Avoiding the Perfect Storm: The Biologic and Clinical Case for Reevaluating the 7-Day Expectation for Methicillin-Resistant Staphylococcus aureus Bacteremia Before Switching Therapy
Avoiding the Perfect Storm: The Biologic and Clinical Case for Reevaluating the 7-Day Expectation for Methicillin-Resistant Staphylococcus aureus Bacteremia Before Switching Therapy
Ellie J. C. Goldstein 2
Section Editor 2
Ravina Kullar () 2 3
James A. McKinnell 0 1 2
George Sakoulas 2 4
0 Department of Medicine, Torrance Memorial Medical Center
1 Infectious Disease Clinical Outcomes Unit (ID-CORE), Los Angeles Biomedical Research Institute, David Geffen School of Medicine, University of California
2 Received 1 April 2014; accepted 10 July 2014; electronically published 21 July 2014. Department of Medical Affairs, Cubist Pharmaceuticals , 65 Hayden Ave, Lexington, MA 02421
3 Department of Medical Affairs, Cubist Pharmaceuticals , Lexington, Massachusetts
4 Division of Pediatric Pharmacology and Drug Discovery, University of California San Diego School of Medicine , La Jolla
Persistent methicillin-resistant Staphylococcus aureus (MRSA) bacteremia (MRSAB) is associated with poor outcomes and serious complications. The MRSA guidelines define treatment failure and persistent bacteremia as lasting ≥7 days; however, this definition requires reevaluation. Aggressively reducing the bacterial inoculum promptly is critical because factors already in place before clinical presentation are driving resistance to the few antibiotics that are available to treat MRSAB. Alternative approaches to treat MRSAB should be considered within 3-4 days of persistent MRSAB. With rapid molecular diagnostics emerging in clinical microbiology laboratories and biomarkers as a potential for early patient risk stratification, a future shorter threshold may become possible.
Persistent methicillin-resistant Staphylococcus aureus
(MRSA) bacteremia (MRSAB) is associated with
serious complications, including prolonged hospitalization,
increased morbidity, and high mortality [
the 2011 Infectious Diseases Society of America
(IDSA) MRSA guidelines define persistent bacteremia
and treatment failure as lasting ≥7 days [
definition is largely based on observational studies and expert
opinion and warrants evaluation [
]. In fact, <1500
patients have been enrolled in randomized controlled
trials specifically directed to investigate the treatment of
Recent scientific literature has described biologic
mechanisms used by MRSA that emerge during
prolonged bacteremia, allowing the organism to evade
immunologic and antimicrobial killing. The emergence of
immunologic evasion mechanisms and antimicrobial
defenses affects MRSA killing by both
pharmacotherapy and innate immunity, which may result in poor
clinical outcomes [
]. In this article, we present evidence
that the goal of MRSAB treatment should be clearance
of the infection much sooner than the current suggested
goal of 7 days. There are important consequences of
waiting and watching prolonged MRSAB, even when
patients seem clinically stable.
The objectives of this article are to (1) discuss the
clinical significance of early clearance of MRSAB; (2)
explain the biologic importance of early, effective
treatment for MRSAB; and (3) identify novel and emerging
treatment approaches, including rapid molecular
diagnostics and biomarkers, to mitigate or prevent the
emergence of these more resilient MRSA phenotypes.
PERSISTENT MRSAB POSES HIGH RISK OF
Before examining the science behind the dangers of persistent
MRSAB, it is important to review existing clinical evidence for
documented risks of persistent MRSAB, which encompasses
both relapse and persistently positive blood cultures. As the
IDSA guidelines support, there are clear data indicating that
persistent MRSAB past the threshold of 7 days is associated with
poor clinical outcomes [
]. The probability of a metastatic
infection increases with longer durations of bacteremia, to
approximately 45% after ≥10 days of MRSAB [
]. Hawkins et al [
showed that mortality rates for persistent MRSAB (defined as
≥7 days) were significantly higher than those of nonpersistent
controls (54.8% and 31.4%, respectively; P < .01). In another
investigation, the 30-day crude mortality rate of patients with
persistent MRSAB (defined as ≥7 days) was more than 3-fold higher
than for patients with nonpersistent MRSAB (58.1% vs 16.7%,
respectively; P < .001), and the 30-day cumulative survival was
significantly lower for patients with persistent MRSAB (41.9%) than
for those with nonpersistent MRSAB (83.3%) [
MRSAB is highly associated with relapse, defined as return of
MRSAB 2 weeks after negative blood cultures (odds ratio [OR]
10.1; 95% confidence interval [CI], 2.0–49.6) [
typing of isolates demonstrated that recurrent isolates were identical
to the primary bloodstream isolates in 91% of the patients [
However, MRSAB persisting for as few as 3 days on therapy
has been associated with poor outcomes. Khatib et al [
conducted a prospective observational study among 245 cases of
S. aureus bacteremia (125 MRSA) in 234 patients. Persistence
(defined as bacteremia ≥3 days) was identified in 49 of 125
MRSA cases (39.2%). Metastatic foci and complications were
uncommon in patients with bacteremia for 1–2 days. However,
they were significantly more common in those with bacteremia
for 3 days and increased even more in patients with longer
durations of bacteremia. Factors associated with duration of
bacteremia included an endovascular source, vancomycin
treatment, and metastatic infection. Another small retrospective
study that also examined patient immunologic markers
determined that ≥4 days of S. aureus bacteremia was associated
with increased mortality [
]. Therefore, given the adverse
clinical events documented in several independent studies,
shortening the definition of persistent MRSAB to 3–4 days is a more
sensitive breakpoint in the early detection of high-risk patients
and providing alternative therapy.
THE INGREDIENTS OF ESTABLISHING THE
“TREATMENT FAILURE PERFECT STORM” IN
The first step in understanding the biologic importance of
prompt treatment for MRSAB is appreciating that
microorganisms and humans share the ability to produce antimicrobial
molecules. The principle human antimicrobial molecules, cationic
host defense peptides (HDPs), such as cathelicidins and
thrombocidins, are fundamental components of the innate immune
]. In general, HDPs are electrostatically designed to
attract to, bind to, and insert into bacterial surfaces that are relatively
negatively charged, causing membrane disruption and
subsequent bacterial death. Staphylococcus aureus has developed
mechanisms of resistance to HDPs by making their surface more
positively charged and changing membrane fluidity (Figure 1)
]. A noteworthy study of a rabbit model of osteomyelitis by
Azmi et al  has shown the in vivo selection of daptomycin
nonsusceptible MRSA without administration of any antibiotics
(Figure 2). A key aspect of this study is that antimicrobial
resistance without antibiotic exposure was a result of prolonged
infection in the animals. It is believed that the antimicrobial peptides
produced by the innate immune system of the animal triggered
changes in membrane fluidity and charge, resulting in significant
resistance to killing by daptomycin. The relationship between
HDP resistance and antimicrobial defenses is not only limited
to daptomycin. Vancomycin selective pressure in vitro and in
vivo independently selects for resistance to HDP [
]. Thus, a
patient receiving vancomycin during persistent uneradicated
highinoculum infection is anticipated to have the selective pressure
imposed by HDPs compounded further. Experts on the MRSA
treatment guidelines recognize this concern and recommend
high-dose daptomycin therapy (10 mg/kg/d) in vancomycin
treatment failure settings, possibly with combination therapy [
EMPLOYING RAPID DIAGNOSTICS AND
BIOMARKERS TO SHORTEN MRSAB DURATION
Various investigators have identified delay in the initiation of
appropriate antimicrobial therapy as an integral determinant
of clinical outcomes for severe diseases, including MRSAB
]. A key hurdle to overcome in management of these
serious infections is the inherent lapse of time required for growth
and workup of bacteria from patient samples in the clinical
microbiology laboratory. For example, in patients with MRSAB,
there is a 48-hour minimum from the time a blood sample is
obtained for culture to pathogen identification without use of
recently available molecular-based testing. In a patient with
established MRSAB, confirmation of blood sterilization may take
3–5 days. The importance of rapidly identifying an organism
and treating the patient appropriately has been highlighted
with the increased development and usage of rapid diagnostic
tests, such as rapid polymerase chain reaction (rPCR) and
matrix-assisted laser desorption/ionization time-of-flight
(MALDI-TOF). Bauer et al  evaluated the clinical outcomes
of rPCR MRSA/S. aureus blood culture test combined with an
Antimicrobial Stewardship Program (ASP) at The Ohio State
University Wexner Medical Center. In the post-rPCR group,
the mean delay in switching to the most effective therapy
( from vancomycin to daptomycin) was 4.5 days, versus 10
days in the pre-rPCR MRSA group. Likewise, Huang et al
] evaluated the impact of MALDI-TOF with an ASP in
patients with bacteremia and candidemia. Overall, this
intervention decreased the time to organism identification (84.0 vs
55.9 hours; P < .001), effective antibiotic therapy (30.1 vs 20.4
hours; P = .02), and optimal antibiotic therapy (90.3 vs 47.3
hours; P < .001), leading to decreased mortality rates (20.3%
vs 14.5%; P = .02) and recurrent bacteremia (5.9% vs 2.0%;
P < .001). At this time, MALDI-TOF is still limited to
identification after blood culture bottle growth. This may explain why
the delay to identification and appropriate antibiotic therapy,
although improved from conventional methods, still often
exceeds 24 hours on average.
Despite rapid molecular methods to speciate and perform
susceptibility testing, no method exists that risk-stratifies
patients at the time of clinical presentation. However, recent
data suggest that this is possible using biomarker cytokines
produced by the patient innate immune system. In a study by Rose
et al [
], elevated serum concentrations of the
anti-inflammatory cytokine interleukin-10 measured by commercially available
enzyme-linked immunosorbent assays identified all patients
who died of S. aureus bacteremia. The mortality rate was 0%
among 24 patients with normal interleukin 10 (IL-10)
concentrations but 23% among 35 patients with elevated IL-10
concentrations on the day of admission (Figure 3A). In the same study,
elevated interleukin 1β levels were associated with rapid
bacteremia clearance (<4 days), and these levels were not elevated in
patients with prolonged bacteremia (Figure 3B). Although the
serum concentrations of interleukin 1β, IL-10, and other
cytokines can currently be ordered by most clinicians through
sendout reference laboratories, their incorporation into mainstream
clinical practice would require these assays to be brought “in
house” to hospital clinical laboratories, as is slowly being
done with procalcitonin assays.
IMPORTANCE OF SOURCE CONTROL AND
OPTIMIZATION OF PHARMACOTHERAPY FOR
Before discussing pharmacotherapy, it is important to mention
the crucial role of source control in the management of
MRSAB. The failure to remove infected prosthetic devices and
intravascular material has been highly correlated with recurrence.
Fowler et al [
] revealed that among 244 patients with S. aureus
bacteremia, 56% of the 23 patients from whom the infected
devices were not removed experienced relapse of infection or death,
compared with 16% of the 221 patients whose devices were
removed or who did not have a device (P < .01). Yoon et al [
showed that retention of implicated medical devices was an
independent predictor of MRSAB persistence (OR, 10.35; 95% CI,
1.03–104.55). Accordingly, the IDSA MRSA guidelines
recommend that clinicians identify the source and extent of infection
and eliminate and/or debride other infection sites [
Therapeutic Options Superior to Vancomycin
Although vancomycin has been considered the standard
therapy for MRSAB, it has also been associated with persistent
MRSAB, including relapse. The slow clinical response observed
with vancomycin was originally evaluated by Levine et al [
more than 2 decades ago; 44 patients with MRSA infective
endocarditis were randomly assigned to receive either vancomycin
or vancomycin plus rifampin for 28 days. The median duration
of bacteremia was 9 days (7 days for the vancomycin group and
9 days for the vancomycin plus rifampin group), and the
median duration of fever was 7 days. Alternative therapies have been
shown to be more beneficial clinically than vancomycin for
MRSAB. The studies described below provide data in
realworld clinical scenarios, showing that the comparison agent
led to better clinical outcomes than vancomycin. Most of the
studies compared vancymycin with daptomycin, the agent
most commonly used after vancomycin therapy and
recommended in the IDSA MRSA guidelines [
Murray et al [
] conducted a matched, retrospective study in
170 patients, comparing the clinical effectiveness of daptomycin
versus vancomycin for MRSAB with a vancomycin minimum
inhibitory concentration (MIC) >1 mg/L. The primary outcome
was clinical failure, defined as 30-day mortality or bacteremia
persisting for ≥7 days. Clinical failure at 30 days was significantly
lower in the daptomycin than in the vancomycin arm (20.0% vs
48.2%, respectively; P < .001). Furthermore, both the 30-day
mortality and persistent bacteremia rates were significantly lower in
the daptomycin group than in the vancomycin group (mortality,
3.5% vs 12.9% [P = .047]; persistent bacteremia, 18.8% vs 42.4%
[P = .001]). Logistic regression analysis confirmed the association
between vancomycin treatment and the increased risk of clinical
failure (adjusted OR, 4.5; 95% CI, 2.1–9.8).
Kullar et al [
] conducted a 2-phase quasi-experimental study
in 170 patients with MRSAB susceptible to vancomycin; phase I
included 70 patients with initial blood MRSA isolates exhibiting
vancomycin MICs >1 mg/L and treated with vancomycin, and
phase II included 100 patients who were switched to daptomycin
after initial vancomycin therapy, according to the institutional
treatment pathway. The clinical success rate was 35% higher in
phase II (75.0% vs 41.4% for phase I; P < .001). The most
frequent component of clinical failure in both phases was ≥ 7
days of bacteremia, however rates of persistent bacteremia were
significantly higher in patients in phase I vs phase II (44.3% vs
21%; P < .001). Treatment during phase I was independently
associated with failure (adjusted OR, 4.37; 95% CI, 1.68–6.76;
P < .001), and hospital readmission rates were significantly higher
(33% vs 21% for phase II; P = .08). Moore et al [
] conducted a
similar study and found that vancomycin treatment was
independently associated with clinical failure (OR, 3.13; 95%, CI, 1.00–
9.76). A comparison of 60-day mortality between
vancomycinand daptomycin-treated patients revealed a higher probability
of survival in the daptomycin-treated group (P = .02). McDaneld
et al [
] conducted a meta-analysis of 7 retrospective clinical
studies evaluating the clinical outcomes of daptomycin used as
first-line or salvage therapy for MRSA infections, compared
with vancomycin. Daptomycin therapy in bacteremic patients
led to lower 60-day (8% vs 20%; P = .046) and 30-day (3.5% vs
12.9%; P = .047) mortality rates and increased treatment success
(68.6% vs 43.1% [P = .008]).
Jang et al [
] evaluated linezolid salvage therapy with or
without ertapenem versus salvage therapy with vancomycin
plus gentamicin or rifampin in 35 patients with persistent
MRSAB. The early microbiologic response (ie, negative blood
cultures within 72 hours) was significantly increased in the
linezolid-based salvage therapy compared with the vancomycin
group (75% vs 17%, respectively; P = .006). Notably, the S.
aureus–related mortality rate was lower for patients treated with
linezolid salvage regimens than for those continually treated
with vancomycin-based regimens (13% vs 53%; P = .03).
Data on the use of vancomycin in combination with other
antimicrobials were recently reviewed [
]. Although combination
therapy with vancomycin is common, the published data
supporting the addition of gentamicin, rifampin, or other agents to
vancomycin are limited, and such combinations may cause
harm and are not currently recommended. Evidence from
several in vitro pharmacokinetic/pharmacodynamic models has
shown the benefit of combining daptomycin with other
antimicrobials to prevent emergence of resistance and improve killing
]. Three independent animal models of soft tissue infection,
endocarditis, and osteomyelitis have demonstrated that
daptomycin combined with rifampin improved S. aureus clearance
and prevented daptomycin resistance compared with
daptomycin monotherapy [
]. Moreover, high-dose daptomycin
therapy (human equivalent, 10 mg/kg/d) has shown promise
in rabbit endocarditis models for the prevention and treatment
of daptomycin-resistant infections [
] and is recommended in
the MRSA treatment guidelines for patients in whom
vancomycin therapy has failed [
One novel approach to treating persistent MRSAB has
entailed the combination of daptomycin with β-lactams [
vitro analyses have shown that β-lactam antibiotics affect the
surface charge of MRSA, yielding better daptomycin binding,
and results in synergistic killing [
]. β-Lactams with
penicillinbinding protein 1 enhance daptomycin anti-MRSA activity the
]. Data from the Cubicin Outcomes Registry and
Experience have also suggested that some patients treated with
daptomycin in combination with a β-lactam show a trend toward
improved outcomes, compared with those receiving daptomycin
monotherapy, particularly for bacteremia involving presumed or
confirmed endocarditis and osteomyelitis, with a lack of benefit
in soft-tissue infections [
]. It is becoming increasingly apparent
that β-lactam antibiotics increase the vulnerability of MRSA to
killing not just by daptomycin but also by the human innate
immune system. Daptomycin and vancomycin do not share this
], which may explain the historical difference in
bacteremia duration for MRSA (8–9 days) versus
methicillin-susceptible S. aureus bacteremia (3–4 days) [
]. Thus, the combination
of β-lactams with daptomycin or vancomycin warrants further
investigation in clinical trials.
Among β-lactam antibiotics, ceftaroline is the only available
agent with in vitro and in vivo MRSA activity [
et al [
] evaluated the effectiveness and safety of ceftaroline
in patients, including those with MRSAB. A total of 527 patients
were included in the retrospective study; 67% were treated for
off-label indications, and 148 (28%) had bacteremia. Most
patients (80%) were switched to ceftaroline as salvage therapy, and
clinical success was achieved in 88% (426 of 484 patients). The
lack of multivariable analysis for patients with MRSAB makes it
difficult to interpret these findings. Further research on
ceftaroline monotherapy for MRSAB is needed, because clinical uses
for this treatment are increasing.
Ceftaroline has a fairly short half-life, and a higher dosage of
600 mg intravenously every 8 hours may be required to achieve
sufficient percentage of time above MIC (%T > MIC) for
difficult infections [
]. In a review of ceftaroline treatment for
MRSA infective endocarditis and deep-seated infections [
ceftaroline was given nearly exclusively at the higher dose of
600 mg intravenously every 8 hours. In a larger review by
Casapao et al [
], most patients (86%) were given the approved dose
of 600 mg intravenously every 12 hours. There are limited safety
data on the use of ceftaroline at 600 mg intravenously every 8
hours, but pharmacokinetic and limited clinical experience
suggests that this may be an appropriate approach for complicated
Ceftaroline has also shown positive results in combination
with daptomycin for MRSAB. Rose et al [
] showed that
daptomycin plus ceftaroline as initial combination therapy for
MRSAB resulted in rapid and sustained bactericidal activity
and prevented daptomycin resistance. In the largest clinical
study evaluating the use of daptomycin plus ceftaroline [
26 cases of sustained staphylococcal bacteremia (20 MRSA, 2
vancomycin-intermediate S. aureus, 2 methicillin-susceptible
S. aureus, 2 methicillin-resistant Staphylococcus epidermidis)
were treated successfully with the combination therapy. In
vitro analyses of select isolates from these patients demonstrated
ceftaroline-daptomycin synergy, accompanied by increased
daptomycin surface binding and increased vulnerability to
innate immunity killing of MRSA induced by ceftaroline.
Bacteremia cleared in a median of 2 days after daptomycin plus
ceftaroline was started, after persisting a median of 10 days
before initiation of this salvage regimen. Despite clinical
data limited to the above findings, the current Sanford Guide
recommends using daptomycin plus ceftaroline for the
treatment of refractory MRSAB, including cases due to
vancomycinintermediate S. aureus.
We have reviewed the strands of clinical and basic science
evidence in the literature pointing to a potentially catastrophic
microbiologic situation that unfolds in high-inoculum
endovascular MRSA infections. The longer MRSAB persists
uncontrolled, the greater the more pharmacotherapy is hindered. In
recent years, because of the emerging threat of
multidrug-resistant pathogens in the setting of dwindling novel antibiotic
resources, ASP has taken center stage as a way physicians
and pharmacists can work together to minimize patient
antibiotic exposure, streamline antimicrobial therapy, improve
patient outcomes, and reduce the emergence of antibiotic
resistance. Given that the in vivo environment is not an
antibiotic-free world but rather an environment in which HDPs
produced by the innate immune system are produced and
select bacterial fitness, prompt eradication of infection and
reduced exposure of MRSA to HDP-driven antibiotic
resistance is critical to ASPs.
Although clinical data are lacking, we recommend that the
7day threshold to seeking alternative combination antibiotic
therapy be shortened to 3–4 days. Aggressive source control is
vital in this approach. With molecular diagnostics slowly
emerging in clinical microbiology laboratories and biomarkers
showing potential for early patient risk stratification, an even
shorter threshold may be possible. Clinical outcomes studies
evaluating these measures are warranted.
Potential conflicts of interest. R. K. is employed by Cubist
Pharmaceuticals and owns Cubist Pharmaceuticals stock; J. A. M has received research
grant support to his institution from Pfizer and Cubist; and G. S. has
received speaking honoraria from Cubist, Forest, and Novartis
Pharmaceuticals, consulting fees from Cubist and Forest Pharmaceuticals, and research
grant support from Forest Pharmaceuticals.
All authors have submitted the ICMJE Form for Disclosure of Potential
Conflicts of Interest. Conflicts that the editors consider relevant to the
content of the manuscript have been disclosed.
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