REVIEW ARTICLE

Vancomycin in Combination with Other Antibiotics

for the Treatment of Serious Methicillin-Resistant
Staphylococcus aureus Infections
Stan Deresinski
Division of Infectious Disease and Geographic Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, and Division
of Infectious Disease, Santa Clara Valley Medical Center, San Jose, California

Vancomycin is often combined with a second antibiotic, most often rifampin or gentamicin, for the treatment

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of serious methicillin-resistant Staphylococcus aureus infections. Published data from experiments evaluating
these and other vancomycin-based combinations, both in vitro and in animal models of infection, often yield
inconsistent results, however. More importantly, no data are available from randomized clinical trials to support
their use, and some regimens are known to have potential toxicities. Clinicians should carefully reconsider
the use of vancomycin-based combination therapies for the treatment of infection due to methicillin-resistant
S. aureus.

Vancomycin is often combined with other antibiotics
for the treatment of serious infection due to Staphy-
lococcus aureus, a practice that emerged largely in re-
sponse to the recognition of important shortcomings
of this glycopeptide antibiotic. These shortcomings in-
clude poor tissue and intracellular penetration, lack of
activity against organisms growing in biofilm, slow bac-
tericidal effect, lack of interference with toxin produc-
tion, and lack of activity against some S. aureus isolates,
including heteroresistant and vancomycin-intermediate
S. aureus (VISA) strains [1, 2]. The practice of com-
bination antistaphylococcal therapy, however, deserves
close examination.
THEORETICAL BASIS FOR COMBINATION
THERAPY WITH VANCOMYCIN
FOR S. AUREUS INFECTION
Theoretical reasons for the use of antibiotics in com-
bination with vancomycin for the treatment of serious
Received 15 February 2009; accepted 17 May 2009; electronically published 2
September 2009.
Reprints or correspondence: Dr Stan Deresinski, 2900 Whipple Ave, Ste 115,
Redwood City, CA 94062 (polishmd@stanford.edu or polishmd@earthlink.net).
Clinical Infectious Diseases 2009; 49:10729
 2009 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2009/4907-0013$15.00
DOI: 10.1086/605572
methicillin-resistant S. aureus (MRSA) infection in-
clude the following:
To broaden coverage to include VISA and heterore-
sistant VISA and to improve activity against isolates
with a minimum inhibitory concentration (MIC) at
or approaching the breakpoint for susceptibility
To prevent the emergence of reduced susceptibility
to vancomycin
To achieve bactericidal synergy
To provide activity against stationary-phase organ-
isms and organisms growing in biofilm
To penetrate cells and tissues not reached by vanco-
mycin
To inhibit toxin production
These theoretical reasons are analyzed in detail
below.
Broadening the spectrum of antistaphylococcal
activity. Vancomycin therapy is often initiated in pa-
tients with suspected staphylococcal bacteremia to pro-
vide antibacterial activity against both methicillin-sus-
ceptible S. aureus (MSSA) and MRSA. Evidence indi-
cates, however, that vancomycin monotherapy is inferior
to b-lactam therapy for the treatment of MSSA blood-
stream infection and endocarditis [35]. Furthermore,
the strategy of switching from vancomycin to a b-lactam
when methicillin susceptibility is identified does not ap-

1072 CID 2009:49 (1 October) Deresinski

pear to overcome this deficit [5]. These observations suggest that
a possibly superior approach to the initial empirical treatment
of patients with sepsis known or highly suspected to be due to
S. aureus is the administration of vancomycin together with a
cephalosporin or, preferably, a semisynthetic penicillin, followed
by the discontinuation of the glycopeptide or the b-lactam when
susceptibility data becomes available.
Infections with strains of MRSA that have elevated vanco-
mycin MICs within the range considered susceptible (eg, 2.0
mg/mL) and with strains exhibiting heteroresistance appear to
be risk factors for the failure of vancomycin therapy [68]. The
coadministration of other antibiotics with MRSA activity could
potentially provide broader coverage to include these more-re-
calcitrant strains. This strategy could, however, be defeated if
the second agent has a low threshold for the development of
resistance, as is the case with rifampin [9].
Enhancing antibacterial activity. Vancomycin is subject to
an inoculum effect [10] and is poorly active against organisms
in the stationary-growth phase [11] as well as against organisms
growing in biofilm [12]. The weak bactericidal activity (tol-
erance) of vancomycin against some MRSA is associated with
reduced therapeutic efficacy [13]. Coadministration of certain
antibiotics may help overcome some of these deficiencies by,
for example, having more-favorable activity against biofilm
colonies [12].
Preventing the emergence of strains with reduced suscep-
tibility to vancomycin. Prolonged exposure, both in vitro and
in vivo, to vancomycin may lead to the emergence of reduced
susceptibility to this glycopeptide antibiotic [1416]. The ad-
dition of a second antibiotic that is rapidly bactericidal and
that has a high threshold for the development of resistance
could narrow the mutant-selection window [17] and has the
potential to prevent the emergence of reduced susceptibility to
vancomycin.
Enhancing tissue and intracellular penetration. Vanco-
mycin penetration into a number of compartments, including
the lungs [18, 19], subcutaneous tissue [20], cortical bone [21],
and cerebrospinal fluid [22], is limited, as is its intracellular
activity [23]. Coadministration of drugs with more-favorable
penetrative characteristics, such as rifampin [23], may have the
potential to overcome these deficiencies.
Reducing staphylococcal toxin production. Production of
at least some toxins is reported to be increased by b-lactam
antibiotics and to be diminished by clindamycin and linezolid,
whereas vancomycin has no significant effect [24, 25]. These
findings have led to suggestions that a toxin-inhibiting anti-
biotic be added to vancomycin for the treatment of selected
infections.
EMPIRICAL BASIS FOR SOME COMBINATION
THERAPIES WITH VANCOMYCIN
FOR S. AUREUS INFECTION
Vancomycin plus rifampin. Rifampin has a number of char-
acteristics that make it potentially effective when used in com-
bination with vancomycin, including its potent bactericidal ac-
tivity [26], modest activity against nongrowing cells [27], and
ability to penetrate cells [28, 29] and a variety of tissues and
compartments, such as bone [30] and cerebrospinal fluid [31].
Rifampin is reported to enhance the activity of vancomycin
against S. aureus in biofilm [12, 32] and against S. aureus that
have been ingested by polymorphonuclear leukocytes [23]. In
addition, subinhibitory concentrations of rifampin inhibit PVL
production by S. aureus [24].
Evaluation of the antistaphylococcal activity of the combi-
nation of rifampin and vancomycin in vitro is dependent on
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methodology [3335]. Separate studies have concluded that
both synergy [26] and antagonism [36] represent their domi-
nant interaction against S. aureus, but a recent extensive review
examining published studies concluded that in vitro studies
most often demonstrated indifference [34]. A number of stud-
ies, however, have found vancomycin and rifampin to be syn-
ergistic against MRSA growing in biofilm [37].
The effect of methodology is illustrated by the finding that
the combination of vancomycin and rifampin is more effective
than either agent alone in the treatment of experimental en-
docarditis in a rabbit model of MRSA infection caused by a
strain for which antagonism had been demonstrated by the
checkerboard method, whereas synergy was observed by time-
kill analysis [34]. In a rabbit model of endocarditis, the addition
of rifampin did not significantly reduce the bacterial load in
heart valves but did significantly reduce bacterial density in
several organs [38]. Other investigators have also failed to iden-
tify a benefit from the addition of rifampin to vancomycin in
the treatment of experimental MRSA endocarditis [39]. In an
experimental model of osteomyelitis due to MRSA, rifampin
alone was as effective as the combination of rifampin and van-
comycin, and the combination did not reliably prevent the
emergence of resistance to rifampin [40], an observation that
could be predicted from in vitro results [41]. Rifampin resis-
tance, however, may not be all bad, because the associated rpoB
mutations cause reduced fitness of S. aureus [42]. A recent
review concluded that experiments in animal models suggested
that the addition of rifampin to vancomycin in the treatment
of endocarditis or meningitis had no benefit, whereas there was
a possible benefit for osteomyelitis and an apparent benefit for
abscesses [35].
In contrast to the large number of preclinical studies, there
is only a single published randomized clinical trial examining
the efficacy of the combination of vancomycin and rifampin.
In that study, 42 patients with native-valve MRSA endocarditis
Vancomycin Combination Therapy CID 2009:49 (1 October) 1073
(right-sided in 34) were treated with vancomycin and were
randomized to also receive either rifampin or no additional
antibiotic [43]. Although there was no difference in clinical
outcomes between the 2 treatment groups, the addition of rif-
ampin was associated with prolongation of bacteremia by 2
days: the median duration of bacteremia was 7 days (range, 3
8 days) among those who received vancomycin alone and was
9 days (range, 310 days) among those treated with the com-
bination. It should be noted, however, that follow-up was in-
complete for 21 patients who refused planned phlebotomies or
who absconded, so that the final outcome analysis was based
only on the remaining 21 patients.
Rifampin use may also have adverse effects. A recent ret-
rospective cohort study analyzed 84 patients with native-valve
S. aureus endocarditis (78.6% of which was caused by MRSA),
half of whom received rifampin in addition to a cell wallactive
agent (vancomycin in 83.3%) [44]. Although rifampin admin-
istration was associated with more-prolonged bacteremia and
other adverse outcomes, confounding factors precluded a con-
clusion with regard to efficacy. Rifampin administration was
associated with drug-drug pharmacokinetic interactions in 22
(52%) of 24 patients and with hepatotoxicity in 9 (21%), where-
as only 1 patient (2%; P ! .014) receiving vancomycin alone
developed hepatotoxicity. All patients with hepatotoxicity, how-
ever, had preexisting chronic hepatitis C virus infection. Rif-
ampin resistance emerged in 9 (21%) of recipients of this drug,
with all instances occurring in patients who still had bacteremia
at the time rifampin was added, among whom it occurred in
56%.
Thus, although rifampin has a number of theoretically ben-
eficial characteristics as a companion agent to vancomycin,
empirical results obtained in the laboratory are often contra-
dictory, and there are no clinical trial results that support the
use of rifampin coadministration.
Vancomycin plus gentamicin. A number of studies have
demonstrated in vitro synergy between gentamicin and van-
comycin against many MRSA isolates [45], although this phe-
nomenon was not detected with any of 3 VISA strains in an
in vitro pharmacodynamic model [46]. Gentamicin enhanced
the bactericidal activity of vancomycin against MRSA in an in
vitro model of infected fibrin-platelet clots [47]. Using an in
vitro pharmacodynamic model with simulated endocardial veg-
etations, Tsuji and Rybak [48] found evidence that a single 5
mg/kg dose of gentamicin enhanced early killing of MRSA by
vancomycin and resulted in 99.9% killing at 32 h. Findings
such as these, as well as evidence that combinations of gen-
tamicin and a b-lactam shorten the duration of bacteremia in
animal models of MSSA endocarditis and in patients with right-
sided endocarditis due to MSSA (albeit at the price of ne-
phrotoxicity) [49], have contributed to the use of the combi-
nation of vancomycin and gentamicin by many clinicians.
1074 CID 2009:49 (1 October) Deresinski
There are no published randomized clinical trials comparing
the combination of vancomycin alone to vancomycin plus an
aminoglycoside in patients with serious MRSA infections. How-
ever, the combination of vancomycin plus gentamicin (given
for the first 4 days of therapy) was numerically inferior to
daptomycin alone in the treatment of MRSA bacteremia and
endocarditis in a randomized trial, although statistical signifi-
cance was not achieved [50]. Unfortunately, even the low dose
of gentamicin (1 mg/kg every 8 h) and the short duration in
that study was associated with significant nephrotoxicity [51,
52]. Netilmicin may be less nephrotoxic than gentamicin, but
the addition of the former to vancomycin therapy in a rabbit
model of MRSA endocarditis provided no advantage [39].
It can be concluded from the foregoing that the adminis-
tration of gentamicin with vancomycin for the treatment of
MRSA infection is associated with potential toxicity in the ab-
sence of evidence of clinical benefit, making its use difficult to
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justify [53].
Vancomycin plus rifampin and gentamicin. Current
guidelines for the treatment of prosthetic valve endocarditis
(PVE) due to MRSA recommend the use of the 3-drug com-
bination of vancomycin, rifampin, and gentamicin, with the
aminoglycoside administered for only the first 2 weeks of ther-
apy [54]. In contrast, the guidelines do not recommend the
addition of rifampin to vancomycin for the treatment of native-
valve endocarditis due to MRSA. The recommendation for the
3-drug combination in the treatment for MRSA PVE appears
to be an extrapolation from the recommendation for the treat-
ment of PVE due to S. epidermidis [54], which, apparently, is
predominantly based on a retrospective analysis of a total of
26 patients receiving various regimens, with or without con-
comitant surgical therapy (table 1) [55]. In that study, 19 of
the 26 patients received combined medical and surgical therapy,
leaving only 7 for whom antibiotic therapy was assessable
only 1 of whom received vancomycin monotherapy. All 3 pa-
tients who received vancomycin plus rifampin were cured, as
were all 3 who received all 3 antibiotics, whereas the single
recipient of vancomycin alone experienced therapy failure.
A recent publication analyzed 86 adults with PVE due to
coagulase-negative staphylococci (two-thirds methicillin resis-
tant), most of whom were treated with vancomycin together
with rifampin and/or gentamicin [56]. In-hospital mortality
did not vary significantly among groups, with rates of 27%
among those treated with vancomycin alone (n p 15), 33%
among those given vancomycin plus rifampin (n p 12), 20%
among those given vancomycin plus gentamicin (n p 16), and
19% among those given all 3 antibiotics (n p 16).
Thus, the evidence for the recommendation of 3-drug therapy
for PVE due to MRSAwhich carries with it the potential for
increased risk of adverse reactionsis, at best, unconvincing.
Vancomycin plus a b-lactam. Although this combination
 Table 1. Retrospective Analysis of Treatment Outcomes among Patients with
Prosthetic-Valve Endocarditis Due to Staphylococcus epidermidis Infection
Antibiotic therapy
Vancomycin
Vancomycin plus rifampin
Vancomycin plus aminoglycoside
Vancomycin plus rifampin and aminoglycoside
Total
NOTE. Data are from Karchmer et al [55].
is not used for definitive therapy, vancomycin is often admin-
istered together with an antistaphylococcal b-lactam antibiotic
during the initial empirical phase (when the methicillin sus-
ceptibility of the infecting pathogen remains undetermined)
without concern regarding their potential interaction. Favorable
antistaphylococcal interactions between these 2 antibiotics
have, however, been frequently identified in vitro. Thus, cefe-
pime and vancomycin are often synergistic in vitro against both
MSSA and MRSA [57], and cefazolin and imipenem are each
frequently synergistic with vancomycin in vitro against MRSA
[58], as is cefpirome and vancomycin [59]. The carbapenems
doripenem, panipenem, meropenem, and imipenem were each
synergistic with vancomycin by the checkerboard method
against 92% of 27 strains of MRSA [60]. Synergy was observed
for 46% of 50 MRSA isolates by the checkerboard method and
for 5 of 5 by time-kill analysis with the combination of van-
comycin and cefotaxime, whereas antagonism was not detected
[61]. Ceftobiprole, which itself has activity against MRSA, was
synergistic with vancomycin against a vancomycin-resistant
strain of MRSA, markedly lowering the vancomycin MIC [62].
In an in vivo study, the addition of nafcillin to vancomycin
was significantly more effective than either agent alone in ex-
perimental endocarditis due to a vancomycin-resistant strain
of S. aureus carrying the vanA gene complex [63].
The interaction may also operate in the reverse direction,
because reduced vancomycin susceptibility achieved by serial
passage of MRSA in the presence of the glycopeptide antibi-
otic is associated with increased susceptibility to methicillin
[64]. Consistent with these observations, the combination of
a b-lactam antibiotic and vancomycin is reported to be syn-
ergistic against MRSA with reduced susceptibility to vanco-
mycin [65]. MRSA with reduced susceptibility to vancomycin
have altered penicillin-binding proteins, including down-reg-
ulation of PBP2a, potentially providing an explanation for in-
creased susceptibility to b-lactam antibiotics [66]; loss of the
mecA gene has also been reported [67]. Synergy could not,
however, be demonstrated in vivo in a murine model of in-
fection [68].
Although these experimental studies all report a beneficial
No. cured/total no.
Medical and Medical
surgical only Total
3/5 0/1 3/6
4/5 3/3 7/8
5/5 0/0 5/5
3/4 3/3 6/7
15/19 6/7 21/26
interaction between vancomycin and b-lactams, b-lactam ex-
posure has also been reported to cause reduced susceptibility
of some strains of MRSA to vancomycin [69]. Furthermore,
although vancomycin has no effect on staphylococcal toxin
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production [24], subinhibitory concentrations of b-lactams en-
hance their production [24, 25] and, as a result, could have a
detrimental effect on therapy in some cases.
Overall, these results suggest that, in addition to possibly
being preferable for initial empirical therapy before methicillin
susceptibility results are available, the combination of vanco-
mycin with a b-lactam antibiotic may provide benefit in de-
finitive therapy for serious MRSA infection. In the absence of
clinical trials confirming these results, however, the combina-
tion cannot be recommended for this purpose.
Vancomycin plus clindamycin, linezolid, or quinupristin-
dalfopristin. The ability of subinhibitory concentrations of
clindamycin and linezolid to diminish production of several
toxins by S. aureus [24, 25] has led to their use in combination
with vancomycin. It is reported, however, that clindamycin
frequently antagonizes the antistaphylcoccal activity of van-
comycin [70, 71]. Although linezolid and vancomycin are re-
ported to be indifferent when studied by the checkerboard
method [70], by the time-kill method it was found that the
addition of linezolid decreased the rate of vancomycin killing
of MRSA by 1001000-fold [72]. Antagonism between these 2
antibiotics was also found by another group of investigators
using time-kill analysis [73, 74].
The observed in vitro interaction between quinupristin-dal-
fopristin (QD) and vancomycin has been variable, ranging from
frequent antagonism to frequent synergy [75]. QD has been
reported to reduce the bactericidal activity of vancomycin
against macrolide-lincosamide-streptogramin B (MLSB)resis-
tant S. aureus [76] but, in contrast, to enhance the bactericidal
activity of vancomycin in time-kill studies and in a rabbit model
of endocarditis, regardless of the presence or absence of con-
stitutive MLSB resistance [77]. An open-label, nonrandomized
prospective study reported that patients treated with the com-
bination of vancomycin and quinupristin-dalfopristin who had
been selected because of persisting infection experienced more-
Vancomycin Combination Therapy CID 2009:49 (1 October) 1075
rapid clearance of MRSA than did those who continued re-
ceiving vancomycin alone [78]. The study is, however, available
only in abstract form, and the lack of adequate public infor-
mation precludes confidently drawing conclusions from it.
Miscellaneous antibiotics, biologicals, and physical agents.
In vitro synergy with vancomycin against S. aureus has been
detected with levofloxacin [59] and with moxifloxacin [79]. Kill-
ing of MRSA and VISA strains by vancomycin was modestly
reduced by the addition of tigecycline [80] but, in contrast, this
glycylglycine enhanced the activity of vancomycin against S. au-
reus in biofilm [12]. Other agents that have been reported to
improve the activity of vancomycin against S. aureus growing in
biofilm include clarithromycin [81] and fusidic acid [32], with
the 3-drug combination of vancomycin, rifampin, and fusidic
acid being among the most potent in an extensive study [32].
Coexposure to trimethoprim-sulfamethoxazole enhances the
bactericidal activity of vancomycin against S. aureus that have
been ingested by polymorphonuclear leukocytes [23]. Clinical
data on the use of these miscellaneous agents in combination
with vancomycin are almost nonexistent except for the occasional
case report, such as that of successful salvage therapy with a
combination of daptomycin, vancomycin, and rifampin in 2 pa-
tients with recurrent osteoarticular infections who had experi-
enced failure of prior therapy with either daptomycin alone or
the combination of vancomycin and rifampin [82].
Administration of granulocyte colony-stimulating factor did
not improve the survival of mice with experimental MRSA
sepsis treated with vancomycin [83], but other biologicals show
promise. The antistaphylococcal activity of the endopeptidase
lysostaphin is additive to that of vancomycin [84], and a fa-
vorable interaction was observed in eradicating MRSA growing
in biofilm [85]. The combination of the 2 agents was modestly
more effective than either agent alone in a murine model of
MRSA infection [86], and lysostaphin enhanced the activity of
vancomycin in a rabbit model of MRSA endocarditis [87]. The
a-helical peptides cercopin A and magainin II were each syn-
ergistic with vancomycin in vitro against a VISA strain and
significantly improved survival, relative to that achieved with
each of the 3 given alone, in a murine model of VISA sepsis
[88]. Therapy with the combination of the cathelicidin peptide
BMP-28 and vancomycin was superior to that with either alone
in a rat model of MRSA ureteral stent infection [89]. Cloned
lysin encoded by the S. aureus bacteriophage FMRII was syn-
ergistic with vancomycin against VISA in vitro [90]. The in-
teraction between vancomycin and antibody has also been in-
vestigated. Tefibazumab, a monoclonal antibody recognizing
clumping factor A on the surface of S. aureus, enhanced the
activity of vancomycin in an experimental model of endocar-
ditis [91]. Aurograb (NeuTec Pharma), a human recombinant
single-chain antibody fragment (scFv) that binds to GrfA, an
ABC transporter on the surface of S. aureus, is synergistic with
1076 CID 2009:49 (1 October) Deresinski
vancomycin [92]. Finally, exposure to a electrical current (2000
mA) significantly enhanced the activity of vancomycin against
MRSA growing in biofilm [93].
CONCLUSION
In a recent survey, infectious disease clinicians were asked how
they would manage a patient who was apparently experiencing
failure of vancomycin therapy for a bacteremic illness caused
by MRSA with a vancomycin MIC of 2 mg/mL [94]. In response,
72% indicated they would continue vancomycin but would add
a second antibiotic, most often rifampin or gentamicin. The
available data reviewed here, however, would not appear to
provide support for this approach, nor do they provide support
for the use of such combinations for initial definitive treatment
of MRSA infection. The optimal therapy for serious MRSA
infection is undetermined and will remain so in the absence
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of randomized clinical trials.
Acknowledgments
Potential conflicts of interest. S.D. has consulted with and/or has
served on the speakers bureau and/or advisory board of Merck, Pfizer,
Wyeth, Cubist, Schering, Targanta, Johnson & Johnson, Theravance, and
Cepheid.
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