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<< Emergency Department Infections In The Era Of Community-Acquired MRSA

Treatment

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Treatment

Treatment

Use of antibiotics, as well as choice and route of administration, should not only be determined by the likelihood of typical pathogens but should also take into account the type of SSTI and the severity of the clinical presentation (systemic signs, anatomic factors, patient comorbidities).

Antimicrobials should be prescribed judiciously, taking into account typical susceptibility patterns and incorporating regional or local antibiogram patterns. Antibiotics of choice have varied over time as resistance patterns have changed and additional options and data have become available. Unnecessary or indiscriminate use of antimicrobials with a broader range than necessary contributes to the development of antibiotic resistance and increases an individual’s risk of developing an infection with a resistant organism.

Consensus guidelines for treatment are vague, reflecting the lack of quality prospective data. In addition, available studies use inconsistent inclusion criteria and terminology, making interpretation of their results problematic.

Overview Of Available Antimicrobial Agents

Oral agents with activity against CA-MRSA include trimethoprim-sulfamethoxazole (TMP-SMX), clindamycin, tetracyclines, and linezolid. Currently available parenteral agents include vancomycin, linezolid, daptomycin, tigecycline, and telavancin. (See Table 8.)


Trimethoprim-Sulfamethoxazole

The antibiotic TMP-SMX is commonly used to treat CA-MRSA infections in outpatients and is an especially important antibiotic option in uncomplicated SSTIs. It is not FDA-approved for the treatment of any staphylococcal infections. Virtually all CAMRSA isolates are sensitive to TMP-SMX; however, outcome and efficacy data are limited. In vitro susceptibility testing revealed that 95% to 100% of CAMRSA strains are susceptible to TMP-SMX.2,27,48 One in vitro study of the susceptibility of CA-MRSA to commonly prescribed oral agents demonstrated that TMP-SMX is rapidly bacteriocidal and was significantly more effective against MRSA compared with other orally available agents, including clindamycin, minocycline, and linezolid.75 Clinical efficacy data, however, are limited to observational and retrospective studies.50,51,76-78

No data indicate that TMP-SMX is active against S pyogenes. This is an important consideration in patients with cellulitis and complicated SSTIs. Data to support IV TMP-SMX use in more severe infections are also lacking.6

The optimal dosage of TMP-SMX is uncertain. No prospective studies are available to guide recommendations. One double-strength tablet contains 160 mg of trimethoprim and 800 mg of sulfamethoxazole. Some experts recommend 1 double-strength tablet twice daily, and others recommend 2 doublestrength tablets twice daily to optimize tissue concentration; however, higher doses may increase the incidence of adverse effects.79,80 TMP-SMX is a pregnancy category C drug and is not recommended for women in the third trimester of pregnancy or for children younger than 3 months. Adverse reactions associated with TMP-SMX include hematologic suppression (rarely) and Stevens-Johnson syndrome.

Clindamycin

Clindamycin is an important antibiotic option for the treatment of SSTIs and is commonly prescribed for CA-MRSA. It is FDA-approved for the treatment of serious infections due to S aureus, though not specifically approved for MRSA. It has been used successfully to treat invasive CA-MRSA infections in children and is capable of inhibiting bacterial toxin production, including PVL.81

The susceptibility rate of CA-MRSA to clindamycin is not as high as its susceptibility rate to TMPSMX. A 2007 study in one Boston outpatient facility revealed that nearly half (48.2%) of CA-MRSA isolates were clindamycin-resistant.50 Emergency clinicians should be aware of their regional clindamycin susceptibility profile, since CA-MRSA susceptibility variation by geographic region has been reported.

Importantly, antibiotic susceptibility tests indicating that an isolate is susceptible to clindamycin may be misleading, as some strains of CA-MRSA (phenotype iMLSB) have demonstrated an inducible resistance to the drug. Resistance to erythromycin is a marker for inducible resistance to clindamycin.82A specialized laboratory test, the erythromycinclindamycin D-zone test (named for its characteristic shape on agar media) is recommended for detection of inducible clindamycin resistance in erythromycin- resistant/clindamycin-susceptible isolates.83-85Nevertheless, data regarding the clinical significance of inducible clindamycin resistance are conflicting.86

Clindamycin does have an advantage over TMPSMX in that it provides better coverage of S pyogenes, making it a monotherapy option for treatment of cellulitis (see Cellulitis). Clindamycin is an important drug in the armamentarium against CA-MRSA and offers advantages over TMP-SMX in some clinical scenarios. However, due to concerns over possible resistance, some experts discourage use of clindamycin as monotherapy in moderately or severely ill patients.6

The recommended adult dosage of clindamycin is 150 to 450 mg orally every 6 to 8 hours. The IV dose is 600 to 900 mg every 8 hours.79,80 Clindamycin is classified as pregnancy category B.

Diarrhea is a common adverse effect and is infrequently associated with Clostridium difficile diarrhea. Observational data suggest that C difficile may occur more often with use of clindamycin than with use of other antimicrobials.87

Tetracyclines

Long-acting tetracyclines used to treat SSTIs include doxycycline and minocycline. Doxycycline is FDAapproved for S aureus infections, but it is not specifically approved for MRSA.

Data supporting the use of these agents for CAMRSA are limited to observational and retrospective studies. In one small case series, doxycycline and minocycline appeared to be effective treatments for SSTIs caused by tetracycline-susceptible strains of MRSA.88 Effectiveness was also seen in a retrospective cohort study of outpatients with uncomplicated skin infections.89

Susceptibility of CA-MRSA to tetracyclines varies geographically, and a long-acting tetracycline is a reasonable option for an infection if local sensitivity profiles indicate high susceptibility. Doxycycline and minocycline are effective in the treatment of superficial SSTIs, but data are lacking to support use in more invasive infections. As with TMP-SMX, efficacy against S pyogenes is questionable, so their use in nonpurulent cellulitis is not recommended.6,8

The recommended dosage of doxycycline or minocycline is 100 mg twice daily.79,80 Tetracyclines are pregnancy category D drugs and are contraindicated in pregnant women and children because of deposition in teeth and bones.

Rifampin

Rifampin should never be used alone for the treatment of CA-MRSA. Although CA-MRSA often demonstrates susceptibility to the drug in in vitro profiles, resistance develops rapidly during treatment.90Rifampin is sometimes used as adjuvant therapy in complicated invasive MRSA infections, although data supporting this use are limited.77 Additionally, there is in vitro evidence of an antagonistic effect when rifampin is combined with TMP-SMX.75

Fluoroquinolones

Fluoroquinolones should not be used to treat SSTIs due to MRSA. Many MRSA strains have been shown to be fluoroquinolone-resistant, and even in susceptible strains, resistance can develop rapidly.2,48,91None of the fluoroquinolones are FDA-approved for the treatment of MRSA infections; however, ciprofloxacin and levofloxacin are FDA-approved for the treatment of complicated skin infections while ciprofloxacin, levofloxacin, and moxifloxacin are FDA-approved for the treatment of uncomplicated skin infections due to S aureus in adults.

Macrolides

Erythromycin, clarithromycin, and azithromycin are all FDA-approved for the treatment of uncomplicated skin infections. Due to high rates of resistance, however, these drugs should not be used for CAMRSA.2,48

Vancomycin

Vancomycin is the standard of care for patients with MRSA requiring parenteral treatment and hospitalization; however, S aureus strains with reduced susceptibility to vancomycin have emerged, and there have been increasing MICs for S aureus (the socalled “MIC creep”).92,93 In addition, vancomycin is inferior to beta-lactams for S aureus bacteremia and endocarditis, and some data suggest inferior efficacy compared with antistaphylococcal beta-lactams for MSSA. Other data suggest that linezolid may be more efficacious for CA-MRSA-related pneumonia. Tissue penetration is variable.

The recommended vancomycin dosage is 15 to 20 mg/kg (every 8-12 hours if renal function is normal; adjusted dosing interval if the patient has reduced creatinine clearance rate); the maximum dose is 2 g. In critically ill patients, a loading dose of 25 to 30 mg/kg can be used. After patients are admitted, measurements of vancomycin trough levels subsequently inform the dosage.79,80,94 Vancomycin is classified as pregnancy category C.

In general, the alternatives to vancomycin (linezolid, daptomycin, tigecycline, and telavancin) are not recommended for empiric use in the ED. They should be reserved for use in patients who are unable to tolerate vancomycin or in patients with infections with known or suspected resistance to vancomycin.

Linezolid

Linezolid is FDA-approved for the treatment of SSTIs and nosocomial pneumonia due to MRSA in adults and children. S aureus resistance is rare, and when it does occur, it is associated with long-term use of the drug.

In addition to being active against virtually all CA-MRSA isolates, linezolid is active against S pyogenes. Linezolid also has the ability to suppress toxin production.

Linezolid appears to penetrate pulmonary tissues and lung epithelial lining fluid more effectively than vancomycin and may therefore offer an advantage over the latter. There are no head-to-head studies of vancomycin versus linezolid in treating CA-MRSArelated CAP, but there are studies comparing the 2 drugs in the treatment of HA-MRSA in ventilator and nosocomial pneumonias. Although efficacy data for use of linezolid in pneumonia are positive, there is concern about its use in endocarditis because it lacks bacteriocidal activity (this activity is important in treating endovascular infections).

The recommended dosage for linezolid is 600 mg twice daily for both oral and IV formulations. Linezolid has excellent oral bioavailability79,80 and is a pregnancy category C drug. Adverse effects include myelosuppression and peripheral and optic neuropathies (mostly with prolonged use). Linezolid is a weak inhibitor of monamine oxidase and has been associated with serotonin syndrome in patients on selective serotonin reuptake inhibitors. Linezolid is also very expensive compared with other orally available drugs for CA-MRSA.

Daptomycin

Daptomycin is FDA-approved for complicated SSTIs in adults and children and for S aureus bacteremia and right-sided endocarditis.95 Daptomycin is inactivated by pulmonary surfactant and thus should not be used for pneumonia.96 Resistant strains can emerge during therapy. There may be cross-resistance with vancomycin; exposure to vancomycin may affect bacterial susceptibility to daptomycin due to cell wall changes.

The recommended dosage for daptomycin is 4 mg/ kg IV daily. Higher doses of 6 mg/kg are recommended for treating bacteremia and endocarditis.79,80 Daptomycin is classified as pregnancy category B. An important side effect is muscle toxicity.

Tigecycline

Tigecycline is a tetracycline derivative that is FDAapproved for SSTIs due to MRSA and MSSA and for intra-abdominal infections caused by MSSA in adults. The recommended dosage of tigecycline is 100 mg IV 1 time, then 50 mg IV every 12 hours.80,97The drug is pregnancy category D and is not recommended in children younger than 8 years. Tigecycline is contraindicated in pregnancy and children due to potential deposition in teeth and bones.

Telavancin

Telavancin was recently approved by the FDA for treatment of complicated SSTIs in adults.98 It is a pregnancy category C drug and has been associated with serious nephrotoxicity.

Treatment Of Uncomplicated SSTIs

Abscess

Incision and drainage is the primary treatment for skin abscesses and furuncles. Adequate incision and drainage with thorough exploration for loculations is important for resolution of the abscess. Packing of the wound is usually recommended; however, a recent small clinical pilot study involving 48 patients has challenged the dogma that packing is necessary. Results showed similar outcomes in patients who did and did not receive packing, with less pain experienced by the latter group.99

Is Incision And Drainage Sufficient In The Era Of CAMRSA?

Prior to the emergence of CA-MRSA, the recommended treatment for uncomplicated abscesses was incision and drainage alone, without the need for antimicrobials. Several older studies corroborated the efficacy of this approach, demonstrating no benefits with the addition of antibiotics.100-103 Despite this evidence, many practitioners have continued to prescribe beta-lactam antibiotics for abscesses after incision and drainage.104

Data on the use of antibiotics to treat abscesses due to CA-MRSA are limited. No study has specifically examined the impact of comorbidities or cellulitis. Nevertheless, available data—mostly from observational or small studies—suggest that antibiotics are unnecessary for the treatment of uncomplicated or simple skin abscesses, even in the era of CA-MRSA.

Abscess Size

Expert opinions and treatment recommendations, including The Sanford Guide to Antimicrobial Therapy, state that incision and drainage alone is likely sufficient for abscesses smaller than 5 cm. This size cutoff is based on only one small study: a prospective observational study by Lee et al involving 69 children with abscesses that grew CA-MRSA. Results indicated that incision and drainage alone failed to resolve infected sites greater than 5 cm in diameter.49 The incision and drainage procedure was not standardized across the study, so it is possible that inadequate procedures and not abscess size or use of antibiotics was the culprit in treatment failure. In addition, the use of “less than 5 cm” as the definition of a “small” abscess not requiring antibiotics may be inappropriate for some bodily locations.

Several small retrospective studies of simple abscesses caused by CA-MRSA found no differences if a beta-lactam drug or drug active against CA-MRSA was used for treatment, suggesting that incision and drainage alone is sufficient.37,46,105 A retrospective cohort study of 441 abscesses due to CA-MRSA and MSSA found full resolution in 99.6% of patients treated with discordant antibiotics and in 98.8% of those treated with concordant antibiotics.106 In the prospective observational study by Lee et al discussed previously, 94% of subjects treated with discordant antibiotics improved.49

Treatment information available for 406 patients in the EMERGEncy ID Net study by Moran et al also suggests that incision and drainage alone is sufficient to cure MRSA infections. In the study, 19% of patients had incision and drainage alone, and 66% received both incision and drainage and antibiotics (most commonly the beta-lactam agents cephalexin and dicloxacillin). In 100 of 175 MRSA infections for which antibiotic treatment was provided (57%), antibiotic therapy was discordant with the results of susceptibility testing; however, there was no difference in outcomes between patients whose MRSA isolate was discordant and those in whom the isolate was concordant with the prescribed antibiotic.2

In a prospective, randomized, double-blind singlesite study by Rajendran et al of uncomplicated skin abscesses, 87.8% of which were identified as CA-MRSA isolates, cure rates after incision and drainage were 84.1% in patients who also received cephalexin and 90.5% in those who received placebo. The high cure rates again suggest that incision and drainage alone is sufficient.52Unfortunately, there was no treatment arm receiving a drug active against CA-MRSA, so any potential improvement in outcome could not be determined.

A small difference in outcome with the addition of an antibiotic effective against CA-MRSA was found in a retrospective cohort study of 531 patients by Ruhe et al.50 Most patients underwent incision and drainage. Treatment failure occurred in 45 of these patients (8%). A significant difference was found in rates of treatment failure, with a 5% failure rate for those receiving antibiotics effective against CA-MRSA and a 13% failure rate for those receiving antibiotics ineffective against CA-MRSA. Use of a CA-MRSA-inactive antibiotic was an independent predictor of treatment failure (adjusted odds ratio, 2.80; 95% CI, 1.26-6.22). A second retrospective review of 399 patients at a single outpatient site in Boston also found that the use of a concordant antibiotic was associated with increased likelihood of clinical resolution (adjusted odds ratio, 5.91) when controlling for incision and drainage and HIV status.51A review of available evidence by Hankin in 2007 supports that incision and drainage alone for simple abscess is adequate.107

When Should Antibiotics Be Considered For An Abscess?

Determining which abscesses will benefit from empiric antibiotic coverage is an area of controversy that has not been specifically studied.108 Guidelines from CDC and IDSA regarding this question are based primarily on expert opinion.4,5 Factors integral to deciding whether to add empiric antimicrobial coverage after an incision and drainage procedure include associated cellulitis; lymphangitis; signs and symptoms of systemic illness (eg, fever, hemodynamic instability); associated comorbidities such as diabetes mellitus, HIV, and other immunosuppressive states; extremes of age; location of the abscess (eg, proximity to joints or vital structures, areas that may be difficult to drain completely, and areas prone to complication such as the central face); and lack of response to initial incision and drainage (although the drainage may have been inadequate or further incision and drainage may be needed).

One retrospective single-site study of 50 consecutive cases with a high prevalence of CA-MRSA measured compliance with a treatment algorithm based on categorization of SSTIs into 3 arms: cellulitis/ folliculitis, simple abscess, and complicated abscess. The failure rate was only 3% when treatment conformed to the algorithm, but it climbed to 62% when the algorithm was not followed. The study design selected for complicated infections with significant comorbidities.109

Data are needed to determine whether adding antibiotics limits the progression to more severe or invasive disease, decreases the time to resolution of the infection, and decreases the rate of recurrence (and the subsets of patients in which this occurs). See Table 9, for factors that should be taken into account when considering whether to add antibiotics to the management of abscesses.


Antibiotics For Purulent Infections With Cellulitis

Prior to the emergence of CA-MRSA, the usual practice was to treat SSTIs with drugs that have good activity against MSSA and S pyogenes, typically penicillinase- resistant semisynthetic penicillins such as dicloxacillin or with first-generation cephalosporins such as cephalexin. This practice is no longer acceptable in the era of CA-MRSA. Purulent infections have a high likelihood of CA-MRSA, and treatment should include an antimicrobial agent that is active against it. When there is an abscess with cellulitis, the decision to also cover for S pyogenes is murky. With purulent cellulitis, CA-MRSA should probably be covered. Note that the literature contains no detailed descriptions of what constitutes an abscess with cellulitis versus cellulitis with purulent drainage.

Cellulitis

Cellulitis is likely to be due to S pyogenes, and treatment should include an antimicrobial agent that is active against this organism. As mentioned previously, CA-MRSA’s role in nonpurulent SSTIs is unknown. The decision to cover for both S pyogenesand CA-MRSA in uncomplicated cellulitis without purulent drainage is controversial, with little guiding data.

Coverage for both CA-MRSA and S pyogenes should be considered in the following scenarios:

  • An abscess with significant cellulitis
  • Cellulitis with purulent drainage
  • “Pure” cellulitis, particularly with signs of systemic toxicity, presence of comorbidities, or in a critical anatomic location

Possible choices for covering both CA-MRSA and S pyogenes include the following agents:

  1. A combination of TMP-SMX (or possibly doxycycline or minocycline, depending on local sensitivity) PLUS beta-lactam antibiotic (cephalexin or dicloxacillin)
  2. Clindamycin alone (but beware of local resistance patterns and the possibility of inducible resistance)
  3. Linezolid alone (however, it is expensive and potentially has more side effects)

Disposition And Duration Of Treatment For SSTIs

Ideally, patients should have a follow-up reevaluation of their infection within 24 to 48 hours of treatment to verify the clinical response.4,5 There are no studies to guide admission decisions. Expert opinion, as well as common sense, suggest that patients should be admitted if they have a SSTI accompanied by signs or symptoms of systemic toxicity.

The IDSA guidelines recommend that treatment for uncomplicated cellulitis should continue for 5 days. One study has demonstrated this duration is as effective as a 10-day treatment course.110 Other expert opinions suggest that the clinical response should guide the duration of therapy. This may not be practical for many ED patients with limited access to outpatient follow-up care, however.

Treatment Of Complicated SSTIs

Coverage for complicated SSTIs should include an agent that is active against CA-MRSA. Parenteral treatment should be considered for extensive soft tissue infections with signs of systemic illness including fever or in the presence of diabetes mellitus or an immune deficiency disease.

Vancomycin is the standard of care for moderate to severe infections. Clindamycin may also be considered, because it covers S pyogenes and some anaerobes, and also offers the advantage of decreasing exotoxin production. Emergency clinicians should be aware of local resistance patterns, however, as well as the possibility of inducible resistance. Due to potential resistance problems, many experts do not recommend clindamycin as monotherapy for complicated SSTIs or invasive infections.

Linezolid has been shown to be as effective as vancomycin for SSTI.111 One study demonstrated that linezolid is preferable for treating MRSA in complicated SSTIs,112 although another study disputed this finding.113

Linezolid, daptomycin, and tigecycline have demonstrated efficacy in prospective controlled trials involving serious MRSA infections.114 The agents have not been studied in head-to-head trials, however, so their relative efficacies are unknown.

The incidence of CA-MRSA in diabetic foot infections is unknown, but current expert recommendations (eg, The Sanford Guide to Antimicrobial Therapy) advocate including CA-MRSA coverage.80The current IDSA guidelines for diabetic foot infections were written before the dramatic rise in CAMRSA infections and recommends coverage in areas with a high prevalence of the bacterial strain.115

Treatment Of Necrotizing Infections

Necrotizing infections require prompt recognition, critical care resuscitation, surgical debridement, and broad-spectrum antibiotics. Empiric antimicrobials should include vancomycin for coverage of MRSA. The inclusion of an agent capable of inhibiting toxin formation (eg, clindamycin or linezolid) is also believed to be of benefit. The Sanford Guide to Antimicrobial Therapy discourages adding linezolid to vancomycin because of a potential antagonistic interaction.80

Treatment Of Severe Community-Acquired Pneumonia

The current IDSA/American Thoracic Society guidelines for treatment of severe CAP include the addition of vancomycin or linezolid for coverage of suspected CA-MRSA.116 High failure rates for MRSA in nosocomial infections treated with vancomycin have been attributed to its poor penetration into lung tissue. Linezolid is a viable alternative to vancomycin, but no head-to-head studies have compared the drugs’ efficacy in treating CAP. Several studies of nosocomial HA-MRSA have informed recommendations for CA-MRSA-related pneumonia in the absence of specific clinical trials. A retrospective, pooled subgroup analysis found higher cure rates and improved survival with linezolid versus vancomycin,117 although 2 prospective studies showed comparable cure rates for the drugs,118,119 and a randomized study comparing them found no significant differences.120 Daptomycin is inactivated by pulmonary surfactant and should not be used for pneumonia.

Wallin et al has recommended adding clindamycin or linezolid to treatment for life-threatening infections due to their ability to counteract toxin production. The CDC’s CA-MRSA guidelines suggest consulting with the hospital infectious diseases department regarding linezolid use in this situation.5

Publication Information
Authors

Denise Nassisi

Publication Date

October 1, 2010

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