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Current Treatment Options for Community-AcquiredMethicillin-Resistant
Staphylococcus aureus Infection
Robert C. Moellering, Jr.
Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
During the past decade, there has been a marked increase in the prevalence of community-acquired methicillin-
resistant Staphylococcus aureus infection in the United States and elsewhere. The most common such infections
are those involving the skin and skin structures. Although a number of these lesions (including small furuncles
and abscesses) respond well to surgical incision and drainage, oral antimicrobial agents are commonly used
to treat these infections in outpatients. Unfortunately, with the exception of linezolid, none of the agents
presently being used in this fashion has been subjected to rigorous clinical trial. Thus, current therapy is
based largely on anecdotal evidence. For more-serious infections requiring hospitalization, parenteral anti-
microbials such as vancomycin, teicoplanin, daptomycin, linezolid, and tigecycline are presently available and
have demonstrated effectiveness in randomized, prospective, double-blind trials.
Although occasional infections due to community-
acute problem in the United States, where 1 clone
acquired (or community-associated [CA]) methicillin-
(USA300) has achieved predominance and, over the
resistant
Staphylococcus aureus (MRSA) have been re-
course of ∼5 years, has spread throughout the country.
ported for a number of years [1], the current epidemic
This organism now comprises 60%–75% of
S. aureus
of CA MRSA infection in the United States and else-
isolates in most areas of the United States where it has
where began in the late 1990s, when 4 fatal cases of CA
been sought [7, 8]. USA300 and related Panton-Val-
MRSA infection in Native American children were re-
entine leukocidin–containing clones, such as USA400,
ported in the United States [2, 3]. In nearly the same
USA500, USA1000, and USA1110, are capable of caus-
time frame, CA MRSA infections were reported in a
ing a variety of very serious infections, including nec-
number of other parts of the world, including Australia,
rotizing fasciitis, pyomyositis, septic thrombophlebitis
Switzerland, France, the United Kingdom, New Zea-
of the extremities, the "pelvic syndrome" (septic ar-
land, Finland, Canada, and Samoa [4]. The majority
thritis of the hips, pelvic osteomyelitis, pelvic abscesses,and septic thrombophlebitis in children), Waterhouse-
(but not all) of the isolates causing these infections
Friderichsen syndrome, rapidly progressive pneumonia,
contain genes encoding the Panton-Valentine leukoci-
and ocular infections [2, 5]. Nonetheless, the majority
din and possess unique cassettes containing the
mecA
of infections currently caused by these organisms are
gene, which is associated with methicillin resistance
relatively minor, purulent and/or pustular skin and
(
mecIV or, less commonly,
mecV or
mecVI) [5, 6]. Al-
soft-tissue infections [9]. Until the advent of CA MRSA
though infections due to CA MRSA have occurred
infection,
S. aureus infections in the United States were
throughout the world, they have become a particularly
routinely treated with oral antistaphylococcal penicil-lins, such as dicloxacillin, or cephalosporins, such ascephalexin or cefadroxil [10, 11]. Alternative anti-
Received 15 October 2007; accepted 8 December 2007; electronically published
29 February 2008.
microbial drugs were rarely used and were even less
Reprints or correspondence: Dr. Robert C. Moellering, Jr., Dept. of Medicine,
frequently subjected to rigorous clinical evaluation.
Beth Israel Deaconess Medical Ctr., 110 Francis St., Ste. 6A, Boston, MA 02215(
[email protected]).
Nonetheless, a variety of oral agents, such as trimeth-
Clinical Infectious Diseases
oprim-sulfamethoxazole (TMP-SMX), clindamycin,
2008 by the Infectious Diseases Society of America. All rights reserved.
doxycycline (and less commonly minocycline), line-
zolid, rifampin, and occasionally, fluoroquinolones,
1032 •
CID 2008:46 (1 April) • Moellering
Oral antimicrobial agents for treatment of community-acquired methicillin-
resistant Staphylococcus aureus infection.
1–2 double-strength tablets (160/800 mg) every 12 h
100 mg every 12 h
100 mg every 12 h
300–600 mg every 6-8 h (pediatric dosage, 2–8 mg/
400–600 mg every 12 h
Fusidic acid (usually given in
combination with rifampin)
have been used by clinicians in the United States for these
are no randomized, prospective trials of the agents most com-
infections. In Australia, the United Kingdom, and several other
monly used to treat skin and soft-tissue infection due to CA
countries, fusidic acid (usually in combination with rifampin
MRSA; thus, we are forced to rely solely on anecdotal evidence.
to prevent the emergence of resistance) has also been used in
This may soon change, however. The National Institutes of
the outpatient setting. A newly released topical agent, retapa-
Health has recently funded 2 clinical trials in the United States
mulin, has been approved for minor skin infections, such as
that will provide data on the effectiveness of oral antimicrobial
impetigo, but has not been approved for MRSA and will not
agents for skin and soft-tissue infections due to CA MRSA in
be further discussed here [12]. For more-serious infections re-
adults and children [15]. Unfortunately, it will likely be several
quiring hospitalization, a variety of parenteral agents are avail-
years before the results of these studies are available.
able, including vancomycin (and outside the United States,
At present, in the United States, TMP-SMX and clindamycin
teicoplanin), daptomycin, linezolid, and tigecycline (table 1 and
are the most commonly used antimicrobial drugs for the out-
patient treatment of CA MRSA infections. Fusidic acid plus
Providing definitive recommendations for antimicrobial
rifampin combination therapy is frequently used in other parts
therapy of skin and soft-tissue infections due to CA MRSA is
of the world. It appears that TMP-SMX is the agent primarily
problematic for several reasons. First, many of these infections
preferred for the therapy of adults in the United States, and
(especially furuncles, pustules, and small abscesses) will likely
clindamycin is favored by many pediatricians [2].
respond favorably to effective surgical incision and drainage
The use of TMP-SMX to treat CA MRSA infections is pri-
and may not even require antimicrobial therapy. Evidence in
marily based on a 1992 study by Markowitz et al. [16], which
support of this can be gleaned from a recent study of CA MRSA
was a randomized, nonblinded trial involving 101 injection
infections seen in emergency departments across the United
drug users with
S. aureus infections (47% of the infections were
States [7]. Because the majority of patients in this study un-
due to MRSA, and 65% were bacteremic). Intravenous TMP-
derwent surgical incision and drainage of their lesions, the
SMX therapy was compared with vancomycin therapy. Infec-
authors concluded that it was impossible to draw strong con-
tions were cured in 57 of 58 vancomycin recipients and in 37
clusions concerning the relative efficacy of antimicrobial ther-
of 43 TMP-SMX recipients (
P ! .02). Interestingly, all of the
apy. In another study from San Francisco, patients with CA
treatment failures occurred in patients with methicillin-suscep-
MRSA skin and soft-tissue infections were randomized to re-
tible strains of
S. aureus (MSSA), and the authors concluded
ceive cephalexin or placebo after undergoing incision and
very conservatively that "vancomycin is superior to TMP-SMX
drainage (essentially a double-placebo study) [13]. The patients
in efficacy and safety when treating intravenous drug users who
in this study did well, and in fact, placebo was slightly betterthan cephalexin therapy, strongly supporting the value of ap-
Parenteral agents for the treatment of community-
propriate incision and drainage in treating these infections. In
acquired methicillin-resistant Staphylococcus aureus infection.
essence, this was a double-placebo study, because all of theinfections were caused by MRSA, against which cephalexin
therapy should not be effective. When the lesions are large, are
1 g intravenously every 12 h
surrounded by cellulitis, or do not involve drainable foci and
4 mg/kg intravenously every 24 h
occur in patients with fever or other systemic symptoms, most
600 mg intravenously every 12 h
100 mg intravenously once, then 50
clinicians treat with antimicrobial drugs, even in the absence
mg intravenously every 12 h
of controlled trials defining benefit [14]. Unfortunately, there
Therapy for CA MRSA Infection •
CID 2008:46 (1 April) • 1033
have staphylococcal infections. However, all treatment failures
areas where the prevalence of clindamycin resistance is low,
occurred in patients with MSSA infections at any site. There-
however, susceptibility to clindamycin does not always predict
fore, TMP-SMX may be considered as an alternative to van-
outcome. Organisms that exhibit resistance to erythromycin
comycin in selected cases of MRSA infection" [16, p. 390]. In
and susceptibility to clindamycin (which accounted for almost
vitro evidence supporting the use of TMP-SMX to treat MRSA
80% of the USA300 isolates in a recent study in San Francisco
infections may be gleaned from a recent study in which TMP-
[21]) may exhibit resistance either because of efflux (in which
SMX exhibited greater bactericidal activity against MRSA than
case they remain clinically susceptible to clindamycin) or via
did linezolid, rifampicin, clindamycin, or minocycline [17]. In-
the inducible expression of the MLS gene, which methylates
terestingly, adding rifampicin to the TMP-SMX regimen
the binding site for erythromycin and clindamycin and renders
showed a trend toward antagonism in vitro [17]. As already
the organism resistant. Because clindamycin does not induce
noted, there are no randomized, prospective trials to define the
the production of the methylase, these organisms will be found
effectiveness of TMP-SMX therapy for CA MRSA infections.
to be susceptible by clinical microbiology laboratory testing,
However, a recent retrospective chart review of skin and soft-
unless a specific test, such as the double-disk D-test, is used to
tissue infections seen during the period 1998–2005 at the Fen-
detect this type of inducible resistance [23]. The clinical sig-
way Community Health Center in Boston, Massachusetts, con-
nificance of this finding is that a single-step mutation can con-
cluded that empirical therapy of CA MRSA infections treated
vert these organisms to clindamycin resistance. There are nu-
with TMP-SMX was associated with a favorable response, com-
merous anecdotal reports of clinical failure of clindamycin
pared with therapy with agents to which the organisms were
because of the emergence of such resistance during treatment
resistant (OR, 5.91), when controlled for incision and drainage
[24–27]. Unfortunately, the frequency with which this occurs
and HIV infection status [18]. A small randomized, prospective
is not known, but it is probably relatively low. Thus, it is likely
study of TMP-SMX (160/800 mg twice daily) versus doxycy-
that most patients infected with organisms that are found to
cline (100 mg twice daily) resulted in 3 clinical failures in 14
be susceptible to clindamycin by laboratory testing will respond
patients treated with TMP-SMX. There were no treatment fail-
favorably to the drug. Nonetheless, to be certain of therapeutic
ures in the small (20-patient) doxycycline treatment arm [19].
outcome, it is prudent to test for inducible resistance (in or-
A potential drawback of using TMP-SMX alone for the treat-
ganisms that are resistant to erythromycin) using the afore-
ment of skin and soft-tissue infections in the absence of avail-
mentioned D-test.
able cultures is that the efficacy of TMP-SMX for infections
Another potential advantage of clindamycin (and of linezolid
due to group A streptococci is probably less than optimal,
and fusidic acid) is that it suppresses production of Panton-
although this has not been rigorously studied in the context of
Valentine leukocidin and other virulence factors in MRSA. In-
skin and skin-structure infections. Another issue regarding the
terestingly, subinhibitory concentrations of oxacillin or nafcillin
use of TMP-SMX in this context relates to the appropriate
actually increase production of these toxins [28, 29].
dosage. Most clinicians have used a dosage of 2 double-strength
The long-acting tetracyclines (minocycline and doxycycline)
TMP-SMX tablets twice daily, although this has not been uni-
were used extensively in Japan for the treatment of MRSA
versally used, and it has not been definitely proven that 2 dou-
infections before the availability of vancomycin there. Until
ble-strength TMP-SMX tablets twice daily is superior to 1 dou-
recently, however, they have not been used as frequently in the
ble-strength tablet twice daily. Interestingly, in the study by
United States for that purpose. Ruhe et al. [30] published a
Cenizal et al. [19] that was quoted above, the treatment failures
small retrospective record review of 24 patients with tetracy-
occurred when patients received lower dosages (1 double-
cline-susceptible MRSA infections treated with long-acting tet-
strength tablet twice daily) of TMP-SMX.
racyclines and noted a clinical cure rate of 83% among those
Clindamycin has been widely used by pediatricians for ther-
patients. In an accompanying literature review, the authors
apy of skin and soft-tissue infections, including those due to
found 73 additional patients in 9 studies who were treated for
CA MRSA [2]. Although there are no randomized, prospective,
MRSA infections with long-acting tetracyclines. In general, the
controlled trials of the use of clindamycin therapy for CA MRSA
response rates in these studies varied from 80% to 100%. An-
infections, available anecdotal experience suggests that it is
other small, recently published, prospective trial suggested a
likely to be effective, provided that the organism is susceptible
response rate of 100% among 20 patients treated with doxy-
in vitro [2]. Currently, the prevalence of clindamycin resistance
cycline after incision and drainage of their abscesses due to
among CA MRSA in the United States varies considerably by
MRSA infection [19]. Finally, Ruhe et al. [31] published a ret-
geographic location [20–22]. In San Francisco, the prevalence
rospective cohort study involving 276 patients who had 282
of clindamycin resistance has been !12% to date [21]. In Bos-
episodes of MRSA skin and soft-tissue infections and who pre-
ton, however, a recent study has revealed that 49%–76% of CA
sented to the emergency department or outpatient clinic at 2
MRSA isolates are clindamycin resistant [22]. Even in those
tertiary medical centers in Arkansas from October 2002 through
1034 •
CID 2008:46 (1 April) • Moellering
February 2007. Treatment failure occurred in only 4 of 90 pa-
been approved for the treatment of bacteremia and right-sided
tients treated with tetracyclines but was seen in 24 of 192 pa-
endocarditis due to
S. aureus (including MRSA) on the basis
tients treated with b-lactam antimicrobials (
P p .035). The ma-
of a study that revealed that daptomycin therapy was nonin-
jority of patients in this study had abscesses that were surgically
ferior to vancomycin therapy for this indication [38]. In the
drained, and this undoubtedly explains the high cure rate as-
subgroup of patients with MRSA infections, daptomycin ther-
sociated with long-acting tetracycline therapy and the fact that
apy was numerically but not statistically significantly superior
a high percentage of these patients appeared to respond to
to vancomycin therapy. Daptomycin has not been studied ex-
inappropriate (b-lactam) therapy.
tensively for infections due to CA MRSA. It should be noted,
Although the initial isolates of CA MRSA from the United
however, that MRSA strains with heteroresistance to vanco-
States were almost universally susceptible to the tetracyclines
mycin may exhibit heteroresistance to daptomycin (clinical sig-
[9], several recent studies have documented increasing resis-
nificance has not been fully determined to date), even when
tance to the tetracyclines among USA300 strains in San Fran-
the MRSA strains have never been exposed to daptomycin [39].
cisco and Boston [21, 22]. If this trend continues, it will likely
Linezolid has clearly been demonstrated to be effective for
have a significant impact on the effectiveness of the long-acting
the treatment of MRSA infections on the basis of controlled,
tetracyclines for the treatment of CA MRSA infections.
clinical trials and may be superior to vancomycin for the treat-
Rifampicin has excellent in vitro activity against CA MRSA
ment of complicated skin infections due to MRSA [40]. Al-
infections but cannot be used as a single agent to treat such
though resistance to linezolid in MRSA has been described, this
infections because of the rapid emergence of resistance that
has not been a significant clinical problem to date [41].
occurs even during therapy [32]. Combinations of rifampin
Tigecycline is the fourth parenteral drug available for the
and TMP-SMX have been shown to exhibit in vitro antagonism
treatment of serious MRSA infections. In controlled clinical
[17]. There are no published studies demonstrating the benefit
trials, it has been shown to be noninferior to vancomycin for
of such combination therapy, but nonetheless, some clinicians
this indication [42, 43]. Nonetheless, the number of patients
have added rifampin to TMP-SMX or long-acting tetracycline
with MRSA infections in studies to date are relatively limited.
regimens. Rifampin is also commonly used with fusidic acid
Because these 3 agents have not been tested against one
to prevent mutual emergence of resistance during therapy. Li-
another in controlled trials, their relative efficacies are not
nezolid is the only orally available agent for which efficacy
known. However, some preliminary observations may be useful
against MRSA infection has been demonstrated in controlled
in guiding their application for particularly severe infections
trials [33]. This drug has excellent activity against infections
due to CA MRSA. For serious skin and skin-structure infec-
due to group A streptococci and has also demonstrated efficacy
tions, such as necrotizing fasciitis, linezolid may be particularly
for diabetic foot infections [34]. Because it is a relatively ex-
useful because of its ability to impair toxin production [28].
pensive drug, however, the use of linezolid for treating out-
The addition of clindamycin to a vancomycin regimen for this
patients has been limited thus far.
purpose is also reasonable. The same rationale leads to the
The agents currently available for parenteral therapy of se-
consideration of the use of linezolid for the treatment of pneu-
rious CA MRSA infections are listed in table 2. These include
monia due to CA MRSA. It should be noted, however, that,
vancomycin (or teicoplanin), daptomycin, linezolid, and tige-
although linezolid has been shown to be noninferior (and pos-
cycline. Vancomycin (or teicoplanin, in countries where it isavailable) remains the gold standard of therapy for serious
sibly superior) to vancomycin for the treatment of hospital-
MRSA infections. That standard, however, is now tarnished by
associated pneumonia and ventilator-associated pneumonia
decreasing efficacy because of increasing resistance among
due to MRSA, there are no published data supporting its use
MRSA strains [35, 36]. Unfortunately, this resistance is not
for CA pneumonia [44]. Daptomycin is inactivated by pul-
easily demonstrable by clinical microbiology laboratory testing,
monary surfactant and should not be used for CA pneumonia
because many of the strains that fail to respond to therapy with
due to CA MRSA [45].
vancomycin exhibit a heteroresistance phenomenon, which re-
As noted above, a number of parenteral agents are available
quires special methodology for detection [37]. A detailed dis-
for the treatment of serious infections due to CA MRSA. The
cussion of mechanisms associated with the diminishing efficacy
efficacy of daptomycin, linezolid, and tigecycline for MRSA
of vancomycin therapy for MRSA infections is beyond the scope
infections has been demonstrated in prospective, controlled
of this paper, but such mechanisms are reviewed in detail in
clinical trials. Unfortunately, with the exception of linezolid,
articles by Sakoulas and Moellering [35] and Tenover and
no such data are available for the oral agents that are currently
Moellering [36].
widely used for the therapy of CA MRSA infections in out-
Daptomycin is a new lipoglycopeptide antimicrobial drug
patients. It is hoped that 2 trials being initiated under National
that is rapidly bactericidal for MRSA infection. It has recently
Institutes of Health sponsorship will provide much needed data
Therapy for CA MRSA Infection •
CID 2008:46 (1 April) • 1035
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Potential conflicts of interest.
R.C.M. has served as a consultant to
Agents Chemother
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Pfizer, Cubist, and Wyeth.
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Additional services for Medical History: Making Sense of the ‘Chemical Revolution'. Patients' Voices on the Introduction ofNeuroleptics in the 1950s Medical History / Volume 60 / Issue 01 / January 2016, pp 54 - 66DOI: 10.1017/mdh.2015.68, Published online: 10 December 2015 Link to this article: How to cite this article:Benoît Majerus (2016). Making Sense of the ‘Chemical Revolution'. Patients' Voices on theIntroduction of Neuroleptics in the 1950s. Medical History, 60, pp 54-66 doi:10.1017/mdh.2015.68
Benefits of Exercise in the Workplace: Ryan Henderson 32 BENEFITS OF EXERCISE IN THE WORKPLACE The general idea of this study is about the benefits that exercise has in the workplace, primarily a manual labor workplace such as construction. Heavy research has been done on this topic along with experimentation. The study shows why it is important for an organization or