Overview

Impetigo

Bacterial skin infections are popular in children and occur frequently. Impetigo is one of these common infections, which affects the superficial layers of the epidermis, gram-positive bacteria are the main causative pathogen for impetigo, particularly in areas that are hot humid climates. It presents as erythematous plaques with a yellow crust, these lesions can be painful or itchy, highly infectious, and easily transmitted causing widespread outbreaks. This disease can be symptomatically diagnosed based on typical clinical manifestations.^1,2

Treatment approaches

The treatment routes of impetigo include relief measures, symptomatic management, topical, and oral antibiotics. The disease management can be tailored based on specific criteria, which are the causative pathogen (mostly Staphylococcus aureus and Streptococcus pyogenes), presentation, and the pathophysiology of impetigo.¹

Aetiology

Impetigo represents about 10% of skin infections in children. There is gender equality in incidence when considering all ages, but among adults, men are predominantly impacted. Impetigo is most prominent in children between ages 2-5 years old, particularly bullous impetigo (fluid-filled blisters present), which is caused almost exclusively by S aureus and accounts for 90% of cases in children above 2 years old.

Epidemiology

S aureus is the main pathogen for nonbullous impetigo (blisters not present), which accounts for 80% of cases. The combination of both pathogens S aureus and Group A beta-hemolytic Strep (GABHS) are responsible for impetigo in 10% of cases. Today, Methicillin-resistant S aureus (MRSA) has become more frequent, particularly in hospitalised patients. Moreover, community-acquired MRSA is surging rapidly, this is more prevalent in daycare centres, close proximities, and prisons. 

Evaluation 

Physical examination and history are the cornerstone to diagnose impetigo. Bacterial cultures are considered to confirm the diagnoses and should be conducted when MRSA is suggested. In refractory cases, a skin biopsy is recommended. 

Treatment and management

Overview

Treatment of impetigo involves topical antibiotics alone or a combinational strategy with systemic antibiotics. The used antibiotic should cover both S aureus and S pyogenes. However, the type of impetigo that can’t be treated is usually resolved on its own (self-limiting), and antibiotics can help reduce the spread of lesions and the duration of the disease. Moreover, antibiotic treatment decreases the risk of developing complications including bones, kidneys, lungs and acute rheumatic fever as well.

Topical antibiotic therapy

Topical antibiotic therapy is the first-line treatment of choice in uncomplicated, localised, non-bullous impetigo. Before application of topical antibiotics, the crust should be removed with soap and water. The standard treatments are fusidic acid, mupirocin, and retapamulin.^2,3

Retapamulin³

• Novel bacterial protein synthesis inhibitor acts as bacteriostatic by binding to a particular site on the bacterial ribosome (50s subunit)
• In vitro, it is of high efficacy against MRSA, but of low activity against gram-negative bacteria and enterococci 
• Retapamulin (Altabax) was approved by the FDA in 2007. Available as a topical ointment 
• Strength of 10 mg/ 1g to be used in adults and paediatrics (9 months and older)
• Indicated for lesions caused by  S. pyogenes and Methicillin susceptible S. Aureus
• Not recommended for MRSA, despite showing vulnerability to MRSA, this was not linked to clinical success rates in phase III clinical trials, this suggested due to diversity in virulence traits associated with the Panton-Valentine leukocidin (PVL) gene, which is found in specific strains of bacteria.
• The safety of Retapamulin 1% ointment was evaluated, the most prevalent adverse event was reported to be about 1.4% pruritus at the application site, and less than 2% of cases will report nausea, diarrhoea, headache, and nasopharyngitis. It was reported that less than 1 % have erythema at the site of application, contact dermatitis or pain. 
• It is considered pregnancy category B by the FDA

Mupirocin

• Mupirocin is produced by a bacteria called Pseudomonas fluorescens, which is why it is also known as pseudomonic acid A.
• It can be considered as bacteriostatic, acting as a competitive inhibitor of DNA replication by impairing bacterial isoleucyl-tRNA synthetase.
• It possesses a high activity against the majority of Gram-positive bacteria, unlike Gram-negative bacteria
• No cross-resistance was demonstrated with other types of antimicrobials. Mupirocin was approved by the FDA in 1987
• Available as an ointment 2%
• Indicated in patients aged 2 months and older 
• Applied on the skin three times daily for eight days. According to the safety profile, it was reported in 1.5% of subjects' pain, burning or stinging. 1 % had itching and less than 1 % had dry skin, erythema, contact dermatitis, swelling, nausea, tenderness, and rash.
• It is pregnancy category B.

Ozenoxacin

• Ozenoxacin is an antibacterial drug that belongs to the non-fluorinated quinolone family 
• It acts by inhibiting the enzymes responsible for bacterial DNA replication such as topoisomerase IV and DNA gyrase 
• By referring to the bactericidal activity of ozenoxacin which is tested based on killing curve experiments, it has exhibited high potency against S. aureus and S.pyogenes compared to mupirocin and fusidic acid. It was approved by the FDA in 2017
• The used formulation is 1% topical cream. It is indicated for adults and paediatrics of 2 months and above
• It can be used twice daily for 5 days by applying it on the affected skin area as a thin layer 
• Ozenoxacin was found to have a low systemic toxicity as demonstrated by clinical trials, there was no detectable systemic absorption in terms of different concentrations, dermal extensions, and formulation in healthy and damaged skin.
• The 1 % topical formulation has no reasonable dermal irritation.
• There is no available data on the indication of ozenoxacin in pregnant women.

Fusidic acid

• Fusidic acid is a non-approved topical antibiotic. 
• It is available in cream or ointment formulations.
• Fusidic acid is indicated widely in Europe, Parts of Asia, and Australia. In 1962, fusidic acid was discovered by Godtfredsen et al through an isolation process from a culture of Fusidium coccineum. It is classified under the family of fusidanes. 
• Fusidic acid exhibits a structure resembling other antibiotics originating from fungi despite lacking steroid characteristics, this particular structure is called an asteroid-type structure which can invade the tissues like steroids. 
• It acts by impairing the process of bacterial protein synthesis. It has high efficacy against gram-positive bacteria. 
• The predominant reported side effect was pain then a burning sensation. There is no adequate evidence of its use in pregnant women. 

Systemic antibiotics

Systemic antibiotics are indicated in all cases and types of impetigo with extensive tissue involvement, more than five lesions, immunocompromised patients, systemic symptoms and signs of infection, lesions in the oral cavity, and lymphadenopathy.²

The first-line preferred treatments are amoxicillin-clavulanate, cephalosporins, and dicloxacillin. These antibiotics belong to the Beta-lactamase-resistant antibiotics group.

Doxycycline or clindamycin is the treatment of choice in the presence of MRSA which is confirmed by cultures (positive for MRSA). Also, in the areas that have of high prevalence of MRSA.

Trimethoprim-sulfamethoxazole is active against MRSA, but it should be considered in cases by which the causative agent is not group A streptococci, or in combination with anti-streptococcal antibiotic.

Essential side effects

Cephalosporins

• Common allergic reactions such as rash and swelling. The chances of resulting in anaphylaxis are very low.⁴
• Drug-induced immune hemolytic anaemia by which the drug binds to the red blood cell membrane. In case the body produces IgG antibodies against the drug, then it will bind to these red blood cells causing an immune response that reacts with the abnormal red blood cells resulting in hemolysis. Cefotetan and ceftriaxone are the two most common cephalosporins that cause this side effect. 
• Vitamin K deficiency.
• Disulfiram-like reactions, occur because cephalosporins contain a structure called methyl-tetrazole-thiol side chain which can impair the function of dehydrogenase enzyme leading to the accumulation of acetaldehyde. Moxalactam, cefoperazone, and cefamandole are most likely to cause this side effect.

Dicloxacillin

Hepatotoxicity: Dicloxacillin has not demonstrated high liver enzymes as a side effect during treatment. However, it has been linked to cholestatic hepatitis resulting in liver injury. It has been suggested that this is associated with a hypersensitivity reaction due to the beta-lactam structure of the antibiotic.⁵

Doxycycline

Doxycycline is associated mostly with gastrointestinal symptoms such as vomiting, nausea, diarrhoea, and abdominal pain. Also, it causes photosensitivity, which results in erythematous rash, an allergic immune-mediated reaction condition characterised by red, raised skin areas that can develop all over the body. Thus, patients should avoid sunlight during treatment.⁶

Clindamycin

Clindamycin can cause serious adverse events on the breastfed infant's gastrointestinal flora. Thus, in such cases, an alternative drug is preferred. The infant should be monitored closely for side effects on the gastrointestinal flora such as diarrhoea. 

The formulation that is used vaginally has not been demonstrated to have these side effects, although 30% of the dose is absorbed.⁷

Summary

• Impetigo is one of these common infections, which affects the superficial layers of the epidermis, gram-positive bacteria is the main causative pathogen for impetigo.
• It presents as erythematous plaques with a yellow crust, these lesions can be painful or itchy, and highly infectious.
• The treatment routes of impetigo include relief measures, symptomatic management, and topical and oral antibiotics.
• Topical antibiotic therapy is the first-line treatment of choice in uncomplicated, localised, non-bullous impetigo.
• Retapamulin is a bacteriostatic topical antibiotic. The most prevalent adverse event was reported to be about 1.4% pruritus at the application site.
• Mupirocin is a bacteriostatic topical antibiotic. According to the safety profile, it was reported in 1.5% of subjects' pain, burning or stinging.
• Ozenoxacin is an antibacterial drug and was found to have a low systemic toxicity as demonstrated by clinical trials.
• Fusidic acid is a non-FDA approved topical antibiotic. The predominant reported side effect was pain then a burning sensation.
• Systemic antibiotics are indicated in all cases and types of impetigo with extensive tissue involvement, more than five lesions, and immunocompromised patients.