Optimizing Therapy for Methicillin-Resistant

Staphylococcus aureus Bacteremia

Sara E. Cosgrove, M.D., M.S.1 and Vance G. Fowler, Jr., M.D., M.H.S.2

ABSTRACT

Methicillin-resistant Staphylococcus aureus bacteremia in patients in intensive care

units is associated with significant morbidity and mortality. Prompt clinical attention is
essential to ensure good outcomes, including identification and management of the source

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of infection and any associated complications. Foreign-body sources of infection should be
removed or replaced in the majority of cases, and debridement of infectious foci should
be undertaken. Particular attention should be given to evaluation for the presence of cardiac
involvement because inadequately managed S. aureus endocarditis is life threatening.
Selection of an appropriate antibiotic regimen is also an essential factor for optimal
management.

KEYWORDS: Endocarditis, vancomycin, glycopeptide, daptomycin

R ates of infections caused by methicillin- ISSUES IN THE CLINICAL MANAGEMENT

resistant S. aureus (MRSA) in intensive care units
(ICUs) in the United States have increased dramati-
cally over the past decade.1 Many of these infections
are MRSA bacteremias, which occur frequently in
the ICU in association with the use of mechanical
ventilation and central venous catheters. In addition to
the increase in cases, a growing body of evidence now
suggests that patients with MRSA bacteremia have
worse outcomes than similar patients with methicillin-
susceptible S. aureus bacteremia (MSSA).2,3 These
findings highlight the importance of expedient and
aggressive management of patients with this infection.
Successful management depends first and foremost
on determining the extent of infection and then on
making appropriate decisions about choice and length
of therapy. This article addresses issues and controversies
in the clinical management of S. aureus bacteremia
and reviews currently available therapies for MRSA
bacteremia.
OF MRSA BACTEREMIA
Determining the Source and Extent of Infection
The report of even a single positive blood culture for
S. aureus should prompt initiation of empirical anti-
biotic therapy, obtaining follow-up blood cultures,
and a thorough investigation to determine the source
and extent of infection. Common sources of S. aureus
bacteremia in the ICU include intravenous catheters
and other intravascular devices, soft tissue infections,
and ventilator-associated pneumonia.2,46 Approxi-
mately one third of patients with S. aureus bacteremia
will develop metastatic complications resulting from
either hematogenous seeding of a distant site or local
extension of infection, and patients frequently have
involvement of more than one site.4,68 Common
sites of metastatic infection include bone and joints,
especially when prosthetic material is present; the
epidural space and intervertebral disks; heart valves;

1
Johns Hopkins University School of Medicine, Baltimore, Maryland;
2
Division of Infectious Diseases, Duke University Medical Center,
Durham, North Carolina.
Address for correspondence and reprint requests: Sara E. Cosgrove,
M.D., M.S., Johns Hopkins Medical Institutions, Osler 425, 600 N.
Wolfe St., Baltimore, MD 21287 (e-mail: scosgro1@jhmi.edu).
624
Optimizing Antimicrobial Therapy for Serious Infections in the
Critically Ill; Guest Editor, David L. Paterson, M.D., Ph.D.
Semin Respir Crit Care Med 2007;28:624631. Copyright # 2007
by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York,
NY 10001, USA. Tel: +1(212) 584-4662.
DOI 10.1055/s-2007-996409. ISSN 1069-3424.

and intra-abdominal organs such as the kidneys and
spleen.
A careful history and physical exam may reveal
reports of focal pain or examination findings of point
tenderness, joint effusions, new cardiac murmurs, or
peripheral stigmata of endocarditis.911 Radiographic
imaging studies should be obtained if concerning signs
and symptoms are detected [e.g., spinal magnetic reso-
nance imaging (MRI) to rule out an epidural abscess or
osteomyelitis in a patient with significant back pain].
Echocardiography of the heart should be obtained in all
patients to evaluate for endocarditis.
Factors associated with complicated S. aureus
bacteremia were examined in a cohort of 724 patients
in which complicated bacteremia was defined as the
presence of at least one of the following: attribu-
table mortality, metastatic infection at the time of
onset, embolic stroke, or recurrent infection within
the 12-week follow-up period.4 The strongest indicator
of clinical complication was a positive follow-up blood
culture 48 to 96 hours after the initial positive blood
culture. Other independent predictors were community
acquisition of infection, skin examination suggesting
acute systemic infection, and persistent fever at
72 hours. Patients with any of these findings should
be managed aggressively by ensuring both that all
metastatic foci are identified and that an appropriate
duration of therapy is given.
Many experts recommend that patients with
S. aureus bacteremia undergo transesophageal echocar-
diography (TEE) based on several investigations dem-
onstrating the superiority of this diagnostic test relative
to transthoracic echocardiography (TTE) for the detec-
tion of endocarditis among patients with S. aureus
bacteremia.9,12,13 TEE is more sensitive than TTE in
identifying complications of endocarditis such as intra-
cardiac abscess and valvular perforation, processes that
occur commonly in endocarditis due to S. aureus.14 In
a cohort of patients with S. aureus bacteremia who
underwent both TTE and TEE, 26 of 103 (25.2%)
prospectively identified patients had definite endocardi-
tis by TEE compared with only 7 (6.8%) by TTE.10
TEE has two major purposes in the management of
S. aureus bacteremia: (1) the detection of significant
cardiac complications associated with S. aureus bacter-
emia in high-risk settings, such as patients with pros-
thetic valves, permanent cardiac devices, prolonged
bacteremia or fever, or cardiac conduction abnormalities;
and (2) the intracardiac assessment of patients at low
risk for endocarditis in whom short courses of therapy
are desired. In this latter setting, a TEE of native valves
that does not identify any findings concerning for
endocarditis makes the diagnosis of endocarditis un-
likely, although other criteria, such as the absence of
other metastatic foci, must be met before the decision
is made to give a short course of therapy (Table 1).
MRSA BACTEREMIA/COSGROVE, FOWLER 625
Table 1 Criteria for a 14-Day Course of Therapy for
Staphylococcus aureus Bacteremia
1. Bacteremia is catheter-associated and the catheter has
been removed
2. Endocarditis should be excluded with a transesophageal
echocardiogram
3. The patient has no implanted prostheses (e.g., prosthetic
valves, cardiac devices, or arthroplasties)
4. Follow-up blood cultures drawn 2 to 4 days after the initial
set of blood cultures are negative for S. aureus
5. The patient defervesces within 72 hours of initiating effective
antistaphylococcal therapy
6. The patient has no localizing signs or symptoms of metastatic
staphylococcal infection
The removal of infected intravascular material
and prosthetic devices is essential in the management
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of S. aureus bacteremia because recurrence is strongly
associated with failure to do so. Among 244 hospitalized
patients with S. aureus bacteremia, 56% of the 23 patients
whose infected foreign bodies were not removed expe-
rienced relapse of infection or death, compared with 16%
of the 221 patients whose devices were removed or did
not have a device (P < .01).15 In patients with permanent
pacemakers or implantable cardiac defibrillators and
S. aureus bacteremia, failure to remove the device was
associated with increased risk of recurrent bacteremia
or death (52.4 vs 25%).16
Duration of Antimicrobial Therapy
The optimal duration of antibiotic therapy for S. aureus
bacteremia depends on the extent of infection. Histor-
ically, all patients with S. aureus bacteremia were treated
with long courses (4 to 6 weeks) of therapy, largely due
to concerns that endocarditis or other complications may
be present but undiagnosed.17,18 Retrospective studies
performed in the early 1990s suggested that 10 to
14 days of therapy might be appropriate for patients
with catheter-associated S. aureus bacteremia in the
absence of clinical evidence of early metastatic compli-
cations.5,19 In these two retrospective studies, late relapse
occurred in 17 to 66% of patients treated with less than
10 days of therapy and in none of the patients treated
with at least 10 to 15 days of therapy. However, it is
important to note that the numbers of patients in each
study were small and that the proportions of patients
with MRSA bacteremia were likely minimal.
A meta-analysis of 11 studies performed to
address the efficacy of short-course therapy for catheter-
associated S. aureus bacteremia found a pooled esti-
mate of the rate of late complications to be 6.1%
(CI 2.0 to 10.2%).17 However, the authors concluded
that, because the studies included were not adjusted to
protect against a variety of biases that could lead to
626 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6
inaccurate results, short-course therapy could not be
recommended until a means existed to identify low-
risk patients. Finally, a more recent post hoc analysis
of a randomized, clinical trial of patients with S. aureus
bacteremia and endocarditis in which one third of
patients had MRSA examined the effect of duration
of therapy on outcomes.20 Success rates were signifi-
cantly lower among patients who received less than 14
days of antibiotic therapy compared with those receiv-
ing longer duration, including the group of patients
with catheter-associated S. aureus bacteremia. All pa-
tients with catheter-associated bacteremia in this study
had a negative transesophageal echocardiogram and no
other foci of infection identified.
These results suggest that longer courses of
therapy may now be needed, even for catheter-associated
S. aureus bacteremia, in the current era in which patients
with S. aureus bacteremia are older and have more serious
underlying disease and in which rates of MRSA are
higher. If a 14-day course of therapy is considered, we
believe that the patient should meet the clinical charac-
teristics detailed in Table 1. Four- to six-week courses of
therapy are recommended for patients who do not meet
these criteria, based on extent of infection.
ANTIBIOTIC OPTIONS FOR MRSA
BACTEREMIA
The antimicrobial agents currently available in the
United States for the treatment of MRSA bacteremia
are noted in Table 2 and discussed in the following
section.
Agents with Established Efficacy
VANCOMYCIN
Vancomycin has been the mainstay of therapy for MRSA
bacteremia for the past 40 years, and its use has cured
countless patients. However, physicians have generally
used vancomycin by necessity rather than by preference,
given its association with slower bacterial clearance and
worse response rates in patients with MSSA bacteremia
and endocarditis compared with antistaphylococcal
b-lactam agents,8,2124 and its association with pro-
longed duration of bacteremia when used for treatment
of MRSA bacteremia and endocarditis.2527
Reports of vancomycin failures in patients
without evidence of vancomycin resistance using con-
ventional microbiological testing have increased over
the past decade. Some failures are in patients with
hetero-resistant MRSA where subpopulations of
organisms have minimal inhibitory concentrations
(MIC) of vancomycin indicative of reduced suscepti-
bility (4 to 32 mg/mL). In these patients, hetero-
resistance is associated with a high bacterial load and
2007
an initially low serum vancomycin level, which in turn
may lead to the induction or selection of hetero-
resistant strains and failure of vancomycin treat-
ment.28 The frequency of hetero-resistance in U.S.
isolates appears to be low, occurring in only three of
22 isolates in a study of patients with persistent (
10
days, n 11) or recurrent (
30 days, n 11) MRSA
bacteremia.29 In patients with fully susceptible MRSA
isolates, vancomycin MICs of 2 mg/mL are associated
with clinical failure and worse clinical outcomes.30,31
It is unclear whether higher doses of vancomycin
with the goal of achieving higher vancomycin trough
levels can improve patient outcomes; the ideal vancomy-
cin trough level continues to be investigated.31 Current
guidelines for MRSA bacteremia and endocarditis rec-
ommend vancomycin troughs of 10 to 15 mg/mL.32
Troughs at this level are best obtained dosing vancomy-
cin at 15 mg/kg every 12 hours rather than using the
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traditional dose of 1 g every 12 hours.
The use of 3 to 5 days of low-dose synergistic
gentamicin with vancomycin in the treatment of MRSA
bacteremia and native valve endocarditis has not been
shown to improve patient outcomes, although it appears
to reduce the duration of bacteremia by about a day in
patients with MSSA native valve endocarditis.33,34
However, the potential for nephrotoxicity with this
practice may be higher than previously appreciated. In
a recent randomized controlled trial comparing dapto-
mycin monotherapy to combination therapy (low-dose,
short-course gentamicin plus either an antistaphylococ-
cal penicillin or vancomycin), patients receiving combi-
nation therapy were significantly more likely to develop
renal dysfunction than those receiving daptomycin.27
Based on this evidence of potential harm, and the failure
to convincingly demonstrate clinically significant bene-
fit, we recommend not using synergistic gentamicin in
the management of most cases of S. aureus bacteremia
and native valve endocarditis, particularly in patients
with renal impairment and in the elderly. If the decision
is made to use synergistic gentamicin in the management
of MRSA bacteremia or endocarditis, susceptibility test-
ing should be obtained because many MRSA isolates are
resistant to gentamicin.
Some clinicians advocate the use of rifampin in
combination with vancomycin or other agents in the
treatment of S. aureus infections because rifampin is
highly active against staphylococci and has excellent
tissue penetration. However, this practice has not been
shown to improve outcomes in MRSA bacteremia or
native valve endocarditis.25 Rifampin resistance develops
quickly if it is used as monotherapy, and may be more
likely to occur if there is an infection with a high
bacterial burden; therefore, if it is used for S. aureus
bacteremia or endocarditis, we recommend waiting to
add rifampin until the patients blood cultures have
cleared to minimize the risk.35
 MRSA BACTEREMIA/COSGROVE, FOWLER 627

Table 2 Currently Available Antibiotics for Methicillin-Resistant Staphylococcus aureus Bacteremia

Usual Dose* Side Effects Comments

Agents with established

efficacy
Vancomycin 1522.5 mg/kg Red man syndrome Slowly bactericidal
IV q 12 h Neutropenia Failures reported despite MICs
Thrombocytopenia in susceptible range
Daptomycin 6 mg/kg IV Elevated CPK Bactericidal
q 24 h Cannot be used for pneumonia
Emergence of resistance during
therapy reported
Although not FDA approved,
doses of 812 mg/kg can be
considered in some cases
Agents for salvage therapy
Linezolid 600 mg PO/IV q 12 h Bone marrow suppression, particularly Bacteriostatic
thrombocytopenia Oral form with excellent

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Rarer side effects include irreversible bioavailability
sensory motor polyneuropathy and Failures have been reported when
optic neuritis associated with therapy used for S. aureus bacteremia
> 28 days; serotonin syndrome when
co-administered with serotonergic
agents; and lactic acidosis
Trimethoprim- 1015 mg/kg/day in two Rash Bactericidal
sulfamethoxazole or three divided doses Hypersensitivity reactions
Quinupristin/ 7.5 mg/kg IV q 12 h (e.g., erythema multiforme) Bactericidal if susceptibility to
dalfopristin Myalgia and arthralgia both components of drug
Pain/inflammation at infusion site Side effects have limited clinical
Thrombophlebitis use but infusion site reactions
are improved with administration
via central line
Clindamycin 600900 mg IV q 68 h Clostridium difficile diarrhea Bacteriostatic
Not indicated for monotherapy given
history of failures in treatment of
MSSA bacteremia/endocarditis
Tigecycline 100 mg IV once, then Nausea and vomiting Bacteriostatic
50 mg IV q 12 h Serum levels may be inadequate
to treat bacteremia
Activity against anaerobes and
many gram-negative organisms
*For adults with normal renal function.
CPK, creatine phosphokinase; FDA, U.S. Food and Drug Administration; MIC, minimum inhibitory concentration; MSSA, methicillin-susceptible
Staphylococcus aureus.

DAPTOMYCIN carditis.27 Eighty-nine patients (38%) had infection due

Daptomycin is a concentration-dependent, bactericidal
cyclic lipopeptide that was approved by the U.S. Food
and Drug Administration (FDA) in 2006 for the treat-
ment of S. aureus bacteremia and right-sided endocardi-
tis. Daptomycin at a dose of 6 mg/kg daily was found to
be as effective as standard therapy, consisting of initial
low-dose gentamicin plus either vancomycin or an anti-
staphylococcal penicillin in a prospective, randomized
trial of 235 patients with S. aureus bacteremia or endo-
to MRSA, and in this subgroup daptomycin was at least
as effective as vancomycin (Fig. 1). Twenty of 45 (44.4%)
patients were successfully treated with daptomycin com-
pared with 14 of 43 (32.6%) patients treated with
vancomycin, although this difference was not statistically
significant.27,36
In this study, patients receiving daptomycin were
more likely to fail therapy due to persisting or relapsing
infection than those receiving standard therapy (15.8%
628 SEMINARS IN RESPIRATORY AND CRITICAL CARE MEDICINE/VOLUME 28, NUMBER 6
Figure 1 Success rates for patients with methicillin-resistant Staphylococcus aureus bacteremia or endocarditis treated with
daptomycin or standard therapy.36
vs 9.6%). Six of the 19 daptomycin-treated patients who
failed therapy had emergence of reduced susceptibility to
daptomycin during the study, and of the six, five patients
had MRSA infections (three patients with complicated
bacteremia with deep-seated infections and two patients
with left-sided endocarditis). The emergence of reduced
susceptibility to daptomycin noted in the study raises
some concerns about its use for bacteremias in which a
deep focus of infection has not been surgically debrided,
and underscores the importance of a careful evaluation of
patients with S. aureus bacteremia for the presence of
endocarditis or other metastatic sites of infection. Be-
cause doses of daptomycin up to 12 mg/kg daily for
2 weeks have been found to be safe in healthy volunteers,
it has been suggested that higher doses of daptomycin be
tried in seriously ill patients; however, whether this
dosing strategy would reduce the risk of emergence of
resistance is unknown.37,38 Finally, daptomycin should
not be used in patients with pneumonia because it is
inactivated by pulmonary surfactant.39
Agents for Salvage Therapy
When salvage therapy for MRSA bacteremia is needed,
consultation with an infectious disease specialist is rec-
ommended to optimize the choice of agent or combina-
tion of agents as well as the dosing regimen. Use of the
following agents for the treatment of MRSA bacteremia
or endocarditis should be considered only if a patient has
failed therapy with or is unable to tolerate standard agents.
2007
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LINEZOLID
Linezolid is a bacteriostatic oxazolidinone with activity
against MRSA. It has not been systematically studied
and does not have FDA approval for use in MRSA
bacteremia. Successful use of linezolid for MRSA bac-
teremia has been reported, including in six of 12 (50%) of
patients with bacteremia or endocarditis due to S. aureus
with reduced susceptibility to vancomycin who received
linezolid alone or in combination with either or both
rifampin and fusidic acid40,41; however, many failures
have also been reported.4244
A meta-analysis of the subgroup of 144 patients
with S. aureus bacteremia in five studies comparing
vancomycin to linezolid for nosocomial pneumonia,
skin and soft tissue infection, or other S. aureus infections
showed no difference in rates of clinical cure between
vancomycin and linezolid [25 of 70 (36%) vs 28 of 74
(38%)], respectively).45 Among the 53 patients with
MRSA bacteremia and available data for analysis, clinical
cure occurred in 14 of 25 (56%) linezolid patients and 13
of 28 (46%) vancomycin patients. However, these results
must be considered hypothesis-generating because the
patients did not have long-term follow-up and represent
a small subset of patients in several clinical trials.
In addition, a recent European randomized clin-
ical trial comparing linezolid to vancomycin, oxacillin, or
dicloxacillin in the treatment of seriously ill patients with
catheter-associated bloodstream infections and catheter-
site infections was terminated early because patients in
the linezolid arm had a higher chance of death than

those in any standard therapy arm.46 This difference was
seen in patients with infections due to gram-negative
organisms alone or mixed gram-negative and gram-
positive organisms, but not in patients with only gram-
positive infections; thus it is unclear whether the use
of linezolid for documented catheter-associated gram-
positive infections is effective. Nevertheless, we believe
that this agent should not be used routinely for MRSA
bacteremia.
TRIMETHOPRIM-SULFAMETHOXAZOLE
Trimethoprim-sulfamethoxazole (TMP-SMX) was
compared with vancomycin in a randomized control trial
evaluating treatment of S. aureus infections in 101 drug
users.26 In this study, over half of patients had an
intravascular infection, including tricuspid valve endo-
carditis, thrombophlebitis, pseudoaneurysm, or bacter-
emia. Cure rates were 86% for TMP-SMX-treated
patients and 98% for vancomycin-treated patients,
although all 47 patients with MRSA infection in both
arms were cured. These results and those from a recent
study demonstrating that TMP-SMX was rapidly bac-
tericidal in vitro against MRSA isolates makes this drug
a plausible agent for a salvage regimen for MRSA
bacteremia.47
Other Potential Salvage Agents
Quinupristin-dalfopristin, a streptogramin antibiotic,
has been studied as salvage therapy in patients with
MRSA infections, including 43 patients with bacteremia
and endocarditis; the majority of bacteremias were asso-
ciated with secondary sources such as bone and joint and
soft tissue.48 Overall, clinical success rates for patients
with bacteremia were 70.5% and with endocarditis were
55.6%. Success rates for bacteremia and endocarditis
were much lower in the subgroup wherein a documented
bacteriological response was required for eradication
(55.6% and 0%, respectively). Clinical use of quinupris-
tin-dalfopristin has been limited by adverse events asso-
ciated with its use, such as myalgia, arthralgia, and
infusion site reactions.49
Clindamycin should not be considered for mono-
therapy of S. aureus bacteremia because its use for this
indication is associated with a high risk for treatment
failure and relapse.50 Tigecycline, a bacteriostatic gly-
cylcycline antibiotic, has in vitro activity against MRSA;
however, no clinical studies have evaluated it for use in
bacteremia or endocarditis. Peak serum concentrations
of tigecycline do not exceed 1 mg/mL, which may limit
its utility in treatment of bacteremia.51
CONCLUSIONS
The prevalence of MRSA bacteremia is increasing in the
United States and abroad. Effective management in-
MRSA BACTEREMIA/COSGROVE, FOWLER 629
volved more than picking the right antibiotic; aggressive
efforts to identify and, when indicated, to debulk the
source of infection and associated metastatic foci are
critical. Despite the active development of some prom-
ising agents, the current armamentarium for MRSA
bacteremia is inadequate to meet the growing clinical
need. Novel strategies and agents both for treating and
for preventing disease are needed.
DISCLOSURE
Dr. Cosgrove has served as an adviser/consultant to
Cubist, Ortho-McNeil, and Theravance/Astellas, and
has received a grant from Merck. Dr. Fowler has served
as an adviser/consultant to Biosynexus, Cerexa, Cubist,
Inhibitex, Johnson and Johnson, Merck; has received
grants and research support from Cubist, Inhibitex,
Merck, Nabi, National Institutes of Health, and Therav-
Downloaded by: University of British Columbia. Copyrighted material.
ance; and is on the speakers bureau for Cubist and Pfizer.
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