TREAT­MENT IN A POST AN­TIBI­OTIC ERA

The Poultry Bulletin - - FRONT PAGE -

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.

Vac­cine de­vel­op­ment

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.

Phage ther­apy

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.

Im­proved biose­cu­rity

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.

Con­clu­sions

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.

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