Increasing Prevalence of MRSA Skin Infections in General Population and Current Treatment Strategies

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Abstract

In this review, literature highlights the upward trends in community prevalence of methicillin-resistant Staphylococcus aureus infections. Community-associated MRSA skin infections are coming into their own as a distinct therapeutic challenge, complicated by their ubiquitous occurrence in a variety of institutional environments. Strategies for the treatment consist of both medication and non-drug choices. There is a wide variety of pharmacological agents available for management, but extensive studies are still required to put in place evidence-based consensus treatment guidelines.

Introduction

This review addresses issues concerning the increasing prevalence of methicillin-resistant Staphylococcus aureus (MRSA) skin infections in the general population and current treatment strategies. MRSA diseases have constituted a formidable clinical challenge for several years. Although the pathogen has been typically associated with health care environments and patients who have been exposed to some form of hospitalization-related treatment (i.e. health care-associated MRSA), an emerging development has been the increasing occurrence of community-associated or community-acquired MRSA types, resulting in a new challenge to the medical community.

Increasing Prevalence of MRSA Skin Infections in General Population and Current Treatment Strategies

The classical mechanism of resistance of MRSA to beta-lactam antibiotics is alteration of target penicillin-binding proteins which makes them have a low affinity for the penicillins. This is mediated by the mecA gene, carried on the staphylococcal cassette chromosome (SCC). However, through alternative mechanisms several MRSA strains now possess resistance to multiple classes of antibiotics.

Community-acquired MRSA differs from health care-associated MRSA in a few respects (Rybak & LaPlante, 2005). Isolates of community MRSA are generally susceptible to non-beta-lactam antibiotics, while the hospital-acquired MRSA isolates typically show resistance to multiple antibiotics. Also, community isolates are genotypically distinct from health care-derived types, with a novel methicillin resistance gene element previously unreported among the health care-derived isolates. In addition, population isolates typically occur in patients who do not have any of those MRSA associated risk factors. Community-associated MRSA isolates have a greater likelihood of encoding virulence factors, such as enterotoxins, and the bicomponent cytotoxin Panton-Valentine leucocidin, which was previously reported to be produced by less than 5% of Staphylococcus aureus isolates. It is believed that the genetic patterns observed in community-associated MRSA isolates suggest that they must have resulted from methicillin-sensitive strains that successfully incorporated the SCCmec IV element which is uniquely characteristic of community-acquired MRSA.

According to guidelines from the Centers for /Disease Control and Prevention, the criteria for distinguishing between community-associated and health care-associated MRSA are as follows (Rybak & LaPlante, 2005):

  • The diagnosis must be made in an outpatient setting or by culture showing MRSA within 48 hours after admission to the hospital
  • The patient must not have experienced any of the following during the years before an infection: hospitalization; admission to a nursing home, skilled nursing facility, or hospice; dialysis; or surgery.
  • The patient must be without permanent indwelling catheters or medical devices that pass through the skin into the body.

The increasing prevalence of community-associated MRSA skin infections is of additional concern because owing to their high virulence, such skin infections can lead to severe necrotizing pneumonia with a high mortality rate.

Review of the Literature

Prevalence in Health Care-Related Settings

In a prospective observational study in California, Frazee and co-workers (Frazee et al., 2005) attempted to determine the prevalence of MRSA among emergency department patients with skin and soft tissue infections identify demographic and clinical variables related to MRSA, and antimicrobial susceptibility and genotype characterize MRSA. Over 51% of the 119 patients studied had MRSA infections, which constituted 75% of the S. aureus cultures isolated. 76% of the cases fit the clinical definition of community acquired MRSA. 99% of MRSA isolates had the SCC mec IV allele (typical of community-associated MRSA), 94.1% had the Panton-Valentine leukocidin genes and 87.1% belonged to a single clonal group (ST8:S). A limitation of the study lay in the use of a patient population which was essentially a convenience sample.

In a 2005 report (Moran et al., 2005), Community-associated MRSA was found to be the most common pathogen among patients with skin and soft tissue infections seeking treatment at a Los Angeles (USA) area emergency department. The proportion caused by MRSA increased from 29% in 2001 to 2002 to 64% in 2003 to 2004. Interestingly, the study found that no clinical or historical features reliably predict MRSA etiology.

Roesch and co-workers reported on the elimination of a community-acquired MRSA infection in a nurse with atopic dermatitis (Roesch et al., 2005).

Johnston and co-workers described an investigation of soft-tissue infections caused by community-acquired MRSA strains in two healthcare workers employed in an outpatient clinic for patients with human immunodeficiency virus infection (Johnston et al., 2006). External sample cultures from multiple surfaces in the clinic have developed toxin-producing CA-MRSA strains, indicating that fomites may play a role in the transmission of those MRSA strains.

Prevalence in Military Facilities

In a study at the Norfolk naval base, Zinderman and co-workers reported an outbreak of 235 community-acquired MRSA infections among military recruits (Zinderman et al., 2004). The close contact between recruits and the physical demands of the training may have led to the spread of MRSA in this unique environment. Control measures included better sanitation and professional aggressiveness.

In an interesting report from the military environment (Pagac et al., 2006), recent outbreaks of mysterious skin lesions on multiple personnel at several military facilities were initially blamed on spiders. Requests for inspection and management of the pests were made to remedy the situation. Greater scrutiny of the situation led to a hypothesis that instead of spiders, an infectious outbreak of community-acquired CA-MRSA should be investigated as the etiology. This bacterial etiology was verified by subsequent cropping of the lesions on staff at one plant. The authors noted that barracks, as well as other close quarter military living conditions, are ripe environments for the establishment, persistence, and spread of community-acquired MRSA, and recommended that military medical staff would find CA-MRSA as an etiologic agent more likely than spider bites for cutaneous eruptions where multiple lesions occur in one person or multiple patients with similar lesions.

In a review by Cloran, MRSA was noted as being a pathogen of growing concern among community-based practices in medicine, particularly those in the military (Cloran, 2006). The risk of colonization and infection by community-acquired MRSA is significantly higher among military members than that of the general population. The unique environment of the deployed, military aviator (impaired hygiene practices, close contact in warm, space-limited cockpits, and shared life-support equipment) may increase the risk of CA-MRSA colonization, infection, and transmission and therefore warrants the flight surgeon’s clinical attention.

Prevalence in Correctional Facilities

A retrospective investigation of skin and soft tissue infections caused by community-associated MRSA strains among inmates in a Wisconsin correctional facility suggested a shift in MRSA genotype (Stemper et al., 2006). The case timeline indicated a displacement of USA400 clone by USA300 clone. From the results of the investigation, the USA300 index case was associated with an infected new tattoo.

In a review of MRSA skin infection prevalence, Lu and Holtom (Lu & Holtom, 2005)noted that young and healthy persons in crowded conditions are at risk, including athletes, military personnel, jail inmates, and children in daycare.

Prevalence Among Athletes and in Sports Facilities

Saben reported on a case of community-acquired MRSA skin infection in a football player (Saben, 2004).

Using a retrospective cohort study and nasal-swab survey of players and staff members during the 2003 football season, Kazakova and co-workers reported an investigation of an outbreak of abscesses due to MRSA among members of a professional football team (St. Louis Rams) and examined the transmission and microbiologic characteristics of the outbreak strain (Kazakova et al., 2005). S. aureus recovered from bite, nasal and ecological cultures was analyzed using pulsed-field gel electrophoresis (PFGE) and resistance and toxin gene typing. Team MRSA was contrasted with other isolates from the population and hospital isolates. During the football season, there was an incidence of 9% of MRSA skin and soft tissue infections. All of the infections developed at turf-abrasion sites. MRSA infection was significantly associated with the position of the lineman or linebacker, and a higher index of body mass. No MRSA was found in nasal or environmental samples; however, S-susceptible to methicillin. aureus was retrieved from whirlpools and tap gel and 35 out of 84 nasal swabs from players and staff (42%). MRSA from a rival football team and from other population clusters and irregular cases had PFGE trends which could not be differentiated from those of the Rams ‘ MRSA; Panton-Valentine leukocidin gene and staphylococcal-cassette-chromosome gene complex mec type IVa resistance (clone USA300-0114)

Prevalence: Other Data

It has been suggested that sexual habits could also be a contributory factor to the spread of community acquired MRSA. Lee and his colleagues studied community-associated MRSA skin infections among HIV-positive people having sex with men by conducting a case-control study of 35 patients and 76 controls subjects (N. E. Lee et al., 2005). They found that community-associated MRSA skin infections were associated with high-risk sex and drug-using behaviors and with environmental exposures but not with immune status.

 In a Switzerland study (Aramburu et al., 2006), the incidence of MRSA skin infections in Geneva was monitored over a three-year period from 2002 to 2004 using a voluntary reporting system. Of the 58 cases reported, most were family related, and the prevalence was commonest in people under 40 years. 71% of the cases were infected and 29% were colonized. Most infected cases presented with skin lesions such as furunculosis, impetigo or abscess, and most cases had no underlying disease. It was interesting that 65% of the cases had traveled abroad, which underlines the challenge posed by virulence in a global setting. It was also noted that 69% of the isolates carried the Panton-Valentine leukocidin (PVL) toxin. The study concluded there was a need for continued surveillance to adequately describe transmission patterns and the spread of the pathogen.

A recent epidemiological study conducted in Atlanta, Georgia examined the proportion of infections caused by community-acquired MRSA, associated clinical characteristics, and the molecular epidemiology of community-acquired MRSA among persons with community-onset S. aureus skin and soft-tissue infection, using an active, prospective laboratory surveillance to identify Staphylococcus aureus from skin and soft-tissue sources (King et al., 2006). It was found that MRSA accounted for 72% of community-onset skin and soft-tissue infection due to Staphylococcus aureus. Of these, 99% were found to be of the MRSA USA 300 clone type (using pulsed-field gel electrophoresis and antimicrobial susceptibility patterns). Factors found to be significantly associated with community-acquired MRSA included African-American race, female sex, and hospitalization within the past twelve months. Inadequate initial antibiotic therapy among those with community-acquired MRSA (65 percent) was statistically significantly more common than among those with methicillin-susceptible Staphylococcus aureus skin and soft tissue infection (1 percent). An important limitation of the study lay in the non-availability of some MRSA isolates for molecular typing, leading to the use of antimicrobial susceptibility testing as a parameter for their epidemiological classification.

Treatment Strategies: Pharmacologic Measures

In a retrospective cohort study at two tertiary medical centers involving 492 adult patients with 531 independent episodes of community-acquired MSRA (Ruhe et al., 2007), the impact of active antimicrobial treatment and other potential risk factors on the outcome for patients with uncomplicated community acquired MRSA skin and soft tissue infections was examined, using treatment failure as the primary outcome of interest. The results showed that treatment failure occurred in 45 (8%) of 531 episodes of community-onset MRSA skin and soft tissue infections. Therapy was effective in 296 (95 percent) of 312 patients receiving an active antibiotic compared to 190 (87 percent) of 219 patients not receiving an active antibiotic (P=.001). In contrast, the use of an inactive antimicrobial agent was an independent predictor of treatment failure. The study’s conclusions weighed in on the benefit of empirical treatment of patients with skin infections likely due to MRSA using antimicrobial agents with activity against the organism.

A randomized open-label study compared oral linezolid and intravenous vancomycin for management of complicated skin and soft-tissue infections caused by MRSA (Sharpe et al., 2005). Linezolid was associated with greater rates of clinical cure and improvement, a 3-day shorter median length of stay, and reduced outpatient charges, all at acceptable significance levels. Further treatment failures and resulting lower-extremity amputations (P=.011) were associated with the vancomycin therapy. In comparison, linezolid was associated with a shortened length of stay and emergency costs. However, the results of the study may not necessarily apply to MRSA infections that do not involve the lower extremities.

In a randomized pharmacoeconomic study of linezolid versus vancomycin (McKinnon et al., 2006), 717 patients were enrolled in a multinational, open-label, clinical trial of skin and soft tissue infections caused by suspected or proven methicillin-resistant Staphylococcus aureus. It was found that linezolid therapy was associated with improved clinical outcomes and significantly lower treatment costs than was vancomycin. The largest cost advantage was demonstrated in patients with documented MRSA infections.

In a valuable prospective cohort study of 201 patients discharged after hospitalization for both community-acquired methicillin-resistant as well as methicillin-sensitive Staphylococcus aureus infections, outcomes based on clinical response and re-infection were studied (Miller et al., 2007). Contrary to the widespread belief that patients with CA-MRSA skin infection may have more serious outcomes than those with CA-MSSA skin infection, the study found similar outcomes in these two groups after hospital discharge. A lack of receipt of incision and drainage was correlated with clinical nonresponse at day 30. The data also suggested that close contacts of persons with CA-MRSA skin infection may have a higher likelihood of acquiring an infection.

A retrospective analysis of clinical presentation and treatment 2004 outbreak in Los Angeles (Iyer & Jones, 2004) concluded that the first line treatment is incision and drainage in combination with linezolid, vancomycin, or combination trimethoprim/sulfamethoxazole and rifampin.

Another study conducted simultaneously in two pediatric emergency departments in the southeastern United States and southern California showed that all community-associated MRSA isolates tested were sensitive to vancomycin, trimethoprim-sulfamethoxazole, rifampin, and gentamicin (Hasty et al., 2007). One isolate was clindamycin resistant at each centre. The sensitivities at both institutions were similar despite their geographical distance, suggesting that optimal diagnostic and management strategies for CA-MRSA will likely be widely applicable if results from a larger, more collaborative study yield similar findings.

Linezolid also inhibits toxin production, which may prove to be of significant benefit since the gene encoding for the production of Panton–Valentine leukocidin toxin (which promotes inflammation and tissue necrosis) is almost always found in community-acquired MRSA strains (de Almeida & Bush, 2006). Although the empirical use of trimethoprim–sulfamethoxazole, minocycline, doxycycline, and clindamycin is often recommended, few published clinical data are available to substantiate their use, and most data precede the recent emergence of MRSA as a common pathogen in community-acquired skin and soft-tissue infections.

It has also been noted that the lipopeptide daptomycin and the tetracycline tigecycline are additional treatment options, although they are hampered by their parenteral-only route of administration; in addition, few patients with MRSA infection were enrolled in trials that studied these drugs (de Almeida & Bush, 2006).  It was suggested that linezolid should be considered as one of the antimicrobial agents of choice for empirical treatment of skin and soft-tissue infections in areas with a high prevalence of community-acquired MRSA, especially with its 100% oral bioavailability, which potentially eliminates the need for hospital admission in many cases.

Barnes and co-workers reported on the successful utilization of alternative oral antibiotic therapy to patients with community-acquired MRSA soft tissue infections, using both retrospective and concurrent review methodologies (Barnes, Dooley, Hepburn, & Baum, 2006). The following antibiotics were successful in effecting remission: clindamycin, trimethoprim/sulfamethoxazole, doxycycline/minocycline, fluoroquinolones, and a beta-lactam antibiotic (with abscess drainage).  They concluded that community-acquired MRSA skin and soft tissue infections can be successfully treated with orally administered antibiotics to which the organism has demonstrable in vitro susceptibility.

In Frazee’s study discussed earlier on, the antimicrobial susceptibility among MRSA isolates was reported to be trimethoprim/sulfamethoxazole 100%, clindamycin 94%, tetracycline 86%, and levofloxacin 57% (Frazee et al., 2005).

Johnson argued for the merits of the tetracyclines, of which minocycline is the most potent against staphylococci and with which there is the most clinical experience in treating MRSA infections (Johnson, 2006). Tetracyclines are highly orally bioavailable, inexpensive, and well tolerated, and remain active against nearly 100% of S. aureus isolates (whether methicillin-resistant or methicillin-susceptible) in many U.S. locales. These agents represent an economical option that avoids certain problems associated with clindamycin and trimethoprim–sulfamethoxazole.  He advocated that these agents deserve more attention in commentaries and should be studied in clinical trials to establish their comparative efficacy for treatment of MRSA infections.

A recent report described the successful use of doxycycline in treating patients with community-associated MRSA skin infections that have earlier failed treatment or experienced infection recurrence with other antimicrobial agents (Carter, Ebers, Younes, & Lacy, 2006). The results were all the more promising as no doxycycline adverse effects were noted in the patients’ medical records and no patient discontinued therapy before resolution of infection.

The potential merits of using cephalosporins were advocated in a recent review (Hedrick, 2006). Cephalosporins are an effective broad-spectrum empirical treatment for uncomplicated skin and soft tissue infections, with considerable activity against methicillin-susceptible S. aureus. Additionally, the use of antimicrobials in infectious strains that may be resistant does not seem to be correlated with adverse outcomes reported by patients, indicating that cephalosporins may still be present be effective in treating community-acquired MRSA-associated skin infections.

Treatment Strategies: Non-Pharmacologic Measures

From the results of a recent study (Fleming, Brown, & Tice, 2006), it was recommended that clinicians have an awareness of high-risk patients, perform routine culturing of soft tissue infections, and prescribe antibiotics based on culture and sensitivities. Awareness, prevention, early diagnosis, and implementation of effective antibiotic management by nurse practitioners were also advocated to help limit an epidemic of community-acquired MRSA.

It has been recommended that in order to prevent MRSA infections from spreading in health-care settings, health-care providers should use standard precautions and appropriate hand hygiene between treating patients, clean exam room surfaces with commercial disinfectant or diluted bleach (1 spoonful of bleach in 1 quarter of water) and carefully dispose of dressings and other materials that come into contact with them pus, nasal discharge, blood, and urine (Centers for Disease Control and Prevention, 2003).

In a controversial study, a team at the University of Texas Southwestern Medical Center reported on the management and outcome of children with skin and soft tissue abscesses caused by community-acquired MRSA (M. C. Lee et al., 2004). A total of sixty-nine children presenting to for management of skin and soft tissue abscesses caused by culture-proved CA-MRSA were prospectively followed and retrospective chart review was performed 2-6 months after the initial visit. We concluded from their findings that incision and drainage without adjunctive antibiotic therapy was an effective management of MRSA skin and soft tissue abscesses with an initial diameter of less than 5 cm in immunocompetent children.

In a rejoinder to the Lee publication, Miller and Spellberg challenged the notion that withholding antibiotics in community acquired MRSA skin and soft-tissue infections is beneficial. They pointed out that that the study was limited by a small sample size, which biased the significance of the treatment failures recorded, and that there was not enough investigation of uncommon but very serious outcomes with the treatment failures. They drew from their own experience to buttress the latter point. They concluded that nothing short of large, randomized, prospective studies will be required to definitively clarify whether short antibiotic courses or no antibiotics in conjunction with surgical drainage results in different outcomes of patients with skin/soft tissue infections caused by S. aureus.

Discussion

Prevalence

Although health care-associated MRSA infections have been known for many years, an emerging problem is that of MRSA infections that originate outside the hospital setting.

Since the first report of community-associated MRSA in 1982 (Centers for Disease Control and Prevention, 2001), onward march of the pathogen has been steady.  Outbreaks of community-associated MRSA skin infections have occurred in sports facilities, child care centers, correctional facilities, military barracks, and hospital emergency departments. Outbreaks have been reported at several locations in the United States, as well as in countries in Europe and Asia.

Risk factors have been found to include routine exposure to hospital facilities, high-risk sexual conduct, and drug use.

It has been identified as a growing problem for health care management because of its virulence and propensity for developing into life-threatening infections. It is also a challenge in the sense that treatment strategies have not been fine-tuned in the medical community, as collection of evidence in clinical trials is still ongoing.

Treatment Strategies

It is important that an early accurate diagnosis be made, considering the commonality of occurrences in which community-associated MRSA skin infections have been misdiagnosed as spider bites or some other kind of skin/soft tissue infection. This may be facilitated by paying attention to the following hints: history of contact with a prison facility or sports facility, previous treatment of the patient or a close contact for a spider bite, recurrent impetigo- or furunculosis-like skin diseases (Rybak & LaPlante, 2005).

Current consensus in the literature is that the first step in treatment is incision and drainage of abscesses, if any, followed by microbial culture and antibiotic sensitivity tests. If the patient has a recurrent infection, nasal swabs for determining carrier status are recommended. Intranasal mupirocin is recommended for patients testing positive for carrier status (Rybak & LaPlante, 2005).

Patients should be instructed on techniques for limiting the spread of the infection by avoiding contact with personal items and shared objects. Similarly, the spread can be controlled in health care settings by having practitioner implement appropriate infection control measures.

There are limited trials to demonstrate unequivocally the efficacy of therapeutic agents used in management of community-associated MRSA. However, current drugs being used include the tetracyclines (especially minocycline and doxycycline), clindamycin, the fluoroquinolones, and trimethoprim/sulfamethoxazole alone or in combination with rifampicin.

Clindamycin has been reported to be susceptible to inducible resistance. This can be pre-determined by the disk diffusion method (D-test), and current recommendations advise that this test must be carried out on the isolate if clindamycin is to be used.

The fluoroquinolones are associated with development of resistance, and caution is advised in their utilization.

Expectedly, the cephalosporins are not a popular choice, although some limited studies indicate their potential utility.

For severe infections, the mainstay of treatment has been vancomycin, but recent studies show the development of glycopeptide resistance, as well as the efficacy of new alternatives. One such is linezolid. Linezolid is orally active and has good target penetration. Other alternatives are the streptogramin combination drug quinupristin-dalfopristin and the lipopeptide daptomycin, which has been found useful in the treatment of multidrug-resistant strains.

It is important to note that more research is needed to definitively recommend therapeutic choices for community-acquired MRSA treatment because the number of randomized clinical trials done so far is limited, the patient groups investigated have been relatively small and limited in scope, and there is not much done to map the toxin-producing variants of the pathogen with current antibiotics available.

Conclusion

Community-associated MRSA skin infections are a recent and advancing menace in the society. The prevalence cuts across a wide variety of institutional settings, including hospital emergency departments, child care centers, sports facilities, military locations and prisons. The pathogen, while sharing a common origin with the health care-associated MRSA, has unique virulence and molecular properties which make it constitute a different kind of challenge. Treatment strategies used comprise proper wound management including incision and drainage, microbial culture and sensitivity tests, and aggressive treatment with appropriate antibiotics. The evidence in favor of using particular drugs still requires further wide-ranging clinical trials in order to arrive at streamlined therapeutic guidelines. Implementation of measures for controlling the spread of infection through contact is also a crucial element of the management strategy. 

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