Novel classes of antibiotics or more of the same?

Abstract

The world is running out of antibiotics. Between 1940 and 1962, more than 20 new classes of antibiotics were marketed. Since then, only two new classes have reached the market. Analogue development kept pace with the emergence of resistant bacteria until 10-20 years ago. Now, not enough analogues are reaching the market to stem the tide of antibiotic resistance, particularly among gram-negative bacteria. This review examines the existing systemic antibiotic pipeline in the public domain, and reveals that 27 compounds are in clinical development, of which two are new classes, both of which are in Phase I clinical trials. In view of the high attrition rate of drugs in early clinical development, particularly new classes and the current regulatory hurdles, it does not seem likely that new classes will be marketed soon. This paper suggests that, if the world is to return to a situation in which there are enough antibiotics to cope with the inevitable ongoing emergence of bacterial resistance, we need to recreate the prolific antibiotic discovery period between 1940 and 1962, which produced 20 classes that served the world well for 60 years. If another 20 classes and their analogues, particularly targeting gram-negatives could be produced soon, they might last us for the next 60 years. How can this be achieved? Only a huge effort by governments in the form of finance, legislation and providing industry with real incentives will reverse this. Industry needs to re-enter the market on a much larger scale, and academia should rebuild its antibiotic discovery infrastructure to support this effort. The alternative is Medicine without effective antibiotics.

Figure 1

The number of new classes of antibiotics which have reached the market, and predictions of novel classes of antibiotics which are needed during the next 100 years.

Figure 2

The number of systemic compounds and classes in development and predictions of the number which will reach the market. Based on estimates of drugs in development which are published in the public domain. New classes are in brackets. *Assumptions: percent of compounds which reach the market (CMR International 2009) – 6.25% in Phase I, 25% in Phase II, 50% in Phase III and 75% in Pre-registration. Phase II includes drugs which are in Phase I/II, II ready, II and IIa. Phase III includes drugs in II/III, III ready and III. Market predictions are shown with – which indicates a range of years due to current uncertainty of the length of time – which is required to complete Phase III trials, for example for hospital-acquired pneumonia/ventilator-associated pneumonia.