Managing CA-MRSA Infections: Current and Emerging Options

Key words: Methicillin-resistant Staphylococcus aureus (MRSA), Skin and soft tissue infections (SSTIs), Infection control, Daptomycin resistance

Methicillin-resistant Staphylococcus aureus (MRSA) strains are resistant to currently available β-lactam antibiotics, including penicillins and cephalosporins.¹ The Clinical and Laboratory Standards Institute (CLSI) defines MRSA as an oxacillin minimal inhibitory concentration (MIC) of 4 µg/mL or greater.

The first MRSA infection emerged in England in 1961 in the hospital environment shortly after methicillin was introduced. The incidence of MRSA infections has increased steadily since then.² Infections that occur in otherwise healthy persons who have not recently (ie, within the past year) been hospitalized or had a medical procedure (such as dialysis, surgery, or intravenous catheter insertion) are known as community-associated MRSA (CA-MRSA) infections. Risk factors for CA-MRSA infection are listed in Table 1. Differences between CA-MRSA infections and health care–associated MRSA infections are

summarized in Table 2.

EPIDEMIOLOGY AND CLINICAL MANIFESTATIONS
Initially, MRSA was recognized as an important pathogen in patients who frequented health care facilities and in persons who were in contact with patients who had MRSA infection. Injection drug users (IDUs) with a history of antibiotic exposure-usually from illicitly purchased medications-are another group in whom a high prevalence of MRSA infection has been recognized.³

In the mid-1990s, reports of CA-MRSA infections emerged in Australia, New Zealand, the United States, the United Kingdom, France, Finland, Canada, and Samoa. These infections were notable because they occurred in persons who had no previous contact with the health care system. Four fatal cases of CA-MRSA infection that occurred in children in Minnesota and North Dakota during 1997 - 1999 were initially reported.⁴ Soon after, CA-MRSA infections were identified among men who have sex with men as well as incarcerated persons in San Francisco, Los Angeles, Atlanta, and Boston.⁵

CA-MRSA infections are now a common and serious problem. In a surveillance study covering the years 2001 through 2002 involving 3 communities in the United States, 1647 cases of CA-MRSA infection were reported. Eight percent to 20% of all MRSA isolates collected were not associated with traditional risk factors and were classified as CA-MRSA. Most of these isolates were associated with clinically relevant infections that required treatment. Many patients were children who required hospitalization.⁶

Approximately 80% of the infections caused by CA-MRSA in the United States are skin and soft tissue infections (SSTIs), manifesting as furuncles, folliculitis, impetigo, cellulitis, or small abscesses.⁷ Necrotic skin lesions are also a common presentation and are often incorrectly attributed to bites by brown recluse spiders or other insects. Generally, CA-MRSA SSTIs are not life-threatening; however, in some circumstances, as in cases complicated by invasive infection (eg, bacteremia, necrotizing fasciitis), they can become difficult to treat and even cause death. (see "

") Unfortunately, now new and more dangerous syndromes associated with CA-MRSA are being reported. These include:

Necrotizing fasciitis. In one study of 843 patients with MRSA SSTIs, the strain identified was USA300 staphylococcal cassette chromosome (SCC) type IV, which is the signature of CA-MRSA.⁸ Associated conditions or risk factors included previous MRSA infection, hepatitis C virus infection, diabetes, current or past injection drug use, cancer, and HIV infection.

Pyomyositis. This illness is more commonly seen in the tropics but is increasingly recognized in temperate climates, especially in patients with HIV infection. It is predominantly caused by S aureus. CA-MRSA is likely to become a more common cause of pyomyositis as the global prevalence of this organism increases. In analyzing 45 previously healthy children in whom episodes of bacterial myositis or pyomyositis occurred, Pannaraj and colleagues⁹ found that S aureus was the cause in 26 of these children (57.8%). CA-MRSA was isolated in 15 of these patients (57.7%).

Necrotizing community-acquired pneumonia (CAP). CA-MRSA is infrequently reported as a cause of CAP. It has been associated with post–influenza virus infection and influenzalike illness (post–influenza pneumonia). During the 2003 - 2004 influenza season, 15 cases of MRSA CAP from 9 states were reported to the CDC. Four deaths (fatality rate, 26.7%) occurred among these cases. Ten cases of severe MRSA CAP that occurred between December 2006 and January 2007 and included 6 deaths (fatality rate, 60%) among previously healthy persons in Louisiana and Georgia were reported to the CDC in January 2007.^10,11

Infective endocarditis (IE). IE is a common and often devastating complication of S aureus bacteremia. Risk factors for IE in the setting of bacteremia include the presence of a prosthetic valve and underlying valvular defects, injection drug use, intravascular catheter infection, and persistent bacteremia. Given that S aureus is a major cause of IE-particularly in the IDU population-reports of IE attributed to CA-MRSA are now appearing in the literature.¹²

Septic arthritis/osteomyelitis. CA-MRSA bone and joint infection may be caused by direct injury or as a complication of S aureus bacteremia.¹³

Sepsis with or without Waterhouse-Friderichsen syndrome. The Waterhouse-Friderichsen syndrome is characterized by petechial rash, coagulopathy, cardiovascular collapse, and bilateral adrenal hemorrhage. The syndrome is generally associated with fulminant meningococcemia; however, in 2005, 3 fatal cases attributed to S aureus infection in children were reported. Two of the infections were caused by CA-MRSA.¹⁴

Gonzalez and colleagues¹⁵ identified 14 previously healthy children older than 10 years (range, 10 to 15 years) who presented to the hospital with severe sepsis; from this group, 12 had sepsis caused by CA-MRSA. The predicted mortality rate was 40.8%. Interestingly, the majority of these patients (57%) had a history of blunt trauma at the initial apparent site of presentation.

Other manifestations. Suppurative lymphadenitis,¹⁶ ophthalmic infections (preseptal cellulitis, lid abscess, conjunctivitis, corneal ulcers, endophthalmitis, orbital cellulitis, blebitis¹⁷), otitis media,¹⁸ sinusitis,¹⁹ and food-borne GI illness²⁰ have all been associated with CA-MRSA.

MANAGEMENT OF CA-MRSA INFECTIONS
Most CA-MRSA infections involve the skin and skin structures. Purulent SSTIs without associated sepsis or hemodynamic instability are generally managed with surgical incision and drainage. Topical antimicrobial therapy is sometimes used to treat limited skin infections. However, no topical agent has been approved for MRSA SSTIs because of lack of data supporting effectiveness. The most commonly administered topical agents are bacitracin (alone or in combination with polymyxin and neomycin) and mupirocin.

Oral therapy
The drug of choice for oral systemic therapy in the ambulatory setting has not been established. Most CA-MRSA strains remain susceptible to clindamycin, trimethoprim/sulfamethoxazole (TMP/SMX), doxycycline, minocycline, vancomycin, teicoplanin (not available in the United States), chloramphenicol, rifampicin, and linezolid. Familiarity with local antibiotic patterns is crucial for selecting empirical antibiotic therapy, and culture results and susceptibility data are critical to tailoring treatment.²¹

lists oral agents commonly used for treatment of CA-MRSA infections.

Clindamycin (300 to 450 mg every 6 to 8 hours) has good activity against MRSA and also is capable of inhibiting bacterial toxin production. Careful monitoring of local clindamycin susceptibility patterns is important because of reports of increasing rates of resistance in different regions. In addition, isolates that appear susceptible to clindamycin and resistant to erythromycin by standard susceptibility testing have a relatively high likelihood of mutating, such that resistance to clindamycin develops. The double disk diffusion test (D-zone test) detects those S aureus isolates. Thus, in the setting of erythromycin resistance, this test is strongly recommended before initiation of treatment with clindamycin.²² Susceptibility to erythromycin, which is not recommended for treatment of MRSA infections, ranges from 5% to 64% in different geographical areas.²³ In regions where the prevalence of clindamycin resistance is low, it is acceptable to initiate therapy with this drug empirically and carefully monitor the clinical response. Clindamycin may still be effective even when the D-zone test result is positive in a few circumstances.

TMP/SMX or tetracyclines (ie, doxycycline and minocycline) alone are not recommended as empirical therapy in the treatment of nonpurulent skin infections, because group A streptococci, which are usually resistant to these antibiotics, may be involved in coinfection. Resistance of group A streptococci to the tetracyclines has been well documented, but resistance to TMP/SMX is less clear.³ For treatment of nonpurulent cellulitis of uncertain cause, some physicians add an active β-lactam antibiotic to cover streptococci.

Few data exist on the efficacy of the long-acting tetracyclines doxycycline and minocycline in MRSA infection. In one retrospective study of 24 patients with serious tetracycline-susceptible MRSA infections, clinical cure was achieved in 83%.²⁴

Linezolid, which is as effective as vancomycin for the treatment of SSTIs, is active against almost all isolates of CA-MRSA and streptococci; however, it should be reserved for patients who do not respond to or cannot tolerate traditional agents. The disadvantages of using linezolid include cost, hematological adverse effects, and the potential to induce resistance among S aureus strains.²⁵

Rifampin monotherapy and fluoroquinolones should not be used to treat MRSA infections, because they can exacerbate the emergence of resistant strains. Rifampin does have excellent activity against MRSA. However, for skin infections, it has been used in combination with TMP/SMX, with good results,²⁶ although solid data from controlled trials are not available to support this approach. Fluoroquinolones should not be used to treat SSTIs caused by MRSA, because widespread resistance has already become prevalent in many regions.²⁷

Parenteral therapy
Parenteral therapy should be considered in patients with extensive soft tissue involvement, fever, or other signs of systemic illness and in patients with diabetes, immunosuppression, or other significant comorbid conditions. Such patients also should be evaluated for evidence of invasive disease.

Management of invasive infections
Vancomycin is still considered first-line treatment for invasive infection in hospitalized patients. Recent studies have demonstrated the emergence of treatment failures of MRSA bacteremia in correlation with increasing vancomycin MICs that are still considered within the “susceptible” range (2.0 mg/mL vs less than 0.5 mg/mL).^28,29 Because of this observation, the CLSI changed the susceptibility and resistance breakpoints from 4 mg/mL or less to 2 mg/mL or less for “susceptible” and from 8 to 16 mg/mL to 4 to 8 mg/mL for “intermediate” resistance. A significant concern remains for patients infected with MRSA in which the vancomycin MICs are at the upper range of the susceptible zone; the levels of vancomycin required to treat such patients result in renal toxicity.³⁰ In addition, therapeutic failures also have been associated with MRSA strains that demonstrate heterogeneous resistance. These strains are not detected by routine laboratory methods. Therapeutic failure also has been associated with vancomycin intermediate-resistant S aureus (VISA).³¹

Of even greater concern, true vancomycin-resistant S aureus (VRSA) is now a threatening reality. Seven cases of VRSA infection were identified in the United States during the years 2002 to 2006; 5 were reported in Michigan, 1 was reported in Pennsylvania, and 1 was reported in New York.³² All VRSA isolates carried the vanA gene, which mediates vancomycin resistance and apparently was donated by vancomycin-resistant enterococci strains by conjugal transfer within a polymicrobial bio-film. Those strains were found to have a median vancomycin MIC of 512 µg/mL.

The optimal alternative parenteral agent for patients who fail to respond or cannot tolerate vancomycin is not known. Parenteral clindamycin may be given in regions where the likelihood of resistance is low, but this agent is considered bacteriostatic and may not be an effective choice for treatment of deep-seated infections.³

Among the newer agents, linezolid, daptomycin, quinupristin/dalfopristin (QD), and tigecycline all have FDA approval for treatment of SSTIs, and ceftobiprole may be approved shortly. Daptomycin also has an indication for treatment of bacteremia and endocarditis.

Daptomycin, a novel cyclic lipopeptide, has rapid bactericidal activity against MRSA by producing depolarization of the bacterial cell membrane. This drug has been approved by the FDA for the treatment of complicated SSTIs at a dosage of 4 mg/kg/d and also for the management of bacteremia and right-sided endocarditis at dosages of 6 mg/kg/d. In a randomized trial that included 45 patients with complicated SSTIs caused by MRSA, the efficacy of daptomycin was similar to that of vancomycin; the clinical success rate was 83%.³³ In a randomized trial of patients with S aureus bacteremia with or without right-sided endocarditis, daptomycin monotherapy was not inferior to vancomycin plus gentamicin; 53 of 120 patients had a successful outcome with daptomycin compared with 48 of 115 who received vancomycin (99 patients had MRSA infections).³⁴ Daptomycin should not be used to treat pneumonia, because its activity is inhibited by pulmonary surfactants ( see "Emergence of daptomycin resistance in Staphylococcus aureus infection").

Linezolid serves as an alternative to glycopeptides. It inhibits the initiation of protein synthesis at the 50S ribosome. This antibiotic, although bacteriostatic for MRSA, has excellent bioavailability and tissue penetration, particularly in the epithelial fluid lining of the lungs, making this antibiotic a potentially useful option in cases of MRSA pneumonia. But a recent report of S aureus endocarditis in a patient receiving linezolid for a skin infection and a report of clinical failure in a patient treated with linezolid for endocarditis have suggested that linezolid use may promote rapid emergence of resistant S aureus strains and that linezolid may have poor efficacy when used alone for the treatment of severe invasive S aureus infections.^35,36

Tigecycline, a parenteral glycylcycline-minocycline derivative, was approved by the FDA in June 2005 for the treatment of complicated SSTIs (cSSSIs [complicated skin and skin-structure infections]) and intra-abdominal infections. It is active in vitro against MRSA strains, but its indication is limited to MRSA SSTIs. A study that combined data from 2 clinical trials demonstrated that tigecycline is as effective as combination vancomycin and aztreonam for the management of MRSA cSSSIs³⁷; the cure rate was 78.4% for tigecycline versus 76.5% for vancomycin plus aztreonam. The dosing schedule is 1 dose of 100 mg delivered intravenously followed by 50 mg delivered intravenously every 12 hours for up to 14 days.

QD is a streptogramin antibiotic that is FDA-approved for the treatment of vancomycin-resistant enterococcal infections and cSSSIs caused by methicillin-susceptible S aureus (MSSA). QD has activity in vitro against MRSA and also VISA strains. Clinical experience using this agent in the treatment of nosocomial MRSA pneumonia has been disappointing, however, with a clinical response rate of only 19% compared with 40% for vancomycin.³⁸

Ceftobiprole is a novel advanced-generation pyrrolidinone cephalosporin with the capacity to bind to penicillin-binding protein 2a, which is encoded by the mecA gene located on an SCC. In a recent multicenter noninferiority trial that compared ceftobiprole with vancomycin, the clinical cure rate was 91.8% among patients receiving ceftobiprole and 90.0% among patients receiving vancomycin for management of gram-positive cSSSIs.³⁹ When these drugs were compared in the treatment of patients with a broad range of SSTIs caused by various pathogens, the clinical cure rate ranged from 86.2% in cases of foot infections in persons with diabetes to 93.5% in cases of cellulitis.⁴⁰ The clinical cure rate was 94.6% among those patients who received ceftobiprole for S aureus infections and 91.8% for those patients who received vancomycin plus ceftazidime for such infections. The cure rate for MRSA infections specifically was 91.4% among patients who received ceftobiprole and 86.1% for patients who received vancomycin plus ceftazidime.^40,41

For a review of infection control measures, see "Infection control for MRSA."

FUTURE THERAPEUTICS
A number of investigational drugs may eventually enter the antibiotic armamentarium to fight MRSA infections. They include semisynthetic glycopeptides and a glycylglycine endopeptidase.

Semisynthetic glycopeptides such as dalbavancin, telavancin, and oritavancin are characterized by their prolonged plasma half-lives. The half-life of dalbavancin, for example, is 6 to 12 days, permitting once-weekly dosing. Clinical trials evaluating the efficacy of dalbavancin demonstrated that it is not inferior to vancomycin in the treatment of catheter-related infection caused by gram-positive pathogens (including MRSA)⁴² and that it is also as effective as linezolid for the treatment of cSSSIs, with a clinical success rate of 91% compared with 89% for linezolid in patients with MRSA infections.⁴³

Lysostaphin is a glycylglycine endopeptidase. It cleaves the pentaglycine cross-bridge structure unique to the staphylococcal cell wall and is considered to be a potential agent for use in S aureus infections. A study of 257 S aureus isolates collected from hospitalized patients in Beijing found that all S aureus strains were sensitive to lysostaphin, with MICs ranging from 0.03 to 2 µg/mL.⁴⁴ The antibacterial activity of lysostaphin was greater than that of vancomycin and other reference agents. Lysostaphin showed rapid bactericidal activity against the test strains of MSSA and MRSA.

Immunointervention is another strategy being explored to combat S aureus infections. Pooled intravenous Staphylococcus antibody preparations, which neutralize Staphylococcus superantigen toxins, are being prepared for the treatment of toxic shock syndrome. These preparations also neutralize the Panton-Valentine leukocidin toxin in vitro.⁴⁵

Another agent that may prove useful in immunointervention is tefibazumab. It is a humanized monoclonal antibody that is directed at the microbial surface compounds recognizing adhesive matrix molecule clumping factor A, a protein on the S aureus surface that binds to human fibrinogen.⁴⁶

A new modality of vaccine, a polyclonal human IgG with high levels of antibody to capsular polysaccharide type 5 and type 8, is currently being studied. A recent phase 2, randomized, double-blind study evaluated 40 patients with documented S aureus bacteremia; 21 patients received standard therapy plus the vaccine at 200 mg/kg of body weight in 2 infusions 24 hours apart and 18 received standard therapy plus placebo. Compared with the control patients, the vaccine recipients had a shorter median time to the resolution of fever (2 days vs 7 days; P = .09) and a shorter length of hospital stay (9 days vs 14 days; P = .03). There was no difference in the mortality rates.⁴⁷

References:

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