STAT E O F T H E A RT R E V I E W

Advances in the medical management of

skin and soft tissue infections
Sarah L McClain,1 Jefferson G Bohan,1 Dennis L Stevens1 2
1
Boise Veterans Affairs Medical
Center, 500 W Fort St, Boise, ID A B S T RAC T
83702, USA
2
Skin and soft tissue infections are some of the most common infectious disease
University of Washington School of
Medicine, Seattle, WA 98195, USA diagnoses in both inpatient and outpatient settings. With bacterial resistance
Correspondence to: S L McClain
sarah.mcclain@va.gov
to antimicrobials growing, decision making on empiric antibiotics is becoming
Cite this as: BMJ 2016;355:i6004 increasingly difficult. Additionally, the most recent guidance from a professional
doi: 10.1136/bmj.i6004
society on the treatment of skin and soft tissue infections was published in 2014
by the Infectious Diseases Society of America and is now two years old. New
antimicrobial agents have been developed and approved for the treatment of skin
and soft tissue infections since then, and more are in the pipeline. This review
summarizes the evidence on treatments that are new or in development and the
potential repurposing of old antimicrobials. The clinical utility of these treatments is
also discussed.

Introduction This review discusses the evidence surrounding new

The management of skin and soft tissue infections (SSTIs)
in ambulatory and inpatient settings is challenging. The
incidence is twice as high as that of pneumonia and
urinary tract infections combined.1 Also, antimicrobial
resistance to available treatments remains a problem,
particularly with resistant staphylococci.
In 2010 the US Food and Drug Administration (FDA)
published guidance changing the terminology for more
severe SSTIs from complicated skin and skin structure
infections (cSSSIs) to acute bacterial skin and skin struc-
ture infections (ABSSSIs). The 2010 draft guidance was
finalized in 2013 and served to update the FDA’s 1998
document that provided clinical trial guidance for the
drug industry.2 cSSSIs were defined as infections that
involved deeper soft tissue, required significant surgi-
cal intervention, or occurred in patients with significant
underlying disease complicating the response to treat-
ment.2 ABSSSI is defined as cellulitis/erysipelas, wound
infection, and major cutaneous abscess, with a minimum
lesion size of 75 cm2.3 Milder SSTIs such as impetigo and
minor cutaneous abscesses are excluded from the ABSSSI
designation. Alternatively, the 2014 guideline on SSTI
from the Infectious Diseases Society of America (IDSA)
differentiates SSTIs by the presence of purulence and
severity of illness rather than using ABSSSI designation.4
Antimicrobial resistance makes selecting empiric anti-
microbial treatment difficult; choosing definitive therapy
is nearly impossible, especially if a microbiological diag-
nosis is absent. Recently, several antimicrobials have
been approved to treat SSTIs, with more in the pipeline.
A limitation of using these new drugs is the lack of guide-
line consensus about their clinical utility. Because of these
concerns, evidence based decision making about empiric
and definitive antimicrobial therapy is im­perative.
treatments, potential repurposing of old antimicrobials,
and treatments that may become available in the future. It
primarily focuses on the treatment of SSTIs in adults, but
data about new antimicrobials in children are presented
where available.
Incidence and prevalence
The incidence of SSTIs in ambulatory and inpatient
settings in the United States has been relatively stable
from 2005 to 2010, at 47.9 to 48.5 cases per 1000 per-
son years.1 Of those SSTI cases, 95% were treated in the
ambulatory care setting and 60% were diagnosed as
abscesses or cellulitis. Streptococci and staphylococci are
the primary SSTI pathogens.5 Community associated met-
icillin resistant Staphylococcus aureus (MRSA, USA300
strain) is of particular importance in the US, given the
high rates of purulent SSTIs treated in the community.
SSTIs accounted for 62.9% of infections with MRSA strain
USA300 from 2000 to 2013, increasing the need for addi-
tional treatment options.6 The prevalence of MRSA dif-
fers between the US and the rest of the world. In areas of
lower MRSA prevalence, such as the United Kingdom and
northern Europe, treatment guidelines may vary consid-
erably from the IDSA guidance, with more emphasis on
β lactams effective against meticillin susceptible Staphy-
lococcus aureus (MSSA).7
Diagnostic considerations
Epidemiology plays an important role when diagnos-
ing SSTIs with potentially diverse etiologies.4 Obtaining
careful, complete, and accurate medical histories may
provide insight into clinical and microbiological diag-
nosis and treatment. Specifically, patients’ immune sta-
tus, geographical locale, travel history, recent trauma or

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Terms used in search strategy
Drug related terms
Free text terms—“tedizolid”, “brilacidin”, “oral sodium
fusidate”, “sodium fusidate”, “delafloxacin”
MESH terms—“anti-infective agents”, “fosfomycin”,
“fusidic acid”
MESH supplementary concepts—“dalbavancin”,
“oritavancin”, “iclaprim”, “ABT 492”, “omadacycline”,
“torezolid phosphate”
Indication related terms
Free text terms—“SSTI”, “skin and soft tissue infection”,
“acute bacterial skin and skin structure infection”,
“ABSSSI”, “major cutaneous abscess”
MESH terms—“soft tissue infections”, “skin diseases,
infectious,” “cellulitis,” “paronychia”, “skin diseases,
bacterial”, “wound infection”, “impetigo”, “cervicofacial
actinomycosis”, “bacillary angiomatosis”, “ecthyma”,
“erysipelas”, “erythema chronicum migrans”,
“erythrasma”, “granuloma inguinale”, “pinta”,
“rhinoscleroma”, “staphylococcal scalded skin
syndrome”, “furunculosis”, “carbuncle”, “cutaneous
syphilis”, “erythema induratum”, “lupus vulgaris”, “yaws”
surgery, previous antimicrobial therapy, and exposure
to animals are crucial to limit the differential diagnosis.4
Recognition of clinical findings and understanding ana-
tomical relations of skin and soft tissue are also essential
for establishing the correct diagnosis. In patients who are
immunocompromised or have evidence of systemic signs
of infection such as tachycardia, hypotension, or organ
dysfunction, more invasive techniques including tissue
biopsy or aspiration need to be used.4 Radiographic evi-
dence may help to determine the level of infection and
presence of gas or abscess. Lastly, surgical debridement
or exploration may be diagnostically and therapeutically
important, especially in immunocompromised patients or
those with necrotizing infections.4 More definitive diag-
nostic information can be found in the full IDSA SSTI
guideline.
Methods
We did a structured PubMed search to identify primary lit-
erature published from 1 January 2006 through 1 March
2016 using indication related and drug related free text
terms, MESH terms, and MESH supplementary concepts
(box). We used filters to select clinical trials, prospective
and retrospective cohort studies, guidelines, and review
articles. We screened 2400 articles and applied exclusion
criteria based on title, then abstract, then full text. We
also screened reference lists of pertinent articles. Topics
of interest included pharmacology, pharmacokinetics,
pharmacodynamics, dosing, adverse effects, FDA/Euro-
pean Medicines Agency (EMA) approved indications,
and outcomes related to drugs approved since 2014 or
in phase II or III clinical development. We also searched
clinical trials databases.
Treatment overview
SSTI treatment is generally divided into two different
groups: purulent infections (for example, furuncles,
carbuncles, abscesses) and non-purulent infections (for
example, cellulitis, erysipelas). Topical antimicrobial
For personal use only
therapy can be considered for nasal decolonization in
patients with recurrent SSTIs or for treatment of mild,
uncomplicated SSTIs, such as bullous or non-bullous
impetigo. 4 Despite incision and drainage or topical
therapy, some SSTIs will need systemic antimicrobial
tr­eatment.
The IDSA treatment algorithm (figure) incorporates
the presence or absence of purulence, along with clini-
cal status, when providing treatment recommenda-
tions. According to this algorithm, moderate or severe
purulent infections require empiric oral or intravenous
antistaphylococcal antimicrobial therapy, respectively,
along with incision and drainage plus culture and sensi-
tivity.2 Non-purulent infections may be treated with oral
or intravenous antibiotics targeted against streptococci
for mild and moderate infections, respectively. Severe
non-purulent infections including necrotizing fasciitis
may require broad spectrum antibiotics, toxin inhibition,
and surgical intervention.2
New antimicrobial agents
Dalbavancin
Properties and activity
Dalbavancin, a semi-synthetic lipoglycopeptide, binds
the terminal D-alanyl-D-alanine residues, thus inhibit-
ing the transpeptidation and transglycosylation steps of
peptidoglycan synthesis, in the bacterial cell wall.8 In
addition, dalbavancin’s structure features a lipophilic
side chain allowing it to anchor to the bacterial cell
membrane, thereby increasing potency and improving
half life.
Dalbavancin has in vitro activity against Gram positive
organisms, including Staphylococcus aureus (MSSA and
MRSA), coagulase negative staphylococci (CoNS), Strepto-
coccus spp, and Enterococcus spp.9 Dalbavancin also has
in vitro activity against rarer Gram positive pathogens,
including Listeria monocytogenes, Micrococcus spp, and
Corynebacterium spp.10 Dalbavancin has shown eightfold
and 16-fold greater in vitro activity against S aureus than
daptomycin and vancomycin, respectively.11 Vancomycin
susceptibility can be used as a surrogate for dalbavancin
susceptibility with 97.7-100% accuracy.12 13 Furthermore,
dalbavancin retains in vitro activity against pathogens
with reduced susceptibility to vancomycin, such as van-
comycin intermediate S aureus (VISA), although most
minimum inhibitory concentrations (MICs) fall above
the FDA’s breakpoint of 0.12 μg/mL.14
Staphylococcal resistance to dalbavancin has been
reported in less than 1% of isolates and occurs similarly
to vancomycin resistance despite higher potency, through
cell wall thickening and increased D-alanine-D-alanine
binding sites.11 14 Lastly, dalbavancin has in vitro activity
against enterococci carrying VanB but not VanA, making
it ineffective against most vancomycin resistant Entero-
coccus spp (VRE) in the US.14
Dalbavancin was approved for ABSSSI by the FDA in
2014 and EMA in 2015. The dosing was initially 1000
mg followed by an additional 500 mg seven days later.
In 2016 a single dose regimen of 1500 mg was approved
on the basis of results of a randomized trial showing non-
inferiority to the two dose regimen.9 15
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Purulent skin and soft tissue infections (SSTIs)—Mild infection: for purulent SSTI, incision and drainage is indicated. Moderate infection: patients with purulent
infection with systemic signs of infection. Severe infection: patients who have not responded to incision and drainage plus oral antibiotics, those with systemic
signs of infection such as temperature >38°C, tachycardia (heart rate >90 beats per minute), tachypnea (respiratory rate >24 breaths per minute), or abnormal white
blood cell count (>12 000 or <4000 cells/µL), or immunocompromised patients. Non-purulent SSTIs—Mild infection: typical cellulitis/erysipelas with no focus of
purulence. Moderate infection: typical cellulitis/erysipelas with systemic signs of infection. Severe infection: patients who have not responded to oral antibiotic
treatment, those with systemic signs of infection (as defined above under purulent infection), those who are immunocompromised, or those with clinical signs
of deeper infection such as bullae, skin sloughing, hypotension, or evidence of organ dysfunction. C&S=culture and sensitivity; I&D=incision and drainage;
MRSA=meticillin resistant Staphylococcus aureus; MSSA=meticillin susceptible Staphylococcus aureus; TMP/SMX=trimethoprim-sulfamethoxazole. First
appeared in “Practice guidelines for the diagnosis and management of skin and soft tissue infections: 2014 update” by the Infectious Diseases Society of America;
adapted with permission from Oxford University Press

Pharmacokinetics and dosing by intermittent hemodialysis and with low permeability

Dalbavancin has linear, dose dependent pharmacokinet-
ics. It widely distributes into tissues, with extensive and
reversible protein binding of approximately 93%, and
achieves therapeutic concentrations in blister fluid for
at least seven days.9 Dalbavancin does not interact with
the cytochrome P450 system and has no important drug
interactions. Approximately one third of dalbavancin is
excreted unchanged in urine, with another 20% being
excreted in feces up to 70 days after the initial dose. The
terminal half life of dalbavancin is 346 hours, allowing
for one or two doses to provide an entire course of ther-
apy. No dosage adjustments are needed for patients with
normal renal function (creatinine clearance ≥30 mL/min)
or those receiving hemodialysis.9
Interestingly, patients with creatinine clearance below
30 mL/min but not receiving hemodialysis have a higher
area under of the curve for dalbavancin and reduced
clearance, so dosage adjustment is needed to 1125 mg
for a single dose or 750 mg followed by 375 mg for the
two dose series.16 Dalbavancin is not significantly cleared
continuous hemodialyzers; however, dalbavancin clear-
ance matched or exceeded renal clearance in patients
with normal creatinine clearance using high permeability
continuous dialyzers.17 No dosage adjustment is needed
in patients with hepatic impairment owing to little effect
on dalbavancin’s metabolism and clearance.16 Dalba-
vancin does not prolong the QTc interval and was shown
to have no effect on heart rate or PR or QRS intervals.18
Evidence summary
The first phase III, randomized, double blind study of
dalbavancin for SSTIs was published in 2005 and com-
pared two doses of dalbavancin against 14 days of lin-
ezolid treatment. Dalbavancin showed non-inferiority to
linezolid with a lower frequency of adverse effects.19 This
study was followed by two identical randomized, double
blind, double dummy, multicenter phase III trials, DIS-
COVER 1 and 2 (table 1). Two doses of dalbavancin were
compared with at least three days of intravenous vanco-
mycin, followed by an optional switch to oral linezolid

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Table 1 | Phase III clinical evidence summary for dalbavancin, oritavancin, and tedizolid in acute bacterial skin and skin structure infections
Patient Secondary Statistical
Trial Design Intervention population Demographics Primary endpoint* endpoints* analyses Results
Dalbavancin
Randomized, Randomized, Dalbavancin 1000 mg Adults with ITT (n=854): mean Clinical success (no Microbiologic Non-inferiority, Primary endpoint:
double blind double blind, double IV on day 1, 500 mg cSSSIs† and at age 47; males further antibiotics response and margin 12.5% 88.9% response to
comparison of once dummy, multicenter; on day 8 v linezolid least one sign 62%; abscess 32%; needed) at TOC overall response at dalbavancin v 91.2%
weekly dalbavancin conducted in 2003- 600 mg every 12 h for of systemic cellulitis 28%. mITT visit 14±2 days EOT and TOC response to linezolid,
versus twice daily 04 14 days infection (64%, n=550): S after completion lower limit of
linezolid therapy for aureus 89%; MRSA CI=−7.28%; met non-
cSSSIs19 51%; GAS 5.6% inferiority criteria
DISCOVER-1 and Randomized, Dalbavancin 1000 mg Adults with ITT (n=1312): mean Early clinical Clinical status Non-inferiority, Pooled analysis of
DISCOVER-220 double blind, double IV on day 1, 500 mg on ABSSSIs‡ and at age 49.5; males response at 48-72 at EOT; clinical margin 10% primary endpoints for
dummy, multicenter; day 8 v IV vancomycin least one sign of 58%; white 89.3%; hours (cessation response at EOT both trials: 79.7% for
conducted in 2011- for ≥3 days followed systemic illness abscess 25.5%; of spread of dalbavancin v 79.8%
12 by optional switch to cellulitis 53.5%; erythema, no for vancomycin-
oral linezolid for 10-14 pathogen isolated increase in size, linezolid, 95% CI
days at baseline 51%: S temperature −4.5 to 4.2); met
aureus 77%; MRSA ≤37.6°C) non-inferiority criteria
24%; GAS 11%
Oritavancin
SOLO-121 Randomized, Oritavancin 1200 Adults with mITT (n=954): mean Composite of Investigator Non-inferiority, Primary efficacy
double blind, double mg IV on day 1 or ABSSSIs and age 45; males 63%; cessation of assessed clinical margin 10% endpoint at early
dummy multicenter; vancomycin 1000 mg signs of systemic white 58%; abscess spreading or cure at PTE; clinical evaluation:
conducted in 2011- or 15 mg/kg IV every inflammation 29%;cellulitis 50%; reduction in lesion decrease in lesion 82.3% for oritavancin
12 12 h for 7-10 days positive infection size, absence size by ≥20% v 78.9% for
site culture 61%: S of fever, and no vancomycin, 95% CI
aureus 45% use of rescue −1.6 to 8.4; met non-
antibiotics at ECE inferiority criteria
SOLO-222 Randomized, Oritavancin 1200 Adults with mITT (n=1005): Composite of Investigator Non-inferiority, Primary efficacy
double blind, double mg IV on day 1 or ABSSSIs and mean age 45; males cessation of assessed clinical margin 10% outcome at ECE
dummy, multicenter; vancomycin 1000 mg signs of systemic 68%; white 71%; spreading or cure at PTE; (mITT): 80.1% for
conducted in 2011- or 15 mg/kg IV every inflammation abscess 32.5%; reduction in lesion decrease in lesion oritavancin v 82.9%
13 12 h for 7-10 days cellulitis 30.9%; size, absence of size by ≥20% for vancomycin, 95%
positive infection fever and no use of CI −7.5 to 2.0; met
site culture 70%: S rescue antibiotics non-inferiority criteria
aureus 74%; MRSA at ECE
29%
Tedizolid
ESTABLISH-1 and Randomized, Tedizolid 200 mg daily ESTABLISH-1: ITT (n=1333): Early clinical Investigator Non-inferiority, Pooled analysis for
ESTABLISH-223 double blind, double for 6 days v linezolid adults with median age 44; response at 48-72 assessed response margin 10% primary efficacy
dummy, multicenter; 600 mg twice daily for ABSSSIs; males 63%; abscess hours*§ at day 7, EOT, and endpoint in both
ESTABLISH-1 10 days; ESTABLISH-1 ESTABLISH-2: 25%; cellulitis 46%; PTE trials§: 81.6% for
conducted in 2010- patients received oral patients ≥12 baseline cultures: S tedizolid v 79.4%
11; ESTABLISH-2 drugs; ESTABLISH-2 years with aureus 50%; MRSA for linezolid, 95% CI
conducted in 2011- patients received ≥2 ABSSSIs 21.5%; GAS 4% −2.0 to 6.5; met non-
13 IV doses inferiority criteria
GAS=group A streptococci; MRSA=meticillin resistant Staphylococcus aureus; TOC=test of cure; EOT=end of treatment; ITT=intention to treat; ECE=early clinical evaluation; PTE=post-therapy evaluation.
*US FDA issued draft guidance for industry for ABSSSI drug development in 2010 and final guidance in 2013. In final document, primary efficacy endpoint became lesion response at 48-72 hours, defined as ≥20%
size reduction from baseline in patients who did not receive rescue therapy and are alive. Resolution of ABSSSI 7-14 days after completion of therapy is suggested as secondary endpoint.3
†Complicated skin and soft tissue infections (cSSSIs) defined as infection that involved deeper soft tissue or required significant surgical intervention (major abscesses, burns, traumatic or surgical wound infection,
deep SSTIs such as extensive/ulcerating cellulitis).16
‡Acute bacterial skin and skin structure infection required the presence of cellulitis, major abscess, or wound infection, each with ≥75 cm2 of erythema.
§ESTABLISH-1 definition for primary endpoint differed slightly owing to draft industry guidance available from FDA at time study was designed. Pooled data published in 2015 updated endpoint to reflect 2013 final
guidance document.

for a total of 10-14 days, in 1312 patients with ABSSSIs.20
Similarly, dalbavancin showed non-inferiority for the pri-
mary endpoint of early clinical response, defined as ces-
sation of the spread of erythema and absence of fever at
48-72 hours. Adverse events occurred less frequently in
the dalbavancin arm (overall P=0.5), with nausea, head-
ache, and diarrhea being most common. Median dura-
tion of adverse effects was three days for dalbavancin
compared with four days for the comparator.9 20 Notably,
patients in this study had more severe disease than did
those included in previous studies of dalbavancin, as
DISCOVER enrollment limited patients with abscess to no
more than 30% and approximately 50% of patients had
two or more systemic inflammatory response syndrome
criteria at enrollment.20
Limited data in children are available for dalbavancin.
A phase I study in patients aged 12-17 years used stand-
ard adult dosing (1000 mg) for children weighing at least
60 kg and a dose of 15 mg/kg for those weighing under 60
kg.24 Dalbavancin was well tolerated and pharmacokinet-
ics were similar among children receiving each dosing
strategy, although the values were slightly lower than
those measured in adults.
Clinical application
Dalbavancin has shown safety and efficacy for treating
ABSSSIs, and its place in therapy is similar to that of other
glycopeptides. The biggest advantage of dalbavancin is
convenience; however, economic considerations must be
weighed carefully against other treatment options (table
2). The single dose, short infusion time, lack of need for
routine monitoring, and absence of drug-drug or drug-
laboratory interactions are desirable characteristics.
Dalbavancin may help in avoiding hospital admissions

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Table 2 | Economic impact of antimicrobial agents used to treat skin and soft tissue infections ceptibility to vancomycin, MIC values often exceed the
Cost per day Cost (AWP*) based on standard laboratory breakpoints, warranting cautious use
(AWP*) based on standard dosing regimen in clinical settings.26
Medication Dosing regimen dosing regimen and duration indicated
Newer agents Pharmacokinetics and dosing
Ceftaroline 600 mg IV twice daily $366.24 7 days: $2563.68 Oritavancin was approved for ABSSSIs by the FDA in
Dalbavacin† 1500 mg IV once daily $383.14 One dose: $5363.96
2014 and the EMA in 2015. Oritavancin is administered
Daptomycin‡ 500 mg IV once daily $534.59 7 days: $3742.13
intravenously as a single 1200 mg dose. Oritavancin has
Oritavancin† 1200 mg IV once daily $248.57 One dose: $3479.98
linear pharmacokinetics, and it extensively distributes
Tedizolid 200 mg IV once daily $296.10 6 days:$1776.60
into tissues.32 Plasma protein binding of oritavancin is
200 mg PO once daily $371.70 6 days: $2230.10
Telavancin‡ 750 mg IV once daily $428.92 7 days: $3002.44
approximately 85%.32
Older agents Oritavancin clearance primarily occurs through the
Cefazolin 2 g IV every 8 h $198.00 7 days: $1386.00 reticuloendothelial system, and excretion from this sys-
Clindamycin 900 mg IV every 8 h $62.64 7 days: $438.48 tem occurs slowly, with less than 1% recovered in the feces
300 mg PO every 8 h $7.14 7 days: $49.98 and 5% in urine after two weeks of collection.26 32 The half
Doxycycline 100 mg PO twice daily $12.30 7 days: $86.10 life of oritavancin is approximately 245 hours, allowing a
Linezolid 600 mg IV twice daily $192.00 10 days: $1920.00 single dose to provide an entire course of therapy.33 No dos-
600 mg PO twice daily $368.00 10 days: $3680.00 age adjustments are needed for mild to moderate renal or
Trimethoprim/sulfamethoxazole 160 mg/800 mg PO twice daily $2.30 7 days: $16.10 hepatic impairment. Oritavancin has not been adequately
Vancomycin 1000 mg IV every 12 h $30.96 7 days: $216.72 evaluated in severe hepatic or renal impairment, but it is
IV=intravenously; PO=orally.
not significantly cleared by low or high flux hemodialysis
*Average wholesale price as of 6 March 2016, US dollars ($1=£0.79; €0.94).
†One dose was considered to provide two weeks of therapy for purpose of cost per day calculations. or continuous renal replacement therapy.32 34 Oritavancin
‡Dosing rounded to nearest vial size. has not been associated with QTc prolongation.35
Oritavancin is a non-specific, weak inhibitor of CYP2CP
solely for administration of intravenous antibiotic. Dalba- and CYP2C19 and an inducer of CYP3A4 and CYP2D6,
vancin may also have a niche in treating patients who find leading to drug interactions, most notably with warfarin
adherence difficult, those who live remotely and would (31% increase in mean area under the curve).32 Owing
have difficultly being monitored on outpatient parenteral to its ability to bind the phospholipid reagent, orita-
antimicrobial therapy, and those with a history of inject- vancin also has some important drug-laboratory interac-
ing drug misuse to avoid central line placement. tions with commonly used coagulation tests, including
activated partial thromboplastin time (aPTT), activated
Oritavancin clotting time, and prothrombin time/international nor-
Properties and activity malized ratio.32 As a result of these interactions, the use
Oritavancin is a semisynthetic lipoglycopeptide with at of unfractionated heparin is contraindicated for 120
least three mechanisms of action (MOAs). Similarly to hours after administration of oritavancin owing to the
other glycopeptides, oritavancin inhibits transglycosyla- potential for false elevation of the aPTT. For patients who
tion, a step of cell wall synthesis, by binding the terminal need aPTT monitoring within 120 hours of oritavancin
D-alanyl-D-alanine.25 It also binds peptide bridging seg- administration, a non-phospholipid dependent coagula-
ments to inhibit transpeptidation, which also contributes tion test, such as the factor Xa assay, is recommended.32
to its activity against vancomycin resistant organisms.
Oritavancin is thought to inhibit transpeptidation more Evidence summary
than transglycosylation.26 Lastly, oritavancin interacts The major clinical trials for oritavancin, SOLO I and II,
with the cell membrane, causing depolarization and were both randomized, double blind studies of a single
permeabilization, ultimately leading to rapid, concen- dose of intravenous oritavancin 1200 mg versus vanco-
tration dependent bactericidal activity.25 Activity on mycin 1000 mg or 15 mg/kg intravenously twice daily for
the cell membrane has been attributed to oritavancin’s seven to 10 days in nearly 2000 adults with ABSSSI.21 22
activity against stationary phase bacteria, such as those The primary endpoint was a composite of cessation of
in biofilms.27 spreading infection or reduction in lesion size, absence
Oritavancin has in vitro activity against many Gram of fever, and no use of a rescue antibiotic 48-72 hours
positive organisms, including S aureus (MSSA, MRSA, after oritavancin administration. Secondary endpoints
VISA, vancomycin resistant S aureus (VRSA)), CoNS, were investigator determined clinical cure seven to 14
streptococci, and enterococci, including VRE.28 Addi- days after end of treatment and lesion size reduction of
tionally, oritavancin has shown in vitro activity against L at least 20% 48-72 hours post-oritavancin. Oritavancin
monocytogenes, Micrococcus spp, and Corynebacterium showed non-inferiority to vancomycin in both studies for
spp.29 Vancomycin sensitivities can be used as a surro- all efficacy endpoints. The most common adverse reac-
gate for oritavancin sensitivities, with 99.4% cross sus- tions occurring in more than 3% of patients were nausea,
ceptibility; however, vancomycin non-susceptibility to headache, vomiting, diarrhea, and limb and subcutane-
enterococci is not an accurate predictor of oritavancin ous abscesses. Oritavancin was well tolerated, with sim-
non-susceptibility.30 31 Oritavancin non-susceptibility is ilar rates of adverse reactions to vancomycin. In SOLO
thought to be exceedingly rare.31 Although oritavancin I, nausea was (non-significantly) more common in the
has in vitro activity against S aureus with reduced sus- oritavancin group.21

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 STAT E O F T H E A RT R E V I E W
A pediatric phase I study is recruiting patients under
18 with suspected or confirmed bacterial infections to
assess the pharmacokinetics of oritavancin. The starting
dose of oritavancin for this study seems to be 15 mg/kg.36
Clinical application
Oritavancin’s place in therapy for ABSSSIs is similar to
that of other glycopeptides (table 1). Oritavancin’s con-
venience is a shared feature with dalbavancin, which
must be carefully weighed with economic and patient
specific factors when considering all treatment options
for SSTIs (table 2). The use of oritavancin could improve
and simplify patient care scenarios in which older treat-
ment options are less desirable owing to toxicity or mon-
itoring requirements. Oritavancin also provides more
robust activity against resistant Gram positive organisms.
The three hour infusion time and large volume of dextrose
it must be prepared in have been criticized; however, a
new formulation with a shorter infusion time is being
investigated.37 Drug-drug and drug-laboratory interac-
tions with anticoagulants are also problematic in some
patients, but a study of oritavancin in patients on chronic
warfarin treatment is under way.38
Tedizolid
Properties and activity
Tedizolid, an oxazolidinone prodrug, is metabolized by
endogenous phosphatases from tedizolid phosphate to
tedizolid, the active metabolite. The MOA of oxazolidi-
none involves binding the 23S ribosomal RNA of the 50S
subunit, thus preventing formation of the 70S initiation
complex and causing inhibition of protein synthesis.39
Tedizolid’s spectrum of activity is similar to that of lin-
ezolid, with bacteriostatic in vitro killing and suggested
bactericidal in vivo killing due to granulocyte augmen-
tation in some animal models of Gram positive organ-
isms including MRSA and VRE.40 41 Tedizolid has greater
potency than linezolid, with lower MIC50 and MIC90 values
against organisms including staphylococci, streptococci,
and enterococci, which may be due to greater ribosomal
binding affinity.39 Despite tedizolid’s increased potency,
linezolid resistance does predict tedizolid resistance.42
However, tedizolid has maintained activity against some
staphylococci and enterococci expressing the chloram-
phenicol resistance gene (cfr), suggesting that tedizolid
may be used to treat infections caused by linezolid resist-
ant organisms in addition to vancomycin and daptomycin
resistant organisms.43 44
Pharmacokinetics and dosing
Tedizolid has greater than 90% oral bioavailability and
linear, two compartment pharmacokinetics indicating
central and peripheral compartment absorption.45 46 Tedi-
zolid is a reversible inhibitor of monoamine oxidase in
vitro; however, in contrast to linezolid, preclinical studies
suggest a lack of clinically significant drug interactions
with serotonin modulating agents.39 The terminal half life
is longer and the volume of distribution larger than lin-
ezolid’s, and excretion of tedizolid is primarily fecal with
small fractions excreted renally.46 Similar pharmacokinet-
ics have been observed in adolescents.47
For personal use only
Tedizolid has been approved by the EMA and FDA for
the treatment of ABSSSIs including cellulitis and skin
abscesses.45 The dose of tedizolid is 200 mg, adminis-
tered orally or intravenously, once daily, with no dose
adjustment needed for patients with renal or hepatic
impairment.48 49
Evidence summary
ESTABLISH-1 and 2 were phase III clinical trials that eval-
uated tedizolid compared with linezolid. ESTABLISH-1
randomized 667 patients with cellulitis, major cutaneous
abscesses, or wound infection to either tedizolid 200 mg
by mouth daily for six days or linezolid 600 mg by mouth
twice daily for 10 days. The primary outcome was early
clinical response at 48-72 hours. With a 10% margin, tedi-
zolid was non-inferior to linezolid. Early and sustained
clinical response rates were similar between groups.50
ESTABLISH-2 randomized 666 patients with similar
infections to either tedizolid 200 mg intravenously daily
for six days or linezolid 600 mg intravenously twice daily
for 10 days, with the option for oral step-down therapy
after at least two intravenous doses in both groups. The
primary outcome studied was early clinical response
48-72 hours after starting treatment. With a 10% margin,
tedizolid was non-inferior to linezolid. Clinical response
rates were similar at all time points.51 Notably, clinically
significant adverse effects were significantly decreased
with tedizolid compared with linezolid, including nausea
(P=0.02) and thrombocytopenia (P<0.001).23 One pre-
clinical study suggests that prolonged therapy beyond
six days of tedizolid may also have advantages of less
myelosuppression and neuropathy than linezolid.52
Clinical application
Tedizolid’s place in therapy is similar to that of linezolid
owing to its microbiologic spectrum and MOA; however,
tedizolid provides some advantages over linezolid, such
as a more convenient dosing regimen and fewer side
effects and drug interactions, specifically with serotonin
modulating agents.53 Owing to the MOA, tedizolid may
also be beneficial in treating necrotizing fasciitis because
of its ability to suppress toxin production. These charac-
teristics could be appealing for clinicians when treating
patients with multiple comorbidities, but use would need
to be balanced against the pharmacoeconomic advan-
tages of linezolid (table 2). Future studies are planned
in diabetic patients with wound infections and pediatric
patients with ABSSSI.54 55
Retapamulin
Properties and activity
Retapamulin, a topical pleuromutilin antibiotic, exerts
action by binding to an allosteric site of the 50S ribosomal
subunit, thus altering the conformational shape of the
peptidyl transferase center and inhibiting protein syn-
thesis. The barrier to resistance is thought to be higher
owing to the allosteric binding.56 Retapamulin has activ-
ity against both staphylococci and streptococci, including
MRSA strains. Additional data show activity against Pro-
pionibacterium, Fusobacterium, and other Gram positive
cocci.57 58
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 STAT E O F T H E A RT R E V I E W
One study showed that retapamulin remained active
against S aureus isolates resistant to meticillin, fusidic
acid, or mupirocin with 99.9% inhibition.59 However,
in 2014 retapamulin resistance increased to 9.5% for
S aureus, of which more than 50% of the isolates were
also meticillin resistant and less than 1% were linezolid
resistant, suggesting that retapamulin resistance may
be increasing slowly in both MSSA and MRSA.60 Resist-
ance to retapamulin primarily occurs as a result of muta-
tions in the rplC gene and needs three different stepwise
mutations to reduce susceptibility significantly.61 Slower
growth rates have been noted in resistant strains, which
led to the emergence of more susceptible, faster growing
strains.62
Pharmacokinetics and dosing
Retapamulin is a topical antibiotic with minimal absorp-
tion. In studies, measurable blood concentrations of reta-
pamulin were found in only 3-11% of patients using the
recommended dose.63
Retapamulin is approved by the FDA for treatment of
impetigo and by the EMA for treatment of impetigo and
staphylococcal skin infections.63 It is dosed by applying a
thin layer topically to the affected area twice daily for five
days. Owing to limited systemic exposure, retapamulin
does not need dose adjustment in patients with renal or
hepatic impairment.
Evidence summary
A randomized, double blind, phase III study conducted
in 17 international centers randomized 139 patients to
receive retapamulin and 71 patients to receive placebo
topically twice daily for five days to treat impetigo. The
primary endpoint was end of therapy response rate
measured at day seven. Success rates at day 7 differed
significantly at 85.6% for retapamulin and 52.1% for
placebo (difference 33.5%, 95% confidence interval
20.5% to 46.5%). The most common adverse effect
related to retapamulin compared with placebo was appli-
cation site pruritis (6.5% v 1.4%).64
A phase III non-inferiority study randomized 519
patients with impetigo to retapamulin or fusidic acid.
With a 10% margin, retapamulin was non-inferior to
fusidic acid for the primary endpoint of clinical success
at end of therapy in both the intention to treat and per
protocol populations.65 Both clinical trials enrolled adult
and pediatric (age ≥9 months) patients.
In a murine wound infection model, topical retapa-
mulin was compared with oral linezolid with a primary
endpoint of bacterial load reduction. Retapamulin
reduced bacterial loads more significantly than did oral
linezolid.66
Clinical application
Retapamulin should primarily be used to treat mild
to moderate impetigo with minimal systemic signs or
symptoms of infection. Retapamulin may be particularly
useful in patients known to be carriers of MRSA or who
have a history of previous MRSA infections. Retapamulin
may be beneficial in patients who have had systemic side
effects (such as diarrhea) from antibiotic use, owing to
For personal use only
minimal systemic exposure of the topical formulation.
It may also be useful in treating wound infections but
needs to be studied further for this indication. Retapa-
mulin is being studied for use in reducing MRSA nasal
carriage.67
Phase III agents
Ozenoxacin
Pharmacology
Ozenoxacin represents a new generation of non-fluori-
nated, quinolone antibiotics and exerts its MOA by inhib-
iting DNA gyrase and topoisomerase IV, affecting DNA
replication, transcription, repair, and recombination.68
Ozenoxacin has greater bactericidal activity against
Gram positive organisms including MRSA, CoNS, and
streptococcal species than do other fluoroquinolone anti-
biotics.69 Resistance to ozenoxacin occurs as a result of
mutations in the grlA and gyrA genes coding topoisomer-
ase IV and DNA gyrase, respectively. Interestingly, muta-
tions to grlA did not confer resistance whereas grlA-gyrA
double mutants and grlA-gyrA triple mutants conferred
a lower level of resistance to S aureus than with other
fluoroquinolones.68
In a phase I open label study involving 46 patients
(adult and pediatric), systemic bioavailability was unde-
tectable in all but four samples, indicating minimal sys-
temic exposure to topical ozenoxacin.70 Another phase I
trial studied the skin tissue exposure of topical ozenoxa-
cin 2% dosed either once or twice daily. Results indicated
that the drug does not penetrate well into the dermis,
steady state conditions are reached at day three, and
skin concentrations correlate linearly with total amount
of drug administered.71
Evidence summary
Japan has approved a 2% ozenoxacin topical preparation
for use in superficial skin infections, and other countries
including the US and Europe are still evaluating a 1%
preparation.72 A phase III clinical trial randomized 465
patients aged at least 2 years with impetigo to ozenoxa-
cin 1% cream, placebo, or retapamulin ointment applied
twice daily for five days. The primary endpoint was clini-
cal success or failure at the end of therapy. In the inten-
tion to treat population, ozenoxacin was associated with
significantly higher clinical success rates than placebo at
34.8% compared with 19.2% (P=0.003); retapamulin’s
clinical success was similar to ozenoxacin’s (37.7%).73
Ozenoxacin has been tolerated well in studies, with mini-
mal side effects related to the drug.
Clinical application
Ozenoxacin’s place in therapy is likely to be similar
to that of other topical agents including retapamulin.
An advantage of ozenoxacin is the new generation of
quinolone antibiotics it represents, to which bacteria
likely have not yet developed resistance. Also, its MOA
is different from that of other newer topical antimicro-
bials, increasing the diversity of topical antimicrobials
and maintaining active agents in the face of increasing
resistance. All clinical trials registered to date have been
completed.
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Iclaprim
Pharmacology
Iclaprim, a diaminopyrimidine derivative, is a bacterial
dihydrofolate reductase inhibitor. Inhibition of dihydro-
folate reductase leads to a shortage of nucleosides, inter-
fering with DNA synthesis and leading to cell death.74
Iclaprim’s microbiologic spectrum is broad against Gram
positive organisms, including MRSA, VISA, VRSA, CoNS,
streptococci, and E faecalis. It also has activity against
atypical organisms and some Enterobacteriaceae.74
Iclaprim’s half life is about three hours, and it widely
distributes throughout tissues. Oral and intravenous
preparations are being developed.
Evidence summary and clinical application
Two phase III clinical trials, ASSIST-1 and ASSIST-2,
have evaluated the use of iclaprim in cSSSIs. In each
study, iclaprim 0.8 mg/kg intravenously every 12 hours
was compared with linezolid 600 mg intravenously
every 12 hours for 10-14 days in adults.74 Iclaprim
showed non-inferiority to linezolid with regard to clini-
cal cure rates at end of treatment. Iclaprim was well tol-
erated overall, and the frequency of adverse events was
similar in the two groups, with the rate of any probably
related adverse effects being 6.0% for iclaprim and 9.4%
for linezolid.74
Transient QTc interval prolongation of 4-6 ms has been
reported.74 Although no cardiac adverse events were
attributed to iclaprim induced QTc prolongation, cau-
tion may be warranted in patients with prolonged QTc at
baseline or receiving concomitant drugs that also prolong
the QTc interval.74 In 2008 and 2009 the FDA and EMA
respectively rejected the approval of iclaprim and called
for additional studies to demonstrate efficacy.
Two new phase III studies of iclaprim in ABSSSI,
REVIVE-1 and REVIVE-2, are active and recruiting.75 76
Of note, iclaprim is being studied at a fixed dose of
80 mg intravenously every 12 hours in these trials,
in c­ontrast to the previously studied 0.8 mg/kg dose.
Iclaprim would be an attractive treatment option for
SSTIs given its oral and intravenous preparations,
as well as its activity against trimethoprim resistant
org­anisms.74
Brilacidin
Pharmacology
Brilacidin represents the first member of a new class of
antibiotics, defensin mimetics, and is a cationic, hydro-
phobic molecule designed to work similarly to innate host
defense proteins. Brilacidin causes dose dependent depo-
larization of the bacterial membrane in S aureus, similarly
to daptomycin, and has broad spectrum of action, includ-
ing MRSA and VRE.77
Brilacidin has concentration dependent, bactericidal
activity with linear pharmacokinetics.78 It has a long half
life of 15-23 hours and post-antibiotic effect, allowing
single dose administration. Brilacidin is also thought to
have anti-inflammatory properties and seems to be active
in the stationary phase of bacterial growth, making it
useful for infections with biofilms. The MOA means that
development of resistance may be unlikely.
For personal use only
Evidence summary and clinical application
Phase II studies of brilacidin have been completed in
more than 300 patients with ABSSIs.78 In the phase IIb
study, two single dose brilacidin strategies (0.6 mg/kg
intravenously × 1 and 0.8 mg/kg intravenously × 1) and
one three dose brilacidin strategy (0.6 mg/kg × 1 followed
by 0.3 mg/kg × 2) were compared against daptomycin
4 mg/kg intravenously daily for seven days. All three
brilacidin dosing strategies performed similarly to dap-
tomycin for the FDA endpoint of early clinical response at
48-72 hours and the EMA endpoint of sustained clinical
response (days 7-8 and 10-14). Brilacidin was generally
well tolerated.
All of the brilacidin dosing strategies used in the phase
IIb study were lower doses than those used in the phase
IIa studies and seemed to be better tolerated, with less
paresthesia and hypoesthesia observed. These adverse
events have not been associated with neurotoxicity and
are reported to have acute onset and rapid resolution.
Hypertension also seems to be an adverse effect with
brilacidin, in a dose dependent and transient fashion.
Phase III studies in ABSSSI are planned.78
Brilacidin’s novel MOA, high barrier to resistance, and
favorable efficacy and safety profile make it a welcome
addition to the SSTI treatment armamentarium. Brilacidin
is also being developed in topical form for mucositis and
for otic and ocular administration.79
Delafloxacin
Pharmacology
Delafloxacin, a novel, anionic (non-zwitterionic) fluoro-
quinolone, works by equally inhibiting DNA gyrase and
topoisomerase IV.80 It is potently active compared with
other fluoroquinolones against Gram positive organisms,
including MSSA and MRSA, especially in inherently acidic
environments.81 82 Delafloxacin has a similar Gram nega-
tive spectrum of activity to other fluoroquinolones and
is also active against anaerobic organisms.83 Because of
the MOA, mutations in gyrA and glrA would be needed to
confer resistance. Additionally, delafloxacin has not been
shown to readily select mutants in vitro, possibly owing to
R groups at the C-7 and C-8 structural positions.81
Three phase I studies were conducted to determine
safety, tolerability, and pharmacokinetics of intrave-
nously administered delafloxacin in healthy volun-
teers.84 Two additional studies examined delafloxacin
administered orally.85 Delafloxacin’s terminal half life is
about 12 hours when administered intravenously and
six to eight hours when administered orally; however, in
the latter studies, the half life lengthened after multiple
oral doses. Steady state is expected to be achieved by
day three. Food had no significant effect on total expo-
sure. Delafloxacin excretion is approximately two thirds
in urine and one third in feces, primarily as unchanged
drug.86
The studies also found that delafloxacin was well toler-
ated, with the most common adverse effects being gas-
trointestinal and occurring more frequently at doses of
800 mg or above. Notably, no QTc interval prolongation
occurred, which differentiates delafloxacin from other
fluoroquinolones.87
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Evidence summary
Two phase II studies have been completed comparing
delafloxacin with tigecycline, vancomycin, or linezolid
in patients with SSTIs.88 89 The first study randomized
150 patients with cSSTIs, including wound infection,
abscess, and cellulitis, and measured cure rates at the
test-of-cure visit 14-21 days after the last dose adminis-
tered. They found no significant difference in cure rates
between delafloxacin 300 mg, delafloxacin 450 mg, and
tigecyline standard dosing at 94.3%, 92.5%, and 91.2%,
respectively; any treatment related adverse effect rates
were lower with delafloxacin 300 mg (44.9%, 62.7%, and
72.0%, respectively).
The second study randomized 256 patients with
ABSSSI, including cellulitis, wound infection, abscess,
or burn infection, and measured cure rates at the follow-
up visit. The study found that delafloxacin significantly
improved cure rates compared with vancomycin (70.4%
v 54.1%; P=0.031), with no difference in cure rates
between delafloxacin and linezolid (70.4% v 64.9%;
P=0.496). Adverse effects related to delafloxacin were
primarily mild and gastrointestinal in nature, similar to
previous phase I studies. Rates of at least one adverse
effect for delafloxacin, linezolid, and vancomycin were
74.4%, 72.0%, and 64.6%, respectively.
Clinical application
Delafloxacin’s place in therapy will likely reside in
the area of polymicrobial, difficult to treat infections,
owing to its broad spectrum and activity against mul-
tidrug resistant S aureus. Other benefits include oral
and in­travenous formulations and negligible effect on
the QTc interval. Further studies will need to confirm
its safety profile, especially measuring the outcome of
Clostridium difficile infection owing to the broad spec-
trum of a­ctivity. Phase III clinical trials for delafloxacin
in SSTIs have been completed and are awaiting analysis
and publication.90 91
Avarofloxacin
Pharmacology
Avarofloxacin, a broad spectrum fluoroquinolone antibi-
otic, targets DNA gyrase and topoisomerase IV, much like
other fluoroquinolones. However, this agent has potent
bactericidal activity against MRSA, including fluoroqui-
nolone resistant strains, and is being developed to treat
ABSSSIs.92 During a phase II clinical trial, avarofloxacin
was effective against S aureus isolates with MIC values
of 0.25 μg/mL or below.93 As avarofloxacin has balanced
activity against DNA gyrase and topoisomerase IV, muta-
tions at both sites will likely be needed before resistance
develops.
Evaluated by phase I, placebo controlled, double
blind, and open label trials in healthy volunteers,
av­arofloxacin’s half life is between 12.9 hours and
16.7 hours, and oral bioavailability is around 66%.94
In­travenous doses of up to 150 mg twice daily have been
tolerated, with gastrointestinal adverse effects, head-
ache, and contact dermatitis being the most prominent.
These adverse effects were similar with oral administra-
tion.94
For personal use only
Evidence summary
A phase II randomized, double blind, multicenter, non-
inferiority study randomized 161 patients who had ABSS-
SIs to either avarofloxacin or linezolid.95 The primary
endpoint evaluated cure rates with a non-inferiority mar-
gin of 15% in the intention to treat population. In the pri-
mary analysis, avarofloxacin did not meet non-inferiority
criteria; however, the post hoc analyses using 2010 FDA
guidance standards and endpoint criteria (lack of lesion
spread and afebrile) indicated non-inferiority compared
with linezolid (61.4% v 57.7%; P=0.024).96
Clinical application
With the available phase II data, avarofloxacin’s place
in therapy will be difficult to determine until outcomes
of phase III clinical trials are available. Despite current
results, this drug does have potential to compete with
delafloxacin, as both are potent, broad spectrum, anti-
MRSA fluoroquinolones.
Omadacycline
Pharmacology
Omadacycline, a semi-synthetic derivative of mino-
cycline, is the first member of the new 9-aminomethyl
class of tetracycline drugs in clinical development. It
inhibits protein synthesis similarly to other tetracyclines,
although binding the bacterial ribosome.97 Omadacycline
has broad activity against Gram positive, Gram nega-
tive, atypical, and anaerobic pathogens.98 It also retains
activity against multidrug resistant organisms, including
MRSA and VRE.97 98 Similarly to tigecycline, omadacycline
has shown activity in the presence of both efflux and ribo-
somal protection tetracycline resistance genes.
Omadacycline has good bioavailability and will likely
be available in both intravenous and oral preparations.98
In a phase I study, no metabolites were found and it
achieved high concentrations in the urine while being
eliminated by renal and gastrointestinal routes.98
Evidence summary and clinical application
In a phase II study, omadacycline showed comparable
efficacy to linezolid for treatment of cSSTI and was well
tolerated, with the most common side effects being gas-
trointestinal (18.9% with omadacycline; 18.5% with
linezolid).99 A phase II clinical trial comparing omada-
cycline to linezolid for ABSSSI is active.100 In the future,
omadacycline may be beneficial in treating SSTIs caused
by resistant organisms owing to its broad activity and oral
formulation.
Fosfomycin
Pharmacology
Fosfomycin, a phosphonic antibiotic, inhibits phospho-
enolpyruvate transferase, an enzyme involved in early
phases of bacterial cell wall peptidoglycan synthesis.101
Fosfomycin has broad activity, including MRSA, VRE,
resistant Enterobacteriaceae, and Pseudomonas aer-
uginosa. In the US, fosfomycin trometamol is an oral
formulation approved for the treatment of urinary tract
infections. Outside of the urinary tract, intravenous fos-
fomycin, which has approval in some countries outside
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 STAT E O F T H E A RT R E V I E W
of the US, is generally used in combination with other
antimicrobials owing to the potential for development
of resistance. Several resistance mechanisms have been
described, including target site modification, decreased
cellular uptake, and inactivation by fosfomycin resistance
kinases.101 102
Intravenous fosfomycin is widely distributed into tis-
sues and does not undergo significant metabolism.117
The half life of fosfomycin is approximately two hours
and may be prolonged to 3.6-3.8 hours in people with
advanced age or critical illness.103 As fosfomycin’s
elimination is primary renal, the half life also increases
proportionally with the degree of renal insufficiency.103
Standard dosing varies by indication and ranges from
12-24 g in two to four divided doses; dosage adjust-
ments are needed in patients with impaired renal
fu­nction.103
Evidence summary and clinical application
Fosfomycin has several attributes that could make the
intravenous preparation desirable for future research
in the treatment of SSTIs. In addition to a broad antimi-
crobial spectrum, intravenous fosfomycin achieves high
concentrations in bone and peripheral soft tissues when
administered intravenously in the setting of diabetic foot
infections and also shows synergy with linezolid against
MRSA.104 105 It also has several immunomodulatory
effects, including decreased production of pro-inflam-
matory cytokines, in vitro inhibition of B cell and T cell
activation, and improved susceptibility of some bacteria
to phagocytosis.106 Lastly, fosfomycin is thought to help
to mitigate the nephrotoxicity of glycopeptides, which are
commonly used in SSTI treatment.106
Ceftobiprole
Pharmacology
Ceftobiprole, a broad spectrum cephalosporin, inhib-
its cell wall synthesis by binding with strong affinity to
penicillin binding proteins, including PBP2a, responsible
for resistance in S aureus with the mecA gene.107 Cefto-
biprole’s spectrum of action includes Gram positives,
including MRSA, penicillin resistant Streptococcus pneu-
moniae, Enterococcus faecalis, Gram negatives, includ-
ing susceptible Pseudomonas spp, and some anaerobes.
It has shown bactericidal activity and low likelihood of
resistance development.
The intravenous formulation is ceftobiprole medocaril
sodium, a pro-drug, which is rapidly converted to the
ceftobiprole drug by plasma esterases.107 No clinically
significant drug interactions are expected with ceftobi-
prole owing to its minimal metabolism and low protein
binding (16%).106 Elimination of ceftobiprole occurs pri-
marily through renal excretion as unchanged drug, and
the half life is approximately three hours.107
Evidence summary
Two phase III trials have been completed in patients
with cSSSIs. The first was a multicenter, randomized,
double blind trial of ceftobiprole 500 mg intravenously
every 12 hours versus vancomycin 1000 mg intrave-
nously every 12 hours in adults.108 The primary outcome
For personal use only
was cure rate seven to 14 days after the completion of
therapy, and ceftobiprole was found to be non-inferior
to vancomycin. The second study was a multicenter,
randomized, double blind trial in adults with cSSSIs
comparing a different dosing strategy of ceftobiprole,
500 mg intravenously every eight hours infused over two
hours, with vancomycin 1000 mg intravenously every
12 hours plus ceftazidime 1000 mg intravenously every
eight hours.108 The primary outcome was rate of clinical
cure seven to 14 days after the completion of therapy,
and ceftobiprole was again found to be non-inferior to
the comparator regimen. In both studies, adverse events
were not significantly different from comparators and
most commonly included gastrointestinal symptoms
and headache.108 109
Clinical application
Ceftobiprole has yet to receive FDA approval after site
inspections and audits found unverifiable data; however,
ceftobiprole has since been granted qualified infectious
disease product status by the FDA and clinical phase
III development is being pursued again in the US.107 110
Ceftobiprole is approved for use in Canada for cSSSIs,
dosed at 500 mg intravenously every 12 hours, with
dose adjustments needed in patients with decreased renal
function.111 Ceftobiprole also has approval in 13 Euro-
pean countries and Australia for community acquired
and hospital acquired pneumonia. Ceftobiprole’s role
would likely be in the treatment of severe SSTIs owing to
its broad spectrum of activity, and it would be the first β
lactam to provide coverage against both MRSA and sus-
ceptible Pseudomonas aeruginosa.
Phase II agents
Lefamulin
Pharmacology
Lefamulin (formerly BC-3781), a semi-synthetic pleuro-
mutilin antibiotic, works by inhibiting bacterial protein
synthesis through binding the peptidyl transferase center
of the ribosome.112 Before the development of intrave-
nous and oral formulations of lefamulin, the only other
pleuromutilin developed for use in humans was topical
retapamulin. Lefamulin’s spectrum of activity includes
Gram positive organisms such as staphylococci (including
MRSA), streptococci, and enterococci (including VRE),
as well as Haemophilus influenzae, Moraxella catarrhalis,
and atypical organisms.112
Evidence summary and clinical application
A phase II, double blind, multicenter study compared
lefamulin 100 mg or 150 mg intravenously every 12
hours against vancomycin 1000 mg intravenously every
12 hours for five to 14 days in 207 adults admitted to hos-
pital with ABSSSI.113 The primary outcome was clinical
success at the test of cure visit seven to 14 days after treat-
ment. Success rates were comparable across all treatment
groups, and lefamulin was well tolerated overall, with
patients most commonly experiencing nausea, headache,
or diarrhea. Lefamulin would be the first systemic pleu-
romutilin compound and would offer advantages of both
oral and intravenous administration.
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GLOSSARY OF ABBREVIATIONS
ABSSSIs—acute bacterial skin and skin structure infections
aPTT—activated partial thromboplastin time
CoNS—coagulase negative staphylococci
cSSSI—complicated skin and skin structure infection
EMA—European Medicines Agency
FDA—Food and Drug Administration
IDSA—Infectious Diseases Society of America
MIC—minimum inhibitory concentration
MOA—mechanism of action
MRSA—meticillin resistant Staphylococcus aureus
MSSA—meticillin susceptible Staphylococcus aureus
SSTI—skin and soft tissue infection
VISA—vancomycin intermediate Staphylococcus aureus
VRE—vancomycin resistant enterococci
VRSA—vancomycin resistant Staphylococcus aureus
Auriclosene
Pharmacology
Auriclosene (formerly NVC-422), an aganocide com-
pound and the first in the synthetic stable chlorourine
class, preferentially inactivates sulfur groups in amino
acid residues of surface proteins and has broad spectrum
antibacterial activity, including multidrug resistant MRSA
and VRE.114 115 Because auriclosene has activity against
multiple surface proteins, development of resistance will
likely be difficult.
Evidence summary and clinical application
A phase II study of auriclosene in 129 children aged
2-12 years with non-bullous impetigo compared three
different concentrations of auriclosene (0.1%, 0.5%,
and 1.5%) administered topically three times daily for
seven days.114 Clinical response was defined as clinical
success or improvement at end of treatment (day 8) and/
or follow-up on day 15 and was attained in more than
85% of patients across all concentrations tested. Adverse
events were infrequent and included itching and rash.
Auriclosene is a novel treatment agent that would provide
another option for topical treatment of mild SSTIs.
Conclusion
SSTIs place a substantial burden on patients and health-
care systems each year. Increasing resistance among
Staphylococcus aureus, in particular, presents major
challenges to healthcare providers. The antimicrobi-
als included in this review do not yet have established
places in therapy, as they were approved or in clinical
development when the 2014 ISDA SSTI guidelines were
published. Many new treatment options offer improved
convenience and safety. Several agents also have novel
MOAs or offer advantages in treatment of resistant organ-
isms. Alternatively, many SSTIs can be treated with more
cost effective oral agents. Several recent studies, along
with years of clinical experience, continue to support
the use of oral agents such as clindamycin and trimetho-
prim/sulfamethoxazole for patients with mild to mod-
erate SSTIs.116 117 Practitioners must carefully consider
several patient specific factors to appropriately select
and in­dividualize SSTI treatment regimens. Although it
For personal use only
is exciting to see our SSTI armamentarium expanding,
we must be conscientious antimicrobial stewards and
use these agents responsibly to ensure their future utility.
Contributors: JGB did the literature search. SLM, JGB, and DLS wrote the
draft article and revised the manuscript. SLM is the guarantor.
Competing interests: We have read and understood the BMJ policy on
declaration of interests and declare the following interests: none.
Provenance and peer review: Commissioned; externally peer reviewed.
Patient involvement: Owing to the technical nature of this review, patient
involvement was not requested by BMJ.
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