Efficacy of mupirocin in methicillin-resistant Staphylococcus aureus brun wound infection

Abstract

Methicillin-resistant Staphylococcus aureus strains (MRSA) have become increasingly prevalent as nosocomial pathogens, especially in burn wounds. MRSA constituted 38% of all S. aureus isolates in our 25-bed burns unit despite the utilization of a combination of 1% silver sulfadiazine and 0.2% chlorhexidine as topical therapy. Mupirocin, a new antibiotic, has proved in vitro and in vivo to be highly effective in the treatment of MRSA infections. A prospective clinical trial with mupirocin ointment in MRSA burn wound infection was untertaken. Forty-five children with 59 discrete burn wounds and from whom MRSA were isolated were treated with 2% mupirocin ointment under occlusive dressings, applied twice daily for 5 days. The average burned area treated was 8% (range, 2 to 20%) of the total body surface area. The burn wounds were assessed clinically and bacteriologically daily. Mupirocin eliminated MRSA in all 59 wounds treated, with the maximum therapeutic response seen within 4 days. In three wounds, gram-negative organisms persisted after 5 days of topical therapy. Treatment was well tolerated by all children. We recommend that mupirocin in its present polyethylene glycol base should be used only on a selective basis, when current prophylactic topical therapy has failed to control MRSA infection in burns of less than 20% of the total body surface area, and that it should be applied only for a limited period of 5 days. The safety and the efficacy of mupirocin in burns exceeding 20% of the total body surface area need to be established.

Full text

Vol.
33,
No.
8
ANTIMICROBIAL
AGENTS
AND
CHEMOTHERAPY,
Aug.
1989,
p.
1358-1361
0066-4804/89/081358-04$02.00/0
Copyright
©
1989,
American
Society
for
Microbiology
Efficacy
of
Mupirocin
in
Methicillin-Resistant
Staphylococcus
aureus
Burn
Wound
Infection
H.
RODE,l*
D.
HANSLO,2
P.
M.
DE
WET,1
A.
J.
W.
MILLAR,'
AND
S.
CYWES'
Departments
of
Paediatric
Surgery1
and
Medical
Microbiology,2
University
of
Cape
Town,
Institute
of
Child
Health,
Red
Cross
War
Memorial
Children's
Hospital,
Rondebosch
7700,
South
Africa
Received
8
February
1989/Accepted
18
May
1989
Methicillin-resistant
Staphylococcus
aureus
strains
(MRSA)
have
become
increasingly
prevalent
as
noso-
comial
pathogens,
especially
in
burn
wounds.
MRSA
constituted
38%
of
all
S.
aureus
isolates
in
our
25-bed
burns
unit
despite
the
utilization
of
a
combination
of
1%
silver
sulfadiazine
and
0.2%
chlorhexidine
as
topical
therapy.
Mupirocin,
a
new
antibiotic,
has
proved
in
vitro
and
in
vivo
to
be
highly
effective
in
the
treatment
of
MRSA
infections.
A
prospective
clinical
trial
with
mupirocin
ointment
in
MRSA
burn
wound
infection
was
undertaken.
Forty-five
children
with
59
discrete
burn
wounds
and
from
whom
MRSA
were
isolated
were
treated
with
2%
mupirocin
ointment
under
occlusive
dressings,
applied
twice
daily
for
5
days.
The
average
burned
area
treated
was
8%
(range,
2
to
20%)
of
the
total
body
surface
area.
The
burn
wounds
were
assessed
clinically
and
bacteriologically
daily.
Mupirocin
eliminated
MRSA
in
all
59
wounds
treated,
with
the
maximum
therapeutic
response
seen
within
4
days.
In
three
wounds,
gram-negative
organisms
persisted
after
5
days
of
topical
therapy.
Treatment
was
well
tolerated
by
all
children.
We
recommend
that
mupirocin
in
its
present
polyethylene
glycol
base
should
be
used
only
on
a
selective
basis,
when
current
prophylactic
topical
therapy
has
failed
to
control
MRSA
infection
in
burns
of
less
than
20%
of
the
total
body
surface
area,
and
that
it
should
be
applied
only
for
a
limited
period
of
5
days.
The
safety
and
the
efficacy
of
mupirocin
in
burns
exceeding
20%
of
the
total
body
surface
area
need
to
be
established.
Methicillin-resistant
Staphylococcus
aureus
strains
(MRSA)
have
since
1961
become
increasingly
prevalent as
pathogenic
and
invasive
organisms
(1,
2,
4,
9,
22-24).
These
highly
resistant
strains
are
often
found
in
burn
units
despite
the
reported
significant
reduction
in
S.
aureus
burn
wound
infection
by
using
a
combination
of
1%
silver
sulfadiazine
and
0.2%
chlorhexidine
digluconate
as
topical
therapy
(11,
20).
MRSA
may
cause
significant
and
even
lethal
infections,
with
an
associated
mortality
of
20
to
40%
among
those
clinically
infected
(12,
14,
26,
30).
An
encouraging
development
in
the
control
of
MRSA
has
been
the
introduction
of
mupirocin,
a
new
nonsystemic
topical
antibiotic
with
excellent
in
vitro
and
in
vivo
activity
against
clinical
isolates
of
S.
aureus,
including
antibiotic-
resistant
strains
(7,
8,
33, 36,
39).
Mupirocin
is
produced
by
submerged
fermentation
of
Pseudomonas
fluorescens
NCIB
10586
(15,
19).
It
contains
the
9-hydroxy-nonanoic
acid
moiety
and
acts
by
inhibition
of
bacterial
protein
synthesis
by
specifically
and
reversibly
binding
to
bacterial
isoleucyl
tRNA
synthetase,
thereby
preventing
isoleucine
incorporation
into
growing
protein
chains.
Its
action
thus
differs
from
that
of
other
commonly
used
antibiotics.
Because
of
the
high
prevalence
of
MRSA
in
our
25-bed
burns
unit
(approximately
38%
of
all
S.
aureus
isolates)
and
the
failure
of
current
topical
therapeutic
agents
to
eradicate
MRSA,
a
prospective
clinical
trial
with
2%
mupirocin
oint-
ment
in
MRSA
burn
wound
infection
was
undertaken.
MATERIALS
AND
METHODS
Forty-five
children
(age
range,
8
months
to
12
years;
mean,
38
months)
were
included
in
the
study.
The
basis
for
selection
was
an
infected
burn
wound
not
responding
to
topical
therapy
and
from
which
an
MRSA
was
cultured.
No
*
Corresponding
author.
patient
who
had
impaired
renal
function,
was
clinically
unstable
during
the
postinjury
phase,
or
had
burn
wounds
exceeding
20%
of
the
total
body
surface
area
was
considered
for
mupirocin
therapy.
Thermal
injuries
were
caused
by
hot
liquids
in
28 of
these
patients,
by
fire
in
14,
and
by
hot
objects
in
2.
One
child
sustained
a
caustic
burn
to
the
forearm
and
hand.
The
average
burned
area
treated
was
8%
(range,
2
to
20%)
of
the
total
body
surface
area.
Forty-one
children
were
considered
to
have
acquired
nosocomial
infections,
with
a
mean
time
from
admission
to
the
first
positive
culture
of
24
days
(range,
2
to
48
days).
Treatment
with
mupirocin
was
started,
on
average,
5
days
post-MRSA
isolation.
Four
children
were
readmitted
with
breakdown
of
their
previously
healed
injuries
and
entered
into
the
study.
Two
patients
had
11
separate
sites
bacteriologically
and
clinically
assessed.
Five
other
patients
had
two
discrete
wounds
each,
and
38
single
wounds
were
treated,
thereby
giving
a
total
of
59
distinct
wounds
treated
with
occlusive
mupirocin
dressings
during
the
trial
period.
Mupirocin
used
in
the
study
was
supplied
by
Beecham
Pharmaceuticals
under
the
trade
name
of
Bactroban.
Two
topical
agents
were
utilized
on
the
45
children
for
an
average
treatment
period
of
29
days
prior
to
the
introduction
of
mupirocin.
Thirty-four
children
were
treated
with
10%
povidone-iodine
ointment
every
12
h,
and
11
were
treated
with
1%
silver
sulfadiazine
and
0.2%
chlorhexidine
applied
daily.
Before
commencement
of
mupirocin
therapy,
swabs
for
culture
were
taken
from
each
affected
bum
wound
surface,
from
the
corresponding
intact
skin
on
the
side
opposite
to
that
of
the
burn
wound,
and
from
the
anterior
nares.
Each
burn
wound
was
exposed,
gently
wiped
with
dry
gauze
swabs
to
remove
all
visible
topical
ointment,
and
cleaned
with
saline
washes.
Daily,
cotton
culture
swabs
1358

EFFICACY
OF
MUPIROCIN
IN
MRSA BURN
WOUND
INFECTION
TABLE
1.
Effect
of
mupirocin
against
MRSA
and
gram-negative
bacteria
in
59
discrete
burn
wounds
No.
of
wounds
with
residual
organisms
(species)"
Wound
organisms
During
therapy
at:
Pretreatment
24
h
48
h
72
h
96
h
120
h
MRSA
43
8 3
0
1
0
MRSA
+
Streptococcus
pyogenes
3
0
0
0
0
0
MRSA
+
Streptococcus
faecalis
1
0
0
0
0
0
MRSA
+
Escherichia
coli
1
0
0
0 0
0
MRSA
+
Pseudomonas
aeruginosa
3
2
2
(PA)
2
(PA)
1
(PA)
0
MRSA
+
Proteus
mirabilis
4
0
0
1
(PM)
1
(SA)
1
(PM/SA)
1
(PM)
MRSA
+
Streptococcus
faecalis
+
Pseudomonas
aeruginosa
1
1
(SA/PA)
1
(PA)
1
(PA)
1
(PA)
MRSA
+
Proteus
mirabilis
+
Klebsiella
pneumoniae
3
0
1
(PM)
1
(PM)
1
(SA/PM)
1
(PA)
1
(SA)
1
(PM)
a
SA,
S.
aureus
(MRSA);
PA,
Pseudomonas
aeruginosa;
PM,
Proteus
mirabilis.
Shills
indicate
presence
of
both
types
of
organism
in
one
wound.
moistened
with
normal
saline
were
then
rolled
over
the
wound
surface
10
times
for
30
s.
After
samples
were
taken,
2%
mupirocin
ointment
was
liberally
applied
(+2-mm
thick-
ness)
to
the
burned
surface
at
12-h
intervals
for
5
days.
Occlusive
bulk
dressings
were
utilized.
No
systemic
antibi-
otics
were
used
during
the
trial
period.
Organisms
isolated
were
identified
by
standard
methods
(13).
The
identity
of
S.
aureus
was
based
on
production
of
DNase
or
coagulase
or
both.
Antimicrobial
susceptibility
patterns
(including
those
of
topical
agents)
were
assessed
by
agar
diffusion
methods
(17,
28,
35).
The
wounds
were
inspected
daily
and
after
5
days
of
treatment
were
assessed
as
bacteriologically
cured
when
MRSA
was
eliminated,
as
improved
when
MRSA
was
re-
placed
by
a
different
organism,
and
as
failed
if
the
original
MRSA
was
still
present.
Similarly,
the
wounds
were
re-
garded
as
clinically
cured
if
no
further
treatment
was
re-
quired,
as
improved
if
the
wound
contained
healthy-looking
granulation
tissue,
and
as
failed
if
the
wound
was
unchanged
or
had
deteriorated.
The
clinical
study
period
was
completed
only
when
all
areas
of
partial-
or
full-thickness
burn
wounds
had
either
healed
spontaneously
or
were
successfully skin
grafted.
Immediately
following
the
trial
period,
burn
swabs
were
taken
regularly
twice
weekly
from
all
unhealed
wounds
until
skin
cover
was
obtained.
Treatment
was
well
tolerated
by
all
children,
and
no
patient
was
withdrawn
from
the
study.
Informed
parental
consent
was
obtained,
and
the
study
protocol
was
approved
by
the
Human
Ethics
and
Research
Committee
of
the
University
of
Cape
Town.
RESULTS
The
presence
of
MRSA
was
proved
in
every
wound
prior
to
the
first
topical
application
of
mupirocin.
Nasal
carriage
of
MRSA
was
identified
in
19
patients,
and
eight
swabs
from
the
opposite
uninvolved
areas
yielded
MRSA.
There
was,
however,
no
correlation
between
the
presence
or
absence
of
MRSA
at
these
sites
and
the
inability
to
eliminate
the
staphylococcus
from
the
burn
wounds.
Bacteriological
elimination
of
MRSA
was
achieved
within
5
days
in
all
59
wounds
(Table
1).
In
48
wounds,
MRSA
could
no
longer
be
cultured
after
24
h
of
mupirocin
applica-
tion.
The
temporary
reappearance
of
MRSA
on
day
4
in
five
discrete
wounds
most
likely
represents
autocontamination,
since
the
same
organisms
were
found
on
other
surface
areas
in
these
patients.
Pretreatment
surface
swabs
revealed
the
cohabitation
of
MRSA
and
gram-negative
bacteria
in
12
of
the
wounds
(Table
1).
Two
of
these
wounds
had
residual
Proteus
mira-
bilis
and
one
had
Pseudomonas
aeruginosa
at
the
end
of
the
trial
period.
Twenty
of
the
wounds
healed
spontaneously
after
the
eradication
of
MRSA,
and
in
39
the
purulent
granulation
tissue
was
replaced
with
healthy
granulation
tissue,
resulting
in
subsequent
100%
graft
take.
Routine
posttreatment
surface
swabs
failed
to
show
re-
lapse
of
MRSA
burn
wound
infection
after
the
5-day
course
of
therapy.
DISCUSSION
Since
1983,
MRSA
have
become
increasingly
prevalent
as
pathogenic
organisms
within
our
burns
unit,
despite
restric-
tions
on
antibiotic
usage,
improved
internal
environmental
control,
and
appropriately
selected
topical
antibacterial
agents.
The
infections
in
our
patients
developed
usually
within
3
weeks
of
injury.
The
presence
of
significant
nasal
carriage
of
the
organisms
among
the
patients
(19
out
of
45)
and
the
high
incidence
of
MRSA
in
the
burns
unit
support
the
concept
that
contact
transmission
from
patient
to
patient
was
the
most
likely
source
of
the
MRSA
infection
(3,
31).
Infection
by
MRSA
leads
to
significant
burn
wound
mor-
bidity,
with
ongoing
sepsis,
graft
loss,
and
the
ever-present
threat
of
invasive
burn
wound
infection
with
an
associated
mortality
of
20
to
40%
(12,
14,
26,
30).
Although
commonly
used
antistaphylococcal
antiseptics
and
topical
agents
have
bactericidal
activity
against
MRSA,
a
significant
number
of
these
organisms
are
not
eliminated
(16,
22, 25,
31).
Resistance
to
methicillin
implies
resistance
to
all
1-lactam
antibiotics.
Although
not
fully
understood,
it
appears
that
methicillin
resistance
results
from
the
elaboration
by
MRSA
of
a
novel
penicillin-binding
protein
involved
with
the
final
stages
of
cell
wall
synthesis.
This
results
from
the
transduc-
tion
of
an
existing
gene(s)
which
determines
resistance
rather
than
the
selection
of
mutants
among
less-resistant
or
-susceptible
strains
(18).
Diminished
inhibition
of
autolytic
enzymes
by
the
antibiotic-tolerant
strain
(34)
and,
more
recently,
evidence
of
acquired
resistance
due
to
the
produc-
tion
of
increased
amounts
of
,-lactamase
by
certain
strains
of
S.
aureus
(27)
are
additional
factors.
Mupirocin
is
a
new
nonsystemic
antibiotic,
exclusively
developed
for
topical
use.
It
has
a
high
degree
of
activity
against
all
staphylococci,
including
MRSA,
with
MICs
of
0.015
to
0.06
p.g/ml
and
an
MBC
of
16
[Lg/ml
for
a
99.9%
kill
(7).
Naturally
occurring
relatively
resistant
strains
requiring
for
inhibition
an
MIC
of
2
jig/ml
occur
with
a
frequency
of
VOL.
33,
1989
1359

ANTIMICROB.
AGENTS
CHEMOTHER.
only
10'-,
but
it
is
possible
to
produce
tolerance
to
40
,ug/ml
with
small
progressive
incremental
concentrations
of
mupi-
rocin
(7).
The
development
of
resistance
is
probably
due
to
the
acquisition
of
a
plasmid
(32).
Topical
application
of
mupirocin
with
a
concentration
of
20,000
,ug/ml
and
effective
penetration
through
1.5-mm
burn
eschar
would
make
it
unlikely
for
these
resistant
strains
to
become
a
clinical
problem
during
short-term
therapy
(33).
The
formulation
of
2%
mupirocin
in
a
polyethylene
glycol
base
was
able
to
eradicate
MRSA
rapidly
from
all
the
burn
wounds
and,
in
addition,
to
eliminate
streptococci
from
three
additional
wounds.
This
confirms
the
findings
of
pre-
vious
studies
that
mupirocin
is
highly
active
against
gram-
positive
bacteria
(37).
However,
part
of
the
antibacterial
effect
could
have
been
due
to
the
antibacterial
activity
of
the
polyethylene
glycol
base
(10).
Although
mupirocin
failed
to
eradicate
Pseudomonas
aeruginosa
and
Proteus
mirabilis
from
three
wounds,
the
activity
of
mupirocin
against
Esch-
erichia
coli
and
Klebsiella
pneumoniae
may
be
of
clinical
significance
in
topical
burn
wound
therapy.
Relative
insus-
ceptibility
to
mupirocin
is
not
surprising,
as the
MICs
for
enteric
gram-negative
bacilli
range
from
64
to
6,400
FLg/ml
(37).
Mupirocin
in
a
polyethylene
glycol
ointment
base
(USNF)
contains
a
mixture
of
polyethylene
glycol
400
(58.8%)
and
polyethylene
glycol
3350
(39.2%).
Less
than
0.3%
of
topi-
cally
applied
mupirocin
is
absorbed
across
intact
skin,
but
penetration
may
be
expected
to
be
enhanced
through
burnt
skin
(21).
It
has
a
half-life
in
serum
of
less
than
30
min
and
is
rapidly
converted
to
monic
acid
and
excreted
in
the
urine
(90%).
The
polyethylene
carrier
base
is
similarly
absorbed
from
the
burn
wound
and
is
normally
excreted
by
the
kidney
in
the
form
of
oxalic
acid
bound
to
calcium
(29).
In
hemo-
dynamically
unstable
patients
and
patients
with
poor
renal
function,
the
excretion
of
polyethylene
glycol
may
be
im-
paired,
leading
to
reversible
nephrotoxicity
and
specific
and
severe
metabolic
derangement
(5).
The
average
burn
wound
size
in
our
study
was
8%
(range,
2
to
20%)
of
the
total
body
surface
area,
and
mupirocin
was
applied
topically
only
to
stable
patients
with
intact
renal
function.
The
application
of
mupirocin
was
accompanied
not
only
by
the
disappearance
of
MRSA
but
also
by
the
rapid
formation
of
healthy
granulation
tissue
in
the
nonepithelized
burn
wounds.
In
vitro
studies
with
human
fetal
lung
fibro-
blasts
have
shown
mupirocin
in
low
concentrations
to
pro-
mote
cell
growth,
which
may
explain
this
phenomenon
(6).
It
can
be
concluded
that
mupirocin,
with
its
novel
mode
of
action,
lack
of
cross
resistance
with
other
antibiotics,
active
penetration
through
eschar,
and
in
vivo
efficacy,
may
play
an
important
role
in
the
future
treatment
of
MRSA
burn
wound
infection.
The
cost
of
mupirocin
in
a
polyethylene
glycol
formulation
was
found
to
be
more
than
comparable
with
that
of
other
locally
obtainable
antistaphylococcal
topical
agents.
Our
final
recommendations
are
that
2%
mupirocin
should
be
utilized
as
a
specific
therapeutic
agent
against
MRSA
and
should
not
be
used
for
prophylaxis.
Furthermore,
the
safety
and
efficacy
of
mupirocin
in
larger
burns
(exceeding
20%
of
the
total
body
surface
area)
need
to
be
determined.
ACKNOWLEDGMENTS
We
are
indebted
to
A.
Forder
for
his
advice
and
critical
comments
and
to
the
Medical
Superintendent
of
the
Red
Cross
War
Memorial
Children's
Hospital
for
permission
to
publish.
This
study
was
partly
funded
by
a
grant
from
Beecham
Pharma-
ceuticals.
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