The Empirical Combination of Vancomycin and a β-Lactam for Staphylococcal Bacteremia
The Empirical Combination of Vancomycin and a β-Lactam for Staphylococcal Bacteremia
Kevin W. McConeghy 1 2
Susan C. Bleasdale 0 1
Keith A. Rodvold 0 1 2
0 Department of Medicine, University of Illinois at Chicago
1 Received 26 June 2013; accepted 16 August 2013; electronically published 28 August 2013. Chicago, College of Pharmacy, Department of Pharmacy Practice , M/C 886, 833 S Wood St, Office 164, Chicago IL 60612
2 Department of Pharmacy Practice, College of Pharmacy
The high prevalence of methicillin resistance among Staphylococcus aureus bacteremias leads to common use of vancomycin as empirical therapy. However, investigators have reported poor outcomes with vancomycin treatment for methicillin-susceptible Staphylococcus aureus bacteremia. We review the evidence supporting empirical combination of both vancomycin and a β-lactam agent for Staphylococcus aureus bacteremia. Vancomycin therapy for methicillin-susceptible Staphylococcus aureus bacteremia is associated with 2-3 times the risk of morbidity and mortality compared to an antistaphylococcal penicillin (oxacillin and nafcillin) or first-generation cephalosporin (cefazolin). De-escalation of empirical vancomycin to definitive β-lactam therapy still appears inferior to initial β-lactam therapy. Although there is no clinical trial supporting combination therapy, a scientific rationale for benefit exists and should be weighed against the risks (adverse events, antibiotic resistance, and cost) of additional pharmacotherapy. The empirical combination of vancomycin and a β-lactam (either nafcillin, oxacillin, or cefazolin) for staphylococcal bacteremia may improve infection-related clinical outcomes.
The pharmacotherapy for serious infections is guided
by key principles that include (1) empirical therapy
with broad-spectrum antimicrobials, dose-adjusted to
achieve pharmacodynamic targets and effectively treat
potential drug-resistant organisms; (2) broad-spectrum
therapy, subsequently de-escalated to treat the causative
pathogen; (3) a hospital-wide system of infection control
measures and antimicrobial stewardship to decrease the
spread of antimicrobial resistance and improve clinical
outcomes; (4) source control, a critical component of
treatment that includes removal of infected catheters,
abscess drainage, and surgical intervention; and (5)
timely initiation of appropriate therapy, which can be
life-saving [1, 2].
Staphylococcus aureus bacteremia remains a
significant healthcare burden, with an estimated 10.3 episodes
per 1000 hospital discharges, and a life-threatening
infection with an estimated 30-day mortality of 21% in
the United States [3, 4]. In the patient with positive
blood cultures, Gram stain, or a high clinical suspicion
of serious staphylococcal bacteremia, initial therapy
includes either an antistaphylococcal penicillin (nafcillin
or oxacillin), first-generation cephalosporin (cefazolin),
or vancomycin depending on clinical suspicion for
methicillin-susceptible or methicillin-resistant
Staphylococcus aureus (MSSA and MRSA, respectively). Delays
in initiation of appropriate empirical antibiotics for
staphylococcal bacteremia are a critical determinant of
outcome. A treatment delay of 44 hours is associated
with a nearly 4-fold increase in the odds of
infectionrelated mortality (odds ratio [OR], 3.8; 95% confidence
interval [CI], 1.3–11.0) . Investigators have suggested
that the empirical combination of both a β-lactam and
anti-MRSA agent to cover both potential
staphylococcal pathogens (MSSA and MRSA) may improve clinical
outcomes [6, 7].
The purpose of this manuscript is to review the
clinical evidence supporting combination therapy with
vancomycin and an antistaphylococcal penicillin or
firstgeneration cephalosporin for empirical treatment of
Staphylococcus aureus bacteremia, and provide recommendations as to
where combination therapy would be of greatest benefit.
Studies were obtained by a search of Medline ( January 1962–
May 2013); Medical Subject Heading terms included
Staphylococcus aureus, bacteremia, vancomycin, nafcillin, cefazolin, and
empirical therapy, limited to English-language literature and
screened for topical relevance.
USE OF EMPIRICAL VANCOMYCIN
MONOTHERAPY FOR STAPHYLOCOCCAL
MRSA in the United States is endemic in the community and
hospital setting. In one study, approximately 50% of emergency
department visits for skin and soft tissue infections were
positive for MRSA . Risk factors for community-acquired MRSA
(USA300 strain) bloodstream infections include age 59 or younger,
intravenous drug use, homelessness or marginal housing,
hepatitis C infection, human immunodeficiency virus (HIV) infection,
and prior skin and soft tissue infection . Hospital-acquired
staphylococcal isolates were reported to be 54% methicillin
resistant during 2009–2010 . Risk factors for nosocomial
MRSA bacteremia include admission for surgery, prolonged
length of stay, age 65 or older, mechanical ventilation, and
central venous catheter . Other important risk factors to be
considered include colonization with MRSA, severity of illness,
immunosuppression, and prior healthcare exposure .
Vancomycin is the standard treatment for MRSA . Delays in
starting appropriate antimicrobial therapy for MRSA
bacteremia are associated with increased morbidity and mortality [14–18].
A meta-analysis of 9 studies demonstrated that the odds of
mortality are nearly doubled with inappropriate empirical therapy
for MRSA bacteremia compared to appropriate initial therapy
( pooled OR, 1.99; 95% CI, 1.6–2.4) .
Because of the prevalence of MRSA, any patients with
suspected staphylococcal bacteremia should be empirically treated
with an anti-MRSA agent (most commonly vancomycin) until
MRSA infection is excluded, because delays in antibiotic
therapy can increase mortality.
VANCOMYCIN MONOTHERAPY COMPARED TO
β-LACTAMS FOR MSSA BACTEREMIA
MSSA bacteremia should be treated with an antistaphylococcal
penicillin (nafcillin or oxacillin) or first-generation
cephalosporin (cefazolin) as several cohort studies have reported poor
clinical outcomes with vancomycin-treated MSSA bacteremias.
These results are summarized in Table 1 [19–24]. Stryjewski
30-day in-hospital mortality
33% vs 41%
20% vs 7%
56% vs 37%
41% vs 11%
OR, 6.5 (1.0–53)
HR, 2.3 (1.1–4.9)
OR, 3.5 (1.2–13)
OR, 6.5 (1.4–29)
OR, 3.3 (1.2–9.5)
HR, 4.8 (2.1–11)f
HR, 1.6 (1.2–2.2)f
et al reported a prospective analysis of treatment failure among
patients with MSSA bacteremia (N = 240) treated with
vancomycin or cefazolin . Failures were reported with 31.2% of
vancomycin-treated and 13% of cefazolin-treated patients
(P = .02). This occurred despite the cefazolin group having a
higher proportion of patients with metastatic cancer (36.7% vs
11.7%) and infective endocarditis (17.4% vs 5.2%). Kim et al
performed a propensity score–matched case-control analysis
(n = 27) of vancomycin-treated cases compared to β-lactam–
treated cases and demonstrated an increased odds of
infectionrelated mortality with vancomycin (37% vs 11%; adjusted OR,
3.3; 95% CI, 1.2–9.5) . Schweizer et al reported a
retrospective cohort (N = 267) of MSSA bacteremia and demonstrated
that patients treated with cefazolin or nafcillin had a lower
30day mortality risk than vancomycin-treated patients (3% vs
20%, respectively; hazard ratio [HR], 0.21; 95% CI, .09–.47) .
A prospective, observational study of MSSA bacteremia by
Chang et al demonstrated that odds of persistent bacteremia
(blood cultures positive >7 days) or relapse were 6.5 times higher
with vancomycin compared to nafcillin (OR, 6.5; 95% CI,
1.0–53) . Khatib et al reported on 120 cases of hospitalized
patients with MSSA bacteremia and demonstrated a higher
mortality risk in vancomycin-treated versus β-lactam–treated
patients (27.5% vs 12.1%; HR, 2.3; 95% CI, 1.1–4.9; P = .03) . A
large (N = 293 094) retrospective cohort of hemodialysis
outpatients also demonstrated that treatment of MSSA bacteremia
with cefazolin versus vancomycin was associated with a
significantly lower combined risk of hospitalization or death (HR, 0.6;
95% CI, .5–.8) .
Whether outcomes differ between β-lactams (nafcillin vs
cefazolin) has not been widely evaluated. One propensity score–
matched case-control study evaluated nafcillin versus cefazolin
for MSSA bacteremia and demonstrated equivalent rates of
treatment failure (15% vs 15%) . A retrospective cohort
study of MSSA bacteremia also found similar 90-day mortality
rates for oxacillin versus cefazolin (32% vs 40%, respectively;
adjusted OR, 0.9; 95% CI, .5–1.8) .
Although these studies differ in underlying severity of illness,
source of bacteremia, definitions of outcome, and method of
analysis, there is a consistent conclusion that nafcillin or
cefazolin improved treatment-related outcomes compared to
vancomycin for MSSA bacteremia. The risk of treatment failure
(recurrent infection or death) is 2- to 3-fold higher with
vancomycin than nafcillin or cefazolin across these reports. As current
evidence suggests that nafcillin and cefazolin are more clinically
effective, de-escalation from empirical vancomycin is common
practice. The study by Schweizer et al demonstrated a 30-day
lower mortality risk in patients who were de-escalated from
vancomycin compared to continuing therapy (HR, 0.31; 95% CI,
.1–.95) . The median time to de-escalation in the Schweizer
report was 3.0 days (interquartile range, 2.4–3.9) and among
those who died, time to nafcillin or cefazolin de-escalation was
4.0 days versus 2.5 days among those who lived.
DE-ESCALATION FROM VANCOMYCIN IS
INFERIOR TO INITIAL THERAPY WITH
NAFCILLIN OR CEFAZOLIN
Evidence suggests that the practice of vancomycin
monotherapy with de-escalation to a β-lactam still results in worse
outcomes than initiating empirical β-lactam therapy for MSSA.
Lodise et al studied a cohort of 72 MSSA infective endocarditis
patients and demonstrated an increased risk of
infectionrelated mortality in vancomycin compared to β-lactam–treated
controls (39.3% vs 11.4%; P = .005) . Additionally, those
initially treated with vancomycin and de-escalated to a β-lactam
had 4-fold increased mortality risk than those initially treated
with a β-lactam (9/22 [40.9%] vs 5/44 [11.4%]). The median
time to de-escalation was 3.0 days. Khatib et al also reported
that persistent rates of MSSA bacteremia (blood cultures
positive for >3 days) were similar between patients continued on
vancomycin or de-escalated to β-lactams (47% vs 56%,
respectively), whereas those initially treated with either a β-lactam
or both vancomycin and β-lactam were lower (37% and 0%,
respectively) . The reported mean time to vancomycin
deescalation was 75 hours.
Addition of β-lactam therapy to even the short window of
empirical therapy (eg, 3 days) for MSSA is associated with
improved clinical outcomes compared to initial vancomycin
monotherapy. To achieve adequate coverage of both MSSA and
MRSA, empirical coverage should include both a β-lactam and
IMPACT OF RAPID DIAGNOSTIC TESTING ON
Modern polymerase chain reaction testing methods are
improving time to identification of infectious pathogens including
Staphylococcus aureus. There are several MRSA tests currently
available in the United States . Of these, the Xpert MRSA/
SA BC test has demonstrated improvements in time to
initiation of antistaphylococcal therapy for MSSA (mean, 5.5 hours
vs 49 hours) and reduced empirical initiation of vancomycin
therapy . An alternative approach is matrix-assisted laser
desorption/ionization-time of flight mass spectrometry, which
has the ability to rapidly identify Staphylococcus aureus and
methicillin-resistant organisms . Limitations compared to
rapid MRSA testing include its use is pending Food and Drug
Administration approval, the methodology typically requires
bacterial culture of the organism, and acquisition of the testing
equipment is expensive. Although these tests reduce time to
identification of Staphylococcus aureus, they have not been
widely implemented in US hospitals. Also, to effectively reduce
the empirical therapy window, the results must be promptly
communicated to and acted upon by the clinician. However,
the impact of rapidly available microbiology results on
prescriber practice has not been widely evaluated. Rapid testing is
a promising solution but until widespread implementation,
determining the most appropriate empirical therapy regimen is
RISKS ASSOCIATED WITH COMBINATION
Empirical addition of nafcillin or cefazolin to vancomycin
monotherapy for Staphylococcus aureus is a novel regimen,
albeit with well-characterized agents; therefore, the risks should
be carefully considered. Bactericidal activity has been evaluated
in vitro for the combination of oxacillin and vancomycin for 10
clinical MSSA isolates, and antagonism was not observed .
Addition of a β-lactam to vancomycin monotherapy carries a
risk of allergic reaction, but serious reactions including
anaphylaxis are relatively uncommon with penicillin (0.04%) and
cephalosporins (0.02%) and can be screened for with a careful
history [32, 33]. Nafcillin may cause interstitial nephritis and
induces liver cytochrome enzymes that could interfere with
concomitant drug therapies (eg, warfarin), and both
medications may rarely cause leukopenia or thrombocytopenia.
However, the relatively short duration of empirical therapy (3
days) until susceptibilities are determined would limit these
risks. Increasing β-lactam use could potentially lead to
increased MRSA rates; this risk would appear greater if
broadspectrum cephalosporins and β-lactam/β-lactamase inhibitors
were used instead of nafcillin and cefazolin [34, 35].
Broadspectrum β-lactams would also provide unnecessary
gramnegative activity. Additionally, experimental evidence suggests
that methicillin and vancomycin resistance have an inverse
relationship and that the combination of β-lactams and
vancomycin may improve killing effect and limit resistance
development [36–38]. The high risk of morbidity and mortality in
staphylococcal bacteremia should be weighed against the risks
of empirically adding nafcillin or cefazolin to vancomycin
ALTERNATIVES TO COMBINATION THERAPY:
DAPTOMYCIN AND LINEZOLID
A possible alternative to discussing empirically combining
vancomycin with nafcillin or cefazolin would be recommending
linezolid or daptomycin for bacteremia. However, neither agent
has definitively improved outcomes with staphylococcal
bacteremia. Daptomycin was compared to vancomycin in a
randomized controlled noninferiority trial of S. aureus (both MRSA
and MSSA) bacteremia and endocarditis with similar treatment
success (41.7% vs 44.2%, respectively; risk difference [RD],
2.4%; 95% CI, −10.2% to 15.1%) . Linezolid was compared
to vancomycin in a noninferiority trial for catheter-related
bloodstream infections and demonstrated similar microbiologic
cure rates for MSSA and MRSA bacteremia and mortality (82.1%
vs 83.3%, respectively; RD, 1.2; 95% CI, −16.3 to 13.9) . In
both studies, vancomycin was de-escalated to an
antistaphylococcal penicillin for MSSA. However, similar outcomes were reported
for MSSA and MRSA, suggesting that daptomycin and linezolid
therapy are not superior to de-escalation to a β-lactam but may
be an alternative therapy if β-lactams are contraindicated (ie,
allergy). In contrast, observational data suggest that
combination therapy with a β-lactam and vancomycin results in
improved bacteremia outcomes compared to de-escalation [6, 25].
The acquisition cost of daptomycin (80-kg patient, 6 mg/kg,
US$362/day) and linezolid (600 mg intravenous twice daily, US
$288/day) alone is also higher than vancomycin (1 g twice
daily, US$10/day) and oxacillin (2 g every 4 hours, US$169/
day) combined, although drug monitoring increases
vancomycin costs . Daptomycin and linezolid are noninferior
compared to vancomycin therapy but do not appear to have
superior clinical outcomes in Staphylococcus aureus infective
endocarditis or catheter-related bloodstream infections.
A clinical trial for ceftaroline (cephalosporin with anti-MRSA
activity) and MRSA bacteremia is ongoing (www.clinicaltrials.
gov: NCT01701219) [42, 43]. Serial passages in subinhibitory
concentrations of ceftobiprole, another cephalosporin with
antiMRSA activity, for 28 days did lead to resistance development in
MRSA . Ceftaroline may be an acceptable alternative but is
not approved for bacteremia.
APPROPRIATE SETTING FOR USE OF
COMBINATION THERAPY WITH VANCOMYCIN
AND NAFCILLIN OR CEFAZOLIN
As a guiding principle, initiation of appropriate antimicrobial
therapy is a critical predictor of outcome, especially in serious
infections. In those institutions with a high prevalence of
MRSA requiring empirical vancomycin therapy, combination
of both vancomycin and nafcillin or cefazolin empirically could
improve MSSA clinical outcomes. After susceptibility results
are known, therapy can be de-escalated to the appropriate
antibiotics to limit risk of toxicity. Patients at the highest risk of
morbidity and mortality from S. aureus infection would gain
the greatest benefit from receipt of initial combination therapy.
The cohort studies demonstrating a benefit included patients
with severe sepsis (signs of end-organ dysfunction or decreased
tissue perfusion), complicated bacteremias (such as probable or
proven infective endocarditis), or presence of a prosthetic device,
intravascular device, or nonremovable foci of infection [6, 21].
One might argue that bacteremia with S. aureus, independent
of host risk factors, carries sufficient risk of morbidity and
mortality to support initial combination therapy.
Use of combination therapy in infectious disease practice has
been used for life-threatening gram-negative infections with
the rationale that improved treatment outcomes outweigh the
risks of toxicity, promoting further antibiotic resistance and
increased cost . Similarly, treatment success rates can be <50%
in Staphylococcus aureus bacteremia (both MSSA and MRSA),
demonstrating a need for alternative treatment options .
Newer therapies such as daptomycin, linezolid, and ceftaroline
have not yet demonstrated superiority to vancomycin alone for
empirical treatment of bacteremia. A potential alternative to
combination therapy is adoption of a rapid diagnostic test
capable of discriminating MRSA and MSSA from positive blood
cultures. Additional research focusing on early antimicrobial
initiation (ie, time to antibiotic initiation with vancomycin vs
other agents) in Staphylococcus aureus bacteremia and more
adequately controlling for underlying risk factors for treatment
failure would help solidify the current evidence. Although
randomized trials are the highest level of evidence-based research,
none are currently available. Current observational data provide
evidence that empirical vancomycin therapy carries an
increased risk of mortality in MSSA bacteremia even if therapy is
de-escalated to nafcillin or cefazolin. A shift in focus to
combining vancomycin and an antistaphylococcal penicillin or
first-generation cephalosporin in Staphylococcus aureus
bacteremia could potentially improve overall morbidity and mortality
with this serious infection.
Acknowledgments. We thank Larry H. Danziger for providing
assistance with the manuscript.
Potential conflicts of interest. K. A. R. has served as a consultant to
Cubist Pharmaceuticals and Durata Therapeutics, provided expert
testimony for Johnson & Johnson, is on the speakers’ bureaus of Forest
Laboratories and Pfizer Inc, and has an investigator-initiated grant with Forest
Laboratories. All other authors report no potential conflicts.
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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