1. health and fitness
2. disease

SUPPLEMENT ARTICLE
Alternatives to Vancomycin for the Treatment of
Methicillin-Resistant Staphylococcus aureus Infections
Scott T. Micek
Department of Pharmacy, Barnes-Jewish Hospital, St. Louis, Missouri
Vancomycin has been considered to be the reference
standard for the treatment of invasive methicillin-resistant Staphylococcus aureus (MRSA) infections, as a
result of its relatively clean safety profile, its durability
against the development of resistance, and, for many
years, the lack of other approved alternatives. However,
the advent and testing of new compounds with antiMRSA activity, for comparison with vancomycin, have
rendered results that call into question the efficacy of
vancomycin in the treatment of many serious infections. The reasons for clinical failure of vancomycin are
many and have been hypothesized to include poor penetration of the drug to certain tissues [1–3], loss of
accessory gene–regulator function in MRSA [4], and
potential escalation of vancomycin MICs for MRSA [5].
Additionally, an increasing number of reports of vancomycin-intermediate S. aureus (VISA) and vancomycin-resistant S. aureus (VRSA) have populated the
literature dating back to 1999. Many alternatives for
the treatment of MRSA infections, including linezolid,
daptomycin, tigecycline, and quinupristin/dalfopristin,
Reprints or correspondence: Dr. Scott T. Micek, Dept. of Pharmacy, BarnesJewish Hospital, Mailstop 90-52-411, 216 S. Kingshighway Blvd., St. Louis, MO
([email protected]).
Clinical Infectious Diseases 2007; 45:S184–90
2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4506S3-0005$15.00
DOI: 10.1086/519471
S184 • CID 2007:45 (Suppl 3) • Micek
are currently approved by the US Food and Drug Administration (FDA). Additionally, there are several investigational compounds with demonstrated in vitro
activity against MRSA. The chemical structures of these
agents are shown in figure 1.
LINEZOLID
Linezolid is a synthetic oxazolidinone that inhibits the
initiation of protein synthesis at the 50S ribosome [6].
It is currently approved by the FDA for the treatment
of complicated skin and skin-structure infections
(SSSIs) and nosocomial pneumonia caused by susceptible pathogens, including MRSA. Several retrospective
analyses of pooled data from randomized trials have
compared linezolid with vancomycin in patients with
proven MRSA infection. An analysis of 2 double-blind
studies of patients with MRSA nosocomial pneumonia
found that 75 patients treated with linezolid had survival rates that were significantly higher than those of
85 patients treated with vancomycin (80% vs. 64%;
P p .03) [7]. The authors hypothesized that a possible
explanation for the finding was vancomycin’s poor penetration of the lung, particularly when the standard
dosage is 1 g administered every 12 h. However, aggressive dosing strategies for vancomycin (goal trough
concentrations of 115 mg/mL, or 4⫺5⫻ the MIC value)
may not offer an advantage over traditional dosing
strategies [8, 9]. A follow-up, randomized, double-blind
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Vancomycin remains the reference standard for the treatment of systemic infection caused by methicillinresistant Staphylococcus aureus (MRSA). However, as a result of limited tissue distribution, as well as the
emergence of isolates with reduced susceptibility and in vitro resistance to vancomycin, the need for alternative
therapies that target MRSA has become apparent. New treatment options for invasive MRSA infections include
linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin. Additionally, a number of new anti-MRSA
compounds are in development, including novel glycopeptides (dalbavancin, telavancin, and oritavancin),
ceftobiprole, and iclaprim. The present article will review clinical issues surrounding the newly marketed and
investigational agents with activity against MRSA.
trial is under way that compares these 2 agents in hospitalized
patients with nosocomial pneumonia due to MRSA. Similarly,
retrospective evaluations of complicated skin and soft-tissue
infections (SSTIs) caused by MRSA have found that, compared
with vancomycin, linezolid is associated with significantly
higher clinical cure rates and reduced lengths of hospitalization
[6, 10]. A retrospective analysis of pooled data from 5 randomized studies did not find linezolid to be superior to vancomycin in patients with secondary MRSA bacteremia [11].
Linezolid should also be considered for necrotizing infections, including skin lesions [12], fasciitis [13], and pneumonia
[14] caused by community-associated MRSA, particularly the
USA300 strain. The severity of these infections may be associated with allotypes of mobile genetic elements found in
USA300 that code for pathogenic toxins, including PantonValentine leukocidin, enterotoxin Q, and enterotoxin K [15].
It has been hypothesized that antibiotics with the ability to
inhibit protein synthesis may demonstrate efficacy against susceptible toxin-producing strains. Linezolid, along with clindamycin, has recently been found to reduce production of
Panton-Valentine leukocidin, a-hemolysin, and toxic-shock
syndrome toxin–1, whereas vancomycin and nafcillin have been
found to increase such production in an in vitro model [16].
Despite the apparent advantages of linezolid in the treatment of MRSA infections, concerns about safety often limit
its use. Of particular concern is the association of linezolid
with serotonin toxicity and thrombocytopenia [17, 18]. Linezolid exhibits weak reversible inhibition of monoamine
oxidase and can induce toxicity when used in combination
with agents that have serotonergic activity, most commonly
selective serotonin reuptake inhibitors. Twenty-nine cases of
linezolid-associated serotonin toxicity were recently reported.
Postmarketing information submitted to the FDA regarding
29 patients with serotonin toxicity showed that 61% had received concomitant treatment with a selective serotonin reuptake inhibitor [17]. Three patients died, possibly because of
serotonin toxicity, and another 13 patients required medical
treatment [13]. Linezolid used concomitantly with selective
serotonin reuptake inhibitors in hospitalized patients has also
been evaluated in a retrospective study [19]. This study found
a high probability of serotonin toxicity in association with 2
of 72 concomitant uses. The authors suggest that linezolid
Novel Antibiotics for MRSA • CID 2007:45 (Suppl 3) • S185
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Figure 1. Molecular structures of novel antibiotics for methicillin-resistant Staphylococcus aureus infections
SSTIs (899 patients [87 patients with
MRSA])
Bacteremia and endocarditis (246 patients [89 patients with MRSA])
Fowler et al. [29]
SSTIs (546 patients [0 with documented MRSA and 8 with presumed MRSA])
Bacteremia (53 patients with MRSA)
b
SSTIs (285 patients with MRSA)
Nosocomial pneumonia (160 patients
with MRSA)
Infection treated
(no. of patients in study)
Arbeit et al. [28]
DPT
Breedt et al. [25]
TIG
Shorr et al. [11]
Wiegelt et al. [6]
Wunderink et al. [7]
LZD
Drug, authors [reference]
Efficacy
The rate of adverse events was similar between
treatment groups (LZD, 80%; VM, 70%), as
c
were the rate of serious adverse events (LZD,
47%; VM, 39%) and the rate of treatment discontinuation (LZD, 37%; VM, 39%); all differences were NS
Adverse events similar between 2 groups, but
there were increased rates of nausea and
vomiting in the TIG group and higher rates of
rash and increases in LFT results in the VM/
ATN group
Clinical cure rate: LZD, 56% (14 of 25 patients);
VM, 46% (13 of 28 patients); OR, 1.47 (95%
CI, 0.50–4.34)
Clinical response rate: TIG, 84%; VM/ATN, 87%
(P p NS). Pathogen eradication rate: TIG,
85%; VM/ATN, 93% (P p .02).
DPT (6 mg/kg iv q24h); OR VM (1 g
d
q12h) or PRPs (2 g q4h) plus GM
(1 mg/kg iv q8h)
Clinical success rate at day 42 of treatment: DPT, Overall incidence of adverse events was similar
44%; comparators, 42%. Clinical success rate
between treatment groups. Rate of serious ade
(patients with MRSA): DPT, 44%; comparators,
verse events: DPT, 52%; comparators, 45%.
Increases in creatine kinase levels were more
32%.
common in the DPT group (7% vs. 1%) (P p
.04).
Frequency and distribution of adverse events
were similar between treatment groups
Drug-related adverse events were reported in
similar numbers of patients in both treatment
a
arms
Not reported
Safety
Clinical cure rate: LZD, 89% (124 of 140 patients); VM, 67% (97 of 145 patients) (P !
.001)
DPT (4 mg/kg iv q24h for 7–14 days); Clinical success rate (all evaluable patients): DPT,
comparators (results pooled) in83%; comparators, 84%. Clinical success rate
d
cluded PRPs (4–12 g/day iv) or VM
(patients with MRSA): DPT, 75%; comparators,
(1 g iv q12h)
68%.
TIG (100 mg/day, with an initial 100mg loading dose); VM (1 g q12h)
plus ATN (2 g q12h)
LZD (600 mg) or VM (1 g each q12h);
ATN is added in studies of
pneumonia
LZD (600 mg iv or po q12h) or VM
(1 g q12h)
LZD (600 mg q12h) or VM (1 g q12h); Clinical cure rate: LZD, 59% (36 of 61 patients);
both plus ATN for 7–12 days
VM, 36% (22 of 62 patients) (P ! .01). Survival
rate: LZD, 80% (60 of 75 patients); VM, 64%
(54 of 85 patients) (P p .03).
Regimen
Table 1. Overview of novel antimicrobial agents available to treat methicillin-resistant Staphylococcus aureus (MRSA).
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S186
TLV (7.5 mg/kg/day iv); standard therapy: VM (1 g q12h), NAF or OX (2
g q6h), and Clox (0.5–1 g q6h)
SSTIs due to gram-positive pathogens CTB (500 mg q12h); VM (1 g q12h)
(784 patients [125% with MRSA])
f
Clinical cure rate: CTB, 93%; VM, 93%. MRSA
clinical response rate: CTB, 92%; VM, 90%.
Overall test-of-cure rate: TLV, 80%; standard therapy, 77%. MRSA test-of-cure rate: TLV, 82%;
standard therapy, 69%. MRSA microbiological
eradication rate: TLV, 84%; standard therapy,
74%
Overall success rate: DBV, 87%; VM, 73%
Clinical efficacy at test-of-cure: DBV, 89%; LZD,
91%
There were few serious treatment-related adverse events, the incidences of which were
similar between treatment groups
Fewer serious adverse events were noted with
TLV; the most common adverse events were
similar between treatment groups and included
nausea, psychiatric disorder, headache, vomiting, and dyspnea
Adverse events were generally mild and were
comparable in the 2 treatment groups
Adverse events involving the GI tract were the
most common adverse events in both treatment groups; a higher proportion of patients
receiving LZD had adverse events that were
judged by investigators to be treatment related
f
e
d
c
b
a
Diarrhea, nausea, and thrombocytopenia were most commonly associated with LZD, and anemia, nausea, and pruritus were most commonly associated with VM.
Pooled analysis of results from 5 studies.
Details regarding the nature of the serious adverse events are not available. Investigators assessed each event as serious or not serious.
Clox, flucloxacillin, NAF, and OX.
Serious adverse events included infections and infestations, cardiac disorders, respiratory, thoracic, and mediastinal disorders, nervous system disorders, psychiatric disorders, and laboratory abnormalities.
Phase 2 study.
NOTE. ATN; aztreonam; Clox, cloxacillin; CR-BSIs, catheter-related bloodstream infections; CTB, ceftobiprole; DBV, dalbavancin; DPT, daptomycin; GI, gastrointestinal; GM, gentamicin; iv, intravenously; LFT,
liver function test; LZD, linezolid; MRSA, methicillin-resistant Staphylococcus aureus; NAF, nafcillin; NS, not significant; OX, oxacillin; po, by mouth; PRPs, penicillinase-resistant penicillins; q4h, every 4 h; q6h, every
6 h; q8h, every 8 h; q12h, every 12 h; q24h, every 24 h; SSTIs, skin and soft-tissue infections; TIG, tigecycline; TLV, telavancin; VM, vancomycin.
Basilea Pharmaceutica
[33]
CTB
Stryjewski et al. [32]
SSTIs (167 patients [48 patients with
MRSA])
CR-BSIs (75 patients [14 patients with DBV (1000 mg on day 1, followed by
MRSA])
500 mg iv on day 8); VM (1 g q12h
for 14 days)
Raad et al. [31]
TLV
SSTIs (660 patients [287 patients with DBV (1000 mg on day 1, followed by
MRSA])
500 mg iv on day 8); LZD (600 mg
iv or po q12h for 14 days)
Jauregui et al. [30]
DBV
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S187
may be used concomitantly with selective serotonin reuptake
inhibitors, with careful monitoring, and they recommend
prompt discontinuation of the serotonergic agent if serotonin
syndrome is suspected [19]. The occurrence of thrombocytopenia has proven to be not significantly different than that
encountered in patients with nosocomial pneumonia or orthopedic infections. Of note, patients with renal insufficiency
may be at higher risk of developing this toxicity [20, 21].
Finally, there have been sporadic reports of peripheral neuropathy, typically in patients with osteomyelitis or other underlying diseases, and lactic acidosis [22, 23].
TIGECYCLINE
DAPTOMYCIN
Daptomycin is a cyclic lipopeptide that causes depolarization
of the bacterial cell membrane. The indicated dose for MRSA-
S188 • CID 2007:45 (Suppl 3) • Micek
GLYCOPEPTIDES
Dalbavancin. Dalbavancin is a semisynthetic lipoglycopeptide that inhibits cell wall synthesis and has in vitro activity
against MRSA [34]. The unique feature of this investigational
agent is its long half-life (6–10 days), which allows for onceweekly dosing. In a randomized, double-blind trial, dalbavancin
(1000 mg given intravenously on day 1 and 500 mg given
intravenously on day 8) has been compared with linezolid in
the treatment of SSSIs [30]. Overall clinical success rates are
presented in table 1. In this trial, 51% of the isolates were found
to be MRSA. In a phase 2, open-label study of the treatment
of catheter-related bloodstream infections, once-weekly treatment with dalbavancin was compared with treatment with vancomycin [31]. MRSA was identified at baseline in 5 patients
who received dalbavancin, and, in the overall intention-to-treat
analysis, dalbavancin was found to result in a success rate significantly higher than that noted with vancomycin (87% vs.
50%; P ! .05). The most common adverse events included nausea and diarrhea or constipation; however, dalbavancin may
also be associated with hypotension, hypokalemia, and increases
in alanine aminotransferase and aspartate aminotransferase levels measured in liver function tests, although, to date, the reports of these adverse events are conflicting [34].
Telavancin. Telavancin is another semisynthetic lipoglycopeptide that has a dual mechanism of action, including inhibition of cell wall synthesis and disruption of membrane
barrier function [35]. It has a half-life of 7–9 h, which allows
once-daily dosing (7.5–10 mg/kg/day). The disruption of
membrane barrier function translates to rapid bactericidal ac-
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Tigecycline is the first drug approved in the class of glycylcyclines, a derivative of minocycline. A modified side chain on
tigecycline enhances binding to the 30S ribosomal subunit, inhibiting protein synthesis and bacterial growth across a broad
spectrum of pathogens, including MRSA [24]. In addition, this
structural modification circumvents resistance mechanisms that
plague tetracycline and other antibiotics in this class. Tigecycline is approved in the United States for the treatment of complicated SSSIs due to MRSA. The drug is also approved for the
treatment of complicated intra-abdominal infections but only
for those caused by methicillin-susceptible S. aureus. At this
time, the published experience with tigecycline for the treatment of MRSA infections is limited to 2 double-blind comparison studies of vancomycin and aztreonam in patients with
complicated SSSIs and case reports [25, 26]. Tigecycline has a
large volume of distribution and produces high concentrations
in tissues outside of the bloodstream, including bile, the colon,
and the lung. Conversely, serum concentrations of tigecycline
rapidly decrease after infusion, and the area under the concentration-time curve (AUC) after administration of multiple
50-mg doses every 12 h is ∼3 mg7h/mL [27]. On the basis of
studies of the pharmacodynamic properties of tetracycline, the
target AUC for tigecycline should be 2–4 times the MIC, in an
effort to optimize efficacy in the treatment of MRSA infections.
Given a tigecycline MIC90 range of 0.25–0.5 mg/mL for MRSA,
caution should be used when using tigecycline for the treatment
of patients with suspected or proven bacteremia [27]. The results of further clinical evaluation should be cumulated and
assessed to determine whether to accept or refute this potential
limitation. The approved dose is a 100-mg intravenous loading
dose followed by 50 mg given every 12 h. Nausea and vomiting
are the predominant adverse events, and they increase in frequency with dose escalation.
associated complicated SSTIs is 4 mg/kg once daily, and that
for bloodstream infections, including right-side endocarditis, is
6 mg/kg once daily [28]. Of note, daptomycin should not be
used in the treatment of MRSA pneumonia, because the activity
of the drug is inhibited by pulmonary surfactant. The results
of daptomycin trials in patients with complicated SSTIs and
bacteremia/endocarditis are shown in table 1 [28, 29]. In brief,
of the patients who had MRSA isolated, 20 (44%) of 45 were
successfully treated with daptomycin, and, of the patients in
the bacteremia/endocarditis trial, 14 (32%) of 44 patients were
successfully treated with vancomycin. The difference between
daptomycin and standard therapy in the treatment of MRSA
infections was not statistically significant. Significantly, for 6
patients who experienced microbiological failure while receiving daptomycin, it was reported that, during therapy, the MICs
for the isolated pathogen increased from 0.25 or 0.5 mg/mL to
2 or 4 mg/mL [29]. The mechanism for resistance development
while receiving therapy is, at present, not understood, but it is
likely to be a consequence and a concern in patients who require
prolonged courses of daptomycin therapy.
ylococci are susceptible to ceftaroline [43]. Phase 2 studies of
this agent in patients with SSTIs are under way.
ICLAPRIM
Iclaprim is a diaminopyrimidine that inhibits the enzyme dihydrofolate reductase. Data on iclaprim are limited. However,
it has activity against MRSA, and preliminary results from a
phase 3 trial in patients with complicated SSTIs showed noninferiority of iclaprim to linezolid at the test of cure [44]. In
this study, ∼25% of the infections were due to MRSA.
CONCLUSIONS
Several antibiotics with anti-MRSA activity, including linezolid,
tigecycline, and daptomycin, have been approved by the FDA.
Additionally, there are a number of compounds in development
that will likely provide a broader armamentarium for clinicians
in the management of infections due to MRSA. The emergence
of vancomycin-intermediate and vancomycin-resistant strains
of S. aureus has also created a need for agents with expanded
coverage. The in vitro activity of new and investigational agents
against VISA and VRSA has recently been reviewed elsewhere
[45]. In brief, linezolid, daptomycin, tigecycline, and quinupristin/dalfopristin, as well as the new investigational compounds dalbavancin, telavancin, oritavancin, ceftobiprole, and
iclaprim, have demonstrated in vitro activity against VISA and
VRSA.
CEFTOBIPROLE AND CEFTAROLINE
Ceftobiprole is an investigational cephalosporin engineered to
bind tightly to penicillin-binding protein 2a, a peptidoglycan
transpeptidase that confers b-lactam resistance in S. aureus isolates harboring the mecA gene [40, 41]. This compound is the
first of the b-lactam antibiotics to have activity against MRSA
as well as penicillin-resistant streptococci. Importantly, in preclinical, multipassage resistance-selection studies, ceftobiprole
demonstrated a low potential to select for resistance; the highest
MIC found in the presence of prolonged serial passages with
ceftobiprole at subinhibitory concentrations was 8 mg/mL in 1
of 10 strains after 50 passages [42]. Ceftobiprole is administered
twice daily by the intravenous route and has been granted fasttrack status by the FDA for the indications of complicated SSSIs
and health care–associated pneumonia [41]. Two phase 3 trials
for complicated SSSIs have been completed (STRAUSS and
STRAUSS II), with preliminary results reportedly demonstrating noninferiority of ceftobiprole to comparators overall and
in patients with MRSA [40, 33]. The most common adverse
effects were nausea and taste disturbances.
Ceftaroline is another broad-spectrum cephalosporin with
gram-positive and gram-negative bactericidal activity. Early
testing indicates that MRSA and vancomycin-resistant staph-
Acknowledgments
Supplement sponsorship. This article was published as part of a supplement entitled “Bugging the Bugs: Novel Approaches in the Strategic
Management of Resistant Staphylococcus aureus Infections,” jointly sponsored by the Dannemiller Memorial Educational Foundation and Emeritus
Educational Sciences and supported by an educational grant from OrthoMcNeil, Inc., administered by Ortho-McNeil Janssen Scientific Affairs, LLC.
Potential conflicts of interest. S.T.M. has received research/grant support from Ortho-McNeil.
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