Persistence of gentamicin residues in milk after the intramammary treatment of lactating cows for mastitis


Tan, X.; Jiang, Y-wen.; Huang, Y-jun.; Hu, S-hua.

Journal of Zhejiang University. Science. B 10(4): 280-284

2009


This study was designed to investigate persistence of gentamicin residues in milk after the intramammary treatment of lactating cows for mastitis. Milk samples were collected at a 1-d interval after the last administration from 34 individual cows that had received intramammary infusions of gentamicin. The doses and treatment times evaluated in this study represented those that have been applied by veterinarians in practice. The tetrazolium chloride assay was used to determine whether there were significant residues of the antibiotic in the samples. Persistence of detectable drug residues in milk from 33 cows (28 cows, <or=6 infusions at <or=0.7 g gentamicin; and 5 cows, 2 infusions at 0.8 g gentamicin) did not exceed 5 d; but 1 cow (5 infusions at 0.8 g gentamicin) had detectable residues in its milk for 9 d. Our results suggest that a 5-d milk withdrawal period might be insufficient to secure the clearance of the contamination of gentamicin, because treatment times and dosages contribute to the antibiotic clearance. A larger scale of samples are needed for further investigations.

280
Tan
et
aL
/
J
Zhejiang
Univ
Sci
B
2009
10(4):280-284
Journal
of
Zhejiang
University
SCIENCE
B
ISSN
1673-1581
(Print);
ISSN
1862-1783
(Online)
www.zju.edu.cn/jzus;
www.springerlink.com
E-mail:
Persistence
of
gentamicin
residues
in
milk
after
the
intramammary
treatment
of
lactating
cows
for
mastitis
*
Xun
TAN,
Ye-wen
JIANG,
Yi-jun
HUANG,
Song-hua
HUn
(Department
of
Veterinary
Medicine,
Zhejiang
University,
Hangzhou
310029,
China)
tE-mail:
Received
June
3,
2008;
Revision
accepted
Jan.
16,
2009;
Crosschecked
Jan.
6,
2009
Abstract:
This
study
was
designed
to
investigate
persistence
of
gentamicin
residues
in
milk
after
the
intramammary
treatment
of
lactating
cows
for
mastitis.
Milk
samples
were
collected
at
a
1-d
interval
after
the
last
administration
from
34
individual
cows
that
had
received
intramammary
infusions
of
gentamicin.
The
doses
and
treatment
times
evaluated
in
this
study
represented
those
that
have
been
applied
by
veterinarians
in
practice.
The
tetrazolium
chloride
assay
was
used
to
determine
whether
there
were
sig-
nificant
residues
of
the
antibiotic
in
the
samples.
Persistence
of
detectable
drug
residues
in
milk
from
33
cows
(28
cows,
<6
infusions
at
<0.7
g
gentamicin;
and
5
cows,
2
infusions
at
0.8
g
gentamicin)
did
not
exceed
5
d;
but
1
cow
(5
infusions
at
0.8
g
gentamicin)
had
detectable
residues
in
its
milk
for
9
d.
Our
results
suggest
that
a
5-d
milk
withdrawal
period
might
be
insufficient
to
secure
the
clearance
of
the
contamination
of
gentamicin,
because
treatment
times
and
dosages
contribute
to
the
antibiotic
clearance.
A
larger
scale
of
samples
are
needed
for
further
investigations.
Key
words:
Gentamicin,
Mastitis,
Intramammary
infusion,
Residue
doi:10.1631/jzus.B0820198
Document
code:
A
CLC
number:
R15
INTRODUCTION
Antibiotic
residues
in
milk
are
of
great
concern
to
dairy
farmers,
milk
processors,
regulatory
agencies,
and
consumers.
The
presence
of
antimicrobial
drug
residues
in
milk
can
provoke
allergic
reactions
in
some
hypersensitive
individuals
(Dewdney
et
al.,
1991;
Dayan,
1993)
and
may
induce
resistant
popu-
lations
of
bacteria
that
do
not
respond
to
treatments
commonly
used
for
human
illnesses
(Nijsten
et
al.,
1996;
van
den
Bogaard
et
al.,
2001).
Drug
residues
also
alter
the
processing
qualities
of
raw
milk
by
inhibiting
starter
cultures
used
in
the
preparation
of
cheese
and
other
fermented
dairy
products
(Brady
and
Katz,
1988).
Pasteurization
and
other
forms
of
heat
treatment
eliminate
pathogenic
microorganisms
but
Corresponding
author
Project
supported
by
the
Science
and
Technology
Department
of
Zhejiang
Province
(Nos.
2005C12015
and
2007C32025)
and
the
Education
Department
of
Zhejiang
Province
(No.
20061319),
China
have
limited
or
variable
effects
on
drug
residues
(Moats,
1988).
In
order
to
keep
antibiotic
residues
out
of
the
food
chain
of
humans,
regulatory
authorities
have
established
the
withdrawal
period
for
antibiotics
that
must
be
observed
by
producers
before
the
milk
from
the
treated
cows
can
be
sent
to
market.
In
China,
the
withdrawal
period
for
all
antibiotics
in
lactating
cows
is
5
d
(Tan
et
al.,
2007).
Nevertheless,
drug
residues
in
marketed
milk
continue
to
occur
(Wu
et
al.,
2002;
Deng
et
al.,
2004;
Bai
et
al.,
2005;
He
and
Wang,
2007).
Other
than
the
report
by
Tan
et
al.(2007), very
little
empirical
work
has
been
done
in
China
to
verify
whether
the
present
5-d
withdrawal
period
can
be
used
as
a
reliable
measure
to
prevent
milk from
being
significantly
contaminated
with
approved
antibiotics,
let
alone
with
drugs
that
are
not
approved
for
use
in
dairy
cows
but
commonly
used
on
dairy
farms.
Worldwide,
mastitis
is
the
most
common
dis-
ease
in
dairy
cattle.
The
use
of
antibiotic
therapy
to
treat
and
prevent
udder
infections
in
cows
is
a
key
Tan
et
al.
/
J
Zhejiang
Univ
Sci
B
2009
10(4):280-284
281
component
of
mastitis
control
(Hillerton
et
al.,
1999).
However,
intramammary
infusion
of
antibiotics
for
mastitis
therapy
was
cited
as
a
major
reason
for
milk
contamination
(McEwen
et
al.,
1991;
Wilson
et
al.,
1998).
Gentamicin,
an
aminoglycoside
antibiotic
known
to
be
useful
in
the
treatment
of
conform
and
other
gram-negative
pathogens
(Burrows
et
al.,
1987),
is
extralabely
applied
for
the
treatment
of
mastitis
by
intramammary
route
on
some
Chinese
farms.
Al-
though
the
withholding
time
for
gentamicin
after
intramammary
administration
has
not
been
officially
recommended,
farmers
and
veterinarians
often
im-
plement
milk
discard
time
of
5
d,
as
mentioned
above
for
approved
drugs.
This
study
was
conducted
to
investigate
if
there
were
significant
residues
of
this
drug
in
milk
over
a
5-d
withdrawal
period
after
in-
tramammary
infusions.
MATERIALS
AND
METHODS
Animals
Thirty-four
mastitic
cows
in
a
commercial
herd
in
a
suburb
of
Hangzhou
City,
China
were
used
in
this
study.
A
case
of
clinical
mastitis
was
defined
as
that
a
cow
had
one
quarter
that
was
enlarged
or
reddened
and
milk from
this
quarter
was
visibly
abnormal.
The
selected
cows
were
all
lactating
Holsteins
in
their
3rd-4th
lactation
cycles.
They
were
milked
thrice
a
day
into
individual
buckets,
at
an
8-h
interval
(at
06:00,
14:00,
22:00),
through
the
duration
of
the
study.
These
cows
varied
considerably
in
their
daily
milk
production
at
the
time
of
this
experiment
(kg
milk/d
on
the
day
of
enrollment,
mean=14.4,
ranging
9.2-A
9.7).
Treatment
and
milk
sampling
Commercial
gentamicin
sulfate
infusion
(80
mg/2
ml,
with
sodium
carbonate
and
natrium
bisul-
furosum
as
adjuvant)
was
infused
into
the
affected
quarter
of
each
cow
once
daily
following
morning
mincing,
with
a
frequency
from
2
to
6
infusions
at
a
dose
range
of
0.3
to
0.8
g
(Table
1).
The
doses
and
treatment
times
evaluated
in
this
study
represented
those
that
have
been
applied
by
veterinarians
in
practice.
The
animals
had
not
been
treated
with
any
antibiotic
at
least
30
d
prior
to
gentamicin
admini-
stration.
Milk
samples
were
taken
from
each
whole
milking
from
each
cow
at
a
1-d
interval,
starting
24
h
after
the
last
dose
of
antibiotic
and
continuing
until
no
gentamicin
could
be
detected.
Assay
The
gentamicin
was
detected
by
the
tetrazolium
chloride
assay,
a
microbiological
screening
test
ap-
proved
in
China
for
the
evaluation
of
antibiotic
resi-
dues
in
milk
(Ministry
of
Health
of
the
People's
Re-
public
of
China,
Standardization
Administration
of
the
People's
Republic
of
China,
2003).
The
antibi-
otic-free
milk
was
supplied
by
Hangzhou Meilijian
Dairy
Company.
The
tetrazolium
chloride
was
pur-
chased
from
Sinopharm
Chemical
Reagent
Company
(Beijing,
China)
and
the
standard
gentamicin
from
National
Institute
for
the
Control
of
Pharmaceutical
and
Biological
Products
(Beijing,
China).
Milk
sam-
ples
(9
ml
each)
were
heated
in
water
at
80
°C
for
5
min,
cooled
to
37
°C,
and
then
1
ml
of
culture
of
Streptococcus
thermophilus
diluted
1:1
(v/v)
with
skimmed
milk
was
added
to
each
sample.
The
sam-
ples
were
incubated
in
water
at
36
°C
for
another
2
h,
then
0.3
ml
of
4%
(v/v)
tetrazolium
chloride
was
added
to
each
sample,
and
they
were
incubated
again
at
36
°C. The
color
change
of
each
sample
was
viewed
after
15
min;
samples
that
turned
red
were
considered
as
negative
for
antibiotic
residues,
and
those
that
did
not
change
color
were
considered
as
positive.
Antibiotic-free
milk
was
analyzed
along
with
the
milk
samples
to
verify
test
accuracy.
Pre-
liminary
experiments
showed
that
the
minimum
limit
of
this
assay
for
detection
of
standard
gentamicin
was
200
µg/kg
milk,
which
meets
the
standard
for
the
maximum
residual
concentration
approved
by
the
Ministry
of
Agriculture
of
China
(Bureau
of
Hus-
bandry
and
Veterinary,
Ministry
of
Agriculture
of
the
People's
Republic
of
China,
2003).
RESULTS
The
results
are
shown
in
Table
1.
All
the
cows
had
milk
with
gentamicin
residues
in
the
first
milking
after
their
last
treatment.
The
milk
samples
from
the
2
cows
treated
6
times
at
dose
of
0.3
g
were
gentamicin-
positive
for
1
d
after
the
last
dose.
Gentamicin
per-
sisted
for
1-5
d
in
the
milk
samples
from
the
26
cows
that
had
received
2
to
6
infusions
at
doses
ranging
282
Tan
et
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/
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Zhejiang
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2009
10(4):280-284
from
0.4
to
0.7
g.
Among
the
6
cows
given
0.8
g
gentamicin
per
dose,
the
5
treated
twice
required
1
to
5
d
for
their
milk
to
become
antibiotic-negative;
however,
the
one
treated
5
times
did
not
produce
gentamicin-negative
milk
until
9
d
after
the
last
administration.
Table
1
Persistence
of
tetrazolium
chloride
(TTC)-
positive
milk
following
the
intramammary
infusion
of
gentamicin
for
mastitis
therapy
Gentamicin
(g/dose)
ni
n
c
t
(d)
0.3
6
2
1
0.4
2
4
1-4
4
2
1-2
0.5
3
2
1
4
4
1-5
5
2
2-3
6
8
1-5
0.6
5
1
3
0.7
6
3
1-5
0.8
2
5
1-5
5
1
9
number
of
intramammary
infusions;
n
c
:
number
of
cows;
t:
period
of
persistence
of
TTC-positive
in
milk
(days
shortest
to
longest)
With
regard
to
the
longest
days
of
detectable
gentamicin
residues
in
response
to
different
therapy
regimens,
our
results
show
that
the
persistence
of
residues
in
milk
tended
to
be
extended
with
increased
treatment
times
at
a
given
dose,
with
an
exception
of
milk
from
the
cows
treated
with
0.4
g
gentamicin
per
dose.
Similarly,
cows
received
elevated
doses
of
gentamicin
at
the
same
infusions
seemed
to
have
prolonged
drug
residues
in
milk.
DISCUSSION
Gentamicin
is
potentially
ototoxic
and
nephro-
toxic
and
is
known
to
cause
immune
deficiencies
leading
to
drug
resistant
bacteria
in
animals
and
hu-
mans
(Ramsden
et
al.,
1980;
Frazier
et
al.,
1988;
Garg
et
al.,
1991;
Thibault
et
al.,
1994;
Weir
and
Mdzumdar,
1994).
Therefore,
its
residues
in
animal-
originated
foods
are
of
particular
public
concern.
In
many
countries
such
as
the
US,
the
drug
is
not
ap-
proved
for
use
in
dairy
cattle
and
the
extralabel
use
of
this
drug
is
not
encouraged
(Payne
et
al.,
1999;
Smith
et
al.,
2005).
In
China,
gentamicin
has
also
been
ex-
cluded
from
the
approved
drugs
for
dairy
cows.
However,
extralabel
use
of
this
antibiotic
is
in
fact
very
common.
With
the
extensive
use
of
gentamicin
in
dairy
cows,
some
mastitis
pathogens
showed
re-
sistance
to
this
drug
(Wang
et
al.,
2006).
In
order
to
improve
its
therapeutic
effect
on
mastitis,
many
vet-
erinarians
often
administer
larger
doses
and
more
frequent
treatments,
a
practice
that
is
likely
to
in-
crease
the
risk
of
drug
residues
in
cow's
milk.
In
the
present
study,
the
periods
for
which
the
milk
of
individual
cows
contained
detectable
residues
of
gentamicin
were
wide
variable.
However,
as
re-
ported
in
the
study
of
Pedersoli
et
al.(1995),
increased
treatment
times
were
prone
to
prolong
milk
residues
when
cows
were
treated
at
the
same
doses
of
gen-
tamicin.
This
trend
was
particularly
obvious
in
the
cows
that
had
received
intramammary
infusions
of
the
antibiotic
at
doses
of
0.5
and
0.8
g.
In
addition
to
the
treatment
times,
the
dose
of
aminoglycoside
antibiotics
was
also
found
to
influ-
ence
the
elimination
of
drug
residues
in
milk
fol-
lowing
intramamary
infusions
(Moretain
and
Bois-
seau,
1993).
In
the
present
study,
increased
doses
tended
to
extend
the
persistence
of
drug
residues
as
well.
For
example,
the
cows
that
were
treated
5
times
at
doses
of
0.5
g
had
gentamicin
residues
for
2-3
d.
However,
the
cow
receiving
5
treatments
at
a
daily
dose
of
0.8
g
required
9
d
for
its
milk
to
become
an-
tibiotic-undetectable.
Extended
residue
periods
were
also
observed
in
milk
from
the
cows
treated
4
times
as
well
as
from
those
treated
6
times
at
increased
doses
of
gentamicin.
In
context,
despite
the
fact
that
only
1
of
34
cows
had
detectable
drug
residues
for
more
than
5
d,
our
results
do
not
suggest
that
a
5-d
withdrawal
interval
might
be
long
enough
to
prevent
milk
from
being
contaminated
with
this
antibiotic.
Notably,
although
tetrazolium
chloride
assay may
be
reliable
for
testing
drug
residues
in
milk
samples
from
individual
mas-
titic
cows
(Tan
et
al.,
2007),
this
microbial
inhibitor
test
may
be
less
sensitive
or
accurate
than
other
tests
such
as
liquid
and
gas
chromatography
(Schenck
and
Callery,
1998;
Anderson
et
al.,
1998;
Popelka
et
al.,
2003).
It
is
thus
reasonable
to
speculate
that
more
milk
samples
would
have
been
detected
to
have
sig-
nificant
antibiotic
residues
after
5
d
using
more
sen-
sitive
tests.
Tan
et
al.
/
J
Zhejiang
Univ
Sci
B
2009
10(4):280-284
283
Overall,
our
results
indicate
that
simply
follow-
ing
a
5-d
withdrawal
period
after
extralabel
use
of
gentamicin
in
lactating
cows
may
not
ensure
the
safety
of
milk
products.
To
reduce
the
potential
for
significant
antibiotic
residues,
an
ideal
method
is
to
test
milk
samples
from
individual
treated
cows
and
then
discard
the
milk
with
positive
results.
However,
this
would
be
impracticable
on
many
farms
in
China.
Therefore,
veterinarians
should
be
discouraged
to
use
gentamicin
in
dairy
cattle
and
be
aware
that
there
are
other
drugs
to
treat
bovine
mastitis
that
are
less
po-
tential
for
residues.
References
Anderson,
K.L.,
Moats,
W.A.,
Rushing,
J.E.,
O'Carroll,
J.M.,
1998.
Detection
of
milk
antibiotic
residues
by
use
of
screening
tests
and
liquid
chromatography
after
in-
tramammary
administration
of
amoxicillin
or
penicillin
G
in
cows
with
clinical
mastitis.
Am.
J.
Vet.
Res.,
59(9):
1096-1100.
Bai,
J.,
Liang,
W.,
Sun,
H.,
Cao,
J.,
Huang,
S.,
2005.
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nation
of
residue
of
antibiotics
in
pure
milk
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