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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
on the efficacy of oral antimicrobial drugs for treating these comes of infections by methicillin-resistant Staphylococcus aureus at an
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19. Cenizal MJ, Skiest D, Luber S, et al. Prospective randomized trial of empiric therapy with trimethoprim-sulfamethoxazole or doxycycline for outpatient skin and soft tissue infections in an area of high prev-alence of methicillin-resistant Staphylococcus aureus. Antimicrob Potential conflicts of interest.
R.C.M. has served as a consultant to Agents Chemother 2007; 51:2628–30.
Pfizer, Cubist, and Wyeth.
20. Chavez-Bueno S, Bozdogan B, Katz K, et al. Inducible clindamycin resistance and molecular epidemiologic trends of pediatric community-acquired methicillin-resistant Staphylococcus aureus in Dallas, Texas.
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