combination with the technical difficulty to develop new antibiotics have made many pharmaceutical companies scale-down or abandon their antibiotic development programs. This has resulted in a loss of skills and specialized personnel in the field.
Antibacterial agents in clinical development – an analysis of the antibacterial clinical development pipeline, including Mycobacterium tuberculosis
This 2017 report from the World Health Organization (WHO) shows a serious lack of new antibiotics under development. The analysis identifies 51 new antibiotics and biologicals in clinical development to treat priority antibiotic-resistant pathogens (as defined by WHO), tuberculosis and Clostridium difficile. Only eight of these drug candidates are classified as truly innovative, highlighting the difficulties in research and development of new antibiotics. Considering a success rate of 14% from phase I trials to approval, only ten of the substances can be expected to reach the market within 10 years. One or two of these are potentially active against Gram-negative pathogens.
The antibiotic resistance problem can not be solved, only managed
In the long run, we need to find alternative ways to prevent and treat bacterial infections and not rely solely on antibiotics. However, we will still need antibiotics in the short- to medium-term time frame. It is, therefore important to learn from past mistakes to preserve any new antibiotic that reaches the market and to maintain and possibly enhance what power is left in the old ones. It is important to understand that the problem of antibiotic resistance cannot be “solved” by the discovery of one or a few new antibiotics. Antibiotic resistance will eventually develop to any antibiotic, but prudent use will slow the process. That is, if a new antibiotic reaches the market, it should be used responsibly, or it will soon be ineffective due to bacterial resistance development. This means that another model than high-volume sales must be found for regaining development costs and making profits for pharmaceutical companies. This process of separating sales volumes from profit is commonly referred to as “delinkage” . Also, different bacterial diseases require different antibiotics. Thus, there needs to be a continuous supply of new antibiotics and a continuous needs analysis by the public health sector.
Innovation in the antibiotic area is slowly increasing again. Funding specifically aimed at antibiotic development and disease diagnostics tools have increased. Collaborations between universities and pharmaceutical companies have been initiated to find new antibiotics and diagnostics (for example New Drugs 4 Bad Bugs: ENABLE and CARB-X). Even competitions have been launched to speed up the process (see for example the Longitude prize and the Antimicrobial Resistance Diagnostic Challenge). Alternative methods to treat bacterial infections, like using bacteriophages (viruses that kill bacteria) or antimicrobial peptides, are also explored. Although these approaches are important, they have this far not been successfully transformed into medical products. There are also limitations to their use. Still, they could be a welcome complement to antibiotics. Researchers are also looking into reviving older antibiotics that are not used for different reasons.
In order to reach sustainable solutions regarding use and supply of antibiotics there is a need for innovative thinking as well as new economic models. Antibiotic use should be restricted, but at the same time those in need of treatment have to get it – all across the world. Furthermore, those developing antibiotics need to recuperate their costs. It is not a simple task to combine these different needs into a sustainable antibiotic discovery and development process, but it needs to be done. Novel initiatives to develop new economic models where for example the economic risks, as well as profits for developing an antibiotic are shared between different stakeholders are under way. Ideas have also been put forth for public financing strategies.
New antibiotics from soil bacteria
Many of the antibiotics we use today were originally found as natural products in soil microbes. However, most microbes from the external environment are difficult to grow in a laboratory. A new method to grow bacteria from soil has allowed a group of scientists to grow 50% of the bacteria in soil samples as compared to 1% before. A promising new antibiotic compound targeting Gram-positive bacteria (like MRSA) was then discovered in a soil-bacterium isolated by this method. The antibiotic was named teixobactin and interferes with two distinct steps in the cell-wall assembly of the targeted bacteria. The new bacterial isolation-method and other similar approaches re-open the possibility for antibiotic discovery in environmental bacteria. It will be interesting to see if these efforts transforms into useful drugs in the future.
|Antibacterial products in clinical and preclinical development: an overview and analysis||Report. A WHO pipeline analysis of antibacterial products targeting the priority pathogens list, Mycobacterium tuberculosis and Clostridium difficile. Includes an assessment of innovativeness. See also the WHO Global Observatory on Health R&D Data and visualizations for the clinical pipeline and preclinical pipeline.|
|Antibiotics Currently in Global Clinical Development||Document. A pipeline analysis of antibiotics in clinical trials by The Pew Charitable Trusts, provided as a structured list and periodically updated. The data includes systemic antibiotics and drugs for Clostridium difficile.|
|Global priority list of antibiotic-resistant bacteria to guide research, discovery, and development of new antibiotics||Document. WHO priority pathogens list is the first global effort to guide and promote research and development of new antibiotics. The list comprises 12 bacterial pathogens placed in three priority categories: critical, high and medium (7 pages).|
|Global AMR R&D Hub’s Dynamic Dashboard||Database with information on AMR research and development (R&D) investments, antibacterials in the pipeline and R&D incentives. Note that the information on the investments dashboard does not include data from the pharmaceutical industry.|
|REVIVE Antimicrobial Encyclopaedia||Online encyclopaedia from GARDP. Defines and explains a broad set of terms relating to antibiotics and antibiotic resistance. Focuses particularly on words that are linked to research and development.|
|From Lab Bench to Bedside: A Backgrounder on Drug Development||Article that gives a simple and brief introduction to the drug-development process.|
|What is a clinial trial?||Fact sheet. Overview and facts about clinical trials.|
|Why can’t we find new antibiotics?||Video explaining antibiotic discovery and problems related to developing new drugs (2:43 min). Need to click “browse free” for limited access to a few articles.|