The Impact of Treating Staphylococcus Aureus Infection and Colonization on the Clinical Severity of Atopic Dermatitis
Condition: Atopic Dermatitis
MeSH terms: Staphylococcal Infections; Dermatitis, Atopic; Dermatitis; Eczema
Study type: Interventional
Phase: Phase 4

Summary: 
      Staphylococcus aureus (S. aureus) infection is perceived not only as a common secondary
      complication of atopic dermatitis (AD), but also as a culprit in the worsening of this
      condition. In addition, the recent development of community acquired methicillin-resistant S.
      aureus (CA-MRSA) has presented a new challenge to our management of AD, both in treatment of
      acute infections and maintenance therapy. The investigators would like to perform a
      randomized investigator-blinded placebo-controlled study of children aged 6 months to 17
      years with moderate to severe atopic dermatitis with clinical signs of secondary bacterial
      infection to study: 1) the prevalence of CA-MRSA in our patient population; 2) the
      relationship of sensitivity of the S. aureus organism cultured from the infected lesion(s) to
      clinical response to oral cephalexin therapy and severity of the AD; and 3) whether
      concurrent treatment of S. aureus infection initially with nasal mupirocin ointment and
      sodium hypochlorite (bleach) baths can result in long-term S. aureus eradication and clinical
      stability.
    

Detailed description: 
      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.

      Blinding Mupirocin, sodium hypochlorite, and placebos will be stored in identical tubes and
      bottles. Patients will be randomly assigned numbers 1-40 upon initial participation of study.
      Based on their number, they will be assigned treatment A (treatment) or B (placebo). The
      investigator will be blinded.

      Assessment & Bacteriology At all visits, the %BSA affected by AD as estimated from 4 body
      regions (head/neck, upper limbs, trunk, and lower limbs), and the Physician's Assessment of
      Individual Signs grading the 6 signs of AD (erythema, edema/induration/papulation,
      excoriation, oozing/weeping/crusting, scaling, and lichenification) will be determined. The
      results will be used to calculate the EASI score, a validated composite score that ranges
      from 0 (clear) to 72 (validated very severe). Additional assessments conducted at each visit
      will be the IGA and the patient's assessment of itch using a visual analog scale (VAS).
      Adverse events will be recorded at each visit. Swabs will be plated on blood agar and grown
      for 48 hours at 37oC. S. aureus will be identified by testing for coagulase activity.
      Antimicrobial susceptibility will be assessed using the agar disc diffusion method.
      Sensitivity and resistance to several antimicrobials will be determined.

      Treatment & Safety One-half cup of household bleach (sodium hypochlorite 6%) will be placed
      in a full bathtub of water (40 gallons), diluting sodium hypochlorite to a concentration of
      0.005%. For most children, ¼ cup per half tub will be added. Patients will soak in sodium
      hypochlorite baths twice a week for 3 months. Mupirocin ointment or placebo will be applied
      to the nares for the subjects and families as detailed above. Cephalexin has proven to be
      safe and efficacious for all ages. Potential adverse effects include abdominal pain,
      diarrhea, transient elevation of liver enzymes, and allergic reactions. Inappropriate use of
      cephalexin has led to resistant bacteriologic strains. Mupirocin ointment has been shown to
      be safe and effective in neonates and children. Adverse reactions to mupirocin include
      burning, stinging, pain or itching at the site of application. In less than 1% of patients,
      nausea, contact dermatitis, and skin tenderness/swelling have been reported. While long-term
      regimens may be associated with development of resistance, short courses of treatment with
      mupirocin are associated with remarkably little bacterial resistance. Sodium hypochlorite in
      low concentrations is a safe and widely used agent. Potential AEs include skin and eye
      irritation. Our previous experience is that most children with AD tolerate bathwater with
      dilute sodium hypochlorite without complication.

      End points Primary outcome measure- change in EASI score from baseline to various timepoints
      during the study. Safety end points will include the incidence of all AEs reported by patient
      or parent/guardian, or observed by the investigator.
    

Intervention name(s): Sodium hypochlorite (bleach) baths; Mupirocin ointment; Water; Petrolatum Ointment
Intervention type(s): Drug; Drug; Drug; Drug
Intervention description(s): Sodium hypochlorite (bleach) baths twice weekly for 3 months; Intranasal mupirocin 2% ointment BID x five days (3 times total for subjects; one time only for family members); Water baths twice weekly for three months; Intranasal petrolatum ointment twice daily for five days
Other intervention name(s): Bleach; Centany; H2O; Vaseline
Intervention MeSH terms: Mupirocin; Sodium Hypochlorite; Eusol; Petrolatum
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary purpose: Treatment