What Is New in the Management of Skin and Soft Tissue Infections in 2016?

Garyphallia Poulakou; Efthymia Giannitsioti; Sotirios Tsiodras

Curr Opin Infect Dis. 2017;30(2):158-171.

Diagnosis

Diagnosis of uSSTIs such as erysipelas and cellulitis relies often on clinical features only. Specimens for culture can be taken in purulent SSTIs or in lesions undergoing surgical incision and/or debridement or imaging-guided drainage.^[9] Optimal sampling for microbiology is advisable via surgical procedure from the area of peripheral expansion of the lesion. However, in some uSSTIs, surgical incision and drainage may be adequate treatment; in a recent meta-analysis encompassing 1969 patients, the antimicrobial treatment did not confer any additional benefit.^[47] Superficial sampling with swabs and particularly in chronic-infected ulcers can overestimate as 'true pathogens' microorganisms that represent colonization. Blood cultures are rarely positive in SSTIs and are recommended in patients with underlying comorbidities and systematic inflammatory response.^[9,48] Recent studies in pediatric patients with uSSTI argue against the necessity of blood cultures as routine practice.^[49,50] Accumulating data have emphasized the role of ultrasound applications as an important adjunctive diagnostic tool in the management of SSTIs in the ED. Ultrasound may guide drainage and microbiological sampling, assessment of disease proliferation and the need for surgical intervention and ultimately may contribute to selection of appropriate treatment.^[51–53] In a prospective study of 151 pediatric patients with SSTI, sensitivity and specificity of point-of-care ultrasonography for abscesses were 96 and 87%, respectively, outperforming those of clinical examination (84 and 60%, respectively).^[54] In a study of 32 patients with ulcers including diabetic foot infections, swabbing after ultrasonic debridement of the ulcer was equally reliable to biopsy.^[55] The use of LRINEC score along with 'a pain out of proportion' and a five-fold increase in C-reactive protein (CRP) levels may increase the diagnostic threshold for necrotizing fasciitis,^[56] which remains an important diagnostic challenge in the ED.^[57]

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Table 1. Definitions of complicated and uncomplicated skin and soft tissue infections and acute bacterial skin and soft structure infections
Uncomplicated SSTI	Complicated SSTI	ABSSSI
Superficial infections	Deep soft tissue infection	SSTIs with lesions with a minimum surface area of 75 cm²
Cellulitis	Lesion requiring surgical procedure	Criteria
Erysipelas	Large abscesses	Erythema and/or induration extending ≥5 cm from the peripheral margin of the infection
Folliculitis	Infected postoperative wounds	Systemic signs of infection (such as fever)
Furunculosis	Infected burns	(and/or) proximal lymphadenopathy
Ecthyma	Infected chronic ulcers	Types of infections included
Impetigo	Necrotizing infections	Cellullitis, erysipelas
Infections that can be treated with surgical incision alone	Rapidly expanding infections	Major cutaneous abscesses
Small abscesses	Bacteremic infections and/or with septic shock	Wound infections
Absence of significant comorbidities	Significant underlying diseases or comorbidities compromising treatment outcomes	Excluded: impetigo and minor cutaneous abscess, animal or human bites, burns, necrotizing fasciitis and myonecrosis, diabetic foot infection, chronic wound infection, ecthyma gangrenosum, underlying osteomyelitis or septic arthritis, concurrent medical conditions that would obscure evaluation of outcome (i.e. neutropenia)

SSTI, skin and soft tissue infection.
Adapted from [7,9,10].

Table 2. Risk factors for skin and soft tissue infections and particular pathogens
Risk factors for SSTI	Risk factors for SSTI by MRSA	Risk factors for CA-MRSA	Risk factors for SSTI by gram negatives
Trauma (laceration, abrasion, crush, burn and so on)	Previous colonization	Contact sports	Surgical site infections
Intravenous drug use	Contact with colonized persons	Military service	Axillary cavity
Human and animal bites	Antibiotic treatment in the previous 12 months	Incarceration	Gastrointestinal tract
Conditions that predispose to infection	Hospitalization in the previous 12 months	Overcrowded housing	Female genital tract
Diabetes mellitus	Previous infection by MRSA	Poor hygienic conditions	Inguinal area and perineum
Previous cellulitis	Residence of long-term care facility	Intravenous drug use	Penetrating injury (Pseudomonas aeruginosa)
Radical mastectomy with lymph node resection	Recent travel in Latin America, South East Asia and Africa	Young children with daycare exposure	Injury sustained in fresh water (Vibrio vulnificus)
Saphenous vein harvesting	Previous ICU admission		Injury sustained in salt water (Aeromonas hydrophila)
Neutropenia	Cardiovascular disease		Human bite (Eikenella corrodens)
Hypogammaglobulinemia	Diabetes mellitus		Animal bite (Capnocytophaga sp, Pasteurella multocida)
Chronic renal disease	Peripheral vascular disease		Diabetes mellitus
Cirrhosis	Chronic wounds		Cirrhosis
Alcoholism	Immunosuppression		Intravenous drug use
	Chronic renal disease		Subcutaneous drug use
	Dialysis
	Central venous catheters and implantable devices
	Intravenous drug use

CA-MRSA, community-acquired MRSA; MRSA, methicillin-resistant Staphylococcus aureus; SSTI, skin and soft tissue infection.
Adapted from [1,9,16].

Table 3. Recent studies assessing treatment failure and/or recurrence in skin and soft tissue infections [21,37–45]
Author, year	Study design	Medical setting	Patients (n)	Primary outcome	Microbiology	Failure or recurrence rate	Failure or recurrence definition	Factors associated with treatment failure	Abx
Lee [37]	Prospective	14 primary care clinics	106	Failure within 90 days from initial visit	S. aureus	Overall 22 of 106 (21%) (13 for MRSA, 9 for MSSA, P=0.7)	Within 90 days of initial visit one of: new course or change in antibiotic therapy, additional incision or drainage, SSTI at a new site, SSTI at the same site, emergency department visit or hospital admission	≥7 days duration of infection, lesion diameter size ≥5 cm	76% TMP-SMX, 11% doxycycline, 7% clindamycin, 9% cephalexin (overall discordance 5%)
Walsh [38]	Retrospective	2 academic medical centers	163	Appropriateness of Abx treatment duration for SSTIs in hospitalized patients	11 MSSA, 10 MRSA, 8 polymicrobial gram(+), 6 Streptococci, 4 other gram(+), 5 mixed gram (+) and gram (–), 3 gram (–)	30-day readmission rate (6 of 163)	30-day readmission secondary to recurrent SSTI	ND	ND
Haran [39]	Retrospective	4 emergency departments	467	Determine if age was associated with outpatient department treatment failure for purulent SSTI	ND	12.4%	Need for change in Abx, surgical intervention or hospital admission within 30 days from emergency discharge	Older age (>65 years), higher CCI score, infection involving hand structures and IV vancomycin at ED^a	Cephalosporin, clindamycin, doxycycline, vancomycin, metronidazole, TMP-SMX, fluoroquinolones and azithromycin
Li [40]	Retrospective	4 hospitals of a healthcare conglomerate in China	527 patients hospitalized with cSSTI	Epidemiology and outcomes of patients hospitalized with cSSTI	Available for 184 of 527 (32.5%). Gram (+) 61.41% (MRSA 7.6%), gram (–) 46.2%	35 of 527 (6.64%) (20 of 527, 3.8% ≤3 months)	Reinfection/recurrence	ND	Various
Mistry [41]	Retrospective	Tertiary care hospital, ED department with 23-h OU	192 children	Clinical failure of OU treatment	Available for 105 of 192 patients, 66.7% MRSA	43 of 192 (22.4%) (primary reason for failure was ward admission for 98% of cases)	One of: unexpected ward hospitalization directly from OU, return ED evaluation within 72 h after OU discharge, change in antibiotic therapy due to poor clinical response, need for incision and drainage after OU admission	Fever on ED presentation, ultrasound performance in the ED prior to OU admission	i.v Clindamycin 176, TMP-SMX 3, vancomycin 1, cefazolin 3 and other 4
May [42]	Retrospective	ED department	197.371	Incidence and factors associated with ED visits for recurrent SSTI infections	ND	32.098 (16.3%) had at least one recurrence, 10.419 (5.3%) more than one recurrence	Repeat SSTI, ED visit within 6 months from initial visit	Nonsenior adults, female patients, non-Hispanic white patients, insurance status, geography and income, admitted patients, higher CCI, drug or alcohol abuse, liver disease, obesity, history of drainage or aspiration
Hemmige [21]	Retrospective	Single center university of Chicago medical center's ID clinic	85	Incidence and risk factors for recurrent SSTI among HIV patients	Available for 23 of 85 (mostly S. aureus)	30 of/85 (35.3%) at least one recurrent SSTI during follow up, 14 of 85 (16.5%) multiple recurrences	Recurrent SSTI was defined as either an SSTI at a new site or recurrence at the original site greater than 30 days after the initial SSTI, with resolution of the signs and symptoms of the original infection in the interim	Presence of intravascular catheter, nonhepatitis liver disease, lymphedema, history of IVDU and HIV VL>1000 c/ml	20 combination therapy, 20 b lactam, 21 clindamycin, 8 TMP-SMX, 5 fluoroquinolones, 3 vancomycin and 3 no antimicrobials
Macia-Rodriguez [43]	Retrospective	Single center university hospital	308 hospitalized patients	Factors associated with mortality and readmissions	Local cultures performed for 144 patients, 95 of 144 were positive, 66 of 95 gram (+) (MRSA 11 of 66), 53 of 95 gram (–), 11 of 95 anaerobes	34 of 308 readmitted for SSTI within 6 months from discharge	Readmission for SSTI within 6 months from discharge	Presence of malignancy and immunosuppression	33.1% amoxicillin/clavulanate, 26% cloxacillin and 29.5% combination
Eells [44]	Prospective	Tertiary care hospital	87 patients with S. aureus skin infection without bacteremia, osteomyelitis, endocarditis or hardwareassociated infection	Clinical response after 30 days of follow up	S. aureus	40 of 87 (46%)	Any of the following: relapse of skin infection, new skin infection, receipt of prolonged antibiotic therapy for skin infection, receipt of new antibiotic therapy or change in therapy for skin infection, new incision and drainage	Poor adherence to postdischarge antibiotic therapy, diabetes and illicit drug use	46 TMP-SMX, 29 clindamycin, 4 amoxicillinclavulanate, 3 linezolid, 2 cephalexin, 1 dicloxacillin and 1 doxycycline
May [45]	Subanalysis of a parent study	2 EDs	Patients treated for a cutaneous abscess with incision and drainage. 193 completed either 1- or 3-month follow up	Failure to improve within 1 week following initial treatment, SSTI recurrence at 1 and/or 3 months of treatment of the index infection	27.5% MRSA, 18.7% MSSA, 47.7% other, 6.2% no growth/missing	Combined SSTI recurrence occurred in 28% of 193 patients	Failure defined as no change in/or increased pain, swelling, erythema, drainage of the current abscess or new or persistent fever. Recurrence defined as the presence of a new abscess at the same or different locations at least 2 weeks after resolution of the initial abscess	Previous contact with someone infected with MRSA, history of SSTI within the past 12 months and clinician use of wound packing	7.3% b lactams, 39.4% clindamycin, 17.6% TMP-SMX, 9.8% TMP-SMX + b lactams, 1% other and 24.9% none

^aVancomycin as one-time dose in ED was associated with worse patient outcome. Maybe in part due to the frequency that vancomycin is under dosed in ED. Also, it was not followed with MRSA antibiotics for home in one out of three patients treated [39].
Abx, antibiotic; CCI, Charlson comorbidity index; ED, emergency department; ID, infectious disease; IV, intravenous; IVDU, intravenous drug use; MRSA, methicillin-resistant Staphylococcus aureus; MSSA, methicillinsensitive Staphylococcus aureus; ND, not defined; OU, observation unit; SSTI, soft skin tissue infection; TMP-SMX, trimethoprim/sulfamethoxazole.
Adapted from [21,37–45].

Table 4. Update of information about novel antimicrobials for ABSSSI according to activity, administration route, indications and market status (marketed to phase II agents from top to the bottom part of the table)
Antibacterial	Class	Activity vs. gram (–)	Gram (+) spectrum	Studies/indications	Administration	Dose	Status, comments
Ceftaroline	Cephalosporin	Yes	MSSA, MRSA, S. pyogenes, S. agalactiae, Streptococcus anginosus group S. dysgalactiae	ABSSSI, CABP	iv only, q12 h regimen, over 5–60 min	600 mg	Marketed, direct Coombs test seroconversion, watch for hypersensitivity reactions [89], adjustment for Cr clearance, q8 h regimen for patients with evidence of systemic inflammation and/or comorbidities [85]
Oritavancin [92]	Semisynthetic lipoglycopeptide	No	S. aureus, MRSA, VISA, VRSA, GAS, S. anginosus, E. faecalis, E. Faecium/VRE (Van A,B,C,D)	ABSSSI	iv only, 1 dose over 3 h	1200 mg	Marketed, bactericidal, CYP450 interactions [93], give warfarin 12 h after, FDA warning re: osteomyelitis, new formulation, may lead to early discharge
Dalbavancin [94]	Lipoglycopeptide	No	S. aureus, MRSA (low MICs), VISA, GAS, Enterococci (inactive against Van A)	ABSSSI	iv, 1 dose over 30 min	1000 mg then 500 mg q 7 days; 1500 mg once	Marketed, bactericidal decrease dose to 25% for creatinine clearance <30 ml/min, not dialyzable, case reports in BSI, PJI [95], may lead to early discharge
Tedizolid [83]	Oxazolidinone prodrug	No	S. aureus, MRSA, VISA, GAS, S. anginosus group, S. agalactiae, E. faecalis (vancomycin susceptible only)	ABSSSI	iv and oral, once daily for 6 days	200 mg	Marketed, no dose adjustment for age, renal/hepatic impairment, better hematological profile than linezolid, ongoing studies for HABP, VAP, may lead to early discharge with iv to per os switch
Fusidic acid	Fusidane, bacterial elongation factor inhibitor [96]	No	MSSA, MRSA, higher MICs for streptococci and enterococci	ABSSSI, PJI	Oral, twice a daily regimen	Phase II study regimen, 1500 mg CEM-102 loading dose, then 600 mg bid × 10–14 days	Phase III for ABSSSI in USA, use in combination with rifampin for PJI97], resistance development should be monitored [98]
Iclaprim [99,100]	Dihydrofolate reductase inhibitor	Yes	MSSA, MRSA, GAS, S. pneumoniae	ABSSSI, HABP	iv over 2 h, twice daily	80 mg	Phase III. Active against TMP-resistant bacteria, Ongoing ABSSSI studies (REVIVE 1,2) [101,102]
Lefamulin [103,104]	Pleuromutilin, protein synthesis inhibitor [105,106]	Yes	MSSA, MRSA, CoN Staph, GAS, VRE	ABSSSI, CABP	Oral, q12 h iv g12 h, over 60 min	600 mg; 150mg	Phase III, planned indications ABSSI, studies ongoing [107]
Omadacycline [108]	Tetracyclines (9-aminomethylcycline) [109]	Yes	MSSA, MRSA, GAS, group B streptococci, VRE [110]	CABP, ABSSSI, cUTI	Oral		Phase III studies ongoing or completed [111,112]
Delafloxacin [113]	Fluoroquinolone	Yes	MSSA, MRSA, Streptococci, Enterococci [113]	ABSSSI, CABP	Oral		Phase II study in ABSSSI published, with cure rates better than vancomycin and similar to linezolid [114]. Phase III for ABSSSI completed [115]
CG-400549	Enoyl-ACP reductase (Fabl) inhibitor [116,117]	Yes, E. coli not Pseudomonas spp	Staphylococci-specific, MSSA, MRSA, not Enterococci	ABSSSI, osteomyelitis	Oral		Phase II study completed [118]
Debio 1450	Fabl inhibitor, Debio 1452 prodrug	No	Staphylococci specific, including MDR (VISA, daptomycin or linezolid-resistant strains)	ABSSSI, osteomyelitis	iv, oral		Phase II study completed [119]
Brilacidin	Defensin mimetic [120]	No	Staphylococci, b-hemolytic Streptococci and E. faecium	ABSSSI	Iv		Phase II completed [121]
MRX-I	Oxazolidinone	No	MSSA, MRSA and VRE [122]	ABSSSI	Oral		Phase II active, not recruiting [123] same or better efficacy than linezolid in both systemic and local infection models [122]
Nemonoxacin	Quinolone	Yes	MSSA, MRSA and E. faecalis [124,125]	CABP, DFI, ABSSSI	Oral		Phase II on diabetic foot infections completed [126], more active than levofloxacin and moxifloxacin against Gram (+) cocci [127], ongoing CABP studies

ABSSSIs, acute bacterial skin and skin structure infections; CABP, community-acquired bacterial pneumonia; cUTI, complicate urinary tract infection; GAS, group A streptococcus; HABP, hospital acquired bacterial pneumonia; MRSA, methicillin-resistant S. aureus; MSSA, methicillin susceptible S. aureus; PJIs, prosthetic joint infections; VRE, vancomycin-resistant enterococci.
Adapted from [83,85,89,92–127].

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