The Impact of Treating Staphylococcus Aureus Infection and Colonization on the Clinical Severity of Atopic Dermatitis

Background Atopic dermatitis (AD) is a chronic condition of pruritus and eczematous lesions that affects 15-20% of children. It commonly presents early in life and is associated with other atopic diseases. Pathogenesis is multifactorial with genetic, immunologic, and environmental components. Generally, decreased production of ceramides by keratinocytes in both normal and affected skin causes disruption in skin barrier function, resulting in increased permeability to environmental irritants and allergens, and transepidermal water loss. There also is an immunologic derangement in the body's response to skin injury, manifested by an increased Th2 response in the acute lesions. In addition, the change in incidence of disease by time and climate suggests that environmental factors are important. Staphylococcus aureus (S. aureus) infection is not only a secondary complication of AD, but also a culprit in exacerbations of AD. Of children with AD, 76-100% are colonized with S. aureus, compared to 2-25% of healthy controls. In addition, S. aureus is the most common cause of infected AD. The qualities of atopic skin may explain this high rate of colonization and infection. 1) Patients with AD have poor expression of the natural antimicrobial peptides (βdefensin2 and cathelicidin) during inflammation, likely increasing the risk of cutaneous bacterial and viral infections. 2) The disrupted lipid layer of atopic skin results in low sphingosine, which normally exerts a potent antimicrobial effect on S. aureus. 3) S. aureus contains adhesins, which readily bind to laminin and fibronectin that are exposed in patients with AD and skin injury. Consistently, the extent of S. aureus colonization correlating with the severity of AD has been shown. This may be explained by 4) S. aureus superantigens (Enterotoxins A & B, TSST-1) in the worsening of AD - via the recruitment of T cells & APCs and the upregulation of cytokines without organism elimination. The Th2 cell pathway is preferentially activated, releasing cytokines (IL-4, IL-5, & IL-13), which induces further inflammation and glucocorticoid insensitivity.

First generation cephalosporins have been the mainstay of treatment for acute impetiginized lesions, but the emergence of community acquired methicillin resistant S. aureus (CA-MRSA) has presented a new challenge. Over the past decade, CA-MRSA rates as high as 74% have been found in some regions of the U.S. MRSA has been detected at equal rates in AD and non-AD patients. Although CA-MRSA has greater antimicrobial susceptibility than hospital acquired MRSA, CA-MRSA is often resistant to typical first-line oral agents, including cephalosporins. However, despite the contrary evidence, patients still clinically improve when prescribed first generation cephalosporins. This observation requires confirmation. The deleterious effects of S. aureus in activating AD and observation of improvement with treatment have led researchers to consider eradication (or suppressed growth) of this organism as an important component of treatment of AD. The anterior nares are the major location for S. aureus colonization. Mupirocin ointment represents the mainstay of therapy for eradicating S. aureus nasal carriage, with low resistance rates against CA-MRSA. Recently, sodium hypochlorite (bleach) has become popular with many US pediatric dermatologists. Bleach has long been used safely and efficaciously as a dental antiseptic. This agent has also been shown in concentrations as low as 0.005% to be effective against S. aureus in wounds and ulcers. We have observed that use of sodium hypochlorite improves the clinical appearance of AD, but no studies have been done to confirm this. Several studies have attempted to show that eradication of S. aureus improves the severity of AD. Most studies using topical mupirocin on affected skin lesions for up to two weeks have shown that when S. aureus decolonization can be achieved, patients show clinical improvement. However, skin is recolonized with S. aureus in subsequent months, resulting in worsening disease and making long term treatment difficult. Many studies do not treat both nasal carriage and skin colonization. Although intranasal mupirocin ointment may be sufficient to eliminate S. aureus in healthy hosts, this organism's affinity for the specific features of atopic skin argues for the concomitant use of direct topical antiseptics, such as dilute bleach, in this particular patient population. In addition, most studies have neglected the possibility that family members are likely to be colonized as well, contributing to recolonization. Recolonization can also be affected by failure to continue to aggressively treat atopic skin with appropriate topical therapy during and following eradication. Recently, a small study was performed on adults with AD, using mupirocin, chlorhexidine wash, cephalexin, and potassium permanganate showed significant clinical improvement in subjects. Finally, it is of interest to determine if the exacerbation of atopic dermatitis with CA-MRSA infection is greater than with methicillin-sensitive S. aureus (MSSA) infection. At least one virulence factor, Panton-Valentine leukocidin, has been found in CA-MRSA that is not found in MSSA. Understanding the relevance of the emergence of CA-MRSA to AD is pivotal in appropriately treating secondary infections in patients with AD. Successful eradication of S. aureus colonization from patients with moderate to severe AD may decrease the future number of secondary infections and improve the overall severity of their disease.

Aims of study - #1: Assess the impact of CA-MRSA on secondary S. aureus infections in children with atopic dermatitis. #2: To study whether eradication of S. aureus with nasal mupirocin ointment and sodium hypochlorite baths in conjunction with appropriate skin care regimen with emollients and topical steroids or calcineurin inhibitors can result in long-term S. aureus eradication and clinical improvement. #3: To study the impact of CA-MRSA on overall severity of AD. We will determine the predictive value of CA-MRSA versus MSSA on the overall severity of AD based on the EASI score.

Study population Patients aged 6 months to 17 years with moderate to severe AD by investigator global assessment (IGA) and clinical signs of bacterial skin infection (weeping, crusting, pustular lesions) are eligible. Exclusion criteria include current or recent use (within past eight weeks) of topical or oral antibiotics and allergy to the cephalosporins or mupirocin. Up to 40 patients recruited will be enrolled.

Study Design This study will be a randomized investigator-blind placebo-controlled study. Prior to intervention, qualitative bacterial cultures and sensitivities of the nares and the most severely infected lesions will be obtained from all subjects. Severity of AD will be scored by both the IGA and EASI scoring systems. Patients will continue daily emollient application and clinician-determined topical anti-inflammatory therapy. All subjects will receive cephalexin TID for two weeks. Twenty subjects and their household members will receive intranasal mupirocin ointment BID for five days. The subjects will receive cephalexin 50mg/kg/day (maximum of 2grams/day) divided TID for two weeks. These subjects will continue the five day regimen of mupirocin once monthly for three months and receive sodium hypochlorite baths twice weekly for three months. The other twenty subjects and their household members will receive placebo intranasal ointment with the same schedule. At four weeks and 12 weeks after initiation of therapy, qualitative bacterial cultures and sensitivities of the nares and the most severely superinfected area will be obtained from all subjects. One potential pitfall is the inability to perform quantitative bacterial cultures, as our laboratory cannot do these and the send-out cost is prohibitive; it is possible that the numbers of staphylococcal organisms will decrease, but be undetectable.