File, Thomas M. Jr MD
In January 2011, the Infectious Diseases Society of America (IDSA) released their first guideline for management of methicillin-resistant Staphylococcus aureus (MRSA) infections (available at www.idsociety.org).1 The following are selected recommendations from this new guideline (specific recommendations are graded as to the strength of recommendation, with A being the strongest, and the level of evidence, with I being the highest.):
* For simple abscesses or boils, incision and drainage alone is likely to be adequate (A-II).
* Antibiotic therapy is recommended for abscesses associated with the following conditions: severe or extensive disease (eg, involving multiple sites of infection) or rapid progression in the presence of associated cellulitis, signs and symptoms of systemic illness, associated comorbidities or immunosuppression, extremes of age, abscess in an area difficult to drain (eg, face, hand, and genitalia), associated septic phlebitis, and lack of response to incision and drainage alone (A-III).
* For outpatients with purulent cellulitis (eg, cellulitis associated with purulent drainage or exudate in the absence of a drainable abscess), empirical therapy for community-associated MRSA (CA-MRSA) is recommended pending culture results. Empirical therapy for infection due to b-hemolytic streptococci is likely to be unnecessary (A-II). For outpatients with nonpurulent cellulitis (eg, cellulitis with no purulent drainage or exudate and no associated abscess), empirical therapy for infection due to b-hemolytic streptococci is recommended (A-II). For empirical coverage of CA-MRSA in outpatients with skin and soft tissue infection (SSTI), oral antibiotic options include the following: clindamycin (A-II), trimethoprim-sulfamethoxazole (TMP-SMX) (A-II), a tetracycline (doxycycline or minocycline) (A-II), and linezolid (A-II). If coverage for both b-hemolytic streptococci and CA-MRSA is desired, options include the following: clindamycin alone (A-II) or TMP-SMX or a tetracycline in combination with a b-lactam (eg, amoxicillin) (A-II) or linezolid alone (A-II).
* Five to 10 days of therapy is recommended but should be individualized on the basis of the patient's clinical response.
As the authors of the guideline acknowledge, the benefit of antibiotics in addition to incision and drainage for simple abscess is controversial. Additional prospective, large-scale studies that are currently underway will provide more definitive answers to this question. The guideline also indicates that, although linezolid is Food and Drug Administration (FDA) approved for skin infections, it has not been shown to be superior to less expensive alternatives in the treatment of these mild infections. In addition, the use of rifampin with another active drug for the treatment of these infections is not recommended in the absence of data to support benefit. Regarding clindamycin, the D-zone test is recommended for erythromycin-resistant, clindamycin-susceptible isolates to detect inducible clindamycin resistance.
* For hospitalized patients with complicated SSTI (cSSTI; defined as patients with deeper soft tissue infections, surgical/traumatic wound infection, major abscesses, cellulitis, and infected ulcers and burns), in addition to surgical debridement and broad-spectrum antibiotics, empirical therapy for MRSA should be considered pending culture data. Options include the following: intravenous vancomycin (A-I), oral (PO) or intravenous linezolid 600 mg twice daily (A-I), daptomycin 4 mg/kg per dose IV once daily (A-I), telavancin 10 mg/kg per dose IV once daily (A-I), and clindamycin 600 mg IV or PO 3 times a day (A-III). A b-lactam antibiotic (eg, cefazolin) may be considered in hospitalized patients with nonpurulent cellulitis with modification to MRSA-active therapy if there is no clinical response (A-II).
* Seven to 14 days of therapy is recommended but should be individualized on the basis of the patient's clinical response.
The Guideline lists several parenteral agents for MRSA, including tigecycline. However, because of a recent FDA warning indicating an increased risk in all-cause mortality with tigecycline versus comparator drugs in a pooled analysis of clinical trials, the drug was not included in these guidelines. On the other hand, the greatest increase in risk of death with tigecycline was seen in patients with ventilator-associated pneumonia, an unapproved use, and there was no significant difference in mortality in complicated skin infection trials (1.4% vs 0.7%; 95% confidence interval, −0.3 to 1.7; www.fda.gov/Drugs/DrugSafety/ucm224370.htm#ds). We have found tigecycline particularly useful as a good option for polymicrobial, anaerobic/aerobic infections that include MRSA-especially for patients with nonsevere infections. Similarly, ceftaroline was not FDA approved at the time of the writing of this guideline, but the guideline recognized this cephalosporin as a potential option pending approval. Again, this can be a nice option especially when MRSA and Enterobacteriaceae are part of a mixed infection.
Cost and susceptibility test results will influence the appropriate use of all these newer agents. As indicated in the guideline, none of these newer agents have demonstrated superiority to vancomycin for MRSA in the primary outcome of randomized clinical trials of complicated skin infections.
* For children with minor skin infections (such as impetigo) and secondarily infected skin lesions (such as eczema, ulcers, or lacerations), mupirocin 2% topical ointment can be used (A-III). Tetracyclines should not be used in children 8 years of age (A-II).
* In hospitalized children with cSSTI, vancomycin is recommended (A-II). If the patient is stable without ongoing bacteremia or intravascular infection, empirical therapy with clindamycin 10 to 13 mg/kg per dose IV every 6 to 8 hours (to administer 40 mg/kg per day) is an option if the clindamycin resistance rate is low (eg, 10%) with transition to oral therapy if the strain is susceptible (A-II). Linezolid 600 mg PO/IV twice daily for children older than 12 years and 10 mg/kg per dose PO/IV every 8 hours for children aged 12 years is an alternative (A-II).
Recurrent Skin Infections
* Preventive educational messages on personal hygiene and appropriate wound care are recommended for all patients with SSTI. Instructions should be provided to maintain good personal hygiene with regular bathing and cleaning of hands with soap and water or an alcohol-based hand gel, particularly after touching the infected skin or an item that has directly contacted a draining wound (A-III). Avoid reusing or sharing personal items (eg, disposable razors, linens, and towels) that have contacted infected skin (A-III).
* Environmental hygiene measures should be considered in patients with recurrent SSTI in the household or community setting: focus cleaning efforts on high-touch surfaces (ie, surfaces that come into frequent contact with people's bare skin each day, such as counters, door knobs, bath tubs, and toilet seats) that may contact bare skin or uncovered infections (C-III). Commercially available cleaners or detergents appropriate for the surface being cleaned should be used according to label instructions for routine cleaning of surfaces (C-III).
* Decolonization may be considered in selected cases if: a patient develops a recurrent SSTI despite optimizing wound care and hygiene measures (C-III), or ongoing transmission is occurring among household members or other close contacts despite optimizing wound care and hygiene measures (C-III).
* Decolonization strategies should be offered in conjunction with ongoing reinforcement of hygiene measures and may include the following: nasal decolonization with mupirocin twice daily for 5 to 10 days (C-III). Nasal decolonization with mupirocin twice daily for 5 to 10 days and topical body decolonization regimens with a skin antiseptic solution (eg, chlorhexidine) for 5 to 14 days or dilute bleach baths (C-III). (For dilute bleach baths, 1 teaspoon per gallon of water [or one fourth cup per one fourth tub or 13 gallons of water] given for 15 minutes twice weekly for 3 months can be considered.)
* Oral antimicrobial therapy is recommended for the treatment of active infection only and is not routinely recommended for decolonization (A-III). An oral agent in combination with rifampin, if the strain is susceptible, may be considered for decolonization if infections recur despite above measures (CIII).
* In cases where household or interpersonal transmission is suspected, personal and environmental hygiene measures in the patient and contacts are recommended (A-III).
Recurrent staphylococcal furunculosis is common and a frustrating condition for patients. This guideline suggests that most experts define recurrent disease as 2 or more discrete infections at different sites within a 6-month period. The approach to this is controversial, and there are subsequently many different strategies that have been suggested. The guideline suggests a multifaceted approach that actively engages the patient in personal and environmental hygiene measures applicable to the household or community setting while also focusing on strategies for decolonization. The concern for emergence of mupirocin resistance is mentioned, and a warning that if "bleach baths" are recommended, patients need to be given clear instructions, given the potential for skin irritation if not adequately diluted.
BACTEREMIA AND ENDOCARDITIS
* For adults with uncomplicated bacteremia (defined as patients with positive blood culture results and the following: exclusion of endocarditis preferably by transthoracic echocardiogram, no implanted prostheses, follow-up blood cultures performed on specimens obtained 2 to 4 days after the initial set that do not grow MRSA, defervescence within 72 hours of initiating effective therapy, and no evidence of metastatic sites of infection), vancomycin (A-II) or daptomycin 6 mg/kg per dose IV once daily (AI) for at least 2 weeks. For complicated bacteremia (defined as patients with positive blood culture results who do not meet criteria for uncomplicated bacteremia), 4 to 6 weeks of therapy is recommended, depending on the extent of infection. Some experts recommend higher dosages of daptomycin at 8 to 10 mg/kg per dose IV once daily (B-III).
* For adults with infective endocarditis, intravenous vancomycin (AII) or daptomycin 6 mg/kg per dose IV once daily (A-I) for 6 weeks is recommended. Some experts recommend higher dosages of daptomycin at 8 to 10 mg/kg per dose IV once daily (B-III).
* In children, vancomycin 15 mg/kg per dose IV every 6 hours is recommended for the treatment of bacteremia and infective endocarditis (A-II). Duration of therapy may range from 2 to 6 weeks depending on source, presence of endovascular infection, and metastatic foci of infection.
The guideline reemphasizes the principle that methicillin-sensitive S. aureus should preferably treated with a beta-lactam agent, which has been known to be more effective than vancomycin for infections due to susceptible isolates. In addition, with the exception of prosthetic valve endocarditis, neither rifampin or gentamicin is recommended in combination with vancomycin. In one study, the duration of bacteremia was longer in the rifampin combination therapy group than in the vancomycin monotherapy group. For prosthetic valve endocarditis, the recommendation is intravenous vancomycin plus rifampin 300 mg PO/IV every 8 hours for at least 6 weeks plus gentamicin 1 mg/kg per dose IV every 8 hours for 2 weeks (B-III) in addition to valve replacement. Data for pediatric infections is limited, and alternative therapy listed includes daptomycin as an option (C-III).
* For hospital-acquired MRSA or CA-MRSA pneumonia, intravenous vancomycin (A-II) or linezolid 600 mg PO/IV twice daily (A-II) or clindamycin 600 mg PO/IV three times daily (B-III) if the strain is susceptible is recommended for 7 to 21 days, depending on the extent of infection.
* In children, intravenous vancomycin is recommended (A-II). If the patient is stable without ongoing bacteremia or intravascular infection, clindamycin 10 to 13 mg/kg per dose IV every 6 to 8 hours (to administer 40 mg/kg per day) can be used as empirical therapy if the clindamycin resistance rate is low (eg, 10%) with transition to oral therapy if the strain is susceptible (A-II). Linezolid 600 mg PO/IV twice daily for children older than 12 years and 10 mg/kg per dose every 8 hours for children 12 years of age is an alternative.
Linezolid would seem to have some theoretical advantages that include better pharmacokinetics into the lung and the possibility to reduce toxin production for CA-MRSA. Despite this, there remains controversy based on the different results of pooled analyses and meta-analyses of clinical trials. Of note, the results of the Zephyr study were not available at the time of the completion of the guideline. This study of MRSA ventilator-associated pneumonia, which was reported at IDSA in Oct 2010 (Kunkle et al, Abstract LB-49), found a clinical benefit of linezolid over vancomcyin in the response rates of the per protocol population (57.5% vs 46.5%, P = 0.042), although there was no significant difference in mortality.
* Antibiotics available for parenteral administration include intravenous vancomycin (B-II) and daptomycin 6 mg/kg per dose IV once daily (B-II). Some antibiotic options with parenteral and oral routes of administration include the following: TMP-SMX 4 mg/kg per dose (TMP component) twice daily in combination with rifampin 600 mg once daily (B-II), linezolid 600 mg twice daily (B-II), and clindamycin 600 mg every 8 hours (B-III).
* The optimal duration of therapy for MRSA osteomyelitis is unknown. A minimum 8-week course is recommended (AII). Some experts suggest an additional 1 to 3 months (and possibly longer for chronic infection or if debridement is not performed) of oral rifampin-based combination therapy with TMP-SMX, doxycycline/minocycline, clindamycin, or a fluoroquinolone, chosen on the basis of susceptibilities (C-III).
* For children with acute hematogenous MRSA osteomyelitis and septic arthritis, intravenous vancomycin is recommended (AII). If the patient is stable without ongoing bacteremia or intravascular infection, clindamycin 10 to 13 mg/kg per dose IV every 6 to 8 hours (to administer 40 mg/kg per day) can be used as empirical therapy if the clindamycin resistance rate is low (eg, 10%) with transition to oral therapy if the strain is susceptible (A-II). The exact duration of therapy should be individualized, but typically, a minimum of 3- to 4-week course is recommended for septic arthritis, and a 4- to 6-week course is recommended for osteomyelitis.
As indicated in the guideline, definitive management of osteomyelitis requires debridement of necrotic bone. The guideline suggests that the addition of rifampin to vancomycin may have some benefit, but the data are mostly circumstantial and if used should not be initiated until bacteremia has cleared (as reviewed for bacteremia above). Clindamycin achieves good bone penetration and has shown good results in noncritically ill children, but data for adults are limited. Duration of therapy is not well defined, and the guideline recommendation for continued oral therapy after 8 weeks of intravenous therapy is nonrobust and primarily indicated if inflammatory markers, such as erythrocyte sedimentation rate and C-reactive protein level, remain elevated.
PROSTHETIC JOINT INFECTION
* For early-onset (2 months after surgery) or acute hematogenous prosthetic joint infections involving a stable implant with short duration (<3 weeks) of symptoms and debridement (but device retention), initiate parenteral therapy plus rifampin 600 mg daily or 300 to 450 mg PO twice daily for 2 weeks followed by rifampin plus a fluoroquinolone, TMP-SMX, a tetracycline or clindamycin for 3 or 6 months for hips and knees, respectively (A-II). Prompt debridement with device removal whenever feasible is recommended for unstable implants, late-onset infections, or in those with long duration (3 weeks) of symptoms (A-II).
Long-term oral suppressive antibiotics (eg, TMP-SMX, a tetracycline, a fluoroquinolone [which should be given in conjunction with rifampin because of the potential emergence of fluoroquinolone resistance, particularly if adequate surgical debridement is not possible], or clindamycin) with or without rifampin may be considered in selected cases, particularly if device removal is not possible (B-III).
Debridement and device removal using a 2-stage exchange arthroplasty is recommended for late-onset infections, unstable implants, or a prolonged duration (3 weeks) of symptoms . For late-onset infections (30 days after implant placement), implant removal was critical to success. For ankle fractures, 6 weeks of therapy after hardware removal seems to be effective. The recommendation for long-term oral suppressive therapy is based on level III data; future guidelines for prosthetic joint infections are being finalized, and it will be interesting to read recommendations for suppressive therapy when this guideline becomes available.
Additional recommendations for CNS infections, vancomycin dosing, interpretation of vancomycin minimum inhibitory concentrations (briefly, if minimum inhibitory concentration is greater than 2 µg/mL, consider alternative agent), and vancomycin failures are provided, and the reader is referred to the guideline for specific details.
© 2011 Lippincott Williams & Wilkins, Inc.