RUMA, the Responsible use of Medicines in Agriculture Alliance, celebrated its 10th Anniversary with a reception in the House of Lords on 11th December.
RUMA was established as a consortium, now of 19 members, to provide guidelines for the responsible use of antimicrobials (and later vaccines) in agriculture: its establishment contributed very significantly and collectively to the control of antibiotic resistance in livestock management.
From the time of the discovery of penicillin by Fleming and its development over the following 80 years there have been major developments in antibiotic molecular species and formulations and a vast expansion in usage in human and animal medicine and in horticulture, all with remarkable results.
Garrod in 1968 placed the situation in context: “No one recently qualified , even with the liveliest imagination, can picture the ravages of bacterial infection which continued until little more than 30 years ago.” Those in veterinary practice in the early days of the availability of penicillin will attest to the remarkable effects of the drug. The massive use of antibiotics inevitably led to antibiotic resistance, particularly in the human field with multi-resistance being evident in many of the severe pathogens of humans.
The extensive use of antibiotics in veterinary medicine paralleled that in human medicine, but one major difference was their use as growth promoters. This consists of adding small quantities of antibiotic, well below the therapeutic dose, to enhance growth, a fact discovered by Jukes in the USA in 1940 when chickens were fed a fermented ration containing the microorganism Streptomyces aureofaciens used to produce chlortetracycline. Chicks showed a dramatic increase in weight gain and greatly decreased the lifespan of broilers to 6 to 7 weeks before slaughter.
The use of antibiotics for growth promotion and which were used also in human medicine (e.g. virginiamycin) and the possibility of multi-resistance via the food chain derived from growth promoters occasioned much debate.
Increasing concerns were raised by various bodies, including the WHO and the UK Government. The Swann Committee (1969) set up to report on antimicrobial use in man and animals concluded there was a significant problem, particularly in antibiotic use in animal feed for growth promotion.
Swann recommended that a committee be set up with authority to review and recommend antibiotic use in man, animals and horticulture. Such a committee was not established until a further review of the situation 20 years later by the House of Lords Science and Technology Committee on Resistance to Antibiotics and other Antimicrobial Agents, which reported in 1998 and reminded the Government of the increasing problem of resistance and pressed for the long-awaited “Swann Committee”.
Advising prudence
The Scientific Advisory Committee on Antibiotic Resistance (SACAR) was the result. The House of Lords Report was well received by the Government and advice to medical practitioners to show prudence in prescribing antibiotics was provided via information documents and cartoons for patients.
The comments in the Report on animal use, especially antibiotic use in growth promotion, were, however, less well received, especially by the pharmaceutical industry.
A major development, of national significance, was the establishment of RUMA, which brought together a wide range of organisations with interests in production and manufacture, use and dispensing of antibiotics and also those having a strong stake in the issue of resistance.
Whereas animal use had been regarded as important in the development of resistance in the human field, RUMA showed that collective action could be taken and there is little doubt that this collective leadership has been important in the control of resistance.
In 1989, an EU ban on the use of four growth promoting antibiotics came into effect; these were spiramycin, tylosin, bacitracin zinc and virginiamycin. This was later ratified by the UK. There was a dramatic fall in the sales of antimicrobial growth promoters: in 1998, 141 tonnes of active growth promoting ingredient were sold; by 2005 this had reduced to 14 tonnes. Remaining antibiotic growth promoters (monensin, avilamycin,salinomycin and flavimycin ) came under an EU wide ban in 2006.
Though the underlying dangers of antibiotic resistance are now well accepted, the face of resistance is changing dramatically. The beta lactam antibiotics are the most commonly used antimicrobial agents, but the beta lactamases, enzymes that hydrolyse the beta lactams, are the major cause of resistance to these compounds.
There is an ever growing diversification and proliferation of beta lactamases, more than 350 having been identified. Extended spectrum beta lactamases (ESBLs) are of increasing concern and an additional concern is the CTX-M enzymes including the CTX-M type beta lactamase which is particularly widespread in the UK and other countries. Though the situation in the UK is relatively satisfactory, there is increasing evidence of substantial variation in antibiotic resistance in Europe.
The flow of antibiotic resistant genes into the environment and their then subsequent acquisition by pathogens has been recognised by ROAR (Reservoirs of Antibiotic Resistance Network) which originated from the Alliance for the Prudent Use of Antibiotics (AUPA) in the USA. The ROAR network emphasises that antibiotic resistance is not a problem confined to hospitals: it is an environmental problem.
There are many questions posed by ROAR which require detailed attention. Some include the role of commensal bacteria, normally found in the gut and elsewhere of man and animals, reservoirs of resistant genes and the potential of these to pass resistance to diseasecausing organisms: how are they spread between a host or several hosts and can they be transferred in the food chain?
Environmental issues will loom in future considerations of resistance. An example is the widespread use of detergents and disinfectants including quaternary ammonium compounds (QACs) (biocides). QAC-resistant genes are significant because they are often located with antibiotic-resistant genes on the same pieces of DNA.
As our knowledge of resistance and its threat grows there will be need for major contributions from RUMA. RUMA has already demonstrated its competence to deal with the issues of resistance, it is certain that much more will be demanded of it in the coming years.
