REVIEW ARTICLE

Treatment of Staphylococcus aureus Colonization

and Prophylaxis for Infection with Topical
Intranasal Mupirocin: An Evidence-Based Review

Downloaded from https://academic.oup.com/cid/article-abstract/37/7/933/422431 by University of Florida user on 13 July 2019

Kevin B. Laupland1,2,3,4 and John M. Conly1,3,4
Departments of 1Medicine, 2Critical Care Medicine, and 3Pathology and Laboratory Medicine, and 4 Centre for Antimicrobial Resistance,
University of Calgary and the Calgary Health Region, Calgary, Alberta, Canada

Most Staphylococcus aureus infections are endogenously acquired, and treatment of nasal carriage is one
potential strategy for prevention. We critically appraised the published evidence regarding the efficacy of
intranasal mupirocin for eradication of S. aureus nasal carriage and for prophylaxis of infection. Sixteen
randomized, controlled trials were appraised; 9 trials assessed eradication of colonization as a primary outcome
measure, and 7 assessed the reduction in the rate of infection. Mupirocin was generally highly effective for
eradication of nasal carriage in the short term. Prophylactic treatment of patients with intranasal mupirocin
in large trials did not lead to a significant reduction in the overall rate of infections. However, subgroup
analyses and several small studies revealed lower rates of S. aureus infection among selected populations of
patients with nasal carriage treated with mupirocin. Although mupirocin is effective at reducing nasal carriage,
routine use of topical intranasal mupirocin for infection prophylaxis is not supported by the currently available
evidence.

Staphylococcus aureus is one of the most important
pathogens worldwide and has emerged as a prominent
organism infecting critically ill persons [1–4]. The im-
pact of S. aureus infection on human health has dra-
matically increased as a result of its remarkable ability
to become resistant to antimicrobials [5–8]. Although
asymptomatic nasal colonization with S. aureus is com-
mon, it appears to be an important factor in the de-
velopment of most infections due to this organism [2,
9, 10]. As a result, efforts have been made to eliminate
S. aureus colonization in an attempt to reduce the in-
cidence of infection. Techniques include use of systemic
antimicrobials, normal bacterial flora augmentation,
antiseptic washes, and topical antimicrobials [10–13].
For a number of potential reasons, including efficacy
and minimization of systemic antibiotic use, topical
Received 21 February 2003; accepted 31 May 2003; electronically published 8
September 2003.
Reprints or correspondence: Dr. Kevin B. Laupland, Foothills Medical Centre,
Rm. C210M, 1403 29th St. NW, Calgary, Alberta, Canada T2N 2T9 (kevin
.laupland@calgaryhealthregion.ca).
Clinical Infectious Diseases 2003; 37:933–8
 2003 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2003/3707-0009$15.00
intranasal therapies have been recognized as a preferred
method.
Mupirocin has emerged as the topical antibacterial
agent of choice for elimination of S. aureus nasal car-
riage [14]. Mupirocin is produced by Pseudomonas flu-
orescens and inhibits bacterial protein synthesis by re-
versibly binding to bacterial isoleucyl–tRNA-synthetase.
It is a novel compound, and many antibiotic-resistant
strains of S. aureus naive to its use are susceptible [15].
However, with repeated exposure to mupirocin, resis-
tance is known to develop [16–18]. Significant potential
exists for mupirocin as an agent to reduce nasal col-
onization and subsequent systemic S. aureus infection.
To minimize the risk of excess use and development of
resistance, its application should be guided by clinical
evidence. Therefore, we critically appraised studies in-
vestigating the efficacy of intranasal mupirocin for erad-
ication of S. aureus nasal carriage and its role as pro-
phylaxis for infection.
METHODS
A structured search of worldwide medical literature was
conducted to find clinical trials of intranasal admin-

Mupirocin for S. aureus • CID 2003:37 (1 October) • 933

istration of mupirocin for eradication of nasal colonization and
prevention of infection. MEDLINE, Embase, and Cochrane da-
tabases were searched for articles from 1966 through November
2002 using the subject term “mupirocin,” and the results were
restricted to clinical trials involving humans. The authors’ per-
sonal files and bibliographies of selected reports were reviewed
in an attempt to identify additional articles. Only prospective
investigations with a concurrent control group were considered.
Critical appraisal was guided by the principles of Sackett et al.
[19]. Studies were assessed for adequacy of randomization and
blinding and for completeness of follow-up. Reported out-
comes were considered to be statistically significant if P values
were !.05.
RESULTS
Intranasal Mupirocin for Eradication of S. aureus Carriage
Nine prospective trials evaluating mupirocin for eradication of
nasal colonization with S. aureus fulfilled inclusion criteria [13,
20–27]. Four clinical trials that assessed the development of
clinical infection as the primary outcome measure also eval-
uated clearance of nasal colonization [28–31]. As a result of
heterogeneity among study populations and outcomes, quan-
titative summarization was not performed [32].
Health care workers. A number of placebo-controlled
trials evaluating intranasal mupirocin for eradication of S.
aureus carriage have been conducted among healthy health
care workers. Doebbeling et al. [21] reviewed 6 independent,
double-blind, randomized, placebo-controlled clinical trials
(DBRPCTs) and subsequently reported data from follow-up
studies [22, 23, 33]. On the basis of an intent-to-treat (ITT)
analysis, they found that application of mupirocin twice per
day to the nares for 5 days led to a significantly lower rate of
positive nasal culture results at 48–72 h (22 [13%] of 170
mupirocin recipients vs. 157 [93%] of 169 placebo recipients);
the lower rate of carriage persisted at 4-week follow-up (18%
vs. 88%). Mupirocin resistance was only identified in 5 (1%)
of 339 participants using the disk diffusion method (zone di-
ameter, <17 mm), and all isolates were found to be susceptible
using the broth dilution method (MIC, <0.12 mg/mL). These
authors later reported long-term follow-up data for 68 patients
[22, 33]. Six months after treatment, rates of nasal positivity
were 48% and 72% for mupirocin and placebo recipients,
respectively, and at 1 year, the rates were 53% and 76%,
respectively.
Fernandez et al. [24] conducted a DBRPCT that was designed
similarly to that reported by Doebbeling et al. [21]. Among 68
individuals randomized to receive either mupirocin or placebo,
culture positivity rates were 13% and 91% immediately after
treatment and 67% and 94% at 6 months after treatment,
respectively.
934 • CID 2003:37 (1 October) • Laupland and Conly
HIV-infected individuals. Martin et al. [20] conducted a
DBRPCT that compared mupirocin (twice per day for 5 days)
with placebo in 76 HIV-infected patients with stable nasal carriage
of S. aureus. At 1-week follow-up, 4 (12%) of 34 mupirocin
recipients and 33 (92%) of 36 placebo recipients had positive
culture results. This study was limited by incomplete follow-up
data, and patients were excluded from further analysis if they
missed an appointment. At weeks 2, 6, and 10 after treatment,
rates of persistently negative cultures were 34% and 88%, 38%
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and 77%, and 57% and 69% for mupirocin and placebo recip-
ients, respectively. Of 19 mupirocin-treated patients who became
recolonized, 16 (84%) were recolonized with the initial strain,
as determined by PFGE. No mupirocin-resistant isolates were
identified using the disk diffusion method.
Patients undergoing hemodialysis. Bommer et al. [13]
conducted a patient-blinded trial comparing mupirocin (3
times per daily for 10 days) with placebo among 54 patients
undergoing long-term hemodialysis. They performed nasal cul-
tures for S. aureus at days 3, 8, 10, 21, 42, 70, and 140 days
after commencement of treatment, and they found significantly
lower rates of positivity among mupirocin recipients than
among placebo recipients on day 10 (8 [24%] of 33 patients
vs. 19 [90%] of 21 patients, respectively) and day 140 (19 [58%]
of 33 patients vs. ∼95% of patients, respectively). They cultured
samples from multiple skin sites and found a significantly lower
rate of skin colonization on day 10 for mupirocin (33%) than
for placebo (75%); this difference remained significantly lower
at week 6 of follow-up, with rates of culture positivity of ∼40%
and 88%, respectively. This study did not include ITT analysis,
because 5 patients took the treatment intermittently and were
excluded. Furthermore, although nasal eradication did not oc-
cur for 24% of mupirocin-treated patients, the investigators did
not assess resistance to this agent or the potential impact of
horizontal transmission of mupirocin-resistant strains.
Mupirocin versus other active therapies for health care
workers and patients. Soto et al. [25] compared intranasal
mupirocin and bacitracin in a double-blind, randomized trial
involving health care workers and found significantly lower
rates of culture positivity among mupirocin recipients (1 [6%]
of 16 vs. 10 (56%) of 18 subjects 72–96 h after treatment, and
3 (20%) of 15 vs. 10 (77%) of 13 subjects at 30-day follow-
up). ITT analysis was not performed.
Perez-Fontan et al. [26] reported a small study of patients
undergoing ambulatory peritoneal dialysis and their assisting
partners who were nasal carriers and allocated them to treat-
ment with either mupirocin or neomycin sulphate 3 times per
day for 7 days. None of 12 mupirocin-treated patients and 6
of 10 neomycin-treated patients had positive culture results 1
week after treatment; the 3-month follow-up rates were 5 (42%)
of 12 and 3 (75%) of 4, respectively. This study was limited by
an unclear randomization process, uncertain blinding, unequal
follow-up for small numbers of patients, and inclusion of some
patient’s partners as subjects.
Parras et al. [27] compared the use of intranasal mupirocin
with the use of a combination of topical fusidic acid and oral
trimethoprim-sulfamethoxazole (TMP-SMZ) for eradication of
methicillin-resistant S. aureus in an open-label trial involving
11 health care workers and 73 hospitalized patients. Similar
rates of nasal culture positivity were observed for recipients of
mupirocin and the fusidic acid–TMP-SMZ combination: 0 of
37 and 0 of 36 patients at week 1, one (4%) of 24 and 1 (5%)
of 19 patients at week 4, and 3 (21%) of 14 and 2 (29%) of 7
patients at month 3, respectively. No resistance to mupirocin
was noted using the agar dilution method. Limitations to this
study were the open-label design and inclusion of a hetero-
geneous group of patients and health care workers.
Intranasal Mupirocin to Prevent Clinical S. aureus Infection
Seven articles were appraised that prospectively compared mu-
pirocin recipients with a control group with clinical infection
as the primary outcome [28–31, 34–36]. As a result of heter-
ogeneity among study populations and outcomes, quantitative
summarization was not performed.
Surgical site infections. The most recent and largest study
investigating mupirocin as preventive therapy was reported
by Perl et al. [29]. This DBRPCT included 4030 patients
who underwent general, gynecologic, neurologic, and cardio-
thoracic surgery and assessed the effect of preoperative intra-
nasal administration of mupirocin (twice per day for up to 5
days) on the prevention of the primary outcome of surgical
site infection. Clear outcomes were defined a priori, and the
duration of follow-up was 30 days. Of 3864 patients in the ITT
analysis, 2.3% of mupirocin recipients and 2.4% of placebo
recipients developed surgical site infection, but this was not
significant. However, in secondary analysis of 891 nasal carriers,
significantly fewer mupirocin-treated patients (4%) developed
nosocomial S. aureus infection, compared with placebo recip-
ients (7.7%). They observed a low rate of mupirocin resistance
(6 [0.6%] of 1021 isolates) using the Etest (AB Biodisk; MIC,
14 mg/mL). Only 83% of patients received >3 doses before
surgery. Despite this, nasal colonization was cleared in 84% of
mupirocin recipients, compared with 27% of placebo recipi-
ents. Therefore, the short treatment duration may be of lim-
ited significance.
Kalmeijer et al. [30] conducted a DBRPCT in Rotterdam,
The Netherlands, involving 614 patients undergoing elective
orthopedic surgery who required insertion of implant material.
Mupirocin and placebo were applied intranasally twice per day
to 315 and 299 patients, respectively, on the day before surgery
and the day of surgery. The outcome analyzed was the devel-
opment of any surgical site infection for 1 month after surgery.
The baseline rate of colonization was 30% among mupirocin
recipients and 29% among placebo recipients; 15 (16%) of 95
mupirocin recipients tested positive 3–5 days after treatment,
compared with 61 (71%) of 86 placebo recipients. No signif-
icant difference was observed in the subsequent incidence of
surgical site infection between mupirocin and placebo groups
(12 [4%] of 315 patients vs. 14 [5%] of 299 patients, respec-
tively). Furthermore, no difference was observed between
groups with regard to the incidence of S. aureus surgical site
infection. All isolates were mupirocin susceptible. A limitation
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of this study is that the sample size was based on a high es-
timated treatment effect of a 75% reduction in the incidence
of infection. As a result, this study was underpowered to identify
less dramatic but potentially clinically significant treatment ef-
fects. They may have underestimated the effectiveness of short-
course mupirocin treatment, because a minimum of only 2
doses were required. However, eradication rates of 84% and
22% were observed in the mupirocin and placebo groups, re-
spectively. The short treatment duration may be of limited
significance.
Patients undergoing dialysis. The Mupirocin Study Group
conducted a study of 267 patients undergoing continuous am-
bulatory peritoneal dialysis in 9 European health care centers
who had nasal cultures persistently positive for S. aureus [31].
Patients were treated with either mupirocin (134 patients) or
placebo (133 patients) twice per day for 5 days initially, and
then this treatment was repeated monthly. Patients were fol-
lowed up for 18 months. No overall significant differences in
the rates of catheter tunnel or exit site infections or peritonitis
were found. They did observe a statistically significant differ-
ence in the secondary analysis of exit-site infections due to S.
aureus: there were 14 and 44 infections among mupirocin- and
placebo-treated patients, respectively. There were no apparent
differences observed in the rates of mupirocin resistance.
Boelaert et al. [28] conducted a DBRPCT in Brugge, Belgium,
involving 34 patients undergoing long-term hemodialysis who
had documented S. aureus nasal colonization. They allocated
16 patients to receive intranasal mupirocin and 18 to receive
placebo 3 times per day for 2 weeks, followed by 3 times per
week for 9 months. Cultures were performed during the third
week of the study and then bimonthly thereafter. They observed
a decrease in the rate of colonization during the follow-up phase
of the study (4 [6%] of 66 mupirocin recipients vs. 62 [58%]
of 106 placebo recipients). Significantly fewer infections were
observed with mupirocin treatment (1 [6%] of 16 patients)
than with control treatment (6 [33%] of 18 patients). However,
these results may be biased by the shorter duration of follow-
up for the mupirocin group than for the placebo group (104
vs. 147 patient-months, respectively). Furthermore, they did
not report a strict a priori definition for infection, and the
impact of these infections was, therefore, not clear. The blinding
process was also not well described. No difference in bacteremia
Mupirocin for S. aureus • CID 2003:37 (1 October) • 935
occurrence was observed. No mupirocin-resistant isolates were
identified using the agar dilution method.
Skin infection. Raz et al. [35] evaluated the efficacy of
maintenance therapy with nasal mupirocin in reducing the
number of recurrent skin infections among immunocompetent
persons with persistent nasal carriage. All patients were treated
with a 5-day course of mupirocin; 17 were then randomized
to undergo successive monthly treatments for 1 year, and 17
others were to receive placebo. Cultures and clinical assessments
were performed monthly. A significant reduction in the number
of clinical skin infections occurred among patients treated with
maintenance therapy, compared with placebo (26 vs. 52 infec-
tions, respectively). Eight recipients of maintenance mupirocin
therapy and 2 placebo recipients remained nasal-culture neg-
ative during follow-up. Only 1 of the 10 patients who remained
free of colonization had a skin infection, whereas all 24 of those
with positive culture results had skin infections. Total duration
of use of systemic antibiotics was 142 days in the mupirocin
maintenance group and was significantly shorter than the du-
ration for the placebo group (357 days). Mupirocin resistance,
as determined by disk diffusion, was observed in 1 (6%) of 17
patients in the maintenance group and in none of the placebo-
treated patients. Limitations of the study were the small size
and the lack of explicit a priori criteria for establishing infec-
tion. Blinding appeared adequate such that this was not likely
a major bias.
Manuskiatti et al. [34] attempted to evaluate the use of in-
tranasal mupirocin to prevent skin infections among patients
undergoing laser resurfacing. These investigators tested 4 reg-
imens (including oral ciprofloxacin, intranasal mupirocin oint-
ment, oral ketoconazole, and oral fluconazole) in an apparently
randomized fashion among 356 consecutive patients over dif-
fering time periods. One hundred sixty-four patients were al-
located to the mupirocin or “control” arm (not defined). Eleven
mupirocin recipients developed infection, compared with none
of the control subjects (inadequate denominator data pro-
vided). However, ciprofloxacin was also given to an undisclosed
number of these patients in an unequal distribution, which
confounded results. This was a very limited, poorly designed
study. Randomization procedures were not specified, the actual
number of patients in each group was unclear, treatments over-
lapped, and blinding procedures and ascertainment of outcome
were poorly defined.
Intensive care unit (ICU)–acquired infections. Nardi et
al. [36] studied the addition of mupirocin or placebo to a
topical selective digestive decontamination (SDD) regimen that
consisted of tobramycin, polymyxin E, and amphotericin B in
a DBRPCT involving ICU-infections in Udine, Italy. They ran-
domized 223 patients to receive mupirocin (intranasal and or-
opharyngeal) or placebo in addition to SDD. A significantly
lower rate of pneumonia occurred among patients treated with
936 • CID 2003:37 (1 October) • Laupland and Conly
the mupirocin regimen (9 [8%] of 119 patients), compared
with those who received placebo (20 [19%] of 104 patients).
This was largely because S. aureus was less frequently isolated
from mupirocin-treated patients (1 patient) than from placebo-
treated patients (9 patients). Inclusion of mupirocin in the SDD
protocol was associated with a 36% reduction in overall antibiotic
costs (costs were $181 for the mupirocin arm and $283 for the
placebo arm). They did not report any difference in overall in-
fection rate among the treatment groups, even though this was
suggested to be the primary outcome. The significant difference
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in pneumonia rates likely represents a secondary analysis. They
did not evaluate the incidence of antimicrobial resistance, despite
the use of an antimicrobial-intensive regimen.
One other study reported in the Italian literature fulfilled
search criteria, but only the English-language abstract was re-
viewed [37]. In this DBRPCT conducted in Florence, Italy, 48
consecutive patients in the intensive care unit who were under-
going ventilation were randomized to receive intranasal mupi-
rocin or placebo 3 times per day for 3 days. Ventilator-acquired
pneumonia occurred at comparable rates among study patients.
Critical appraisal of this study was not performed.
DISCUSSION
Several studies conducted with varied populations demon-
strated that mupirocin was highly effective in eradicating nasal
colonization with S. aureus when compared with placebo in
the short term. The efficacy of mupirocin was also comparable
to a systemic regimen and superior to other topical antibac-
terials in a few small trials. However, 2–14-day therapeutic
courses of mupirocin did not typically result in long-term clear-
ance of S. aureus colonization. This is not surprising, because
S. aureus carrier status is known to be dynamic over time, and
certain individuals are at increased risk for chronic colonization
[10]. Repeated application of mupirocin is a potential option
for reducing colonization in the long term, but the evolution
of resistance is a risk. Several of the studies included in this
review described resistance associated with mupirocin therapy,
but the rates were typically low. However, the long-term effect
on resistance development is not known because no studies
included several years of follow-up. In addition, the techniques
used varied between studies, and, in some studies, no assess-
ment of mupirocin resistance was conducted. It is reasonable
to expect that prolonged use among patients at risk for reco-
lonization will result in resistance, although the time frame for
this event is poorly defined. For these patients, therapies such
as normal flora augmentation may be preferred [11].
Ultimately, the most important goal of intranasal mupirocin
application is to reduce subsequent clinical infection. The body
of literature currently does not support routine administration
of prophylactic intranasal mupirocin to patients in an attempt
to decrease the rate of clinical infection. There may be a role
in some selected cases, such as those involving patients or per-
sonnel who have been epidemiologically implicated in the
transmission of S. aureus to others. Although subgroup analyses
have suggested some effect in reducing infection, when applied
to highly selected patients, the benefits observed appear to be
minimal. Clinically important outcomes may include reduction
in overall infection incidence or in some other measure, such
as length of hospital stay, overall cost, consumption of anti-
microbials, or mortality. A reduction in the overall incidence
of infection is more meaningful than a reduction in the number
of S. aureus infections specifically because of the possibility of
organism replacement, where S. aureus colonization and in-
fection is reduced only to allow infection with a different, po-
tentially more virulent organism. In the single study to have
evaluated nasal mupirocin to reduce infections in patients un-
dergoing peritoneal dialysis, no overall difference in infection
occurrence was seen [31]. Although the proportion of peri-
tonitis in patients treated with mupirocin as compared with
placebo demonstrated a trend toward fewer S. aureus infections
(18 [25%] of 72 vs. 24 [40%] of 60; P p .09), a significantly
higher rate of infections due to gram-negative or mixed or-
ganisms (20 [28%] of 72 vs. 7 [12%] of 60; P p .03, by Fisher’s
exact test) was observed [31]. The potential cost or clinical
outcome difference associated with organism replacement is
not known. The cost associated with use of mupirocin is sig-
nificant and may exceed the benefit if the incidence and costs
of treatment of infectious complications are low. One study
involving patients undergoing peritoneal dialysis suggested that
mupirocin use was not cost-effective [38].
Although the available literature does not support routine
use of topical intranasal mupirocin to prevent subsequent in-
fections, there may be yet-identified patient populations that
could benefit. For a significant effect to be seen, one may spec-
ulate as to the characteristics of patients who would benefit the
most. Ideally, mupirocin should be used for patients when the
period of risk for infection is acute. Chronic infection risk, such
as with dialysis patients, has demonstrated minimal clinical
benefit but increased risk for resistance. Examples of patients
with acute disease who may be candidates for prophylactic
mupirocin treatment include patients who have undergone car-
diac surgery, patients with multiple trauma (especially those
with head injuries), and, possibly, other selected critically ill
patients [38–41]. The selection of patients with high rates of
nasal colonization or documented carriers is also important for
mupirocin therapy to be effective. Clinical prediction of nasal
carriage is not sufficiently discriminating; culture data are
needed. The requirement for incubation of cultures before mu-
pirocin therapy is started can result in delays that may lessen
its effectiveness. The development of rapid diagnostic tech-
niques to identify S. aureus nasal carriage may be a requisite
advance before mupirocin therapy can used as prophylaxis.
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