Upsala journal of medical sciences
-
Antibiotic resistance is becoming an increasing threat, with too few novel antibiotics coming to market to replace those lost due to resistance development. Efforts by the pharmaceutical industry to screen for and design novel antibacterials have not been successful, with several companies minimizing or closing down their antibacterial research units, leading to a loss of skills and know-how. At the same time, antibiotic innovation in academia is not filling the void due to misaligned incentive structures and lack of vital knowledge of drug discovery. ⋯ Part of the problem has been a paradigm shift within both industry and academia to focus on 'rational' drug development with an emphasis on single targets and high-throughput screening of large chemical libraries, which may not be suited to target bacteria. The very particular aspects of 'targeting an organism inside another organism' have not been given enough attention. In this paper, researcher interviews have complemented literature studies to delve deeper into the specifics of the different scientific and structural barriers, and some potential solutions are offered.
-
The increase in antibiotic resistance and the dearth of novel antibiotics have become a growing concern among policy-makers. A combination of financial, scientific, and regulatory challenges poses barriers to antibiotic innovation. However, each of these three challenges provides an opportunity to develop pathways for new business models to bring novel antibiotics to market. ⋯ Instead regulatory agencies could encourage development of companion diagnostics, test antibiotic combinations in parallel, and pool and make transparent clinical trial data to lower R&D costs. A tax on non-human use of antibiotics might also create a disincentive for non-therapeutic use of these drugs. Finally, the new business model for antibiotic innovation should apply the 3Rs strategy for encouraging collaborative approaches to R&D in innovating novel antibiotics: sharing resources, risks, and rewards.
-
The rise of antibiotic-resistant bacterial strains, causing intractable infections, has resulted in an increased interest in phage therapy. Phage therapy preceded antibiotic treatment against bacterial infections and involves the use of bacteriophages, bacterial viruses, to fight bacteria. Virulent phages are abundant and have proven to be very effective in vitro, where they in most cases lyse any bacteria within the hour. ⋯ Phages are effective only if enough of them can reach the bacteria and increase in number in situ. Taken together, this entails high demands on resources for the construction of phage libraries and the testing of individual phages. The effectiveness and host range must be characterized, and immunological risks must be assessed for every single phage.
-
The emergence and spread of antibiotic resistance among human pathogens is a relevant problem for human health and one of the few evolution processes amenable to experimental studies. In the present review, we discuss some basic aspects of antibiotic resistance, including mechanisms of resistance, origin of resistance genes, and bottlenecks that modulate the acquisition and spread of antibiotic resistance among human pathogens. ⋯ Because of this, we propose that the emergence and spread of antibiotic resistance can only be understood in a multi-parameter space. Measuring the effect on antibiotic resistance of parameters such as contact rates, transfer rates, integration rates, replication rates, diversification rates, and selection rates, for different genes and organisms, growing under different conditions in distinct ecosystems, will allow for a better prediction of antibiotic resistance and possibilities of focused interventions.
-
Human use of antibiotics has driven the selective enrichment of pathogenic bacteria resistant to clinically used drugs. Traditionally, the selection of resistance has been considered to occur mainly at high, therapeutic levels of antibiotics, but we are now beginning to understand better the importance of selection of resistance at low levels of antibiotics. The concentration of an antibiotic varies in different body compartments during treatment, and low concentrations of antibiotics are found in sewage water, soils, and many water environments due to natural production and contamination from human activities. ⋯ Recent studies have shown that resistant bacteria can be selected at concentrations several hundred-fold below the lethal concentrations for susceptible cells. Resistant mutants selected at low antibiotic concentrations are generally more fit than those selected at high concentrations but can still be highly resistant. The characteristics of selection at low antibiotic concentrations, the potential clinical problems of this mode of selection, and potential solutions will be discussed.