Skin and soft-tissue infections (SSTIs) represent a broad spectrum of infections ranging from superficial pyodermas to deep, necrotizing infections.1,2 Most uncomplicated infections may be managed with topical therapies or simple surgical interventions; however, complicated SSTIs generally require systemic antimicrobial therapy and are likely to require surgery.1,2 The common terminology throughout the infectious disease literature has been SSTIs; however, in 2013 the FDA updated their industry guidance for treatment of acute bacterial skin and skin structure infections and changed the terminology from complicated SSTIs to acute bacterial skin and skin structure infections (ABSSSI) to better describe the type of infection suitable for treatment with newer antimicrobials.3
ABSSSI are some of the most commonly encountered infections and represent a major reason for seeking medical care worldwide. The combined emergence of antimicrobial resistance over the last few decades and the lack of newly developed antimicrobial agents complicate matters further.
Only within the last few years has the antimicrobial armamentarium seen substantial growth. In particular, two newly approved lipoglycopeptides supplement the currently available options for ABSSSI: dalbavancin and oritavancin.
ABSSSI are a prominent occurrence in both the inpatient and ambulatory population. Rates of infections have increased significantly over the past decades. When considering hospital admission rates for ABSSSI from 2000 to 2004, Edelsberg and colleagues found a 29% increase in the number of admissions, while admissions for other infection types remained constant.4 Of note, increases in ABSSSI-related admissions were largest in the nonolder adult population (under age 65) and in patients from urban areas.4
A more recent analysis of the Health-Core Integrated Research Database from 2005 to 2010 found over 2.2 million ABSSSI episodes, with more than 90% diagnosed in the ambulatory setting.5 Hospitalizations for ABSSSI are now more common than for community-acquired pneumonia. These hospitalizations, particularly those associated with staphylococcal ABSSSI, are associated with a longer length of stay, higher hospital costs, and increased mortality.6
Gram-positive organisms, specifically Staphylococcus aureus and Streptococcus species, are the most common causes of ABSSSI. The distribution of these pathogens varies among infection types; however, among culture-positive ABSSSI, S. aureus predominates.7 Data from the SENTRY surveillance program found S. aureus to be the causative pathogen in 48.1% of all ABSSSI, followed by Pseudomonas aeruginosa (9.4%) and Enterococcus species (8.8%).8 Beta-hemolytic Streptococcus species accounted for only 4.2% of culture-positive infections. Despite the lack of culture positivity for Streptococcus species in numerous epidemiologic assessments, these pathogens still account for a significant proportion of nonpurulent cellulitis, particularly in ambulatory patients.1,9,10
Within the past decade, methicillin-resistant S. aureus (MRSA) infections have transitioned from a dominant healthcare-associated pathogen to a major cause of both community-acquired (CA) and healthcare-associated ABSSSI.1,7,11 In an analysis of ambulatory antibacterial therapy for uncomplicated skin infections in otherwise healthy adults, MRSA accounted for approximately 32% of all culture-confirmed infections and 77% of all S. aureus cultures.7
The emergence of CA-MRSA and other resistant phenotypes has altered the approach that clinicians must take when considering empiric antimicrobial therapy. The CDC continues to list MRSA as a “serious” threat and strongly advocates for the development and approval of novel therapeutic agents.12
Overview of current therapy
Vancomycin. A slowly bactericidal glycopeptide, vancomycin has activity against many Gram-positive organisms, including pathogens frequently implicated in ABSSSI. It is now a mainstay of therapy for the treatment of serious ABSSSI.13 Vancomycin disrupts the cell wall synthesis pathways by binding to the terminal D-alanyl–D-alanine amino acids on cell wall precursors, preventing transpeptidation reactions.13 It is dosed based on actual body weight and administered I.V. every 8 to 12 hours for patients with normal kidney function.14,15
Current practice guidelines from the Infectious Diseases Society of America (IDSA) recommend I.V. vancomycin as a first-line empiric treatment for management of severe purulent (abscess, furuncle, carbuncle) and nonpurulent (cellulitis, erysipelas, necrotizing infection) ABSSSI.1
Although vancomycin has been the treatment of choice, its slow bactericidal activity, associated toxicities (including nephrotoxicity and ototoxicity), hematologic abnormalities (thrombocytopenia and neutropenia), infusion-related reactions, need for therapeutic monitoring, and frequent dosing schedule have led to concerns about its continued utility.13
Vancomycin should be monitored using serum concentrations.1 In addition to necessary routine monitoring, the frequency of dosing required can make vancomycin a suboptimal choice for patients utilizing outpatient I.V. antibiotics for ABSSSI.
Resistance to vancomycin is also an increasing concern due to an emergence of vancomycin-resistant S. aureus, vancomycin-intermediate S. aureus (VISA), and heteroresistant VISA (a possible precursor to VISA).13 Additionally, S. aureus has most recently been displaying an “MIC creep” (a gradual increase in minimum inhibitory concentration of a drug required to inhibit bacterial growth) toward vancomycin, with the majority of isolates demonstrating an MIC of 1 mcg/mL rather than 0.25 mcg/mL as in previous decades.16
As a result, an increased number of treatment failures and/or toxicities due to the use of elevated dosages needed to overcome the higher MICs are being observed.16 Vancomycin utility in enterococci is also diminishing, as vancomycin-resistant enterococci (VRE) rates are approximately 83% in Enterococcus faecium and 10% in Enterococcus faecalis (up from 8%).17
Daptomycin. This cyclic lipopeptide antibiotic has rapid bactericidal activity against various Gram-positive organisms, such as S. aureus (including MRSA) and enterococci (including VRE). It was first approved by the FDA in 2003 for treatment of ABSSSI.18 Daptomycin binds in the septum of dividing bacteria, inducing rapid depolarization of cell membrane potentials and disrupting synthesis of DNA, RNA, and proteins, ultimately leading to cell death.18 It is administered via I.V. infusion. Daptomycin is recommended as an option for empiric treatment of severe purulent ABSSSI in adults in the current IDSA guidelines for treatment of severe complicated ABSSSI.1
Although generally well tolerated for short courses, daptomycin use is not without risk. The use-limiting toxicity associated with daptomycin is rhabdomyolysis. Creatine phosphokinase should be monitored at baseline and weekly (at minimum) during treatment.18 If rhabdomyolysis is suspected, serum creatinine and urine myoglobin should be monitored. Renal toxicity, acute kidney injury, and eosinophilic pneumonia have also been associated with daptomycin.18
Resistance to daptomycin has been observed in the last few years. While still infrequent, daptomycin nonsusceptible strains of staphylococci (MIC greater than 1 mcg/mL) and enterococci (MIC greater than 4 mcg/mL) have been documented.18-20
Telavancin. A lipoglycopeptide antibiotic originally derived from vancomycin, telavancin has concentration-dependent bactericidal activity against various Gram-positive organisms including S. aureus (both methicillin-sensitive S. aureus and MRSA), streptococci, and vancomycin-susceptible E. faecalis. Telavancin was first FDA approved for treatment of ABSSSI in 2009.21 Similar to the mechanism of action of vancomycin, telavancin inhibits bacterial cell wall synthesis and disrupts the bacterial membrane.21,22 It is administered via I.V. infusion.21
Clinical success rates range between 80% and 96%.23-26 Like daptomycin, telavancin is recommended in the current IDSA guidelines for ABSSSI as an option for empiric treatment of severe purulent ABSSSI in adults. Telavancin is only available as an I.V. infusion.1,27
Toxicities associated with telavancin include nephrotoxicity (with a black box warning for telavancin regarding increased mortality in patients with moderate-to-severe kidney impairment), prolonged QT interval, hypersensitivity reactions, and prolongation of prothrombin time (PT) and activated partial thromboplastin time (aPTT).21 Despite a narrow spectrum susceptibility profile and comparable efficacy, the nephrotoxicity, black box warning, and increased cost compared with vancomycin have largely limited its clinical usage.
Overview of new agents
Oritavancin. This semisynthetic lipoglycopeptide antibacterial is approved by the FDA for ABSSSI caused by susceptible isolates of S. aureus, Streptococcus pyogenes, Streptococcus agalactiae, Streptococcus dysgalactiae, Streptococcus anginosus, Streptococcus intermedius, Streptococcus constellatus, and E. faecalis in adult patients.28 Oritavancin has activity against both vancomycin-susceptible and vancomycin-resistant enterococcus.28
Oritavancin exerts antibacterial activity through multiple mechanisms, including inhibition of cell wall synthesis through inhibition of transpeptidation and disruption of bacterial cell membrane potential. It also has an increased affinity for binding sites, allowing it to increase membrane permeability in both stationary and growth phases of bacterial development.29 The currently approved FDA susceptibility breakpoints are 0.12 mcg/mL or less for S. aureus and E. faecalis and 0.25 mcg/mL or less for Streptococcus species.30
Oritavancin is highly protein bound and is not significantly metabolized by either the liver or kidneys.29 It is administered by I.V. infusion over 3 hours and accumulates in the tissues, slowly releasing over a terminal half-life of 393 hours, so repeated dosing is not necessary when treating ABSSSI.30,31
In contrast to vancomycin, blood concentration monitoring is not required with oritavancin.30 Instead, patients receiving oritavancin should be monitored for signs of infusion-related reactions or signs of hypersensitivity during infusion. If these reactions occur, the infusion should be slowed or stopped.32 Oritavancin artificially prolongs the PT and falsely elevates the aPTT, and use of I.V. unfractionated heparin sodium is contraindicated for 120 hours after oritavancin administration.32
The most frequently reported adverse reactions were injection site reactions, nausea/vomiting, and pruritus.28,30 There have been reports of transient increases in liver enzymes, which have been hypothesized to be a result of the high intracellular accumulation.28,33 There are also reports of an increased frequency of osteomyelitis as compared with patients who received vancomycin, so patients should be monitored carefully for signs or symptoms of osteomyelitis.32
Dalbavancin. A semisynthetic lipoglycopeptide, dalbavancin has been approved by the FDA for ABSSSI caused by susceptible, Gram-positive isolates of S. aureus, S. pyogenes, S. agalactiae, and S. anginosus.34 Dalbavancin inhibits transpeptidation within bacterial cell wall synthesis, binding with increased affinity to the binding site compared to the glycopeptides.29
In a large study comparing almost 82,000 isolates, dalbavancin demonstrated lower MIC90 values against S. aureus (1 mcg/mL versus 0.06 mcg/mL), coagulase-negative staphylococci (2 mcg/mL versus 0.06 to 0.12 mcg/mL), and beta-hemolytic streptococci (0.5 mcg/mL versus 0.03 mcg/mL or less) compared with vancomycin.35 Dalbavancin has also shown activity against vancomycin-susceptible and resistant strains of enterococci.35
Additionally, when dalbavancin was tested against over 62,000 strains of either methicillin-resistant, daptomycin-resistant, linezolid-resistant, or tigecycline-resistant S. aureus, the drug retained an MIC90 of 0.06 to 0.12 mcg/mL.36 Subsequently, the currently FDA-approved susceptibility breakpoint is set at 0.12 mcg/mL or less for S. aureus, S. pyogenes, S. agalactiae, and S. anginosus.37
Dalbavancin is widely distributed and extensively protein bound, with a terminal elimination half-life of 147 to 258 hours.29 Dalbavancin is given as a 30-minute I.V. infusion either as a single-dose regimen or a two-dose regimen with the second dose given 1 week after the first dose.34 Dose adjustments are needed for patients with kidney impairment based on creatinine clearance.34 Should an infusion-related reaction of flushing, urticaria, and/or rash occur, it is recommended to slow the infusion rate or stop the infusion.34,38
The most common adverse reactions of dalbavancin are nausea (5.5%), headache (4.7%), and diarrhea (4.4%).34 Some more serious, but rare, potential adverse reactions include reversible alanine aminotransferase elevation greater than three times the upper limit of normal (0.8%) and hypersensitivity leading to anaphylaxis.34 Therefore, dalbavancin is contraindicated in patients with known hypersensitivity to the drug; however, it is unclear if there is cross-reactivity with other glycopeptides.38
Unlike vancomycin, dalbavancin does not require any therapeutic monitoring to assess treatment efficacy; however, it is recommended to monitor for clinical response to therapy between 48 to 72 hours after treatment initiation and to monitor for the development of Clostridium difficile-associated disease up to 2 months after administration.38
Pediatric considerations for management of ABSSSI
Treatment of staphylococcal infections in the pediatric population is becoming challenging as S. aureus becomes increasingly resistant to the agents currently available for pediatric use. Overcoming the lack of treatment alternatives in this patient population is more difficult, as many of the newer agents, including lipoglycopeptides, are not indicated for pediatric use.
Telavancin, oritavancin, and dalbavancin have demonstrated efficacy in the treatment of multidrug-resistant Gram-positive infections but have had limited exposure in the pediatric population. A recent pharmacokinetic study of dalbavancin in children ages 12 to 17 years evaluated the drug exposure in children as compared with adults by scaling to body weight using a population pharmacokinetic model.39 Patients weighing more than 60 kg received a 1,000 mg dose, while those weighing less than 60 kg received a 15 mg/kg dose.
Following a single dose of dalbavancin, similar pharmacokinetic profiles were revealed for the two weight groups, and both yielded similar drug exposures to the adult population. Although not statistically significant, the renal clearance of dalbavancin was approximately 42% higher in the higher weight group. As with the adult data, dalbavancin displayed unique pharmacokinetic properties that would allow for extended interval dosing.
Similar statistics are true for oritavancin.40 There is currently no published data available for the use of oritavancin in the pediatric population.
Other antistaphylococcal agents
Daptomycin was approved by the FDA in 2003 but without a pediatric indication. Even though the package insert still indicates that the safety and efficacy of daptomycin in pediatric patients has not been established, numerous clinical trials have evaluated the pharmacokinetic profile of daptomycin in children from neonates to age 17 years.41-44 A recent review of daptomycin use in pediatric patients highlights the current available information.45
A better class of antimicrobials
Considering the increasing rates in both inpatient and outpatient medical visits for ABSSSI, the new lipoglycopeptides represent a class of antimicrobials with promise for treatment of these infections. (See Agent comparison for the treatment of ABSSSI.) Dalbavancin and oritavancin display potent in vitro activity against Gram-positive organisms and equivalent clinical success rates against standard of care agents. Both are I.V. options that may be useful for severe disease but have pharmacokinetic and pharmacodynamic principles that may make them useful to spare hospitalizations. Finally, the adverse reaction profiles of these agents make them an attractive option for the treatment of ABSSSI.
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