In a group of nine patients undergoing total hip replacement,. 500 milligrams or 1 gram of cephaloridine was mixed with each packet. ofSimplex cement.
CEPHALOSPORINS
IN
STUDIES SEAN
From
HUGHES,
the
Royal
The properties the
temperature,
CHRISTINE
National
A.
of each cement
a total
of between
bathing fluid. the antibiotic, In
Hand mixing the mixture
a group
cephaloridine drainage fluid the amount of after operation. the urine and implanted with hours
after
Many
of
of
ofdry being
nine
and
following
totaljoint
stable
patients
have
confirmed
anaerobic,
prosthetic
the
that
can
a wide
total
spectrum
of
deep
to reduce
1973;
the
time of operation, Eftekhar (1 969) results, the concept incidence
antibiotics
deep infection replacement. vented
to
negative
techniques
(Ericson,
be
96
to
from developing For deep-seated
also
for
reprints
vitro
in buffer
500
after
at body
activity
after
185 days. Antibiotic more slowly for some
was eventually
replacement,
recovered
In an even milligrams
from
the
distribution
of
or
of
1 gram
passed by the patients, and the operation, were collected and patients for up to fourteen days and was subsequently found in and 3.6 per cent of antibiotic ofit during the first forty-eight
should
be
sent
joint preGram-
anaerobic.
the
Unit,
} Gla.xo
Glaxo
The
exothermic
Royal Research
Laboratories
to have
Postgraduate
the
no effect
upon
the
mechani-
cement, to diffuse out a local effect, and to offer
slowly, minimal
risk
of allergic or other side-effects. There have been several studies of the suitability of antibiotics for incorporation into bone cement in recent years. Medcraft and Gardner because of its low allergenic effective, however, against Levin (1975) into Simplex
of
tested P bone of
range and,
and
varied.
studied
that
the
the pattern
no
effective
organisms
could
be
retained their activity but long-term retention
Picknell, release
of antibiotics mixed although some were
bactericidal,
Gram-negative
All the antibiotics the hardening process
activity
concluded
(1 974) studied fusidic acid and toxic potentials; it is not Gram-negative bacteria.
a wide cement
broad-spectrum
inhibition
(1977)
preparation and
or
during
to Mr
the
primary to be
process,
detected. through
Dash,
to prevent
the
aerobic
to be stable
and
introduced cement
cement
F. Hughes, MS., F.R.C.S., Orthopaedic OHS, England. C. A. Field, B.Sc., bacteriologist M. R. K. Kennedy, B.Sc., bacteriologist Dash, Head of Medical Department, for
hip
both
include
Hughes,
Gram-positive
whether
needs
bone
after
Lidgren
after infections
in bone
bactericidal
organisms,
antibiotic
Requests
antibiotic
by an antibiotic
needs
S. P. W12 Miss Miss C. H.
an
or a have of
of infection
Alternative
systemic
of adding
after then
immersion,
cal stability of retaining primarily
infection
(Fitzgeraldetal.
Lindberg 1973; Coventry et a!. 1974; Benson and Field 1978). In 1 970, Buchholz and Englebrecht idea
activity
ford
examinedin
lost antibacterial
still
in the cement
hardening
Gram-negative,
cause
replacement
replacement.
use
was after
DASH
Green
bathed
powder and cement powder resulted when stored at 4 degrees Celsius.
undergoing
and
direct contamination at the bacteraemia. Charnley and introduced, with excellent air
were
When
or cephalothin
of antibiotic
Kamme et a!. 1974; Benson and Hughes 1975; Hunter and Dandy 1977). The source of the infection may be air pollution or
ultra-clean
cement.
H.
Research,
and cephalothin
cefuroxime
C.
Glaxo
was mixed with each packet ofSimplex cement. All the urine removed from the wound for the first forty-eight hours after cephaloridine was assayed. Urine was collected from some Cephaloridine gradually leached out ofthe cement in vivo, drainage fluid in generally similar amounts. Between 1.6 the cement was recovered during the period ofstudy, most
Gram-positive
aerobic
antibiotic
KENNEDY,
and
1 bone
with cephalexin there the buffer for two days
32 per cent
K.
operation.
workers
organisms,
23 and
London,
Type
cephaloridme,
containing
VIVO R.
cefuroxime
CMW
CEMENT
iN
MARGARET
Hospital,
with
thirty-five to eighty-five days whereas passed rapidly out of the cement into weeks;
FIELD,
cephalexin,
of them
AND
VITRO
Orthopaedic
ofcephaloridine,
Incorporation
iN
BONE
Mizen of
and
various
of release
was
Sutherland
penicillins
and
consistent
with
the leaching of antibiotic from or near the surface of the bone cement. Elson et a!. (1 977a, b) have continued the work of Buchholz and Englebrecht (1970) and of Buchholz and Gartmann (1972) by studying in vitro and in vivo the release of gentamicin from Palacos
Medical
School,
Hammersmith
Limited,
Greenford,
Middlesex,
England.
Limited,
Greenford,
Middlesex,
England.
Hospital,
Ducane
Road,
London
S. P. F. Hughes.
THE
JOURNAL
OF BONE
AND
JOINT
SURGERY
CEPHALOSPORINS
cement.
They
showed effectively
that
The
in
confirmed
the
original
claims
antibiotics mixed into bone control infection in animals.
purpose
of our
laboratory and
cement
Buchholz’s
paper
of
cement
several
and
appropriate
can
potencies
the
behaviour
nine
cephalosporin
in
to the
Celsius content
This
some
gave
might
be The
In
vitro
were
studies.
Discs
prepared
cephalexin,
Type before
200
or
cefuroxime
Laboratories
adding
of thin
diameterformed
hand
When
set.
with
liquid
with
ninety-six
resulting
with
cephaloridine.
I .8 grams mix
each
microtitre
mixed at
was
with
discs.
ne
CMW
P
For
total
mixing
technique
described
antibiotic 1.8
with
grams
period
above. that
the
of
of each
twenty-four and
powder
cephalexin
Samples
noted
cement
of cement
of cephaloridine.
were
4 for
a prosthesis.
Celsius.
a
discs
at
of cephalosporin
the of
milligrams
with
a spoon
cut
patients;
1.5
2.5
used.
nine
the
for
for
(five
or
mix
were
weeks.
stabilities
at
the
into
five
The
over
femoral
per
three.
component
cement
the
used
prosthesis
were
laid
the
polymer.
six
of
these
cephaloridine was
on
by stirring
for
I gram
was
fixed
using
one
Cephalothin
Cefuroxime
Cephalexin
was
adding
was
with
of the
who
to Simplex
powder
before pack,
a pack
men) added
Emphasis
the
minutes
milligrams
other
four was
powder.
antibiotic
least
women,
cephaloridine
cement
of the 500
The
patients
London)
mixing
Cephaloridine,
to
assayed
surrounding
hip replacement,
(Howmedica.
its cups
each
studies.
thorough
spread
stored
and
compared.
undergoing
powder
also
tissues
for the
the
expressed
daily
diffusion
at 4 degrees
intervals
plates;
then
were
concentrations
200
assay and
changed
Aliquots
stored
all
antibiotic
of the hand
with
and
Clinical
of 6 millimetres
tray
6-millimetre
Cephalorid
cement
The
holes
antibiotic
of dry
bone
polymer.
a Cooke’ssterile
the
cement of sterile
of
to these
was
agar
in the
between
period
Blackpool)
of the
plastic
from
milligrams
Limited,
1 millilitre
a sheet
away.
non-radio-opaque
mixing
cephalothin
1 (CMW
over
of
by hand
METHODS
the
on
related
cent
that
investigated.
cefuroxime variations
AND
by
included potency.
per
indication
efficiency was
were
original 10
achieved
powder
were
in buffer
antibiotic
examined MATERIALS
of the
used
patients
discs
containing
bone
cement
were
of the cement
degrees
undergoing total hip replacement. Cephalosporins were chosen for study because of their good activity against the majority of organisms encountered in deep infectior’s of the hip. for
97
CEMENT
Discs
cephalosporins added
BONE
as a percentage
is to report
of cephaloridine
IN
E E 30
a,
a, E 20
V
a) C
0 N
10
o.
1
0
2
4
6
8
0
10
2
4
6
8
10
Percentage
VA
Gram-positive
antibiotic
organisms
Fig.
pushed dry
deep out
weight
were
stability at body
placed
at weekly Celsius.
percentage
were
cephalothin, NC1B
8533
cephaloridine. commonly with
0.5
VOL.
61-B.
10
Bacillus
Bacillus
or they
used per
MB
No.
sodium
1. FEBRUARY
dry,
but
over
mixed
with
adding
the
NCIB
8533
for cefuroxime,
for cefuroxime
1979
Oxoid
discs and
gel
at 37 for
for agar was the
The
cephaloridine and
used
for
the
same
agar
sensitivity
was discs
and
the
of
liquid
forty-eight B
the
I
I
I
I
4
6
8
10
dry
antibiotic
fourteenth
day.
volumes
were
20 degrees
-
patients
degrees
Celsius.
samples
were
After stored
additional
urine
was
measured until
suction
Drainage
drainage fluid
-
situ
was
urine
stored and
they
20 degrees
six-hourly the
hourly
of the Celsius.
collections from
aliquot for
results the
initially
were
was collected
measurement at
ii
collected When
twenty-four
Celsius
had
hours.
patients.
The
was
operation.
made
was before
of cephaloridine
patients
after
few
were
powder
immediately
cement.
by the
first
theatre
amount
unused
hours
the
The
operation
The the
voided
patients the
another.
in the
hardener.
urine
from
at All
that
with
cement
forty-eight
Celsius,
assaying Factor
the
subsequent
stored
Sarcina as
acetabulum
the
first
available to
assay
I
2
cement.
by weighing
All the
assayed
technique.
the
estimated
The
0
10
cement
in hardened
pack.
bathed
8
1
cent
Celsius silica
and
32SDR
chloride.
when
studied.
intervals
cephalexin
I
6
organisms
were
10 per
degrees
stored at
The
and
was
at 37
were
I
4
in
of cephalosporins
milligrams.
containing cement,
diffusion
cephalexin.
for penicillin cent
agar
subtilis
cephalothin
kept
removed
the
subtilis for
when maintained
were by
50
discs
in hardened
was
intervals, Discs
activity
obtained. and
that
potency
organisms
standard
antibiotics
temperature in buffer
degrees
approximately
Thus were
of the
changed
lutea
weighing
plastic.
of antibiotic
The in fluid
and
of the
C
2
Gram-negative
Antibacterial
millimetres
0
at
samples
for were from
third
day
4 degrees were
then
assayed. the
first
and volumes.
stored
twenty-four initially representative
to at 4
98
P. F. HUGHES,
S. Assays
spore
were
suspension
plates.
The
and
by subtilis
amount
drainage
large-plate
was
were
examined
then
closely in the
agar
NC1B
of cephaloridine
fluid
Patients were
performed of Bacillus
CHRISTINE
8533
excreted
A.
FIELD,
diffusion.
using
as inoculum
for
in each
sample
MARGARET a the
of urine
observed
during
follow-up
clinic
their one,
in-patient
four
and
stay. twelve
thereafter these five when
calculated. They months
later.
In
studies.
vitro
four
The
cephalosporins Figure
in
1.
positive tions
of
All
activity
of each
in hardened
cement
is summarised
and
Gram-negative to
10 per
The discs stored of all four cephalosporins In
buffer
at
cent
over
body
after
seven
effective
against
organisms
at
dry
containing activity
after
discs
showed
into
antibiotic for some
the
buffer
of
with
Buchholz
and
than
forty-eight
was hours
that reported in their tests
(1970)
gentamicin. results in Table of the antibiotics
The distribution
a
chest
infection;
from
another
patient
(Case
antibiotic content in bone cement powder 100 milligrams per gram of three by hand mixing
116.4
23.6
Cephalexin
I 13.2
14.8
Cefuroxime
105.2
by with
The lessened
concentrations rapidly after
that this
partly because in most patients.
the
Range (per cent) -12
to
+78
to
+42
0 to
+20
-4
6.0
that an even cement could
was time
of cephaloridine in the urine first twelve hours, a decrease
the
of the diuresis which began at Figure 4 shows, for the seven
patients from whom complete samples were available, the amount ofcephaloridine excreted in the urine during the amount
I indicated through
from mean
Average (per cent)
Cephaloridine
after
was
and
erythromycin
sample
Average concentration of five samples (mg/g)
Antibiotic
actior
cefuroxime
the first
greater
was
for
other four continued until the samples taken over the first one patient (Case 9) were lost, as
Deviation
continued to pass slowly out of the weeks. The recovery rate for the
far Englebrecht
cephalosporins
ampicillin the The from
theoretical
cement
no antibacterial
those
during
1. Assayable incorporating cephalosporins
activity weeks.
Figure 2. The eventual loss of antibacterial activity least partly explained by passage of the cephalosporin into the buffer (Fig. 3). A large proportion of drug
although cement
of them. Collections from one of discontinued on the fourth day
received
six-hourly
concentra-
at
released
DASH
5) were
one
Table
after twelve weeks but those possessed good antibacterial weeks. The results are shown in
twenty-six
H.
of the
had no activity cephalexin still
cephalothin
she
five
C.
weight.
temperature, weeks,
from (Case from day. hours
Gram-
silica gel retained the for at least thirty-nine
cephaloridine
containing vity
were
1.25
KENNEDY,
1).
antibacterial four
K.
collections fourteenth forty-eight was
RESULTS
R.
first
forty-eight 7.8
being
tion between concentration
hours milligrams.
patients did of antibiotic
after The not
operation, considerable
the
mean varia-
seem to be related to the in the cement. With all
100
0
\
75L.
Cephalor,dne
75
50
50
N
25
25
0 100 75
.
Cephalex,n
.
50
50
25
25 0
5
10
15
20
25
.,CephaIoth,n
75
0.
30
35
40
45
5
50
Storage
time
be
2-Stability
achieved
of cephalosporins recovered from
by meticulous
sporins were each stable when mixed with the dry degrees
Celsius.
Clinical fifty-four collected
studies. The age to seventy-one six-hourly from
forty-eight
the
hours
after
15 20
25
30
:a
40
45
50
T,me
2
Fig.
in hardened cement stored buffer bathing 50-milligram
hand
mixing.
The
in buffer bone
cephalo-
for at least twenty-four weeks cement powder and stored at 4 of the patients ranged from years. Urine samples were all nine patients for the first
operation
0.
,,1 days
Fig. Figure
10
and
twenty-four
hourly
at 37 degrees cement discs
Celsius. incorporating
Figure
,n
days
3 3-Percentage of each 10 per cent antibiotic.
cephalosporin
patients, however, the amount excreted decreased markedly after twenty-four hours. As might be expected, there was poor correlation between the amount excreted in forty-eight hours and the volume of urine (r0.185). After the first forty-eight hours the amount of cephaloridine excreted in the urine was very small: from two patients (Cases 3 and 4) none was found;
in another
patient
THE
JOURNAL
(Case
OF
9),
BONE
0.7
AND
milligram
JOINT
was
SURGERY
CEPHALOSPORINS
obtained
on
day;
from
on the
sixth
day;
milligram was recovered on The mean amount excreted
the
third during
milligrams
observation The fluid
the
was
was 8.2 concentration
ranged
(mean
third found
from
6.4
to 26.0
fluid
(r0.014).
excreted to that
The
mean
In four
patients
the
unused
cephaloridine values ranged per tions
Staphylococcus discharge in the after
complications. one
surface
of
cement
(Cases 2 and left hospital.
of follow-up
and
group
since
II.
Amounts drainage
eta!.
1977b),
should bacteria
do
and
it
to have the cement as long a period after
this,
be capable reaching
the
active,
of cephaloridine fluid of nine
Cephaloridine
and of
antibiotic leach
of the must,
out
of
the
Case
Urine
number
The of 2.9 infec-
48 hours
fluid
Total 12.7
-
2
13.4
(13.4)
0.1
13.5
-
3
2.8
2.8
8.9
11.7
4.2
7.4
5.7
6.0
6
16.0
(16.0)’
7
11.1
8
5.6
9
A
Mean A=
Excretion percentage cephaloridine used
6.0
5
operation.
(mg)
6.7
developed without the
and
4.7
3.2
effects
urine
1
3.2
during
in the
Drainage 2 weeks
4
1), a
found patients
excretion
operation;
no adverse
of patients
To
biologically
weighed.
(Case
after
6), a discharge All recovered
infections
in this small
day
(Elson
antibiotic of any
cement.
remaining
Table
similar
was
patient
seventh
as possible. incorporated the growth of the
while
cement
seem logical antibiotic for
antibiotic
in the urine a proportion
In one
on the
No deep
developed year
millilitre
minor superficial by cephaloridine-sensitive
epidermidis. developed
two others they had
have
developed caused
in the bone
per
actually inserted with the prosthesis. from 1 .6 to 3.6 per cent with a mean
cent (Table II). Three patients of the wound
belodged
would therefore impregnated with
drainage among of the
99
CEMENT
operation The inhibiting
It varied the volume
excreted as
BONE
II). in the
was 8.7 milligrams, (Table II).
The amounts of cephaloridine drainage fluid were expressed
2
5, 0.3
and fourth days. the period of
amount
fluid urine
1),
Case
micrograms
per millilitre). correlate with
in the drainage excreted in the
(Case
from
milligrams (Table of cephaloridine
17.0 micrograms and did not
patients
another
IN
30.4
3.2 -
36.4
-
7.3
23.3
3.6
(11.1)*
13.0
24.1
3.3
(5.6)’
5.4
11.0
1.6
>0.7
7.8t
2.9
8.2t
>3.6
8.7
as of
-
17.5t
2.9
Accident
*
specimens
t
excluding
collected the
for
patient
only
forty-eight
in Case
hours
9
E
cement
slowly
and
cephalosporins porous structure. occur, dependent sizes
of the
are
then
diffuse
through
bone.
The
water-soluble and bone cement is a Diffusion through the cement could on the concentration gradient and the
molecules
and
of the
pores
in the
cement.
Once in bone, diffusion occurs from the endosteal to the periosteal surface, passing through the bone fluid space (Hughes, Davies, Khan and Kelly 1978). The structure Hours
after
operation
Fig. Cumulative mixing 500
excretion milligrams
of the cement and the molecular therefore important factors
4
of cephaloridine in the urine of patients (open symbols) or 1 gram (closed symbols) cement pack.
after per
bone sporins bacteria that
Infection
after
total
hip
is
generally
considered to result from bacterial seeding of the site at the time of operation. Late infections have been shown to be associated with a transient bacteraemia quite separate from the A bacteraemia tal animal
VOL.
61-B,
such
No.
operation (Hall 1974). may occur early. In the
a bacteraemia
I, FEBRUARY
1979
they
in
has
caused
experimenorganisms
to
vitro
studies
we tested were near the surface retained
conditions
replacement
size of the antibiotic are the diffusion through
cement. Our
DISCUSSION
in
at body
activity
administration urine during
weeks
Although,
over
cephalothin
in vivo. Moreover, solely by the kidney;
virtually the ensuing
the the
cephalo-
growth cement
of and
under
moist
under
these
lost bactericidal activity more cephalosporins available as sterile
it has the advantage
not metabolised excreted almost
that
for several
temperature.
conditions, cephaloridine rapidly than the other powder,
indicated
able to prevent of the impregnated
the whole twenty-four
in that
cephaloridine after parenteral
it is is
dose is found in the hours (Muggleton,
I 00
S.
O’Callaghan studies
and being
were
than
therefore,
that
be present If
HUGHES,
A.
FIELD,
MARGARET
at
1964). When the clinical it was more readily available
patterns
was
CHRISTINE
reassuring.
antibacterial
levels
cement
for some bone and occurs,
time
after
minerals,
are
subject
to and
the
same
is, Kelly
passive 1976;
an
process
of
Nor
wound
have
do
antibiotics
infections
of
they
advocated
cement because
may
the
cephaloridine of operation
time
in
although,
in drainage fluid, in any haematoma.
previously
injections at the
DASH
use
reduce of
three
as a prophylactic on a joint (Hughes,
1 978) when antibiotics
the risk of infection to cement, further any bacteraemia weeks from
that initial
Our conclusions are that the cephalosporins, which are effective against most of the organisms encountered in deep infection of the hip, can be incorporated into
diffusion Hughes et
a!.
seems no possibility that significant will remain to prevent late seeded
years.
H.
cover may be acquired to prevent may develop in the first few colonisation of the bone cement.
bone
1977). There terial effect
three
C.
Dash, Benson and Field is greatest. By adding
in effective concentrations at the interface bone and cement will be a benefit. Bacteria reach bone by the Haversian system and,
transcapillary exchange-that (Davies, Bassingthwaighte
KENNEDY,
superficial
We
operation, tissues. of
to
1 -gram measure
will
surrounding the presence
two
K.
of the concentration the risk of infection
in is,
of cephaloridine
R.
prevent
of elution were similar The likelihood
to sterilise the a bacteraemia
antibiotic between presumably like
the
in the
helping
F.
Stevens done
cefuroxime. The fact that and in vivo
vitro
P.
antibacinfections
cement
of these
and
that
the in vivo
antibiotics,
kinetics
cephaloridine,
of at least
mirrors
its
one vitro
in
behaviour.
REFERENCES
Benson,
M. K. D., and
facilities. Buchholz, 41,
Ada
H. W., 511-515.
Buchholz, totalen
H.
Charnley, to the
J., and
and
S. P. F. (1975)
Gartmann, Chirurg,
Eftekhar, content
Infection 46, 968-978.
Scandinavica,
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