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Positive nasal Staphylococcus aureus 0(0) 1–7

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or subsequent Staphylococcus aureus

infection in critically ill patients

Kalai C Kanagasingham1, Kwok M Ho1,2 and

J Owen Robinson2,3

Abstract
Staphylococcal infection is associated with significant morbidity and mortality in critically ill patients. Using data from 16,681
patients who had a nasal Staphylococcus aureus polymerase chain reaction (PCR) assay on admission to the intensive care
unit (ICU) of Royal Perth Hospital between March 2006 and September 2016, this retrospective cohort study assessed
whether nasal S. aureus colonisation on admission to an ICU was predictive of concurrent or subsequent S. aureus
infections. Culture-proven S. aureus infections were identified using the hospital microbiology database. Of the 16,681
patients included, 565 (3.4%) had a positive methicillin-resistant S. aureus (MRSA) assay, 146 (0.9%) had a positive
methicillin-sensitive S. aureus (MSSA) assay and eight (0.05%) had both positive MRSA and MSSA assays. Of those 565
patients with a positive MRSA PCR assay, 79 (13.8%) had concurrent or subsequent MRSA infections. Of those 146
patients with a positive MSSA PCR assay, only 5 (3.4%) had MSSA infection. The sensitivity and specificity for the MRSA
PCR assay in predicting concurrent or subsequent MRSA infection were 72.7% (95% confidence intervals (CI) 63.4%–
80.8%) and 97.0% (95% CI 96.8%–97.3%), respectively. The sensitivity and specificity for the MSSA PCR assay in predicting
concurrent or subsequent MSSA infection were 3.3% (95% CI 1.1%–7.6%) and 99.1% (95% CI 98.9%–99.2%), respectively.
Both nasal MRSA and MSSA PCR assays had a high specificity and negative predictive value in predicting MRSA and MSSA
infections, respectively, suggesting that in centres without endemic S. aureus infections, a negative nasal MRSA or MSSA
PCR assay may be useful to reduce unnecessary empirical antibiotic therapy against S. aureus.

Keywords
Bacteraemia, colonisation, infection, polymerase chain reaction, prediction, screening, Staphylococcus aureus

Introduction bacteraemia and increased incidence of metastatic seed-

Staphylococcus aureus infections are common and are 1 ing of infection compared to MSSA bacteraemia.3 On
associated with substantial morbidity and mortality.2–4
In 2015–2016, 1440 cases of hospital-acquired bacterae-
mia due to either methicillin-resistant S. aureus (MRSA; 1
Department of Intensive Care Medicine, Royal Perth Hospital, Perth,
19%) or methicillin-sensitive S. aureus (MSSA; 81%), Australia
2
School of Veterinary and Life Sciences, Murdoch University, Perth,
with an overall incidence of 0.73 per 10,000 days of
Australia
patient care, were reported in Australian public hospi- 3
Department of Infectious Diseases and Microbiology, Royal Perth
tals.5 S. aureus bacteraemia is associated with >10% Hospital, Perth, Australia
hospital mortality,2,3 and MRSA bacteraemia is often
Corresponding author:
empirically treated with antibiotics to which the patho- Kwok M. Ho, ICU, Royal Perth Hospital, Wellington Street, Perth,
gen is not susceptible in vitro while cultures and suscep- Western Australia 6847, Australia.
tibilities are pending, resulting in prolonged Email: kwok.ho@health.wa.gov.au
2 Anaesthesia and Intensive Care 0(0)
the other hand, unnecessary anti-MRSA therapy also
has significant risks at both patient and community
levels, including nephrotoxicity from vancomycin, ana-
phylaxis to teicoplanin6 and development of
vancomycin-resistant Enterococci.7 As such, it is imper-
ative to develop rapid and reliable ways to identify
patients who are at high risk of MRSA infection—in
particular MRSA bacteraemia—so that prompt appro-
priate empirical antibiotics can be initiated while mini-
mising overuse of broad-spectrum antibiotics.8
S. aureus can be found in different body sites such as
the skin, rectum, vagina, gastrointestinal tract and
axilla. Once the bacteria are in contact with the nasal
mucosa, they will interact with epithelial cell ligands,
such as loricrin and cytokeratin 10 (K10), and colonise
the anterior nares.9 It has been estimated that up to
30% of the human population are asymptomatically
and permanently colonised with S. aureus in their ante-
rior nares.9 In critically ill patients, recent studies
have suggested that nasal colonisation with S. aureus
is associated with a higher subsequent risk of S. aureus
infections, including bacteraemia.10–12 In addition,
nasal decolonisation of S. aureus is associated with a
reduced risk of S. aureus pneumonia in critically ill
patients and surgical site infection prior to surgery.13,14
Nonetheless, whether nasal S. aureus colonisation—
confirmed by a polymerase chain reaction (PCR)
assay—on admission to an intensive care unit (ICU)
is predictive of all forms of subsequent MRSA and
MSSA infections is uncertain.
We hypothesised that nasal MRSA and MSSA col-
onisation in the critically ill on admission to an ICU
can be predictive of MRSA and MSSA infections,
respectively. In this retrospective cohort study, we
aimed to determine the associations between a positive
nasal MRSA/MSSA PCR assay on admission to ICU
and concurrent or subsequent S. aureus infections
during the same hospitalisation.
Methods
Patients and setting
Nasal swabs were taken for all patients admitted to the
ICU of Royal Perth Hospital within the first hour of
admission to identify MRSA colonisation for infection
control purposes. Nasal swabs were taken only on
admission to the ICU, including readmissions, but
not during ICU stay. Contact precaution measures
including use of an isolation room would be imple-
mented for patients who were identified as MRSA
colonised. Eradication therapy, such as topical mupir-
ocin, was not used. In this study, 16,681 consecutive
patients who were admitted to the ICU between 30
March 2006 and 30 September 2016 were included.
Patients admitted to the co-located high dependency
unit were not screened for MRSA and were excluded
from this study unless they were subsequently admitted
to the ICU. For patients who had more than one ICU
admission during the same hospitalisation, only the
nasal MSSA and MRSA PCR results in the index
ICU admission were used in this study.
The nasal colonisation for MRSA and MSSA
was determined by a PCR assay using either the
IDI-MRSA (from March 2006 to June 2013) or the
automated BD Max (from July 2013 to the end of
study period) system, with the results available within
three hours in the study centre.15,16 The first-generation
BD Max MRSA assay was not able to identify correct-
ly the mecA empty cassette or the MRSA strains with
methicillin resistance gene mecC and some MRSA mec
right-extremity junction type strains.17 In this study,
patients with a positive MRSA or MSSA PCR assay,
and any concurrent or subsequent culture-confirmed
MRSA or MSSA infections during the same hospital
stay, were identified using the hospital microbiology
database. An infection due to S. aureus was defined
as either growth of S. aureus from a sterile site (e.g.
blood or joint fluid) or identification of S. aureus
from a non-sterile site (e.g. wound or sputum) while
there was clinical and/or radiological evidence of infec-
tion and no other cause/pathogen could be identified.
The microbiology data of the study patients were then
merged with the ICU administrative database for this
clinical audit (CSQU approval number 13773).
Outcomes
The primary outcome of this study was the ability of a
positive nasal MRSA or MSSA PCR assay in predict-
ing concurrent or subsequent culture-proven MRSA or
MSSA infection during the same hospital stay.
Sensitivity, specificity, positive and negative predictive
values, positive and negative likelihood ratios and area
under the receiver operating characteristic curve were
used to describe the ability of a nasal MRSA and
MSSA PCR assay to predict concurrent or subsequent
MRSA and MSSA infections, respectively.
Statistical analyses
Because we did not have prior local data on the
incidence of a positive nasal MRSA or MSSA PCR
assay, the number of patients included was maximised
by including all patients who were admitted to the ICU
after MRSA/MSSA PCR was initiated for routine use as
an infection control measure until initiation of this audit.
Descriptive categorical and continuous data are pre-
sented as the number (%) and median (interquartile
range (IQR)), respectively. In addition to sensitivity
Kanagasingham et al. 3

and specificity, the ability of a positive nasal MRSA
PCR assay to predict concurrent or subsequent
MRSA infection was further assessed by logistic regres-
sion with and without adjusting for important covari-
ates in a subgroup of patients with either MRSA/MSSA
infection or a positive nasal MRSA/MSSA PCR assay.
The covariates used for adjustment were markers of
severity of acute and chronic illnesses which might con-
found the relationship between colonisation and infec-
tion. The time from confirming MSSA/MRSA
colonisation to infection was not analysed because
many of our study patients had concurrent MSSA/
MRSA infections instead of development of such infec-
tions subsequently. All statistical analyses were con-
ducted using IBM SPSS Statistics for Windows v24.0
(IBM Corp., Armonk, NY, USA) and MedCalc for
Windows v12.5 (MedCalc Software Ltd, Ostend,
Belgium), and a two-tailed alpha error of <5% was
taken as significant. De-identified study data are avail-
able on request from the corresponding author.
Results
Of the 16,681 patients eligible and included in the
study, 565 (3.4%) had a positive MRSA PCR assay,
146 (0.9%) had a positive MSSA PCR assay, and eight
(0.05%) had both positive MRSA and MSSA PCR
assays. The rates of MRSA infection (109/16,681;
0.65%) and colonisation (573/16,681; 3.4%) in patients
admitted to our ICU were relatively low. Of the 719
patients who had a positive MRSA or MSSA PCR
assay, 94 (13%) had coexisting or subsequent MRSA
or MSSA infections compared to only 1.0% incidence
of MRSA or MSSA infections among those who did
not have a positive MRSA or MSSA PCR assay
(n ¼ 15,962 patients; Figure 1). Of the 109 and 151
culture-proven MRSA and MSSA infections, 62%
and 92% were isolated from sterile sites, including
blood culture, joint fluid, pleural fluid or tissue (e.g.
heart valve, bone and vascular grafts; Table 1),
respectively.
Of the 883 patients who had either a positive nasal
MRSA/MSSA PCR assay or MRSA/MSSA infection,
infection/sepsis was the commonest clinical admission
diagnosis (n ¼ 160), followed by trauma (n ¼ 75), post-
operative management after major surgery (n ¼ 63),
acute cardiovascular diseases (n ¼ 51), acute neurolog-
ical diseases (n ¼ 50) and acute respiratory diseases
(n ¼ 44). The characteristics of these 883 patients are
described in Table 1.

A total of 16,681 intensive care

index admissions between 30 March
2006 and 30 September 2016

MRSA PCR (+) MSSA PCR (+) Both MRSA and Both MRSA and
alone alone MSSA PCR (+) MSSA PCR (-)

n=565 n=146 n=8 n=15,962

MRSA MSSA MRSA MSSA MRSA MSSA MRSA MSSA

infecon infecon infecon infecon infecon infecon infecon infecon
n=78 n=8 n=2 n=5 n=1 n=0 n=28 n=138
(13.8%) (12.5%)
(1.4%) (1.4%) (3.4%) (0%) (0.2%) (0.9%)

Figure 1. Flow chart showing the patients with and without a positive polymerase chain reaction (PCR) for methicillin-sensitive
Staphylococcus aureus (MSSA) or methicillin-resistant Staphylococcus aureus (MRSA) and subsequent risk of MSSA or MRSA culture-
proven infection. The proportion of patients and incidence rate of MRSA infections (estimated using median length of hospital stay of
15 days) among those without a positive nasal MRSA PCR assay were 0.18% and 0.44 per 1000 patient years, respectively. Two
patients with negative MRSA and MSSA PCR assays had both MRSA and MSSA infections.
4 Anaesthesia and Intensive Care 0(0)

Of those 565 patients with a positive MRSA PCR developed MRSA infection (Figure 1). The proportion
assay, 79 (13.8%) had concurrent MRSA infections on of patients and incidence rate of MRSA infections
ICU admission (n ¼ 72) or developed MRSA infections (estimated using median length of hospital stay of 15
subsequently (n ¼ 7; median ¼ 2 days, IQR 1–11); 78/79 days) among those without a positive nasal MRSA
patients had a positive MRSA PCR assay alone, but PCR assay were 0.18% and 0.44 per 1000 patient
one patient had both positive MRSA and MSSA PCR years, respectively.
assays. Of those 146 patients with a positive MSSA Both nasal MRSA and MSSA PCR assays had
PCR assay, five (3.4%) had concurrent MSSA infec- a high specificity and negative predictive value
tion (n ¼ 1) or developed subsequent MSSA infection but low sensitivity and positive predictive value in
(n ¼ 4; median ¼ 3 days, IQR 1–6), and two (1.4%) predicting concurrent or subsequent MRSA and
MSSA infections, respectively. The sensitivity and spe-
Table 1. Characteristics of patients who had either a positive cificity for a positive MRSA PCR assay for MRSA
PCR assay for MSSA/MRSA or MSSA/MRSA culture-proven infection were 72.7% (95% confidence interval (CI)
infection (N ¼ 883). 63.4%–80.8%) and 97.0% (95% CI 96.8%–97.3%),
respectively. The sensitivity and specificity for a posi-
Median (IQR)
Variable or n (%) tive MSSA PCR assay for MSSA infection were 3.3%
(95% CI 1.1%–7.6%) and 99.1% (95% CI 98.9%–
Age (years) 49 (33–66) 99.2%), respectively (Table 2).
Male 564 (63.9) In the univariable logistic regression analysis, there
APACHE II score 17 (10–23) was a suggestion that a positive nasal MRSA PCR was
Length of intensive care unit stay (hours) 73 (34–166)
associated with an increased risk of having MRSA
Length of hospital stay (days) 15 (5.7–30.1)
Intensive care unit mortality 135 (15.3) infection, but this was not statistically significant
Hospital mortality 179 (20.3) (odds ratio (OR) ¼ 1.55, 95% CI 0.99–2.43, P ¼
MRSA culture-proven infection: 109 (12.3%)a 0.056). This result remained unchanged (OR ¼ 1.64,
Blood culture 31 (29) 95% CI 0.96–2.79, P ¼ 0.068) after adjusting for age,
Wound 54 (50) Acute Physiology and Chronic Health Evaluation II
Joint fluid 3 (3) score and coexisting diseases (Table 3). End-stage
Pleural fluid 6 (6) renal failure requiring dialysis was the only major
Tissue (e.g. heart valve, bone, graft) 28 (26)
MSSA culture-proven infection: 151 (17.1)a
Table 2. Predictive parameters of MSSA and MRSA PCR assays
Blood culture 59 (39)
for concurrent or subsequent MSSA and MRSA culture-proven
Wound 11 (7)
infection, respectively.
Joint fluid 18 (12)
Pleural fluid 14 (9) Mean (95% CI)
Tissue (e.g. heart valve, bone, graft) 48 (32)
Chronic cardiovascular disease 58 (6.6) MRSA PCR
Chronic respiratory disease 50 (5.7) Sensitivity 72.7% (63.4–80.8)
Cirrhosis 36 (4.1) Specificity 97.0% (96.8–97.3)
End-stage renal failure requiring dialysis 54 (6.1)c Positive likelihood ratio 24.5 (21.2–28.2)
Current immunosuppressive therapyb 19 (2.2) Negative likelihood ratio 0.28 (0.21–0.38)
Current immunosuppressive diseaseb 21 (2.3) Positive predictive value 14.0% (12.3–15.8)
Negative predictive value 99.8% (99.7–99.9)
a
Number of patients; some patients had more than one positive culture Area under the receiver 0.849 (0.843–0.854)
specimen. operating characteristic curve
b
According to the APACHE model, current immunosuppressive diseases MSSA PCR
include active leukaemia, acquired immune deficiency syndrome, lym-
Sensitivity 3.3% (1.1–7.6)
phoma, severe autoimmune disease and documented diffuse metastatic
cancer; immunosuppressive therapy includes patients treated with che-
Specificity 99.1% (98.9–99.2)
motherapy, radiation or long-term low-dose steroids (during 30 days Positive likelihood ratio 3.5 (1.5–8.4)
prior to hospitalisation) or recent high-dose steroid (1.5 mg/kg for Negative likelihood ratio 0.98 (0.95–1.01)
5 days). Positive predictive value 3.1% (1.3–7.1)
c
35 patients had a positive nasal MRSA PCR assay without MRSA infec- Negative predictive value 99.1% (99.0–99.2)
tion, six patients had MRSA infections without a positive nasal MRSA PCR Area under the receiver 0.512 (0.504–0.519)
assay and eight patients both nasal MRSA PCR positive assay and MRSA operating characteristic curve
infection.
PCR: polymerase chain reaction; MSSA: methicillin-sensitive CI: confidence interval; MSSA: methicillin-sensitive Staphylococcus aureus;
Staphylococcus aureus; MRSA: methicillin-resistant Staphylococcus aureus; MRSA: methicillin-resistant Staphylococcus aureus; PCR: polymerase chain
IQR: interquartile range; APACHE: Acute Physiology and Chronic Health reaction.
Evaluation.
Kanagasingham et al. 5

Table 3. Logistic regression showing the relationship between a positive nasal MRSA PCR
assay and risk of having concurrent or subsequent MRSA infection after adjusting for other
covariates (N ¼ 883).

Predictors Odds ratio (95% CI) P-value

Age (per year increment) 1.00 (0.99–1.02) 0.687

APACHE II score (per score increment) 1.03 (1.00–1.05) 0.054
Positive nasal MRSA PCR assay 1.64 (0.96–2.79) 0.068
Chronic respiratory disease 1.96 (0.92–4.16) 0.080
Chronic cardiovascular disease 1.37 (0.59–3.18) 0.472
Current immunosuppressive therapya 2.08 (0.44–9.72) 0.354
Current immunosuppressive diseasea 1.00 (0.28–3.61) 0.995
End-stage renal failure requiring dialysis 2.08 (1.01–4.26) 0.047
Cirrhosis 1.20 (0.47–3.07) 0.711
a
According to the APACHE model, current immunosuppressive diseases include active leukaemia,
acquired immune deficiency syndrome, lymphoma, severe autoimmune disease and documented diffuse
metastatic cancer; immunosuppressive therapy includes patients treated with chemotherapy, radiation or
long-term low-dose steroids (during 30 days prior to hospitalisation) or recent high-dose steroid (1.5
mg/kg for 5 days).
OR: odds ratio; MSSA: methicillin-sensitive Staphylococcus aureus; MRSA: methicillin-resistant
Staphylococcus aureus; PCR: polymerase chain reaction; APACHE: Acute Physiology and Chronic Health
Evaluation.

comorbidity associated with an increased risk of
MRSA infection (OR ¼ 2.08, 95% CI 1.01–4.26,
P ¼ 0.047).
Discussion
A delay in initiating appropriate antimicrobial therapy
for infection, in particular for those with bacteraemia,
is associated with an increased risk of organ failure,
metastatic infection and mortality.3,18–21 In this study,
our results showed that both nasal MRSA and MSSA
PCR assays have a high specificity and negative predic-
tive value but a low sensitivity, especially the MSSA
PCR assay, to predict concurrent or subsequent clinical
staphylococcal infections. These results are consistent
with a recent systematic review on the utility of nasal
MRSA PCR assays in predicting MRSA infections
(pooled specificity was >90%, but positive predictive
value was only 50%),22 suggesting that only a negative
MRSA PCR assay may have clinical utility when
the probability of having subsequent MRSA infection
would be low and empirical vancomycin therapy for
any suspected nosocomial sepsis may not be indicated,
especially in clinical areas where MRSA is not endemic,
as in our study centre. Conversely, a positive MRSA
PCR assay is not particularly helpful with a low sensi-
tivity and low positive predictive value. Initiating
empirical vancomycin based on a positive MRSA
PCR assay result would thus lead to overuse of vanco-
mycin, resulting in increased healthcare costs, risks of
nephrotoxicity and development of organisms resistant
to vancomycin.7,23
Unlike the association between MRSA infection and
nasal MRSA PCR assay, the association between a
positive nasal MSSA swab and systemic MSSA infec-
tion has so far received little attention.24 In this study,
we showed that the prevalence of a positive nasal
MSSA PCR assay in our patients was much lower
than expected compared to the general population.9
This result may be related to the fact that many
study patients might have received broad-spectrum
antibiotics prior to their ICU admissions, or the nasal
MSSA PCR assay was just not as sensitive. In a study
of 79 episodes of S. aureus (MRSA 12% and MSSA
87%) bacteraemia,24 the incidence of a positive nasal
swab culture for MSSA or MRSA was <50%, suggest-
ing that the sensitivity of a nasal swab culture for
MSSA is low. If this study’s results as well as ours
are confirmed by other studies, use of a MSSA PCR
assay to identify patients who are at increased risk of
MSSA infection including MSSA bacteraemia will not
be cost effective. Nonetheless, due to its high negative
predictive value, a negative MSSA PCR assay may still
be useful to exclude concurrent MSSA infection, simi-
lar to the utility of a negative MRSA PCR assay.
This study showed that patients with end-stage renal
failure requiring dialysis admitted to our ICU were at
increased risk of having MRSA infections independent
of their nasal MRSA colonisation status. This result is
consistent with other reports showing end-stage renal
failure is a risk factor of MRSA colonisation, infection
and infection-related mortality.25–30 Within the nested
cohort of our patients who were either colonised
or infected with MSSA/MRSA, the MRSA infection
rate among those with end-stage renal failure was
6 Anaesthesia and Intensive Care 0(0)
high (14/54; 26%) compared to those without end-stage
renal failure (73/668; 12.3%). If our results
are confirmed by other Australian ICUs, perhaps
empirical vancomycin therapy should be considered
in critically ill patients who have end-stage renal failure
when serious systemic infection or bacteraemia is sus-
pected, especially if they are known to be colonised
with MRSA, or in centres where MRSA infection
is endemic.
Finally, we need to acknowledge the limitations of
this study. First, staphylococcal infections are not
endemic in our centre, and this would increase the neg-
ative predictive values of both nasal MSSA and MRSA
PCR assays in predicting staphylococcal infection.
As such, our results may not be generalisable to centres
that have endemic staphylococcal infections. Second,
we only analysed patients with culture-proven staphy-
lococcal infection. It is possible that some staphylococ-
cal infections might have occurred among those who
had been colonised with MRSA or MSSA, but the
microbiological cultures were not taken or they were
treated empirically with antibiotics, reducing the yield
of subsequent microbiological cultures. In addition, we
also did not have data on MRSA contact prior to index
ICU admission. Prospective research including contact
history will be useful to assess whether this can
strengthen the ability of nasal MRSA PCR assay in
predicting MRSA infections. Third, the sensitivity of
using nasal swabs to detect bacterial colonisation may
be subject to variations in the techniques in obtaining
the nasal swabs, as well as how many nasal swabs are
taken. A recent study suggested that significantly more
(P ¼ 0.016) patients with two negative nasal swabs
returned with a recurrent MRSA infection or colonisa-
tion than those who had three consecutive negative
nasal swabs (27.8% versus 17.0%, respectively).31
Finally, the sensitivity of a PCR assay is known to be
dependent on the strains of staphylococcal bacteria,
which can vary substantially between different popula-
tions.32 This important limitation has recently been
overcome with the development of two new genera-
tions of more sensitive MRSA PCR assays.17
Conclusions
Both nasal MRSA and MSSA PCR screening assays
obtained on admission to the ICU had a high specific-
ity in predicting concurrent or subsequent S. aureus
infections, respectively. However, the sensitivity of
both MRSA and MSSA PCR assays were low, espe-
cially for the MSSA PCR assay. These results suggest
that only a negative MSSA and MRSA PCR assay may
have some degree of clinical utility when the probabil-
ity of having staphylococcal infection would be low
and empirical anti-staphylococcal antibiotic therapy
would not be indicated for patients with nosocomial
sepsis, especially in ICUs where S. aureus infections
are not an endemic problem.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with
respect to the research, authorship and/or publication of this
article.
Funding
The author(s) received no financial support for the research,
authorship and/or publication of this article.
ORCID iD
Kwok M Ho https://orcid.org/0000-0002-6705-6004
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