J Infect Chemother xxx (xxxx) xxx

Contents lists available at ScienceDirect

Journal of Infection and Chemotherapy

journal homepage: http://www.elsevier.com/locate/jic

Review Article

Metastatic infection during Staphylococcus aureus bacteremia

Tetsuya Horino*, 1, Seiji Hori 1
Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, Japan

a r t i c l e i n f o a b s t r a c t

Article history: Staphylococcus aureus causes various infections, including skin and soft tissue infections and pneumonia
Received 20 May 2019 via both, community-associated and nosocomial infection. These infectious diseases can lead to bacter-
Received in revised form emia, and may subsequently result in metastatic infections in several cases. Metastatic infections are
25 July 2019
critical complications in patients with S. aureus bacteremia, since the optimal duration of the antimicrobial
Accepted 3 October 2019
Available online xxx
treatment differs in patients with and without metastatic infection. Notably, two weeks of antimicrobial
treatment is recommended in case of uncomplicated S. aureus bacteremia, whereas in patients with
S. aureus bacteremia-associated endocarditis or vertebral osteomyelitis, six weeks of antimicrobial
Keywords:
Staphylococcus aureus
administration is vital. In addition, misdiagnosis or insufficient treatment in metastatic infection is
Bacteremia associated with poor prognosis, functional disability, and relapse. Although echocardiography is recom-
Metastatic infection mended to examine endocarditis in the patients with S. aureus bacteremia, it remains unclear which
Predictive factor patients should undergo additional examinations, such as CT and MRI, to detect the presence of other
Virulence factor metastatic infections. Clinical studies have revealed that permanent foreign body and persistent bacter-
emia are predictive factors for metastatic infections, and experimental studies have demonstrated that the
virulence factors of S. aureus, such as fnbA and clfA, are associated with endocarditis; however, these
factors are not proven to increase the risk of metastatic infections. In this review, we assessed the inci-
dence, predictive factors, diagnosis, and treatment for metastatic infections during S. aureus bacteremia.
© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases.
Published by Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
2. Prevalence of metastatic infection during S. aureus bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
3. Portal site of bacteremia associated with metastatic infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
4. Predictive factors of clinical characteristics for metastatic infection during S. aureus bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
5. Virulence factors of S. aureus associated with metastatic infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6. Type of metastatic infection during S. aureus bacteremia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.1. Infective endocarditis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.2. Vertebral osteomyelitis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.3. Iliopsoas abscess . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.4. Septic arthritis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.5. Ocular infection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
6.6. Septic pulmonary embolism . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
7. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Declaration of Competing Interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

* Corresponding author. Department of Infectious Diseases and Infection Control, Jikei University School of Medicine, 3-25-8 Nishi-shimbashi, Minato-ku, Tokyo, 105-8461,
Japan. Tel þ81-3-3433-1111; Fax þ81-3-5400-1249
E-mail address: horino@jikei.ac.jp (T. Horino).
1
All authors meet the ICMJE authorship criteria.

https://doi.org/10.1016/j.jiac.2019.10.003
1341-321X/© 2019 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.

Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
2 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx

1. Introduction and includes infective endocarditis, vertebral osteomyelitis, iliop-

Staphylococcus aureus was the most common pathogen (28%,
428 of 1470 cases) observed in bacterial bloodstream infections,
followed by Escherichia coli (24%) and coagulase-negative staphy-
lococci (10%) in a multicenter retrospective cohort study [1].
Despite the use of antimicrobial drugs, a high mortality rate was
observed in S. aureus bacteremia [2], and inappropriate treatment
could result in the relapse of S. aureus bacteremia and cause serious
complications. One reason for the inappropriate antimicrobial
treatment was that the optimal duration of antimicrobial treatment
depended on the metastatic infection during S. aureus bacteremia.
The Infectious Disease Society of America (IDSA) guidelines for
methicillin resistant S. aureus (MRSA) infection recommended that
patients with complicated bacteremia should be administered an-
timicrobials for at least four to six weeks, whereas adults with
uncomplicated S. aureus bacteremia required antimicrobial treat-
ment for only two weeks [3]. In reference to the aforementioned
guideline, uncomplicated bacteremia was identified in patients
presenting no endocarditis and implanted prostheses, lacking
MRSA growth in the blood culture two to four days after the onset
of MRSA bacteremia, defervescence within 72 h of antimicrobial
administration, and no metastatic infection. Nevertheless, it is
extremely difficult to exclude metastatic infection in clinical prac-
tice because these infections are asymptomatic in some patients
[4]. Thus, it remains unclear which patients need to undergo
several examinations to detect the presence of metastatic infection,
as these infections are common and serious complications
observed in patients with S. aureus bacteremia. Therefore, in this
review, we assessed the prevalence, risk factors, diagnostic
methods and duration of antimicrobial treatment in the metastatic
infections caused by S. aureus bacteremia.
2. Prevalence of metastatic infection during S. aureus
bacteremia
Metastatic infection is defined as a deep, distal, or secondary
infection, anatomically unrelated to the primary site infection [5],
soas abscess, and septic arthritis. To assess the prevalence of met-
astatic infection during S. aureus bacteremia in adult patients, we
reviewed English literature between 1989 and 2018 in the PubMed
database, using the keywords “staphylococcus aureus”, “bacter-
emia” and “metastatic infection”. Among the 422 articles, basic
research including animal models, case reports and clinical studies
including pediatric patients (less than 15 years old) were excluded.
Furthermore, studies that reported patients with various metastatic
infections caused by S. aureus bacteremia, other than endocarditis,
were included. Finally, 21 clinical studies were included in this
prevalence investigation. The prevalence of metastatic infections
was 5.7 %e75.3% during S. aureus bacteremia (Table 1). In these
studies, the highest prevalence of metastatic infection (75.3%) was
detected by using 18F-fluorodeoxyglucose-positron emission to-
mography (PET) in combination with low-dose computed tomog-
raphy [6]. Thus, the rate of metastatic infection depended on its
definition and the diagnostic methods used.
3. Portal site of bacteremia associated with metastatic
infection
S. aureus can cause various infectious diseases, including
pneumonia and skin and soft tissue infection, all of which further
lead to bacteremia. In particular, loss of integrity of the skin barrier,
via decubitus, surgical wounds, and diabetic foot, is the most
common portal for S. aureus infection. Although several studies
reported that intravenous drug abuse was one of the risk factors for
endocarditis [7e9], local injection site for pain control, including
acupuncture treatment [10,11], should also be considered a po-
tential portal site. In addition, the rate of metastatic infection in
patients with unknown portal sites of S. aureus was higher
compared to that in the patients with detected portal sites [6,7].
Moreover, catheter-related bloodstream infection (CRBSI) was
associated with a lower risk of metastatic infections during
S. aureus bacteremia [4,12]. One of the reasons for lower incidence
of metastatic infection in CRBSI could be the early diagnosis and
treatment compared with that in non-CRBSI [12]. Thus, in patients

Table 1
Incidence of metastatic infection during S. aureus bacteremia.

S. aureus Metastatic infection/Total Rate of metastatic Published Notes Reference

patients infection year

MSSA, MRSA 22/110 20.0 1996 [57]

MSSA, MRSA 74/244 30.3 1998 Neutropenic patients were excluded. [44]
MSSA, MRSA 54/815 6.6 2003 [45]
MSSA, MRSA 39/104 37.5 2004 [17]
MSSA, MRSA 17/177 9.6 2004 [80]
MSSA, MRSA 3/50 6.0 2005 Only soft tissue-associated bacteremia was included. [67]
MSSA, MRSA 35/102 34.3 2005 [81]
only MSSA 11/51 21.6 2007 Only community-associated bacteremia was included. [58]
MSSA, MRSA 95/234 40.6 2008 [82]
MSSA, MRSA 64/85 75.3 2012 Patients with neutropenia or pregnancy were excluded. [6]
only MRSA 86/223 38.6 2012 Only cancer patients were included. [83]
only PSSA 124/588 21.1 2013 [84]
only MRSA 137/877 15.6 2013 [85]
only MSSA 14/73 19.2 2015 [4]
only MSSA 126/400 31.5 2016 [86]
only MRSA 69/262 26.3 2016 Patients who had pneumonia and received renal replacement therapy [87]
were excluded.
MSSA, MRSA 7/122 5.7 2016 Only hospital-associated bloodstream infection was included. [12]
only MSSA 59/252 23.4 2017 [88]
MSSA, MRSA 239/613 39.0 2018 [46]
MSSA, MRSA 14/98 14.3 2018 [47]
MSSA, MRSA 301/758 39.7 2018 [89]

MSSA: methicillin sensitive Staphylococcus aureus.

MRSA: methicillin resistant Staphylococcus aureus.
PSSA: penicillin sensitive Staphylococcus aureus.

Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx 3

with S. aureus bacteremia, physicians should enquire regarding the encoding adhesin, three determinants (sej, eta, hlg) encoding toxin,
appearance of signs and the history of skin damage before the onset and one determinant (ica) involving biofilm production, were
of bacteremia, including medical treatment, atopic dermatitis [13], significantly more common in the invasive diseases due to S. aureus
and insect bites [14], and seek the portal site to control the infec- [23]. Among these virulence factors, some adhesins and toxins
tious sources. were associated with the metastatic infections, in particular
endocarditis. Pe
rez-Montarelo et al. analyzed 833 strains in clinical
isolates (785 strains derived from bacteremia and 48 strains
4. Predictive factors of clinical characteristics for metastatic
derived from colonization) and investigated the relationship be-
infection during S. aureus bacteremia
tween virulence factors of S. aureus and the source of infection
using DNA microarray [24]. In this study, it was demonstrated that
The definition of uncomplicated MRSA bacteremia included the
the presence of sed, splE, and fib genes was associated with endo-
absence of implanted prostheses and the lack of persistent
carditis, whereas undisrupted hlb was associated with skin soft
bacteremia and fever [3]. Rasmussen et al. reported that 53 of 244
tissue infections [24]. Similarly, Nienaber et al. investigated the
(21.7%) patients with S. aureus bacteremia presented with endo-
virulence factors of methicillin sensitive S. aureus (MSSA isolated
carditis, and that the prosthetic valves and cardiac rhythm man-
from 114 patients with endocarditis and 114 patients with soft
agement devices were the risk factors for endocarditis [7]. Similarly,
tissue infection enrolled from seven countries) [25]. They reported
Salvador et al. demonstrated that 64 of 505 (12.7%) patients with
that the adhesins (sdrC, cna, and map/eap) and toxins (tst and sei) of
S. aureus bacteremia had endocarditis, and the automatic
S. aureus derived from the clinical isolates were independently
implantable cardioverter-defibrillator or pacemaker were signifi-
associated with endocarditis [25]. In the experimental models,
cantly associated with the risk of endocarditis [15]. In addition,
Moreillon et al. reported that the clumping factor A affected the
several studies demonstrated that persistent bacteremia or fever
fibrinogen attachment and caused endocarditis using clfA-defective
could predict metastatic infection by S. aureus [4,8,9,16e18].
S. aureus [26]. Similarly, several studies presented that various
Therefore, it is prudent that metastatic infections in patients with
adhesins, including fnbA and clfA, as well as toxins, were associated
implanted prostheses, persistent bacteremia, or persistent fever are
with endocarditis (Table 3); however, some clinical studies have
efficiently assessed. In contrast, several studies reported that
reported that no virulence factor was associated with endocarditis
community associated S. aureus bacteremia was linked with a
due to S. aureus infection [13,27e30]. Thus, although several studies
higher incidence of endocarditis compared to the nosocomial
demonstrated the relationship between metastatic infection and
associated S. aureus infection [8,9,18e20]. Similarly, numerous
the virulence factors of S. aureus, it still remains controversial.
studies reported that various clinical findings were associated with
metastatic infections during S. aureus bacteremia (Table 2); how-
ever, these clinical predictive factors were not confirmed as con-
6. Type of metastatic infection during S. aureus bacteremia
trasting results have also been reported. This may indicate that the
metastatic infection is associated with not only clinical character-
6.1. Infective endocarditis
istics of the patients with S. aureus bacteremia, but also with the
pathogenesis of S. aureus.
Infective endocarditis is one of the severe diseases caused by
various pathogens. Viridans group streptococci derived from oral
5. Virulence factors of S. aureus associated with metastatic lesions, including tooth extraction and tooth caries, were the most
infection common pathogens in infective endocarditis. Recently, the inci-
dence of S. aureus as a causative pathogen of endocarditis has
S. aureus has multiple virulence factors that are associated with increased, and is widespread in several developed countries [31].
complications and prognosis of S. aureus bacteremia [21,22]. Pea- Infective endocarditis is one of the most common and serious
cock et al. demonstrated that three determinants (fnbA, cna, sdrE) metastatic infections during S. aureus bacteremia. Heriot et al.

Table 2
Predictive factors of clinical characteristics for metastatic infection during S. aureus bacteremia.

Predictive factor Metastatic infection Reference

Baseline of patient's characteristics

Intravenous drug abuse Endocarditis [7e9]
Pre-existing valvular disorder Endocarditis [7e9]
Prosthetic valves Endocarditis [7e9]
Cardiac rhythm management devices Endocarditis [7,11,15]
History of prior endocarditis Endocarditis [8]
Presence of a permanent foreign body Deep focus infection [18,43]
Hemodialysis Deep focus infection [43]
Charlson score 3 Deep focus infection [46]
Situation at the onset of S. aureus bacteremia or after treatment
Community acquisition Endocarditis [8,9,18e20,57,80,81]
Unknown primary site of infection Endocarditis [7,8]
Persistent bacteremia after adequate antimicrobial treatment Endocarditis [8,9,16e18,20,47]
Positive blood culture within 14 h after incubation Deep focus infection [5]
Longer duration of symptoms before diagnosis Deep focus infection [43]
Delay in appropriate antimicrobial treatment Deep focus infection [4]
Persistent fever after adequate antimicrobial treatment Deep focus infection [4,18]
High level of CRP at the onset of S. aureus bacteremia or after treatment Deep focus infection [4,9]
Methicillin resistant S. aureus bacteremia Deep focus infection [43]
Vancomycin MIC 2 mg/L Deep focus infection [88]

Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
4 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx
Table 3
Virulence factors of S. aureus associated with infective endocarditis.
Adhesins Products
fnbA Fibronectin binding protein A
clfA Clumping factor A
can Collagen adhesin
map/eap Extracellular adherence protein
sdrC Serineeaspartate repeat protein C
srtA Staphylococcus aureus Sortase A
sraP Serine-rich adhesin for platelets
Toxins
Tst Toxic shock syndrome toxin 1
Sec Staphylococcal enterotoxin C
sei Staphylococcal enterotoxin I
Hla Alpha-toxin
egc operon Enterotoxin gene cluster
global regulators
Sar Staphylococcal accessory regulator
reported that 6e24% of the patients with S. aureus bacteremia were
complicated with infective endocarditis [32]. Chang et al. investi-
gated 505 patients with S. aureus bacteremia (13%, 64 of 505 pa-
tients had complicated endocarditis), and demonstrated that
community-associated S. aureus bacteremia was associated with a
higher incidence of endocarditis compared with the hospital ac-
quired S. aureus bacteremia [8]. Nevertheless, in a study investi-
gating 91 patients with S. aureus bacteremia, Salvador et al.
demonstrated that endocarditis was affected by automatic
implantable cardioverter-defibrillator or pacemaker; however,
multivariate analysis demonstrated that community-acquisition
was not associated with endocarditis [15]. Thus, all patients with
S. aureus bacteremia should undergo echocardiography in order to
evaluate infective endocarditis, since endocarditis could not be
excluded based on patient characteristics. Two types of echocar-
diography are available, transthoracic echocardiogram (TTE) and
transesophageal echocardiogram (TEE). Holland et al. reported that
the rate of detecting endocarditis with transthoracic echocardiog-
raphy was lower than that with transesophageal echocardiography
(2%e15% vs. 14%e28%) [33]. However, in surveilling the manage-
ment of S. aureus bacteremia, Liu et al. revealed that only 19% re-
spondents performed TEE in all patients in whom TTE did not
detect vegetation [34], despite TEE recommended in the guideline.
Since TEE is an invasive procedure, which may be associated with
complications when compared with TTE, the physician may be
unable to perform this procedure during critical illness due to
contraindications or patient refusal [35]. Bai et al. reviewed the
clinical predictors for endocarditis during S. aureus bacteremia and
suggested that TEE should be performed at least in high-risk pa-
tients, who had embolic events, a pacemaker, prosthetic valve,
previous endocarditis, or intravenous drug use [35]. Thus, further
investigation would be required to perform TEE more aggressively.
IDSA guidelines recommended anti-staphylococcal penicillin or
cefazolin, and vancomycin or daptomycin for endocarditis due to
MSSA and MRSA, respectively [36]. Duration of antimicrobial
administration for endocarditis due to S. aureus was recommended
as six weeks for native valve infective endocarditis and six weeks
for prosthetic endocarditis [36] (Table 4).
6.2. Vertebral osteomyelitis
Vertebral osteomyelitis developed after spinal surgery [37], local
injection for lumbago, and bloodstream infection in some patients.
The most common cause of vertebral osteomyelitis was the he-
matogenous spread [38,39], and S. aureus is the most common
pathogen of hematogenous vertebral osteomyelitis [38,40e42],
followed by streptococci. The morbidity of vertebral osteomyelitis
Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
Study design Reference
Experimental model in rat [26,90,91]
Experimental model in rat [26,90e92]
Clinical study [25]
Clinical study [25]
Clinical study [25]
Experimental model in rat [93]
Experimental model in rabbit [94]
Clinical study [25]
Experimental model of rabbit [95]
Clinical study [25]
Experimental model in rabbit [96]
Experimental model in rabbit [97]
Experimental model in rabbit [98]
as a complication during S. aureus bacteremia was 1.6%e11.8%
[4,6,12,43e47]. Although most patients with vertebral osteomye-
litis complained about back or neck pain, only 35%e52% of patients
with vertebral arthritis presented with fever [41,48]. In contrast,
Jensen et al. reported that 97% of patients had fever, and that back
pain was observed in 83% of patients with hematogenous vertebral
osteomyelitis due to S. aureus during presentation [49]. In addition,
Cuijpers et al., along with our previously published work, demon-
strated that some patients with S. aureus bacteremia did not pre-
sent localizing signs and symptoms related to metastatic infection
[4,50]. Thus, vertebral osteomyelitis should not be excluded even in
the patients without back pain or fever. During the laboratory
investigation, an enhanced erythrocyte sedimentation rate (ESR)
and C-reactive protein (CRP) presented high sensitivity toward
vertebral osteomyelitis [39]. Therefore, clinicians should always be
aware that patients may develop metastatic abscess if bacteremia
persists for more than three to five days, even without new back or
neck pain among patients with S. aureus bacteremia. To diagnose
vertebral osteomyelitis, MRI is recommended in patients with
suspected vertebral arthritis since it was more sensitive compared
to CT [39].
Inadequate treatment of vertebral osteomyelitis could result in
gait disturbances and neurological disorders. Patients diagnosed
with vertebral osteomyelitis during S. aureus bacteremia should be
administered adequate antimicrobial agents against S. aureus for a
minimum of six to eight weeks [3,49,51]. Bernard et al. reported
that six weeks of antimicrobial administration was not inferior to
12 weeks for pyogenic vertebral osteomyelitis in a randomized
controlled trial [52]; however, 32 of the 351 patients with vertebral
osteomyelitis (16 of 176 patients in the six-week group and 16 of
175 of those in the 12-week group) revealed treatment failure, and
that S. aureus infection was associated with the treatment failure
[52]. Furthermore, de Graeff et al. demonstrated that epidural ab-
scesses were also associated with antimicrobial treatment failure in
patients with osteomyelitis [53]. IDSA guidelines suggested that
increased or unchanged systemic inflammatory markers, CRP and
ESR, may be utilized for treating failures after four weeks of anti-
microbial administration, although the efficacy of routine exami-
nation remained uncertain [51].
6.3. Iliopsoas abscess
Iliopsoas abscesses are classified as primary and secondary
based on their origin. While primary iliopsoas abscess is defined as
hematogenous or lymphatic seeding from other infectious sources,
secondary iliopsoas abscess is caused by direct spread from the
adjacent or close structures, such as kidneys or intestines. Ricci
 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx
Table 4
Minimal duration of antimicrobial treatment for metastatic infection of S. aureus.
MSSA
Uncomplicated bacteremia 2 weeks
Infective endocarditis
Native valve 6 weeks
Prosthetic valve 6 weeks
Vertebral osteomyelitis 6 weeks
Septic arthritis 2 weeks in small native joint infection
Septic pulmonary embolism 4 weeks
MSSA: methicillin sensitive Staphylococcus aureus.
MRSA: methicillin resistant Staphylococcus aureus.
Iliopsoas abscess; Percutaneous drainage will be required for large (>5 cm) abscess [61].
Ocular infection; Duration of antimicrobial treatment depends on the clinical course of endophthalmitis.
et al. revealed that polymicrobial infections were most frequent in
the secondary iliopsoas abscess [54], whereas S. aureus was the
most common pathogen in primary iliopsoas abscess [54e56].
During S. aureus bacteremia, 0.9%e5.5% patients were complicated
with the psoas abscess [4,6,17,44,57,58]. Therefore, CT scan and MRI
are recommended in patients with back pain during S. aureus
bacteremia to diagnose iliopsoas abscesses and vertebral
osteomyelitis.
Yacoub et al. investigated 41 patients presenting with iliopsoas
abscess and suggested that the antimicrobial treatment alone was
as effective as the percutaneous drainage in small (<3.0 cm) iliop-
soas abscesses [59]. Similarly, Tabrizian et al. reported that the
antimicrobial treatment alone was suitable for small size (<3.5 cm)
iliopsoas abscesses [60]. In contrast, Dave et al. reported that
percutaneous drainage improved back pain immediately and was
effective and safe for large (>5 cm) iliopsoas abscesses [61].
Therefore, percutaneous or open surgical drainage should be
considered in addition to adequate antimicrobial administration for
iliopsoas abscess, in particular, for large size iliopsoas abscess.
6.4. Septic arthritis
Septic arthritis is a critical disease resulting in poor functional
sequelae. Although septic arthritis was known to be caused by
bacterial inoculation as a complication of joint injection or surgery,
including arthropathy caused by septic arthritis, hematogenous
seeding was reported as the most frequent cause of septic arthritis.
The most common causative pathogen leading to septic arthritis in
both the native and prosthetic joint is S. aureus [62e65]. During
S. aureus bacteremia, 1.4%e18.8% patients had complicated septic
arthritis as a metastatic infection [4,6,17,43e46,57,66,67,68]. We
should observe pain, warmness, or swelling of various joints in the
patients with S. aureus bacteremia to prevent overlooking of septic
arthritis, since delay in the diagnosis and treatment may cause
permanent disability [69]. In the patients with suspected septic
arthritis, synovial fluid examination, including analysis, Gram
staining, and culture, was necessary to diagnose septic arthritis.
Carpenter et al. demonstrated that a WBC >50,000/mL in the sy-
novial fluid was associated with the probability of septic arthritis
[69], but this threshold remains unclear.
In the patients diagnosed with septic arthritis due to S. aureus
bacteremia, joint drainage should be performed in addition to the
administration of adequate antimicrobials such as cefazolin and
vancomycin. While two weeks of ceftriaxone was recommended for
gonococcal septic arthritis, the duration of the antimicrobial
administration for septic arthritis associated with other bacteria
remained uncertain. Although IDSA guideline recommended that
the duration of antimicrobial treatment in patients with septic
arthritis due to MRSA was three to four weeks [3], John et al. pre-
sented that the average duration of antimicrobial treatment in
Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
5
MRSA reference
2 weeks [3,33]
6 weeks [36]
6 weeks [36]
6 weeks [51]
3e4-week [3,65]
4 weeks [79]
patients treated without surgery was 41 days in sternoclavicular
septic arthritis and suggested that antimicrobial therapy should be
continued for four weeks even without osteomyelitis [70]. In
contrast, McBride et al. investigated 543 episodes of native joint
septic arthritis and revealed that the rate of treatment failure in the
patients with two weeks antimicrobial administration was not
significantly higher than that in the patients with three to six weeks
in small native joint septic arthritis [65]. Nevertheless, they also
demonstrated that two weeks treatment was associated with
treatment failure in large native joint septic arthritis. Thus, further
studies evaluating the optimal duration of antimicrobial treatment
in septic arthritis during S. aureus bacteremia are needed, in
particular for large native joints.
6.5. Ocular infection
The most common pathogen in all endophthalmitis was
S. epidermidis, followed by the viridans group streptococci and
S. aureus [71]. Endophthalmitis is divided into several types, such as
post-cataract surgery, bleb-related, and traumatic, and endogenous
endophthalmitis, and the most common pathogens depended on
these categories [72]. While coagulase-negative staphylococci were
most common in postcataract surgery endophthalmitis [72],
S. aureus is the most common pathogen, followed by Klebsiella
pneumoniae in endogenous bacterial endophthalmitis [73]. Jung
et al. reported that 9% (56 of 612) of patients with S. aureus
bacteremia had ocular involvement, including 2.5% (15 patients)
with endophthalmitis and 6.7% (41 patients) with chorioretinitis
[74]. Although patients with chorioretinitis could be treated with
only systemic antimicrobial administration in order to prevent the
development of endophthalmitis, intravitreal antimicrobial
administration was necessary for bacterial endophthalmitis in
several cases [72] because systemic antimicrobials were insufficient
to treat the aqueous humor and vitreous infections. Furthermore, in
addition to intravitreal antimicrobials, vitrectomy was performed
in several cases [72]. Therefore, the physician should notice
endophthalmitis in the patients with visual symptoms during
assessment of S. aureus bacteremia, specifically with other meta-
static infection, including endocarditis [74]. The duration of anti-
microbial treatment for endophthalmitis during S. aureus
bacteremia depends on the clinical course of endophthalmitis.
6.6. Septic pulmonary embolism
Septic pulmonary embolism is a serious complication of right-
sided infective endocarditis, cervical thrombophlebitis and
bacteremia. Although more than half of the patients did not have
any respiratory symptoms, such as dyspnea, chest pain and cough
[75e78], many patients with septic pulmonary emboli required ICU
admission [77], and the mortality rate during hospitalization was
6 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx
still high, between 9.0 and 30.0% [75e78]. While some studies re-
ported that the most common pathogen associated with septic
pulmonary embolism was Klebsiella pneumoniae, followed by
S. aureus [75,77], other studies demonstrated that S. aureus was the
most commonly isolated bacteria in the patients with septic pul-
monary embolism [76,78]. This discrepancy in causative pathogens
may be associated with the primary site of infection, as portal sites
of septic pulmonary embolism due to S. aureus were associated
with intravascular catheter, skin and soft tissue infections, while
K. pneumoniae was isolated from liver abscesses and pneumonia
[75e78]. During S. aureus bacteremia, 0.9%e18.8% patients were
diagnosed with septic pulmonary embolism [4,6e9,18,43,57,58]. CT
is recommended to diagnose septic pulmonary embolism, since
chest X-rays are unable to detect some pulmonary lesions [78].
Although the appropriate duration of antimicrobial treatment de-
pends on the clinical course and imaging studies and remains
controversial, in case of septic pulmonary embolism caused by
S. aureus bacteremia a minimum of four to six weeks of therapy will
be required [79].
7. Summary
The insufficient treatment for these serious complications is
associated with poor prognosis, disability, and relapse. To prevent
the misdiagnosis of metastatic infections, patients should be
appropriately examined. However, it is often challenging to
perform all examinations, including TEE, CT, MRI, and PET in all
patients with S. aureus bacteremia. Therefore, further studies are
warranted to identify the risk factors for metastatic infections,
considering the clinical characteristics of the patients and the
virulence factors of S. aureus.
Declaration of Competing Interest
Tetsuya Horino received speaker honoraria from MSD K.K.,
Astellas Pharma Inc., Torii Pharmaceutical Co. Ltd., Pfizer Japan, Inc.,
Taisho Toyama Pharmaceutical Co., Ltd., and Dainippon Sumitomo
Pharma Co., Ltd., Seiji Hori has received speaker honoraria from
KYORIN Pharmaceutical Co., Ltd. and MeijiSeika Pharma Co., Ltd.
Acknowledgments
We would like to thank Editage [http://www.editage.com] for
editing and reviewing this manuscript for English language.
References
[1] Anderson DJ, Moehring RW, Sloane R, Schmader KE, Weber DJ, Fowler Jr VG,
et al. Bloodstream infections in community hospitals in the 21st century: a
multicenter cohort study. PLoS One 2014;9:e91713. https://doi.org/10.1371/
journal.pone.0091713.
[2] Kim C-J, Song K-H, Park K-H, Kim M, Choe PG, Oh M-d, et al. Impact of anti-
microbial treatment duration on outcome of Staphylococcus aureus bacter-
aemia: a cohort study. Clin Microbiol Infect 2018;25(6):723e32. https://
doi.org/10.1016/j.cmi.2018.09.018.
[3] Liu C, Bayer A, Cosgrove SE, Daum RS, Fridkin SK, Gorwitz RJ, et al. Clinical
practice guidelines by the infectious diseases society of America for the
treatment of methicillin-resistant Staphylococcus. aureus infections in adults
and children. Clin Infect Dis 2011;52(3):e18e55. https://doi.org/10.1093/cid/
ciq146.
[4] Horino T, Sato F, Hosaka Y, Hoshina T, Tamura K, Nakaharai K, et al. Predictive
factors for metastatic infection in patients with bacteremia caused by
methicillin-sensitive Staphylococcus aureus. Am J Med Sci 2015;349:24e8.
https://doi.org/10.1097/MAJ.0000000000000350.
[5] Khatib R, Riederer K, Saeed S, Johnson LB, Fakih MG, Sharma M, et al. Time to
positivity in Staphylococcus aureus bacteremia: possible correlation with the
source and outcome of infection. Clin Infect Dis 2005;41(5):594e8.
[6] Vos FJ, Kullberg BJ, Sturm PD, Krabbe PFM, Van Dijk APJ, Wanten GJA, et al.
Metastatic infectious disease and clinical outcome in Staphylococcus aureus
Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
and Streptococcus species bacteremia. Medicine (Baltim) 2012;91(2):86e94.
https://doi.org/10.1097/MD.0b013e31824d7ed2.
[7] Rasmussen RV, Høst U, Arpi M, Hassager C, Johansen HK, Korup E, et al.
Prevalence of infective endocarditis in patients with Staphylococcus aureus
bacteraemia: the value of screening with echocardiography. Eur J Echo-
cardiogr 2011;12(6):414e20. https://doi.org/10.1093/ejechocard/jer023.
[8] Chang F-Y, MacDonald BB, Peacock JE, Musher DM, Triplett P, Mylotte JM, et al.
A prospective multicenter study of Staphylococcus aureus bacteremia. Medi-
cine (Baltim) 2003;82:322e32.
[9] Moing VL, Alla F, Doco-Lecompte T, Delahaye F, Piroth L, Chirouze C, et al.
Staphylococcus aureus bloodstream infection and endocarditisda prospective
cohort study. PLoS One 2015;10:e0127385. https://doi.org/10.1371/
journal.pone.0127385.
[10] Robinson A, Lind CRP, Smith RJ, Kodali V. Atlanto-axial infection after
acupuncture. BMJ Case Rep 2015. https://doi.org/10.1136/bcr-2015-
212110.
[11] Seeley EJ, Chambers HF. Diabetic ketoacidosis precipitated by Staphylococcus
aureus abscess and bacteremia due to acupuncture: case report and review of
the literature. Clin Infect Dis 2006;43(1):e6e8.
[12] Kovacs CS, Fatica C, Butler R, Gordon SM, Fraser TG. Hospital-acquired
Staphylococcus aureus primary bloodstream infection: a comparison of events
that do and do not meet the central line-associated bloodstream infection
definition. Am J Infect Contr 2016;44(11):1252e5.
[13] Benenson S, Zimhony O, Dahan D, Solomon M, Raveh D, Schlesinger Y, et al.
Atopic dermatitisda risk factor for invasive Staphylococcus aureus infections:
two cases and review. Am J Med 2005;118(9):1048e51.
[14] Pallangyo P, Nicholaus P. Disseminated tungiasis in a 78-year-old woman
from Tanzania: a case report. J Med Case Rep 2016;10(1):354. https://doi.org/
10.1186/s13256-016-1146-6.
[15] Salvador VBD, Chapagain B, Joshi A, Brennessel DJ. Clinical risk factors for
infective endocarditis in Staphylococcus aureus bacteremia. Tex Heart Inst J
2017;44(1):10e5. https://doi.org/10.14503/THIJ-15-5359.
[16] Gopal BAK, Fowler Jr VG, Shah M, Gesty-palmer D, Marr KA, McClelland RS,
et al. Prospective analysis of Staphylococcus aureus bacteremia in non-
neutropenic adults with malignancy. J Clin Oncol 2000;18:1110e5.
[17] Lesens O, Hansmann Y, Brannigan E, Remy V, Hopkins S, Martinot M, et al.
Positive surveillance blood culture is a predictive factor for secondary meta-
static infection in patients with Staphylococcus aureus bacteraemia. J Infect
2004;48:245e52.
[18] Fowler Jr VG, Olsen MK, Corey GR, Woods CW, Cabell CH, Reller LB, et al.
Clinical identifiers of complicated Staphylococcus aureus bacteremia. Arch
Intern Med 2003;163:2066e72.
[19] Gallardo-García MM, Sa
nchez-Espín G, Ivanova-Georgieva R, Ruíz-Morales J,
Rodríguez-Bailo
n I, Vin
~ uela Gonz

alez V, et al. Relationship between patho-
genic, clinical, and virulence factors of Staphylococcus aureus in infective
endocarditis versus uncomplicated bacteremia: a caseecontrol study. Eur J
Clin Microbiol Infect Dis 2016;35(5):821e8. https://doi.org/10.1007/s10096-
016-2603-2.
[20] Palraj BR, Baddour LM, Hess EP, Steckelberg JM, Wilson WR, Lahr BD, et al. Pre-
dicting risk of endocarditis using a clinical tool (PREDICT): scoring system to
guide use of echocardiography in the management of Staphylococcus aureus
bacteremia. Clin Infect Dis 2015;61(1):18e28. https://doi.org/10.1093/cid/civ235.
[21] Foster TJ, Geoghegan JA, Ganesh VK, Ho €o
€ k M. Adhesion, invasion and evasion:
the many functions of the surface proteins of Staphylococcus aureus. Nat Rev
Microbiol 2014;12(1):49e62. https://doi.org/10.1038/nrmicro3161.
[22] Powers ME, Wardenburg JB. Igniting the fire: Staphylococcus aureus virulence
factors in the pathogenesis of sepsis. PLoS Pathog 2014;10:e1003871. https://
doi.org/10.1371/journal.ppat.1003871.
[23] Peacock SJ, Moore CE, Justice A, Kantzanou M, Story L, Mackie K, et al. Virulent
combinations of adhesin and toxin genes in natural populations of Staphylo-
coccus aureus. Infect Immun 2002;70:4987e96.
[24] Pe
rez-Montarelo D, Viedma E, Larrosa N, Go
mez-Gonza
lez C, De Gopegui ER,
Mun ~ oz-Gallego I, et al. Molecular epidemiology of Staphylococcus aureus
bacteremia: association of molecular factors with the source of infection.
Front Microbiol 2018;9:1e11. https://doi.org/10.3389/fmicb.2018.02210.
[25] Nienaber JJC, Sharma Kuinkel BK, Clarke-Pearson M, Lamlertthon S, Park L,
Rude TH, et al. Methicillin-susceptible Staphylococcus aureus endocarditis
isolates are associated with clonal complex 30 genotype and a distinct
repertoire of enterotoxins and adhesins. J Infect Dis 2011;204:704e13.
https://doi.org/10.1093/infdis/jir389.
[26] Moreillon P, Entenza JM, Francioli P, McDevitt D, Foster TJ, François P, et al.
Role of Staphylococcus aureus coagulase and clumping factor in pathogenesis
of experimental endocarditis. Infect Immun 1995;63:4738e43.
[27] Tristan A, Ying L, Bes M, Etienne J, Vandenesch F, Lina G. Use of multiplex PCR
to identify Staphylococcus aureus adhesins involved in human hematogenous
infections. J Clin Microbiol 2003;41(9):4465e7. https://doi.org/10.1128/
JCM.41.9.4465-4467.2003.
[28] Bouchiat C, Moreau K, Devillard S, Rasigade JP, Mosnier A, Geissmann T, et al.
Staphylococcus aureus infective endocarditis versus bacteremia strains: subtle
genetic differences at stake. Infect Genet Evol 2015;36:524e30. https://
doi.org/10.1016/j.meegid.2015.08.029.
[29] Chi CY, Wang SM, Lin CC, Liu CC. Microbiological characteristics of
community-associated Staphylococcus aureus causing uncomplicated bacter-
emia and infective endocarditis. J Clin Microbiol 2010;48(1):292e4. https://
doi.org/10.1128/JCM.01788-09.
 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx
[30] Hogevik H, So € derquist B, Tung H-S, Olaison L, Westberg A, Ryde
n C, et al.
Virulence factors of Staphylococcus aureus strains causing infective
endocarditisda comparison with strains from skin infections. APMIS
1998;106:901e8.
[31] Fowler Jr VG, Miro JM, Hoen B, Cabell CH, Abrutyn E, Rubinstein E, et al.
Staphylococcus aureus endocarditisda consequence of medical progress. J Am
Med Assoc 2005;293:3012e21.
[32] Heriot GS, Cronin K, Tong SYC, Cheng AC, Liew D. Criteria for identifying pa-
tients with Staphylococcus aureus bacteremia who are at low risk of endo-
carditis: a systematic review. Open Forum Infect Dis 2017;4:1e7. https://
doi.org/10.1093/ofid/ofx261.
[33] Holland TL, Arnold C, Fowler Jr VG. Clinical management of Staphylococcus
aureus bacteremia: a review. J Am Med Assoc 2014;312:1330e41. https://
doi.org/10.1001/jama.2014.9743.
[34] Liu C, Strnad L, Beekmann SE, Polgreen PM, Chambers HF. Clinical practice
variation among adult infectious disease physicians in the management of
Staphylococcus aureus bacteremia. Clin Infect Dis 2019. https://doi.org/
10.1093/cid/ciy1144. in Press.
[35] Bai AD, Agarwal A, Steinberg M, Showler A, Burry L, Tomlinson GA, et al.
Clinical predictors and clinical prediction rules to estimate initial patient risk
for infective endocarditis in Staphylococcus aureus bacteraemia: a systematic
review and meta-analysis. Clin Microbiol Infect 2017;23:900e6. https://
doi.org/10.1016/j.cmi.2017.04.025.
[36] Baddour LM, Wilson WR, Bayer AS, Fowler Jr VG, Tleyjeh IM, Rybak MJ, et al.
Infective endocarditis in adults: diagnosis, antimicrobial therapy, and man-
agement of complications. Circulation 2015;132:1435e86. https://doi.org/
10.1161/CIR.0000000000000296.
[37] McHenry MC, Easley KA, Locker GA. Vertebral osteomyelitis: long-term
outcome for 253 patients from 7 Cleveland-area hospitals. Clin Infect Dis
2002;34(10):1342e50.
[38] Widdrington JD, Emmerson I, Cullinan M, Narayanan M, Klejnow E, Watson A,
et al. Pyogenic spondylodiscitis: risk factors for adverse clinical outcome in
routine clinical practice. Med Sci 2018;6(4):96. https://doi.org/10.3390/
medsci6040096.
[39] Zimmerli W. Vertebral osteomyelitis. N Engl J Med 2010;362:1022e9. https://
doi.org/10.1056/NEJMcp0910753.
[40] Park KH, Cho OH, Lee JH, Park JS, Ryu KN, Park SY, et al. Optimal duration of
antibiotic therapy in patients with hematogenous vertebral osteomyelitis at
low risk and high risk of recurrence. Clin Infect Dis 2016;62:1262e9. https://
doi.org/10.1093/cid/ciw098.
[41] Priest DH, Peacock Jr JE. Hematogenous vertebral osteomyelitis due to
Staphylococcus aureus in the adult: clinical features and therapeutic outcomes.
South Med J 2005;98:854e62.
[42] Mylona E, Samarkos M, Kakalou E, Fanourgiakis P, Skoutelis A. Pyogenic
vertebral osteomyelitis: a systematic review of clinical characteristics. Semin
Arthritis Rheum 2009;39(1):10e7. https://doi.org/10.1016/
j.semarthrit.2008.03.002.
[43] Fowler Jr VG, Justice A, Moore C, Benjamin DK, Woods CW, Campbell S, et al.
Risk factors for hematogenous complications of intravascular catheter-
associated Staphylococcus aureus bacteremia. Clin Infect Dis 2005;40:
695e703.
[44] Fowler Jr VG, Sanders LL, Sexton DJ, Kong L, Marr KA, Gopal AK, et al. Outcome
of Staphylococcus aureus bacteremia according to compliance with recom-
mendations of infectious diseases specialists: experience with 244 patients.
Clin Infect Dis 1998;27:478e86.
[45] Melzer M, Eykyn SJ, Gransden WR, Chinn S. Is methicillin-resistant Staphy-
lococcus aureus more virulent than methicillin-susceptible S. aureus? A
comparative cohort study of British patients with nosocomial infection and
bacteremia. Clin Infect Dis 2003;37(11):1453e60.
[46] Ariaans MBPA, Roovers EA, Claassen MAA, Hassing RJ, Swanink CMA,
Gisolf EH. Increased overall survival after introduction of structured bedside
consultation in Staphylococcus aureus bacteraemia. Eur J Clin Microbiol Infect
Dis 2018;37(6):1187e93. https://doi.org/10.1007/s10096-018-3239-1.
[47] Abelenda Alonso G, Corbacho Loarte MD, Nún ~ ez Ramos R, Cervero Jime
nez M,
Jusdado Ruiz-Capillas JJ. Staphylococcus aureus bacteremia in a secondary level
Spanish hospital: clinical implications of high vancomycin MIC. Rev Espan ~ ola
Quimioter 2018;31(4):353e62.
[48] Courjon J, Lemaignen A, Ghout I, Therby A, Belmatoug N, Gras G, et al. Pyo-
genic vertebral osteomyelitis of the elderly: characteristics and outcomes.
PLoS One 2017;12:e0188470. https://doi.org/10.1371/journal.pone.0188470.
[49] Jensen AG, Espersen F, Skinhøj P, Frimodt-Møller N. Bacteremic Staphylo-
coccus aureus spondylitis. Arch Intern Med 1998;158(5):509e17.
[50] Cuijpers MLH, Vos FJ, Bleeker-Rovers CP, Krabbe PFM, Pickkers P, Van Dijk APJ,
et al. Complicating infectious foci in patients with Staphylococcus aureus or
Streptococcus species bacteraemia. Eur J Clin Microbiol Infect Dis 2007;26(2):
105e13.
[51] Berbari EF, Kanj SS, Kowalski TJ, Darouiche RO, Widmer AF, Schmitt SK, et al.
2015 Infectious Diseases Society of America (IDSA) Clinical practice guidelines
for the diagnosis and treatment of native vertebral osteomyelitis in adults.
Clin Infect Dis 2015;61(6):e26e46. https://doi.org/10.1093/cid/civ482.
[52] Bernard L, Dinh A, Ghout I, Simo D, Zeller V, Issartel B, et al. Anti-
biotic treatment for 6 weeks versus 12 weeks in patients with pyogenic
vertebral osteomyelitis: an open-label, non-inferiority, randomised,
controlled trial. Lancet 2015;385:875e82. https://doi.org/10.1016/S0140-
6736(14)61233-2.
Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
7
[53] de Graeff JJ, Paulino Pereira NR, van Wulfften Palthe OD, Nelson SB,
Schwab JH. Prognostic factors for failure of antibiotic treatment in patients
with osteomyelitis of the spine. Spine 2017 Sep 1;42(17):1339e46.
[54] Ricci MA, Rose FB, Meyer KK. Pyogenic psoas abscess: worldwide variations in
etiology. World J Surg 1986;10:834e42.
[55] Lo
pez VN, Ramos JM, Meseguer V, Pe
rez Arellano JL, Serrano R, Ordo

n~ ez MAG,
et al. Microbiology and outcome of iliopsoas abscess in 124 patients. Medicine
(Baltim) 2009;88(2):120e30. https://doi.org/10.1097/MD.0b013e31819d2748.
[56] Wong OF, Ho PL, Lam SK. Retrospective review of clinical presentations,
microbiology, and outcomes of patients with psoas abscess. Hong Kong Med J
2013;19(5):416e23. https://doi.org/10.12809/hkmj133793.
[57] Cunney RJ, McNamara EB, alAnsari N, Smyth EG. Community and hospital
acquired Staphylococcus aureus septicaemia: 115 cases from a Dublin teaching
hospital. J Infect 1996;33(1):11e3.
[58] Park WB, Kim SH, Kang CI, Cho JH, Bang JW, Park KW, et al. In vitro ability of
Staphylococcus aureus isolates from bacteraemic patients with and without
metastatic complications to invade vascular endothelial cells. J Med Microbiol
2007;56:1290e5.
[59] Yacoub WN, Sohn HJ, Chan S, Petrosyan M, Vermaire HM, Kelso RL, et al. Psoas
abscess rarely requires surgical intervention. Am J Surg 2008;196:223e7.
https://doi.org/10.1016/j.amjsurg.2007.07.032.
[60] Tabrizian P, Nguyen S, Greenstein A, Rajhbeharrysingh U, Divino C. Manage-
ment and treatment of iliopsoas abscess. Arch Surg 2009;144(10):946e9.
https://doi.org/10.1001/archsurg.2009.144.
[61] Dave BR, Kurupati RB, Shah D, Degulamadi D, Borgohain N, Krishnan A.
Outcome of percutaneous continuous drainage of psoas abscess: a clinically
guided technique. Indian J Orthop 2014;48(1):67e73. https://doi.org/10.4103/
0019-5413.125506.
[62] Ross JJ. Septic arthritis of native joints. Infect Dis Clin N Am 2017;31(2):
203e18. https://doi.org/10.1016/j.idc.2017.01.001.
[63] Ferrand J, El Samad Y, Brunschweiler B, Grados F, Dehamchia-Rehailia N,
Se
journe A, et al. Morbimortality in adult patients with septic arthritis: a
three-year hospital-based study. BMC Infect Dis 2016;16:1e10. https://
doi.org/10.1186/s12879-016-1540-0.
[64] Rakow A, Perka C, Trampuz A, Renz N. Origin and characteristics of haema-
togenous periprosthetic joint infection. Clin Microbiol Infect 2018;25(7):
845e50. https://doi.org/10.1016/j.cmi.2018.10.010.
[65] Mcbride S, Mowbray J, Caughey W, Wong E, Luey C, Siddiqui A, et al. Epide-
miology, management and outcomes of large and small native joint septic
arthritis in adults. Clin Infect Dis 2019. https://doi.org/10.1093/cid/ciz265 (in
press).
[66] Cobussen M, van Tiel FH, Oude Lashof AML. Management of S. aureus bac-
teraemia in The Netherlands; infectious diseases consultation improves
outcome. Neth J Med 2018;76:322e9.
[67] Khosrovaneh A, Sharma M, Khatib R. Favorable prognosis of Staphylococcus
aureus bacteremia originating from soft tissues: a prospective study of fifty
cases. Scand J Infect Dis 2005;37(1):6e10.
[68] Ruotsalainen E, J€ arvinen A, Koivula I, Kauma H, Rintala E, Lumio J, et al. Lev-
ofloxacin does not decrease mortality in Staphylococcus aureus bacteraemia
when added to the standard treatment: a prospective and randomized clinical
trial of 381 patients. J Intern Med 2006;259(2):179e90.
[69] Carpenter CR, Schuur JD, Everett WW, Pines JM. Evidence-based diagnostics:
adult septic arthritis. Acad Emerg Med 2011;18(8):782e96. https://doi.org/
10.1111/j.1553-2712.2011.01121.x.
[70] Ross JJ, Shamsuddin H. Sternoclavicular septic arthritis: review of 180 cases.
Medicine (Baltim) 2004;83(3):139e48.
[71] Gentile RC, Shukla S, Shah M, Ritterband DC, Engelbert M, Davis A, et al.
Microbiological spectrum and antibiotic sensitivity in endophthalmitis: a 25-
year review. Ophthalmology 2014;121(8):1634e42. https://doi.org/10.1016/
j.ophtha.2014.02.001.
[72] Durand ML. Endophthalmitis. Clin Microbiol Infect 2013;19:227e34. https://
doi.org/10.1111/1469-0691.12118.
[73] Todokoro D, Mochizuki K, Nishida T, Eguchi H, Miyamoto T, Hattori T, et al.
Isolates and antibiotic susceptibilities of endogenous bacterial endoph-
thalmitis: a retrospective multicenter study in Japan. J Infect Chemother
2018;24:458e62. https://doi.org/10.1016/j.jiac.2018.01.019.
[74] Jung J, Lee J, Yu SN, Kim YK, Lee JY, Sung H, et al. Incidence and risk factors of
ocular infection caused by Staphylococcus aureus bacteremia. Antimicrob
Agents Chemother 2016;60:2012e7. https://doi.org/10.1128/AAC.02651-15.
[75] Lee SJ, Cha SI, Kim CH, Park JY, Jung TH, Jeon KN, et al. Septic pulmonary
embolism in Korea: microbiology, clinicoradiologic features, and treatment
outcome. J Infect 2007;54(3):230e4.
[76] Oh HG, Cha SI, Shin KM, Lim JK, Kim HJ, Yoo SS, et al. Risk factors for mortality
in patients with septic pulmonary embolism. J Infect Chemother 2016;22(8):
553e8. https://doi.org/10.1016/j.jiac.2016.05.008.
[77] Chou DW, Wu SL, Chung KM, Han SC, Cheung BM. Septic pulmonary embo-
lism requiring critical care: clinicoradiological spectrum, causative pathogens
and outcomes. Clinics 2016;71(10):562e9. https://doi.org/10.6061/clinics/
2016(10)02.
[78] Goswami U, Brenes JA, Punjabi GV, LeClaire MM, Williams DN. Associations
and outcomes of septic pulmonary embolism. Open Respir Med J 2014;8:
28e33. https://doi.org/10.2174/1874306401408010028.
[79] Ye R, Zhao L, Wang C, Wu X, Yan H. Clinical characteristics of septic pulmo-
nary embolism in adults: a systematic review. Respir Med 2014;108(1):1e8.
https://doi.org/10.1016/j.rmed.2013.10.012.
8 T. Horino, S. Hori / J Infect Chemother xxx (xxxx) xxx
[80] Aygen B, Yo€rük A, Yýldýz O, Alp E, Kocago
€z S, Sümerkan B, et al. Bloodstream
infections caused by Staphylococcus aureus in a university hospital in Turkey:
clinical and molecular epidemiology of methicillin-resistant Staphylococcus
aureus. Clin Microbiol Infect 2004;10(4):309e14.
[81] Liao CH, Chen SY, Chang SC, Hsueh PR, Hung CC, Chen YC. Characteristics of
community-acquired and health care-associated Staphylococcus aureus
bacteremia in patients treated at the emergency department of a teaching
hospital. Diagn Microbiol Infect Dis 2005;53(2):85e92.
[82] Jenkins TC, Price CS, Sabel AL, Mehler PS, Burman WJ. Impact of routine in-
fectious diseases service consultation on the evaluation, management, and
outcomes of Staphylococcus aureus bacteremia. Clin Infect Dis 2008;46(7):
1000e8. https://doi.org/10.1086/529190.
[83] Mahajan SN, Shah JN, Hachem R, Tverdek F, Adachi JA, Mulanovich V, et al.
Characteristics and outcomes of methicillin-resistant Staphylococcus aureus
bloodstream infections in patients with cancer treated with vancomycin: 9-
year experience at a comprehensive cancer center. Oncologist 2012;17(10):
1329e36. https://doi.org/10.1634/theoncologist.2012-0029.
[84] Nissen JL, Skov R, Knudsen JD, Ostergaard C, Schønheyder HC,
Frimodt-Møller N, et al. Effectiveness of penicillin, dicloxacillin and
cefuroxime for penicillin-susceptible Staphylococcus aureus bacteraemia: a
retrospective, propensity-score-adjusted case-control and cohort analysis.
J Antimicrob Chemother 2013;68(8):1894e900. https://doi.org/10.1093/
jac/dkt108.
[85] Khatib R, Sharma M. Echocardiography is dispensable in uncomplicated
Staphylococcus aureus bacteremia. Medicine (Baltim) 2013;92(3):182e8.
https://doi.org/10.1097/MD.0b013e318294a710.
[86] Wong D, Wong T, Romney M, Leung V. Comparison of outcomes in patients
with methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia who
are treated with b-lactam vs vancomycin empiric therapy: a retrospective
cohort study. BMC Infect Dis 2016;16:224. https://doi.org/10.1186/s12879-
016-1564-5.
[87] Claeys KC, Zasowski EJ, Casapao AM, Lagnf AM, Nagel JL, Nguyen CT, et al.
Daptomycin improves outcomes regardless of vancomycin MIC in a
propensity-matched analysis of methicillin-resistant Staphylococcus aureus
bloodstream infections. Antimicrob Agents Chemother 2016;60(10):5841e8.
https://doi.org/10.1128/AAC.00227-16.
[88] Sullivan SB, Austin ED, Stump S, Mathema B, Whittier S, Lowy FD, et al.
Reduced vancomycin susceptibility of methicillin-susceptible Staphylococcus
aureus has no significant impact on mortality but results in an increase in
Please cite this article as: Horino T, Hori S, Metastatic infection during Staphylococcus aureus bacteremia, J Infect Chemother, https://doi.org/
10.1016/j.jiac.2019.10.003
complicated infection. Antimicrob Agents Chemother 2017 Jun 27;61(7):
e00316e7. https://doi.org/10.1128/AAC.00316-17.
[89] Thwaites GE, Scarborough M, Szubert A, Saramago Goncalves P, Soares M,
Bostock J, et al. Adjunctive rifampicin to reduce early mortality from Staph-
ylococcus aureus bacteraemia: the ARREST RCT. Health Technol Assess 2018
Oct;22(59):1e148. https://doi.org/10.3310/hta22590.
[90] Que YA, François P, Haefliger JA, Entenza JM, Vaudaux P, Moreillon P. Reas-
sessing the role of Staphylococcus aureus clumping factor and fibronectin-
binding protein by expression in Lactococcus lactis. Infect Immun 2001;69:
6296e302.
[91] Que YA, Haefliger JA, Piroth L, François P, Widmer E, Entenza JM, et al.
Fibrinogen and fibronectin binding cooperate for valve infection and invasion
in Staphylococcus aureus experimental endocarditis. J Exp Med 2005;201:
1627e35.
[92] Mancini S, Oechslin F, Menzi C, Que YA, Claes J, Heying R, et al. Marginal role
of von Willebrand factor-binding protein and coagulase in the initiation of
endocarditis in rats with catheter-induced aortic vegetations. Virulence
2018;9:1615e24. https://doi.org/10.1080/21505594.2018.1528845.
[93] Weiss WJ, Lenoy E, Murphy T, Tardio L, Burgio P, Projan SJ, et al. Effect of srtA
and srtB gene expression on the virulence of Staphylococcus aureus in animal
models of infection. J Antimicrob Chemother 2004;53:480e6.
[94] Siboo IR, Chambers HF, Sullam PM. Role of SraP, a serine-rich surface protein
of Staphylococcus aureus, in binding to human platelets. Infect Immun
2005;73:2273e80.
[95] Salgado-Pabo
n W, Breshears L, Spaulding AR, Merriman JA, Stach CS,
Horswill AR, et al. Superantigens are critical for Staphylococcus aureus infec-
tive endocarditis, sepsis, and acute kidney injury. mBio 2013;4. https://
doi.org/10.1128/mBio.00494-13. e00494e13.
[96] Bayer AS, Ramos MD, Menzies BE, Yeaman MR, Shen AJ, Cheung AL. Hyper-
production of alpha-toxin by Staphylococcus aureus results in paradoxically
reduced virulence in experimental endocarditis: a host defense role for
platelet microbicidal proteins. Infect Immun 1997;65:4652e60.
[97] Stach CS, Vu BG, Merriman JA, Herrera A, Cahill MP, Schlievert PM, et al. Novel
tissue level effects of the Staphylococcus aureus enterotoxin gene cluster are
essential for infective endocarditis. PLoS One 2016;11:e0154762. https://
doi.org/10.1371/journal.pone.0154762.
[98] Cheung AL, Yeaman MR, Sullam PM, Witt MD, Bayer AS. Role of the sar locus
of Staphylococcus aureus in induction of endocarditis in rabbits. Infect Immun
1994;62:1719e25.