A brief overview of AD

AD, also referred to as atopic eczema, is one of the most common non-communicable skin diseases, affecting up to 20% of children and 2%–8% of adults in most countries of the world. AD is characterised primarily by scaly, pruritic, erythematous lesions located on flexural surfaces.²

In many instances, AD begins in childhood, while severe cases may persist in adulthood. About 30% of adult cases develop in adulthood. AD is often the first step in the development of other atopic diseases, such as allergic rhinoconjunctivitis or asthma and food allergy.²

Most AD cases can be regarded as mild, whereas less than 10% of patients suffer from severe eczematous skin lesions. The percentage of severe cases seems to be higher in the adult AD population.²

Skin infections in AD

Despite AD patients’ increased risk of recurrent bacterial skin infections, which may lead to life-threatening complications, there is a lack of consensus on how to define and treat associated bacterial colonisation and infection. This is according to a consensus statement recently issued by a panel of experts from the International Eczema Council Skin Infection Group, published in the British Journal of Dermatology.¹

The panel conceded that it is challenging to diagnose skin infections – especially in dark-skinned individuals. Increases in erythema in dark-skinned individuals are more difficult to distinguish.¹

In dark-skinned individuals, perifollicular accentuation is often present and erythema appears violaceous and often muted. This can lead to poor recognition of inflammation, underestimation of disease severity and inadequate intervention. Patients with AD of African descent often have extensor disease rather than the characteristic flexural lesions.¹

In addition, skin infections are associated with concomitant AD flares, and erythema, oozing and crusting and increased cutaneous warmth, which is all clinical features of AD.¹

Clinical features of skin infections

Staphylococcus aureus is the most common infectious organism, although beta-haemolytic streptococci may also be involved. A recent meta-analysis found that the pooled prevalence of S. aureus colonisation of lesional AD skin is 70%, non-lesional AD skin 39% and of the nares 62%.¹

The typical signs of S. aureus infection include weeping, honey-coloured crusts, and pustules, both interfollicular and follicular based (folliculitis). By contrast, the beta-haemolytic streptococcal infection may present with well-defined, bright red erythema, thick-walled pustules, and heavy crusting. In severe cases, cutaneous bacterial infection may cause abscesses – especially with methicillin-resistant S. aureus (MRSA) infection – fever and lymphadenopathy.¹

Several non-bacterial infections can occur concomitantly with a bacterial skin infection and can resemble bacterial infections, including eczema herpeticum (EH), which is caused by the local spread of the herpes simplex virus (HSV). HSV favours AD lesional skin and is commonly observed in the context of AD.¹

Early in the course of EH the characteristic skin lesions are superficial clusters of dome-shaped vesicles and/or small, round, punched-out erosions. As the disease progresses, lesions may become superficially infected with S. aureus and may develop an impetiginised scale.¹

EH typically arises in involved AD skin, most frequently on the face, neck, upper trunk, and antecubital/popliteal areas with AD, and is often accompanied by fever, malaise, and lymphadenopathy.¹

Moderate-to-severe AD, filaggrin loss-of-function mutation, a history of S. aureus skin infection, greater allergen sensitisation and type 2 immunity are important risk factors for EH. Staphylococcal α-toxin and reductions in the tight junction protein claudin-1 result in the greater epidermal spread of the herpes simplex virus in vitro. This infection can spread rapidly and, in severe cases, may lead to keratoconjunctivitis and encephalitis.¹

Fungal colonisation can also complicate the clinical picture of AD. For instance, Malassezia colonisation is thought to drive inflammation in AD in a subset of patients who typically have dermatitis in areas with a high density of sebaceous glands (eg head, neck, and upper chest and back).¹

This seborrhoeic distribution overlaps with but is distinct from, the distribution of allergic contact dermatitis or airborne allergy, which typically involve the upper face, eyelids and periorbital regions, anterior neck, postauricular area and exposed areas on the arms. Malassezia is a commensal yeast. Although it is not more abundant on AD skin, patients with AD are more frequently sensitised to Malassezia.¹

In some patients, sensitisation to yeast antigens induces autoreactivity to human proteins via molecular mimicry, leading to sustained skin inflammation. Cross-reactivity between Malassezia-specific IgE and Candida albicans has also been shown.¹

Prevention of infections in AD patients

The approach in preventing infections in AD is based on addressing the predisposing factors for infections. Daily skin hydration and moisturisation are recommended for patients with AD to maintain skin barrier function.³

Patients with AD should take a daily warm shower or bath, followed by gentle drying and application of a moisturiser or a prescribed topical medication. The choice of moisturiser should be based on the patient’s or parent’s preference and experience.³

In general, a thick or ointment-based moisturiser (eg petrolatum) is better than cream in retaining moisture in the skin. Application of petrolatum has been indicated to up-regulate antimicrobial peptides and induce key barrier differentiation markers such as filaggrin and involucrin, in patients with AD.³

The use of standard topical anti-inflammatory medications, including topical corticosteroids (TCS) and topical calcineurin inhibitors (TCI), has been reported to improve skin barrier functions based on transepidermal water loss.³

A number of antibacterial/steroid topical combinations are commercially available. These include combinations with 1% hydrocortisone or with a potent TCS such as betamethasone valerate 0.1%.⁴

Fusidic acid has major advantages over other available topical antimicrobial agents. It shows very good penetration into the skin. High in vitro skin permeability to both the fusidic acid and betamethasone valerate components of the combination product formulation has also been documented.⁴

Furthermore, fusidic acid has high anti-staphylococcal activity even against MRSA. Unlike neomycin and gentamicin, it has a very low potential to sensitise and induce contact allergic dermatitis. It also has very good cosmetic acceptability, unlike clioquinol and chlortetracycline, which can mark clothes and bedding.⁴

TCS and TCI have been reported to decrease S. aureus colonisation in AD lesions. Topical anti-inflammatory treatments have been associated with increased microbial diversity in AD lesions.³

Although multiple case reports have found an association between EH and the use of anti-inflammatory medications in AD, this was not supported by a recent multicentre study, which reviewed more than 200 cases of EH. The authors found that the use of TCS, TCI, systemic CS, or cyclosporine was not associated with the onset of EH.³

Uncontrolled AD inflammation is likely the primary risk factor for EH (or bacterial infections), rather than the anti-inflammatory treatment. Therefore, in the absence of an active infection, anti-inflammatory treatment should confer protection against infections in patients with AD.³

Because of the current Covid-19 pandemic, there has been some concern about whether systemic anti-inflammatory medications for AD may increase the risk of patients with AD for this viral infection.³

Case series, mainly from Italy, thus far, has not supported an increased risk of SARS-CoV-2 infection in patients with AD treated with systemic anti-inflammatory medications.³

Management of infection complications in AD

For patients with AD who have signs and symptoms of systemic illness, hospitalisation and empirical intravenous antibiotics are recommended. The empirical antibiotic regimen should provide coverage against S. aureus.⁵

For critically ill patients, coverage for both MRSA and MSSA with vancomycin and an anti-staphylococcal beta-lactam is appropriate because vancomycin is inferior to nafcillin or first-generation cephalosporins for the treatment of serious MSSA infections.⁵

For severe but non–life-threatening infections, vancomycin may be used alone as empirical therapy, pending culture results. Clindamycin can also be considered if there is no concern for an endovascular infection and the local prevalence of clindamycin resistance is less than 15%.⁵

Bacteraemia because  S. aureus requires the use of a bactericidal intravenous agent initially. For MRSA, vancomycin is the drug of choice. For MSSA, cefazolin and nafcillin are both acceptable first-line agents, though nafcillin can cause venous irritation and phlebitis when administered peripherally.⁵

As long as there are no concerns for ongoing bacteraemia or an endovascular focus, completion of therapy with an oral agent to which the isolate is susceptible is appropriate in children with S.aureus bacteraemia.⁵

Duration of therapy should be determined by the clinical response, but typically seven to 14 days is recommended. Infective endocarditis is a rare complication of AD. Careful auscultation for a heart murmur is recommended.⁵

For patients with AD with uncomplicated, non-purulent skin infection, a beta-lactam antibiotic that covers both S. aureus and β-hemolytic streptococci (eg, cefazolin or cephalexin) may be sufficient pending clinical response or culture, considering local epidemiology and resistance patterns.⁵

In contrast, for patients with AD with a skin abscess, history of MRSA colonisation, close contacts with a history of skin infections, or recent hospitalisation, coverage for MRSA should be considered.⁵

Clindamycin, doxycycline, trimethoprim-sulfamethoxazole, and linezolid are all acceptable oral options for MRSA skin infections in both children and adults, assuming the isolate is susceptible in-vitro.⁵

Patients with AD with minor, localised skin infections such as impetigo may be treated with topical mupirocin ointment. The duration of therapy typically ranges from five to 10 days depending on clinical response.⁵

HSV testing should be done, but treatment with systemic antiviral should not be withheld pending the results. Coinfection of EH with S aureus is also common and concurrent treatment with an anti–S aureus antibiotic should be considered.⁵

There are no formal guidelines regarding the preferred route of administration of antivirals or indications for hospitalisation in patients with EH. For patients with extensive skin involvement, signs of systemic illness, and those less than a year old, parenteral acyclovir should be considered initially. Fever and mild systemic symptoms often accompany mucocutaneous HSV infections, particularly with the initial episode.⁵

Once clinical improvement is reported, a transition to an oral agent to complete the course of therapy is appropriate. For mild cases, oral acyclovir can be considered and was associated with faster healing and resolution of pain in a randomised, placebo-controlled trial of 60 adults and adolescents with EH.⁵

Valacyclovir, the L-valyl ester prodrug of acyclovir, has a three to five-fold greater bioavailability than oral acyclovir, which can be dosed less frequently, and with plasma concentrations are comparable with parenteral acyclovir.⁵

Topical antivirals do not have an appreciable benefit in HSV mucocutaneous disease and do not have a role in the treatment of EH. Patients with herpetic lesions on or around the eye should be emergently evaluated by an ophthalmologist.⁵

Rarely, EH can be complicated by HSV meningoencephalitis, which should be treated with a prolonged course of intravenous acyclovir and managed in conjunction with a neurologist and infectious disease specialist.⁵

Patients with AD with recurrent EH may benefit from long-term suppressive therapy, though this has not been studied. The need for ongoing therapy should be reassessed after six to 12 months. The development of resistance to acyclovir is rare in EH but may be suspected in cases of recalcitrant EH or frequent recurrences of EH despite suppressive therapy and good adherence to long-term therapy.⁵

Conclusions

Bacterial infection in AD is common and causes significant morbidity. Overt bacterial infection is easily recognized. However, a less overt manifestation of infection may be more difficult to diagnose, especially given the greater risk of infection with flares (themselves associated with increased erythema and oozing).

The prevention of infection in AD should emphasize skin barrier repair and maintenance of anti-inflammatory medications without relying on antibiotics. The need for antibiotics in patients with severe AD exacerbations remains controversial.

This is because some of the signs and symptoms associated with severe AD exacerbation resemble that of bacterial skin infections. It is possible that there is a threshold at which S. aureus levels and the extent of host tissue damage evolve into an infection.

Studies are needed to investigate the biomarkers that assist in determining this threshold. Acute-phase response markers such as C-reactive protein and erythrocyte sedimentation rate may be helpful in determining the need for antibiotics in patients with severe AD exacerbation who are suspected of having infections.

Future studies should also address whether anti-inflammatory treatments, especially those that specifically target type 2 inflammation, may benefit patients with AD with active infection. This is based on the premise that suppressing type 2 inflammation may lead to the improvement of immunity against microbial pathogens.

REFERENCES:

1. Alexander H, Paller AS, Traidl-Hoffman C, et al. The role of bacterial skin infections in atopic dermatitis: expert statement and review from the International Eczema Council Skin Infection Group. British Journal of Dermatology, 2018.
2. Wollenberg A, Barbarot S, Bieber T, et al. Consensus-based European guidelines for the treatment of atopic eczema (atopic dermatitis) in adults and children: part I. JEAVD, 2018.
3. Boguniewicz J, Boguniewicz M, Ong PY, et al. The infectious complications of atopic dermatitis. Ann Allergy Asthma Immunol, 2021.
4. Chu AC. Antibacterial/steroid combination therapy in infected eczema. Acta Derm Venereol, 2008.
5. Wang V, Boguniewicz J, Boguniewicz M and Ong PY. The infectious complications of atopic dermatitis. CME Review, 2020.