Keywords
methicillin-resistant
Staphylococcus aureus
- combination antibiotic therapy - vancomycin - daptomycin
Methicillin-resistant Staphylococcus aureus (MRSA) is the most common
antibiotic-resistant human pathogen, with an estimated 1,650 cases of blood stream
infection
and 500 deaths annually in Australia,[1] 11,000 deaths annually
in the United States,[2] and an annual excess cost to Europe's
health care system of €380m.[3] MRSA bacteremia has a mortality
of 20 to 30%, exceeding that of methicillin-sensitive S. aureus (MSSA) at least in
part due to the shortcomings of vancomycin, the standard therapy for MRSA bacteremia.
Vancomycin still remains the principal agent of choice in the treatment of MRSA.[4] However, multiple shortcomings of glycopeptide monotherapy have
been recognized and include poor tissue penetration, slow bactericidal effect, and
emergence
of resistance during therapy. Combination therapy may theoretically overcome some
of these
deficiencies.
Consequently, when exploring therapeutic combinations, the addition of a second agent
is
usually directed to address one or more of the above vancomycin deficiencies: to broaden
the
spectrum of activity (to include resistant isolates such as heteroresistant vancomycin
intermediate S. aureus [hVISA]) and increase the bacteriocidal activity of vancomycin
through synergy. Other potential benefits of adding antibiotics include enhancing
treatment
by providing better tissue or biofilm penetration and reducing toxin production especially
in toxin-mediated infections. The alternative to combination therapy is to find a
better
agent than vancomycin. Several agents with useful activity against MRSA have reached
the
market in recent years, including daptomycin, linezolid, tigecycline, and
quinupristin/dalfopristin. However, none of these agents has been shown to be superior
to
vancomycin, with clinical trials showing daptomycin is noninferior for S. aureus
bacteremia (SAB) and endocarditis[5] and linezolid noninferior
for S. aureus catheter-related blood stream infection,[6] and although linezolid achieved improved clinical cure for MRSA pneumonia, it
did not result in reduced mortality.[7] Hence, combination
therapy is an attractive possibility for improving outcomes from severe MRSA infections.
Most data on combination therapy come from in vitro experiments. These have three
possible
outcomes: synergy (increased bacteriocidal activity in excess of the additive actions
of the
two drugs), antagonism, and indifference. The most common in vitro methods used to
measure
synergy (in increasing order of complexity) are agar diffusion, checkerboard testing,
time-kill curves, and simulated pharmacodynamic (PD) models. Agar diffusion methods
use
combinations of antibiotics either as antibiotic discs or Etest strips (Biomerieux,
Paris,
France; paper strips of graduated antibiotic concentration), allowing them to diffuse
through the agar, and qualitatively examines bacterial growth in different zones of
the
agar. For example, two Etest strips (one for each antibiotic) can be placed at right
angles
on the agar plate, and bacterial growth examined near the intersection (where the
combination concentration is highest) compared with the outer quadrants. Checkerboard
testing uses multiple different dilutions of antibiotic combinations set out on an
agar
plate as a grid, ranging from below to above the minimum inhibitory concentration
(MIC) for
each agent. This allows a quantitative estimate of synergy and results are reported
as a
fractional inhibitory concentration (FIC). An FIC of ≤ 0.5 indicates synergy, ≥ 2.0
antagonism, and an FIC between these values indicates indifference. Time-kill methodology
is
dynamic rather than examining synergy at a single time point and thus is more likely
to
correlate with clinical use. Bacteria are cultured in liquid media in the presence
of
various concentrations of either single or combination antibiotics, and the speed
of
bacterial killing is quantified over time. In time-kill studies, synergy is defined
as a
reduction in ≥ 2 log colony forming units (cfu) of bacteria/mL compared with the cfu/mL
of
the most potent single drug. Finally, in vitro pharmacokinetic (PK)/PD models attempt
to
simulate antibiotic dosing within a human or animal host. An example is the fibrin
clot
model, where an ex vivo human blood clot is seeded with bacteria and exposed to dynamic
concentrations of antibiotic, simulating a usual dosing interval.
Combinations of Two Primarily Active Agents
Combinations of Two Primarily Active Agents
Vancomycin and Linezolid
Linezolid is an oxazolidinone, a new class of antibiotic with a mechanism of action
directed at the early steps of protein synthesis. Its introduction into clinical medicine
heralded the first new antibiotic with activity against MRSA since the introduction
of
vancomycin.
Linezolid and vancomycin combination therapy are reported to demonstrate indifference
using checkerboard assays,[8] but synergy with time-kill
assays.[9] Other studies, using similar methodology, were
unable to demonstrate synergy but observed antagonism[10]
[11] or indifference.[12]
Subsequent animal data have similarly been conflicting with an experimental rabbit
endocarditis model,[13] observing some effect with the
addition of linezolid, while a rat MSSA osteomyelitis model[14] showed indifference with no additional sterilization or cure rates compared
with vancomycin alone. The inconsistency of these results suggests that there are
a
variety of mechanisms involved in determining antibiotic interactions, which may include
the infecting bacterial strain, infection site, and host responses. Thus, this combination
should be used with caution as the described antagonism may lead to suboptimal
outcomes.
Nevertheless, this combination is still considered in toxin-mediated infections, as
subinhibitory concentrations of linezolid inhibit S. aureus toxin production.[15]
[16] This modulation of virulence factors through reduced
pathogen toxin synthesis may theoretically attenuate disease and influence outcomes.
This
hypothesis has not been shown in vivo to be effective, with no animal model data
available. Although a single case report has been published showing the effectiveness
of
linezolid in the treatment of MSSA toxic shock syndrome,[17]
no comparative data of the combination of linezolid with vancomycin in toxin-mediated
clinical syndromes has been published.
Vancomycin and Daptomycin
Daptomycin is a lipopeptide, which acts on the cell membrane through a complex process
resulting in cell membrane depolarization and permeabilization, ion leakage, and
ultimately cell death.[18] There is a paucity of in vitro
and in vivo data for this combination due to concerns about the relationship between
reduced vancomycin susceptibility and daptomycin nonsusceptibility.[19] This cross-resistance was first documented in vitro when a
collection of VISA isolates underwent susceptibility testing and 80% were found to
be
daptomycin nonsusceptible, despite these isolates not having been exposed to
daptomycin.[20] This association was later confirmed by
serial passage studies, with all S. aureus isolates developing daptomycin
nonsusceptibility in the presence of vancomycin.[21]
Subsequently, several clinical cases have described the same phenomenon.[22] Although the precise mechanism remains unclear, experts
speculate that increased cell wall thickness, as occurs in VISA, may also prevent
daptomycin penetration to its site of action.[23]
[24]
Nevertheless, Tsuji and Rybak performed Etest synergy testing and time-kill experiments
on one vancomycin heteroresistant and one vancomycin intermediate clinical S.
aureus isolate. There was moderate agreement between the two methodologies with
vancomycin/daptomycin combination showing either indifference or an additive effect
(but
not synergy).[25] This combination, albeit with the addition
of rifampin, has been used in one published report of two cases. Both patients had
orthopedic infections that relapsed after initial vancomycin/rifampin therapy and
were
cured with several weeks of triple therapy.[26] As both
patients also underwent surgical debridement and prosthesis removal, the effectiveness
of
daptomycin/vancomycin remains unknown, but based on the above concerns, this combination
is unlikely to be successful in most cases.
Vancomycin and Tetracyclines including Tigecycline
hVISA was first isolated in Japan in the 1990s.[27] Given
the lack of treatment options against hVISA, combination therapy was studied. Time-kill
experiments using the Mu3 strain, the first recognized hVISA isolate, revealed antagonism
when using minocycline/vancomycin in combination. The authors went on to examine possible
bacterial changes that may result in this antagonism and found that cell wall thickening
did not play a major role.
Tigecycline is a semisynthetic derivative of minocycline and is the first glycylcyline
antibiotic licensed for clinical use.[28] It offered great
promise as a new agent with a broad spectrum of activity against gram-negative and
-positive bacteria, including multiresistant organisms. However, postmarketing experience
has resulted in more selective indications, as it is associated with increased mortality
when used in certain clinical settings.[29] Nevertheless,
given its spectrum of activity, using it in combination with vancomycin remains an
attractive option. Mercier et al performed time-kill studies and found vancomycin
and
tigecycline to be indifferent when used with four MRSA (three of which were VISA)
isolates.[30] Petersen et al obtained similar results
using checkerboard and time-kill experiments on 10 S. aureus isolates.[31] There have been few experimental animal studies evaluating
tigecycline combinations.[28] A rabbit osteomyelitis model
found no difference between combination therapy compared with vancomycin or tigecycline
monotherapy.[32] Similarly, no difference was observed in
bactericidal activity in a biofilm model for this combination.[33]
The main conclusion from the available data is that there is no benefit with tetracycline
and vancomycin combinations. Unless tigecycline is required for a coexistent
multiresistant gram-negative infection, combination with vancomycin is not recommended
for
the treatment of MRSA infections.
Daptomycin and Tigecycline
Time-kill and Etest experiments demonstrated an indifferent effect when using this
combination.[25] These results are in contrast to a
subsequent study, which showed this combination to be synergistic based on time-kill
studies and checkerboard titration assays using 10 S. aureus isolates.[34] To corroborate their results, the authors went on to
perform an animal surgical site infection model. Tigecycline/daptomycin still showed
synergy.[34] No clinical data are available. The role of
tigecycline is likely to be limited as discussed previously and thus further studies
are
unlikely to occur with this combination.
Daptomycin and Linezolid
The impact of biofilm-associated infection remains significant especially in light
of the
aging population and increased joint replacements undertaken. Linezolid/daptomycin
combination was studied by Parra-Ruiz et al in their validated in vitro PK/PD biofilm
formation model.[35] This study observed that
linezolid/daptomycin combination therapy showed better efficacy than either agent
alone
and confirmed the results of one previous study using a simulated endocardial vegetation
model.[36] Although a single published case report showed
clinical benefit, this occurred in the setting of triple therapy with daptomycin,
linezolid, and rifampin.[37] Thus, the benefit of this
combination is unclear especially as checkerboard and time-kill experiments showed
antagonism.
Vancomycin and Quinupristin–Dalfopristin
Quinupristin–dalfopristin is an injectable streptogramin antibiotic with in vitro
activity against MRSA. The combination of quinupristin–dalfopristin with vancomycin
has
resulted in mixed results[38] with studies demonstrating
both antagonism[39] and synergy.[40]
[41]
[42]
[43] There remain very limited published clinical data to
guide the use of this combination.[44]
[45] Given that quinupristin–dalfopristin is not recommended
for MRSA bacteremia due to reports of treatment failures and emergent resistance,
and
there are no published original studies since 2002 on the combination of
quinupristin–dalfopristin with vancomycin, it is unlikely to be further advanced as
a
clinical treatment option.
β-Lactam Combination Therapy
β-Lactam Combination Therapy
Empirical therapy for SAB often includes both vancomycin and antistaphylococcal penicillin
such as nafcillin. This is not only because incorrect initial empiric therapy for
MRSA
bacteremia is associated with a twofold increase in mortality[46] but also because vancomycin monotherapy for MSSA infections is associated with
higher rates of hospitalization,[47] treatment failure,[48] and mortality[49]
[50] compared with β-lactam therapy (e.g., with nafcillin or
cefazolin). Given the increasing prevalence of community-acquired MRSA infection,[51]
[52]
[53] β-lactam combination therapy is often used in patients
with positive blood cultures where the Gram stain shows clustered gram-positive cocci
for
the first 24 to 48 hours of therapy, but before identification and susceptibility
profile of
the organism has been determined. Hence a potentially synergistic combination is unwittingly
being increasingly used in the subset that turn out to have MRSA infection. Considering
the
very definition of MRSA is that it is resistant to antistaphylococcal penicillins,
it is
counter-intuitive to hypothesize that β-lactams might have any benefit when added
to
standard therapy for MRSA infections. However, unexpected synergy between β-lactams
and both
vancomycin and daptomycin has been found to occur in vitro, initially only in VISA
and hVISA
strains, and then more broadly in MRSA.
Vancomycin/β-Lactam Combinations
In Vitro Studies
At least 16 in vitro studies have explored synergy between vancomycin and β-lactams
against MRSA isolates,[54]
[55]
[56]
[57]
[58]
[59]
[60]
[61]
[62]
[63]
[64]
[65]
[66]
[67]
[68]
[69] all but one of which found evidence of synergy in
some or all of the tested strains ([Table 1]). These
studies varied in their methodology (checkerboard synergy testing or time-kill curves),
types of strains tested (MRSA vs. hVISA vs. VISA) and the β-lactams used, but a
consistent finding across nearly all the studies was synergistic bacterial killing
in
most but not all strains tested. There are no consistent characteristics
in these reports in the strains where synergy was not demonstrated. However, there
was a
general tendency across these studies (and within some studies[56]
[66]) to an increasing degree of synergy with increasing
vancomycin MICs. The one study that did not demonstrate synergy did not actually include
any MRSA isolates. In this study, Joukhadar et al tested 10 clinical isolates of
methicillin sensitive
S. aureus and found evidence of neither synergy nor antagonism in any strain,
both using fixed drug concentrations, and in a dynamic model simulating clinical
dosing.[62]
Table 1
In-vitro and animal studies investigating synergy between vancoymcin and
beta-lactams against MRSA
|
Author (y)
|
Setting
|
Organism
|
Base antibiotic(s)
|
Beta-lactam(s)
|
Finding
|
Comments
|
|
Seibert et al (1992)[54]
|
In vitro
|
MRSA
|
Vancomycin
|
Cefpirome
Cefoperazone
Ceftazidime
|
Synergy with cefpirome/Vancomycin and cefoperazone/Vancomycin but not
ceftazidime/Vancomycin
|
Synergy with “most” MRSA strains
|
|
Palmer and Rybak (1997)[55]
|
In vitro
|
MRSA
|
Vancomycin
|
Pip-Tazo
Imipenem
Nafcillin
|
Synergy with Vancomycin/Imipenem and Vancomycin/Nafcillin, for hVISA but not
VISA
|
Time-kill studies in infected fibrin clots
|
|
Climo et al (1999)[56]
|
In vitro
Rabbit endocarditis model
Rabbit renal abscess model
|
MRSA
MRCNS
|
Vancomycin
|
Oxacillin
Ceftriaxone
Ceftazidime
Amoxy-clav
|
In vitro synergy for all combinations
In vivo only nafcillin tested—synergy for sterilizing vegetations and renal
abscesses
|
Synergy was proportional to Vancomycin MIC
|
|
Lozniewski et al (2001)[57]
|
In vitro
|
MSSA
MRSA
|
Vancomycin
|
Cefepime
|
Synergy in 3/10 MRSA by checkerboard, and 3/3 and 2/3 MRSA by time-kill
assays
|
|
|
Domaracki et al (2000)[58]
|
In vitro
|
MRSA
MRCNS
|
Vancomycin
|
Oxacillin
|
Synergy in 14/21 strains
|
Sub-MIC concentrations of Vancomycin
|
|
Drago et al (2007)[59]
|
In vitro
|
MRSA
|
Vancomycin
Teicoplanin
|
Cefotaxime
Cefepime
Imipenem
Pip-Tazo
|
Vancomycin + Cefotaxime synergistic in 43/50 strains
|
|
|
Kobayashi (2005)[60]
|
In vitro
|
MRSA
|
Vancomycin
Teicoplanin
|
Various carbapenems
|
Synergy in 25/27 of MRSA strains with Vancomycin, 20/27 with Teico
|
|
|
Ribes et al (2010)[61]
|
In vitro
Murine peritonitis model
|
hVISA
VISA
|
Vancomycin
Linezolid
|
Imipenem
|
Linezolid plus imipenem most effective Combo in vivo
|
Linezolid plus Vancomycin antagonistic
|
|
Joukhadar et al (2010)[62]
|
In vitro
|
MSSA
|
Vancomycin
|
Oxacillin
|
Indifference
|
Note not MRSA
|
|
Silva et al (2011)[63]
|
In vitro
|
MRSA
MRCNS
|
Vancomycin
|
Imipenem
|
Synergy in 21/22 strains
|
|
|
Hagihara et al (2012)[64]
|
In vitro
|
MRSA
hVISA
VISA
|
Vancomycin
|
Cefazolin
|
Synergy for all strains
|
In vitro PK/PD model
|
|
Fernandez (2012)[65]
|
Rat endocarditis model
|
MRSA
VISA
|
Vancomycin
|
Ceftobiprole
|
Synergy for Vancomycin + ceftobiprole
|
|
|
Leonard (2012)[66]
|
In vitro
|
hVISA
MRSA
MSSA
|
Vancomycin
|
Nafcillin
|
23/25 h VISA strains synergy. Also against MRSA and MSSA, but least effect
against MSSA
|
5 strains had PK/PD simulations—also demonstrated synergy
|
|
Werth et al (2013)[68]
|
In vitro
PK-PD model
|
hVISA
Daptomycin R VISA
|
Daptomycin
Vancomycin
|
Ceftaroline
|
Daptomycin + ceftaroline synergistic against both strains; Vancomycin plus
ceftaroline only against the daptomycin S strain
|
|
|
Werth et al (2013)[69]
|
In vitro
|
VISA
hVISA
|
Vancomycin
|
Ceftaroline
Oxacillin
|
Vancomycin/Oxa synergy in 3/5 VISA. Vancomycin/ceftaroline in 5/5 VISA
|
Inverse correlation between Vancomycin and β-lactam susceptibility
|
|
Dilworth et al (2014)[67]
|
In vitro
|
MRSA
VISA
|
Vancomycin
|
Pip-Tazo
Oxacillin
|
Synergy in all strains for both oxa and Pip-Tazo
|
|
Abbreviations: (h)VISA, (heteroresistant) vancomycin intermediate
Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus
aureus; MSSA, methicillin susceptible Staphylococcus aureus; MRCNS,
methicillin-resistant coagulase negative Staphylococcus; Pip-Tazo,
piperacillin–tazobactam; PK-PD, pharmacokinetic/pharmacodynamic.
Table 2
In-vitro and animal studies investigating synergy between daptomycin and
beta-lactams against MRSA
|
Author (y)
|
Setting
|
Organism
|
Base antibiotic(s)
|
β-lactam(s)
|
Finding
|
Comments
|
|
Silva et al (1988)[71]
|
In vitro
|
MRSA
Enterococci
Peptococci
|
Daptomycin
|
Aztreonam
Ceftriaxone
|
Synergy against all MRSA strains tested
|
Time-kill curves
|
|
Rand and Houck (2004)[72]
|
In vitro
|
MRSA (18 strains)
|
Daptomycin
|
Oxacillin
Amp-Sul
Tic-Clav
Pip-Tazo
|
All combinations synergistic
|
Sub-MICs of daptomycin
|
|
Snydman et al (2005)[70]
|
In vitro
|
MRSA
MSSA
VRE
|
Daptomycin
|
Oxacillin
Ceftriaxone
Cefepime
Imipenem
|
Indifference of all combinations for MSSA
Synergy in 7/10 MRSA isolates
|
|
|
Cilli et al (2006)[74]
|
In vitro
|
VRE
MRSA
MRSE
|
Daptomycin
|
Amp-Sul
Tic-Clav
Pip-Tazo
|
Synergy in > 70% of MRSA strains
|
|
|
Tsuji and Rybak (2006)[25]
|
In vitro
|
hVISA (2 strains)
|
Daptomycin
Vancomycin
|
Ampicillin-Sulbactam
|
Synergy with Vancomycin/AS but indifference with daptomycin/AS
|
Etest and time kill
|
|
Mehta et al (2012)[73]
|
In vitro
|
MRSA (Dap S and Dap R)
|
Daptomycin
|
Nafcillin
Cefotaxime
Amoxy-Clav
Imipenem
|
Synergy with all blac combinations, esp oxacillin
|
|
|
Garrigós et al (2012)[80]
|
Animal model
|
MRSA
|
Daptomycin
|
Cloxacillin
|
Combo better cure rates, but only mildly. Daptomycin-Rif was better
|
Rat tissue cage model (foreign body infection)
|
|
Rose et al (2012)[77]
|
Case report
In vitro PK/PD model
|
DNS MRSA
|
Daptomycin
|
Ceftaroline
|
Synergy
|
|
|
Werth et al (2013)[69]
|
In vitro
|
hVISA
DNS hVISA
|
Daptomycin
Vancomycin
|
Ceftaroline
|
Combination synergistic for both strains with daptomycin, for one strain with
Vancomycin
|
Time-kill curves
|
|
Leonard and Rolek (2013)[76]
|
In vitro
|
VISA
|
Daptomycin
|
Nafcillin
|
Synergy in 11/20
|
Increasing synergy with increasing daptomycin MIC
|
|
Werth et al (2014)[78]
|
In vitro
PK-PD model
|
hVISA
Daptomycin R VISA
|
Daptomycin
Vancomycin
|
Ceftaroline
|
Daptomycin + ceftaroline synergistic against both strains; Vancomycin plus
ceftaroline only against the daptomycin S strain
|
|
|
Barber et al (2014)[75]
|
In vitro
|
MRSA (20 isolates)
|
Daptomycin
|
Ceftobiprole
|
Dapto plus ceftobiprole synergistic in all isolates
|
Time-kill curves
|
Abbreviations: (h)VISA, (heteroresistant) vancomycin intermediate
Staphylococcus aureus; MRSA, methicillin-resistant Staphylococcus
aureus; MSSA, methicillin susceptible Staphylococcus aureus; MRCNS,
methicillin-resistant coagulase negative Staphylococcus; Pip-Tazo,
piperacillin–tazobactam; PK-PD, pharmacokinetic/pharmacodynamic; DNS, Daptomycin
non susceptible.
Animal Studies
The few studies that have assessed combinations of vancomycin with β-lactams in animal
models have all found evidence of synergy.[56]
[61]
[65] Climo et al found faster sterilization of infection
with vancomycin plus nafcillin in MRSA rabbit endocarditis and renal abscess
models.[56] Ribes et al tested various combinations of
linezolid, vancomycin, and imipenem in a murine peritonitis VISA model using time-kill
curves, and found faster bacterial killing with vancomycin plus imipenem compared
with
vancomycin alone, in both strains tested.[61] Finally,
Fernandez et al investigated the anti-MRSA cephalosporin ceftobiprole against an MRSA
and a VISA strain in a rat endocarditis model. They found good activity of ceftobiprole
against both strains in terms of sterilizing vegetations and preventing mortality;
the
combination of vancomycin plus ceftobiprole led to faster killing on time-kill curves,
but similar rates of mortality and of sterilization of vegetations compared with
ceftobiprole alone.[65]
Human Studies
There are currently no published prospective controlled trials of vancomycin/β-lactam
combination therapy in patients with MRSA bacteremia, but one observational study
has
recently been published.[67] In this single-center
retrospective cohort study, Dilworth et al described the outcomes of 50 patients with
MRSA bacteremia who received combination therapy with vancomycin and at least 24 hours
of β-lactam (at their clinicians' discretion), and compared them with 30 patients
treated at the same hospital, during the same time period with vancomycin alone. They
found a higher rate of microbiological eradication in the combination therapy group
(96
vs. 80%, p = 0.02), which persisted on a multivariate model attempting to control
for potential confounders (adjusted odds ratio for achieving microbiological eradication
in the combination group = 11.24, p = 0.01).
Daptomycin/β-Lactam Combinations
In Vitro Studies
At least 10 in vitro studies have examined the combination of daptomycin with various
β-lactams against MRSA and VISA strains ([Table 2]).[25]
[70]
[71]
[72]
[73]
[74]
[75]
[76]
[77]
[78]
[79] The findings of these studies are remarkably similar
to the vancomycin/β-lactam synergy articles cited earlier: synergy for most but not
all
strains tested, and an increasing degree of synergy with increasing MICs to both
vancomycin and daptomycin. No studies have found evidence of antagonism with this
combination.
Animal Studies
A recently published animal study mirrored the findings of the in vitro studies.
Garrigós et al used a rat tissue cage model of MRSA infection to study the combination
of daptomycin with cloxacillin, and found superior cure rates with the combination
than
with daptomycin alone.[80]
Human Studies
As for the vancomycin/β-lactam combination, there are no clinical trials of daptomycin
with β-lactams either published or in trials registries. However, limited observational
data suggest this combination may be effective, particularly MRSA with poor response
to
daptomycin. In a case series of seven patients with persistent MRSA bacteremia for
more
than 1 week despite high-dose daptomycin, all cleared their bacteremia within 48 hours
once nafcillin or oxacillin was added to their therapy.[81] In a second case series of 22 patients with persistent MRSA bacteremia
despite daptomycin for a median of 10 days, the addition of ceftaroline lead to
clearance of bacteremia in all cases, in a median of 2 days.[82]
Summary
Although the studies on β-lactam combination therapy are heterogeneous, there are
some
consistent findings (with either vancomycin or daptomycin as the companion agent):
adding a β-lactam leads to synergistic bacterial killing in the majority of strains
tested and in all animal models tested. The most consistent data come from more
resistant strains and from antistaphylococcal penicillins or ceftaroline rather than
other β-lactams. β-lactam combination therapy (with either vancomycin or daptomycin)
is
not recommended in Infectious Diseases Society of America (IDSA) or other guidelines
at
this stage, but the emerging data are intriguing, and at least one phase 2b randomized
controlled trial (RCT) of this strategy is underway (Australia and New Zealand Clinical
Trials Registry number ACTRN12610000940077). A key question that emerges from these
data
is: what is the mechanism of the observed synergy? The mechanisms have not been entirely
elucidated, but are becoming clearer over time. Increasing vancomycin resistance in
S. aureus is paradoxically associated with decreasing MICs to oxacillin, and
this so-called “see-saw effect”[68]
[83] is at least in part due to alteration of the
MecA gene in some strains of VISA and vancomycin resistant Staphylococcus
aureus (VRSA),[84]
[85] and possibly to other structural changes in
penicillin-binding proteins. β-lactams have been shown to enhance binding of daptomycin
to the bacterial cell wall.[79] Finally, Sakoulas et al
recently reported exciting data derived from ex vivo study of human blood which adds
another potential advantage for the use of β-lactams for MRSA—they lead to increased
activity of innate host defense peptides such as cathelicidin LL-37,[86] which in turn allows more efficient bacterial
killing.
Other Combination Therapy
Other Combination Therapy
Rifampin
Vancomycin/Rifampin
Rifampin is attractive as an adjunctive agent as it is bactericidal,[87] has activity against cells in stationary growth
phase,[88] and is better able to penetrate cells,[89]
[90] tissues, and biofilms[91]
[92] than vancomycin.[93]
[94] However, most in vitro studies demonstrate either
antagonism or indifference for the combination of rifampin with vancomycin.[25]
[87]
[95]
[96]
[97]
[98]
[99]
[100]
[101]
[102] There is some in vitro evidence of synergy in the
presence of biofilm production[33]
[103] and in animal models of osteomyelitis[96]
[104] or foreign body infections.[101]
[105]
[106] Bayer and Lam found in a rabbit MRSA endocarditis
model that the combination of vancomycin and rifampin improved valvular sterilization
and overall cure.[107] However, these findings have not
been replicated in other animal endocarditis models.[108]
[109] A systematic review of in vitro and animal
experiments specifically addressing the benefit of adding rifampin to other antibiotics
for S. aureus infections concluded that the effect of rifampin therapy was often
inconsistent and method dependent.[92]
Clinical studies to date have not provided evidence in support of the combination
of
vancomycin with rifampin for severe MRSA infections. Levine et al randomized 42 patients
with MRSA endocarditis to vancomycin or vancomycin plus rifampin.[110] The median duration of bacteremia was longer in
the combination arm (9 vs. 7 days) and rates of treatment failure were similar.
Similarly, Riedel et al determined in a retrospective cohort of 84 patients with S.
aureus native valve infective endocarditis (IE) that the addition of rifampin was
associated with longer duration of bacteremia and increased mortality compared with
controls.[111] There was also a higher incidence of
hepatotoxicity and significant drug–drug interactions for patients receiving
rifampin.[112] Jung et al conducted a RCT in patients
with MRSA nosocomial pneumonia.[112] Clinical cure at day
14 was achieved in 54% (22 of 41) of patients in the vancomycin plus rifampin arm
compared with 31% (13 of 42) in the vancomycin alone arm (p = 0.047). Although
these data are promising, the study was unblended and single center, and vancomycin
dosing (1 g q12h) was lower than current recommendations. Based on the Levine et al[110] and Riedel et al[111]
studies, the IDSA MRSA treatment guidelines recommend against the addition of
rifampin to vancomycin for MRSA bacteremia or native valve IE (level A-I; good evidence,
at least one properly RCT).[4]
Nonetheless, Thwaites et al have cogently argued that equipoise exists for the addition
of rifampin to standard therapy for SAB and a RCT comparing standard therapy to standard
therapy plus adjunctive rifampin for SAB in the United Kingdom is currently being
conducted (the adjunctive rifampicin to reduce early mortality from Staphylococcus
aureus bacteraemia [ARREST] study).[113] In a review of
four previously published RCTs,[110]
[112]
[114]
[115] Thwaites et al determined that adjunctive rifampin
for serious staphylococcal infections was associated with a reduction in
infection-related deaths by 55% (p = 0.02).[113]
Notably, two of these studies principally focused on MSSA infections treated with
oxacillin,[114]
[115] and the combined findings in this systematic review
probably do not apply to MRSA and vancomycin therapy. In the ARREST trial, MRSA
bacteremia is not a prespecified subgroup. Thus, despite this being the largest planned
RCT for SAB to date, the study may be underpowered to make specific conclusions
regarding the MRSA subgroup, particularly as reductions in numbers of MRSA bacteremia
in
the United Kingdom may result in MRSA bacteremia being a minority of infections.[116]
There is stronger but still inconclusive evidence for the use of adjunctive rifampin
for prosthetic joint infections (PJIs), where biofilm assumes a critical importance.
For
example, Peel et al[117] and Aboltins et al[118] have reported on successful outcomes with debridement
and retention of carefully selected patients with PJI prescribed prolonged courses
of
rifampin and fusidic acid. However, these studies suffer from their retrospective
and
observational nature, a limited number of patients with MRSA (n = 39), and
notably MRSA infection (compared with coagulase negative staphylococci) remained an
independent risk factor for treatment failure.[117] The
combination of a fluoroquinolone with rifampin has also been demonstrated to be
effective in treating selected PJIs with a debridement and retention approach in both
a
small RCT[119] and several retrospective cohort
studies.[120]
[121]
[122] However, the RCT reported by Zimmerli et al[119] only included 15 PJI patients, included a relatively
ineffective control arm (ciprofloxacin monotherapy), and when reanalyzed by intention
to
treat found no significant difference between the rifampicin and nonrifampicin
containing arms. Somewhat controversially,[123] based
largely on this single RCT, the 2013 IDSA guidelines recommend that rifampin be added
to
initial parenteral therapy for MRSA PJI, followed by prolonged combination oral therapy
with rifampin with a companion agent such as a fluoroquinolone.[124]
Daptomycin/Rifampin
In vitro and animal studies demonstrate an overall pattern of either antagonism or
indifference with the addition of rifampin to daptomycin. For example, in an in vitro
IE
model, the combination of daptomycin with either rifampin or gentamicin antagonized
or
delayed the bactericidal activity of daptomycin alone.[125] Similarly, in time-kill experiments and a rabbit endocarditis model, the
combination of daptomycin and either rifampin or gentamicin demonstrated no enhancement
of the effectiveness of daptomycin against MRSA compared with daptomycin alone.[126] There are currently only case reports or small case
series of clinical studies involving the combination of daptomycin and rifampin.[127]
[128]
[129]
Gentamicin
Vancomycin/Gentamicin
Several studies have demonstrated a consistent in vitro synergism between
aminoglycosides and vancomycin.[130]
[131] However, clinical studies do not support the
addition of an aminoglycoside to vancomycin. In a retrospective evaluation of 87
patients with persistent SAB, 48 of whom had MRSA infection, those treated with an
aminoglycoside had lower incidence of recurrence within 6 months, but there was no
significant association with mortality or other outcomes.[132] In analyzing data from the daptomycin registrational RCT,[5] Cosgrove et al found that 27/122 (22%) of patients who
received initial low-dose gentamicin therapy (in combination with either nafcillin
or
vancomycin) experienced a clinically significant decline in renal function, compared
with 8/100 (8%) of those who did not receive gentamicin.[133] Based on these clinical studies, the IDSA recommends that gentamicin
should not be added to vancomycin for the treatment of MRSA bacteremia or native valve
endocarditis.[4]
Daptomycin/Gentamicin
The combination of daptomycin with gentamicin has been tested in vitro with varying
results; synergy has been demonstrated in some studies,[70]
[134]
[135]
[136] but not in others.[25]
[125]
[126]
[137]
[138]
[139]
[140] Unfortunately, a RCT comparing daptomycin to
daptomycin combined with gentamicin was terminated early after recruiting only 24
patients (Clinical trials NCT00638157). Thus, the combination of daptomycin with
gentamicin cannot be recommended at this stage.
Other Combinations
Daptomycin-nonsusceptible S. aureus (DNS) not infrequently emerges during
daptomycin therapy.[5]
[141] Among agents tested in combination with daptomycin,
trimethoprim–sulfamethoxazole has shown promise in a PK/PD model for the treatment
of
DNS.[36]
[142] Although clinical experience is currently
limited[143]
[144] for DNS infections that are refractory to standard
treatment, the combination with trimethoprim–sulfamethoxazole should be considered.
In vitro studies have determined that subinhibitory concentrations of clindamycin,
linezolid, and rifampin can block production of toxins such as Panton–Valentine leukocidin
and α-toxin by S. aureus.[145]
[146]
[147] Clinical experience of the use of these agents in
severe toxin-mediated staphylococcal infections (e.g., toxic shock syndrome or necrotizing
pneumonia) is limited.[148] Two retrospective studies
suggest that there may be a clinical benefit for suppression of toxins in such cases.[149]
[150] Treatment guidelines from the United Kingdom and
France recommend that antitoxin therapy be instituted where toxin-mediated staphylococcal
disease is suspected or apparent[151]
[152] and in the absence of robust evidence for the
treatment of these life-threatening infections, these recommendations are clearly
sensible.
Studies of combination therapy for MRSA involving novel antibiotics are also beginning
to
emerge. In a small number of clinical MRSA isolates tested in vitro (five VISA and
five
hVISA), oritavancin (a novel lipoglycopeptide antibiotic) appears to be synergistic
when
used in combination with either gentamicin, linezolid or rifampin,[153] as does telavancin (a second novel lipoglycopeptide
antibiotic), when used with gentamicin, ceftriaxone, rifampin, or meropenem.[154] Since only these two drugs became Food and Drug
Administration approved in 2014, and are not approved for treatment of MRSA bacteremia,
clinical experience is limited and the implications of these in vitro studies are
unclear
at this stage. Despite its lack of activity as a single agent against MRSA, fosfomycin
appears to be synergistic with linezolid against clinical MRSA isolates in an in vitro
model[155] mirroring the β-lactam concept, where a
seemingly inactive agent makes an important contribution when combined with an active
agent.
Conclusion
Because of the limitations of vancomycin, the standard therapy for serious MRSA infections,
many combinations of antibiotics have been tested, primarily in in vitro models.
Unfortunately, studies of the majority of these combinations have reported mixed or
negative
data. However, several β-lactam antibiotics have consistently been shown to be synergistic
for the majority of MRSA strains (including hVISA and daptomycin nonsusceptible strains),
when combined with either vancomycin or daptomycin. Although these combinations appear
promising, limited clinical data are available, and clinical trials are only just
beginning
to be performed. Currently, there is insufficient evidence to recommend any combination
therapy for serious MRSA infections in actual patient care.
