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Animal Health
Wednesday, February 1, 2017 7:56:49 PM
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Secondary plant compounds to reduce the use of antibiotics? Initial in vitro trials give reason for hope

 

I. Heinzl and T. Borchardt

 

 

"Without urgent, coordinated action by many stakeholders, the world is headed for a post-antibiotic era, in which common infections and minor injuries which have been treatable for decades can once again kill," says Dr Keiji Fukuda, WHO's Assistant Director-General for Health Security (WHO Report, April 2014). "Effective antibiotics have been one of the pillars allowing us to live longer, live healthier, and benefit from modern medicine. Unless we take significant actions to improve efforts to prevent infections and also change how we produce, prescribe and use antibiotics, the world will lose more and more of these global public health goods and the implications will be devastating."
 

In this article laboratory trials are presented which show the good efficacy of secondary plant compounds against commonly occurring pathogens in farm animals.

 

The discovery of penicillin in 1929 by Alexander Fleming was the starting point for the triumph of antibiotics. But even then, during an interview with the New York Times, Fleming already pointed out the possibility of resistances.
 
Antibiotics were and are the method of choice against bacterial diseases and they additionally show a positive influence on the performance parameters like daily gain and feed conversion in farm animals. These effects are particularly ascribed to the change of the gut flora. The composition of the intestinal flora influences the development of the gut as well as the immune system of the animal. From the fifties onwards antibiotics were routinely used in animal husbandry to increase performance.
 

Antibiotics enabled us to treat formerly lethal, bacterial diseases. Nowadays infectious diseases do not play a decisive role with regard to the most frequent causes of death in the industrialized world (1-5%). In developing countries, in contrast, with up to more than 40%, they are still the most frequent cause of death. We will return to this point, if antibiotics lose their efficacy because of resistances. Whilst we are aware of this problem and are trying to reduce the use of antibiotics, yet antibiotics are still needed, we should not let this powerful weapon become blunt.

 

How Antibiotic Resistance is generated?
 
Some bacteria due to mutations are less sensitive to certain antibiotics than others. That means that, if these special antibiotics are used, the insensitive ones survive. Due to the fact that their competitors have been eliminated they are able to reproduce better. This resistance can be transferred to daughter cells by means of "resistance genes". Other possibilities are the intake of these resistance genes from dead bacteria  1  (see figure 1), through a transfer of these resistance genes by viruses  2  or from other bacteria by means of horizontal gene transfer  3 . Every application of antibiotics causes a selection of resistant bacteria.  A short-term use or an application at low dosage give the bacteria a better chance to adapt, and therefore promotes the generation of resistance (Levy, 1998).
 
 
Antibiotics are promoting the Development of Resistance:
 - Pathogenic bacteria possessing resistance genes are conserved and competitors that do not possess these genes are killed
 - Useful bacteria possessing the resistance genes are conserved and serve as a gene pool of antibiotic resistance for others
 - Useful bacteria without resistance, which probably could keep the pathogens under control, are killed

Measures
 
Only in the EU about 25,000 people die of infections from resistant germs every year, but the estimated number of unreported cases is probably a lot higher because of incomplete documentation. In 2011, antibiotic resistance was the main agenda point of the World Health Day organized by the WHO. In August last year the US Food and Drug Administration held a general meeting with the topic "Antimicrobial Resistance Monitoring in the Food Supply".
 
Since 2006 antibiotic growth promoters have been banned in the EU, but already starting from 2000 certain growth promoters were prohibited successively or have not been used anymore because of lack of acceptance by the consumer (BMG, 2011). There are already comprehensive regulations in place concerning the use of antibiotics in farm animals. Stated in these directions is that such important treatment tools must no longer be applied prophylactically to healthy animals. Yet, the metaphylactic use of antibiotics is still allowed. This means that, if there is one animal in one production unit showing signs of sickness, the others can be treated prophylactically with the antibiotic. If 50,000 broilers are kept together in one barn, the possibility that one chick becomes sick, is rather high.
 

One possibility to limit the development of new resistance is the global restriction of antibiotic use in animal production to pure therapeutic application. This requires a very good hygiene management, as veterinary medicine here often has to compensate deficiencies. It has often been demonstrated that the worse hygienic conditions are, the better the effects when antibiotics are applied.

 

One way to reduce antibiotics: Secondary Plant Compounds
 
Ingredients from herbs and spices have already been used for centuries in human medicine. In modern animal husbandry they are also on the rise. A lot of secondary plant compounds have antimicrobial characteristics, e.g. Carvacrol and Cinnamon aldehyde. They effectively act against Salmonella, E. coli, Pseudomonas aeruginosa, Klebsiella pneumoniae, Entero- and Staphylococcus and Candida albicans. Some compounds influence digestion and others act as antioxidants. An optimal combination has both - positive influence on health and performance. Comprehensive knowledge about the single ingredients, their possibly negative but also positive interaction (synergies) is essential for solution orientated developments. Today secondary plant compounds are offered on the market as granulates or as microencapsulated and liquid products respectively.
 

Granulates and microencapsulated products are suitable for the addition to feed. In acute situations, however, a liquid version would be more appropriate for a quick application in the waterline.

 

The antimicrobial Effects of Secondary Plant Compounds against Reference Livestock Pathogens in vitro

In so called "agar diffusion tests" (method available on request), the sensitivity of reference strains –representative for the different species of pathogens - were evaluated with different concentrations of a specific blend of secondary plant compounds. The effectiveness of the active substances was determined by the extent to which they prevent the development of bacterial overgrowth. The diameter of a bacteria free zone around an applied component can be translated into the antimicrobial efficacy against a densely grown bacterial population on a petri dish.
 
The bigger the bacteria free zone, the higher the antimicrobial effect.
 

+++       22 – 29 mm ZOI (zone of inhibition)

++         15 – 21 mm ZOI

+           10 – 14 mm ZOI

-                 < 10 mm ZOI.

 

 

Table 1: Inhibition of field isolated standard pathogens by different concentrations of Activo® Liquid


 

Secondary Plant Compounds 

 

(Activo®Liquid)

 

Central Poultry Diagnostic Laboratory, Kondapur, Hyderabad (India)

10%

2%

1%

 

E. coli (reference strains)

++

+

+

 

Proteus vulgaris (reference strains)

+

+

+

 

Pseudomonas fluorescens

++

+

-

 

Salmonella pulmorum

++

++

+

 

Salmonella gallinarum

++

++

+

 

Staphylococcus aureus (reference strains)

+++

++

++

 

 

In this trial, the blend of secondary plant compounds and organic acids (Activo® Liquid) showed an antimicrobial effect on all tested bacteria occurring in farm animals. The degree of growth inhibition positively correlated with the concentration of Activo® Liquid.

 

Sensitivity of Antibiotic Resistant Field Pathogens to Activo® Liquid in vitro
 

It cannot be excluded that resistant pathogens not only acquired effective weapons to render antibiotics harmless, but also developed general mechanisms to get rid of otherwise harmful substances. In a follow up laboratory trial we evaluated, whether the Activo® Liquid composition is as effective against ESBL producing E. coli and Methicillin resistant S. aureus as to non-resistant members of the same species.

Trial Design: Farm isolates of four ESBL producing E. coli, two Methicillin resistant Staphylococcus aureus strains were compared to nonresistant reference strains of the same species with respect to their sensitivity against Activo® Liquid. In a Minimal Inhibitory Concentration Assay (MIC) under approved experimental conditions (Vaxxinova Diagnostic, Muenster, Germany) the antimicrobial efficacy of Activo® Liquid in different concentrations was evaluated.

 

Table 2:  Efficacy of Secondary Plant Compounds against ESBL-producing E. coli and MRSA

 
 

Secondary Plant Compounds 

(Activo®Liquid)

  Laboratory: Vaxxinova, Muenster, Germany

0.10%

0.20%

0.40%

1%

 

E.coli reference ATCC25922

+

++

++

++

 

ESBL 1 (Pig)

-

++

++

++

 

ESBL 2 (Pig)

+

++

++

++

 

ESBL 3 (Poultry)

+

++

++

++

 

ESBL 4 (Poultry)

-

++

++

++

 

S. aureus reference ATCC29213

-

+

+

++

 

MRSA 1 (Pig)

-

+

+

++

 

MRSA 2 (Pig)

-

+

+

++

  -   no effect   +   growth inhibiting        
++ bactericide                   

 

The efficacy of Secondary Plant Compounds (Activo® Liquid) against the tested strains could be demonstrated in a concentration dependent manner with antimicrobial impact at higher concentrations and bacteriostatic efficacy in dilutions up to 0,1% (ESBL) and 0,2% (MRSA)(table 2).

 

Conclusion:
 
In order to contain the emergence and spread of newly formed resistance mechanisms it is of vital importance to reduce the use of antibiotics. A general rethinking is necessary to rise to the challenge and give new approaches a chance. These approaches however, will only be successful in combination with good management practices. Antibiotics must not be used for growth promotion or metaphylactic treatment, but only as a pure curative instrument. In In vitro-trials the liquid blend of secondary plant compounds and organic acids (Activo® Liquid) showed very antimicrobial effects against prevalent livestock pathogens. This indicates the possibility to use secondary plant compounds for prophylaxis and for metaphylaxis and to reduce the use of antibiotics with their help. The positive influence on performance parameters, as shown in many other trials, is an additional incentive for farmers to use these flavoring substances in the feed.
 

The high efficacy of secondary plant compounds against ESBL Producing Escherichia coli and Methicillin resistant Staphylococcus aureus (MRSA) can be a further step towards the reduction of antibiotic use. Due to the specific mode of action of antibiotics, resistance mechanisms are likely to emerge, since only subtle changes in the Pathogen can lead to the generation of antibiotic resistance.  To support antibiotic treatment, Activo® Liquid, a blend of natural compounds with broad spectrum efficacy can be a safe supplement for the control of pathogenic organisms, minimizing the development of antibiotic resistance.

 

 

For more of the article, please click here.

 

Article made possible through the contribution of I. Heinzl and T. Borchardt

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