Council Regulation (EC) No 2821/98 of 17 December 1998 amending, as regards withdrawal of the authorisation of certain antibiotics, Directive 70/524/EEC concerning additives in feedingstuffs
Date: 1998-12-17
Institutions: Council of the European Union
Subjects: animal nutrition, antibiotic, drug surveillance, food additive, food chemistry, medicinal product

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Official Journal of the European Communities

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I

(Acts whose publication is obligatory)

COUNCIL REGULATION (EC) No 2821/98

of 17 December 1998

amending, as regards withdrawal of the authorisation of certain antibiotics,
Directive 70/524/EEC concerning additives in feedingstuffs

THE COUNCIL OF THE EUROPEAN UNION,

Having regard to the Treaty establishing the European
Community,

Having regard to the 1994 Act of Accession, and in
particular Article 151 in conjunction with Annex XV,
Title VII(E)(4) thereof,

Having regard to Council Directive 70/524/EEC of 23
November 1970 concerning additives in feedingstuffs (1),
and in particular Article 11(3) thereof,

Having regard to the proposal from the Commission,

(1) Whereas the Kingdom of Sweden was authorised
under Annex XV to the Act of Accession to main-
tain its legislation in force before accession until 31
December 1998 with regard to the prohibition of
the use in feedingstuffs of additives belonging to
the groups of antibiotics; whereas on 2 February
1998 Sweden submitted applications for adjust-
ments accompanied by detailed scientific grounds
for the antibiotics avilamycin, bacitracin zinc, flavo-
phospholipol, ardacin and avoparcin, spiramycin,
tylosin phosphate and virginiamycin; whereas the
Commission is required to take a decision on the
adjustment applications submitted by Sweden not
later than 31 December 1998;

(2) Whereas, under Article 11 of Directive 70/
524/EEC, a Member State which, as a result of new
information or of a reassessment of existing infor-
mation made since the provisions in question were
adopted, has detailed grounds for establishing that
the use of one of the additives listed in the Direc-
tive constitutes a danger to animal or human health
or the environment may temporarily suspend the
authorisation to use that additive;

(1) OJ L 270, 14. 12. 1970, p. 1. Directive as last amended by
Commission Directive 98/19/EC (OJ L 96, 28. 3. 1998, p. 39).

(3) Whereas the Republic of Finland, after expiry of
the derogation granted to it under the Act of
Accession, prohibited the use on its territory of
tylosin phosphate and spiramycin in feedingstuffs
from 1 January 1998 on the basis of the detailed
grounds it had submitted on 12 March 1997 under
the obligations laid down in the Act of Accession;

(4) Whereas on 15 January 1998 the Kingdom of
Denmark prohibited the use on its territory of
virginiamycin in feedingstuffs; whereas it commu-
nicated the detailed grounds for that decision to
the other Member States and the Commission on
13 March 1998 and 1 April 1998;

(5) Whereas, by virtue of Article 3a(e) of Directive
70/524/EEC, authorisation of an additive is not to
be given if, for serious reasons concerning human
or animal health,
its use must be restricted to
medical or veterinary purposes;

(6) Whereas

the authorisation of

the glycopeptide
avoparcin was withdrawn on 30 January 1997 (2) as
an interim protective measure taken as a precau-
tion; whereas that prohibition has to be reviewed
by the Commission not later than 31 December
1998, on the basis of the results of the various
investigations concerning the development of resis-
tance by the use of antibiotics, in particular glyco-
peptides, and the programme of surveillance of
antimicrobial
resistance in animals which have
received antibiotics, to be carried out in particular
by the persons responsible for putting the additives
concerned into circulation; whereas,
since the
Commission has received no new information to
date, there is no reason for the prohibition to be
reviewed;

(2) Commission Directive 97/6/EC of 30 January 1997 amending
in

70/524/EEC concerning

Council Directive
feedingstuffs (OJ L 35, 5. 2. 1997, p. 11).

additives

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(7) Whereas it was also decided as a precaution on 12
January 1998 (1) not to renew the authorisation of
another glycopeptide, ardacin, until the results of
research still to be carried out on avoparcin were
available;

mides are in clinical use in human medicine,
namely lincomycin and clindamycin; whereas two
streptogramins are clinically important in human
medicine in the treatment of last resort of vanco-
mycin resistant enterococci, namely pristinamycin
and the combination dalfopristin/quinupristin;

(8) Whereas the Commission consulted the Scientific
Committee on Animal Nutrition (SCAN) on
whether the use of tylosin phosphate and spira-
mycin should for
reasons concerning
serious
animal or human health be restricted to veterinary
medicine; whereas after examining the Finnish
grounds for prohibiting the said macrolides as feed
additives, the Committee stated in its opinion of 5
February 1998 that
the data presented did not
provide sufficient evidence that the use of macro-
lides as feed additives presented a significant risk to
human or animal health and that, in the absence of
sufficient research data on the epidemiology and
spread of macrolide resistance, there was no reason
for a ban on the use of the substances in question
as additives;

(9) Whereas SCAN acknowledges, however, that the
wider use of macrolides as feed additives in the
long run will contribute to the overall selective
pressure for resistant bacteria to a significantly
larger extent than would result from the use of
macrolides for veterinary therapy alone; whereas
SCAN acknowledges the probability that resistant
enterococci or erm-resistance genes will be trans-
ferred from animals to humans will be higher, the
higher the prevalence of resistant enterococci in
animals is; whereas SCAN is of the opinion that
the possibility that an increase in the resistance
pool at animal level might pose risks to humans
has been neither proven nor disproved, but that
such a risk might be expected to be demonstrated;

(10) Whereas SCAN also notes that

tylosin-resistant
enterococci isolated from pigs are almost all simul-
taneously resistant to erythromycin, an important
macrolide antibiotic in human medicine notably in
the treatment of respiratory infections; whereas it
finds that, even if cross-resistance to lincosamides
and streptogramins has not been tested in Finland,
macrolide resistance in enterococci is, according to
the literature, often or mostly encoded for by
different erm-genes also conferring resistance to
lincosamides and streptogramin B; whereas there is
a clinical problem in human medicine if the enter-
ococci resistant to macrolides include also a major
resistance to streptogramin B; whereas two lincosa-

(1) Commission Directive 97/72/EC of 15 December 1997 am-
ending Council Directive 70/524/EEC concerning additives in
feedingstuffs (OJ L 351, 23. 12. 1997, p. 55).

animal

(11) Whereas SCAN also notes that some experiments
on mice have shown that
in vivo transfer of
erythromycin resistance from enterococci to other
bacteria is possible; whereas it also specifies that
erythromycin-resistant
enterococci may
time
colonise humans for a longer or shorter
period or may transfer their macrolide-resistance
genes to the resident bacterial flora of humans,
notably to human bacteria such as staphylococci or
group A streptococci, which would constitute a
clinical problem in human medicine,
either
directly after ingestion or via gene exchange in the
environment, but
the frequencies of such
transfers cannot be estimated;

that

(12) Whereas,

in the light of the various abovemen-
tioned factors, the Commission, for its part, takes
the view that there are sufficient grounds for a ban;
whereas the risk of reducing the effectiveness of
human medicinal products such as erythromycin
in particular and possibly lincomycin, clindamycin,
pristinamycin and the new combination dalfo-
pristin/quinupristin, which is due to be authorised
as a human medicinal product shortly, as a result of
selection of cross-resistance caused by tylosin phos-
phate and spiramycin, should be avoided;

(13) Whereas, moreover, spiramycin is used in human
medicine and whereas therefore the resistances
selected by the use of spiramycin as an additive
increase the pool of spiramycin-resistance which
could be transferred from animals to humans and
thus make spiramycin less effective in human
medicine;

(14) Whereas the Commission consulted SCAN on
whether or not streptogramin-resistant E. faecium
and staphylococci selected by the use of virginia-
mycin as a growth promoter constituted a public
health risk at present or could constitute such a
risk if streptogramins took a pivotal role for treat-
ment of serious human infections in the future;

(15) Whereas after examining the grounds put forward,
the Committee concluded in its opinion of 10 July
1998 that the use of virginiamycin as a growth
promoter did not constitute a real immediate risk

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to public health in Denmark since Denmark had
provided no new evidence to substantiate the
transfer of streptogramin resistance from organisms
of animal origin to those resident in the human
digestive tract, which would compromise the future
use of human medicinal products; whereas
it
stresses that there is currently no need for strepto-
gramins in Denmark as the existing therapeutic
treatments for treating enterococci and staphylo-
cocci infections are still effective there;

(16) Whereas, none the less, SCAN acknowledges that a
reservoir of resistant genes within the animal popu-
lation poses a potential risk for humans; whereas,
contrary to the Commission, it is of the opinion
that a full risk assessment cannot be made until, in
particular, quantitative evidence of the extent of
transfer of antimicrobial resistance from livestock
sources is obtained;

(17) Whereas SCAN is also concerned about the devel-
opment of vancomycin resistance amongst entero-
cocci and methicillin-resistant strains of Staphylo-
coccus aureus, which are increasingly responsible
infections, particularly in the
for nosocomial
United States and southern Europe; whereas that
could make it necessary to use streptogramins as
therapeutic agents of
to treat germs
which have developed resistance to other anti-
biotics;

last resort

(18) Whereas, furthermore, SCAN notes in its opinion
that
the virginiamycin-resistant enterococci and
staphylococci isolated from poultry and pigs all had
cross-resistance to pristinamycin used in human
medicine or the combination dalfopristin/quinu-
pristin, which is due to be authorised as a human
medicinal product shortly;

(19) Whereas SCAN also indicates that transfer of the
sat A gene conferring resistance to virginiamycin
occurs in vitro between isogenic strains of Entero-
coccus faecium; whereas virginiamycin-resistant E.
faecium were detected in 22 % of food originating
from pigs and in 54 % of that originating from
poultry; whereas there are genetic factors for vir-
giniamycin resistance existing within the human
population, although it is not known how wide-
spread they are; whereas two strains of E. faecium
resistant to virginiamycin and pristinamycin, one
isolated from a Dutch farmer and the other from
his poultry, have the same genetic fingerprint;
whereas even if general conclusions about
the
transfer of resistant enterococci from animals to
humans should not be drawn from a single case,
the Commission sees it as an indication that this
might be confirmed by other cases in the future;

(20) Whereas,

after

the SCAN opinion, Denmark
produced major fresh evidence in August 1998
demonstrating a transfer in vivo under experi-
mental conditions in the gastro-intestinal tract of
rats of the sat A gene, via a plasmid, between
isogenic strains of E. faecium;

(21) Whereas,

the foregoing,

in the light of

the
Commission, for its part, takes the view that the
risk of reducing the effectiveness of human medi-
cinal products such as pristinamycin and the new
combination dalfopristin/quinupristin, which is
due to be authorised shortly as a human medicinal
product, as a result of cross-resistance caused by
virginiamycin should be avoided;

(22) Whereas bacitracin zinc, a cyclic polypeptide, is
also used in human medicine mainly for topical
treatment of infections of the skin and mucosal
surfaces; whereas publications show that it could
possibly be used for the treatment of vancomycin
resistant enterococci, which represent a clinical
problem in human medicine; whereas selected
resistances from the use of bacitracin zinc as a feed
additive inevitably increase the reservoir of resis-
tances to bacitracin zinc; whereas the percentage of
Enterococcus faecium resistant to bacitracin zinc is
higher in chickens which have received bacitracin
zinc than in chickens which have not received it;
whereas these resistances could be transferred from
animals to humans and reduce the effectiveness of
bacitracin zinc used as a human medicinal product;
whereas the effectiveness of bacitracin zinc in
human medicine should therefore be preserved;

(23) Whereas according to the conclusions of the World
Health Organisation conference held in Berlin in
October 1997, the Economic and Social Commit-
tee of the European Union, the International Office
of Epizootics and the conference on antibiotic
resistance held in Copenhagen in September 1998,
antibiotic resistance must henceforth be regarded
as a major, complex problem of
international
dimensions; whereas, in the sense of the recom-
mendations arising from these conferences, it is
desirable to set up a system of general surveillance
of antimicrobial resistance resulting from the use of
antibiotics; whereas, furthermore, the phenomena
of resistance encountered not only in hospitals but
also in the general population should be addressed;

(24) Whereas medicinal products belonging to new
classes of antibiotics are not ready to be approved
in the immediate future; whereas it is therefore
imperative to preserve the effectiveness of those
human medicinal products which are still effective;

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(25) Whereas one of the ways of achieving that aim,
along with others relating to use of human medi-
cinal products, is not to increase the reservoir of
resistances in animals, especially where such resis-
thereby
tances could be transferred to humans,
reducing the effectiveness of human medicinal
products; whereas numerous scientific data demon-
strate such a transfer not only for the organisms
responsible for zoonoses but also for commensals;

(26) Whereas one of the ways of preventing such a
phenomenon, which originates in the use in live-
stock farming of antibiotics administered either as
a veterinary medicinal product or as a feed additive,
is no longer to authorise the use of antibiotics
authorised as human medicinal products or known
to select cross-resistance to antibiotics used in
human medicine as additives, restricting the use of
such substances for fundamental reasons to human
medicine;

(27) Whereas, for the sake of protecting human health,
the authorisations for
the antibiotics bacitracin
zinc, spiramycin, virginiamycin and tylosin phos-
phate should be withdrawn;

(28) Whereas, on the basis of current scientific and
technical knowledge, it would appear, however, that
the evidence presented by the Kingdom of Sweden
does not justify withdrawal of the authorisations for
the antibiotics monensin sodium and salinomycin
sodium, of the ionophore group, since no iono-
phore is to date used in veterinary or human medi-
cine and the two substances, in the current state of
knowledge, do not select cross-resistance to antibi-
otics used in human or veterinary medicine;

(29) Whereas the prohibition on the use of the antibi-
otics bacitracin zinc, spiramycin, virginiamycin and
to be perceived as an
tylosin phosphate ought
interim protective measure taken as a precaution,
which could be reconsidered in the light of the
investigations which will have been carried out and
of the established surveillance programme;

(30) Whereas, on the basis of current scientific and
technical knowledge, it would also appear that the
evidence presented by the Kingdom of Sweden
does not justify a ban on the antibiotic flavophos-
pholipol of the phosphoglycopeptide group since
no substance belonging to the same group is to
date used in veterinary or human medicine and
flavophospholipol, in the current state of know-
ledge, does not select cross-resistance to antibiotics
used in human or veterinary medicine;

that

(31) Whereas, on the basis of current scientific and
technical knowledge it would appear
the
evidence presented by the Kingdom of Sweden
does not justify a ban on the antibiotic avilamycin,
belonging to the group of orthosomycins, since no
substance belonging to that group is to date used in
human medicine; whereas that decision will be
reviewed in the light of additional studies to be
supplied by the person responsible for the entry
into circulation of avilamycin, concerning the
mechanisms of
the development of
resistance in certain micro-organisms and in partic-
ular Enterococcus faecium, and any cross-resistance
to everninomycin, which is currently under devel-
opment with a view to future approval for use in
human medicine or to other substances used in
human medicine having the same site of action as
avilamycin;

resistance,

(32) Whereas the maintenance of the authorisations for
monensin sodium, salinomycin sodium, flavophos-
pholipol and avilamycin will have to be reviewed in
the light of the results of the work on antimicrobial
resistance carried out by the working group set up
by the Scientific Steering Committee;

(33) Whereas after 31 December 1998 the Kingdom of
Sweden is required to apply the Community legis-
lation on feed additives in its entirety;

(34) Whereas a transitional period to comply with the
provisions of this Regulation is necessary in the
Member States where one or more of the additives
referred to in Article 1 are authorised at present;

(35) Whereas,

in the absence of an opinion of

the
Standing Committee
the
Commission has been unable to adopt the provi-
sions it envisaged under the procedures laid down
in Articles 23 and 24 of Directive 70/524/EEC,

Feedingstuffs,

on

HAS ADOPTED THIS REGULATION:

Article 1

The entries in Annex B to Directive 70/524/EEC for the
following antibiotics shall be deleted:

— bacitracin zinc,

— spiramycin,

— virginiamycin,

— tylosin phosphate.

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Article 2

Article 3

The Commission shall reexamine the provisions of this
Regulation before 31 December 2000 on the basis of the
results given by

— the different investigations concerning the induction
of resistances by the use of the antibiotics concerned,
and

— the surveillance programme of microbial resistance in
animals which have received antibiotics, to be carried
out
responsible for
putting the additives concerned into circulation.

in particular by the persons

This Regulation shall enter into force on the day of its
publication in the Official Journal of the European
Communities.

It shall apply from 1 January 1999.

However, where, on the date on which this Regulation
enters into force, a Member State has not banned, in
accordance with Community law, one or more of the
antibiotics referred to in Article 1 of this Regulation, such
antibiotic or antibiotics shall remain authorised in that
Member State until 30 June 1999.

This Regulation shall be binding in its entirety and directly applicable in all Member
States.

Done at Brussels, 17 December 1998.

For the Council

The President

W. MOLTERER