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Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections

Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections
Literature review current through: Jan 2024.
This topic last updated: Nov 29, 2023.

INTRODUCTION — Methicillin resistance in Staphylococcus aureus (MRSA) is defined by the Clinical Laboratory Standards Institute (CLSI) as an oxacillin minimum inhibitory concentration (MIC) ≥4 mcg/mL [1]. According to the European Committee on Antimicrobial Susceptibility Testing (EUCAST), S. aureus with oxacillin MIC values >2 mg/L are mostly methicillin resistant [2].

Issues related to treatment of skin and soft tissue infections in adults caused by MRSA will be reviewed here.

General issues related to skin and soft tissue infections are discussed separately. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Other issues related to MRSA are discussed further separately:

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Epidemiology".)

(See "Rapid detection of methicillin-resistant Staphylococcus aureus".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Prevention and control".)

(See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

CLINICAL APPROACH — Patients with skin and soft tissue infections known or suspected to be due to MRSA may present with cellulitis, abscess, or both [3-5]. Issues related to evaluation of cellulitis and for presence of abscess are discussed further separately. (See "Cellulitis and skin abscess: Epidemiology, microbiology, clinical manifestations, and diagnosis", section on 'Diagnosis'.)

Patients with cellulitis should be managed with antibiotic therapy. A critical part of treatment is source control. Patients with an abscess should undergo incision and drainage, and debrided material should be sent for culture and susceptibility testing [6,7]. (See "Techniques for skin abscess drainage".)

The role of antibiotic therapy for patients with abscess depends on individual clinical circumstances. (See "Skin abscesses in adults: Treatment", section on 'Indications for antimicrobial therapy'.)

ANTIBIOTIC SELECTION — Empiric coverage for MRSA is generally warranted for treatment of skin and soft tissue infections, given the high community prevalence of MRSA. Clinical and epidemiologic factors alone do not adequately predict the likelihood of MRSA infection (table 1) [8]. Empiric antibiotic therapy with activity against MRSA is particularly important in the following circumstances [8-10]:

Prior episode of MRSA infection

Recurrent infection in the setting of underlying predisposing condition(s)

Skin and soft tissue infection not associated with purulence, in the setting of inadequate clinical response (within 72 hours) to antibiotic therapy with no activity against MRSA

Antibiotic therapy should be tailored to susceptibility data when available. Therapy should preferentially include a narrow spectrum antibiotic. Patients with mild infection (localized involvement with no systemic symptoms) may be treated with oral antibiotic therapy. Treatment with parenteral antibiotic therapy is warranted in the circumstances described below. (See 'Oral antibiotic therapy' below and 'Parenteral antibiotic therapy' below.)

Considerations in antibiotic selection include local antibiotic susceptibility profiles and individual patient circumstances, including underlying comorbidities and concurrent medications [11].

Oral antibiotic therapy — Patients with mild infection (localized involvement with no systemic symptoms) due to known or suspected MRSA may be treated with oral antibiotic therapy. Antibiotic dosing is summarized in the table (table 2).

Oral antibiotic agents of choice include trimethoprim-sulfamethoxazole (TMP-SMX), tetracyclines (such as doxycycline or minocycline), or clindamycin [4,12-15]. In general, the choice between agents is guided by individual clinical circumstances including local antibiotic resistance patterns, allergy history, and concomitant medications.

The efficacy of clindamycin and TMP-SMX for treatment of uncomplicated skin infection is comparable; in two randomized trials including patients with uncomplicated skin infections, cure rates for clindamycin and TMP-SMX were between 78 and 83 percent [16,17]. Use of the tetracyclines is supported by susceptibility testing and observational and retrospective reports; their efficacy for treatment of skin and soft tissue infections due to MRSA has not been rigorously evaluated or compared in clinical trials [15,18-21].

In the setting of empiric antibiotic therapy, the efficacy of the above agents against the potential pathogen group A Streptococcus (GAS) should be considered. Clindamycin and TMP-SMX are active against GAS; doxycycline has uncertain activity [17,22,23]. (See "Acute cellulitis and erysipelas in adults: Treatment".)

Alternative oral agents include oxazolidinones (linezolid and tedizolid), the fluoroquinolone delafloxacin, and the tetracycline omadacycline; use of these drugs is limited by cost, clinical experience, and adverse drug effects. They should be reserved for patients who do not respond to or cannot tolerate other agents. (See 'Alternative agents' below.)

Careful monitoring of local clindamycin resistance rates is important; some favor avoiding empiric clindamycin therapy when local MRSA resistance rates to clindamycin exceed 10 to 15 percent [12]. In addition, isolates that appear susceptible to clindamycin and are resistant to erythromycin by standard susceptibility testing techniques may be capable of inducing resistance to clindamycin in the presence of the drug [24]. Clinicians should confer with the microbiology laboratory regarding evaluation of such isolates for inducible clindamycin resistance with D testing prior to treatment with clindamycin [25,26]. (See "Overview of antibacterial susceptibility testing", section on 'Inducible clindamycin resistance testing'.)

Fluoroquinolones should not be used for treatment of skin and soft tissue infections due to MRSA; resistance may develop during therapy [18,27].

Parenteral antibiotic therapy — Treatment with parenteral antibiotic therapy is warranted in the following circumstances [12]:

Extensive soft tissue involvement

Signs of systemic toxicity

Rapid progression of clinical manifestations

Persistence or progression of symptoms after 48 to 72 hours of oral therapy

Immunocompromise

Proximity of soft tissue infection to an indwelling device (such as a prosthetic joint or a vascular graft); soft tissue infection should be considered a manifestation of device infection if it originates on the skin directly overlying the prosthesis site

Treatment of bacteremia is discussed separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

Antibiotics of choice — Parenteral agents of choice for treatment of skin and soft tissue infection when MRSA is known or suspected include vancomycin and daptomycin. In areas where teicoplanin is available, some use it as the drug of choice for initial therapy of gram-positive pathogens, while others favor its use for patients with intolerance to vancomycin [28]. Alternative agents are discussed below. (See 'Alternative agents' below.)

Vancomycin is the antibiotic agent for which there is the greatest cumulative clinical experience for treatment of skin and soft tissue infection caused by MRSA [4,29]. Daptomycin is an acceptable alternate to vancomycin that does not require monitoring of drug levels [30,31]. Dosing is summarized in the table (table 3).

Patients with S. aureus infection due to an isolate with vancomycin minimum inhibitory concentration (MIC) at the high end of the susceptible range (≥2 mcg/mL) may not respond to therapy as well as those with infection due to an isolate with a lower MIC [32]. In such cases, poor clinical response to vancomycin therapy should prompt use of daptomycin or another agent. (See "Staphylococcus aureus bacteremia with reduced susceptibility to vancomycin".)

Issues related to vancomycin and daptomycin are discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia", section on 'Preferred agents'.)

Alternative agents — The choice of alternative agents with activity against MRSA may be based on logistics of administration, side-effect profiles, availability, cost, and known antibiotic susceptibility (table 3). All of the alternative agents have been shown to be comparable to vancomycin for treatment of MRSA skin and soft tissue infections [33-39]; however, data comparing the alternative agents are limited.

Tigecycline and quinupristin-dalfopristin should not be used for treatment of skin and soft tissue infections due to MRSA; their use is limited by adverse effects.

Short-acting agents (parenteral or oral dosing) — Short-acting agents with parenteral or oral dosing include oxazolidinones (linezolid and tedizolid), the fluoroquinolone delafloxacin, and the tetracycline omadacycline; these agents may be used in the inpatient setting (with parenteral dosing) or outpatient setting (with oral dosing).

Linezolid and tedizolid — Linezolid and tedizolid are oxazolidinones; both have bacteriostatic activity against MRSA and streptococci. Use of these drugs is limited by cost and toxicity (tedizolid may have less toxicity than linezolid); they should be reserved for patients who do not respond to or cannot tolerate other agents. In some centers, drug levels of linezolid are available and allow dosage adjustments that may limit the drug's toxicity. (See "Linezolid and tedizolid (oxazolidinones): An overview".)

Linezolid and vancomycin have been observed to have equivalent clinical cure rates overall for treatment of MRSA infection [33,40]. One systematic review including 3144 patients with skin and soft tissue infections noted linezolid appears to be at least as effective as vancomycin [40]. Linezolid has been shown to be as effective as vancomycin for the treatment of skin and soft tissue infection [33,41-44].

Tedizolid has been shown to be non-inferior to linezolid for treatment of skin and soft tissue infection [45-47].

Issues related to linezolid are discussed further separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

Delafloxacin — Delafloxacin is a fluoroquinolone approved in June 2017 by the US Food and Drug Administration (FDA) for treatment of bacterial skin and soft tissue infections [48-50]. Delafloxacin has activity against staphylococci, including methicillin-resistant strains. It also has activity against gram-negative bacteria (including Pseudomonas aeruginosa and Enterobacteriaceae) as well as some anaerobes including Clostridioides difficile; it does not have activity against enterococci [51].

Delafloxacin susceptibility should be confirmed prior to use of delafloxacin; resistance among MRSA isolates has been reported [52].

Efficacy data for delafloxacin include a randomized trial of 850 adults with skin and soft tissue infection treated with delafloxacin or vancomycin plus aztreonam; objective response at 48 to 72 hours was comparable between the groups (83 versus 80 percent), and the frequency of adverse events between the groups was similar [53]. The manufacturer reported that the drug was statistically noninferior to the combination of vancomycin and aztreonam at the endpoint of early clinical response at 48 to 72 hours in two phase III clinical trials and that the drug was well-tolerated [53-56].

Omadacycline — Omadacycline is a tetracycline approved in October 2018 by the FDA for treatment of bacterial skin and soft tissue infections. It has activity against S. aureus (methicillin-susceptible and -resistant isolates), Staphylococcus lugdunensis, Streptococcus pyogenes, Streptococcus anginosus group (includes S. anginosus, S. intermedius, and S. constellatus), Enterococcus faecalis, Enterobacter cloacae, and Klebsiella pneumoniae.

In a randomized trial including more than 600 patients with skin and soft tissue infections treated with omadacycline or linezolid (intravenous [IV] therapy with transition to oral therapy allowed after three days; total duration 7 to 14 days), the clinical response (at least 20 percent reduction in lesion size after 48 to 72 hours of therapy) was comparable between the groups (85 percent) [57]. The drugs had a similar safety profile, and the efficacy of omadacycline was similar for methicillin-susceptible and methicillin-resistant S. aureus infections.

Short-acting parenteral agents — Short-acting parenteral agents include ceftaroline and ceftobiprole (dosed twice daily); use of these agents requires inpatient management.

Ceftaroline (and ceftobiprole) — Ceftaroline and ceftobiprole are fifth-generation cephalosporins with broad-spectrum activity against gram-positive and gram-negative organisms. Ceftaroline has activity against MRSA and staphylococci with reduced susceptibility to vancomycin, daptomycin, or linezolid as well as gram-negative pathogens [58,59]. Ceftobiprole has activity against MRSA, penicillin-resistant Streptococcus pneumoniae, enterococci, and Enterobacteriaceae [60,61].

For treatment of complicated skin and skin structure infection, ceftaroline has been found to be non-inferior to vancomycin plus aztreonam [36], and ceftobiprole has been observed to be as effective as vancomycin (with or without ceftazidime) [39,62].

Ceftobiprole is not available in the United States but is available in Canada and Europe.

Iclaprim — Iclaprim is a parenteral agent with bactericidal activity against gram-positive bacteria including MRSA. It is an inhibitor of the enzyme dihydrofolate reductase, blocking a key step in thymidine synthesis [63]. In randomized trials, it has been observed to be noninferior to vancomycin for treatment of skin and soft tissue infections [63,64]. It is not yet available for use in the United States.

Long-acting parenteral agents — Long-acting parenteral agents include dalbavancin, oritavancin, and telavancin. Dalbavancin has a half-life of 14 days and oritavancin has a half-life of 10 days. These agents are administered as a single dose, which may be useful for patients who warrant parenteral therapy but do not otherwise require inpatient management. Telavancin is dosed once daily.

Dalbavancin, oritavancin, and telavancin — Dalbavancin, oritavancin, and telavancin are lipoglycopeptides that inhibit cell wall synthesis and disrupt cell membrane permeability; they have bactericidal activity against MRSA and other gram-positive organisms [65-67].

Dalbavancin and oritavancin are long-acting agents; these agents may be useful for patients who warrant parenteral therapy but do not otherwise require inpatient management and may simplify adherence [68].

Dalbavancin has been demonstrated to be non-inferior to vancomycin followed by oral linezolid for treatment of skin and soft tissue infection in two studies including more than 1200 patients [37]. We favor administration as a single dose (1500 mg IV); this approach was shown to be noninferior to a two-dose regimen (1000 mg IV followed by 500 mg IV one week later) in a randomized trial including 698 patients with acute bacterial skin and skin structure infection treated with the single-dose or two-dose regimen; favorable clinical outcome (≥20 percent reduction in the area of erythema at 48 to 72 hours) was observed in 81.4 versus 84.2 percent, respectively (difference -2.9 percent, 95% CI -8.5 to 2.8 percent) [68]. Adverse effects associated with dalbavancin include gastrointestinal intolerance (nausea, diarrhea, constipation), transaminitis, hypokalemia, and hypotension.

Oritavancin has been demonstrated to be non-inferior to vancomycin for treatment of skin and soft tissue infection in randomized trials including nearly 1000 patients [34,38,69]. Oritavancin may artificially prolong activated partial thromboplastin time (aPTT) for up to 5 days, prolong prothrombin time (PT) and international normalized ratio (INR) for up to 12 hours, and prolong activated whole blood clotting time (ACT) for up to 24 hours [70]. For patients who require aPTT monitoring 5 days of oritavancin administration, a non-phospholipid dependent coagulation test (such as a Factor Xa assay) may be used; alternatively, an anticoagulant not requiring aPTT may be used. Other adverse effects of oritavancin include nausea, vomiting, and headache.

Telavancin has been demonstrated to be at least as effective as vancomycin for treatment of skin and soft tissue infection in several trials [35,71,72]. Adverse effects of telavancin include taste disturbance, nausea, vomiting, and renal dysfunction.

DURATION OF THERAPY — The appropriate duration of therapy for treatment of skin and soft tissue infection depends on the nature of the clinical presentation, and the clinical response should guide duration of therapy.

Patients with mild infection who warrant outpatient management with oral antibiotic therapy should have repeat evaluation after 24 to 48 hours to verify that there is a clinical response [3]. Patients with MRSA responsive to oral therapy are typically treated for 5 days; extension of the duration (up to 14 days) may be warranted in the setting of severe infection and/or slow response to therapy. Lack of response may be due to infection with resistant organism(s), inadequate adherence or source control, or presence of a deeper, more serious infection than previously realized.

Patients with infection warranting parenteral therapy (in the absence of bacteremia or involvement beyond soft tissue) are typically treated for a total duration of 5 to 14 days. Once there are signs of clinical improvement with no evidence of systemic toxicity, antibiotics may be transitioned from parenteral to oral therapy (table 2).

The management of patients with bacteremia is discussed separately. (See "Clinical approach to Staphylococcus aureus bacteremia in adults" and "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of bacteremia".)

RECURRENT INFECTION — Recurrent MRSA infection is common. In one study, infections recurred in 51 percent of subjects by six months [73].

The initial clinical approach to patients with recurrent skin and soft tissue infection when MRSA is known or suspected is the same as for patients with a first episode. Patients should be evaluated and treated for underlying conditions that may predispose to infection. (See 'Clinical approach' above.)

Antibiotic selection should be guided by careful review of prior and current culture and susceptibility data (see 'Antibiotic selection' above):

For patients with hemodynamic instability and a prior MRSA isolate with a vancomycin minimum inhibitory concentration at the high end of the susceptible range (≥2 mcg/mL), empiric treatment should consist of daptomycin or ceftaroline (or in combination) rather than vancomycin [74].

For patients who are clinically stable, the choice between whether to treat empirically with an antibiotic agent used previously and a different agent should be guided by individual clinical circumstances (such as allergy history and concomitant medications).

Antibiotic therapy should be tailored to culture and susceptibility data when available.

The duration of therapy for recurrent infection is the same as for an initial episode. (See 'Duration of therapy' above.)

Issues related to the prevention of MRSA infection and decolonization strategies are discussed separately. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Prevention and control".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Skin and soft tissue infections" and "Society guideline links: Management of Staphylococcus aureus infection".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topic (see "Patient education: Methicillin-resistant Staphylococcus aureus (MRSA) (The Basics)")

Beyond the Basics topic (see "Patient education: Methicillin-resistant Staphylococcus aureus (MRSA) (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

General approach – Patients with skin and soft tissue infections known or suspected to be due to methicillin-resistant Staphylococcus aureus (MRSA) may present with cellulitis, abscess, or both. Patients with cellulitis should be managed with antibiotic therapy. Patients with abscess should undergo incision and drainage and warrant antibiotic therapy in most circumstances as discussed separately. (See 'Clinical approach' above and "Acute cellulitis and erysipelas in adults: Treatment".)

Empiric treatment of MRSA – Empiric coverage for MRSA is often warranted, particularly for patients with systemic toxicity, purulent drainage, abscess, an immunocompromising condition, or other risk factors for MRSA (table 1). Antibiotic therapy should be tailored to culture and susceptibility data when available. (See 'Antibiotic selection' above and "Acute cellulitis and erysipelas in adults: Treatment".)

Oral antibiotics – Patients with mild infection (localized involvement with no systemic symptoms) may be treated with oral antibiotic therapy. Oral antibiotic agents of choice include trimethoprim-sulfamethoxazole, tetracyclines (such as doxycycline or minocycline), and clindamycin; dosing is summarized in the table (table 2). In general, the choice between these agents is guided by individual clinical circumstances. (See 'Oral antibiotic therapy' above.)

Indications for parenteral antibiotics – Patients with the following factors warrant parenteral therapy (see 'Parenteral antibiotic therapy' above):

Extensive soft tissue involvement

Signs of systemic toxicity

Rapid progression of clinical manifestations

Persistence or progression of symptoms after 48 to 72 hours of oral therapy

Immunocompromise

Proximity of soft tissue infection to an indwelling device (such as a prosthetic joint or a vascular graft); soft tissue infection should be considered a manifestation of device infection if it originates on the skin directly overlying the prosthesis site

Parenteral antibiotics – Parenteral agents of choice for treatment of skin and soft tissue infection when MRSA is known or suspected include vancomycin or daptomycin (table 3).

If vancomycin or daptomycin is not an option, alternative parenteral agents are available for treatment of skin and soft tissue infection when MRSA is known or suspected; the optimal approach to choosing between these agents is uncertain. Pending further study, the choice may be based on logistics of administration, side-effect profiles, availability, antimicrobial susceptibility testing results, and cost (table 3) (see 'Alternative agents' above):

Short-acting agents with parenteral or oral formulations – These include linezolid, tedizolid, delafloxacin, and omadacycline; these agents may be used in the inpatient setting (with parenteral dosing) or outpatient setting (with oral dosing).

Short-acting parenteral agents with no oral formulation – These include ceftaroline and ceftobiprole (where available); use of these agents requires inpatient management.

Long-acting parenteral agents – These include dalbavancin, oritavancin, and telavancin. Dalbavancin has a half-life of 14 days, and oritavancin has a half-life of 10 days; these agents may be useful for patients who warrant parenteral therapy but do not otherwise require inpatient management.

Duration of therapy – The duration of therapy for treatment of skin and soft tissue infection due to MRSA depends on the nature of the clinical presentation and should be guided by clinical response. Patients with skin or soft tissue infection responsive to oral therapy are typically treated for 5 days; extension of the duration (up to 14 days) may be warranted in the setting of severe infection and/or slow response to therapy. Patients with infection warranting parenteral therapy (in the absence of bacteremia or involvement beyond soft tissue) are typically treated for a total duration of 5 to 14 days. Once there are signs of clinical improvement with no evidence of systemic toxicity, parenteral antibiotics may be transitioned to oral therapy. (See 'Duration of therapy' above.)

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