Few antibiotics under development

We are running out of antibiotics and have reached a point where there are very few, if any, treatment alternatives left for some bacterial infections. At the same time, there are very few antibiotics in the clinical pipeline.

In the early days of antibiotic use, resistant infections did occur, but a steady flow of new antibiotics provided alternative treatments. Once resistance to a specific antibiotic became a significant issue, it was possible to simply switch to other treatments. However, antibiotics stopped being developed. The most recent discovery of a new antibiotic class that reached the market was in 1987. Since then, innovation in the field has stagnated, with only a few novel antibiotic classes currently in the drug pipeline. TThe consequences are being felt worldwide, as an increasing number of bacterial infections are becoming difficult to treat once again. Of particular concern is the lack of antibiotics effective against Gram-negative bacteria. Figure 1 illustrates the discovery timeline of the major antibiotic classes.

Why so few antibiotics in development?

Here are some of the reasons:

• Scientific challenges: Developing an antibiotic is extremely difficult. First, the drug must reach the appropriate target in the body at a sufficiently high concentration without causing toxicity to the patient. Additionally, it must enter and remain inside the bacterial cell, a challenge that has proven to be particularly problematic. Efforts to screen large existing libraries of small molecules have yet to yield new antibiotics.
• Financial and regulatory hurdles: Developing an antibiotic is extremely costly and often takes ten years or more. Each new formulation must undergo rigorous testing for both activity and patient safety, and only a minority of candidates will successfully navigate the entire drug development process. The rapid development of resistance can undermine the effectiveness of new antibiotics, which may result in low profitability for the developing company. Furthermore, novel antibiotics would need to be used sparingly to minimize the risk of resistance development. Companies have also highlighted the unclear nature of regulatory requirements, creating uncertainty about the likelihood of approval for new drugs.
• Lack of know-how: The combination of poor financial incentives and the technical challenges associated with developing new antibiotics has led many pharmaceutical companies to scale down or abandon their antibiotic development initiatives. This has resulted in a loss of expertise and specialized personnel in the field.

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.

Existing initiatives

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 ENABLE-2 and CARB-X). Even competitions have been launched to speed up the process, see for example the Longitude prize. 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 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 the 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.

Selected Resources