Skin and Soft Tissue Infection Control Information

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The  skin  is  the  largest  organ  of  the  body,  creating a  protective  barrier  to  prevent  entry  of  pathogenic particles.  While  this  physical  barrier  serves  as  the first  line  of  immunologic  defense,  the  skin  also supports a complex microbial ecosystem comprised of a number of bacterial species, primarily the Grampositive  Staphylococci, Micrococci,  Corynebacteria, and  Propionibacteria,  and  the  Gram-negative Acinetobacter (1, 2). These microbial species are referred to as commensal organisms because they can exist harmoniously and non-pathogenically on the skin so long as the integrity of the skin is maintained. These resident bacteria  also  serve  to  protect  their  host  by  competing  out  other,  more pathogenic bacteria through a number of methods (2). Any breach of this physical barrier could alter this relationship, allowing these commensal and other pathogenic bacteria to gain entry to and serve as pathogenic agents
within  the  underlying  tissue.  Skin  damage  results  in  a  number  of  ways, including dermatologic irritations, burns, lacerations, abrasions, infection, blunt force trauma and surgery. All wounds have the potential to become infected. In large part the chances increase with anatomic site. The closer the wound is to the anatomic sites known  to  serve  as  reservoirs  of  both  aerobic  and  anaerobic  bacteria, namely the respiratory and gastrointestinal tracts, the greater the chance of infection onset. The SENTRY Antimicrobial Surveillance Program has been recording information on and ranking pathogens isolated from skin and soft tissue infections (SSTIs) serious enough to require hospitalization. Within the United States the causative agents have been fairly static since this program was initiated, with Staphylococcus aureusaccounting for almost
50%  of  all  analyzed  cases  (3). A  summary  of  seven  years  of  analyses 1998-2004) ranks the leading ten pathogens detected in 5,837 cases of SSTIs (Table 1). A subsequent report compared molecular techniques with those of culture with regard to identifying pathogens associated with various wounds. They identified limitations associated with culturing methodologies that may skew the detection rates of some bacterial species, most notably the strict anaerobes, thus adversely affecting treatment regimens (4). In
this analysis, which used sequencing to identify pathogens within a number of  samples,  a  host  of  difficult-to-culture,  bio-film  associated  anaerobic genera were identified from three different forms of skin ulcers (4, 5, 6). Medical Diagnostic Laboratories, L.L.C. (MDL) has developed a panel of tests  including  the  most  frequently  detected  pathogens  associated  with surgical site infections (SSIs) and SSTIs to aid physicians in the diagnosis and proper treatment of a host of wound types. Table 1. Incidence rates of pathogens isolated from SSTI and SSI within the United States as reported by the SENTRY Antimicrobial Surveillance Program  and  the  CDC’s  Guidelines  for  Prevention  of  Surgical  Site Infection. Both  reports  summarize  infectious  rates  over  a  seven  year  time frame. ND indicates “not determined” in that study (3, 7). Skin and Soft Tissue Infections (SSTI) Panel Staging of Wounds Wounds  are  classified  according  to  their  degree  of  severity  on  a  four point scale (8). Stage 1is typified by alteration in skin color, texture and temperature with no overt lesion present and does not involve the dermis. Stage 2describes instances whereby the epidermal and dermal layers of skin are breached as a result of a tear in the epidermal layer that can include infection  and  tissue  necrosis;  drainage  at  the  site  is  not  an  uncommon characteristic. Stage  3 wounds  are  distinguished  from  Stage  2  wounds based on the depth of the trauma. In these instances, the damage extends to,  but  no  further  than,  the  subcutaneous  fat  layer  of  the  skin. Stage  4 wounds are by far the most serious, affecting both bone and muscle as well as supporting structures. Necrosis and drainage are extensive. Ulcers The term ulcer is ascribed to any slow healing, open sore on the surface of  the  skin  or  mucous  membrane  that  is  accompanied  by  tissue  loss, disintegration and necrosis. Diabetic foot, venous and pressure ulcers are three common ulcer types routinely seen clinically.
Diabetic Foot Ulcers According  to  the  2011  Diabetes  Fact  Sheet  published  by  the American Diabetes Association (9), there are currently 25.8 million Americans, 8.3%
of  the  current  population,  suffering  from  Diabetes  Mellitus.  Within  this population  approximately  15%,  or  4  million  individuals,  will  develop  foot ulcers, 6% of which will require hospitalization for infection and complication (10). Statistical analysis of medical costs within the United States in 2007 report a total of $116 billion dollars in direct costs spent for the treatment of diabetes, with 33% ($38 billion) of this amount used specifically for the care and treatment of foot ulcers (11). These numbers are staggering when you
consider the number of newly diagnosed cases continues to rise. Diabetic  foot  ulcers  are multifactorial  in  origin,  the  result  of  a  host  of biological issues brought about by uncontrolled blood sugar levels. First, diabetics are more prone to infection as a result of changes in their skin, leaving  it  dry  and  susceptible  to  cracking  and  fissuring.  Diabetics  also experience atrophy of the small muscles of the foot leading to structural
deformity which results in increased amounts of pressure on the ball and heel of the foot leading to accelerated callous formation. The diabetic callous differs from that of the non-diabetic population in that they are often much thicker and more prone to cracking, infection and ulcer formation (Figure 1)  (12).  This  increased  pressure  leads  to  accelerated  callous  formation which, if not properly attended, can readily become ulcers in the diabetic patient.  Compounding  matters  are  two  other  anomalies  associated  with diabetes, sensory neuropathy and vascular disease. Diabetic neuropathy describes  the  sensory  nerve  damage  that  hinders  a  person’s  ability  to feel their extremities, allowing them to unknowingly continue on with their daily routines despite being injured. Poor circulation to the extremities as a result of narrowing and hardening of blood vessels complicates matters further by increasing the level of cell death and decreasing the numbers of immune mediators capable of trafficking to the affected areas. Ulcers detected early are highly treatable and curative as they are often infected with  aerobic,  Gram-negative  cocci. As  the  infection  progresses  and  the ulcer grows deeper, the infections predominantly become polymicrobial in nature  and  often  limb  threatening  (12).  Prompt  and  proper  treatment  is essential  in  order  to  save  the  affected  toe,  foot  or  leg  from  amputation. Despite  physicians’  best  efforts,  almost  66,000  lower-limb  amputations were performed in 2006 (9).
Pathogenic Agent
Detection in SSTIs
(N = 5,873)
Detection in SSI
(N = 17,671)
S. aureus 2,602 3,534
P. aeruginosa 648 1,414
Enterococcus species 542 2,121
E. coli 422 2,121
Enterobacter species 282 1,237
Klebsiella species 248 530
Streptococci 237 884
P. mirabilis 166 530
CoNS 161 2,474
Serratiaspecies 125 ND
Bacteroides fragilis ND 353
Other Gram Positive Aerobes ND 353
Medical Diagnostic Laboratories, L.L.C.
& Promp t nalized   Perso
That’s Our Way
Pr essional o f
Compression of the affected area to minimize edema and swelling is the
primary form of treatment (16).
Wound Repair
What  makes  the  skin  unique  is  its  ability  to  repair  itself  and  recover from  these  various  insults. Tissue  repair  and  remodeling  is  a  multistep process that is orchestrated by a number of key cell types and factors working in concert with one another to seal-off the site in order to localize infection, decrease blood loss and initiate cellular replication to regenerate the  damaged  tissue.  Typically,  these  events  occur  as  a  continuum  of overlapping stages, some lasting only a few hours and others potentially for several years. Initiation begins with the process of Hemostasis, typically not considered an actual stage in the process, then to Inflammation (early), transiting into the Proliferation Stage (intermediate) and culminating with Maturation (late) (Figure 3) (17).
Figure  3.  The  stages  and  duration  of  the  wound  repair  process.
Adapted from (17). Pathogens Often Isolated from SSTIs and SSIs Pathogen association with various SSTI and SSI is often dictated by the anatomic  location;  the  infectious  agent  is  typically  considered  normal flora within that region. For the first phase MDL has selected the following pathogenic agents for inclusion in the Skin and Soft Tissue Infection panel. Bacteroides  fragilis: Bacteroides  are  Gram-negative,  anaerobic  bacilli
associated with a number of different types of infections that are typically polymicrobial in nature. Anatomic sites affected include the central nervous system, head, neck, chest, abdomen, pelvis, skin and soft tissue. Due to their fastidious growth requirements, Bacteroidesspecies are extremely hard to identify by culturing methodologies and, as a result, are believed to be under reported pathogenic agents (18). B. fragilis is considered normal flora of the gastrointestinal tract and is commonly associated with SSI of the abdomen and abscesses. E.  coli:  E.  coli are  Gram-negative,  facultative,  rod-shaped  bacteria that  naturally  inhabit  the  gastrointestinal  tract.  Outside  their  normal environment, E.  coli can  cause  infection,  particularly  within  the  urinary tract.  They  are  also  associated  with  skin  infections  in  regions  in  close proximity to the rectum, particularly with incontinent individuals. Individuals undergoing surgical procedures associated with the gastrointestinal tract and lower regions of the spine are also at risk of contracting infection (19, 20, 21). Klebsiella species: Klebsiella species  are  Gram-negative,  facultative rods that colonize the skin and gastrointestinal tract. These opportunistic pathogens are a leading cause of nosocomial infections second only to
E. coli, and account for 8% of all hospital-acquired infections (19, 21, 22). Such  infections  typically  arise  within  the  respiratory,  biliary  and  urinary tracts as well as surgical sites. The ubiquitous nature of these bacteria, in combination with increased treatment with broad-spectrum antibiotics, has led to the development of resistant strains. Two species, K. pneumoniae and K. oxytoca, account for the majority of infections with K. pneumoniae
serving as an important cause of community-acquired pneumonia in the elderly and K. oxytocamore commonly associated with UTIs. Prevotella species: Prevotella species  are  Gram-negative,  anaerobic bacilli  that  colonize  the  vaginal  and  oral  cavities.  Depending  on  their anatomic location, these bacteria cause a wide-range of infections. Oral cavity  colonization  is  associated  with  sinus  and  periodontal  infections, Figure 1. An image of a diabetic foot ulcer that initiated from a thickened callous. (13)
Pressure Ulcers Pressure ulcers, also known as bed sores, typically arise as a result of
prolonged and persistent pressure applied to the skin, usually developing at bony areas like the hips, heels, elbows, shoulders, back and back of the head. Friction and shear forces also play parts in wound development as the skin is often pulled unnaturally either as the result of a caregiver repositioning  an  individual  by  dragging  them  across  a  surface  or  the repositioning of a mechanical bed that allows the individual to slide along
a  surface  (14,15).  Sores  develop  as  a  result  of  decreased  blood  flow o the compressed tissue, leading to increased cellular death and often develop quickly, making them difficult to manage. Those at greatest risk of developing pressure sores have limited mobility and are often unable to shift their position to alleviate the pressure; this includes those confined to a wheelchair or a bed (15). The incidence of developing such sores
increases with age, as the skin becomes more fragile, regenerates more slowly and sensory and mental perception begin to wane (15). Diabetics, as a result of their associated vascular issues, are also at greater risk of developing pressure sores. If not treated promptly and properly, serious complications  including  cellulitis,  bone/joint  infection,  sepsis  and  even melanoma  can  occur  (15). A  joint  study  performed  by  the  Centers  for Disease Control and Prevention (CDC) and National Center for Health
Statistics (NCHS) evaluated the incidence rate of pressure sores within nursing home facilities. Their study found 11% of 159,000 nursing home residents  had  pressure  sores  and  that  half  of  them  were  classified  as stage 2 sores on the Shea Pressure Sore Scale (14). Figure 2. Percentage of nursing home residents with pressure ulcers by stage. (CDC/NCHS National Nursing Home Survey). These values were reported for the year 2004 whereby approximately 159,000 (11%) of nursing home residents were reported to have some form of pressure ulcer. (14) Venous Stasis Ulcers Venous stasis ulcers arise as a result of the natural aging process. Bicuspid valves  within  leg  veins  begin  to  lose  their  elasticity,  allowing  blood  to pool. Individuals with deep vein thrombosis and edema have a sedentary lifestyle or who are obese are at greater risk of developing these valvular
issues. The loss of valvular function leads to increased veinous pressure which puts more strain upon the affected valves, damaging them further, and elicits an immune response that affects tissues within these regions. 367   SSTI Panel Antibiotic Resistance by Real-Time PCR [Enterococcus  faecalis,  Escherichia  coli, Group A  Streptococcus,  Group  B  Streptococcus, Klebsiella species, Proteus mirabilis, Pseudomonas aeruginosa, Community  Associated  MRSA  (CAMRSA):  amoxicillin-clavulanic  acid,  ampicillin  (for E. faecalis), cephalothin (cephalexin), clindamycin, doxycycline,  trimethoprim-sulfamethoxazole, ciprofloxacin,  cefepime,  piperacillin-tazobactam,
imipenem, gentamicin] Benefits of this system include:
•  Real-Time PCR.
•  Simple and convenient sample collection.
•  No refrigeration is required before or after collection.
•  Specimen stable for up to five days.
•  Test additions are available up to 30 days after receipt of the specimen.
•  24 – 48 hour turnaround time.
•  High diagnostic specificity and sensitivity.
•  One vial, multiple pathogens.

Antibiotic Treatment for Skin and Soft Tissue
Infections.

 
Skin and soft tissue infections (SSTI), surgical site infections (SSI), and
wounds are a major issue of morbidity and mortality in the community and
healthcare system (reviewed in 33, 34, 35). Skin or our epidermal layer
provides us with a protective barrier between the microbial environment
and  our  sub-dermal  tissue,  organs,  and  blood  stream.  Whenever  that
barrier  is  breached  by  trauma,  surgery,  or  infectious  abscess,  a  strong
immune  response  is  triggered  to  the  infecting  organism.  SSTI,  SSI,
and  wound  infections  can  be  caused  by  a  single  bacterium  or  can  be
polymicrobial depending on the site and length of time of the infection (33).
The  initial  stages  of  these  infections  usually  involve  the  Gram-positive
Staphylococcus  and  occasionally  Streptococcus,  especially  for  those
infections above the waist. The major cause and ever increasing in number
are  SSTIs  due  to  methicillin-resistant Staphylococcus  aureus (MRSA),
which are resistant to the ß-lactam class of antibiotics (36). Other bacteria
in addition to Staphylococci and Streptococci can cause infections, such as
the facultative anaerobic Gram-negative rods Escherichia coli, Klebsiella
species, Proteus  mirabilis,  and  Pseudomonas  aeruginosa,  or  Grampositive Enterococcus,  especially  for  those  infections  below  the  waist
although less frequently (33).The enterics, Pseudomonas, Enterococcus,
Gram-positive and Gram-negative anaerobic bacteria are usually present
in SSTIs and wounds, such as animal or human bites, lasting for weeks
or SSIs, especially those associated with the gut or OB/GYN surgeries
(33,34). Chronic wounds lasting weeks can be due to facultative anaerobic
bacteria such as Bacteriodes fragilis, Peptostreptococcus, and facultative
anaerobic  Gram-negative  rods  such  as Pseudomonas  aeruginosa and
Enterobacter species. Drainage  of  the  abscess  is  recommended  for
uncomplicated SSTI often associated with Staphylococcus. Topical, oral
(PO),  intramuscular  (IM),  and  intravenous  (IV)  antibiotics  are  used  to
treat these infections depending on the clinical presentation and severity
of the infections (Table 2) (36). Antibiotics suggested by the Infectious
Disease Society of America (IDSA, provider survey, and the Clinical and
Laboratory  Standards  Institute  (CLSI)  were  selected  for  this  antibiotic
susceptibility assay (37). Other antibiotics recommended to treat MRSA
(non-community-associated  MRSA)  infections  include  vancomycin  (IV),
linezolid (PO, IV), and daptomycin (IV). These antibiotics are not included
in the antibiotic susceptibility panel due to very low levels of resistance.
Table 2.
peritonsillar abscess and pneumonia, while those colonizing the GI tract
have  been  isolated  from  cases  of  peritonitis,  intra-abdominal  abscess,
postoperative wound infections, pelvic inflammatory disease, vulvovaginal
and perianal infections. Infections of the soft tissue include gangrene and
necrotizing fasciitis (23).
Proteus  mirabilis: Proteus species  are  a  Gram-negative,  facultative
bacilli  that  colonize  the  gastrointestinal  tract  and  are  a  source  of
nosocomial infection within hospitals and long-term care facilities (19, 24).
Usually associated with UTI, Proteus mirabilishas also been isolated from
abscesses, SSI, decubitus ulcers and burns (24).
Pseudomonas  aeruginosa:  Pseudomonas  aeruginosa is  a  Gramnegative  bacillus  associated  with  a  number  of  different  opportunistic
infections  and  is  particularly  problematic  for  ventilated  patients,  burn
patients and those with chronic debilities (19, 21, 26). Infections of the skin
include those affecting the feet and toenails (tinea), hot tub/swimming pool
infections (folliculitis) and burn wound sepsis (27). Recently, the ability of
P. aeruginosato form bio-films has been postulated as a mechanism for
long standing wounds that will not heal. (28).
Streptococcus  pyogenes (GAS): GAS  is  a  Gram-negative,  coccus
that resides harmlessly on the skin as a commensal until the protective
skin barrier is breeched and it becomes pathogenic. GAS is a causative
factor,  along  with Staphylococcus  aureus,  for  impetigo.  While  impetigo
itself  is  not  life-threatening,  it  can  lead  to  more  serious  complictions,
including  cellulitis  and  MRSA  affecting  the  skin  and  poststreptococcal
glomurelonephritis affecting the kidney (29).
Streptococcus agalactiae(GBS): GBS is a Gram-positive coccus that
causes  a  number  of  serious  infections  in  both  pregnant  women  and
adults with underlying health issues, like diabetes mellitus, heart disease
and malignancy. Aside from its role in neonatal sepsis, GBS has been
associated  with  infections  within  the  over-seventy  years  of  age  group,
particularly the bedridden and those afflicted with congestive heart failure,
where UTI, pneumonia and soft tissue infections are the most frequent
manifestations  (19,  21,  30).  Streptococci,  along  with  Staphylococci,
are  the  leading  causative  agents  associated  with  the  potentially  lifethreatening skin infection, cellulitis (30).
Staphylococcus  aureus with  methicillin  resistance  screening:
Staphylococcus  aureus is  a  Gram-positive  coccus  that  is  largely
considered to be normal flora of the skin. However, upon breach of this
protective barrier, Staph can become highly pathogenic, particularly within
individuals having chronic disorders such as diabetes, cancer, vascular
and  lung  disease,  eczema  and  individuals  with  weakened  immune
systems.  Infections  of  the  skin  often  go  untreated  as  initial  infections
resemble  pimples  or  spider  bites,  allowing  the  infection  to  progress  to
greater  degrees  of  severity.  Infections  are  further  complicated  by  the
emergence and circulation of methicillin-resistant strains (19, 21, 32).
Clinical Benefits of Testing
MDL  offers  highly  sensitive  and  specific  quantitative  Real-Time  PCR
(qPCR) based assays for the detection of skin and soft tissue infection
associated pathogens utilizing the OneSwab®
platform:
366   Skin  &  Soft  Tissue  Infections  (SSTI)  Panel
by  Real-Time  PCR  [Bacteroides  fragilis,
Enterococcus  faecalis,  Escherichia  coli,  Group A
Streptococcus, Group B Streptococcus, Klebsiella
species, Prevotella Groups 1 & 2, Proteus mirabilis,
Pseudomonas  aeruginosa,  Staphylococcus
aureus,  methicillin  resistant  Staplyococcusa
aureus  (MRSA),  Community  Associated  MRSA
(CA-MRSA)]
Table 2. Summary of Treatment Options.
Abbreviations: PO (per OS oral) IM (intramuscular); IV (intravenous); MRSA

a

(Methicillin-Resistant  Staphylococcus  aureus)  and  CA-MRSA  (Communityassociated  MRSA).  Enterobacteriaceae  includes  enterics  such  as E.  coli, Klebsiella species, and Proteus species.a Methicillin-Resistant Staphylococcus  aureus isolates  are  resistant  to  the ß-lactam class of antibiotics (e.g. penicillin, ampicillin, amoxicillin, piperacillin, cephalosporins, carbepenems). For hospital-associated MRSA (HA-MRSA or MRSA), vancomycin (IV), linezolid (PO, IV), and daptomycin (IV) are effective. These  antibiotics  are  not  included  in  the  panel  due  to  very  low  levels  of resistance.

b
Community-associated  MRSA  (CA-MRSA),  Type  IV  SCC  and  PantonValentine Leukocidin postive, unlike HA-MRSA, are often susceptible to other non-ß-lactam  common  antibiotics  such  as  trimethoprim-sulfamethoxazole, doxycycline, and clindamycin.

c
Streptococcus  species  are  susceptible  to  the  ß-lactam  class  of  antibiotics
(e.g.  penicillin,  ampicillin,  cephalosporins,  carbepenems).  For  penicillin
allergic patients at risk for anaphylaxis, clindamycin, vancomycin, doxycycline,
fluoroquinolones can be alternatives.

d
For  anaerobic  bacteria,  metronidazole  is  used,  often  in  combination with  ampicillin,  amoxicillin,  cephalosporins  with  anaerobic  activity,  and/or fluoroquinolones.

e
For  Enterococcus  spp.,  combination  therapy  of  ampicillin,  penicillin,  or vancomycin  (for  susceptible  strains),  plus  an  aminoglycoside,  is  usually indicated  for  serious  Enterococcal  infections,  unless  high-level  resistance to  both  gentamicin  and  streptomycin  is  documented;  such  combinations are  predicted  to  result  in  synergistic  killing  of  the  Enterococcus.  High-level gentamicin resistance screening is not performed in this antibiotic susceptibility assay
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31(1)
Antibiotic
Routes of
Administration
Effective Not Effective
Amoxacillin-clavulanic acid  PO
Staphylococcus
Streptococcus c
Enterococcus
Enterobacteriaceae
Anaerobes d
MRSA a
CA-MRSA b
Pseudomonas
Cephalothin
Cephalexin
IV
PO
Staphylococcus
Streptococcus c
Enterobacteriaceae
MRSA a
CA-MRSA b
Pseudomonas
Enterococcus
Anaerobes
Clindamycin PO, IM, IV
Staphylococcus
CA-MRSA b
Streptococcus c
Anaerobes d
MRSA a
Enterobacteriaceae
Pseudomonas
Enterococcus
Doxycycline PO
Staphylococcus
MRSA a
CA-MRSA b
Streptococcus c
Enterococcus
Enterobacteriaceae
Anaerobes d
Pseudomonas
Not for pregnancy
or children < 8yrs
Trimethoprim-sulfamethoxazole PO, IV
Staphylococcus
MRSA a
CA-MRSA b
Streptococcus c
Enterobacteriacea
Enterococcus
Anaerobes
Pseudomonas
Ciprofloxacin PO, IV
Staphylococcus
Streptococcus c
(Levofloxacin for Strep.)
Enterococcus
Enterobacteriaceae
Anaerobes d
Pseudomonas
MRSA a
CA-MRSA b
Not for pregnancy
Cefepime IM, IV
Staphylococcus
Streptococcus c
Enterobacteriaceae
Pseudomonas
MRSA a
CA-MRSA b
Enterococcus
Anaerobes
Piperacillin-tazobactam  IV
Staphylococcus
Streptococcus c
Enterococcus
Enterobacteriaceae
Anaerobes d
Pseudomonas
MRSA a
CA-MRSA b
Imipenem IM, IV
Staphylococcus
Streptococcus c
Enterococcus
Enterobacteriaceae
Anaerobes d
Pseudomonas
MRSA a
CA-MRSA b
Gentamicin IM, IV Combination antibiotic e