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The National Research Program on antibiotic resistance (NRP 49)

Interview with Prof. Jean-Claude Piffaretti (President of the NPR 49), Istituto Cantonale Batteriosierologico, Lugano

The National Research Program on antibiotic resistance (NRP 49) is due to start in July 2001. What are the objectives and what were the reasons for its implementation?

In Switzerland and virtually world-wide, concerned institutions (public health, veterinary medicine, food industry, agriculture, etc.) are becoming increasingly aware of the evolution and dissemination of bacterial antibiotic resistance. If the situation continues to develop along the current trend, antibiotics against certain clinically important bacteria may become unavailable.
The use of antibiotics is the key factor for the selection of genes that code for resistance not only in pathogens, but also in other habitats (commensals, environment). These genes can disseminate and their transfer to or within pathogens can aggravate therapies or even make them impossible.
The NRP 49 'Antibiotic Resistance' has the following objectives: (i) development of novel scientific methodologies for a prospective antibiotic resistance surveillance system; ii) gaining a representative survey of the actual resistance situation in Switzerland in all concerned sectors (human and animal populations, cattle-breeding, food, environment, etc.); iii) determination of the extent of mobility of resistant bacteria or of resistant genes and estimation of the risk for medical therapy resulting from their presence; iv) stimulation of molecular studies on antibiotic resistance in order to develop new antibiotics and new methods for in vitro detection; v) determination of social, legal, ethical and economic impacts of antibiotic resistance itself and of a possible change in the regulations of the utilisation of antibiotics.

In order to achieve this multidisciplinary program,12 million Swiss francs have been granted by the Federal Council for a period of five years. Where appropriate, the efficiency of the program will further be enhanced by a co-ordination of research within the NRP 49 with international, particularly European, research programs.

How can bacteria become resistant to antibiotics?

Bacteria can acquire antibiotic resistance either by mutational modification of their genome or by incorporating genes originating from other micro-organisms by gene transfer. Bacteria can exchange genetic material in several different ways: transformation (acquisition of naked DNA originating from other bacteria); transduction (a bacterial "virus", a bacteriophage, serves as a vector, vehicle, between two bacteria); conjugation (which implies a coupling between two bacteria). An element that favours the dissemination of resistance genes is the fact that they are often plasmid-borne, i.e. a type of mini-chromosomes which are 1/100 to 1/1000 the size of a normal chromosome. However, their mobility is far superior. Once the bacterium has acquired resistance genes, it wins a selection advantage compared to bacteria susceptible for antibiotics in an environment containing antibiotics ("environment" also includes humans and animals that are submitted to antibiotic therapy).
Bacterial strains are often resistant to 4 - 5 classes of antibacterial agents or even more. Acquisition and transfer of antibiotic resistance genes is related to the selection pressure exerted by the intensive use of these substances, which explains the world-wide alarming situation in human medicine. Some examples: Staphylococcus aureus resistant to methicillin (MRSA) or with a diminished sensibility to vancomycin (VISA), enterococci resistant to vancomycin (VRE), pneumococci insensitive to penicillin, strains of multi- resistant Mycobacterium tuberculosis, Gram-negative bacteria which produce b-lactamases with broadened substrate spectra.

The development of resistance is obviously a natural phenomenon. Under which circumstances does resistance become a problem?

Antibiotics are, as expressed in the original meaning of the term, antimicrobial substances produced by micro-organisms (bacteria or fungi). Taking this fact into account, one has to assume that these substances are broadly distributed in the environment, albeit at low concentrations. The resistant bacteria are therefore often present in nature even before the use of antibiotics takes place. Hence, the application of these substances that favour the selection of resistant strains can transform susceptible populations into resistant ones. Unless the bacterial populations are involved in pathogenicity this is hardly relevant. If, however, pathogens are involved, therapeutic problems may arise.

How fast do bacteria acquire resistance and is it possible to develop antibiotics to which the bacteria cannot become resistant?

It is difficult to estimate the time required for a bacterial species to acquire resistance against a particular antibiotic. It depends on different factors, including: intensity of particular antibiotic utilisation and hence of selection pressure, nature of the physiological target of the antibiotic, localisation of resistance genes (chromosome, plasmids or other mobile genetic elements) and consequently the possibility of transfer, potential adverse effects of the resistance on the bacterial physiology (decrease of "fitness"), and finally the habitat where the resistance occurs.
What is very clear is the fact, that whatever the efficiency of a new family of antimicrobial molecules introduced on the market may be, the very high number of bacteria in a population and their huge diversity will sooner or later lead to the emergence of resistant individuals. Depending on selection pressure present (e.g. an intensive utilisation of the new antibiotic) the susceptible population will diminish and finally disappear. For the time being, impeding the build-up of resistance is the most that can be done.

How would it be possible to control the use of antibiotics, in particular if the resistance development and the clinical situation is considered potentially perilous?

First of all, it is important to remember, that, according to the available data, the situation in Switzerland is generally still acceptable. It is not yet at such an alarming stage as is the case for other countries. Nevertheless, the problem needs to be addressed seriously. Therefore, if we really want to diminish the importance of antibiotic resistance the best means available is the reduction of antibiotic utilisation, i.e. not to use them unless they are truly indispensable. In 1999, Switzerland pioneered in this area by banning the use of antibiotics as feed additives in cattle-breeding. Much is yet to be done, for example, in human medicine. A better education not only of the medical personnel but also of the consumers of antibiotics, the patients, is important. They should not demand antibiotics from their physicians. Here we touch regulatory and ethical domains. If this could be regarded as essential, would the legal basis for limiting the therapeutic freedom of the physician be available? When can the health of the patient be endangered (who wants the most promising and efficient drugs) in the interest of society (who wants an antibiotic resistance level as low as possible and therefore a use of antibiotics as restricted as possible)? The NPR 49 also needs to address these questions.