Skin and soft tissue infections caused by Gram positive organisms

Infection of the skin and soft tissue (SSTI) is a common clinical condition and presents in both mild
and severe forms. In the United States (US) between 1993 and 2005 there was an increase in the
annual emergency department visit for SSTI from 1.2 million to 3.4 million patients(1). The severity
of SSTI has increased in US as seen by a 29% increase in total hospital admissions for SSTI between
2000 and 2004(2). SSTIs are a common indication for antibiotic use and can increase the burden of
healthcare costs. In Botswana, an increased prevalence of SSTI caused by methicillin resistant
Staphylococcus aureus (MRSA) was seen between 2000 and 2007(3).

The skin

The skin forms a physical barrier between the environment and the internal, vulnerable
compartments of the human body. It is an important immune organ containing antigen presenting
cells and antimicrobial peptides.

Our skin is also home to a diverse population of microbes, which can be commensals (non-
pathogenic permanent flora) or transient colonisers. The entire community of microbes on the
human body is referred to as the human microbiome and the skin microbial flora forms part of it(4).

Many skin pathogens can be found living as commensals. An imbalance of microbial populations, or
change in host immune status, may drive a shift of commensals to pathogens. Organisms that
breach the immune and physical barrier of the skin can cause a SSTI(5). Gram positive organisms are
the most common cause of SSTI’s, especially Staphylococcus aureus and beta-haemolytic
Streptococci(6).

Frequency of pathogens isolated from SSTIs among hospitalized patients in the SENTRY Antimicrobial Surveillance
Programs. Adapted from Dryden MS. Int J Antimicrob Agents 2009; 34 Suppl 1: S2–7
Gram positive organisms
Bacteria are categorized as Gram-positive or Gram-negative based on their staining characteristics. Commented [EH1]: Poorly constructed sentence I think…
Gram positive bacteria are the main cause of SSTIs and they have a thick cell wall made of too many appearances of the word gram
peptidoglycan. Gram negatives on the other hand have a thin cell wall but a highly complex outer
membrane. To improve the management of SSTI’s a clear understanding of Gram positive organisms
is necessary. Below follows a summary of Gram positives that commonly cause SSTIs:

Staphylococcus aureus
This organism is a highly successful opportunistic pathogen with over 200 virulence factors. In Commented [EH2]: a
humans, it colonises the nares of 20-40% of people from where it can be shed onto skin. Commented [EH3]: , it …
S.aureus is the most commonly isolated organism in SSTIs(6). Its possesses surface adhesins to aid in
colonization and cellular invasion. Fibronectin, fibrinogen and collagen are three extracellular matrix
molecules in epithelial cells and connective tissue and S.aureus binds effectively to these targets.
Clumping factor binds fibrinogen, fibronectin binding protein binds fibronectin(7, 8).

S.aureus produces toxins such as alpha toxin which lyse cytoplasmic membranes. Super antigens are
toxins that cause a severe systemic inflammatory immune response through cytokine release.

S.aureus can evade professional phagocytes by persisting intra cellularly in epithelial cells. If
phagocytosed by a macrophage, it can survive through upregulation of antiapoptotic factors. The
infected macrophage acts as a ‘Trojan horse’ disseminating the organism(9).

Methicillin resistant Staphylococci are resistant to beta lactam antibiotics. The resistance is mediated
by a modification in penicillin binding protein 2a (PBP-2a) encoded by the mecA gene. The mecA
gene is on a mobile genetic element: Staphylococcal chromosomal cassette (SCCmec).

Since 1990’s there has been increasing spread of community acquired methicillin resistant S.aureus
(CA-MRSA) SSTIs(2). Patients with CA-MRSA have had no hospital contact (HA-MRSA) and these
organisms are efficiently spread through contact and chronic carriage in the community setting. The
distinction between CA-MRSA and HA-MRSA is becoming less as the community acquired strains
spread in hospitals. There are documented retrospective studies of CA-MRSA outbreaks in well-
defined populations such as athletes, and prisoners. Well defined risk factors for CA-MRSA are still
unknown and it is challenging for clinicians to know whether to consider CA-MRSA in empirical
antibiotic regimens for SSTIs(10).

Common risk factors for MRSA colonization(10)

Previous history of MRSA infection or colonization

Previous use of antimicrobial agents
Advanced age
Chronic open wounds
Underlying diseases or conditions

Repeated contact with the healthcare system

Invasive procedures
Parenteral drug use
 A well described virulence factor of S.aureus is the Panton-Valentine leucocidin (PVL). PVL causes
cell death , especially of neutrophils. PVL positive strains of S.aureus have a tendency to form Commented [EH4]: ,
purulent skin lesions and are also associated with necrotising pneumonia. In studies from developed
countries there is a strong association between PVL and CA-MRSA. In Cape Town, a prevalence of 9%
was found in MRSA isolates. A concerning finding of that study was a high prevalence of PVL in MSSA
(40%). A study in five major African cities found an overall PVL prevalence of 57% mostly in MSSA. In
industrialised countries the prevalence of PVL in MSSA is 0.5-1.4%. Wide spread PVL in MSSA
indicates a major potential for massive emergence and spread of successful highly virulent PVL-
positive S.aureus should methicillin resistance become more prevalent(11-13).

When to add empirical antibiotic cover for MRSA is challenging and requires knowledge on the local
epidemiology. For hospital acquired SSTIs, empiric regimens should contain antibiotic active against
MRSA.

Beta haemolytic Streptococci

Streptococci are Gram-positive cocci and are differentiated from Staphylococci based on their
arrangement in chains and their negative catalase reaction. Beta haemolytic Streptococci causing
SSTI produce clear zones of haemolysis when cultured on sheep blood agar. They are classified by
their agglutination reaction with Lancefield group carbohydrates (A-T) and groups A, B, C and G are
causative organisms in SSTIs.

Streptococcus pyogenes, group A Streptococcus (GAS), causes a diverse range of infections. GAS
remains universally penicillin sensitive and wide spread use of penicillin has led to a global decline of
GAS disease.

GAS colonises epithelial surfaces especially found in the throat. 15-20% of school children carry GAS
in their throats. Most infection due to GAS is non-severe: bacterial pharyngitis and impetigo.

M protein is an important cause of virulence in this organism and it is encoded by the emm gene.
M protein binds immunoglobulins and fibrinogen. Specific strains of GAS have post infectious
sequelae that are immune mediated: acute rheumatic fever and poststreptococcal
glomerulonephritis.

Aside from its surface proteins, the organism produces a host of enzymes (such as streptolysin O)
which are cytotoxic. Similarly to S.aureus, certain strains of GAS are able to produce toxins which act
as superantigens.

GAS remains universally sensitive to penicillin. Resistance to macrolides is increasing and makes
these agents less attractive options for empiric treatment. Systemic antibiotics should be used for
infections due to GAS during outbreaks of poststreptococcal glomerulonephritis(14, 15).
Clostridium species
Clostridium species such as C.perfringens, C.histolyticum and C.septicum are anaerobic Gram-
positive rods that can cause cellulitis with gas formation. Infections are characterised by Commented [EH5]: Anaerobic gram positive what?
myonecrosis, gas in tissue and systemic toxicity(16).

Corynebacterium species
Erythrasma is caused by Corynebacterium minutissimum, a Gram-positive rod. It is characterised by
red-brown lesions occurring in the intertriginous areas or maceration in the toe clefts. It is
commonly misdiagnosed as Tinea cruris(17).

Erythrasma is caused by Corynebacterium minutissimum.

Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K: Fitzpatrick’s Dermatology in General Medicine, 8 th
Edition

Cutaneous diphtheria can be caused by toxigenic and non-toxigenic strains of C. diphtheriae. It is

characterized by chronic, nonhealing sores or shallow ulcers with a dirty gray membrane. While
toxigenic strains may have disappeared in countries with active immunisation, the non-toxigenic
strains may persist as skin colonisers and form a reservoir for future outbreaks if immunisation
programs wane. Outbreaks in the US have been documented amongst alcoholic, homeless men and
impoverished groups(18, 19).
Nocardia species

Nocardia species are aerobic actinomycetes and cause localised and disseminated infections.
Nocardia are environmental saprophytes and infection arises after traumatic inoculation of foreign
material into skin. Typically, a pyogenic abscess forms or lymphocutaneous spread occurs. Nocardial
infections are indolent and can become chronically destructive with sinus tract formation – a
mycetoma(20).

Actinomyces species
Actinomycosis is an indolent progressive infection caused by anaerobic or microaerophilic
Actinomyces species. Following invasion of the skin, organisms clump together and form purulent
foci. The foci are surrounded by fibrotic tissue and a mass-like structure is formed which may mimic
a malignancy. Sinus tracts may develop, resolve and recur. Oral-cervicofacial disease is the most
common manifestation and presents as soft tissue abscesses of the head and neck. Actinomycosis
should be considered in the differential diagnosis of recurring abscesses(21, 22). Pus formation in
actinomycosis is characterised by the presence of granules, typically yellow in colour and described
as sulphur granules. The granules are clumps of organisms surrounded by neutrophils and are not
made of sulphur and they range in size from micro to macroscopic(23).

Sulphur granules
Source: Mandel, Agents of actinomycosis G. M. Mandell, J.E. Bennet, and D. Raphael Mandell, Douglas, and Bennette's
Principles and Practice of Infectious Disease. Philadelphia: Churchill Livingstone
Common clinical presentations of SSTIs

SSTI can be classified according to the anatomical site of infection. Infection in the superficial layers
of the skin can be described as uncomplicated, and complicated when affecting the deeper layers.

Anatomical site of SSTI

Source: Marschall S. Runge, M. Andrew Greganti; illustrations by Frank H. Netter; contributing illustrators, Carlos A.G.
Machado: NETTER’S INTERNAL MEDICINE, 2nd Edition
Superficial pyodermas are mild infections and when antibiotics are needed, oral therapy is sufficient.
The definitive treatment of purulent infections is incision and drainage (I&D) of the abscess.
Complicated SSTI usually require intravenous (IV) antibiotic and hospital admission (16).

There is compelling data on complicated SSTIs to show that inappropriate initial antibiotic treatment
leads to worse patient outcomes and increased costs. Collecting samples for culture and
susceptibility should be strongly considered in cases of complicated SSTI(6, 10).

Superficial pyodermas

Pyodermas are infections in the epidermis or in hair follicles. If pyodermas are untreated they can
extend to the dermis and result in furuncles or ecthyma.

 Skin
o Impetigo
o Bullous Impetigo
o Ecthyma
 Hair follicles
o Superficial folliculitis

Impetigo is a contagious SSTI that can either be bullous or non-bullous.

Bullous Impetigo is caused by S.aureus. Lesions initially appear as vesicles, and these then form
flaccid fluid filled bullae. If the bullae rupture they form crusted erosions. The same extracellular
exfoliative toxins that cause scalded skin syndrome, cause bullous impetigo. Exfoliative toxin
damages the inter cellular junction of epidermal cells leading to the formation of the thin walled
vesicles. Bullous impetigo occurs primary in neonates and young children(8).

Bullous Impetigo
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K: Fitzpatrick’s Dermatology in General Medicine, 8 th
Edition
Non bullous impetigo can be from either S.aureus or beta-haemolytic Streptococci acting alone or
together. This form begins with erythematous papules that form vesicles which rupture leaving a
dried honey coloured discharge. This is contagious and organisms can be spread through contact.

Ecthyma is a deeper infection than impetigo caused either by S.aureus and/or Streptococci. Lesions
form as vesicles and when they rupture they leave erythematous ulcers with adherent crusts. Unlike
impetigo, ecthyma heals with scarring.

Culture and Gram stain of vesicle fluid, pus or erosions is not necessary for every patient and
empirical antibiotics should be directed against both S.aureus and streptococci. Topical treatment
with mupirocin/fusidic acid for 5 days is as effective as oral antibiotics for impetigo. Fusidic acid
cream is an alternative option to mupirocin cream, but there is rising resistance to both agents in
staphylococcal strains globally(24, 25).

Oral antibiotics for 7 days is preferred for treating extensive lesions of impetigo, or in outbreaks
affecting numerous people. Cloxacillin and amoxicillin-clavulanate are penicillinase stable and are
effective oral options because most staphylococcal cases of impetigo are caused by MSSA. In cases
of MRSA, doxycycline, clindamycin or co-trimoxazole are options for oral treatment. Ecthyma is
preferably treated with oral antibiotics(7, 16).

Folliculitis is inflammation of a hair follicle. Folliculitis caused by S. aureus should be distinguished

from other causes. Pseudofolliculitis barbae is caused by ingrowing of curved hair shafts. This can be
secondarily infected with S. aureus. Sycosis barbae is a deep folliculitis occurring in the bearded
areas of the face and upper lip.

Purulent skin and soft tissue infections

 Furuncles
 Carbuncles
 Abscess

Furuncles (“boils”) are infections of the hair follicle usually caused by S. aureus. Suppuration extends
past the dermis into subcutaneous tissue and abscess forms. Carbuncles are deep and extensive
subcutaneous abscesses involving several hair follicles and sebaceous glands(16).
Carbuncle
Source: Goldsmith LA, Katz SI, Gilchrest BA, Paller AS, Leffel DJ, Wolff K: Fitzpatrick’s Dermatology in General Medicine, 8 th
Edition

Cutaneous abscesses are collections of pus in the dermis and deeper skin tissue. They are painful
and fluctuant and may be encircled by a rim of inflammation. Cutaneous abscesses are most often
caused by S.aureus(26).

Incision and drainage (I&D) is the recommended treatment for abscesses, inflamed carbuncles and
large furuncles. Additional antibiotics following I&D does not improve cure rates in all patients(27).
Cure rates with drainage alone exceed 80% but adjunctive antibiotics should be considered in the
following scenarios (1, 28):

 Clinical signs of systemic involvement (systemic inflammatory response)

 Diabetics
 Extremes of age
 Infected site larger than 5cm

In a randomised control trial performed in the US on uncomplicated cutaneous abscesses caused by

MRSA, the patients treated with trimethoprim-sulfamethoxazole after I&D had a better cure rate
than placebo group. Participants included diabetics but some had lesions smaller than 5cm(1).
Non-purulent skin and soft tissue infections

 Cellulitis
 Erysipelas

Cellulitis refers to a diffuse spreading infection of the dermis. It does not include local collections of
pus such as the inflammation associated with a local abscess or furuncle. In cellulitis there is no pus
collection to drain and the treatment is antimicrobial therapy(14).

Cellulitis typically presents with rapidly spreading erythema, tenderness, and warmth of infected
areas. The beta-haemolytic streptococci are the main causes of non-purulent cellulitis(29). S. aureus
should also be considered in cases of purulent cellulitis due to penetrating trauma, open wounds or
accompanying abscesses(16). Cellulitis may complicate with spread of infection into the blood and
lymphatics. Blood cultures or aspirate cultures should be obtained in patients with systemic signs,
immune compromise or unusual predisposing factors (e.g. animal bite)(6, 16).

Erysipelas has three different definitions – infection of the upper dermis; or cellulitis involving the
face only or for some cellulitis and erysipelas are the same thing. Erysipelas commonly involves the
cheek and bridge of the nose. GAS is the main cause and lymph oedema is a prominent finding(14).
The skin can appear bright red and have an indurated (peau d’orange) appearance(30).

Antibiotic treatment of cellulitis/erysipelas should include agents active against streptococci.

Cloxacillin, amoxicillin-clavulanate, and clindamycin are oral options which can be used for typical
cellulitis(31). Intravenous antibiotics are to be used if there is rapid spread, or systemic signs, or
significant comorbidities. If there is a clinical improvement, a 5-day course is a sufficient duration. In
the absence of an abscess, ulcer or purulent discharge, monotherapy with a beta lactam for
streptococcal cover is recommended(32). Cellulitis due to MRSA is uncommon but has complicated
the empirical treatment of cellulitis. It has been documented in specific patient groups such as
intravenous drug abusers(29). The activity of doxycycline and SMX-TMP against beta-haemolytic
streptococci is uncertain and should not be chosen in empirical regimens for cellulitis. Cellulitis of a
diabetic foot requires gram negative and anaerobic coverage(16).

Macrolide resistance in beta haemolytic streptococci and especially in GAS has been increasing
globally and is a serious concern(33). The major mechanism of macrolide resistance may lead to
cross resistance to lincosamides such as clindamycin(34).
Necrotising SSTIs

Necrotising SSTIs differ from the milder superficial infections, because they are deep infections of
the fascial or muscle compartments. The clinical presentation of the necrotising SSTIs will depend on
the causative organism and distribution of affected tissue. The infection may result in severe
morbidity, amputations, or mortality.

 Necrotising fasciitis type I (polymicrobial)

 Necrotising fasciitis type II (monomicrobial, mainly caused by GAS)
 Gas gangrene (clostridial myonecrosis)

Type I necrotising fasciitis, is a polymicrobial infection and can arise following a perianal abscess,
surgical procedures to the gut or from decubitus ulcers. The patients at risk for polymicrobial
infection include diabetics, the morbidly obese, alcoholics and parenteral drug abusers. Effective
management consists of aggressive debridement of necrotic tissue and intravenous antibiotics.
Empirical antibiotic treatment would need to be active against MRSA, Gram negatives and
anaerobes. Options would include piperacillin-tazobactam or a carbapenem, in addition to an anti-
MRSA agent such as daptomycin (16, 35).

Type II necrotising fasciitis caused by GAS can follow trauma, but often the portal of entry is not Commented [EH6]: Spelling error
visible. Infection spreads rapidly and in the subcutaneous tissue leaving the overlying skin intact.
Infection can lead to necrotic sloughing of large amounts of tissue as infection spreads along the
fascial planes. Streptococcal toxic shock may be a prominent feature of disease and can be fatal.
Clindamycin should be added to ampicillin for treatment of necrotising fasciitis due to GAS because
it inhibits the production of streptococcal pyrogenic toxin. Streptococcal pyrogenic toxins act as
super antigens (14, 35).

Early during infection, it is important to distinguish between cellulitis which responds to

antimicrobial therapy and necrotising infections which require surgical interventions.

Clinical features of necrotising fasciitis include (16, 36) :

 Severe pain that is disproportional to the clinical findings

 Failure to respond to initial antibiotic therapy Commented [EH7]: ??
 Hard wooden feel to subcutaneous tissue extending beyond area of apparent skin
involvement Commented [EH8]: Poorly constructed. This paragraph
 Systemic signs on infection seems to be written in short hand
 Bullous lesions, skin ecchymosis and crepitus (indicating gas formation)

Most patients with necrotising fasciitis will require another debridement within 24-36 hrs. Antibiotic
therapy should continue until no further debridement is needed; the patient has clinically improved
and the fever absent for 48-72 hours(16, 37).
Gas gangrene
C.perfringens is the most common causative organism of gas gangrene. It can be introduced into the
tissue through a dirty wound or through direct traumatic inoculation of spores. C.perfringens is an
anaerobe and traumatic wounds with devitalised tissue are an ideal environment for it to replicate
in. Skeletal muscle tissue undergoes rapid necrosis due to toxins produced by the organism. The
extensive gas formation results in wound crepitus (37, 38).

Surgical debridement and exploration is essential to halt infection and ensure that infection has not
spread into other muscle compartments. Broad empirical cover is needed because a mixture of
Gram negative and positive organisms can cause a synergistic gangrene. Empirical therapy is
vancomycin combined with either piperacillin-tazobactam or a carbapenem. For culture directed
therapy, intravenous ampicillin plus clindamycin will treat clostridial gangrene more efficiently than
mono therapy with a beta lactam(36).

Evaluating response to treatment

Clinical response to antibiotics should be re-evaluated at 48-72 hours after initiation. The results of
cultures collected prior to treatment will also be available. In patients with complicated SSTIs the
antibiotics can be deescalated, including a switch from intravenous to oral forms if there is sufficient
improvement and other key criteria are met(39). A switch to oral antibiotics is associated with a
decreased length of hospital stay because patients can be discharged.

Eligible for oral switch Not eligible for oral switch

Received intravenous antibiotics for >24 h Vomiting or severe diarrhoea

Afebrile for >24 h (core temperature <38°C) Haematological malignancies or neutropenia

Stable clinical infection Impaired gastrointestinal absorption

White blood cell count normalizing, not <4 9 Dementia

109/L or >12 9 109/L

No unexplained tachycardia Evidence of seeding of organism to other sites;

osteomyelitis, septic arthritis

Systolic blood pressure ≥100 mmHg Bacteraemia or infective endocarditis

(10)
Key points

 Mild SSTIs are often treated with empiric antibiotics

 Incision and drainage in superficial purulent pyodermas does not always need adjunctive
antibiotics
 Complicated and necrotising SSTIs need to be identified rapidly
 For complicated SSTI perform cultures for early MRSA detection and consider the need to
cover for MRSA empirically
 Early aggressive surgery is indicated for both complicated SSTIs and necrotising SSTIs
 For complicated SSTI re-evaluate IV antibiotics at 48-72 hours to determine if it is possible to
switch to an oral antibiotic or if the patient is deteriorating to switch to a different IV
antibiotic
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