CA-July13-Doc.8.6

(revision from May meeting)

Swedish position paper on

How to deal with the risk for bacterial resistance in decision for substance approval?

Background

According to BPD article 5 1. (b) (ii) a substance shall only be approved if the biocidal product has no unacceptable effects on the target organisms, such as unacceptable resistance or cross-resistance . The same wording can be found in Article 19 of the BPR. Resistance can be defined as a heritable decrease in susceptibility or a lack of susceptibility of an organism to a particular treatment with an agent under a particular set of conditions (TNsG 2009, Chapter 6.2.3.3). Microorganisms can acquire resistance as a result of genetic changes due to mutation or theacquisition of appropriate genetic material (e.g. plasmid coded resistance genes in bacteria).

In accordance with SCENIHRs opinion[1] the term “cross-resistant” is used to denote a strain possessing a resistance mechanismthat enables it to survive the effects of several antimicrobial molecules withmechanism(s) of action that are related or overlap; and co-resistance specificallyrefers to genetic determinants (such as integrons, transposons or plasmids) encoding forunrelated resistance mechanisms, that are transferred in a single event and expressedjointly in a new bacterial host. Resistance genes located on plasmids may be transferred from one bacterial strain or species to another (horizontal gene transfer). In neither the Directive nor the Regulation is the word co-resistance mentioned, but it can be interpreted to be included in the wording unacceptable resistance.

There are on-going discussionson the risk of development of resistance in other committees too. For example The Scientific Committee on Emerging and newly Identified Health Risks (SCENIHR) has received a request for a scientific opinion on Nanosilver: safety, health and environmental effects and role in antimicrobial resistance[2].

When development of resistance is an issue

Since development of bacterial resistance was an agenda point during the workshop on treated articles at TM IV 2012, there might be the perception that development of resistance is an issue connected with treated articles. Treated articles, especially in the consumer domain, is one area of use where resistance can develop and may be difficult to control. However, it is not restricted to these uses.

Neither is the problem with development of resistance restricted to antibacterial substances. Similar concerns have been raised regarding fungicides; see EFSAs TECHNICAL REPORT Impact of environmental usage of triazoles on development of resistance to medical triazoles in Aspergillus spp.[3] There are, in our opinion, a number of active substances currently under evaluation that should, therefore, be examined in greater detail regarding their potential for development of bacterial resistancethan has so far been the case.

Before carrying on with technical details on any specific substance, CAs must take a general decision on how to deal with the theoretical but currently unquantifiable risk of development of resistant bacterial strains and the potential for spreading of resistance genes. The CA-meeting needs to decide to what extent a precautionary approach should be applied, i.e. whether approval should be denied if development of resistance can be suspected although strong evidence is lacking. Any decision taken by the CA must apply to all disinfectants and preservatives for which a risk for development of resistance, co- or cross-resistance can be suspected.

What are the potential negative consequences of bacterial resistance?

-Loss of effectiveness of antimicrobial substances used in health care, for example the use of silver compounds in treatment of burn wounds.

-Spreading of antibiotic resistance via co-resistance or cross-resistance. The increasing resistance of bacteria to antibiotics is a recognized problem and prioritized by EU-COM in their Action plan[4].

Problems identified during evaluation of dossiers

During its evaluation of silver compounds[5]Sweden as RMS has identified various problems while making efforts to meet the requirements of BPD Article 5 with regards to the development of resistance. The Technical Notes for Guidance (TNsG 2009, Chapter 6.2.3.3) and the SCENIHR opinion on Assessment of the Antibiotic Resistance Effects of Biocides (2009) were consulted. No test guidelines were available and no previous cases could be found to be used as precedents. The applicant and RMS thoroughly reviewed the available literature and took external experts’ advice. However, information is lacking about how wide-spread silver resistant strains or genes are already in the general public and environment today. This makes it difficult to assess whether there is unacceptable risk of bacteria developing resistance and cross and/or co-resistance from an increased use of silver. The envisaged uses of silver compounds involve private homes and the general public, environments which make it difficult to control exposure and effective doses. The RMS suggested resistance monitoring as a requirement for approval of the active substance. The issue was brought up during workshop on treated articles at TM IV 2012, but no conclusion was reached among participants, due to lack of experience with this question.

SE as RMS now seeks from the Commission, ECHA and MS CA endorsement of an approach to address these problems not only for its own evaluations but for all relevant evaluations.

Suggested way forward:

The Swedish CA have the following suggestions for future work:

  1. Evaluation of all disinfectants and preservatives whether they have the potential for development of resistant bacteria, fungi or genes based on the questions:
  2. Is the mode of action such that the development of resistant strains or genes can be induced by genetic changes due to selective pressure? Is it similar to commonly used antibiotics in human and veterinary medicine, and/or
  3. Are there reports on resistant strains or resistance genes in literature or other available information?
  4. If such a potential has been identified, evaluate whether the intended uses are favourable for the development or spreading of resistant microorganisms or their genes. According to TNsG 2009, Chapter 6.2.3.3, factors promoting the development of resistance include
  5. Application in unconfined areas.
  6. Uncontrolled use of the biocide in an inappropriate way – too low doses and/or too short time.
  7. Use pattern: large areas and/or for long periods with frequent application rates.
  8. If, after considering the evaluations made under points 1 and 2, a risk for resistance development has been identified, further investigations need to be carried out in order to quantify the risk. Monitoring of occurrence of resistant bacterial strains or genes in the public and in the environment should be part of the information to be gathered.

SCENIHR states in its opinion on Assessment of the Antibiotic Resistance Effects of Biocides (2009):

“Surveillance programmes must be introduced to monitor the level of bacterial resistance and cross-resistance in all areas of biocide usage.”

Active substance approval when there is a potential for development of resistance

If the information is currently not sufficient to quantify the risk for resistance development, it should be a requirement connected to the approval decision to create necessary data or collect necessary information. The results shall be an indispensable requirement for the evaluation for a renewed approval of the active substance in question.

This would be a similar situation to the Annex I inclusion decision for sulfuryl fluoridewhich includes a requirement for monitoring:

The inclusion decision for sulfuryl fluoride has a requirement for monitoring and reporting of sulfuryl fluoride in remote tropospheric air (COMMISSION DIRECTIVE 2009/84/EC).

(4) Concentrations of sulfuryl fluoride in remote tropospheric air are monitored.

(5) Member States shall also ensure that reports of the monitoring referred to in point (4) are transmitted by authorisation holders directly to the Commission every fifth year, starting at the latest five years after the authorisation. The limit of detection for the analysis shall be at least 0.5 ppt (equivalent to 2.1ngsulfuryl fluoride/m3 of tropospheric air).’

Similar requirements could be placed on active substances for which a potential for resistance development has been identified.

Conclusion

Member States are invited to discuss these proposals and to agree a way forward for a more harmonised approach to issues surrounding resistance.

Reference

TNsG, 2009: Technical Notes for Guidance. Revision of Chapter 6.2 (Common Principles and Practical Procedures for the Authorisation and Registration of Products) of the TNsG on Product Evaluation, and a revision of Chapter 101 (Assessment for the potential for resistance to the active substance) of the TNsG on Annex I Inclusion. (This document was endorsed at the 33rd meeting of representatives of Members States Competent Authorities for the implementation of Directive 98/8/EC concerning the placing of biocidal products on the market (13-15 May 2009). See JRCs website under guidance documents.)

[1]SCENIHR (Scientific Committee on Emerging and Newly Identified Health Risks),

Assessment of the Antibiotic Resistance Effects of Biocides, 19 January 2009

[2]

[3]

[4]Action plan against the rising threats from Antimicrobial resistance.COM(2011)748 final of 15.11.2011.

[5]A detailed review of the gathered information and about the discussions between RMS and applicant are found in the CAR for silver zinc zeoliteDOCUMENT II Appendix 3: Bacterial resistance (submitted to MS in May 2012).