Impetigo is a highly contagious infection of the epidermis, seen especially among children, and transmitted through direct contact. Two bacteria are associated with impetigo: S. aureus and GAS. Over 140 million people are suffering from impetigo at each time point, over 100 million are children. Two forms of impetigo exist, namely impetigo contagiosa, known as the non-bullous form and the second one being bullous impetigo which presents with large and fragile bullae. Treatment options for impetigo include systemic antibiotics, topical antibiotics as well as topical disinfectants.
EDIN: Epidermal Cell Differentiation Inhibitor; ETA: Exfoliative Toxin A; ETB: Exfoliative Toxin B; GAS: Group A Streptococcus (Streptococcus pyogenes); MRSA: Methicillin Resistant Staphylococcus aureus; MSSA: Methicillin Sensitive Staphylococcus aureus; MSCRAMM: Microbial Surface Component Recognizing Adhesive Matrix Molecules; OR: Odds Ratio; PMN: Polymorphonuclear Cells; PSGN: Poststreptococcal Glomerulonephritis; RBC: Red Blood Cell; SSSS: Staphylococcal Scalded Skin Syndrome
Impetigo is a common acute superficial bacterial skin infection (pyoderma) which is highly contagious. It is characterized by pustules and honey-colored crusted erosions ("school sores"). Impetigo involves the epidermis and is seen mostly in preschool children. It is caused by two microorganisms: S. aureus and GAS.
Other bacterial infections that involve deeper parts of the skin are erysipelas and cellulitis. Erysipelas involves the upper dermis and is most commonly caused by b-hemolytic streptococci. Cellulitis involves the deeper dermis and subcutaneous fat and is most commonly implicated by S. aureus and GAS. It can be divided into nonpurulent and purulent cellulitis, and treatment is based on extent of infection and risk factors. Abscesses involve the dermis and deeper skin tissues as a result of pus formation.
Impetigo is observed most frequently among children 2-5 years of age and is transmitted through direct contact . Risk factors for impetigo include poor hygiene, low economic status, crowding and underlying scabies [2,3]. Important consideration is carriage of GAS and S. aureus which predisposes to subsequent impetigo . Over 140 million people are suffering from impetigo at each time point, over 100 million are children [5,6]. In the past impetigo was caused by either S. aureus or group A β-hemolytic streptococci. Currently, however, the most frequently isolated pathogen in cases of impetigo is S. aureus .
The first type of impetigo is impetigo contagiosa, known as non-bullous impetigo and this it is one of the most common skin infection in children .
Differential diagnoses for this type are atopic dermatitis, candidiasis, contact dermatitis and other .
The second type of impetigo, bullous impetigo, is caused exclusively by S. aureus. Differential diagnosis for this type is bullous erythema multiforme, bullous lupus erythematosus, bullous pemphigoid etc [9-11].
Treatment options for impetigo can be divided into topical and systemic. Among topical, mupirocin and fusidic acid are most commonly used. Systemic antibiotic is usually reserved for more severe cases, in which topical therapy is impractical, such as cases of bullous impetigo or widespread lesions .
The aim of this review is to present the current microbiological knowledge of the two organisms mentioned with the relevant virulence factors that enable to initiate skin diseases and how they contribute to the clinical presentation, as well as to show the clinical presentation itself. Lastly, this review will discuss the various treatment options and emerging resistance.
In the United Kingdom, the annual incidence of impetigo was 2.8 percent in 2003 among children up to the age of four and 1.6 percent among children aged five to fifteen years .
Another cross sectional study which took place (n = 265, relative prevalence 5.3%, among 50,237 outpatients) showed a pattern of male predominance in childhood, adulthood and overall (OR 2.0) .
Impetigo is a highly contagious infection, direct contact being the main mode of transmission. Patients with impetigo can easily inoculate themselves and spread the infection to people in close contact after excoriating an infected area. This fact may lead to a rapid dissemination of infection, mostly in grade schools, kindergartens, nurseries and day care centers. It is known today that children usually become infected through contact with other children; however, fomites are another important source of infection. Adults may develop impetigo from contact with children or by fomites as seen when sharing grooming devices, in barber shops, in beauty parlors etc .
The incidence of impetigo is greatest during the summer time due to the close contact among children .
Interestingly, in tropical regions GAS causes impetigo, while in temperate areas it leads to pharyngitis .
GAS, a gram positive bacterium, whose reservoirs are the human mucosal membranes and skin surface, causes an array of infections involving the respiratory tract and soft tissues, ranging in severity from mild to severe. Moreover, it initiates two nonsuppurative sequels: Acute rheumatic fever and PSGN .
The capsule, made from hyaluronic acid, functions as an accessory virulence factor. It prevents phagocytosis by PMN and macrophages of the host. A great variation exists with regard to the level of encapsulation.
The capsule possessed by GAS is similar chemically to the one found in the connective tissue of humans. Hence, it is a poor immunogen, and no antibodies production has been demonstrated in humans against this structure [24,25].
The major somatic virulence factor of GAS is protein M. This protein is known to confer resistance to phagocytosis by PMNs. It also gives GAS the ability to multiply quickly in fresh human blood and to initiate diseases .
Recent reports have demonstrated that pili are involved in the formation of biofilms and in the adherence of GAS to human tonsils, keratinocytes, lung and throat epithelial cells, which distinguishes it as a major adhesin of the organism .
GAS possesses numerous extracellular products during its growth both in vivo and in vitro (such as hemolysin), however, only a limited number have been well characterized. Two types of hemolysin have been described in the literature. The first hemolysin is streptolysin O. This molecule can be inhibited in a reversible manner by oxygen and irreversibly by cholesterol. Apart from being toxic to RBC, it is toxic to other cells and some cell fractions, such as PMNs and platelets. The production of streptolysin O occurs in almost all strains of GAS, as well as in many organisms classified in groups C and G and it is antigenic in origin. The measurement of antibodies targeted to streptolysin O in the human sera can indicate recent streptococcal infection. The second hemolysin to be described is streptolysin S, obtained by strains that grow in the presence of serum . Biopsies taken from pyodermal lesions often reveal GAS. To a much smaller extent, there is involvement of serogroups C and G. GAS associated with impetigo is different from those which are connected to pharyngitis and tonsillitis. Skin strains belong to different M serotypes than the classic throat strains. Various tests, seeking streptococcal antibodies play no part in the diagnosis of impetigo; however, they can support the evidence of recent streptococcal infection in patients with suspicious PSGN. The response of anti-streptolysin O to GAS in patients with impetigo is relatively weak, probably due to inhibition of streptolysin O by skin lipids, such as cholesterol [28-31].
Members belonging to staphylococcus genus are gram positive cocci, with a diameter ranging between 0.5 to 1.5 μm, and occur singly and in pairs, tetrads, short chains and irregular grapelike clusters. Staphylococci are not motile, are not spore-forming and are usually positive to catalase .
S. aureus is a highly successful opportunistic pathogen. It frequently colonizes the mucosal surfaces and the skin. It is found in 30% of the healthy human population within the anterior nares . S. aureus causes a wide variety of diseases. Apart from infections where it is physically present, S. aureus can cause "distant" diseases, through the secretion of various toxins. Those toxins may either be produced in a direct way by the bacteria on the surface which it colonizes or in an indirect manner through the colonization of food or beverages. The ability of the bacterium to cause many different diseases is related to its capacity to adapt and survive in a great variety of environments .
Skin infections, together with respiratory tract ones, are the most common infections caused by this pathogen. Infections of the respiratory tract are mostly nosocomial, whereas those of the skin are usually community acquired. Pneumonia caused by S. aureus usually develops in hospitalized patients with an underlying condition, such as immune deficiencies or infections caused by different viruses. This bacterium may also cause a variety of other, sometimes severe as well as life-threatening diseases; among them are infective endocarditis, osteomyelitis, SSSS and toxic shock syndrome .
Initiation of various skin infections is done through ETA and ETB which are active serine proteases produced by some strains of S. aureus. While ETA is encoded on a prophage, ETB is encoded on a large penicillinase-type plasmid. ETA and ETB lead to epidermal cleavage, through the effect on desmogelin-1 which is a desmosomal cadherin. This cleavage is directly responsible for the clinical manifestation of the blistering skin disease: Pemphigus neonatorum and/or generalized staphylococcal scalded skin syndrome (SSSS) in neonates, and bullous impetigo in young children and adults .
Although similar dermatologic effects exist, strains producing ETB are assumed to be more virulent. Reports have shown that the activity of ETB can be enhanced by EDIN, which facilitates the formation of disseminated foci and serves a risk factor for deep-seated staphylococcal tissue infections following bacteremia .
In order to make a diagnosis based on phenotypic characteristics, and to reveal new, yet unknown mechanisms which confer antibiotic resistance, it is crucial to obtain a culture. Colonies grown should be Gram stained and subcultured and further tested for their genus, species, as well as antibiotic susceptibility .
Out of the clinical isolates of S. aureus, over 90% have elaborated a capsule made of polysaccharides. The capsule was found to exist among 11 serotypes. 75% of clinical infections are attributed to capsule type 5 and type 8. These two are composed of different sugars, among them are fucose and mannose. Both these capsules have antiphagocytic properties and lead to an increase in virulence in several animal models. Animal models of sepsis have shown that antibodies against these capsular types are protective. Although the vaccine showed some promise in an initial Phase 3 trial in ESRD patients on hemodialysis, it was found to be ineffective in a second Phase 3 trial, leading to its development being halted .
Various surface adhesins are carried by S. aureus. These permit the adherence to different host matrix proteins. Those microbial surface components which react with the adherence matrix molecules are reassembled under the acronym MSCRAMM. Most of these molecules are bound to the peptidoglycan component of the cell wall. A conserved mechanism which permits the anchoring of the adhesive molecule exists in gram positive bacteria. This mechanism involves a membrane bound enzyme, called sortase, which has the ability to recognize a conserved amino acid motif (LPXTG) at the carboxyl terminal end of wall attached proteins. Sortase binds the threonine residues of LPXTG in a covalent way to a free acceptor in the peptidoglycan side chain, usually glycine in the case of S. aureus [38,39].
Among the MSCRAMM, clinical significance is attributed to clumping factor B, which assists in the colonization of the nasal epithelium, clumping factor A and fibronectin binding proteins A and B which play a role in the development of endocarditis as well as in ventricular assisted device-related infections. It is important to note that S. aureus harbors many MSCRAMMs at their surface. Hence, inactivation of only one molecule may not be noticed as its function can be complemented by others [40-42].
In a study conducted on 60 patients with impetigo, only one patient grew GAS, six grew S. aureus and GAS and the rest had S. aureus. It is important to note that problems may be encountered when interpreting the results of skin culture and wound, as they are not sterile, and the detection of a common colonizing organism, for example S. aureus, may point to a contamination. In another study, cultures containing GAS solely were found in two out of 71 patients with impetigo .
Impetigo is a highly contagious infection with direct contact being the main mode of transmission .
As previously mentioned, children are the main ones to present with impetigo. Further populations that commonly suffer from impetigo are the homeless and patients who received organ transplants. An investigation of renal transplant recipients has found that impetigo was prominent in the first year following the transplant, with a peak being in the third month, and it did not affect a considerable number of recipients after the first year following the transplantation .
The most common locations for the lesions are head and neck (65.4%), followed by upper extremity (19.6%) and trunk and lower extremities (7.5% each) .
Impetigo contagiosa typically presents with a single, two to four mm erythematous macule, which quickly becomes vesicular or pustular. Due to their delicacy, the vesicles can easily rupture, leaving an exudate with a characteristic "honey-colored" yellow crust over the superficial erosion. Several individual or coalesced macules and patches erupt due to the direct extension of the primary lesion which quickly follows. The macules and patches may be eroded or crusted .
When GAS is in high number, pustules with a thick wall and with an erythematous base are an early manifestation .
The nares and the perioral region are the surfaces that are subjected to environmental trauma and are involved most often. Very often, a linear distribution may be observed when the patient’s fingernails have scratched the skin. Most often the patients only show skin lesions; however, mild lymphadenopathy is a systemic symptom which is frequently encountered [47,48].
An important complication of impetigo contagiosa is acute PSGN, which affects up to 5% of the patients. Few strains of streptococcus are known to commonly affect the kidney, among them are serotypes 1, 4, 12, 25 and 49 .
Appropriate treatment with antimicrobials is generally believed to have no effect on the risk of PSGN  (Table 1).
Bullous impetigo, the second type of disease presentation, is caused exclusively by S. aureus [9-11]. It is characterized by fragile, large, flaccid bullae that can rupture and ooze yellow fluid. It often resolves within a period of two to three weeks without scarring .
This form of impetigo most frequently affects the neonates, and S. aureus can be isolated from the skin lesions. At first the large and fragile bullae can develop on the trunk and extremities, and it may also affect the anogenital area and buttocks of infants, being one of the most common causes of ulceration in these regions. Most frequently, only remnants of the bullae are seen, and they are observed as oval or annular superficial erosions with typical collaret of scale at the periphery of the bulla .
An epidermal separation often occurs due to an exotoxin produced by the pathogen, often made by phage group 2 . S. aureus ETA and ETB, which show extreme specificity in causing loss of cell adhesion in the superficial epidermis, brings about the formation of blisters by splitting the granular cell layer of the epidermis  (Table 2).
Topical antibiotics, systemic antibiotics and topical disinfectants are all considered treatment options for impetigo .
A research which demonstrates the most effective treatment is still lacking .
It should be noted that systemic antibiotics are usually reserved for severe cases, in which administration of topical therapy is not practical as in situations when large number of lesions appear. In all cases, the ideal treatment should be effective, with limited adverse effects, inexpensive and should not promote bacterial resistance [10,48,54].
The advantage of topical antibiotics is the fact of it being applied only in areas needed, this way minimizing resistance to antibiotics and avoiding gastrointestinal and other systemic adverse effects [1,48,55-59].
Among the disadvantages of topical treatments are local allergic reactions and difficulty with application to areas such as the mouth and eyelids. Three different preparations of topical antibiotics are recommended for impetigo: Mupirocin 2% cream or ointment (Bactroban), Retapamulin 1% ointment (Altabax) and Fusidic acid .
Retapamulin is the newest topical antibacterial agent. It’s a novel pleuromutilin . This agent acts on three different key aspects of the protein synthesis of the bacteria and hence resistant strains rarely develop. The U.S Food and Drug Administration approved in 2007 Retapamulin 1% ointment for treating impetigo caused by S. aureus (only to those strains which are susceptible to methicillin), or to impetigo caused by GAS in adult patients and in children bigger than nine months. In this regard, it should be noted that Retapamulin is not approved for intranasal staphylococcal carrier treatment or treatment of MRSA- related skin infections [55,61].
A Canadian review which collected data regarding the treatment between the years 2007-2017 has supported the efficacy of mupirocin and fusidic acid for the treatment of impetigo. Not much information was obtained regarding the clinical efficacy of bacitracin. No evidences were identified regarding either the efficacy or the recommendation towards the use of other antibiotics .
A study which took place in Greece in the years 2013-2016 showed an increased rate of community associated MSSA clone, which carries ETA/ETB genes and is resistant to both fusidic acid and mupirocin. Strains that belong to this clone are associated mainly with superficial skin infections like impetigo, and less commonly SSSS. The prevalence of resistance to mupirocin among this stain from 4.2% in 2013 to 37.7% in 2016, concurrent with increasing rates of resistance to fusidic acid (from 26.8% to 51.9%), whereas the rate of resistance to clindamycin did not change significantly .
In 2011, McNeil, et al. showed that resistance to mupirocin was a problem among SSTIs caused by community-associated MSSA and clindamycin-resistant isolates. In the same study, among 136 S. aureus isolates from patients who had experienced at least three episodes of SSTI, a gene leading to mupirocin resistance was 14.5% prevalent, compared with 7.5% for the first episode, and 5 of 15 mupirocin resistant strains were also clindamycin resistant .
Situations in which topical therapy is impractical, or in impetigo with large bullae, oral antibiotic therapy can be used.
Treatment options are: Amoxicillin/clavulanate, cephalexin, clindamycin, dicloxacillin, doxycycline, minocycline, pristinamycin and trimethoprim/sulfamethoxazole. Seven days treatment is usually sufficient, however, this can be extended in case the clinical response is inadequate and upon confirmation of antibacterial susceptibility. It is still in question which oral antibiotic is the preferred one. Studies have shown no significant difference in the cure rates between oral and topical antibiotics .
Previously, penicillin and erythromycin were the first line treatment, however, due to emerging drug resistance they are no longer used routinely .
Since the rates of resistance vary regionally, health care professionals should check local patterns of resistance to select the proper treatment .
Recent studies point to the fact that MRSA related skin and soft tissue infections are declining, in contrast to past studies which have demonstrated an increase .
Based on culture results, trimetophrim/sulfamethoxazole, clindamycin or tetracyclin are recommended in case of suspecting a MRSA infection .
Trimetophrim/sulfamethoxazole usage in impetigo is limited, due its inadequate coverage of GAS. Clindamycin, due to its association with an increased risk of developing pseudomembranous colitis, should be used in patients in whom penicillin allergy exists or in cases where no response has been achieved to other treatment options. It is important to emphasize that tetracycline may be used for MRSA infections, however should not be used in children below the age of eight. Due to their risk of causing tendinopathy and arthropathies, and due to their low staphylococcal activity, oral fluoroquinolones are not preferred .
Pristinamycin is an oral streptogramin antibiotic with a similar spectrum of activity to macrolides and lincosamides for Gram-positive bacteria, with a reduced risk of drug resistance. It has a bactericidial effect against Staphylococci and Streptococci, and somewhat reduced activity against enterococci. Randomized controlled trials which have compared this antibiotic with penicillin and oxacillin for the treatment of skin and soft tissue infections have shown comparable clinical efficacy. High cure rates (86.7%-91.4%) have been reported when pristinamycin was compared with oxacillin, cefuroxime and amoxicillin in controlled trials for the treatment of respiratory tract infections . Interestingly, one study reported pristinamycin to be superior to penicillin (81% versus 67%), although this difference was not statistically significant .
Antistaphylococcal beta-lactam is usually the first line therapy. The addition of a beta-lactamase inhibitor and the usage of a third generation cephalosporin as well as the usage of clindamycin are often needed in order to provide broad spectrum coverage for polymicrobial infections. Children who are immunocompromised, patients with nosocomial infections, those with penicillin allergy require specific antibacterial strategies, which in most cases involve a broader coverage with increased activity against Gram negative and aerobic organisms  (Table 3).
No recommendation is given today to use disinfectants as they appear to be less effective than topical antibiotics .
Herbal treatments for impetigo can be neither recommended nor dismissed as there is not sufficient evidence. Natural remedies such as coconut oils, olive, garlic, tea effusions and tea tree oil as well as Manuka honey have led to an improvement. In one of the studies being done, oral cephalexin and tea leaf ointment were found to be effective similarly, with a cure rate of 79% vs. 81% .
An open label, phase 2 pilot study which took place in Freiburg, Germany, and was posted in 2017, demonstrated the clinical efficacy of Liposomal polyvinyl-pyrrolidone (PVP)-iodine hydrogel, which has a special mode of action, as it combines both the anti-inflammatory and the antiseptic actions of PVP-iodine with drug delivery and moisturizing properties of liposomes. In the study patients with different dermatoses were observed while on treatment for a maximum period of 4 weeks. Overall, the treatment was well tolerated and hence liposomal PVP-iodine hydrogel has potential utility as a treatment for various dermatoses associated with the colonization of bacteria .
This pilot study was associated with a number of limitations, including the small number of patients and short duration of study treatment. Absence of a placebo or active comparator group also limits the interpretation of efficacy outcomes. The preliminary findings from this pilot study can be used to inform the design of larger scale studies, including randomized, controlled trials in order to assess the impact of treatment on bacterial load and elucidate how the clinical benefit of liposomal PVP-iodine hydrogel can be maximized for patients with various types of inflammatory, infective dermatoses .
Impetigo is a highly contagious bacterial skin infection, caused by GAS and S. aureus, both which have various factors assisting in skin adhesion. It is seen especially in children at the summer time, due to the close proximity between kids which leads to rapid spreading. The clinical presentation of the bullous form of impetigo, which starts with erythematous macules and progresses to vesicles, is due to ETA and ETB, harbored by S. aurues. The areas involved mostly are the nares and perioral regions.
This review emphasized the most important differentials for each form of impetigo (the bullous and the non-bullous one). Atopic dermatitis, candidiasis, contact dermatitis and many other are included. The unique feature for most diseases in the differential was outlined.
The usage of topical treatment for impetigo, mainly with mupirocin and fusidic acid is still prevalent today. It has the advantage of minimizing antibiotic resistancy, although recent study done in Greece demonstrated increased resistancy to these products among certain staphyloccal clone. The percentage of resistance has increased with the repeated use. When systemic therapy is needed, as in cases of the bullous form or wide-spread lesions, various options exist, with an average treatment of 10 days. Various studies testing new treatments haven’t proven adequate efficacy, and larger studies will need to take place.