TREATMENT IN A POST ANTIBIOTIC ERA
The best option is going to be improved biosecurity and disinfection
By this stage, everybody should be aware of the fact that times are changing with regards to the use of antibiotics in both the human and veterinary fields. Prof M. van Vuuren presented a talk at Avi Africa (2015) where he covered the current situation on antibiotics and the resistance to antibiotics in detail. As such, the current problems with the use of antibiotics will not be covered in this article.
The bottom line is that there are major problems with antibiotic resistance and there is growing pressure to reduce the use of antibiotics in animal production.
This research group decided a number of years ago to start research projects on possible disease control options in a post antibiotic era, so that when the crisis hits when antibiotics cannot be used in animal production, there will be well researched options available. A brief summary of some of the work which we, as the Veterinary Biotechnology Research Group at the University of the Free State have done in this regard, formed the basis of the presentation at Avi Africa 2015.
Novel antimicrobials and alternatives
This is an area where we are not currently very active in. However, there are various well-published research projects where researchers are searching for novel antimicrobials. One of these projects involves collection of microbes from the deep sea in the Norwegian fjords. Another is the detection of lantibiotics produced by soil microbes. There are a few fundamental problems with the search for novel antimicrobials. The first of these is that any such novel antimicrobials remain natural products and as such, the genetic mechanisms for pathogenic bacteria to develop resistance will probably exist. One just needs to look at the example of the development of quinolones. This was a breakthrough in the search for novel antimicrobials and once developed they showed unbelievable antimicrobial activity. The mode of action of quinolones was to prevent the DNA of bacteria from unwinding, which prevented the replication of the bacterium. This was not a chemical that the bacterium had been exposed to previously and did not have millions of years of evolution to develop resistance. Yet, in just three years, the bacteria had developed resistance! Another problem with the search for novel antimicrobials is that it takes, on average, 15 years to get a new product to the market. Currently, there are no new antimicrobials in the pipeline. Even if novel antimicrobials are discovered, the likelihood is that they will be reserved for human use and will not be made available for Veterinary use. So, novel antimicrobials will probably not be the solution to the dwindling availability of antibiotics for use in the poultry industry.
There are potential alternatives to antibiotics in the form of herbal products. A product, such as Mentofin, which is mainly marketed to alleviate vaccination reactions, has been shown to have good antimicrobial activities. This antimicrobial activity is not only against bacteria, but also viruses (J. Applied Microbiology, 115 (6) 1278 – 1286) and even coccidia (J. Applied Microbiology 118 (3) 583 – 591). This research group did some work on Mentofin for the control of Eschericia coli and it was found that it had a substantial effect on E. coli infection and significantly reduced clinical signs in experimentally infected chickens.
Improved bacterial vaccines are another possibility to control bacterial diseases in a post antibiotic era. However, the functioning of the immune system is vastly different when attacking bacteria or viruses. When an individual (human or animal) is vaccinated, the immune system will produce antibodies against the antigens in the vaccine. Many of the currently used vaccines are either live attenuated vaccines or inactivated vaccines. These are made using whole pathogens. If the individual has been vaccinated against a virus and the field virus enters the system, the antibodies will bind to the virus. This is normally sufficient to prevent the virus from binding to the host cell. If this happens, the virus has effectively been neutralised. Very high levels of protection are possible with viral vaccines. They generally work well. With bacterial vaccines, the antibodies that are produced bind to the bacterium. This alone is not sufficient to inactivate the bacterium. The bacterium is marked with the antibodies and is attacked by the compliment system, or phagocytic cells. This takes time and is generally not as effective as with viruses.
In order to improve vaccines against bacteria, next generation vaccines, based on molecular techniques are needed. Vaccines against bacterial toxins or specific bacterial antigens are required. These would normally involve the expression of genes of interest in different expression systems. The Vet Biotech research group has a novel
patented expression system that we have had much success with. We have produced a vaccine against a virus that cannot be cultured (Beak and feather disease virus in parrots). We are also working on a vaccine against E. coli making use of selected surface antigens of the bacterium. We are also actively working on improving the current vaccines against infectious coryza. In order to make novel new generation vaccines against bacterial pathogens, substantially more research on the mode of pathogenicity of the bacteria is needed and this is a current focus of much of our research.
This is an area of research that we have been very active in. Bacteriophages are viruses that specifically target bacteria. So, the concept of phage therapy is that you can treat bacterial infections by giving the individual a dose of viruses. Bacteriophages are highly specific to bacteria and will not attack the host cells. In principle, this sounds like a great treatment option. Our focus on this project has been on avian pathogenic E. coli (APEC) strains. We have a growing culture collection of bacteriophages that can attack APEC strains. However, one of the main problems that have come to the fore is the extreme host specificity of the phages. Broad spectrum bacteriophages will not be found. The high levels of host specificity of the bacteriophages do not necessarily mean that they cannot be used for treatment. What would be needed for effective phage therapy are vastly improved diagnostic services where bacterial pathogens are not only identified to the species level, but to the pathotype level. If the correct phage is administered, they will attack the pathogenic bacterium and can be an effective treatment.
Other potential problems with phage therapy include the development of immunity to the phages in the individual. This would not be a problem in broilers, but could be a problem in layers or breeders. Phages also have the capability of transferring virulence genes to bacteria. This aspect needs to be well investigated before the wide spread use of bacteriophages to treat bacterial infections. We could create a new generation of deadly bacterial pathogens if the phages used to treat the bacterial infection can transfer virulence genes.
A relatively new field of research involves the study of the mechanisms of resistance that bacteria have against foreign DNA. There is a host of defence mechanisms in bacteria, some of which show some similarities to adaptive immunity in higher animals. This is the CRISPR/CAS system. This immunity in bacteria could make the use of phages ineffective.
This is an area of research that we have been involved with for many years. Biosecurity is probably the least well-understood field of disease control with many misconceptions that means that biosecurity measures that are employed often do not work. Just an example of a misconception – everyone knows that you cannot disinfectant a dirty poultry house and that the area must be cleaned first. This is obviously correct. How many of the people who understand this concept has a system to clear dirty gumboots before trying to disinfectant them? If you understand that you cannot disinfectant a dirty house, why do you think that you can disinfectant a dirty gumboot! The vast majority of footbaths that I have seen are filthy and will not have any effect on disease control. There are many other examples of misconceptions that seriously hamper the effectiveness of biosecurity.
The full Virukill continual disinfection program has been developed with the aim of controlling diseases in a post antibiotic era. There is a huge amount of information available on this program (you can contact Dean Hewson and staff at Elanco for more information on this, or you can contact me at braggrr@ ufs.ac.za). One of the main advantages of this program is that, if used correctly, will have no negative effects on production parameters. This has been extensively tested and is perfectly safe to use in and on birds. Another major misconception in biosecurity is that if you spray a disinfectant on a bird, or add it to the drinking water and the bird does not die, that the product is safe to use. Just because the bird does not die, does mean that such a product does not have a significant negative impact on production.
Just a few examples of how the correct use of biosecurity can reduce the need for
antibiotics have been obtained from various experiments performed by this group. The Virukill continual disinfection program has been shown to result in a 6 log (a one million reduction) in bacterial load when used in our isolation units. If disinfection alone can result is such a significant reduction in bacterial load, there would be no need for extensive use of antibiotics. In a field experiment, the Virukill continual disinfection program resulted in a decrease in mortality of 2.7% when compared to pre-placement disinfection only. What was even more interesting in that experiment was that during the experiment there was a severe outbreak of bacterial infection and antibiotics were used in the other two groups. No antibiotics were used in the groups on the full Virukill disinfection program. In spite of the fact that no antibiotics were used in the full Virukill continual disinfection pens, in the face of a severe bacterial challenge, the mortality rate in this group was still 2.7% lower than in the best of the other groups. This experiment highlights the fact that good disinfection and biosecurity can be used in place of antibiotics to control bacterial diseases.
The best option for disease control in a post antibiotic era is going to be improved biosecurity and disinfection. The many misconceptions associated with the use of disinfectants and biosecurity means that there is much education still needed in this regard to ensure the optimal results.
There are potential disease options in a post antibiotic era, but many of them still need substantial research. The two most likely options are the use of herbal products, such as Mentofin, where there is published data supporting the claims of disease control and the other the correct use of biosecurity and the Virukill full continual disinfection program.