Few antibiotics under development

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

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.

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 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.

Selected Resources