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Reprints or correspondence: Dr. Scott T. Micek, Dept. of Pharmacy, BarnesJewish Hospital, Mailstop 90-52-411, 216 S. Kingshighway Blvd., St. Louis, MO
(stm8241@bjc.org).
Clinical Infectious Diseases 2007; 45:S18490
2007 by the Infectious Diseases Society of America. All rights reserved.
1058-4838/2007/4506S3-0005$15.00
DOI: 10.1086/519471
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 vancomycins 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 45 the MIC value)
may not offer an advantage over traditional dosing
strategies [8, 9]. A follow-up, randomized, double-blind
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.
Figure 1. Molecular structures of novel antibiotics for methicillin-resistant Staphylococcus aureus infections
SSTIs (546 patients [0 with documented MRSA and 8 with presumed MRSA])
Infection treated
(no. of patients in study)
DPT
TIG
LZD
Efficacy
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).
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 714 days); Clinical success rate (all evaluable patients): DPT,
comparators (results pooled) in83%; comparators, 84%. Clinical success rate
d
cluded PRPs (412 g/day iv) or VM
(patients with MRSA): DPT, 75%; comparators,
(1 g iv q12h)
68%.
LZD (600 mg q12h) or VM (1 g q12h); Clinical cure rate: LZD, 59% (36 of 61 patients);
both plus ATN for 712 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).
S186
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%
There were few serious treatment-related adverse events, the incidences of which were
similar between treatment groups
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
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)
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)
DBV
S187
DAPTOMYCIN
Daptomycin is a cyclic lipopeptide that causes depolarization
of the bacterial cell membrane. The indicated dose for MRSA-
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 (610 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 79 h, which allows
once-daily dosing (7.510 mg/kg/day). The disruption of
membrane barrier function translates to rapid bactericidal ac-
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 24 times the MIC, in an
effort to optimize efficacy in the treatment of MRSA infections.
Given a tigecycline MIC90 range of 0.250.5 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.
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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