Acute Bacterial Skin Infections: Developments Since the 2005 Infectious Diseases Society of America (IDSA) Guidelines

The Journal of Emergency Medicine, Vol. 44, No. 6, pp. e397–e412, 2013 Copyright Ó 2013 Elsevier Inc. Printed in the USA. All rights reserved 0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2012.11.050

Clinical Reviews ACUTE BACTERIAL SKIN INFECTIONS: DEVELOPMENTS SINCE THE 2005 INFECTIOUS DISEASES SOCIETY OF AMERICA (IDSA) GUIDELINES Gregory J. Moran, MD, FACEP, FAAEM, FIDSA,*† Fredrick M. Abrahamian, DO, FACEP,* Frank LoVecchio, MD, MPH,‡§ and David A. Talan, MD, FACEP, FAAEM, FIDSA*† *Department of Emergency Medicine, Olive View-UCLA Medical Center, Sylmar, California, †Division of Infectious Diseases, Olive View-UCLA Medical Center, Sylmar, California, ‡Department of Emergency Medicine, Banner Good Samaritan Medical Center, and §Department of Emergency Medicine, Maricopa Medical Centers, Phoenix, Arizona Reprint Address: Gregory J. Moran, MD, FACEP, FAAEM, FIDSA, Department of Emergency Medicine, Olive View-UCLA Medical Center, North Annex, 14445 Olive View Drive, Sylmar, CA 91342

, Abstract—Background: Patients with acute bacterial skin and skin structure infections (ABSSSI) commonly present to Emergency Departments (EDs) where physicians encounter a wide spectrum of disease severity. The prevalence of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) has increased in the past decade, and CA-MRSA is now a predominant cause of purulent ABSSSI in the United States (US). Objectives: This article reviews significant developments since the most recent Infectious Diseases Society of America (IDSA) guidelines for the management of ABSSSI in the CAMRSA era, focusing on recent studies and recommendations for managing CA-MRSA, newer antimicrobials with improved MRSA activity, new diagnostic technologies, and options for outpatient parenteral antimicrobial therapy (OPAT). Discussion: The increasing prevalence of CAMRSA has led the IDSA and other organizations to recommend empiric coverage of CA-MRSA for purulent ABSSSI. The availability of rapid MRSA detection assays from skin and soft tissue swabs could potentially facilitate earlier selection of targeted antimicrobial therapy. Several newer intravenous antibiotics with expanded MRSA coverage, including ceftaroline fosamil, daptomycin, linezolid, and telavancin, may be utilized for treatment of ABSSSI. OPAT may be an option for intravenous administration of antibiotics in selected patients and may prevent or shorten hospitalizations, decrease readmission rates, and reduce nosocomial infections and complications. Conclusion: The

growing prevalence of CA-MRSA associated with ABSSSI in the US has a significant impact on clinical management decisions in the ED. Recent availability of new diagnostic testing and therapeutic options may help meet the demand for effective antistaphylococcal agents. Ó 2013 Elsevier Inc. , Keywords—CA-MRSA; cellulitis; abscess; infection; antimicrobial

INTRODUCTION Patients in the United States (US) with acute bacterial skin and skin structure infections (ABSSSI), previously referred to as uncomplicated and complicated skin and skin structure infections, commonly present to Emergency Departments (EDs). A wide spectrum of disease severity, ranging from mild cellulitis to serious lifethreatening necrotizing infections, may be encountered in this setting (1). The mechanisms of injury for wound infections vary from animal bites to gunshot wounds, and in most cases, empiric antibiotic therapy must be initiated before culture and susceptibility results are available. ABSSSI are primarily caused by Gram-positive pathogens, including Staphylococcus aureus and Streptococcus pyogenes, as well as certain Gram-negative and anaerobic bacteria, particularly with polymicrobial

RECEIVED: 12 June 2012; ACCEPTED: 2 November 2012 e397

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Figure 1. Annual visits to United States Emergency Departments for selected acute bacterial skin and skin structure infections (ABSSSI) during the emergence of communityacquired methicillin-resistant Staphylococcus aureus (CA-MRSA), 1993–2005, and proportion of antibiotic regimens active against CA-MRSA (reproduced from reference 14, with permission). *ABSSSI commonly caused by S. aureus were included in the case definition and were defined by the International Classification of Diseases, 9th Revision, Clinical Modification codes for: cellulitis and abscess of finger or toe; other cellulitis and abscess (which includes head, neck, trunk, limbs, and buttocks); cellulitis digit not otherwise specified; felon; impetigo; hidradenitis; other specified diseases of the hair and hair follicle (i.e., folliculitis); infective mastitis; nonpurulent mastitis; breast abscess; or carbuncle and furuncle. yAn antibiotic regimen was considered ‘‘active against CA-MRSA’’ if it contained trimethoprimsulfamethoxazole, tetracycline, doxycycline, clindamycin, rifampin, linezolid, or vancomycin, although resistance to some of these agents does occur. Before 2002, too few prescriptions included an anti-CA-MRSA agent for robust estimates.

infections (2–5). Before the year 2000, methicillinresistant S. aureus (MRSA) was a rare pathogen in community-acquired (CA) infections and was more common in nosocomial infections (6,7). However, the prevalence of CA-MRSA has increased greatly in the past decade, and CA-MRSA is now a predominant cause of purulent ABSSSI in the US (8–16). Infections from MRSA more than doubled during a 5-year period in patients who presented with purulent ABSSSI to a Los Angeles ED, increasing from 29% in 2001 to 64% in 2005 (12). Data from the SENTRY Antimicrobial Surveillance Program evaluating causes of various types of skin and soft tissue infections between 1998 and 2004 indicated that S. aureus was a dominant pathogen globally and accounted for 44.6% of isolates in North America; 35.9% of the isolates were methicillin resistant (5). Although the global epidemiology of CA-MRSA is heterogenous, with multiple clones in some regions, USA300 is the most common strain in communityassociated infections in the US (13,15,17–19). Unlike nosocomial or health care-associated strains, CAMRSA tends to be more virulent and may carry genes that encode the Panton-Valentine leukocidin, a leukotoxin associated with tissue necrosis and more severe disease

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(18,20–22). No clinical or epidemiologic risk factors reliably distinguish CA-MRSA from other pathogens, and CA-MRSA skin infections range from simple cutaneous abscesses to fulminant necrotizing fasciitis (1,2,13,23). Although the rate of treatment failures for ABSSSI remains relatively low in the ED, failures are more likely to occur with S. aureus infections (24). The predominance of CA-MRSA correlates with a dramatic increase in ED visits and hospitalizations in both adult and pediatric patients presenting with ABSSSI (14,15,25,26). Data from the National Hospital Ambulatory Medical Care Survey (NHAMCS) indicate that the annual number of ED visits for ABSSSI nearly tripled since surveillance began in 1993, increasing to 3.4 million visits by 2005 (Figure 1) (14). Another study showed that total hospital admissions for ABSSSI increased by 29% between 2000 and 2004, with the greatest number of admissions among younger patients (age < 65 years) and those with superficial infections (e.g., cellulitis, abscess) (27). When the Infectious Diseases Society of America (IDSA) prepared their 2005 guidelines on the management of skin and soft tissue infections, the role of CAMRSA was not yet recognized, and therefore, empiric treatment of this organism was not recommended (28). In response to the significance of CA-MRSA as a pathogen in ABSSSI, the IDSA and other organizations currently recommend coverage of CA-MRSA for ABSSSI, including purulent cellulitis (29). There is evidence that Emergency Physicians have adopted this and include antibiotics with expanded MRSA activity in the management of ABSSSI (1,13–15,30,31). Compared with data from an earlier survey conducted in 2004, the prevalence of MRSA as a cause of purulent ABSSSI remained stable (59% in both study periods), but physicians’ prescribing patterns significantly changed (13). Antibiotic therapy was discordant with susceptibility testing in 57% (100/175) of patients with MRSA infections who received antibiotics in 2004 (13). By 2008, there was a shift from empiric therapy with b-lactams that lacked MRSA activity to use of a MRSA-active agent in 97% (310/318) of patients (15). Among hospitalized patients, an agent with MRSA activity (primarily vancomycin) was used in 90% (72/80) of patients in 2008, compared with 46% (26/56) of patients in 2004. The NHAMCS also noted a shift; whereas antibiotics active against CA-MRSA were rarely used in 1993, by 2005, 38% of regimens included such agents (Figure 1) (14). In light of the increase in CA-MRSA infections, a group of Emergency Physicians met at a roundtable meeting in San Francisco, California, on October 16, 2011 to discuss newer perspectives in the management of ABSSSI. This article summarizes discussions from the meeting and provides a review of significant

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Table 1. Conditions in Which Antimicrobial Therapy is Recommended after Incision and Drainage of an Abscess Caused by Community-acquired Methicillin-resistant Staphylococcus aureus (CA-MRSA) 1. Severe or extensive disease (e.g., involving multiple sites of infection) or rapid progression in presence of associated cellulitis 2. Signs and symptoms of systemic disease 3. Associated comorbidities or immunosuppression (diabetes mellitus, human immunodeficiency virus infection/acquired immunodeficiency syndrome, neoplasm) 4. Extremes in age 5. Abscess in area difficult to drain completely (e.g., face, hand, genitalia) 6. Associated septic phlebitis 7. Lack of response to incision and drainage alone Reproduced from reference (29), with permission.

developments since the 2005 IDSA guidelines for the management of ABSSSI, including a review of recent studies and recommendations for managing CA-MRSA, newer antimicrobials with improved MRSA activity, new diagnostic technologies, and options for outpatient parenteral antimicrobial therapy (OPAT). DISCUSSION Guidelines in the CA-MRSA Era The increasing prevalence of CA-MRSA impacts selection of empiric antibiotics for ABSSSI, emphasizing use of agents with improved MRSA activity (14). This change is reflected in recent treatment guidelines (29,32–35). In 2011, IDSA published their first guidelines specifically on the treatment of MRSA infections, providing recommendations on management of the most common clinical infections associated with MRSA (29). IDSA recommended antimicrobial therapy after incision and drainage of abscesses caused by CAMRSA (Table 1). For ABSSSI, IDSA recommendations for empiric coverage of CA-MRSA in the outpatient setting included (oral antibiotic options): clindamycin, trimethoprim-sulfamethoxazole, a tetracycline (doxycycline or minocycline), and linezolid. In hospitalized patients, IDSA suggested broad-spectrum antibiotics with empiric agents that cover for MRSA pending culture results, including vancomycin, linezolid, daptomycin, telavancin, and clindamycin. Due to the likelihood of resistance development, rifampin is not recommended for monotherapy in the treatment of MRSA infections. The US Centers for Disease Control and Prevention provided similar recommendations for outpatient management of ABSSSI (32). The 2011 Surgical Infection Society guidelines for ABSSSI suggested that coverage for CA-MRSA be considered in most settings for complicated, non-necrotizing infections (abscesses) because MRSA isolates equal or exceed methicillin-susceptible S. aureus (MSSA) strains in surgical-site infections (33). Vancomycin. Although vancomycin remains the most common choice for parenteral treatment of CA-MRSA

infections in the US, evidence of resistance development and decreased efficacy is emerging (29,34–38). Certain intrinsic limitations of vancomycin, such as poor tissue penetration, relatively slow bactericidal activity, and susceptibility issues, may play a role in treatment failures (39–41). Studies in diverse patient populations (post-surgical, diabetics) indicate that vancomycin tissue concentrations are variable (42). Although not specifically in skin infections, patient outcomes have been associated with vancomycin susceptibility, and higher vancomycin minimum inhibitory concentrations (MICs) may correlate with decreased overall treatment success (37,41,43). Treatment failures and increased morbidity have been reported with strains of S. aureus with decreased vancomycin susceptibility (e.g., vancomycin-intermediate S. aureus [VISA], vancomycin-heteroresistant S. aureus [hVISA], and vancomycin-resistant S. aureus [VRSA]), leading to concerns that clinical failures may be associated with gradual loss of vancomycin activity (40,43,44). In recognition of increasing staphylococcal MIC to vancomycin, in 2006 the Clinical and Laboratory Standards Institute (CLSI) lowered vancomycin MIC breakpoints to #2 mg/L for susceptible strains, 4–8 mg/L for intermediate strains, and $16 mg/L for resistant strains (38). Despite these changes, vancomycin ‘‘MIC creep’’ has been documented in MRSA isolates characterized as susceptible by CLSI criteria, and multi-drug-resistant strains of MRSA have been reported (20,45). Considering poor tissue penetration as a factor, small increases in MIC could result in suboptimal vancomycin concentrations at certain sites of infection. In 2009, the American Society of Health-System Pharmacists, the IDSA, and the Society of Infectious Diseases Pharmacists jointly issued a consensus statement on the therapeutic monitoring of vancomycin in adults (34,35). The panel recommended vancomycin 15–20 mg/kg/ dose (based on actual body weight; not to exceed 2 g/dose) every 8 to 12 h, with a loading dose of 25–30 mg/kg considered for seriously ill patients with MRSA infections. For severe infections, such as necrotizing fasciitis caused by MRSA, higher vancomycin trough

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Table 2. Characteristics of Newer Antimicrobials with Skin Indications (51–54) Ceftaroline Fosamil (Teflaro) Indication(s)

Treatment of the following infections caused by designated susceptible bacteria  Acute bacterial skin and skin structure infections (ABSSSI)  Community-acquired bacterial pneumonia (CABP)

 600 mg i.v. q12h infused over 1 h for 5–14 days in ABSSSI  400 mg i.v. q12h infused over 1 h in patients with CrCL > 30 to #50 mL/min; 300 mg i.v. q12h if CrCL $ 15 to #30 mL/min; 200 mg i.v. q12 h in patients with end-stage renal disease (CrCL < 15 mL/min), including hemodialysis

Use in pregnancy and pediatrics

 Pregnancy category B  It is not known if ceftaroline is excreted in breast milk  Safety and effectiveness in pediatric patients have not been established

Most common adverse events (AEs) ($2%)

 Diarrhea, nausea, constipation, vomiting, increased transaminases, hypokalemia, rash, phlebitis

Linezolid (Zyvox)

 Complicated skin and skin Treatment of the following infections structure infections (cSSSI) caused by designated susceptible  Staphylococcus aureus blood- bacteria stream infections (bacteremia),  Vancomycin-resistant including those with right-sided Enterococcus faecium infective endocarditis infections  Nosocomial pneumonia  Complicated skin and skin structure infections, including diabetic foot infections, without concomitant osteomyelitis  Uncomplicated skin and skin structure infections  Community-acquired pneumonia  4 mg/kg i.v. q24h over 0.5 h in  600 mg i.v. or oral q12h for 0.9% NaCl for 7–14 days in 10–14 days in cSSSI (adults cSSSI and adolescents $ 12 years)  400 mg i.v. q12h infused over 1  400 mg PO q12h for 10–14 h in patients with CrCL $ 10 to days for uncomplicated skin #50 mL/min and skin structure infections  4 mg/kg (cSSSI) i.v. q24h in (adults) patients with CrCL $ 30 mL/  600 mg p.o. q12h for 10–14 min; 4 mg/kg (cSSSI) q48h for days for uncomplicated skin CrCL < 30 mL/min, and skin structure infections including those on (adolescents $ 12 years) hemodialysis  Pregnancy category B  Pregnancy category C  It is not known if daptomycin is  It is not known if linezolid is excreted in breast milk excreted in breast milk  Safety and effectiveness in  Dosing for pediatric patients patients under the age of (birth through 11 years of age) 18 years have not been is based on weight established  Constipation, nausea,  Diarrhea, headache, injection-site reactions, nausea, vomiting, insomnia, headache, diarrhea, insomnia, constipation, rash, rash, vomiting, abnormal liver dizziness, fever (in adults) function tests, pruritus, elevated CPK, fungal infection, urinary tract infection, hypotension, renal failure, dizziness, anemia, dyspnea

Telavancin (Vibativ)  Complicated skin and skin structure infections (cSSSI)

 10 mg/kg i.v. q24h infused over 1 h for 7–14 days  7.5 mg/kg i.v. q24h infused over 1 h in patients with CrCL 30–50 mL/min; 10 mg/kg i.v. q48h in patients with CrCL 10– <30 mL/ min

 Pregnancy category C  It is not known if telavancin is excreted in breast milk  The safety and effectiveness of telavancin in pediatric patients has not been studied  Taste disturbance, nausea, vomiting, foamy urine, diarrhea, dizziness, pruritus, rash, infusion-site pain, rigors, generalized pruritus, decreased appetite, infusion-site erythema, abdominal pain

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Dosage & administration (for skin infections)

Daptomycin (Cubicin)

 No clinical drug–drug interaction studies have been conducted to date  There is minimal potential for drug–drug interactions between ceftaroline and CYP450 substrates, inhibitors, or inducers, drugs known to undergo active renal secretion, and drugs that may alter renal blood flow

 The pharmacokinetics of daptomycin were not altered after coadministration with aztreonam, warfarin, simvastatin, or probenecid  The interaction of daptomycin with tobramycin is unclear

Precautions/warnings*

 Monitor renal function in elderly patients. Higher exposure in elderly subjects is mainly attributed to age-related changes in renal function  Seroconversion from a negative to a positive direct Coombs test result occurred in 10.8% and 4.4% of patients receiving Teflaro and comparator drugs, respectively, in the four pooled phase III clinical trials. If anemia develops during or after therapy, a diagnostic work-up for drug-induced hemolytic anemia should be performed and consideration given to discontinuation of ceftaroline

 In patients with renal insufficiency, both renal function and CPK should be monitored more frequently  Eosinophilic pneumonia has been reported in patients taking daptomycin

 Linezolid is not an inducer of CYP450 and is not expected to affect other drugs metabolized by these enzymes  The pharmacokinetics of linezolid were not altered when coadministered with aztreonam or gentamicin; coadministration with rifampin resulted in 21% decrease in linezolid Cmax  Linezolid is a reversible, non-selective inhibitor of monoamine oxidase and has potential for interaction with adrenergic and serotonergic agents  Myelosuppression (including anemia, leukopenia, pancytopenia, and thrombocytopenia) has been reported  Linezolid should not be used in patients taking products that inhibit monoamine oxidase A or B  Linezolid should not be administered to patients with uncontrolled hypertension, pheochromocytoma, thyrotoxicosis, or patients taking any of the following types of medications: directly and indirectly acting sympathomimetic agents, vasopressive agents, or dopaminergic agents  Linezolid should not be administered to patients with carcinoid syndrome or patients taking any of the following medications: serotonin reuptake inhibitors, tricyclic antidepressants, serotonin 5-HT1 receptor agonists, meperidine or buspirone  Lactic acidosis, peripheral and optic neuropathy, and convulsions have been reported with use of linezolid

 Binds to the artificial phospholipid surfaces added to common anticoagulation tests  Interferes with urine qualitative dipstick protein assays, as well as quantitative dye methods

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Drug interactions

 Avoid use during pregnancy unless potential benefit to patient outweighs potential risk to fetus  New-onset or worsening renal impairment  Decreased efficacy noted with moderate/severe baseline renal impairment  Rapid i.v. infusions of glycopeptides can cause ‘‘Red-man syndrome’’like reactions. Administer over at least 60 min to minimize reactions  Caution is warranted when prescribing telavancin to patients taking drugs known to prolong the QT interval  Interferes with some laboratory coagulation tests, including prothrombin time, international normalized ratio, and activated partial thromboplastin time

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i.v. = intravenous; q12h = every 12 hours; CPK = creatinine phosphokinase; Cmax = maximum plasma concentration; CrCL = creatinine clearance; CYP450 = cytochrome P450; p.o. = oral. * Additional warnings/contraindications: Clostridium difficile-associated diarrhea (CDAD) has been reported with use of nearly all antibacterial agents, and may range in severity from mild diarrhea to fatal colitis. Serious hypersensitivity reactions have been reported with b-lactam antibiotics. As with other antibacterial drugs, use may result in overgrowth of non-susceptible organisms, including fungi.

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concentrations (15–20 mg/L) are recommended to optimize vancomycin pharmacodynamics, improve tissue penetration, and prevent resistance development; however, higher rates of nephrotoxicity may be a concern with trough concentrations >15 mg/L (46). Because attainment of a vancomycin area under the curve/MIC of $400 is unlikely in patients who have S. aureus infections with MICs at the high end of the susceptible range, antibiotics other than vancomycin should be considered when vancomycin MIC values are $2 mg/L (34,35). The IDSA MRSA treatment guidelines note that for most patients with ABSSSI who have normal renal function and are not obese, the traditional vancomycin dose of 1 g every 12 h is adequate and trough monitoring is not required (29). Management of ABSSSI: Newer Therapeutic Options Initial empiric therapy for ABSSSI is based on prediction of the most likely pathogens and should be guided by local antimicrobial susceptibility patterns (1,18,47,48). Although CA-MRSA is resistant to available oral b-lactams and many macrolides and fluoroquinolones, most strains are susceptible to trimethoprim/sulfamethoxazole, clindamycin, and tetracyclines such as doxycycline and minocycline (2,15,18). Susceptibility to clindamycin or doxycycline/minocycline is variable depending on region; resistance to trimethoprim-sulfamethoxazole has been reported rarely (2,18,49). For suspected polymicrobial ABSSSI, treatment should include coverage of enteric Gram-negative and anaerobic pathogens. Intravenous (i.v.) antibiotic therapy may be considered in the context of severe disease, rapid progression, indication of systemic illness, or when incision and drainage is not possible or is ineffective (18,50). Although vancomycin remains one of the most frequently used i.v. antimicrobials for the treatment of serious Grampositive infections in the US, development of resistance and other concerns noted previously underscore the need for antibiotics with activity against MRSA. Several i.v. antimicrobials with MRSA activity are approved for treatment of ABSSSI, including ceftaroline fosamil, daptomycin, linezolid, and telavancin (Table 2) (51–54). Although tigecycline is indicated for ABSSSI, data from clinical trials suggest emergence of resistant isolates, a high incidence of adverse events, and an increased risk of mortality with tigecycline treatment (55,56). The US Food and Drug Administration (FDA) has indicated that alternatives to tigecycline should be considered in patients with serious infections due to an increased risk of mortality compared with other drugs used to treat such infections (57). Traditionally, skin infections were characterized into two general categories: 1) uncomplicated skin and skin

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structure infections and 2) complicated skin and skin structure infections (also termed complicated skin and soft tissue infections). To standardize terminology and define end points to be used in support of drugs seeking indications for treatment of skin infections, the FDA released a draft document on ‘‘Acute Bacterial Skin and Skin Structure Infections: Developing Drugs for Treatment’’ in 2010, which provides guidance on the design of clinical trials for systemic drugs to treat ABSSSI (58). ABSSSI includes cellulitis/erysipelas, wound infections, major cutaneous abscess, and burn infections, in which a reliable estimate of treatment effect of the antibiotic can be described for non-inferiority or superiority trial designs. The hallmark characteristic of the conditions included in the ABSSSI definition is infection accompanied by redness, edema, or induration extending to a minimum surface area of 75 cm2. A superiority trial design is recommended in adults and children with milder skin infections (minor cutaneous abscesses and impetigo) for which a treatment effect of the antibacterial therapy has not been characterized. Previously, non-inferiority trials in ABSSSI used the test-of-cure (TOC) visit as the time point for evaluating clinical cure. Current regulatory guidance recommends that ABSSSI trials evaluate clinical response, defined as cessation of lesion spread and resolution (or absence) of fever, at 48–72 h after initiating therapy as the primary end point for clinical trials. Because the FDA guidance was released in 2010, most published clinical trials evaluating the efficacy of antibiotics for skin infections do not meet all of the current criteria. Thus, specific eligibility criteria are provided for the ABSSSI studies described in the next section and should be considered when evaluating results from clinical trials. Ceftaroline fosamil. Ceftaroline, the active form of ceftaroline fosamil, is a broad-spectrum cephalosporin with potent activity against MRSA. Ceftaroline exerts rapid bactericidal activity by binding to key penicillinbinding proteins (PBPs), with enhanced binding affinity for the PBPs of several resistant pathogens, including MRSA and penicillin-resistant Streptococcus pneumoniae (59,60). Ceftaroline exhibits high affinity for staphylococcal PBPs 1, 2, and 3, particularly for MRSA PBP 2A (61,62). In vitro, ceftaroline has potent bactericidal activity against S. aureus, including vancomycin-intermediate, -heteroresistant, and -resistant strains and daptomycin-non-susceptible isolates (59, 63–67). For MRSA, the majority of isolates in microbiologic studies were inhibited by ceftaroline MIC90 of #1 mg/L (4,65,66,68). International surveillance conducted in 2008 showed that ceftaroline was highly active against pathogens associated with ABSSSI, with low MIC values for MRSA isolates in both the US and Europe (4). Ceftaroline has in vitro

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activity against common Gram-negative bacteria, including Haemophilus influenzae (including b-lactamase-positive isolates), non-extended-spectrum b-lactamaseproducing Klebsiella pneumoniae, and Escherichia coli, but not Pseudomonas aeruginosa (63). Ceftaroline has in vitro activity against specific anaerobic bacteria, including Clostridium species, but not including Bacteroides fragilis or Clostridium difficile (69,70). Ceftaroline fosamil may be considered for empiric monotherapy when polymicrobial infections are suspected. Multi-step resistance selection studies indicate that resistance to ceftaroline is expected to be limited (71,72). Two multi-center, double-blind, randomized clinical trials evaluated the efficacy of ceftaroline in ABSSSI (73–75). The Ceftaroline versus Vancomycin in Skin and Skin-Structure Infection (CANVAS 1 and 2) trials enrolled 1378 adult patients with ABSSSI requiring i.v. therapy who were randomly assigned to receive ceftaroline fosamil 600 mg every 12 h (n = 693) or vancomycin plus aztreonam (1 g each; aztreonam was discontinued if a Gram-negative pathogen was not identified or suspected) every 12 h (n = 685) for 5–14 days (73). Eligibility criteria included patients with three or more clinical signs of infection (e.g., fever, purulent discharge, erythema) and involvement of deep soft tissue or infections requiring significant surgical intervention, such as wounds with purulent drainage or $5 cm of cellulitis, major abscess surrounded by $2 cm cellulitis, or cellulitis with surface area $10 cm2, or lower-extremity cellulitis or abscess in patients with diabetes or peripheral vascular disease. Patients were excluded if they had creatinine clearance (CrCL) # 30 mL/min; >24 h of antimicrobial therapy in the previous 96 h, unless there was evidence of clinical and microbiologic failure after 48 h of therapy; evidence of vancomycin- or aztreonamresistant pathogens, including known P. aeruginosa or anaerobic infection; osteomyelitis or septic arthritis; necrotizing fasciitis; human or animal bite; diabetic foot ulcer; decubitus ulcer; gangrene; burn covering > 5% of the body; mediastinitis; or required surgical intervention that could not be performed within 48 h after initiation of therapy. Clinical cure was assessed at the TOC visit, which occurred 8–15 days after the last dose of study drug. Additionally, relevant data were collected during the study for assessment of clinical response at day 3 (76). Integrated analysis showed that disease severity was consistent between the two groups, with cellulitis, major abscess, and infected wound accounting for the majority of infections. S. aureus was the most common pathogen isolated, with MRSA accounting for 40% of infections in the ceftaroline group and 34% in the vancomycin plus aztreonam group. Ceftaroline fosamil was non-inferior to vancomycin plus aztreonam in treated patients with

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ABSSSI caused by Gram-positive and -negative pathogens. The clinical cure rate at TOC was 91.6% for ceftaroline, compared with 92.7% with vancomycin plus aztreonam in the clinically evaluable (CE) population and 92.7% for ceftaroline vs. 94.4% for vancomycin plus aztreonam in the microbiologically evaluable (ME) population. The clinical cure rate for MRSA was 93.4% and 94.3%, respectively. The clinical response rate (cessation of infection spread and absence of fever) on day 3 was 74.0% (296/400) in patients treated with ceftaroline fosamil, compared with 66.2% (263/397) in patients who received vancomycin plus aztreonam, indicating a numerically higher early clinical response with ceftaroline fosamil monotherapy (difference 7.8%; 95% confidence interval [CI] 1.3–14). Susceptibility testing showed that 96.8% of all isolates evaluated in the CANVAS trials were inhibited at ceftaroline MIC of 2 mg/L (59). Consistent with the safety profile associated with the cephalosporin class, ceftaroline is well tolerated. Integrated safety summary of the CANVAS studies showed that the incidence of serious adverse events was 4.3% with ceftaroline and 4.1% with vancomycin plus aztreonam, and the majority of patients (>75%) had either no or mild treatment-emergent adverse events (TEAEs) (77). The most common TEAEs reported with ceftaroline included nausea, headache, diarrhea, and pruritus. Daptomycin.Daptomycin is a cyclic lipopeptide antibiotic with activity against a wide spectrum of Gram-positive organisms, including MRSA (78,79). Daptomycin exerts bactericidal activity in a unique concentrationdependent manner by disrupting cell-membrane function via calcium-dependent binding. It has excellent in vitro bactericidal activity against MRSA (51,80,81). Surveillance analysis of data collected from 32 US medical centers from 2005 to 2010 showed that daptomycin maintained a 99.94% susceptibility rate for MRSA (82). Among MRSA, only 0.11% of isolates were not susceptible to daptomycin, and there was no trend toward higher resistance during the study. Treatment failures associated with daptomycin-non-susceptible isolates have been reported, and resistance was induced by serial passage with increasing concentrations of daptomycin (80,83,84). Although the mechanism of resistance to daptomycin is unclear, genetic mutations have been described in S. aureus isolates with daptomycin MICs > 1 mg/L. There is evidence of cross-resistance with vancomycin. Elevated vancomycin MICs may be associated with similar shifts in daptomycin MICs, although increased vancomycin MICs for S. aureus have not been shown to be a predictor of daptomycin failure (85). Daptomycin is not active against aerobic or anaerobic Gramnegative bacteria.

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Daptomycin was evaluated in clinical trials for the treatment of ABSSSI (86–88). Two randomized, controlled, phase 3 clinical trials evaluated the efficacy of daptomycin 4 mg/kg every 24 h for 7–14 days compared with conventional antibiotics (semi-synthetic penicillins 4–12 g/d or vancomycin 1 g every 12 h) in 1092 patients with ABSSSI (86). Patients with infections caused by Gram-positive organisms, including wound infections (surgical wounds, trauma, and bites), major abscesses, infected diabetic ulcers, and ulcers due to other causes (vascular insufficiency) were included in the study. Patients with minor or superficial infections (e.g., simple abscesses), perirectal abscesses, gangrene, multiple infected ulcers at distant sites, third-degree burns, or known bacteremia at enrollment were excluded, as were those who required amputations or had concomitant infections at another site (e.g., osteomyelitis, endocarditis, septic arthritis). Clinical success, determined at the TOC visit (6–20 days after receipt of last dose), was based on resolution of signs and symptoms such that no further antibiotic treatment was required. MRSA was isolated in 9.3% and 10% of the daptomycin and comparator groups, respectively. Daptomycin had a clinical success rate of 83.4% compared with 84.2% with the comparator treatment group among the 902 CE patients; similar rates were reported in the ME patients. Among patients successfully treated with i.v. therapy alone, patients receiving daptomycin had shorter duration of therapy; 63% of daptomycin-treated patients, compared with 33% in the comparator group, required only 4–7 days of therapy (p < 0.0001). In an open-label, prospective study, 53 patients with ABSSSI at risk for MRSA were treated with daptomycin 4 mg/kg/d for 3–14 days and compared with 212 matched historical controls who received at least 3 days of vancomycin therapy at a dose sufficient to achieve a trough concentration of 5–20 mg/L (87). Eligible patients included adults with ABSSSI (specifics not reported) who had at least three local signs and symptoms of infection, such as pain, tenderness, swelling, erythema, or discharge. Patients were excluded if they had gas gangrene, progressive necrotizing infections, osteomyelitis, documented bacteremia or endocarditis, pathogens identified as nonsusceptible to daptomycin, requirement of non-study antibiotics active against S. aureus for other reasons during the study, 24 h or more of treatment with another i.v. antistaphylococcal antibiotic, infections associated with prosthetic hardware, weight of more than 150 kg or <40 kg, estimated CrCL < 30 mL/min, life expectancy of <3 months, burns over > 30% of body surface area, and pregnant or nursing women. MRSA was isolated in 42% of patients in the daptomycin group and 75% of patients in the vancomycin group (p < 0.001). A higher proportion of patients treated with daptomycin achieved clinical success,

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defined as absence of all pretreatment signs and symptoms of infection or no continued antibiotic therapy deemed necessary, by day 3 (90% daptomycin vs. 70% vancomycin; p < 0.01) and day 5 (98% daptomycin vs. 81% vancomycin; p < 0.01). A retrospective analysis of data from the Cubicin Outcomes Registry and Experience 2004 registry, which includes 45 institutions, assessed clinical response to daptomycin therapy in 165 patients with ABSSSI (88). Patients were eligible for inclusion in the registry if they had infections involving deep soft tissue; infections requiring surgical intervention (ulcers, burns, and major abscesses); infections in patients with significant underlying disease states that complicate response to antibiotic treatment; and infections typically requiring i.v. therapy, such as non-surgical wounds, major abscesses, surgicalsite infections, diabetic foot ulcers, and non-diabetic ulcers. Patients with uncomplicated cellulitis, simple abscess, erysipelas, furuncles, acne, and impetigo were excluded. The majority of patients were treated with daptomycin 4–6 mg/kg once daily, and 86.7% (n = 143) of patients had culture-confirmed MRSA infections. Clinical success, defined as an outcome of cure (resolution of clinical signs and symptoms or no additional need for antibiotic therapy) or improved (partial resolution of clinical symptoms or need for additional antibiotic therapy at end of therapy), was achieved by 89.7% of patients with MRSA and 85% with MSSA infections. In the group that had a successful outcome, median time to clinical response was 3.5 days in patients with MRSA and 2.0 days in those with MSSA infections. Total median days of therapy with daptomycin was 13 days in the patients with MRSA and 11 days in patients with MSSA. Myopathy, manifesting as muscle weakness and pain, and associated with elevated creatine phosphokinase (CPK) concentrations, has been reported with daptomycin, particularly with higher doses (89–92). In clinical trials, the most commonly reported adverse events with daptomycin included constipation, nausea, injection-site reactions, headache, diarrhea, insomnia, rash, vomiting, abnormal liver function tests, pruritus, elevated CPK, fungal infection, urinary tract infection, hypotension, renal failure, dizziness, anemia, and dyspnea (51). In 2010, the FDA issued a warning about the potential for development of eosinophilic pneumonia during treatment with daptomycin (93). Linezolid. Available in both i.v. and oral formulations with approximately 100% oral bioavailability, linezolid is a synthetic oxazolidinone that inhibits initiation of protein synthesis by selectively binding to the 50S ribosomal unit (94,95). Overall concentration of linezolid in soft tissues is similar to plasma concentrations (42). Linezolid exerts bacteriostatic activity against Gram-positive

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pathogens and is highly active against staphylococci, including MRSA, VISA, and VRSA (96,97). Surveillance data since 2009 indicate that linezolid remains active against >99% of S. aureus strains, with very low rates of resistance noted (0.34% overall) (64,98,99). Cases of linezolid resistance have been reported and may be associated with prolonged drug exposure as well as prior linezolid administration (98,100). Resistance to linezolid is likely mediated by mutation of 23S rRNA (101). Linezolid is not active against aerobic or anaerobic Gram-negative pathogens. Numerous studies have evaluated the efficacy of linezolid vs. vancomycin or other comparators in the management of ABSSSI, with variable outcomes due to inconsistent reporting of the clinical and microbiologic efficacy data (102–107). A randomized, open-label, multi-center trial compared linezolid 600 mg every 12 h (n = 592) with vancomycin 1 g every 12 h (n = 588) for 7–14 days (duration of treatment could extend from 4– 21 days) in patients with Gram-positive-complicated ABSSSI (104). Entry criteria included patients with suspected or proven MRSA infections involving substantial areas of skin or deeper soft tissues, such as cellulitis, abscesses, infected ulcers, or burns (<10% of total body surface). Exclusions included patients with Gram-negative infections, osteomyelitis, endocarditis, meningitis, septic arthritis, necrotizing fasciitis, gas gangrene, infected devices that were not removed, superficial skin infections, and hypersensitivity to the study medications. Clinical cure was defined as complete resolution of all pretherapy clinical signs and symptoms of infection (eg, body temperature and white blood cell count). In the intent-to-treat population, 92.2% of patients treated with linezolid were clinically cured at the TOC visit (7 days after the end of therapy), compared with 88.5% of patients treated with vancomycin (p = 0.057). MRSA (42%) was the most commonly isolated pathogen at baseline. In the subset of patients with MRSA infections in the ME population, linezolid outcomes were superior to vancomycin at the TOC visit (88.6% [124/140] vs. 66.9% [97/145], respectively; p < 0.001). Symptom scores returned to baseline at day 4 in 70% of linezolid-treated patients compared with 62% in the vancomycin-treated group (p = 0.044). However, treatment duration was longer in the linezolid group than for patients receiving vancomycin (overall mean treatment duration was 11.8 6 4.9 days for linezolid, compared with 10.9 6 5.3 days for vancomycin; p < 0.004). A meta-analysis identified five prospective, randomized, controlled open-label trials with a total of 2652 patients evaluating linezolid (n = 1361) and vancomycin (n = 1291) in the treatment of MRSA-complicated ABSSSI (107). In all trials, linezolid 600 mg was given either i.v. or orally every 12 h and vancomycin

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1000 mg i.v. was given every 12 h; treatment duration ranged from 4 to 28 days. Efficacy outcomes were reported at the TOC visit (7–21 days after the end of treatment) in all studies. The modified intent-to-treat (MITT) population had culture-confirmed Gram-positive infection (S. aureus) at baseline and success was defined as eradication of the Gram-positive pathogen upon culture. The MRSA-evaluable population met the MITT criteria and had a positive culture for MRSA; success was defined as eradication of MRSA upon culture. Clinical resolution of infection in the CE population initially favored use of linezolid (odds ratio [OR] 1.41; 95% CI 1.03–1.95), but this result was no longer significant after removal of the most heavily weighted study (OR 1.29; 95% CI 0.81– 2.05). In the MITT population, patients on linezolid were more likely to achieve microbiologic eradication compared with those on vancomycin treatment (OR 1.91; 95% CI 1.33–2.76). However, these differences also were non-significant after sensitivity analyses (MITT: OR 1.73; 95% CI 0.87–3.41). MRSA-evaluable patients treated with linezolid (n = 289) were more likely to achieve microbiologic eradication compared with vancomycin-treated patients (n = 273) (OR 2.90; 95% CI 1.90–4.41), an effect that remained significant with sensitivity analysis (OR 2.24; 95% CI 1.26–3.99). There was no difference in mortality between groups. A higher proportion of patients treated with linezolid, compared with vancomycin treatment, reported diarrhea (119/ 1361 vs. 52/1291), nausea (102/1361 vs. 46/1291), and thrombocytopenia (52/1121 vs. 8/1071). In phase 3 clinical trials, adverse events were significantly more common in patients treated with linezolid than in comparator groups, although discontinuation rates were comparable (108,109). Gastrointestinal adverse events, including nausea and diarrhea, and headache are the most common adverse events reported with linezolid. Prolonged use of linezolid (>28 days) has been associated with various adverse events that may affect clinical utility, including peripheral and optical neuropathy, hematological abnormalities, and hyperlactatemia (108,109) (Table 2). More than 50 cases of neuropathy associated with linezolid therapy have been reported, and development of neuropathy warrants discontinuation of therapy; recovery from peripheral neuropathy may be limited (109). Myelosuppression, including thrombocytopenia and anemia, has been observed when linezolid is administered for longer than 14 days, although decreases in platelet count may occur earlier in some patients (104,107,110,111). The incidence of linezolid-related thrombocytopenia is likely higher than the 2.4% reported in early clinical trials, and certain patient populations, such as those with malignancies, may be at increased risk (109). Although no specific treatment exists for linezolid-mediated thrombocytopenia, platelet

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counts typically return to normal after discontinuation of therapy. In the case of anemia, patients can be managed with transfusions, and hemoglobin normalizes after discontinuation of the drug. Linezolid has the potential for significant drug interactions with serotonin modulators (e.g., selective serotonin reuptake inhibitor; serotonin norepinephrine reuptake inhibitor) that may lead to serotonin syndrome, which manifests with marked hypertension, tachycardia, hyperthermia ($40 C), and general muscle rigidity (109,112). Linezolid may also interact with sympathomimetic agents (e.g., diphenhydramine), manifesting as significantly increased blood pressure. An alternative antibiotic should be considered in patients taking these medications. Telavancin. Telavancin is a semi-synthetic, vancomycinderived lipoglycopeptide that inhibits cell-wall synthesis by binding to peptidoglycan chain precursors, causing cell-membrane depolarization (113). Telavancin exerts concentration-dependent, bactericidal activity against Gram-positive pathogens, including drug-resistant staphylococci (MRSA and hVISA), streptococci, and enterococci (114,115). Telavancin demonstrated potent in vitro activity when tested against 24,017 Gram-positive isolates, including S. aureus, coagulase-negative Staphylococcus spp., and various Streptococcus spp. from North America, Latin America, Europe, and Asia (115). In all regions, telavancin was highly active against S. aureus. Analysis of 1530 aerobic Gram-positive isolates identified during clinical studies using telavancin for the treatment of ABSSSI indicated that all evaluated staphylococcal, streptococcal, and enterococcal isolates were inhibited by #1 mg/L of telavancin (116). Telavancin seems to have low potential for resistant mutant selection (117). Evaluation of drug concentrations in skin blister fluid in eight healthy volunteers indicated that telavancin achieves sufficient levels in tissue to eradicate Grampositive pathogens (118). Telavancin is not active against aerobic or anaerobic Gram-negative pathogens. The efficacy of telavancin in the treatment of ABSSSI was evaluated in several clinical trials (119–123). Two identical, randomized, double-blind, active-controlled phase 3 clinical trials (Assessment of TeLAvancin in Skin and skin structure infections [ATLAS] 1 and 2) evaluated the efficacy of telavancin 10 mg/kg i.v. every 24 h compared with vancomycin 1 g i.v. every 12 h for 7–14 days in 1867 patients with ABSSSI caused by suspected or confirmed Gram-positive organisms (120). Eligible patients had cellulitis, major abscess requiring surgical drainage, infected wound or ulcer, or infected burn. Excluded were patients who had prior antibiotic therapy for >24 h within 7 days of enrollment, osteomyelitis, necrotizing fasciitis, chronic diabetic foot ulcers, gangrene, burns of >20% body surface, mediastinitis, uncompli-

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cated ABSSSI, absolute neutrophil count < 500 cells/ mm3, human immunodeficiency virus infection, uncompensated heart failure, a QTc interval > 500 ms, or a requirement for concomitant administration of agents containing cyclodextrin. The primary efficacy end point was clinical response at TOC (7–14 days after the last dose of medication). Clinical cure was defined as resolution of clinically significant signs and symptoms of infection or improvement to such an extent that no further antibiotic therapy was necessary. The baseline pathogen was considered eradicated at end of therapy or TOC if not detected by culture, or presumed to be eradicated if the patient’s clinical response was cure. In the CE population at the TOC visit, clinical cure was achieved in 88.3% (658/745) of patients treated with telavancin and 87.1% (648/744) in the vancomycin group. In CE patients with MRSA infections, the clinical cure rate was 90.6% (252/ 278) with telavancin and 86.4% (260/301) with vancomycin. Microbiologic response rate was 89.9% (250/278) and 85.4% (257/301) for telavancin and vancomycin, respectively, in patients who had MRSA isolated at baseline. In the telavancin group, TEAEs included taste disturbance, nausea, and vomiting. Increased serum creatinine concentration of >1.5 mg/dL and >50% above baseline was noted more frequently in the telavancin group (6.3%) than in the vancomycin group (2.2%; p < 0.05). Although renal dysfunction associated with telavancin seems reversible upon cessation of therapy, renal function should be monitored during therapy and for several days after discontinuation. Telavancin should be used cautiously in patients with pre-existing renal conditions, hypertension, or diabetes, and in patients taking other medications that may affect renal function (e.g., aminoglycosides). Factors associated with development of telavancin-mediated acute renal insufficiency include prior supratherapeutic vancomycin trough levels (>20 mg/L), high body mass index, and use of i.v. contrast dye before telavancin therapy (124). QTc interval prolongation was reported with telavancin therapy, although no associated cardiac adverse events were noted in the ATLAS trials. Telavancin should be used cautiously with other agents such as fluoroquinolones or antidysrhythmics that may prolong the QTc interval (113). Drugs in development. Several investigational agents in clinical development show promise for the treatment of ABSSSI. Dalbavancin is a semi-synthetic lipoglycopeptide with long half-life and bactericidal activity against Gram-positive cocci, including MRSA (125–127). In a phase 3 study evaluating patients with ABSSSI (major abscesses, major burns, traumatic or surgical wound infections, and deep skin-structure infections, such as ulcerating cellulitis), dalbavancin 1000 mg given i.v. on day 1 and 500 mg given on day 8 (n = 571) was comparable to

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linezolid 600 mg (either i.v. or oral) administered every 12 h for 14 days (n = 283) (128). Oritavancin is another investigational lipoglycopeptide currently in development for management of ABSSSI caused by multi-drugresistant, Gram-positive pathogens, including MRSA (127). Clinical trial data indicate that oritavancin is efficacious in treating ABSSSI caused by Gram-positive pathogens (129,130). Omadacycline (PTK796) is a novel aminomethylcycline that is a member of the tetracycline family of antibiotics with a broad spectrum of activity. In vitro data indicate that omadacycline is active against Gram-positive pathogens, including CA-MRSA and b-hemolytic streptococci, as well as pathogens resistant to tetracycline. In phase 2 clinical trials, omadacycline was active against S. aureus, including MRSA, with an MIC90 of 0.25 mg/L, and was comparable to linezolid in treatment of patients with ABSSSI (131,132). Rapid Testing for MRSA Obtaining culture specimens to document the presence of MRSA and for susceptibility testing is an important step to guide selection of antimicrobial therapy (2). Historically, laboratory detection methods for MRSA and S. aureus from wounds or blood cultures required 48–72 h for culture. Recently, several rapid detection assays have been developed that utilize real-time polymerase chain reaction to identify MRSA within hours instead of days, and many of these assays are used to screen for MRSA carriage (133,134). Rapid detection of MRSA from wound specimens is particularly useful in patients with ABSSSI at greater risk for treatment failure, such as individuals who are immunocompromised. The recent availability in the US of a rapid-detection assay to identify MRSA from wound specimens allows for better-informed therapeutic decisions in the ED. The XpertÒ MRSA/SA skin and soft tissue infection (SSTI) assay (Cepheid Inc., Sunnyvale, CA) is approved for rapid detection (within 1 h) of MRSA and S. aureus from wounds. In a multi-center evaluation that included a total of 114 wound specimens, the MRSA/SA SSTI assay performed with a sensitivity of 97.1% for MRSA detection, with 96.2% specificity, 91.9% positive predictive value, and 98.7% negative predictive value; similar percentages were noted for S. aureus (135). Overall agreement between the assay and standard culture was 96.5%. Rapid identification and differentiation of MRSA from wound specimens may allow clinicians to more expediently initiate appropriate antimicrobial therapy in the ED. Outpatient Parenteral Antimicrobial Therapy Patients with ABSSSI who require i.v. antibiotics but do not need hospitalization for 24-h care may be candidates

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for treatment in the outpatient setting. The practice of OPAT has expanded in the US and is a good option that can prevent or shorten hospitalizations, reduce overall treatment costs, decrease readmission rates, and reduce incidence of nosocomial infections (136–139). The IDSA published comprehensive guidelines for OPAT in 2004, noting the effectiveness of OPAT for a variety of infections, including ABSSSI (50,139,140). The decision to hospitalize or utilize OPAT is based on clinical assessment of infection severity and underlying comorbidity. For example, patients with systemic toxicity or rapidly progressive or worsening infections despite antibiotic therapy would not be good candidates for OPAT. When selecting antimicrobials for OPAT, a number of factors should be considered, including probable pathogens, pharmacodynamic and pharmacokinetic properties of selected agents, dosing schedules, toxicity profile, need for drug-level monitoring, and drug stability (139). Although any antimicrobial could theoretically be selected for OPAT, drugs with longer half-lives offer the advantage of once-daily administration, which may reduce risk for complications (i.e., minimizes handling of the i.v. line), improved patient compliance, and lessened disruption of daily activities (138,139,141). Tolerability is another important issue when considering OPAT. Some agents, such as vancomycin, are more likely to cause phlebitis, whereas cephalosporins and aminoglycosides have low potential for phlebitis (142). CONCLUSION CA-MRSA has emerged as a predominant cause of ABSSSI in the US, and ED visits for ABSSSI have risen in direct correlation. The increasing prevalence of CAMRSA is concerning and has led the IDSA and other organizations to recommend empiric coverage of CAMRSA for patients with ABSSSI. Several newer i.v. antimicrobials with MRSA activity, including ceftaroline fosamil, daptomycin, linezolid, and telavancin, are available for managing ABSSSI in the ED and may help meet the clinical demand for alternative antistaphylococcal drugs. Acknowledgments—Financial support was provided by Forest Research Institute, Inc. Scientific Therapeutics Information, Inc., provided editorial assistance, which was funded by Forest Research Institute, Inc.

REFERENCES 1. Abrahamian FM, Talan DA, Moran GJ. Management of skin and soft-tissue infections in the emergency department. Infect Dis Clin North Am 2008;22:89–116.

e408 2. Abrahamian FM, Snyder EW. Community-associated methicillin-resistant Staphylococcus aureus: incidence, clinical presentation, and treatment decisions. Curr Infect Dis Rep 2007;9:391–7. 3. Gunderson CG. Cellulitis: definition, etiology, and clinical features. Am J Med 2011;124:1113–22. 4. Jones RN, Mendes RE, Sader HS. Ceftaroline activity against pathogens associated with complicated skin and skin structure infections: results from an international surveillance study. J Antimicrob Chemother 2010;65(Suppl 4):iv17–31. 5. Moet GJ, Jones RN, Biedenbach DJ, Stilwell MG, Fritsche TR. Contemporary causes of skin and soft tissue infections in North America, Latin America, and Europe: report from the SENTRY Antimicrobial Surveillance Program (1998–2004). Diagn Microbiol Infect Dis 2007;57:7–13. 6. Barrett FF, McGehee RF Jr, Finland M. Methicillin-resistant Staphylococcus aureus at Boston City Hospital. Bacteriologic and epidemiologic observations. N Engl J Med 1968;279:441–8. 7. Naimi TS, LeDell KH, Boxrud DJ, et al. Epidemiology and clonality of community-acquired methicillin-resistant Staphylococcus aureus in Minnesota, 1996–1998. Clin Infect Dis 2001;33: 990–6. 8. Jones RN, Nilius AM, Akinlade BK, Deshpande LM, Notario GF. Molecular characterization of Staphylococcus aureus isolates from a 2005 clinical trial of uncomplicated skin and skin structure infections. Antimicrob Agents Chemother 2007;51:3381–4. 9. Kaplan SL, Hulten KG, Gonzalez BE, et al. Three-year surveillance of community-acquired Staphylococcus aureus infections in children. Clin Infect Dis 2005;40:1785–91. 10. King MD, Humphrey BJ, Wang YF, Kourbatova EV, Ray SM, Blumberg HM. Emergence of community-acquired methicillin-resistant Staphylococcus aureus USA 300 clone as the predominant cause of skin and soft-tissue infections. Ann Intern Med 2006;144: 309–17. 11. Klevens RM, Morrison MA, Nadle J, et al. Active Bacterial Core surveillance (ABCs) MRSA Investigators. Invasive methicillinresistant Staphylococcus aureus infections in the United States. JAMA 2007;298:1763–71. 12. Moran GJ, Amii RN, Abrahamian FM, Talan DA. Methicillin-resistant Staphylococcus aureus in community-acquired skin infections. Emerg Infect Dis 2005;11:928–30. 13. Moran GJ, Krishnadasan A, Gorwitz RJ, et al., EMERGEncy ID Net Study Group. Methicillin-resistant S. aureus infections among patients in the emergency department. N Engl J Med 2006;355: 666–74. 14. Pallin DJ, Egan DJ, Pelletier AJ, Espinola JA, Hooper DC, Camargo CA Jr. Increased US emergency department visits for skin and soft tissue infections, and changes in antibiotic choices, during the emergence of community-associated methicillin-resistant Staphylococcus aureus. Ann Emerg Med 2008;51:291–8. 15. Talan DA, Krishnadasan A, Gorwitz RJ, et al., EMERGEncy ID Net Study Group. Comparison of Staphylococcus aureus from skin and soft-tissue infections in US emergency department patients, 2004 and 2008. Clin Infect Dis 2011;53:144–9. 16. Tillotson GS, Draghi DC, Sahm DF, Tomfohrde KM, Del Fabro T, Critchley IA. Susceptibility of Staphylococcus aureus isolated from skin and wound infections in the United States 2005–07: laboratory-based surveillance study. J Antimicrob Chemother 2008;62:109–15. 17. Chambers HF, Deleo FR. Waves of resistance: Staphylococcus aureus in the antibiotic era. Nat Rev Microbiol 2009;7:629–41. 18. Chua K, Laurent F, Coombs G, Grayson ML, Howden BP. Antimicrobial resistance: not community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA)! A clinician’s guide to community MRSA – its evolving antimicrobial resistance and implications for therapy. Clin Infect Dis 2011;52:99–114. 19. Tenover FC, Goering RV. Methicillin-resistant Staphylococcus aureus strain USA300: origin and epidemiology. J Antimicrob Chemother 2009;64:441–6. 20. Appelbaum PC. Microbiology of antibiotic resistance in Staphylococcus aureus. Clin Infect Dis 2007;45(Suppl 3):S165–70.

G. J. Moran et al. 21. Naimi TS, LeDell KH, Como-Sabetti K, et al. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA 2003;290:2976–84. 22. Voyich JM, Otto M, Mathema B, et al. Is Panton-Valentine leukocidin the major virulence determinant in community-associated methicillin-resistant Staphylococcus aureus disease? J Infect Dis 2006;194:1761–70. 23. Stryjewski ME, Chambers HF. Skin and soft-tissue infections caused by community-acquired methicillin-resistant Staphylococcus aureus. Clin Infect Dis 2008;46(Suppl 5):S368–77. 24. Mistry RD, Scott HF, Zaoutis TE, Alpern ER. Emergency department treatment failures for skin infections in the era of community-acquired methicillin-resistant Staphylococcus aureus. Pediatr Emerg Care 2011;27:21–6. 25. Hasty MB, Klasner A, Kness S, et al. Cutaneous communityassociated methicillin-resistant Staphylococcus aureus among all skin and soft-tissue infections in two geographically distant pediatric emergency departments. Acad Emerg Med 2007;14:35–40. 26. Klein E, Smith DL, Laxminarayan R. Hospitalizations and deaths caused by methicillin-resistant Staphylococcus aureus, United States, 1999–2005. Emerg Infect Dis 2007;13:1840–6. 27. Edelsberg J, Taneja C, Zervos M, et al. Trends in US hospital admissions for skin and soft tissue infections. Emerg Infect Dis 2009; 15:1516–8. 28. Stevens DL, Bisno AL, Chambers HF, et al. Practice guidelines for the diagnosis and management of skin and soft-tissue infections. Clin Infect Dis 2005;41:1373–406. 29. Liu C, Bayer A, Cosgrove SE, et al. Infectious Diseases Society of America. Clinical practice guidelines by the Infectious Diseases Society of America for the treatment of methicillin-resistant Staphylococcus aureus infections in adults and children. Clin Infect Dis 2011;52:e18–55. 30. LoVecchio F, Perera N, Casanova L, Mulrow M, Pohl A. Boardcertified emergency physicians’ treatment of skin and soft tissue infections in the community-acquired methicillin-resistant Staphylococcus aureus era. Am J Emerg Med 2009;27:68–70. 31. Mistry RD, Weisz K, Scott HF, Alpern ER. Emergency management of pediatric skin and soft tissue infections in the community-associated methicillin-resistant Staphylococcus aureus era. Acad Emerg Med 2010;17:187–93. 32. Centers for Disease Control and Prevention. Outpatient management of skin and soft tissue infections in the era of communityassociated MRSA. Available at: http://www.cdc.gov/MRSA/pdf/ flowchart_pstr.pdf. Accessed January 6, 2012. 33. May AK. Skin and soft tissue infections: the new Surgical Infection Society guidelines. Surg Infect (Larchmt) 2011;12:179–84. 34. Rybak M, Lomaestro B, Rotschafer JC, et al. Therapeutic monitoring of vancomycin in adult patients: a consensus review of the American Society of Health-System Pharmacists, the Infectious Diseases Society of America, and the Society of Infectious Diseases Pharmacists. Am J Health Syst Pharm 2009;66:82–98. 35. Rybak MJ, Lomaestro BM, Rotschafer JC, et al. Vancomycin therapeutic guidelines: a summary of consensus recommendations from the Infectious Diseases Society of America, the American Society of Health-System Pharmacists, and the Society of Infectious Diseases Pharmacists. Clin Infect Dis 2009;49:325–7. 36. Sakoulas G, Moellering RC Jr, Eliopoulos GM. Adaptation of methicillin-resistant Staphylococcus aureus in the face of vancomycin therapy. Clin Infect Dis 2006;42(Suppl 1):S40–50. 37. Soriano A, Marco F, Martı´nez JA, et al. Influence of vancomycin minimum inhibitory concentration on the treatment of methicillin-resistant Staphylococcus aureus bacteremia. Clin Infect Dis 2008;46:193–200. 38. Tenover FC, Moellering RC Jr. The rationale for revising the Clinical and Laboratory Standards Institute vancomycin minimal inhibitory concentration interpretive criteria for Staphylococcus aureus. Clin Infect Dis 2007;44:1208–15. 39. Deresinski S. Counterpoint: vancomycin and Staphylococcus aureus—an antibiotic enters obsolescence. Clin Infect Dis 2007; 44:1543–8.

Acute Bacterial Skin Infections 40. Kollef MH. Limitations of vancomycin in the management of resistant staphylococcal infections. Clin Infect Dis 2007;45(Suppl 3):S191–5. 41. Sakoulas G, Moise-Broder PA, Schentag J, Forrest A, Moellering RC Jr, Eliopoulous GM. Relationship of MIC and bactericidal activity to efficacy of vancomycin for treatment of methicillin-resistant Staphylococcus aureus bacteremia. J Clin Microbiol 2004;42:2398–402. 42. Stein GE, Wells EM. The importance of tissue penetration in achieving successful antimicrobial treatment of nosocomial pneumonia and complicated skin and soft-tissue infections caused by methicillin-resistant Staphylococcus aureus: vancomycin and linezolid. Curr Med Res Opin 2010;26:571–88. 43. Van Hal SJ, Lodise TP, Paterson DL. The clinical significance of vancomycin minimum inhibitory concentration in Staphylococcus aureus infections: a systematic review and meta-analysis. Clin Infect Dis 2012;54:755–71. 44. Fridkin SK, Hageman J, McDougal LK, et al., Vancomycin-Intermediate Staphylococcus aureus Epidemiology Study Group. Epidemiological and microbiological characterization of infections caused by Staphylococcus aureus with reduced susceptibility to vancomycin, United States, 1997–2001. Clin Infect Dis 2003;36: 429–39. 45. Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. J Clin Microbiol 2006;44: 3883–6. 46. Bosso JA, Nappi J, Rudisill C, et al. Relationship between vancomycin trough concentrations and nephrotoxicity: a prospective multicenter trial. Antimicrob Agents Chemother 2011;55:5475–9. 47. Fritsche TR, Jones RN. Importance of understanding pharmacokinetic/pharmacodynamic principles in the emergence of resistances, including community-associated Staphylococcus aureus. J Drugs Dermatol 2005;4(6 Suppl):s4–8. 48. Lee SY, Kuti JL, Nicolau DP. Antimicrobial management of complicated skin and skin structure infections in the era of emerging resistance. Surg Infect (Larchmt) 2005;6:283–95. 49. McDougal LK, Fosheim GE, Nicholson A, et al. Emergence of resistance among USA300 methicillin-resistant Staphylococcus aureus isolates causing invasive disease in the United States. Antimicrob Agents Chemother 2010;54:3804–11. 50. Tice AD, Rehm SJ. Meeting the challenges of methicillin-resistant Staphylococcus aureus with outpatient parenteral antimicrobial therapy. Clin Infect Dis 2010;51(Suppl 2):S171–5. 51. Cubicin prescribing information. Lexington, MA: Cubist Pharmaceuticals, Inc; 2010. 52. Teflaro prescribing information. New York: Forest Laboratories, Inc; 2012. 53. Vibativ prescribing information. South San Francisco, CA: Theravance Inc; 2009. 54. Zyvox prescribing information. New York: Pharmacia & Upjohn Co, Division of Pfizer Inc; 2010. 55. Cai Y, Wang R, Liang B, Bai N, Lui Y. Systematic review and meta-analysis of the effectiveness and safety of tigecycline for treatment of infectious disease. Antimicrob Agents Chemother 2011;55:1162–72. 56. Prasad P, Sun J, Danner RL, Natanson C. Excess deaths associated with tigecycline after approval based on noninferiority trials. Clin Infect Dis 2012;54:1699–709. 57. Food and Drug Administration. Tygacil (tigecycline): label change – increased mortality risk. Available at: http://www.fda. gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHuman MedicalProducts/ucm224626.htm. Accessed March 20, 2012. 58. US Food and Drug Administration. Guidance for industry: uncomplicated and complicated skin and skin structure infections – developing antimicrobial drugs for treatment. Rockville, MD: US Food and Drug Administration; 1998. 59. Biek D, Critchley IA, Riccobene TA, Thye DA. Ceftaroline fosamil: a novel broad-spectrum cephalosporin with expanded antiGram-positive activity. J Antimicrob Chemother 2010;65(Suppl 4):iv9–16.

e409 60. Zhanel GG, Sniezek G, Schweizer F, et al. Ceftaroline: a novel broad-spectrum cephalosporin with activity against meticillin-resistant Staphylococcus aureus. Drugs 2009;69: 809–31. 61. Kosowska-Schick K, McGhee PL, Appelbaum PC. Affinity of ceftaroline and other b-lactams for penicillin-binding proteins from Staphylococcus aureus and Streptococcus pneumoniae. Antimicrob Agents Chemother 2010;54:1670–7. 62. Llarrull LI, Fisher JF, Mobashery S. Molecular basis and phenotype of methicillin resistance in Staphylococcus aureus and insights into new b-lactams that meet the challenge. Antimicrob Agents Chemother 2009;53:4051–63. 63. Ge Y, Blosser RS, Sahm D, et al. In vitro activity of T-91825, a new anti-MRSA cephalosporin, against Gram-positive and Gramnegative clinical isolates. Presented at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 14–17, 2003; Chicago, IL. 64. Richter SS, Satola SW, Crispell EK, et al. Detection of Staphylococcus aureus isolates with heterogeneous intermediate-level resistance to vancomycin in the United States. J Clin Microbiol 2011;49:4203–7. 65. Sader HS, Moet G, Jones RN. In vitro activity of ceftaroline tested against recent clinical isolates from the United States (USA). Presented at the 47th Annual Meeting of the Infectious Diseases Society of America; October 29–November 1, 2009; Philadelphia, PA. 66. Sader HS, Fritsche TR, Kaniga K, Ge Y, Jones RN. Antimicrobial activity and spectrum of PPI-0903M (T-91825), a novel cephalosporin, tested against a worldwide collection of clinical strains. Antimicrob Agents Chemother 2005;49:3501–12. 67. Saravolatz L, Pawlak J, Johnson L. In vitro activity of ceftaroline against community-associated methicillin-resistant, vancomycinintermediate, vancomycin-resistant, and daptomycin-nonsusceptible Staphylococcus aureus isolates. Antimicrob Agents Chemother 2010;54:3027–30. 68. Ge Y, Biek D, Talbot GH, Sahm DF. In vitro profiling of ceftaroline against a collection of recent bacterial clinical isolates from across the United States. Antimicrob Agents Chemother 2008; 52:3398–407. 69. Citron DM, Tyrrell KL, Merriam CV, Goldstein EJC. In vitro activity of ceftaroline against 623 diverse strains of anaerobic bacteria. Antimicrob Agents Chemother 2010;54:1627–32. 70. Snydman DR, Jacobus NV, McDermott LA. In vitro activity of ceftaroline against a broad spectrum of recent clinical anaerobic isolates. Antimicrob Agents Chemother 2011;55:421–5. 71. Clark C, Kosowska-Shick K, McGhee P, Appelbaum P. Multistep resistance development studies of ceftaroline (CPT) with Streptococcus pneumoniae, Streptococcus pyogenes, staphylococci, and enterococci. Presented at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12–15, 2010; Boston, MA. 72. Hinshaw RR, Schaadt RD, Murray B, et al. Spontaneous mutation frequency and serial passage resistance development studies with ceftaroline. Presented at the 48th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy/46th Annual Meeting of the Infectious Diseases Society of America; October 25–28, 2008; Washington, DC. 73. Corey GR, Wilcox M, Talbot GH, et al. Integrated analysis of CANVAS 1 and 2: phase 3, multicenter, randomized, doubleblind studies to evaluate the safety and efficacy of ceftaroline versus vancomycin plus aztreonam in complicated skin and skinstructure infection. Clin Infect Dis 2010;51:641–50. 74. Corey GR, Wilcox MH, Talbot GH, et al., CANVAS 1 investigators. CANVAS 1: the first Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65(Suppl 4):iv41–51. 75. Wilcox MH, Corey RG, Talbot GH, Thye D, Friedland D, Baculik T. CANVAS 2 Investigators. CANVAS 2: the second Phase III, randomized, double-blind study evaluating ceftaroline fosamil for the treatment of patients with complicated skin and

e410

76.

77.

78. 79. 80. 81.

82.

83.

84. 85.

86.

87.

88.

89. 90.

91.

92.

93.

skin structure infections. J Antimicrob Chemother 2010;65(Suppl 4):iv53–65. Friedland HD, O’Neal T, Biek D, et al. CANVAS 1 and 2: Analysis of Clinical Response at Day 3 in Two Phase 3 Trials of Ceftaroline Fosamil versus Vancomycin Plus Aztreonam in Treatment of Acute Bacterial Skin and Skin Structure Infections. Antimicrob Agents Chemother 2012;56:2231–6. Corrado ML. Integrated safety summary of CANVAS 1 and 2 trials: Phase III randomized, double-blind studies evaluating ceftaroline fosamil for the treatment of patients with complicated skin and skin structure infections. J Antimicrob Chemother 2010;65(Suppl 4):iv67–71. Einstein BI, Oleson FB Jr, Baltz RH. Daptomycin: from the mountain to the clinic, with essential help from Francis Tally. MD. Clin Infect Dis 2010;50(Suppl 1):S10–5. Sakoulas G. Clinical outcomes with daptomycin: a postmarketing, real-world evaluation. Clin Microbiol Infect 2009; 15(Suppl 6):11–6. Boucher HW, Sakoulas G. Perspectives on Daptomycin resistance, with emphasis on resistance in Staphylococcus aureus. Clin Infect Dis 2007;45:601–8. Rybak MJ, Hershberger E, Moldovan T, Grucz RG. In vitro activities of daptomycin, vancomycin, linezolid, and quinupristindalfopristin against Staphylococci and Enterococci, including vancomycin-intermediate and -resistant strains. Antimicrob Agents Chemother 2000;44:1062–6. Sader HS, Moet GJ, Farrell DJ, Jones RN. Antimicrobial susceptibility of daptomycin and comparator agents tested against methicillin-resistant Staphylococcus aureus and vancomycinresistant enterococci: trend analysis of a 6-year period in US medical centers (2005–2010). Diagn Microbiol Infect Dis 2011;70: 412–6. Marty FM, Yeh WW, Wennersten CB, et al. Emergence of a clinical daptomycin-resistant Staphylococcus aureus isolate during treatment of methicillin-resistant bacteremia and osteomyelitis. J Clin Microbiol 2006;44:595–7. Silverman JA, Oliver N, Andrew T, Li T. Resistance studies with daptomycin. Antimicrob Agents Chemother 2001;45:1799–802. Crompton JA, North DS, Yoon M, Steenbergen JN, Lamp KC, Forrest GN. Outcomes with daptomycin in the treatment of Staphylococcus aureus infections with a range of vancomycin MICs. J Antimicrob Chemother 2010;65:1784–91. Arbeit RD, Maki D, Tally FB, Campanaro E, Eisenstein BI. Daptomycin 98-01 and 99-01 Investigators. The safety and efficacy of daptomycin for the treatment of complicated skin and skinstructure infections. Clin Infect Dis 2004;38:1673–81. Davis SL, McKinnon PS, Hall LM, et al. Daptomycin versus vancomycin for complicated skin and skin structure infections: clinical and economic outcomes. Pharmacotherapy 2007;27: 1611–8. Martone WJ, Lamp KC. Efficacy of daptomycin in complicated skin and skin-structure infections due to methicillin-sensitive and -resistant Staphylococcus aureus: results from the CORE Registry. Curr Med Res Opin 2006;22:2337–43. Bassetti M, Nicco E, Ginocchio F, Ansaldi F, de Florentiis D, Viscoli C. High-dose daptomycin in documented Staphylococcus aureus infections. Int J Antimicrob Agents 2010;36:459–61. Bhavnani SM, Rubino CM, Ambrose PG, Drusano GL. Daptomycin exposure and the probability of elevations in the creatine phosphokinase level: data from a randomized trial of patients with bacteremia and endocarditis. Clin Infect Dis 2010;50:1568–74. Fowler VG Jr, Boucher HW, Corey GR, et al. S. aureus Endocarditis and Bacteremia Study Group. Daptomycin versus standard therapy for bacteremia and endocarditis caused by Staphylococcus aureus. N Engl J Med 2006;355:653–65. Katz DE, Lindfield KC, Steenbergen JN, et al. A pilot study of high-dose short duration daptomycin for the treatment of patients with complicated skin and skin structure infections caused by gram-positive bacteria. Int J Clin Pract 2008;62:1455–64. US Food and Drug Administration. Eosinophilic pnuemonia associated with the use of Cubicin (daptomycin). Available at: http://

G. J. Moran et al.

94. 95. 96.

97.

98.

99. 100. 101. 102.

103.

104.

105. 106.

107.

108.

109. 110. 111. 112.

113.

www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation forPatientsandProviders/ucm220273.htm. Accessed March 20, 2012. Gee T, Ellis R, Marshall G, Andrews J, Ashby J, Wise R. Pharmacokinetics and tissue penetration of linezolid following multiple oral doses. Antimicrob Agents Chemother 2001;45:1843–6. Shinabarger D, Marotti KR, Murray RW, et al. Mechanism of action of oxazolidinones: effects of linezolid and eperezolid on translation reactions. Antimicrob Agents Chemother 1997;41:2132–6. Jones RN, Stilwell MG, Hogan PA, Sheehan DJ. Activity of linezolid against 3,251 strains of uncommonly isolated gram-positive organisms: report from the SENTRY Antimicrobial Surveillance Program. Antimicrob Agents Chemother 2007;51:1491–3. Mutnick AH, Biedenbach DJ, Turnidge D, Jones RN. Spectrum and potency evaluation of a new oxazolidinone, linezolid: report from the SENTRY Antimicrobial Surveillance Program, 19982000. Diagn Microbiol Infect Dis 2002;43:65–73. Farrell DJ, Mendes RE, Ross JE, Sader HS, Jones RN. LEADER program results for 2009: an activity and spectrum analysis of linezolid using 6,414 clinical isolates from 56 medical centers in the United States. Antimicrob Agents Chemother 2011;55:3684–90. Jones RN, Ross JE, Castanheira M, Mendes RE. United States resistance surveillance results for linezolid (LEADER Program for 2007). Diagn Microbiol Infect Dis 2008;62:416–26. Sa´nchez Garcı´a M, De la Torre MA, Morales G, et al. Clinical outbreak of linezolid-resistant Staphylococcus aureus in an intensive care unit. JAMA 2010;303:2260–4. Long KS, Vester B. Resistance to linezolid caused by modification at its binding site on the ribosome. Antimicrob Agents Chemother 2012;56:603–12. Kohno S, Yamaguchi K, Aikawa N, et al. Linezolid versus vancomycin for the treatment of infections caused by methicillinresistant Staphylococcus aureus in Japan. J Antimicrob Chemother 2007;60:1361–9. Stevens DL, Herr D, Lampiris H, Hunt JL, Batts DH, Hafkin B. Linezolid versus vancomycin for the treatment of methicillinresistant Staphylococcus aureus infections. Clin Infect Dis 2002; 34:1481–90. Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C. Linezolid CSSTI Study Group. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob Agents Chemother 2005;49:2260–6. Weigelt J, Kaafarani HM, Itani KM, Swanson RN. Linezolid eradicates MRSA better than vancomycin from surgical-site infections. Am J Surg 2004;188:760–6. Wilcox MH, Tack KJ, Bouza E, et al. Complicated skin and skinstructure infections and catheter-related bloodstream infections: noninferiority of linezolid in a phase 3 study. Clin Infect Dis 2009;48:203–12. Bounthavong M, Hsu DI. Efficacy and safety of linezolid in methicillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft tissue infection (cSSTI): a meta-analysis. Curr Med Res Opin 2010;26:407–21. Rubinstein E, Isturiz R, Standiford HC, et al. Worldwide assessment of linezolid’s clinical safety and tolerability: comparatorcontrolled phase III studies. Antimicrob Agents Chemother 2003;47:1824–31. Vinh DC, Rubinstein E. Linezolid: a review of safety and tolerability. J Infect 2009;59(Suppl 1):S59–74. Attassi K, Hershberger E, Alam R, Zervos MJ. Thrombocytopenia associated with linezolid therapy. Clin Infect Dis 2002;34:695–8. Gerson SL, Kaplan SL, Bruss JB, et al. Hematologic effects of linezolid: summary of clinical experience. Antimicrob Agents Chemother 2002;46:2723–6. US Food and Drug Administration. FDA drug safety communication: updated information about the drug interaction between linezolid (Zyvox) and serotonergic psychiatric medications. Available at: http://www.fda.gov/Drugs/DrugSafety/ucm276251.htm. Accessed January 6, 2012. Chang MH, Kish TD, Fung HB. Telavancin: a lipoglycopeptide antimicrobial for the treatment of complicated skin and skin

Acute Bacterial Skin Infections

114.

115.

116.

117.

118.

119. 120.

121.

122.

123.

124. 125. 126.

127. 128.

structure infections caused by gram-positive bacteria in adults. Clin Ther 2010;32:2160–85. Mendes RE, Sader HS, Jones RN. Activity of telavancin and comparator antimicrobial agents tested against Staphylococcus spp. isolated from hospitalised patients in Europe (2007–2008). Int J Antimicrob Agents 2010;36:374–9. Putnam SD, Sader HS, Moet GJ, Mendes RE, Jones RN. Worldwide summary of telavancin spectrum and potency against Gram-positive pathogens: 2007 to 2008 surveillance results. Diagn Microbiol Infect Dis 2010;67:359–68. Krause KM, Barriere SL, Kitt MM, Benton BM. In vitro activity of telavancin against Gram-positive isolates from complicated skin and skin structure infections: results from 2 phase 3 (ATLAS) clinical studies. Diagn Microbiol Infect Dis 2010;68:181–5. Kosowska-Shick K, Clark C, Pankuch GA, et al. Activity of telavancin against staphylococci and enterococci determined by MIC and resistance selection studies. Antimicrob Agents Chemother 2009;53:4217–24. Sun HK, Duchin K, Nightingale CH, Shaw JP, Seroogy J, Nicolau DP. Tissue penetration of telavancin after intravenous administration in healthy subjects. Antimicrob Agents Chemother 2006;50:788–90. Stryjewski ME, Barriere SL, O’Riordan W, et al. Efficacy of telavancin in patients with specific types of complicated skin and skin structure infections. J Antimicrob Chemother 2012;67:1496–502. Stryjewski ME, Graham DR, Wilson SE, et al. Assessment of Telavancin in Complicated Skin and Skin-Structure Infections Study. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections caused by gram-positive organisms. Clin Infect Dis 2008;46:1683–93. Stryjewski ME, Chu VH, O’Riordan WD, et al., FAST 2 Investigator Group. Telavancin versus standard therapy for treatment of complicated skin and skin structure infections caused by grampositive bacteria: FAST 2 study. Antimicrob Agents Chemother 2006;50:862–7. Stryjewski ME, O’Riordan WD, Lau WK, et al., FAST Investigator Group. Telavancin versus standard therapy for treatment of complicated skin and soft-tissue infections due to gram-positive bacteria. Clin Infect Dis 2005;40:1601–7. Wilson SE, O’Riordan W, Hopkins A, Friedland HD, Barriere SL, Kitt MM, ATLAS Investigators. Telavancin versus vancomycin for the treatment of complicated skin and skin-structure infections associated with surgical procedures. Am J Surg 2009;197:791–6. Marcos LA, Camins BC, Ritchie DJ, Casabar E, Warren DK. Acute renal insufficiency during telavancin therapy in clinical practice. J Antimicrob Chemother 2012;67:723–6. Billeter M, Zervos MJ, Chen AY, Dalovisio JR, Kurukularatne C. Dalbavancin: a novel once-weekly lipoglycopeptide antibiotic. Clin Infect Dis 2008;46:577–83. Jones RN, Stilwell MG, Sader HS, Fritsche TR, Goldstein BP. Spectrum and potency of dalbavancin tested against 3322 Grampositive cocci isolated in the United States Surveillance Program (2004). Diagn Microbiol Infect Dis 2006;54:149–53. Zhanel GG, Calic C, Schweizer F, et al. New lipoglycopeptides: a comparative review of dalbavancin, oritavancin and telavancin. Drugs 2010;70:859–86. Jauregui LE, Babazadeh S, Seltzer E, et al. Randomized, doubleblind comparison of once-weekly dalbavancin versus twice-daily linezolid therapy for the treatment of complicated skin and skin structure infections. Clin Infect Dis 2005;41:1407–15.

e411 129. Dunbar LM, Milata J, McClure T, Wasilewski MM, SIMPLIFI Study Team. Comparison of the efficacy and safety of oritavancin front-loaded dosing regimens to daily dosing: an analysis of the SIMPLIFI trial. Antimicrob Agents Chemother 2011;55: 3476–84. 130. Hartman CS, Bates BM, Wasilewksi MM. Oritavancin in the treatment of complicated skin and skin structure infections: combined results of two phase 3 multinational trials. Poster (L-1514) presented at the 48th Interscience Conference on Antimicrobial Agents and Chemotherapy /46th Infectious Diseases Society of America Annual Meeting; Washington, DC: October 26, 2008. 131. Macone AB, Arbeit RD, Hait HI, Draper MP, Tanaka SK. Identification and susceptibility of pathogens isolated from patients with complicated skin and skin structure infections (cSSSI): results of a PTK796 (PTK) phase 2 clinical trial. Presented at the 50th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; September 12–15, 2010; Boston, MA. 132. Hait H, Arbeit R, Molnar D, Noel GJ, Tanaka SK. In a phase 2 complicated skin and soft tissue infections (cSSTI) trial outcomes assessed early in the course of therapy were consistent with outcomes assessed 10–17 days after completing therapy for patients treated with either omadacycline (OMC; PTK796) or linezolid. Poster presented at 21st European Congress of Clinical Microbiology and Infectious Diseases meeting; May 7–10, 2011; Milan, Italy. 133. Hombach M, Pfyffer GE, Roos M, Lucke K. Detection of methicillin-resistant Staphylococcus aureus (MRSA) in specimens from various body sites: performance characteristic of the BD GeneOhm MRSA assay, the Xpert MRSA Assay, and brothenriched culture in an area with a low prevalence of MRSA infections. J Clin Microbiol 2010;48:3882–7. 134. Stu¨renburg E. Rapid detection of methicillin-resistant Staphylococcus aureus directly from clinical samples: methods, effectiveness and cost considerations. Ger Med Sci 2009;7:Doc06. 135. Wolk DM, Struelens MJ, Pancholi P, et al. Rapid detection of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in wound specimens and blood cultures: multicenter preclinical evaluation of the Cepheid Xpert MRSA/SA skin and soft tissue and blood culture assays. J Clin Microbiol 2009;47:823–6. 136. Heintz BH, Halilovic J, Christensen CL. Impact of a multidisciplinary team review of potential outpatient parenteral antimicrobial therapy prior to discharge from an academic medical center. Ann Pharmacother 2011;45:1329–37. 137. Nguyen HH. Hospitalist to home: outpatient parenteral antimicrobial therapy at an academic center. Clin Infect Dis 2010;51(Suppl 2):S220–3. 138. Paladino JA, Poretz D. Outpatient parenteral antimicrobial therapy today. Clin Infect Dis 2010;51(Suppl 2):S198–208. 139. Tice A, Rehm SJ, Dalovisio JR, et al. Practice guidelines for outpatient parenteral antimicrobial therapy. IDSA guidelines. Clin Infect Dis 2004;38:1651–72. 140. Deery HG 2nd. Outpatient parenteral anti-infective therapy for skin and soft-tissue infections. Infect Dis Clin North Am 1998; 12:935–49. vii. 141. Craig WA. Antibiotic selection factors and description of a hospital-based outpatient antibiotic therapy program in the USA. Eur J Clin Microbiol Infect Dis 1995;14:636–42. 142. Leggett JE. Ambulatory use of parenteral antibacterials: contemporary perspectives. Drugs 2000;59(Suppl 3):1–8.

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ARTICLE SUMMARY 1. Why is this topic important? Community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) is the predominant cause of purulent acute bacterial skin and skin structure infections (ABSSSI) in the United States. Patients with ABSSSI commonly present to Emergency Departments where a wide spectrum of disease severity may be encountered. 2. What does this review attempt to show? This review focuses on recent studies and recommendations for management of ABSSSI in the CA-MRSA era. 3. What are the key findings? Since the 2005 Infectious Diseases Society of America (IDSA) guidelines for the management of ABSSSI, empiric coverage of CA-MRSA for purulent ABSSSI is now recommended. Several intravenous antibiotics with expanded MRSA coverage, including ceftaroline fosamil, daptomycin, linezolid, and telavancin, may be considered for management of ABSSSI. Further, availability of rapid MRSA detection assays from skin and soft-tissue swabs may facilitate earlier selection of targeted therapy. 4. How is patient care impacted? This article offers a review of significant developments since the most recent IDSA guidelines for the management of ABSSSI, including a review of recent studies and recommendations for managing CA-MRSA.