Prevention of Recurrent MRSA Skin Infections: What You Need to Know

December 1, 2008

Methicillin-resistant Staphylococcus aureus (MRSA) was once considered a strictly nosocomial pathogen. Over the past decade, however, MRSA has emerged as a prominent cause of community-associated infections in both adults and children. Although community-associated MRSA strains occasionally cause severe invasive infections, they are most frequently isolated from patients with skin and soft tissue infections.

Community-Acquired MRSA InfectionAntibiotic Drug Resistance: Which Bugs, Which Drugs?Treatment of MRSA InfectionMore

Methicillin-resistant Staphylococcus aureus (MRSA) was once considered a strictly nosocomial pathogen. Over the past decade, however, MRSA has emerged as a prominent cause of community-associated infections in both adults and children. Although community-associated MRSA strains occasionally cause severe invasive infections, they are most frequently isolated from patients with skin and soft tissue infections.1 Furunculosis (“boils”) is the most frequently reported manifestation of community-associated MRSA skin infection, but impetigo, pustulosis, cellulitis (Figure 1), and locally invasive abscesses have also been described.2

The tendency of staphylococcal skin infections to recur is well recognized. Data on the frequency of recurrence, however, are sparse. In a study of 69 children who were treated for MRSA skin or soft tissue abscesses, 12% had a history of previous cutaneous abscesses.3 Other studies, which principally involved men with HIV infection, documented recurrences of MRSA skin infections in 31% to 45% of subjects.4-7

In the absence of an effective S aureus vaccine, many clinicians recommend various topical, intranasal, or systemic antimicrobial agents for patients with recurrent MRSA skin infections in an effort to “decolonize” them of MRSA. However, there is scant evidence that decolonization strategies actually prevent recurrent MRSA skin infections. In this article, I discuss some of the most popular decolonization strategies and review the evidence regarding their safety and effectiveness.

PREVALENCE OF S AUREUS NASAL COLONIZATION

The anterior nares are the principal site of S aureus colonization, although the organism (Figure 2) is also recovered frequently from skin and mucosal surfaces. Nasal colonization usually-but not always-precedes the development of skin infections, and patients with recurrent staphylococcal skin infections are often nasal carriers.1 Thus, it is not surprising that considerable effort has been directed at eradicating the nasal carriage state in patients who have recurrent skin infections.

The 2001-2002 National Health and Nutrition Examination Survey found that 32.3% of noninstitutionalized persons in the United States harbored S aureus in their nares and that 0.8% of this population were nasal carriers of MRSA.8 By 2004, the overall S aureus carriage rate had decreased to 28.7%, but MRSA carriage had increased to 1.5% (P < .01 for both comparisons).9 Thus, an estimated 4.1 million Americans had MRSA nasal colonization in 2004.9

Colonization rates vary substantially from one geographic region to another, and some locales have reported much higher MRSA carriage rates. In Nashville, Tenn, rates of nasal MRSA colonization among healthy children increased from 0.8% in 2001 to 9.2% in 2004.10 And in 2005, 22% of children hospitalized in Corpus Christi, Tex, had MRSA nasal colonization at the time of admission.11

WIDELY USED DECOLONIZATION STRATEGIES
In 2005, the Emerging Infections Network (EIN) surveyed infectious disease physicians about their practices for preventing recurrent MRSA skin infections. Of 413 respondents, 85% reported prescribing decolonization regimens to about 4400 patients (and 56% had attempted to decolonize other members of the families of about 1800 patients) in the preceding year.12

The survey revealed that decolonization regimens varied widely among infectious disease physicians. These regimens included topical antiseptics, intranasal antimicrobials, and systemic antibiotics, used either alone or in combination for varying durations. The most frequently reported intervention, recommended by 93% of respondents, was intranasal mupirocin. Seventy percent of respondents recommended bathing or showering with chlorhexidine gluconate, while 14% favored hexachlorophene. Fifty-five percent recommended oral antibiotic therapy, most frequently with rifampin, trimethoprim/sulfamethoxazole (TMP/SMX), clindamycin, or minocycline.12

A similar range of decolonization regimens was reported by 114 pediatric infectious disease physicians in another EIN survey, conducted in 2006. Only 11% of respondents reported that they did not routinely attempt to decolonize patients with recurrent MRSA skin infections.13

HAND WASHING AND GENERAL HYGIENE
No study has specifically evaluated the effects of hand washing on rates of recurrence of MRSA skin infections. Nevertheless, clinicians are well advised to recommend good hand hygiene to all patients. Hand washing is probably the single most effective intervention for infection control in the home, as it is in the hospital. For example, a randomized controlled trial (RCT) in Pakistan found that pneumonia, diarrhea, and impetigo were significantly less frequent among children in households that received plain soap and hand-washing promotion than in control households.14

Alcohol-based waterless hand sanitizers, which contain 60% to 95% ethanol, are generally more effective for hand antisepsis by health care workers and cause less skin irritation and dryness than does hand washing with soap and water.15 Data on the use of these agents in household settings are limited to 2 studies of families with children in child care. An observational prospective cohort study found that their use was associated with reduced transmission of respiratory infections,16 and an RCT found that their use reduced transmission of GI infections.17 Ethanol is highly active against MRSA in vitro, as will be discussed. The efficacy of alcohol-based hand sanitizers for preventing staphylococcal skin infections has not been studied, however.

Other hygienic interventions that may be useful in preventing skin infections are summarized in the Box. Although none of these interventions has been rigorously studied for the prevention of recurrent MRSA skin infections, all are safe and reasonable recommendations for general hygiene.1,15,18

TOPICAL ANTISEPTICS
Clinicians frequently recommend bathing or hand washing with topical antiseptics for patients with recurrent skin infections. Intuitively appealing as this approach may be, limited data exist to support the efficacy of topical antiseptics or antimicrobial soap in preventing MRSA skin infections.

The 1994 FDA Tentative Final Monograph for Healthcare Antiseptic Drug Products recognizes only 2 biocides as safe and effective for use as antiseptic hand washing agents: povidone-iodine (5% to 10%) and ethanol (60% to 95%).15 These 2 agents, at clinically achievable concentrations, demonstrate better bactericidal activity against MRSA than do other commonly used antiseptics.19

Two studies compared the effectiveness of various antiseptics at reducing MRSA colony counts on experimentally contaminated fingertips. Povidone-iodine (7.5% to 10%) and ethanol (70% to 80%) consistently eliminated more than 99% of bacteria; chlorhexidine (4%) and plain liquid soap achieved bacterial reductions of 96% to 99%; and simply rinsing with tap water eliminated 95.2% of bacteria.20,21

Povidone-iodine. This agent has good antimicrobial activity against MRSA, but its use is frequently associated with skin irritation.15 In addition, concerns about systemic toxicity persist.

In 1980, Block22 reported using topical povidone-iodine in a family of 7 persons, each of whom had severe recurrent furunculosis. Family members applied povidone-iodine to their entire body surface and anterior nares 3 times daily and used it for hand washing. This regimen was associated with a “very marked decrease in frequency of recurrence of staphylococcal furuncles in all family members.” However, it had to be abandoned after 4 children were found to have elevated serum concentrations of thyroid-stimulating hormone. This report served as a warning that systemic absorption of iodine can occur with topical use of povidone-iodine, not only in neonates and burn victims but also in older children with intact skin.

Chlorhexidine gluconate. This agent has been available in the United States since the 1970s. Although chlorhexidine has generally good antimicrobial activity against gram-positive bacteria, it is significantly less active in vitro against MRSA than it is against methicillin-susceptible strains of S aureus.23,24

In an RCT of 114 MRSA-colonized adults, MRSA was eradicated 30 days after treatment in only 8% of subjects who washed once daily for 5 days with chlorhexidine and in 13% of those who washed with placebo (all patients in this study also applied intranasal mupirocin ointment 3 times daily for 5 days). Chlorhexidine users, however, were more likely than controls to report skin fissures (17.7% vs 1.8%; P = .01), itching (41.5% vs 10.9%; P = .001), and burning of the skin (50.0% vs 9.1%; P < .001).25

Chlorhexidine is no more active than plain liquid soap against MRSA in vitro and on experimentally infected hands. Moreover, its efficacy for skin decolonization remains unproved and its use is frequently associated with dermatitis. Available evidence does not support the use of this agent as part of a MRSA decolonization strategy.

Hexachlorophene. This agent was used frequently in hospitals during the 1950s and 1960s, before it was found to be associated with neurological toxicity in infants. The FDA has not recognized hexachlorophene as safe and effective for use as an antiseptic, and it is dispensed only by prescription.15 Two college football teams employed hexachlorophene showers as part of their strategies to contain MRSA skin infection outbreaks, but the role of this antiseptic in the resolution of the outbreaks is unclear.26,27 In vitro, the bactericidal activity of hexachlorophene against MRSA is comparable to that of chlorhexidine and significantly less than that of povidone-iodine.28

Antimicrobial soaps have become ubiquitous in recent years; one study found that 76% of liquid soaps and 29% of bar soaps available commercially contain either triclosan (0.1% to 0.45%) or the related compound, triclocarban.29 Nevertheless, multiple studies have found that antimicrobial soap is no more effective than plain soap at preventing infections of the skin, respiratory tract, or GI tract in household settings.30 Thus, it appears that while the decision to wash one’s hands is critically important, the choice of soap product is less so.

Data regarding the activity of triclosan and triclocarban against MRSA are sparse. In one experimental study, 1% triclosan eliminated MRSA from hands, whereas 4% chlorhexidine did not.31 Two reports have described elimination of MRSA from inpatient neonatal units after the introduction of triclosan-containing soaps (1.0% and 0.3%, respectively), in addition to other infection control measures.32,33

In an RCT involving patients with atopic dermatitis, those who bathed with soap containing 1.5% triclocarban had greater reductions in S aureus colonization and in the severity and extent of skin lesions than did those who used plain soap.34 This study, however, did not specifically focus on patients colonized with MRSA.

Household bleach. The active ingredient of this environmental disinfectant is sodium hypochlorite. The hypochlorite hand rinse has historical significance: Semmelweis demonstrated its effectiveness in preventing mortality from puerperal fever in 1847.35 Hypochlorite is no longer used for hand hygiene, owing to its odor and tendency to cause skin irritation.15

Some clinicians advocate “bleach baths” for patients with recurrent staphylococcal skin infections, despite the absence of published data on the safety or efficacy of this practice. In a review article, Kaplan18 noted that bathing for 15 minutes twice weekly in water to which household bleach has been added (1 teaspoon per gallon of water) might decrease the frequency of furunculosis recurrences. Clinicians and patients should note, however, that one product’s Web site specifically states that bleach “is not for personal usage.”36

INTRANASAL THERAPIESMupirocin. This topical antibiotic has activity against streptococci and staphylococci. Its primary use is for treatment of superficial skin infections, but in recent years it has been frequently prescribed for application to the anterior nares in patients with recurrent staphylococcal skin infections. Indeed, intranasal mupirocin is recommended for staphylococcal decolonization more frequently than any other single intervention.12

Intranasal mupirocin can eradicate nasal S aureus carriage, at least transiently.37-41 In one large study, 339 colonized health care workers were randomly assigned to receive either intranasal mupirocin ointment or a placebo ointment twice daily for 5 days.37,38 At the end of therapy, 13% of mupirocin recipients remained colonized, compared with 93% of placebo recipients. Mupirocin’s effectiveness is only temporary, however; recolonization is the rule. Multiple studies have confirmed that most mupirocintreated patients will again have S aureus recovered from intranasal cultures within 12 months of the end of treatment.37-41

Mupirocin is less active against MRSA than against methicillin-susceptible S aureus in vitro,42 and it is less than optimally effective for decolonization of MRSA carriers as well. In one study, 102 adult inpatients colonized with MRSA were randomly assigned to receive 5 days of intranasal therapy with mupirocin or placebo; all patients also bathed daily with chlorhexidine. On day 26 after completion of therapy, MRSA was recovered from 1 or more sites in 75% of mupirocin recipients and in 82% of placebo recipients (P = .40). Moreover, 56% of mupirocin recipients had MRSA recovered from nasal cultures.43

A central assumption in the rationale for nasal decolonization therapy is that eradicating staphylococcal colonization will prevent recurrent skin infections. Extant evidence, however, contradicts this assumption. Staphylococcal infections still develop in patients who are successfully decolonized by mupirocin and at rates similar to those in patients who do not receive decolonization therapy.

An RCT of 127 nursing home residents colonized with S aureus found a nonsignificant reduction in infection rates in those who received intranasal mupirocin for 14 days compared with those who received placebo (5% vs 15%; P = .10), even though mupirocin recipients were more likely than controls to have negative cultures after therapy (88% vs 13%; P < .001). Furthermore, all 3 mupirocin recipients in whom staphylococcal infections developed had been successfully decolonized and remained free of nasal S aureus at the time of their infections.44

In another study, 134 soldiers colonized with MRSA were randomly assigned (in clusters, by training class) to receive intranasal mupirocin or placebo twice daily for 5 days. Over 16 weeks of observation, skin or soft tissue infections developed in 7.7% of placebo recipients and in 10.6% of mupirocin recipients (rate difference [RD], –2.9%; 95% confidence interval [CI], –7.5% to 1.7%). Moreover, decolonization of MRSA carriers did not significantly change the infection rate in close contacts. Of the colonized soldiers’ training classmates, infections developed in 4.3% (63 of 1459) of the classmates of those in the placebo group and in 3.5% (56 of 1607) of the classmates of those in the mupirocin group (RD, 0.8%; 95% CI, –1.0% to 2.7%).45

These data demonstrate that a single course of intranasal mupirocin is not effective for prevention of recurrent staphylococcal skin infections. Whether repeated courses of mupirocin can achieve this goal has not been as well studied.

In an RCT, S aureus–colonized adults with recurrent furunculosis received monthly courses of intranasal mupirocin (twice daily for the first 5 days of the month) or placebo for 1 year. Results favored the mupirocin group: 9 of 17 patients in this group had further skin infections, compared with 16 of 17 patients in the placebo group (P = .02).46 This study should be interpreted cautiously, however, because the authors did not perform an intent-to-treat analysis; instead they excluded 6 enrolled patients from the final analysis. Moreover, this study did not specifically evaluate patients colonized with MRSA, and it is doubtful that its results could be extrapolated to that population.

The clinical usefulness of mupirocin is also limited by the worldwide emergence of resistant MRSA strains.47-54 In 2000, a survey of 2159 clinical isolates of S aureus found mupirocin resistance (defined in this study as a minimal inhibitory concentration [MIC] of 16 μg/mL or greater) in 18% of MRSA isolates from Europe and in 14% of those from North America.47 Moreover, a 1999-2002 study in Saskatchewan found that more than 50% of 184 MRSA strains showed high-level mupirocin resistance (MIC, 256 μg/mL or greater).54

Limited data suggest that mupirocin might be useful for prevention of health care–associated infections in selected patient populations. 55,56 Therefore, indiscriminate use of intranasal mupirocin in patients with recurrent skin infections-for whom its effectiveness is unproved-might render it less useful for other, potentially more important indications.

Tea tree oil. This is an essential oil derived from the Australian plant Melaleuca alternifolia; it has broad antimicrobial activity.57 A variety of products containing tea tree oil are available, including soaps, shampoos, and creams, and their use has been advocated for such conditions as furunculosis, acne, superficial fungal infections, and herpes labialis.57,58

Tea tree oil is less active than mupirocin against MRSA in vitro,51 and it appears to be no better than mupirocin for MRSA decolonization. A study of 236 adults colonized with MRSA compared 5 days of a tea tree oil regimen (tea tree oil 5% body wash daily plus tea tree oil 10% cream intranasally 3 times daily) to a “standard” regimen (chlorhexidine 4% body wash daily plus mupirocin 2% ointment intranasally 3 times daily). Fourteen days after the completion of therapy, MRSA had been eradicated from 41% of those who received the tea tree oil regimen and from 49% of those who received the standard regimen (P = .29).58

Patients who wish to use “natural” products may find the idea of using tea tree oil appealing. Nonetheless, available data do not support the use of tea tree oil to prevent recurrent MRSA skin infections.

SYSTEMIC ANTIMICROBIALS
In theory, systemically administered antibiotics (such as TMP/SMX, rifampin, clindamycin, or doxycycline) might eradicate colonization from mucosal sites beyond the reach of topical agents and, thus, either alone or in combination with topical and/or intranasal interventions, might eliminate the staphylococcal carrier state. In a review of MRSA decolonization strategies, Boyce59 listed 12 different oral antibiotics that have been used, alone or in combination, for this purpose. Nonetheless, a systematic review of published trials concluded that insufficient evidence exists to recommend systemic antibiotics for MRSA decolonization.60

Limited data suggest that prophylactic administration of systemic antibiotics might reduce the frequency of recurrent S aureus skin infections. In an RCT, new abscesses developed during the treatment period in 2 of 11 adults who received oral clindamycin (150 mg/d) for 3 months, compared with 7 of 11 patients who received placebo.61 Although this difference is of marginal statistical significance, interpretation of this study is hindered by its small sample size and its lack of an intent-to-treat analysis (3 enrolled patients were excluded from the efficacy analysis).

To date, no RCT has specifically evaluated the efficacy of systemic antibiotics for preventing recurrent skin infections caused by MRSA. Moreover, even if 1 or more drugs is found to be effective, the anticipated benefit of prolonged systemic therapy will still need to be weighed against the risks of toxicity and of increasing antimicrobial resistance.

COMBINED REGIMENS
A recent study evaluated a combined regimen of topical, intranasal, and systemic interventions for MRSA decolonization in 146 hospitalized adults. Patients were randomly assigned to receive treatment (2% chlorhexidine washes, 2% mupirocin ointment intranasally, and oral rifampin and doxycycline for 7 days) or no treatment. Three months after completing therapy, 74% of treated patients had culture results that were negative for MRSA, compared with 32% of those not treated (P < .0001). However, at an 8- month follow-up, only 54% of treated patients still had cultures that were negative for MRSA.62

At present, there is no evidence that combinations of topical, intranasal, and oral antimicrobials are effective in preventing MRSA skin infections. On the other hand, combined regimens expose patients to both costs and potential side effects. Such regimens should probably be avoided, at least until the efficacy of one of them is confirmed.

RECOMMENDATIONS
Recurrent staphylococcal skin infections are frustrating for patients, their families and their health care providers. It is understandable that clinicians wish to prescribe something for these patients in the hope of preventing further recurrences. Unfortunately, the published evidence to date does not clearly demonstrate that any topical, systemic, or intranasal therapy-or any combination of the three-is effective for this purpose.

This lack of evidence notwithstanding, clinicians continue to recommend various combinations of decolonization therapies for patients with recurrent skin infections. The potential adverse consequences of such actions are 3-fold:
•Patients are exposed to possible side effects.
•The threat of antimicrobial resistance is increased.
•Money is spent on interventions that are unproved.

Some additional disadvantages of specific popular agents for staphylococcal decolonization are summarized in the Table.

RCTs with large sample sizes are needed to determine the optimal regimen for preventing recurrent MRSA skin infections-assuming that an optimal regimen exists. Future studies along these lines should incorporate intent-to-treat analyses of clinical (number of skin infections) rather than microbiologic (percentage with negative intranasal cultures) outcome measures.

Until an optimal decolonization regimen is identified-or a safe and immunogenic S aureus vaccine is available-hygiene is likely to remain the cornerstone of efforts to prevent recurrent skin infections (see Box). In particular, hand hygiene should be promoted to all affected patients and their families. Frequent hand washing (with plain soap) and the use of alcohol-based waterless hand sanitizers are safe and inexpensive measures with proven value in preventing illness transmission within households.14,16,17

Therapeutic Agents Mentioned in This Article:
Clindamycin* (Cleocin)
Chlorhexidine gluconate (Bactoshield, Exidine, Dyna-Hex, Hibiclens, Hibistat)
Doxycycline* (Periostat, Adoxa, Atridox, Doryx, Oracea, Monodox, Vibramycin, Doxyhexal)
Hexachlorophene (pHisoHex, Septisol)
Minocycline* (Dynacin, Myrac, Soldyn, Minocin, Arestin)
Mupirocin* (Bactroban)
Povidone-iodine* (Acu-dyne, Aerodine, Betadine, Betagen, Biodine, Etodine, Iodex, Mallisol, Minidyne, Operand, Polydine, Povidine)
Rifampin* (Rifadin, Rimactane)
Trimethoprim/sulfamethoxazole* (Bactrim, Cotrim, Septra, Sulfatrim, Tribrissen)
*Available in generic formulation

References:

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• Aiello AE, Larson EL, Levy SB. Consumer antibacterial soaps: effective or just risky? Clin Infect Dis. 2007;45(suppl 2):S137-S147.

• Boyce JM, Pittet D; Healthcare Infection Control Practices Advisory Committee; HICPAC/SHEA/APIC/IDSA Hand Hygiene Task Force. Guideline for hand hygiene in health-care settings. Recommendations of the Healthcare Infection Control Practices Advisory Committee and the HICPAC/SHEA/APIC/ IDSA Hand Hygiene Task Force. MMWR Recomm Rep. 2002;51(RR-16):1-45.

• Loeb M, Main C, Walker-Dilks C, Eady A. Antimicrobial drugs for treating methicillin-resistant Staphylococcus aureus colonization. Cochrane Database Syst Rev. 2003;(4):CD003340.

• Tacconelli E, Carmeli Y, Aizer A, et al. Mupirocin prophylaxis to prevent Staphylococcus aureus infection in patients undergoing dialysis: a meta-analysis. Clin Infect Dis. 2003;37:1629-1638.

• van Rijen MM, Bonten M, Wenzel RP, Kluytmans JA. Intranasal mupirocin for reduction of Staphylococcus aureus infections in surgical patients with nasal carriage: a systematic review. J Antimicrob Chemother. 2008;61:254-261.