Experiments with three new intramammary antibiotic combination products for the treatment of subclinical mastitis in lactating cows


Storper, M.; Bar Moshe, B.; Ziv, G.; Saran, A.

Refuah Veterinarith 38(4): 154-166

1981


The efficacy of 3 new intramammary antibiotic combination products in eliminating streptococci and staphylococci from subclinically infected udders of lactating cows, and the duration of antibiotic residues in milk were determined. Products tested were Amclox (75 mg ampicillin sodium and 200 mg cloxacillin sodium), Kanapen (250 mg kanamycin sulphate and 300 000 units procaine penicillin G), and Ampicet (100 mg ampicillin sodium and 200 mg cephalothine sodium). Each product was infused twice, with a 24 h interval, into the quarters of the udder. The efficacy of each of the products in eliminating streptococcal infections was rather high and compared favourably with the reported efficacy of products containing only penicillin G, only cloxacillin, and a combination of ampicillin and cloxacillin. With Amclox, the average cure rate of Staphylococcus aureus infection was 47.5 %, ranging between 12.1 and 87.8 % in 3 herds. Kanapen eliminated 79.2 and 88.6 % of S. aureus cow infections in 2 herds. Ampicet cured 66.0% of S. aureus cow infections in 5 herds although in one herd only 15.6% of the infections were eliminated. Antibiotic activity was found in milk up to 84 h after Amclox therapy, whereas the required milk withholding periods were 108 h and 48 h after treatment with Kanapen and Ampicet, respectively, (all in herds milking 3 times daily).

154
EXPERIMENTS
WITH
THREE
NEW
INTRAMAMMARY
ANTIBIOTIC
COMBINATION
PRODUCTS
FOR
THE
TREATMENT
OF
SUBCLINICAL
MASTITIS
IN
LACTATING
COWS
M.
STORPER
1
,
B.
BAR
MOSHE
2
,
G.
ZIV
1
and
A.
SARAN
1
1
Kimron
Veterinary
Institute,
P.O.Box
12,
Bet
Dagan
50250
2
Kimron
Veterinary
Institute,
Afula
SUMMARY
The
efficacy
of
3
new
intramammary
antibiotic
combination
products
in
elimina-
ting
streptococci
and
staphylococci
from
subdinically
infected
udders
of
lactating
cows,
and
the
duration
of
antibiotic
residues
in
milk
were
determined.
Products
tested
were
Amclox
(75
mg
ampicillin
sodium
and
200
mg
cloxacillin
sodium),
Kanapen
(250
mg
kanamycin
sulphate
and
300 000
units
procaine
penicillin
G),
and
Ampicet
(100
mg
ampicillin
sodium
and
200
mg
cephalothine
sodium).
Each
product
was
infused
twice,
with
a
24
h
interval,
into
the
quarters
of
the
udder.
The
efficacy
of
each
of
the
pro-
ducts
in
eliminating
streptococcal
infections
was
rather
high
and
compared
favourably
with
the
reported
efficacy
of
products
containing
only
penicillin
G,
only
cloxacillin,
and
a
combination
of
ampicillin
and
cloxacillin.
With
Amclox,
the
average
cure
rate
of
Staphylococcus
aureus
infection
was
47.5
%,
ranging
between
12.1
and
87.8
%
in
3
herds.
Kanapen
eliminated
79.2
and
88.6
%
of
S.
aureus
cow
infections
in
2
herds.
Ampicet
cured
66.0%
of
S.
aureus
cow
infections
in
5
herds
although
in
one
herd
only
15.6%
of
the
infections
were
eliminated.
Antibiotic
activity
was
found
in
milk
up
to
84
h
after
Amclox
therapy,
whereas
the
required
milk
withholding
periods
were
108
h
and
48
h
after
treatment
with
Kanapen
and
Ampicet,
respectively,
(all
in
herds
milking
3
times
daily).
INTRODUCTION
Intramammary
infusion
of
antimic-
robial
drugs
is
the
most
common
method
of
treating
bovine
mastitis.
In
strepto-
coccal
mastitis,
and
in
some
cases
of
staphylococcal
mastitis,
such
therapy
usually
results
in
a
clinical
cure,
but
the
bacteriological
cure
rate
is
low
(6,
9,
12,
14).Therapy
is
usually
initiated
by
the
farmer
without
bacteriological
diagnosis
and
most
cases
of
mastitis
are
unlikely
to
be
examined
for
pathogens
until
after
treatment
has
failed
to
rectify
clinical
manifestations.
The
attending
veterina-
rian
prescribing
the
treatment
faces
a
dilemma;
while
attempting
to
ensure
an
effective
treatment
againSt
the
common
penici
I
linase-producing
strains
of
Staphy-
lococcus
aureus,
he
must
also
consider
the
possibility
of
infection
with
Gram-
negative
organisms.
Treatment
with
in-
tramammary
antibiotic
products
contai-
ning
2
or
more
active
ingredients
may
be
the
logiCal
answer
to
this
problem.
This
report
describes
experiments
with
3
new
intramammary
antibiotic
combination
products
for
use
in
lacta-
Refuah
vet.,
38
(4)
1981
155
ting
cows.
The
products
were
developed
to
provide
a
broad
spectrum
treatment
of
Gram-positive
and
Gram-negative
ud-
der
pathogens
although
the
present
re-
port
investigates
the
elimination
of
the
former
organisms
only,
since
subclinical
mastitis
due
to
Gram-negative
bacteria
is
rare
(5).
MATERIALS
AND
METHODS
Studies
were
conducted.
in
11
large
commercial
dairy
herds,
over
a
21
month
period.
Cows
were
housed,
fed,
and
milked
under
the
usual
local
conditions;
milking
was
carried
out
3
times
daily
in
10
of
the
herds,
and
twice
daily
in
one
herd.
Milking-time
hygienic
measures
in
all
herds
comprised
a
pre-milking
udder
wash
with
tap
water
and
drying
the
ud-
der
with
disposable
paper
towels,
a
"top
flushing"
water
rinse
of
the
long
milk
line,
cluster
and
rubber
liners
with
3
-
4
I
of
tap
water
after
milking
each
cow,
and
post-milking
teat
disinfection
using
an
approved
iodine
teat
dip.
Intramammary
treatment
of
all
cows
at
drying
off
with
approved
"dry
cow"
antibiotic
products
has
been
practiced
in
the
herds
for
8
-10
years.
The
status
of
udder
health
in
the
herds
is
known
as
a
result
of
bacteriolo-
gical
tests
conducted
on
milk
samples
col-
lected
from
all
the
cows
at
least
once
a
year.
Herds
selected
for
the
present
study
were
those
in
which
the
level
of
subclinical
mastitis
due
to
S.
aureus
in-
fection
was
above
normal,
morbidity
being
between
35
and
60
%
of
the
cows.
Cows
selected
for
treatment
in
Herds
A,
B
and
J
were
in
their
first
or
second
lactation,
but
in
the
other
herds
older
cows
were
also
treated.
The
3
new
intramammary
antibiotic
products
(Vitamed,
Tel
Aviv),
available
in
10
ml
disposable
plastic
intramam-
mary
injectors
tested
were:
1.
Amclox,
containing
75
mg
ampicillin
sodium
and
200
mg
cloxacillin
sodium,
b.
Kanapen,
containing
250
mg
kanamycin
sulphate
and
300
000
units
procaine
penicillin
G,
c.
Ampicet,
containing 100
mg
ampicillin
sodium
and
200
mg
cephalothine
sodium
.
In
each
herd,
either
duplicate
quar-
ter
milk
samples
or
duplicate
composite
milk
samples
(8,15)
were
collected
for
bacteriological
analysis
(2)
immediately
before
treatment
and
10
-
14
d
after
treatment.
Each
quarter
of
the
udder
was
infused
twice,
with
a
24
h
interval,
with
a
given
product.
Repeat
treatment
/
with
Kanapen
and
Ampicet
was
made
in
\
some
cases.
A
cow
or
a
quarter
were
considered
infected
with
a
particular
udder
pathogen
if
the
bacteria
were
iso-
lated
from
both
duplicate
milk
samples
taken
before
treatment.
A
cow
or
a
quar-
ter
were
considered
cured
when
that
pa-
thogen
was
no
longer
isolated
from
both
milk
samples
collected
after
treatment.
For
residue
studies,
10
-20
lactating
cows
with
uninfected
udders,
producing
15
-
25
I
of
milk
daily,
were
treated
in
each
herd
with
one
of
the
products
ei-
ther
2
or
3
times
at
24
h
intervals.
Com-
posite
milk
samples
for
antibiotic
residue
assays
were
collected
at
each
milking
from
the
first
milking
after
the
first
treatment
to
the
tenth
milking
after
the
last
treatment.
Concentrations
of
ampi-
cillin
in
milk
were
determined
as
recent-
ly
described
(3).
Levels
of
penicillin
G
were
measured
using
Sarcina
lutea
ATCC
9431
as
a
test
organism
and
kanamycin
residues
were
determined,
after
penicil-
lin
G
activity
had
been
abolished
by
pe-
nicillinase,
using
Bacillus
subtilis
ATCC
6699
as
a
test
organism
(1).
Concentra-
tions
of
ampicillin
could
not
be
quanti-
tatively
distinguished
from
those
of
ce-
156
phalothine;
all
antibiotic
activity
in
these
samples
was,
therefore,
expressed
as
ce-
phalothine.
Sensitivity
limits
of
the
as-
say
methods
for
detecting
antibiotic
re-
sidues
were:
for
penicillin
G
0.01
units/
ml,
for
ampicillin,
cloxacillin
and
cepha-
lothine
0.02
mg/m!,
and
for
kanamycin
0.1
bigirn
I
.
RESULTS
Amclox
S.
aureus
was
isolated
before
Am-
clox
treatment
from
122
quarters
of
56
cows
in
Herds
A,
B
and
C,
and
from
64
quarters
of
46
cows
after
treatment
(Table
1).
The
average
quarter
cure
rate
varied
widely
from
12.1
%
in
Herd
A
to
87.8
%
in
Herd
B
with
an
average
of
47.5
%.
Cure
rate
on
the
basis
of
cows
was
lower
than
the
quarter
cure
rate,
ranging
from
0.0
%
in
Herd
A
to
60.0
%
in
Herd
B,
with
an
average
of
18.0
%.
Kanapen
The
first
course
of
treatment
(Table
2)
eliminated
88.6%
of
35
S.
aureus
cow
infections
in
Herd
D
and
79.2
%
of
24
S.
aureus
cow
infections
in
Herd
E
(an
average
of
85.7
%),
83.3
%
of
42
Strep-
tococcus
agalactiae
cow
infections
in
Herd
D
and
90.8
%
of
the
87
Strep.
aga-
lactiae
cow
infections
in
Herd
E
(an
ave-
rage
of
88.4%),
81.8%
of
11
non-agalac-
tiae
streptococci
cow
infections
in
Herd
D
and
90.0
%
of
10
such
infections
in
Herd
E
(an
average
of
85.7
%
).
Ampicet
Treatment
with
Ampicet
eliminated
more
than
90
%
of
staphylococcal
and
streptococcal
cow
infections
in
Herd
F
(Table
3)
where,
before
treatment,
ap-
proximately
60
%
of
the
coves
had
been
infected
with
these
udder
pathogens.
Elimination
of
79.5
%
of
S.
aureus
and
87.3
%
of
Strep.
agalactiae
cow
infec-
tions
in
Herd
G,
56.8
%
of
S.
aureus
cow
infections
in
Herd
H,
and
15.6
%
and
80.9
%
of
S.
aureus
cow
infections
in
Herd
I
and
J,
respectively,
was
achie-
ved
(Tables
4
and
5).
In
Herd
J,
older
cows
had
a
cure
rate
of
43.3
%,.
The
overall
efficacy
of
Ampicet
in
curing
S.
aureus
cow
and
quarter
infections
was
66.0
%
and
50.7
%,
respectively.
Antibiotic
residues
Concentrations
of
ampicillin
and
cloxacillin
'in
milk
after
2
or
3
intramam-
mary
infusions
of
Amclox
to
cows
milked
2
or
3
times
daily
are
presented
in
Figs
1
and
2.
Ampicillin
concentra-
tions
were
consistently
lower
than
those
of
cloxacillin.
Cloxacillin
was
not
detec-
ted
in
milk
samples
collected
on
the
8th
milking
(96
h
after
treatment)
from
cows
milked
twice
daily
(Fig.
1),
nor
in
milk
samples
collected
on
the
10
th
milking
(80
h
after
treatment)
from
cows
milked
3
times
daily
(Fig.
2).
Kanamycin
concentrations
in
milk
were
considerably
higher
than
those
of
penicillin
G
after
Kanapen
infusion
into
cows
milked
2
(Fig.
3)
or
3
times
daily
(Fig.
4).
Kanamycin
was
not
detected
in
milk
samples
collected
on
the
10
th
milking
(120
h
after
treatment)
from
cows
milked
twice
daily,
and
on*the
10
th
milking
(80
h
after
treatment)
from
cows
milked
3
times
daily.
Antibiotic
concentrations,
expres-
sed
in
terms
of
cephalothine,
in
milk
fol-
lowing
3
infusions
of
Ampicet
to
cows
milked
3
times
daily
are
shown
in
Fig.
5.
Antibiotic
activity
was
found
in
milk
samples
collected
up
to
the
6
th
milking
(48
h
after
the
last
treatment).
Table
1.
Efficacy
of
intramammary
treatment
with
the
product
Amclox
(75
mg
ampicillin
sodium
and
200
mg
cloxacillin
sodium)
in
the
treatment
of
subclinical
Staphylococcus
aurcus
mastitis
Herd
Number
of
before
treatment
s
in
cows
in
quarters
.
infections
after
treatment
in
cows
in
quarters
Cure
rate
in
cows
(%)
in
quarters
(%)
A
20
33
20
29
0.0
12.1
B
5
9
2
2
60.0
87.8
C
31
80
24
33
22.6
58.7
Total
56
122
46
64
18.0
47.5
l
86
L
W
)
"T
a
n
y
e
ni
alg
Table
2.
Efficacy
of
intramammary
treatment
with
the
product
Kanapen
(250
mg
kanamycin
sulphate
and
300
000
units
procaine
penicillin
G)
in
the
treatment
of
subclinical
mastitis
due
to
streptococci
and
staphylococci
Cow
infections
due
to
Staphylococcus
aureus
Before
After
Cure
rate
Non-agalactiae
streptococci
Before
After
Cure
rate
Streptococcus
agalactiae
Before
After
Cure
rate
Herd
treatment
treatment
treatment
(%)
treatment
treatment
(%)
treatment
treatment
(%)
First
35
4
88.6
11
2
81.8
42
7
83.3
D
Second
4
2
50.0
2
0
100.0
7
4
57.1
Third
2
1
50.0
First
24
5
79.2
10
1
90.0
87
8
90.8
E
Second
5
1
80.0
1
0
100.0
8
2
75.0
Third
1
0
100.0
2
1
50.0
Table
3.
Efficacy
of
intramammary
treatment
with
the
product
Ampicet
(100
mg
ampicillin
sodium
and
200
mg
cephalothine
sodium)
in
the
treatment
of
subclinical
mastitis
due
to
streptococci
and
staphylococci
Cow
infection
due
to
Staphylococcus
aureus
Non-agalactiae
streptococci
Streptococcus
agalactiae
Herd
Treatment
Before
After
Cure
rate
Before
After
Cure
rate
Before
After
Cure
rate
treatment
treatment
(%)
treatment
treatment
(%)
treatment
treatment
(%)
First
65
5
92.3
9
0
100.0
85
7
91.8
F
Second
5
1
80.0
7
0
100.0
Third
1
0
100.0
-
-
Table
4.
Efficacy
of
intramammary
treatment
with
the
product
Ampicet
(100
mg
ampicillin
sodium
and
200
mg
cephalothine
sodium)
in
the
treatment
of
subclinical
mastitis
due
to
streptococci
and
staphylococci
Cow
infection
due
to
Staphylococcus
aureus
Before
After
Cure
rate
Herd
treatment
treatment
(%)
Streptococcus
agalactiae
After
Cure
rate
treatment
(%)
G
83
17
79.5
63
8
87.3
H
37
16
56.8
Before
treatment
L8
6
t
U)
8
£
"t
an
y
enj
au
6
8
6
4
2
1.
0.8
0.6
0.4
0.2
0.1
0.08
0.06
0.04
100
10
80-
Ampicillin
o
Cloxacillin
60
40
T
3
0.02
8
16
21
8
16
24
8
16
24
32
40
48
56
64
72
Hours
after
treatments
20-
10-
8-
Ci
6
0)
+
4.
3
1.0-
0.8
-
0.6-
0-4-
C
c
0.2-
0
0.10-
008
006--
0.04
Nib
2
E
O
12
0
1
12
12
24
12
.
24
36
48
60
Hours
after
treatments
84
96
Ampicillin
o
Cloxacillin
Fig.
1.
Concentration
of
ampicillin
(•)
and
cloxacillin
(0)
in
the
milk
of
12
cows
following
2
intramammary
infusions,
at
24
h
intervals,
of
the
product
Amclox.
Cows
were
milked
twice
daily
Fig.
2
.
Concentrations
of
ampicillin
(S)
and
cloxacillin
(0)
in
the
milk
of
10
cows
following
3
intramammary
infusions,
at
24
h
intervals,
of
the
product
Amclox.
Cows
were
milked
3
times
daily
1861
(b)
8
£
'o
n
g
enj
au
0$
,.
.
I
\
Penicillin
G
i
...•
Kanamycin
I
l
t‘
\
....../.
i
•-• ••..
\
i
I\
I
030
004
22
is
24
is
24
"
40
46
56
64
72
SO
Hours
after
treatments
I
TI
24
It
24
es
Hours
IOW
treatments
Fig.-
3.
Concentrations
of
kanamycin
(0)
and
penicillin
G
(0)
in
the
milk
of
10
cows
following
2
intramammary
infusions,at
24
h
intervals,
of
the
product
Kanapen.
Cows
were
milked
twice
daily
Fig.
4.
Concentrations
of
kanamycin
(*)
and
penicillin
G
(0)
in
the
milk
of
20
cows
following
2
Intramammary
infusions,at
24
h
intervals,
of
the
product
Kanapen.
Cows
were
milked
3
times
daily
but
the
first
milking
after
each
treatment
was
omitted
Refuah
vet.,
38
(4)
1981
163
Cephalothine
40-
20-
10
-
8
-
6
-
2.-
rn
c
E
0
8
-
2-
T3
0.1
a
11
6
24
1
1
6
24
8
16
24
32
40
48
I
Hours
after
treatments
Fig.
5
Concentrations
of
cephalothine
in
the
milk
of
12
cows
following
3
intramammary
infusions,
at
24
h
intervals,
of
the
product
Ampicet.
Cows
were
milked
3
times
daily
164
DISCUSSION
The
efficacy
of
the
intramammary
antibiotic
combination
products
exa-
mined
in
eliminating
Strep.
agalactiae
and
non-agalactiae
streptococci
infecti-
ons
in
lactating
cows
was
rather
high
and
compared
favourably
with
the
re-
ported
efficacy
of
intramammary
pro-
ducts
containing
only
penicillin
G
(7,
12,13),
only
sodium
cloxacillin
(4,7),
and
a
combination
of
ampicillin
and
cloxacillin
(7,17).
Comparative
data
are
not
availa-
ble
regarding
the
efficacy
of
intramam-
mary
therapy
with
a
combination
of
ampicillin
and
cloxacillin
in
subclinical
S.
aureus
mastitis
in
lactating
cows,
but
the
efficacy
of
the
combination
was
as-
sessed
in
the
treatment
of
clinical
mas-
titis.
In
one
study
(17),
ampicillin
and
cloxacillin
(75
mg
and
75
mg)
were
in-
fused
3
times
at
24
h
intervals
and
this
treatment
eliminated
39.6
%
of
106
clinical
S.
aureus
infections.
In
that
same
study,
ampicillin
and
cloxacillin
(75
mg
and
200
mg)
therapy
cured
64.1
%
of
92
clinical
S.
aureus
infections
but
ano-
ther
report
(7),
summarizing
experiments
with
ampicillin
and
coxacillin
(100
mg
and
100
mg,
and
100
mg
and
200
mg),
indicated
that
elimination
was
less
than
30
%.
Cure
rates
for
subclinical
S.
aureus
infections
are
usually
higher
than
the
ef-
ficacy
of
the
same
intramammary
drug
product
in
the
treatment
of
clinical
S.
aureus
mastitis
(10,11).
In
the
present
study,
47.5
%
of
122
S.
aureus
quarter
infections
were
eliminated
following
2
infusions
of
Amclox
but
large
variations
in
cure
rate
were
observed
among
the
treated
herds.
Despite
the
fact
that
trea-
ted
cows
in
Herds
A
and
B
were
either
in
their
first
or
second
Iactations,
and
the
ample
documentation
the
bacterio-
logical
cure
rates
in
young
cows
are
con-
siderably
higher
than
in
older
cows
trea-
ted
with
the
same
intramammary
anti-
biotic
product
(7,9,10,11,16,18),
no
age
dependent
cure
rates
were
evident
(Ta-
ble
1).
The
efficacy
of
Kanapen
in
the
trea-
tment
of
S.
aureus
mastitis
appeared
to
be
higher
than
that
of
Amclox,
and
these
differences
should
be
examined
in
view
of
the
88.6
%
cure
achieved
in
Held
D
where
older
cows
were
included
among
the
35
cows
treated
(Table
2).
Large
interherd
variations
in
cure
ra-
te
of
S.
aureus
cow
infections,
ranging
be-
tween
15.6%
(Herd
I)
and
92.3%
(Herd
F),
were
observed
following
treatment
with
Ampicet.
Such
variations
in
res-
ponse
among
different
herds
have
been
observed
elsewhere
(5)
but
no
.
explana-
tion
has
been
offered
for
these
findings.
Other
investigators
(19)
found
that
in-
terherd
difference
in
cure
rates
for
S.
aureus
infections
were
larger
than
va-
riations
between
products
when
the
ef-
ficacy
of
3
dry
cow
antibiotic
products
was
evaluated
in
14
herds.
We
believe
that
a
consistently
good
response
in
many
herds
should
be
an
important
cri-
terion,
in
addition
to
high
cure
rates,
in
evaluating
intramammary
antibiotic
ther-
apy
of
S.
aureus
mastitis.
Intramammary
antibiotic
therapy
given
to
all
cows
subclinically
infected
with
staphylococci
("blitz
therapy")
cannot
be
applied
regularly
in
a
herd
as
part
of
a
mastitis
control
system
because
of
the
expenses
incurred
in
discarding
antibiotic-contaminated
milk
and
the
cost
of
bacteriological
testing.
It
has,
however,
2
important
advantages
over
other
means
of
therapy.
It
reduces
the
level
of
infection
in
a
herd
by
50
-
75
%,
therefore
minimizing
reinfection.
This
may
be
important
in
herds
with
high
Refuah
vet.,
38
(4)
1981
165
(more
than
45
%)
levels
of
staphylococ-
cal
infections
of
cows.
Such
herds
may
be
detected
through
a
high
clinical
in-
cidence
of
mastitis
or
a
consistently
high
cell
count
in
bulk
tank
milk
(7).
Second-
ly,
"blitz
therapy"
can
be
of
value
in
se-
lecting
potentially
more
efficacious
in-
tramammary
antibiotic
products
for
the
treatment
of
clinical
mastitis.
Although
analysis
of
the
efficacy
of
treatment
of
clinical
mastitis
must
be
based
on
fin-
dings
from
clinical
cases,
it
is
extremely
difficult,
if
not
entirely
impossible,
to
gather
sufficient
meaningful
data
from
such
cases
for
analysis.
This
is
due
to
the
sporadic
nature
of
the
disease,
the
multiplicity
of
bacteriological
agents
involved,
herd
and
age
variables,
as
well
as
the
effect
of
concurrent
parenteral
antibiotic
and
non-antibiotic
supportive
therapy.
With
these
in
mind
the
present
study
suggests
that
Kanapen
and
Ampi-
cet
may
be
slightly
superior
to
Amclox
in
the
therapy
of
subclinical,
and
per-
haps
clinical,
streptococcal
and
staphy-
lococcal
mastitis
in
lactating
cows.
The
rather
short
withholding
period
required
for
milk
following
Ampicet
therapy
(6
milkings
after
the
last
treatment)
can
re-
sult
in
a
lower
total
cost
of
therapy
com-
pared
to
the
cost
of
Kanapen
therapy
which
requires
discarding
milk
for
9
mil-
kings
(72
h
after
the
last
treatment)
in
herds
milking
3
times
daily,
and
9
mil-
kings
(108
h)
in
herds
milking
2
times
daily.
ACKNOWLEDGEMENT
This
study
was
supported
in
part
by
a
grant
from
Vitamed
Ltd.,
Tel
Aviv.
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