Current Infectious Disease Reports

, 16:418

Update on Management of Skin and Soft Tissue Infections in the Emergency Department

Authors

    • Department of Emergency MedicineUniversity of Wisconsin School of Medicine and Public Health
  • Mary R. Calderone
    • Department of Emergency MedicineUniversity of Michigan
  • John R. Meister
    • Department of Emergency MedicineUniversity of Wisconsin School of Medicine and Public Health
  • Jamie Santistevan
    • Department of Emergency MedicineUniversity of Wisconsin School of Medicine and Public Health
  • Larissa May
    • Department of Emergency Medicine and Medicine-Section of Infectious DiseaseThe George Washington University School of Medicine
Skin, Soft Tissue, Bone and Joint Infectious Diseases (N Safdar, Section Editor)

DOI: 10.1007/s11908-014-0418-9

Cite this article as:
Pulia, M.S., Calderone, M.R., Meister, J.R. et al. Curr Infect Dis Rep (2014) 16: 418. doi:10.1007/s11908-014-0418-9
Part of the following topical collections:
  1. Topical Collection on Skin, Soft Tissue, Bone and Joint Infections

Abstract

Skin and soft tissue infections (SSTIs) are frequently treated in the emergency department (ED) setting. Recent studies provide critical new information that can guide new approaches to the diagnosis and treatment of SSTIs in the ED. Rapid polymerase chain reaction assays capable of detecting MRSA in approximately 1 h hold significant potential to improving antibiotic stewardship in SSTI care. Emergency ultrasound continues to demonstrate value in guiding appropriate management of SSTIs, including the early diagnosis of necrotizing infections. Since emerging in the 1990s, community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) continues to increase in prevalence, and it represents a significant challenge to optimizing ED antibiotic use for SSTI management. Growing literature reinforces the current recommendation of incision and drainage without antibiotics for uncomplicated abscesses. Selecting antibiotics with CA-MRSA coverage is recommended when treating purulent SSTIs; however, it is generally not necessary in cases of nonpurulent cellulitis. Future advances in ED SSTI care may involve expansion of outpatient parenteral antimicrobial therapy protocols and the recent development of a novel, once weekly antibiotic with activity against MRSA.

Keywords

AbscessCellulitisSkin and soft tissue infectionCA-MRSAAntimicrobialInfectionAntibiotic stewardshipPCRNecrotizing fasciitisBlood culturesEmergency ultrasoundIncision and drainageABSSSIHome infusion therapy

Introduction

Skin and soft tissue infections (SSTIs) are frequently treated in the emergency department (ED) with over 3 million annual encounters [1]. The clinical conditions encountered range from uncomplicated abscesses and cellulitis to life-threatening necrotizing fasciitis. Since the emergence of community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) strains in the 1990s [2], the incidence of abscesses has increased, relative to that of other SSTIs [3, 4]. Numerous recent studies confirm CA-MRSA as the dominant cause of abscesses in North American EDs [59]; however, one study suggests that this may reflect data from urban areas that are not generalizable to the entire population [10]. The most recent literature (2012–present) on SSTI diagnosis and management provides critical new information and guidance for emergency providers seeking to optimize care in the CA-MRSA era.

Diagnosis

CA-MRSA Risk Factors

Numerous sociodemographic and clinical risk factors have been identified for CA-MRSA SSTI, including history of CA-MRSA infection, recent close contact with someone with a similar skin infection or history of CA-MRSA, chronic medical conditions (e.g., renal disease/dialysis, diabetes, peripheral vascular disease, cardiovascular disease, immunosuppression), antibiotic use in the previous year, indwelling device, chronic open wounds, lesion attributed to a spider bite, advanced age, youth (including newborns), intravenous (IV) drug abusers, men who have sex with men, military personnel, recent sexual contact, certain ethnic populations (Alaska natives, native American Indians, Canadian aborigines, and Pacific islanders), competitive athletes, presence of abscess, low body mass index, spontaneity of infection, incarceration, day care, and group home living [9, 1114] A recent case control study of 153 patients presenting to two Canadian EDs with STTIs adds to this evidence base, identifying transient residence (i.e., homeless, incarcerated, or with no fixed address), history of hepatitis C, history of substance abuse, and presentation with an abscess as independent risk factors for CA-MRSA [15]. Although risk factors lack sufficient diagnostic accuracy to rule in or rule out CA-MRSA as the causative organism, they may be useful to risk stratify patients when deciding whether to use antibiotics with CA-MRSA coverage. Nonetheless, given the high prevalence of CA-MRSA causing cutaneous abscesses, evidence-based guidelines from the Infectious Disease Society of America recommend empiric coverage for CA-MRSA in all patients when treating purulent SSTI with antibiotics [16].

Polymerase Chain Reaction Assays

The Infectious Diseases Society of American (IDSA) and ED investigators have acknowledged the potential of rapid molecular diagnostics to significantly improve antibiotic decision making in the ED for patients with SSTI [17, 18]. Commercially available polymerase chain reaction (PCR) assays can accurately detect MRSA from clinical specimens in approximately 1 h [19, 20]. A recent feasibility study conducted in the ED found no increase in length of stay among patients with abscesses who had MRSA PCR swabs obtained from colonization and SSTI sites immediately after triage [21•]. Results from an ED-based pilot study of post incision and drainage (I + D) MRSA PCR swabs demonstrated >95 % sensitivity and specificity and decreased use of broad spectrum antibiotics in the PCR group. Interestingly, 25 % of patients in this study declined to wait for their PCR result after I + D, suggesting that even the rapid turnaround time of approximately 1 h may limit the utility of wound specimen testing for discharged patients [22]. Further research is needed to explore the value of colonization in predicting MRSA as the causative organism in SSTIs, since molecular-based colonization site specimens can be easily obtained in triage and processed during patient wait times. Future efforts designed to incorporate technological advances in infectious disease diagnostics into ED practice are critical to improving antibiotic selection in SSTI care.

The LRINEC Score

Although rare, necrotizing fasciitis is a serious and rapidly progressive infection. Early identification and intervention are key, since delay in operative debridement increases mortality risk [23]. While classically a polymicrobial infection, CA-MRSA is an increasingly important causative organism [24]. Developed using retrospective chart review and logistic regression, the Laboratory Risk Indicator for Necrotizing Fasciitis (LRINEC) is a diagnostic scoring system proposed to assist in the early distinction of necrotizing fasciitis from other types of SSTIs. Points are scored on the basis of laboratory cutoffs for sodium, glucose, creatinine, C-reactive protein, white blood cell count, and hemoglobin. The recommended cutoff of greater than 6 points was reported to have a positive predictive value of 92 % (95 % CI, 84.3–96.0) and a negative predictive value of 96 % (95 % CI, 92.6–97.9) [25, 26].

However, an external validation study suggests the LRINEC should not be used to supplement clinical judgment in the early identification of necrotizing fasciitis. In this retrospective chart review of 52 patients with confirmed necrotizing fasciitis, a score of greater than 6 was associated with a sensitivity of only 52 % (95 % CI 38–66) [27]. This conclusion is further supported by a recent case report of surgically confirmed necrotizing fasciitis in a 37-year-old ED patient who presented with a LRINEC score of zero [28].

Utility of Blood Cultures

Previous research indicates that blood cultures in patients with SSTIs are rarely positive and do not significantly improve clinical management [29]. A recent retrospective study focused on the utility of blood cultures in cases of complicated cellulitis, defined as infections in patients with comorbid conditions including active chemotherapy, dialysis, HIV/AIDS, diabetes mellitus, or organ transplantation. In the study population of over 600 patients, culture results prompted a change of empiric antibiotics only 2 % of the time, with most changes resulting in narrowed coverage. Overall, cultures provided little benefit for complicated cellulitis in this retrospective analysis, and the authors urged further confirmation through prospective trials [30].

Ultrasound

Although most superficial SSTIs are easily diagnosed as cellulitis or abscess on the basis of clinical observation alone, cases of deeper infection often lead to variations in clinical judgment and treatment practices [31]. Several recent studies in the pediatric population build upon prior literature that suggests that ultrasound may play an important role in the appropriate diagnosis and management of SSTIs in the ED [32]. Accurate diagnosis is important because failure to detect an underlying abscess will preclude a necessary I + D, whereas the converse may result in the patient undergoing an unnecessary invasive and painful procedure [33]. A prospective study examined 775 patients in a pediatric ED to assess clinical exam (CE) alone versus CE plus emergency ultrasound (CE + EUS) in the diagnostic evaluation of SSTIs. They found that CE was highly accurate for diagnosis of SSTIs that required drainage and the addition of EUS did not improve diagnostic accuracy in lesions that were clinically evident. In cases not clinically evident, CE + EUS was more sensitive than CE alone; however, specificity was only moderate and not statistically improved from CE alone [34]. A second prospective study of a sample of 66 children looked at how EUS compared with physical exam and history alone for the diagnosis of cellulitis and abscess in children, with the secondary outcome being change in diagnosis and management. In this study, EUS had higher sensitivity for detecting abscess (97.5 %), as compared with physical exam alone (78.7 %). Researchers also found that EUS disagreed with clinical exam and changed the diagnosis in for a total of 24.6 % of patients, with management changing in 13.8 % of cases [35•].

Addressing concerns regarding the influence of operator skill on the reported diagnostic accuracy of bedside ultrasound, a prospective, observational study of ED patients suspected of having abscesses examined the ability of EUS novices to predict positive I + D (pus expressed during the procedure). Prior to the study onset, novice residents and attending physicians underwent a 2-day course for soft tissue ultrasonography. Consistent with previous literature, the sensitivity of novice sonographers to predict positive I + D (97 %) was superior to that of clinical exam alone (76 %) [36]. These findings suggest that minimal training is necessary to achieve adequate skill in the EUS evaluation of soft tissue infections.

Another emerging use of ultrasound for SSTI management is to aid in the early diagnosis of necrotizing fasciitis. Multiple recent ED case reports highlight how EUS findings can facilitate expedited operative management through bypassing of advanced imaging in cases of early necrotizing fasciitis, including Fournier’s gangrene [3739]. The pneumonic STAFF (subcutaneous thickening, air, and fascial fluid) has been proposed to describe ultrasound findings in necrotizing fasciitis [37]. Although EUS may play a role in assisting with early diagnosis, previous literature suggests that it lacks adequate sensitivity (88 %) to rule out the diagnosis [40]. Since outcomes in necrotizing fasciitis depend on early diagnosis and treatment, if clinical suspicion is high, advanced imaging or surgical exploration should be sought regardless of ultrasound findings.

There are many potential benefits to the use of ultrasound as an imaging modality. It is relatively inexpensive, noninvasive, rapid, and easy to learn. EUS can play a role in the diagnosis and management of SSTIs in both adults and children in the emergency department; however, further research is needed to determine whether or not the use of ultrasound leads to changes in management practices and improved patient outcomes.

Treatment

Procedural Advances

Incision and drainage is the mainstay of treatment for cutaneous abscesses and classically involves incision, evacuation of purulent material through manual expression, elimination of loculations, irrigation, and packing. Emerging evidence suggests that traditional approaches to I + D may be suboptimal. A minimally invasive technique that involves two small stab incisions overlying the abscess, insertion of a hemostat to break up septations, and placing a drain through the incisions eliminated the need for traditional packing/dressing changes and demonstrated significantly decreased costs and length of stay in a pediatric population [41, 42].

Iodoform gauze is the most commonly utilized packing material after I + D. A comparison study of iodoform with newly developed silver containing hydrofiber packing material revealed lower pain scores on first follow up visit (48–72 h after initial visit) and faster wound healing with the hydrofiber dressing. The authors acknowledged the increased cost of the hydrofiber packing ($9–12/ribbon [18 in.] vs. $3–4/5 yards of iodoform) but highlighted that the hydrofiber group required less dressing changes, which may reduce overall costs [43]. However, further research is needed, since some studies suggest no significant differences in clinical outcomes with packing after incision and drainage [44], and a small study suggests that packing may result in increased pain [45].

A systemic review in 2009 suggested that primary closure after incision and drainage resulted in faster healing and homologous healing rates to secondary closure [46]. In 2013, an update sought to support these findings via a randomized, controlled trial. The trial failed to demonstrate superiority of primary closure but noted limitations due to smaller abscess and incision sizes encountered in their study population. Nevertheless, rates of healing and treatment failure were similar in their publication, leading the authors to conclude that primary or secondary closure may be safely utilized for simple abscesses [47].

Updates to Current Treatment Guidelines

Current IDSA guidelines on antibiotic use in the management of cellulitis versus abscesses differ significantly, highlighting the importance of clinically distinguishing these two conditions. The guidelines for the treatment of abscesses recommend that simple, uncomplicated abscesses be treated with I + D alone and do not support the routine use of antibiotics in addition to thorough drainage of the wound [16]. Two randomized controlled trials, which were included in a recent meta-analysis, add considerable support for previous evidence that antibiotics do not improve outcomes for uncomplicated abscesses [48, 49, 50••]. However, the guidelines do recommend antibiotic therapy for abscesses associated with the following conditions: severe or extensive disease or rapid progression in the presence of associated cellulitis, signs and symptoms of systemic illness, associated comorbidities or immunosuppression, extremes of age, abscess in an area difficult to drain (e.g., face, hands, or genitalia), associated septic phlebitis, and lack of response to I + D alone [16]. These criteria include several subjective factors that require clinical judgment and may result in practice variability with regard to antibiotic use. For empirical coverage of CA-MRSA in outpatients with SSTI, options for oral antibiotics include clindamycin, trimethoprim/sulfamethoxazole (TMP-SMX), a tetracycline, and linezolid.

Conversely, IDSA guidelines for the management of uncomplicated cellulitis recommend that cases of nonpurulent cellulitis be treated with antibiotics—specifically, those that target β-hemolytic streptococci and not CA-MRSA [16]. Results of a randomized, multicenter, double-blind, placebo-controlled trial support this recommendation, since they demonstrated no improvement in outcomes among patients with uncomplicated cellulitis treated with TMP-SMX in addition to cephalexin versus those treated with cephalexin alone [51••]. For cases of cellulitis with purulence, which account for only 8 % of purulent skin infections [9], the guidelines do recommend antibiotics that target CA-MRSA [16]. Vancomycin remains the primary agent for MRSA coverage for patients with complicated SSTIs (deep soft tissue infections, surgical/traumatic wound infection, major abscesses/cellulitis, and infected ulcers or burns), although IV linezolid, daptomycin, telavancin, and clindamycin are available alternatives [16, 52]. MRSA is increasingly cited as a causative organism in necrotizing fasciitis, and vancomycin should be part of the empiric antibiotics when this condition is suspected [53].

Antibiotic Stewardship

Determining the optimal approach to the use of antibiotics for the ED treatment of SSTIs in the CA-MRSA era remains a challenge. The dangers of poor antibiotic stewardship, which is defined as the optimization of antibiotic use, highlight the importance of effective evidence-based guidelines and accurate diagnostics for the management of SSTIs in the ED. Overuse of antibiotics is associated with negative consequences, such as increased antibiotic resistance due to selective pressure, increased cost of treatment, and increased risk of medication-related adverse effects, such as Clostridium difficile infection [18, 54]. In addition, inappropriate withholding of necessary antibiotics may increase treatment failure rates. Due to rising rates of CA-MRSA resistance to commonly utilized oral agents such as clindamycin and TMP-SMX and geographic resistance variability [5557], local SSTI antibiograms should be developed and utilized to guide selection of an antibiotic with CA-MRSA coverage [8, 18]. Utilizing a governmental database, investigators in Canada report a link between increasing incidence of CA-MRSA to a 49 % increase in antibiotic prescribing for SSTIs between 1996 and 2008, driven primary by increases in clindamycin and TMP-SMX use [7]. The dramatic rise in antibiotic use due to concerns over CA-MRSA underscores the need to optimize antibiotic stewardship for SSTIs.

Although vancomycin is still the most effective and commonly utilized antibiotic for severe infections due to MRSA [52], concerns over emerging vancomycin resistant strains of S. aureus continue to increase [5860]. The development of resistance has been attributed, in part, to frequent overuse and under dosing of vancomycin [6164]. A single-center, retrospective cohort study of vancomycin use found that it is frequently overused and dosed incorrectly in the ED, which often continues after hospital admission. Vancomycin was given most commonly for SSTIs, of which some may have represented simple cutaneous abscesses that could have been managed with I + D alone. Furthermore, it is likely that many of these SSTIs treated with vancomycin represented CA-associated MRSA, which is susceptible to a greater number of antibiotic classes than is health-care-associated MRSA and likely did not require vancomycin [58]. The frequent inappropriate dosing may be due to a flawed “one size fits all” approach of giving a majority of patients 1 gram IV rather than the guideline-recommended 15–20 mg/kg strategy based on the actual body weight. In another retrospective cohort study assessing dosing strategies for vancomycin, only roughly 20 % of patients received an appropriate dose based on this recommendation [65].

Wide variation in practice patterns has been observed regarding ED antibiotic use for uncomplicated SSTI treatment. A prospective observational study collected data on the management of adults presenting to a single urban, academic ED with abscesses and found that nearly 80 % of subjects were treated with both I + D and antibiotics [66]. Furthermore, emergency physicians (EPs) significantly overestimated the percentage of SSTIs that actually grew MRSA from the wound cultures. The greatest predictor of antibiotic usage in addition to I + D was erythema size greater than 2 cm, which may reflect clinical concerns about purulent cellulitis. These results demonstrated that a large percentage of patients with SSTIs, even those with small abscesses, are being treated with antibiotics. Another cross-sectional study using self-reported survey data from EP providers found a significantly lower proportion of EPs prescribing antibiotics in addition to I + D; 73 % of EPs surveyed responded that they prescribed antibiotics only if certain historical factors or physical findings were present on exam (diabetic or immunocompromised, history of MRSA, or surrounding cellulitis) [67]. The observed discrepancy may reflect a major limitation of the study in that it relies on self-reported practices of which the accuracy cannot be verified.

Even though many EPs continue to prescribe antibiotics in addition to I + D, the ability to appropriately target antibiotic therapy remains limited. One retrospective analysis found that despite wide variation in antibiotic regimen selection among EPs, antibiotic regimens are often poorly targeted toward the causative organisms. Clinicians treating the SSTI with a single antibiotic accurately targeted the resultant cultured pathogen only 39 % of the time. Many of these EPs also utilized a common strategy known as double coverage, which refers to the use of at least two antibiotics with gram-positive coverage (most commonly TMP-SMX plus cephalexin) to target MRSA, MSSA, and B-hemolytic streptococcus. Of the adult patients being treated with multidrug double coverage, 67 % grew only Staphylococcus, demonstrating that coverage of Streptococci may be unnecessary [8]. Double coverage was also observed in another ED-based study [68] and may be widespread. This practice serves only to double the potential for adverse effects to antibiotics and promote resistance without offering any additional clinical utility.

The data demonstrating the poorly targeted nature of antibiotic therapy for SSTIs have led to discussions regarding quality measures and vehicles for improvement. One study identified two potential quality measures of antibiotic stewardship. The first measure designates as overuse any use of antibiotics for abscess treated with I + D and discharged with a prescription for antibiotics, while providing an exception that allows the clinician to specify the reason, since 87 % of discharged patients with abscesses in the study were treated with antibiotics. The second proposed quality measure assesses the failure to use antibiotic agents with activity against CA-MRSA once an antibiotic is prescribed to treat a patient with an abscess, since nearly 16 % of the antibiotic regimens prescribed in the study did not cover CA-MRSA [69].

Update on ABSSSI Treatment

In order to standardize clinical trials examining new antimicrobials seeking approval for skin infections, the U.S. Food and Drug Administration (FDA) coined the term acute bacterial skin and skin structure infection (ABSSSI) [70]. This term includes cellulitis/erysipelas, wound infections, major cutaneous abscess, and infections related to burn injuries. In order to capture infections most likely to demonstrate a treatment effect, the definition of ABSSSI requires at least 75 cm2 of redness, edema, or induration. Parenteral antibiotics that are FDA approved for MRSA ABSSSIs include vancomycin, daptomycin, linezolid, tigecycline, televancin, and ceftaroline [71, 72]. Of note, recent concerns over increased mortality risk with tigecycline should significantly restrict its clinical utilization [73].

Several recent, nonexperimental studies aimed to further characterize the effectiveness of linezolid and televancin for treating MRSA ABSSSIs. Favorable clinical cure rates have been observed for oral linezolid therapy, when compared with IV vancomycin therapy, in propensity score-matched patients with SSTIs caused by MRSA [74]. A Cochrane review published in 2013 analyzed nine randomized controlled trials comparing linezolid with vancomycin in the treatment of SSTIs and found that linezolid had both improved clinical and microbiological cure rates when compared with vancomycin [75]. Although inpatient treatment with linezolid costs more than with vancomycin, the overall median length of stay was shorter by 3 days, leading to reduced overall cost [75]. However, clinical success for patients with MRSA-caused complicated SSTIs treated with vancomycin or linezolid was shown to vary by both subpopulation and infection type in another study [76]. Reports of MRSA resistance to linezolid remain rare but suggest that this agent should be reserved for severe SSTIs [11, 52]. Telavancin was approved by the FDA for ABSSSI in 2009 on the basis of the results of the Assessment of Telavancin in cSSSI (ATLAS) trial, which demonstrated its noninferiority to vancomycin [77]. A recent post hoc analysis of the ATLAS studies explored the efficacy of telavancin in patients with abscesses and cellulitis and found similar cure rates [78]. However, concerns have arisen over the potential for increased nephrotoxicity from telavancin, as compared with vancomycin, when utilized in clinical practice [79].

In addition to the currently approved antibiotics for ABSSSI, two promising agents were approved by the FDA in 2014. Tedizolid is an oxazolidinone with activity against gram-positive bacteria including MRSA. It was developed for once daily intravenous or oral administration. Approval follows a recent phase 3, randomized, double-blind, noninferiority trial that compared it with linezolid in patients with complicated SSTIs [80]. The study found that 200 mg once daily dose of oral tedizolid phosphate for 6 days was statistically noninferior to 600 mg of oral linezolid every 12 h for 10 days in terms of early clinical response at 48–72 h following the initiation of therapy [80]. Dalbavancin, a novel second-generation lipoglycopeptide that is dosed once weekly and covers MRSA, was also approved by the FDA in 2014. This unique formulation may have significant implications for the outpatient ED treatment of ABSSSIs.

Novel Approaches to Antibiotic Therapy

Outpatient parenteral antimicrobial therapy (OPAT) programs have become increasingly popular as a method of treating SSTIs in patients requiring IV antibiotics to reduce costs and nosocomial infections and support preferences of patients who prefer treatment at home [72]. A retrospective cohort study of adult patients with cellulitis at an academic ED showed that 17 % of patients referred from the ED to a 24-h Clinical Decision Unit (CDU) were discharged home with OPAT (average treatment duration of 4.7 days). Hospitalization was thus avoided in 33 patients over an 8-month period, which translates to approximately 198 fewer hospital days [81].

Currently utilized regimens for OPAT include the use of a twice-daily IV antibiotic regimen or a once daily IV regimen plus oral probenecid. By impairing renal tubular excretion, probenecid prolongs and increases the serum concentrations of penicillin and several cephalosporins [82]. A recent observational study compared the difference in mean times until nonprogression in patients who received the once daily IV cephazolin plus probenecid versus twice daily cephazolin for home-based cellulitis treatment and found no significant difference [83]. Use of the once daily IV antibiotic regimen for OPAT may improve compliance and avoid additional home visits, thereby representing a more cost-effective program that will increase SSTI-related treatment capacity significantly [83].

Conclusions

The ED is a frequent site for the diagnosis and management of SSTI. The emergence of CA-MRSA as the predominant causative organism of cutaneous abscess has led to a change in current recommendations to include coverage of CA-MRSA when prescribing antibiotics for the management of purulent SSTIs. Conversely, emerging data suggest that there is no additional benefit to using antibiotics active against CA-MRSA in the treatment of uncomplicated cellulitis. While numerous risk factors have been identified for CA-MRSA associated SSTI, accurate clinical predictors of CA-MRSA are lacking. The development of accurate and rapid molecular-based tests to diagnose MRSA may change the paradigm of empiric therapy; however, further research is needed. Incision and drainage remains the mainstay of therapy for uncomplicated cutaneous abscesses, with recent research suggesting that the traditional practice of packing may not result in improved clinical outcomes. New antibiotics that provide coverage for MRSA have become available for the treatment of ABSSSI, but their utility is limited to the inpatient setting, given their cost and parenteral availability. Increasing evidence in support of OPAT and the development of a novel once weekly antibiotic with activity against MRSA may significantly influence future approaches to optimal SSTI management in the ED setting.

Compliance with Ethics Guidelines

Conflict of Interest

Mary Calderone, Jamie Santistevan and John Meister declare no conflicts of interest. Larissa May has served as a consultant for Durata Therapeutics and has received payment for educational presentation from Cepheid and research support from Cepheid. Michael Pulia received payment for educational presentations and research support from Cepheid.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by the authors.

Copyright information

© Springer Science+Business Media New York 2014