Abstract

Skin and soft tissue infections (SSTIs) are common, and complicated SSTIs (cSSTIs) are the more extreme end of this clinical spectrum, encompassing a range of clinical presentations such as deep-seated infection, a requirement for surgical intervention, the presence of systemic signs of sepsis, the presence of complicating co-morbidities, accompanying neutropenia, accompanying ischaemia, tissue necrosis, burns and bites. Staphylococcus aureus is the commonest cause of SSTI across all continents, although its epidemiology in terms of causative strains and antibiotic susceptibility can no longer be predicted with accuracy. The epidemiology of community-acquired and healthcare-acquired strains is constantly shifting and this presents challenges in the choice of empirical antibiotic therapy. Toxin production, particularly with Panton–Valentine leucocidin, may complicate the presentation still further. Polymicrobial infection with Gram-positive and Gram-negative organisms and anaerobes may occur in infections approximating the rectum or genital tract and in diabetic foot infections and burns.

Successful management of cSSTI involves prompt recognition, timely surgical debridement or drainage, resuscitation if required and appropriate antibiotic therapy. The mainstays of treatment are the penicillins, cephalosporins, clindamycin and co-trimoxazole. β-Lactam/β-lactamase inhibitor combinations are indicated for polymicrobial infection. A range of new agents for the treatment of methicillin-resistant S. aureus infections have compared favourably with the glycopeptides and some have distinct pharmacokinetic advantages. These include linezolid, daptomycin and tigecycline. The latter and fluoroquinolones with enhanced anti-Gram-positive activity such as moxifloxacin are better suited for polymicrobial infection.

Introduction

Skin and soft tissue infections (SSTIs) are ubiquitous and the most common of infections, suffered by everyone at some point to a lesser or greater degree and encountered by all doctors. SSTIs reflect inflammatory microbial invasion of the epidermis, dermis and subcutaneous tissues. Indeed, the classical signs of inflammation were described in SSTI by Celsus in the first century as calor, rubor, tumor and dolor (heat, redness, swelling and pain). To these four signs is often added a fifth—fluor (discharge). The skin is the largest organ of the body and, with the underlying soft tissue, which includes the fat layers, fascia and muscle, represents the majority of the tissue in the body. It acts as a tough, flexible, structural barrier to invasion.1

The skin is colonized with an indigenous microbial flora, which typically consists of a variety of species of staphylococci, corynebacteria, propionibacteria and yeasts, in numbers that may vary from a few hundred to many thousands per square centimetre in the moister areas such as the groin and axillae.1 The normal flora may act as a competitive inhibitor of pathogenic microbes. Breaks in the skin, such as leg ulcers, burns and surgical or traumatic wounds, allow colonization with a broader range of bacteria. Colonization of ulcers does not usually result in inflammation, but occasionally infection of the surrounding tissues may result from lateral spread of the colonizing organisms. Clinically, it is important to distinguish between colonization, which does not require antibiotic treatment, and infection, which might.2 Antibiotic stewardship and appropriate use of these therapeutic agents is so important to bacterial ecology and future public health that all physicians must consider in every case of SSTI whether antibiotics are clinically indicated.3 Colonization of skin surfaces or broken skin should never require systemic antibiotics, although it would appear from a major survey on the practice of managing methicillin-resistant Staphylococcus aureus (MRSA) infection in Europe that a significant proportion of practitioners treat MRSA-colonized ulcers with systemic antibiotics.4

Direct infection of the skin occurs by invasion of the epidermis, usually after damage to the skin, and infection may affect any anatomical layer (Table 1). Microbial disease of the skin may also occur by haematogenous spread of bacteria (e.g. meningococcal rash or rickettsial macules in tick typhus) or viruses (measles or chickenpox for instance), or by toxin-mediated damage from an infection elsewhere in the body (such as staphylococcal scalded skin syndrome or streptococcal scarlet fever). Table 2 gives examples of skin manifestations of systemic disease.

Table 1.

Types of infection affecting skin and soft tissue structures

Anatomical structure Infection Microbial cause 
Epithelium varicella varicella zoster virus 
 measles measles virus 
Keratin layer ringworm dermatophyte fungi (Microsporum, Epidermophyton, Trichophyton
Epidermis impetigo Streptococcus pyogenes 
  S. aureus 
Dermis erisipelas S. pyogenes 
Hair follicles folliculitis, boils, carbuncles S. aureus 
Sebum glands acne Propionibacterium acnes 
Subcutaneous fat cellulitis β-haemolytic streptococci 
Fascia necrotizing fasciitis S. pyogenes or mixed anaerobic infection 
Muscle myositis toxigenic strains of S. aureus 
 gangrene C. perfringens 
Anatomical structure Infection Microbial cause 
Epithelium varicella varicella zoster virus 
 measles measles virus 
Keratin layer ringworm dermatophyte fungi (Microsporum, Epidermophyton, Trichophyton
Epidermis impetigo Streptococcus pyogenes 
  S. aureus 
Dermis erisipelas S. pyogenes 
Hair follicles folliculitis, boils, carbuncles S. aureus 
Sebum glands acne Propionibacterium acnes 
Subcutaneous fat cellulitis β-haemolytic streptococci 
Fascia necrotizing fasciitis S. pyogenes or mixed anaerobic infection 
Muscle myositis toxigenic strains of S. aureus 
 gangrene C. perfringens 
Table 2.

Examples of systemic infections causing skin manifestations

Pathogen Disease Skin manifestation 
Varicella zoster virus chickenpox vesicles 
S. aureus toxic shock syndrome rash and desquamation 
 scalded skin syndrome  
Streptococcus pyogenes scarlet fever erythematous rash 
Neisseria meningitidis meningococcal sepsis non-blanching petechiae or haemorrhagic rash 
Salmonella typhi enteric fever, typhoid rose spots 
P. aeruginosa septicaemia ecthyma gangrenosum 
Rickettsia conorii African tick typhus macular rash 
Cryptococcus neoformans cryptococcosis papule on face or trunk 
Pathogen Disease Skin manifestation 
Varicella zoster virus chickenpox vesicles 
S. aureus toxic shock syndrome rash and desquamation 
 scalded skin syndrome  
Streptococcus pyogenes scarlet fever erythematous rash 
Neisseria meningitidis meningococcal sepsis non-blanching petechiae or haemorrhagic rash 
Salmonella typhi enteric fever, typhoid rose spots 
P. aeruginosa septicaemia ecthyma gangrenosum 
Rickettsia conorii African tick typhus macular rash 
Cryptococcus neoformans cryptococcosis papule on face or trunk 

SSTIs are best classified according to the anatomical site of infection (Table 1). Alternatively, they may be classified according to their microbial aetiology or by severity.5 The practice guidelines of the Infectious Diseases Society of America (IDSA) for the diagnosis and management of skin and soft tissue infections6 classifies SSTIs into five categories, comprising superficial, uncomplicated infection (includes impetigo, erysipelas and cellulitis), necrotizing infection, infections associated with bites and animal contact, surgical site infections and infections in the immunocompromised host. By contrast, Eron et al.7 classify these infections according to the severity of local and systemic signs, thereby developing a system that guides the clinical management and treatment decisions for patients with SSTIs. They divide patients with SSTIs into four classes based on the criteria shown in Table 3.

Table 3.

Classification of SSTI according to the severity of local and systemic signs, and associated management7

Category Clinical features Management 
Class 1 SSTI but no signs or symptoms of systemic toxicity or co-morbidities drainage (if required) and oral antibiotics as outpatient 
Class 2 either systemically unwell or systemically well but with co-morbidity (e.g. diabetes) that may complicate or delay resolution oral or outpatient intravenous antibiotic therapy; may require short period of observation in hospital 
Class 3 toxic and unwell (fever, tachycardia, tachypnoea and/or hypotension) likely to require inpatient treatment with parenteral antibiotics 
Class 4 sepsis syndrome and life-threatening infection (e.g. necrotizing fasciitis) likely to require admission to ICU, urgent surgical assessment and treatment with parenteral antibiotics 
Category Clinical features Management 
Class 1 SSTI but no signs or symptoms of systemic toxicity or co-morbidities drainage (if required) and oral antibiotics as outpatient 
Class 2 either systemically unwell or systemically well but with co-morbidity (e.g. diabetes) that may complicate or delay resolution oral or outpatient intravenous antibiotic therapy; may require short period of observation in hospital 
Class 3 toxic and unwell (fever, tachycardia, tachypnoea and/or hypotension) likely to require inpatient treatment with parenteral antibiotics 
Class 4 sepsis syndrome and life-threatening infection (e.g. necrotizing fasciitis) likely to require admission to ICU, urgent surgical assessment and treatment with parenteral antibiotics 

ICU, intensive care unit.

Definitions

Complicated SSTIs (cSSTIs), which are the focus of this review, are a somewhat false distinction as they represent the more severe end of the spectrum of all SSTI, including everything apart from the superficial, uncomplicated infection in the IDSA guidelines,6 or Class 2 onwards in the Eron classification.7 cSSTIs therefore represent a heterogeneous package of disorders: from otherwise healthy people with severe infection to patients with major co-morbidities and relatively minor infection; patients with extensive cellulitis and systemic symptoms who can be managed with antibiotics alone to patients with necrotizing limb-threatening infection that requires life-saving surgery; diabetic foot infections to cutaneous anthrax in an intravenous drug user. It is a very mixed clinical group with even greater variation in the aetiology.

In the USA, the Food and Drug Administration (FDA) issues guidance to the pharmaceutical industry with regard to developing the protocols for trials in this clinical area,8 and it is largely through clinical trials that the concept of cSSTI has evolved. Licensing of most new antibiotics follows the successful demonstration in clinical trials of their efficacy for treatment of cSSTIs. The FDA guidance regards infections that can be treated by surgical incision alone, such as cases of isolated (meaning one solitary area of infection) furunculosis or folliculitis, as uncomplicated infections that should not be included in clinical trials. In contrast, the complicated category includes infections either involving deeper soft tissue or those requiring significant surgical intervention, such as infected ulcers, burns and major abscesses or a significant underlying disease state that complicates the response to treatment. Superficial infections or abscesses in an anatomical site such as the rectal area, where the risk of anaerobic or Gram-negative pathogen involvement is higher, should be considered complicated infections.

SSTIs accompanied by signs and symptoms of systemic toxicity such as fever, hypothermia, tachycardia (>100 beats/min) and hypotension (systolic blood pressure <90 or 20 mmHg below baseline) can be classified as complicated.6,7 In addition, infection in patients likely to require admission to hospital to stabilize their clinical condition and prevent progression of the disease can likewise be classified as cSSTIs. Initial investigations should include blood cultures, full blood count and measurement of C-reactive protein, creatinine, bicarbonate and creatine phosphokinase levels. Soft tissue cultures should be done where possible. If there is evidence of rapid spread of infection an early surgical review is essential to assess the requirement for debridement and drainage.6,7 Sepsis accompanying SSTI requires prompt diagnosis and treatment.9

Aetiology and epidemiology

Common pathogens

The vast majority of SSTIs are caused by S. aureus10 and β-haemolytic streptococci, usually Lancefield groups A, C and G, with group B occurring in diabetics and the elderly.5,6 Clinically, the microbial aetiology can often be predicted with some accuracy in uncomplicated SSTI. Localized pus-producing lesions such as boils, abscesses, carbuncles and localized wound sepsis are usually staphylococcal, while rapidly spreading infections such as erysipelas, lymphangitis or cellulitis are usually caused by β-haemolytic streptococci.

Bacteria associated with SSTIs in hospitalized patients have been recorded over some years in the SENTRY Antimicrobial Surveillance Program database (Figure 1).11 The predominant pathogens included S. aureus (ranked first in all geographical regions), Pseudomonas aeruginosa, Escherichia coli and Enterococcus spp. The broad range of bacterial species reflects the fact that this group of patients is hospitalized and that it is a laboratory-based survey without direct clinical assessment of the relevance of the isolate to the clinical condition. As a result some of the isolates reported may not necessarily have been the causative pathogens. Gram-negative and anaerobic bacteria are more common in association with surgical site infections of the abdominal wall or infections of the soft tissue in the anal and perineal region. Polymicrobial infections involving both Gram-positive and Gram-negative organisms occur particularly where tissue vascular perfusion is compromised, such as diabetic foot infection or infection of ischaemic or venous ulcers. Chronic infections, especially in patients previously treated with antibiotics, are likely to be polymicrobial with Gram-negative and obligate anaerobic pathogens found alongside Gram-positive organisms. Such infections with Gram-positive and Gram-negative microbes clearly require broad-spectrum antibiotic treatment.

Figure 1.

Frequency of pathogens isolated from SSTIs among hospitalized patients in the SENTRY Antimicrobial Surveillance Programs.11 Adapted from Dryden MS. Int J Antimicrob Agents 2009; 34 Suppl 1: S2–7.2

Figure 1.

Frequency of pathogens isolated from SSTIs among hospitalized patients in the SENTRY Antimicrobial Surveillance Programs.11 Adapted from Dryden MS. Int J Antimicrob Agents 2009; 34 Suppl 1: S2–7.2

Antibiotics and surgical drainage are the basis of treatment for staphylococcal infections, but the emergence of strains with resistance to multiple agents has complicated the choice of empirical therapy. It is therefore important that a local knowledge of the epidemiology and susceptibility of pathogens guides the development of antibiotic guidelines for empirical treatment. Methicillin resistance was first detected in S. aureus in 1961,12 shortly after the agent was introduced clinically, and over the last four decades there has been a global epidemic of MRSA.13,14 Considerable variation in the resistance rates of S. aureus to methicillin (or oxacillin) has been noted between countries and continents, with the highest rates in North America (35.9%), followed by Latin America (29.4%) and Europe (22.8%).11 Although these figures probably reflect hospital-acquired infection there has undoubtedly been an increase in true community-acquired MRSA (CA-MRSA) infection in parts of North America15,16 and this trend may now be shifting to Europe.17 In parts of North America this increase in CA-MRSA represents a major change in the epidemiology of staphylococcal infections.15,18 In Texas, the majority of patients hospitalized with community-associated S. aureus infections had MRSA, most of which involved an SSTI. In a Californian clinic 83% of 837 positive cultures from SSTIs were S. aureus and of these 76% were MRSA.19 In a study of 422 patients with SSTIs presenting at emergency rooms across the USA, 59% (range 20%–74%) of the cases were due to CA-MRSA.20

Having recurrent infections, being a child, a member of the armed forces, an athlete or an injecting drug user are recognized risk factors for infection with CA-MRSA in the USA;21 similar risk factors are apparent in Europe as well.22–26 CA-MRSA infection occurs in younger patients and has a significant association with SSTI,22 while hospital attendance, surgery, dialysis, diabetes, indwelling devices and residence in a long-term care facility were risks associated with hospital-acquired (HA)-MRSA.16,21 However, no clinical profile could reliably exclude MRSA.23 In the Netherlands, people in contact with pigs have a higher risk of MRSA carriage than the general population,24 but by and large, with the exception of a few small outbreaks,20–26 CA-MRSA remains focal and contained within Europe in 2010. Should this change, which is likely, European infection doctors believe that empirical therapy for community SSTI would have to be changed.4

Although a number of criteria have been proposed to predict the likelihood of infection with CA-MRSA,16,17 epidemiological and clinical criteria are rarely sufficient to distinguish accurately between MRSA and methicillin-susceptible S. aureus (MSSA) infection at initial presentation.27 The boundaries between HA-MRSA and CA-MRSA are becoming blurred due to the movement of patients and infections between hospitals and the community.28 Nosocomial outbreaks of CA-MRSA following the admission of colonized or infected patients have occurred.29 In the USA, it is becoming increasingly difficult to distinguish between CA-MRSA and HA-MRSA on clinical and epidemiological grounds.21,27 Since HA-MRSA and CA-MRSA strains are often genotypically and phenotypically different, the microbiological characteristics of the isolates may help to distinguish between the two types of infection.16,23,29 For example, CA-MRSA may be susceptible to a wider range of antibiotics (Table 4).23

Table 4.

Examples of characteristics of CA-MRSA and HA-MRSA from US strains23

Characteristic CA-MRSA HA-MRSA 
Susceptibility to CHL usually S often R 
Susceptibility to CLI usually S usually R 
Susceptibility to ERY usually R usually R 
Susceptibility to FLQ usually S usually R 
Susceptibility to SXT usually S usually S 
SCCmec type IV II 
Lineage USA 300, USA 400 USA 100, USA 200 
Toxin production more fewer 
PVL production common rare 
Healthcare exposure less common more common 
Characteristic CA-MRSA HA-MRSA 
Susceptibility to CHL usually S often R 
Susceptibility to CLI usually S usually R 
Susceptibility to ERY usually R usually R 
Susceptibility to FLQ usually S usually R 
Susceptibility to SXT usually S usually S 
SCCmec type IV II 
Lineage USA 300, USA 400 USA 100, USA 200 
Toxin production more fewer 
PVL production common rare 
Healthcare exposure less common more common 

S, susceptible; R, resistant; CHL, chloramphenicol; CLI, clindamycin; ERY, erythromycin; FLQ, fluoroquinolones; SXT, cotrimoxazole.

Antibiotic resistance is not limited to methicillin (Table 4). However, staphylococcal resistance to glycopeptides remains rare,30 although rising MICs of glycopeptides may affect the efficacy of these agents.31 Resistance in strains of MRSA to the more recently licensed anti-MRSA antibiotics linezolid, daptomycin and tigecycline also remains remarkably uncommon. The evolution of strains causing SSTI and serious infection is rarely static and strains of apparently susceptible (at least phenotypically susceptible) but mecA gene-positive S. aureus have emerged to challenge diagnostic laboratories and clinicians.32 Selection pressure and microbial evolution are rarely predictable!

Unusual pathogens

With most community-acquired SSTIs being caused by staphylococci and streptococci it is easy to ignore more unusual causes. Clinical history and risk factors are important when considering such cases (Table 5). Of particular importance is the presence of underlying disease, previous hospital admissions, animal contact and bite history, injecting drug use and travel. For example, a history of travel with water contact may hint at a diagnosis of an infection with a Vibrio spp.33 (which will not be adequately treated by empirical antibiotics active against staphylococci and streptococci), while tick bites could suggest rickettsial or borrelia infection. A drug user with an abscess at an injection site is most likely to have a staphylococcal infection, but unusual bacteria such as Clostridium botulinum or Bacillus anthracis may also be involved.34 Organisms other than staphylococci or β-haemolytic streptococci may be the cause of SSTIs in patients who have had contact with a dog35 or have recently returned from adventurous travel in the tropics.36 It is also important to remember that bacteria are not the only microbes implicated in SSTIs and, in certain circumstances, it is important to consider viral, fungal, protozoal and arthropod causes (Table 5).

Table 5.

Risk factors for SSTIs caused by specific pathogens

Risk factor Characteristic pathogens 
Recurrent hospital admissions MRSA 
Contact sports, recurrent boils/abscesses, visit to certain States in the USA MRSA or MSSA producing PVL 
Diabetes S. aureus (MRSA and MSSA), Group β-haemolytic streptococci, anaerobes, Gram-negative bacilli 
Neutropenia Gram-negative bacilli, P. aeruginosa 
Bite wounds  
 human human oral flora 
 cat Pasteurella multocida 
 dog Capnocytophaga canimorsus 
 rat Streptobacillus moniliformis (also consider tetanus and rabies) 
Animal contact Campylobacter spp. 
 dermatophyte infection 
 Bartonella henselae 
 Francisella tularensis 
 Bacillus anthracis 
 Yersinia pestis 
Water exposure (sea, estuarine, rivers) Vibrio spp. 
Aeromonas hydrophila 
 Mycobacterium marinum 
 P. aeruginosa 
Reptile contact Salmonella spp. 
Injecting drug use MRSA 
 Clostridium botulinum 
 Clostridium tetani 
Travel leishmaniasis 
 cutaneous larva migrans 
 myiasis 
 tropical Africa Cordylobia anthropophaga 
 tropical America Dermatobia hominis 
Risk factor Characteristic pathogens 
Recurrent hospital admissions MRSA 
Contact sports, recurrent boils/abscesses, visit to certain States in the USA MRSA or MSSA producing PVL 
Diabetes S. aureus (MRSA and MSSA), Group β-haemolytic streptococci, anaerobes, Gram-negative bacilli 
Neutropenia Gram-negative bacilli, P. aeruginosa 
Bite wounds  
 human human oral flora 
 cat Pasteurella multocida 
 dog Capnocytophaga canimorsus 
 rat Streptobacillus moniliformis (also consider tetanus and rabies) 
Animal contact Campylobacter spp. 
 dermatophyte infection 
 Bartonella henselae 
 Francisella tularensis 
 Bacillus anthracis 
 Yersinia pestis 
Water exposure (sea, estuarine, rivers) Vibrio spp. 
Aeromonas hydrophila 
 Mycobacterium marinum 
 P. aeruginosa 
Reptile contact Salmonella spp. 
Injecting drug use MRSA 
 Clostridium botulinum 
 Clostridium tetani 
Travel leishmaniasis 
 cutaneous larva migrans 
 myiasis 
 tropical Africa Cordylobia anthropophaga 
 tropical America Dermatobia hominis 

Although there is considerable debate over the value of microbiological culture in the management of SSTIs, there can be no doubt that the rise in multiply resistant bacteria and the possibility of unusual causes of SSTI increase the importance of diagnostic microbiology and antibiotic susceptibility testing for epidemiological purposes and the surveillance of antimicrobial resistance.37 Furthermore, microbiological analysis can help to promote appropriate antibiotic prescribing,38 and laboratory analysis accompanied by good clinical microbiology support should increasingly be used to promote good antibiotic stewardship.39 For microbiological diagnosis, pus or tissue samples have the greatest sensitivity6 and swabs of open, infected wounds can provide valuable diagnostic information if collected before the commencement of antibiotics. Whereas aspiration of the leading edge of cellulitis with a needle is often advocated in North America, this practice is rarely carried out in the UK and is generally deemed too invasive in enclosed cellulitis. Blood cultures should be collected where there are signs of systemic sepsis, such as a raised temperature, tachycardia, hypotension or confusion.

Necrotizing infection

This medico-surgical emergency is a life-threatening, invasive, soft tissue infection caused by aggressive, usually gas-forming bacteria, which primarily involves the superficial fascia and extends rapidly along subcutaneous tissue planes with relative sparing of skin and underlying muscle. Clinical presentation includes fever, signs of systemic toxicity and pain out of proportion to the clinical findings.40 Paucity of cutaneous findings early in the course of the disease can make diagnosis challenging and confirmation of the diagnosis is often made after surgical debridement. Delay in diagnosis and/or treatment correlates with a poor outcome, leading to sepsis and/or multiple organ failure.6,7 Plain radiographs, CT or magnetic resonance imaging may help to diagnose necrotizing fasciitis. Prompt surgical debridement, intravenous antibiotics, fluid and electrolyte management, and analgesia are the mainstays of therapy. Adjuvant treatments such as hyperbaric oxygen therapy and intravenous immunoglobulins are sometimes advocated.6

Infections caused by toxin-producing bacteria

Strains of S. aureus and β-haemolytic streptococci can produce a variety of toxins that may both potentiate their virulence and affect the soft tissues.41,42 Panton–Valentine leucocidin (PVL) appears to be a marker for severity and recurrence.20,43,44 Epidermal loss may occur in staphylococcal infections in which there is production of exfoliatin (scalded skin syndrome toxin) or toxic shock syndrome toxin (TSST). In one recent study,45 100 S. aureus isolates from diverse cases of SSTI were characterized. Virulence factors, including PVL, were detected and the isolates were assigned to clonal groups. Thirty isolates were positive for the gene encoding PVL. Only three PVL-positive MRSA isolates were found, two of which belonged to European clone ST80-MRSA IV and one to USA 300 strain ST8-MRSA IV. The remaining methicillin-susceptible PVL-positive isolates belonged to a variety of different multilocus sequence types. In a large, prospective study of patients with MRSA infection in North America, strains from community-acquired infections, which were most likely to be of the skin and soft tissues, were particularly likely to express exotoxins, especially PVL.46 Other studies have reported a high incidence of PVL production among strains of CA-MRSA.20,43,44

The use of antimicrobials effective against MRSA that also decrease exotoxin production, such as clindamycin and linezolid, is theoretically desirable. Clindamycin decreases the production of TSST-1 by 95% in stationary phase cultures41 and stops the normal peak of α-toxin production during the late exponential phase of growth.46 Clindamycin and linezolid both markedly suppress PVL production as staphylococci approach the stationary phase, to the extent that there may be no PVL detectable 12 h after exposure to the antibiotic.46 Flucloxacillin is bactericidal, but the low, subinhibitory concentrations achievable in vivo in necrotic tissue may further augment PVL toxin and α-haemolysin production.46 Subinhibitory concentrations of clindamycin, linezolid and fusidic acid all induce a concentration-dependent decrease in PVL concentration, whereas low concentrations of oxacillin increase the concentration of PVL up to threefold.47 The severity of streptococcal infections may also be influenced by the expression of superantigens and virulence factor enzymes.48

Infections associated with bites

This review will focus on a brief discussion of aggressive mammals, including humans, and the infections their bites cause. However, there are a good many non-vertebrates and indeed other vertebrates willing to cause trauma and transmit infection. It might be imagined that the least of a victim's problems after a shark attack would be infection but this is not necessarily the case.49 Snake bites can be more than venomous with Aeromonas spp. causing infection50 and damage of a limb by a crocodilian can also lead to infection.51

Human bites can result in serious soft tissue infection. Isolates implicated in human bite infections include Streptococcus anginosus (52%), S. aureus (30%), Eikenella corrodens (30%), Fusobacterium nucleatum (32%) and Prevotella melaninogenica (22%). Candida spp. are found in 8% of SSTIs. Fusobacterium spp., Peptostreptococcus spp. and Candida spp. are isolated more frequently from occlusional bites than from clenched-fist injuries.52 Infections related to dog bites are often polymicrobial, predominantly involving Pasteurella and Bacteroides spp.53 Infected bites presenting <12 h after injury are particularly likely to be infected with Pasteurella spp., whereas those presenting >24 h after the event are likely to be infected predominantly with staphylococci or anaerobes. It is important to seek a history of animal contact when Pasteurella is isolated.35 The unusually named Capnocytophaga canimorsus (dysgonic fermenter type 2 or DF2) causes septicaemia that is often mistaken for fulminant meningococcal disease. Infection usually follows a trivial bite in patients with asplenia or cirrhosis. Typically, Gram-negative bacilli are seen within polymorphs on peripheral blood films. Capnocytophaga is susceptible to penicillin and ciprofloxacin/moxifloxacin.52,53 Clinical infection may result from incorrect management at the time of primary care and erythromycin or flucloxacillin must never be used alone in the prophylaxis of bite wounds. In one small study, 70% of patients with Pasteurella multocida infections had received inadequate or incorrect antibiotics, usually flucloxacillin or erythromycin.54

Other considerations in animal bites and contact are rabies, tetanus and infections with unusual organisms of high pathogenicity, such as Francisella tularensis or Bacillus anthracis.6

Travel

A history of travel is important in the assessment of SSTIs. Although the common causes of SSTI—streptococci and staphylococci—are also common in travellers, unusual microbial causes of infection may present in this group.36 Such infections may be unresponsive to conventional empirical treatment,33 as in the case of Vibrio spp. infection in those exposed to sea and estuarine waters (Table 5). Travel history should be sought and diagnostic microbiology performed. Unusual or non-bacterial infections may present a diagnostic challenge in travellers. Rashes in travellers may be associated with a range of infections, such as primary Lyme disease (erythema chronicum migrans) caused by Borrelia burgdorferi; serpiginous tracks caused by hookworm larvae (cutaneous larva migrans); and rickettsial infection, of which the most common presenting in UK travellers is African tick typhus (Rickettsia conorii) causing a widespread maculopapular rash associated with systemic symptoms. Persistent ulcers may be caused by atypical mycobacteria or protozoa such as Leishmania spp. Enlarging, fluctuant and largely painless abscesses may be caused by arthropod maggot infestation, such as Cordylobia anthropophaga from tropical Africa or Dermatobia hominis from tropical America. All of these infections or infestations may require specialist medical referral to make the diagnosis and initiate appropriate treatment.

Soft tissue infection in immunocompromised hosts

SSTIs in immunocompromised hosts can be challenging as they can be caused by unusual and diverse organisms.55 Such infections may progress rapidly to become life threatening and are difficult to eradicate with antibiotics alone in the absence of an intact immune system. Surgical review and follow-up are often advisable. Establishing a diagnosis and performing susceptibility testing is crucial,6 because many infections are hospital acquired and increasing resistance among both Gram-positive and Gram-negative bacteria makes empirical treatment regimens difficult, if not dangerous. In addition, fungal infections such as cryptococcosis or histoplasmosis may present with cutaneous findings.

Treatment

The management of cSSTIs normally involves a combination of surgical debridement or drainage and empirical antibiotic therapy. The antibiotic management of cSSTIs is well reviewed in the published guidelines.5–7,17 The main choice of antibiotic depends on the clinical presentation. In probable Gram-positive infection where MRSA is not suspected, penicillins, antistaphylococcal penicillins, cephalosporins, clindamycin or co-trimoxazole are indicated.6 Where infection is likely to be polymicrobial such as surgical site infections of the abdominal wall, or in proximity to the genital tract or rectum, diabetic foot infections and bites, antibiotic treatment must cover the broad range of pathogens seen in these cSSTIs. Such treatment may include β-lactam/β-lactamase inhibitor combinations, fluoroquinolones with enhanced Gram-positive activity such as moxifloxacin, co-trimoxazole or tigecycline.2,6 Diabetic foot infections in particular require proper wound care and early surgical intervention as well as aggressive appropriate antibiotic therapy.

The mainstay of treatment for serious MRSA infections has until recently been the glycopeptides vancomycin and teicoplanin. However, concern about the gradual development of resistance and concerns about efficacy30,31 have turned attention to the development of new agents active against Gram-positive bacteria. Those that have been licensed for treating cSSTI are linezolid, daptomycin and tigecycline. The range of oral antibiotics used to treat MRSA infections is very wide across Europe,4 and the choice seems to depend on local susceptibility and personal experience, because there are no comparative trials to support the use of specific older agents. The only new oral agent is linezolid. There is, however, evidence to show that agents such as co-trimoxazole and tetracycline, which are cheap and reasonably well tolerated, have good efficacy against MRSA56 and the rate of therapeutic failure is low.57 Clindamycin may also be clinically effective58 but the rates of resistance may be high and inducible resistance needs to be excluded with the ‘D’ test.

Newer antibiotics are finding a place in the treatment of cSSTI caused by more resistant strains and indeed many of the randomized clinical trials in cSSTI have been industry sponsored. All these trials have been designed specifically for licensing purposes and therefore have only been powered to show non-inferiority. Linezolid has been available for 10 years now and is well established as an effective agent in cSSTI,59–63 with the added advantages of early intravenous-to-oral switch with the oral preparation having 100% bioavailability and excellent tissue penetration.61,64,65 Linezolid use is also associated with significant reduction in the requirement for intravenous treatment and with the length of hospital stay.63 That study also showed a numerical but not statistically significant superiority of linezolid over vancomycin in the per-protocol group and a significant superiority at the end of study in the modified intention-to-treat group, and this is despite the study being powered for non-inferiority. These efficacy data are supported by a meta-analysis suggesting that linezolid may indeed be superior to the glycopeptides.66

Tigecycline is as effective as vancomycin67,68 and has a broader range of activity, covering infections caused not only by resistant Gram-positive bacteria but also by many multiply resistant Gram-negative organisms including those producing extended spectrum β-lactamases. It is recommended for polymicrobial infection that may include MRSA and for necrotizing fasciitis.69 It is only available as an intravenous formulation.

Daptomycin has rapid concentration-dependent bactericidal activity against Gram-positive pathogens.70 Its tissue penetration supports its use in the treatment of cSSTI and daptomycin has been shown to be non-inferior to vancomycin and semi-synthetic penicillins. The registration studies included 1092 patients between the ages of 18 and 85 years with a cSSTI that was due, at least in part, to Gram-positive organisms and required hospitalization and parenteral antimicrobial therapy for at least 96 h.71

Moxifloxacin is probably the most effective fluoroquinolone with extended Gram-positive activity on the basis of in vitro activity.72 The IDSA guidelines recommend fluoroquinolones for the treatment of infections that are likely to be polymicrobial,6 including surgical wound infections involving the abdominal wall, perineum and genital tract. Both animal and human bite infections with their specific and unusual pathogens can also be effectively treated with moxifloxacin. The characteristics of fluoroquinolones in general may explain their demonstrated efficacy in the treatment of cSSTIs. These include a broad spectrum of activity, rapid bactericidal action and adequate tissue concentrations at skin and deep tissue sites. Specifically, moxifloxacin has broad-spectrum activity in vitro against all common pathogens implicated in both uncomplicated and complicated SSTIs.73 Indeed, cSSTI was the first non-respiratory indication for moxifloxacin and the first step towards moving it from the category of a respiratory fluoroquinolone and placing it as a broad-spectrum antibiotic for a range of organisms and conditions. Moxifloxacin has excellent pharmacokinetics and tissue penetration, can be delivered via both intravenous and oral routes allowing a seamless switch and is particularly suitable as monotherapy for infections that are likely to be polymicrobial. The RELIEF study74,75 demonstrated its efficacy in comparison with intravenous piperacillin/tazobactam and oral co-amoxiclav in a wide range of cSSTIs including deep-seated abscess, diabetic foot infection,75,76 infected ischaemic ulcers and surgical site infections. Moxifloxacin has good activity against Gram-positive organisms such as S. aureus and streptococci with the MIC90 values for MSSA ranging from 0.25 to 1.0 mg/L.77,78 However, while some strains of CA-MRSA are susceptible to fluoroquinolones, many strains are resistant. Moxifloxacin may, therefore, be a treatment option for infection caused by susceptible strains of MRSA, which may be more common in community-acquired infections.23,79 Given the unpredictability of fluoroquinolone activity against MRSA, the use of fluoroquinolones should be reserved for definitive treatment once antibiotic susceptibilities are known. The RELIEF study demonstrated efficacy of moxifloxacin in cSSTI caused by strains of MRSA even though the MIC90 was 2 mg/L.74,75 Moxifloxacin is also active against Enterobacteriaceae and anaerobes (e.g. Peptostreptococcus spp., Clostridium perfringens, Clostridium spp. and Bacteroides fragilis), but has relatively poor activity against Pseudomonas spp. Moxifloxacin also has good in vitro activity against other pathogens isolated from patients with either animal or human bite infections (e.g. P. multocida, coagulase-negative Staphylococcus spp., Prevotella spp., Fusobacterium spp. and E. corrodens), and the causes of more exotic cSSTIs, such as B. anthracis, Yersinia pestis, Vibrio spp. and F. tularensis.6,39

Other promising agents for cSSTI, such as dalbavancin with its exceptionally long half-life, ceftobiprole with broad-spectrum activity including MRSA, and iclaprim (a trimethoprim derivative), have all met with major obstacles in the licensing process. They may be important therapeutic options if these barriers can be overcome.

Conclusions

cSSTIs represent a very varied group of clinical conditions. Of primary clinical and epidemiological interest are those infections caused by S. aureus whose predominant causative strains appear to be becoming more resistant and more pathogenic. This convergence of antimicrobial resistance and enhanced virulence requires vigilant epidemiology and creativity in the development of therapeutic options.

Transparency declarations

This article is part of a Supplement sponsored by the BSAC.

M. D. has received speaker honoraria from Pfizer, Wyeth, Novartis and Bayer. He has participated in clinical trials as an investigator and as a data reviewer of a number of studies involving antibiotics mentioned in this review and on advisory boards for Pfizer, Wyeth, Janssen-Cilag, Novartis and Bayer.

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73
Giordano
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Pertel
P
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Sequential intravenous/PO moxifloxacin versus intravenous pipericillin-tazobactam followed by PO amoxicillin/clavulanate for the treatment of complicated skin and skin structure infection
Int J Antimicrob Agents
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26
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357
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74
Gyssens
IC
Dryden
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Efficacy of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin/clavulanic acid in the treatment of major abscess: results of the RELIEF study
European Congress of Clinical Microbiology and Infectious Diseases, Helsinki, 2009
  
Poster 1786. European Society for Clinical Microbiology and Infectious Diseases
75
Gyssens
IC
Dryden
M
Kujath
P
, et al.  . 
Efficacy of IV/PO moxifloxacin in the treatment of complicated skin and skin structure infections: results of the RELIEF study
European Congress of Clinical Microbiology and Infectious Diseases, Helsinki, 2009
  
Poster 1785. European Society for Clinical Microbiology and Infectious Diseases
76
Schaper
N
Dryden
M
Kujath
P
, et al.  . 
Efficacy of IV/PO moxifloxacin and IV piperacillin/tazobactam followed by PO amoxicillin-clavulanate in the treatment of diabetic foot infections: results of the RELIEF study
European Congress of Clinical Microbiology and Infectious Diseases, Vienna 2010
  
Poster 1550. European Society for Clinical Microbiology and Infectious Diseases
77
Edmiston
CE
Krepel
CJ
Seabrook
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, et al.  . 
In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intra-abdominal and diabetic foot infections
Antimicrob Agents Chemother
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2004
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48
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1012
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6
)
78
Jacobs
E
Dalhoff
A
Korfmann
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Susceptibility pattern of bacterial isolates from hospitalised patients with respiratory tract infections (RTI), (moxikativ study)
Int J Antimicrob Agents
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2009
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33
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52
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7
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79
Shopsin
B
Zhao
X
Kreiswirth
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Are the new quinolones appropriate treatment for community-acquired methicillin-resistant Staphylococcus aureus?
Int J Antimicrob Agents
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2004
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24
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32
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4
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