Point-Counterpoint: Should You Cover MRSA?

      Yes. By Guy R. Pupp, DPM, FACFAS, and Mark A. Kachan, DPM. Given the increasing incidence of methicillin-resistant Staphylococcus aureus, one should consider empiric coverage against MRSA in high-risk patients with infected ulcerations in the lower extremity.       The most common pathogens in nosocomial skin and skin structure infections in the United States and Canada in 2000 were Staph aureus. Researchers have stated that approximately 30 to 60 percent of all Staph aureus isolates are methicillin-resistant Staph aureus (MRSA)-related.1,2 There has been a seemingly logarithmic growth over the past decade in the incidence of MRSA as a pathogen in the diabetic foot. Individuals with foot infections caused by MRSA organisms have been associated with poorer outcomes related to an increased risk of amputations and infection-related mortality.       In general, MRSA is almost always spread by direct physical contact and not through the air. The most common source of transmission is patients who already have a MRSA infection or patients who carry the bacteria on their bodies but do not have symptoms. The main mode of transmission to other patients is through human hands, especially the hands of healthcare workers. A person’s hands usually become contaminated with MRSA bacteria via contact with infected or colonized patients. Methicillin-resistant Staph aureus may also spread through indirect contact by touching contaminated objects such as towels, sheets, wound dressings, clothes, workout areas, etc.       Healthcare-associated MRSA occurs most frequently among patients who undergo invasive medical procedures or who have weakened immune systems, and are being treated in hospitals and healthcare facilities such as nursing homes and dialysis centers. It also tends to be common among elderly, chronically ill patients who have a significant history of receiving antimicrobial therapy. Methicillin resistant Staph aureus has become a major nosocomial pathogen in healthcare settings. It has commonly caused serious and potentially life-threatening infections, accounting for 12 percent of all bacteremias, 21 percent of skin infections and 28 percent of surgical site infections.3       In addition to healthcare-associated infections, MRSA can also be problematic in the community. When MRSA causes infections in patients with no established risk factors for MRSA infections outside of the hospital or healthcare facility, these patients may have community-acquired MRSA (CA-MRSA). This version of MRSA can be found in day care centers, schools and prisons, and generally occurs as skin infections that can look like pimples or boils. These skin infections often occur in otherwise healthy people. They are usually mild, limited to the surface of the skin and can be treated successfully with proper hygiene and antibiotics.       However, these MRSA-related infections can become swollen, painful and have draining purulence. If these wound infections are left untreated or are not recognized early, they can progress to life-threatening blood or bone infections because there are few effective antibiotics available for treatment. Community-acquired MRSA strains are usually sensitive to most other non beta-lactam agents commonly used as anti-staphylococcal drugs.       At this time, there are available treatment options for MRSA but they are limited because MRSA is resistant to many antibiotics.

What The Literature Reveals About The Increasing Incidence Of MRSA

      Antibiotic resistance among Staph aureus pathogens has been a problem for over five decades but the incidence of MRSA has truly accelerated in recent years. The National Nosocomial Infections Surveillance (NNIS) System has reported a dramatic increase in the rate of MRSA isolates (40 percent) from 1989 to 2003 in intensive care unit patients.2 Almost 60 percent of Staph aureus isolates in 2003 were healthcare-associated MRSA.2 The incidence of CA-MRSA is also increasing at an alarming rate.4       Staphylococcus aureus is the most predominant infecting pathogen in lower extremity skin and skin structure infections. In a 1999 study, Tentolouris, et. al., found that Staph aureus was the most prevalent pathogen of gram-positive aerobes isolated from foot wounds. This study also found that 40 percent of the Staph aureus isolates consisted of MRSA.5       As mentioned earlier, MRSA is becoming more prevalent in healthcare settings and in the community. According to the Centers for Disease Control and Prevention (CDC), the proportion of infections with antimicrobial resistance has been growing. In 1974, MRSA infections accounted for 2 percent of the total number of staphylococcal infections. In 1995, it was 22 percent. In 2004, this has been reported as high as 63 percent.6,7       Methicillin-resistant Staph aureus has also had a significant impact in incurring longer healing time; an increased cost of care; longer hospital stays; and increased mortality rates as compared to methicillin-susceptible Staphylococcus aureus (MSSA).5,8 In a study of New York City-based hospitals, Rubin, et. al., compared MRSA to MSSA. They found that patients with MRSA had a higher cost of care per patient ($34,000) as compared to MSSA ($31,000), and an increased mortality rate (21 percent) as compared to MSSA (8 percent).8       Researchers have found that infections associated with MRSA cause worse clinical outcomes in diabetic foot infections. The healing time for diabetic foot ulcers infected with MRSA is almost doubled (a healing time of 17.8 weeks without MRSA as opposed to 35.4 weeks with MRSA).5 Studies have also found a direct correlation with poorer wound healing in patients with MRSA-infected wounds.       Wagner, et. al., found a 20 percent healing rate in wounds with MRSA and conservative treatment versus a 61.5 percent healing rate in wounds without MRSA and conservative treatment.9 This study also found that MRSA infection increased the risk of lower extremity amputations. The study authors reported that patients with MRSA had a 52 percent risk for minor amputation as compared to a 30.5 percent risk for patients without MRSA. Patients with MRSA had a 22 percent risk for a major amputation while patients without MRSA had a 4.5 percent risk for major amputation.9 This study also found an increased risk of death (6 percent) may be associated with MRSA infections.9       In a retrospective study, Dang, et. al., examined the prevalence of microorganisms in wound cultures from 2001 compared with those from 1998 in a diabetic foot clinic. This study reported that the incidence of MRSA increased in diabetic foot infections despite infection control efforts.10 In 2002, Fejfarova, et. al., reported an association between the frequency of lower limb amputations in diabetic patients and the presence of resistant pathogens. This study found that 21 percent of all the patients had isolated resistant Staphylococcus species and that 43 percent of these patients who underwent amputations had resistant Staphylococcus species present as well.11

What Are The Risk Factors For Developing MRSA?

      There are several risk factors for both MRSA colonization and infection. In 2002, Graffunder, et. al., listed their assessment of risk factors for nosocomial MRSA. These risk factors included: previous hospitalization, in particular, a length of stay greater than 8.4 days; enteral feeding; surgery; and prior antibiotics.12       With the increasing concerns of medical liability, physicians often unnecessarily prescribe antibiotic therapy for non-infected wounds. In a 2005 study, Weber, et. al., found that fluoroquinolones, especially levofloxacin and ciprofloxacin, to be the most common antibiotics identified as risk factors for MRSA.13 Accordingly, proper clinical evaluation of foot infections is paramount. One must also check for systemic signs of infection including fever, chills, nausea, vomiting, tachycardia, shortness of breath and malaise. Research has shown that systemic signs of infection rarely accompany diabetic foot infections.14       After one has determined that the patient has an infection, the severity of the infection will dictate whether the patient needs oral or parenteral antibiotics, hospitalization and/or surgical intervention.       In 2003, Salgado, et. al., listed risk factors for CA-MRSA. These risk factors included: recent hospitalization ranging from one to 24 months; recent nursing home admissions within 12 months; recent outpatient visits within 12 months; recent antibiotic exposure within 12 months; chronic illness such as end-stage renal disease, diabetes mellitus; malignancy; injection drug use; and close contact with a person with an established MRSA infection.15

Making The Case For Empiric Coverage Of MRSA

      The Detroit Medical Center Update recently published the fact that 75 percent of inpatients in our Detroit area with diabetic staphylococcal infections turned out to have MRSA. Accordingly, when a patient with a longstanding history of similar infections presents to our clinic with a complex diabetic foot infection, we automatically assume MRSA and treat it accordingly.       One should consider empiric coverage against MRSA in high-risk institutions, geographical areas and when treating at-risk patients. These patients include those with previous MRSA infections, exposure to a previous course of antibiotics, recent hospitalization or nursing home stay, and immunocompromised patients.

Ensuring Proper Diagnosis And Culturing Technique

      In 2004, the Infectious Diseases Society of America (IDSA) published evidence-based clinical practice guidelines that specifically focused on diabetic foot infections and the staging of infected ulcers by the severity of infection.16       The diagnosis of diabetic foot infections is based on clinical signs and symptoms of infection. These signs and symptoms include erythema, pain, tenderness, warmth or induration with cellulitis or purulence. Deep probing of the ulcer may reveal poor tissue quality at the base. The IDSA indicated it is unnecessary to culture ulcers that show no clinical sign of infection.16       One may diagnose MRSA through a positive culture that the clinician can obtain via a small biopsy of skin or pus taken with a swab. However, obtaining a deep tissue culture from the base of a cleansed and thoroughly debrided wound provides the most accurate results.17 Once one has obtained the culture results from the lab and knows what the causative organism is, the clinician can select more targeted antibiotics. However, if you are treating a patient for an infection with broad-spectrum empiric antibiotics and he or she has noted improvement in local and systemic symptoms, one should continue this therapy regardless of what the sensitivity results show.17-19       Obtaining a culture from a known or suspected skin infection is especially useful in: recurrent or persistent cases of skin infection; in cases of antibiotic failure; and in cases that present advanced or aggressive infections such as bloodstream infections.

Emphasizing Effective Prevention And Treatment

      The good news is that MRSA is preventable. The first step to prevent MRSA is to prevent healthcare infections in general. Infection control guidelines produced by the Centers for Disease Control and Prevention (CDC) and the Healthcare Infection Control and Prevention Advisory Committee (HICPAC) are central to the prevention and control of healthcare infections and ultimately MRSA in healthcare settings. The CDC advises healthcare professionals to minimize using broad-spectrum antibiotics and monitor antibiotic use. Practitioners should discontinue antibiotic treatment when cultures are negative, when infection is not likely or when infection has resolved.       While the former antibiotic “gold standard” for MRSA infections was vancomycin, a few strains of Staphylococcus aureus have even developed some degree of resistance to vancomycin. The vancomycin-resistant strains may be more difficult to treat. Newer antibiotics are currently being developed to address this problem. The three new agents with demonstrated activity against MRSA are linezolid, daptomycin and quinupristin/dalfopristin with varying success rates.       Researchers have shown that linezolid has a similar efficacy profile to other antibiotic regimens used in treating MRSA infections.20 Recent studies show that linezolid provides a cost-effective treatment for complicated skin and skin structure infections in the diabetic foot.21-22

In Conclusion

      Keep in mind that MRSA may be present in both polymicrobial and monomicrobial foot infections. Indeed, MRSA is of increasing concern in skin and soft tissue infection, and is associated with poor diabetic foot infection outcomes. As podiatrists, we all know that 15 to 20 percent of patients with diabetes in the United States will be hospitalized for a foot complication. Foot ulceration is also the precursor to approximately 85 percent of lower extremity amputations among people with diabetes.       According to the IDSA Diabetic Foot Infection Guidelines, uninfected ulcers do not require antibiotic intervention. However, antibiotic therapy is necessary for virtually all infected wounds but is often insufficient without appropriate wound care. Therapy aimed solely at gram-positive cocci may be sufficient for mild to moderate infections when patients have not recently received antibiotic therapy. Empiric broad-spectrum therapy is appropriate for severe infections pending culture results and is also appropriate for high-risk patients. However, one should base definitive therapy on culture results and local resistance patterns.16       Current research suggest that infections associated with MRSA incur higher costs, higher amputation rates, extended hospital stays and increased morbidity.5,9,11,22 Accordingly, we recommend that physicians treating high risk patients consider the possibility of MRSA when selecting initial empiric antimicrobial therapy.       Institutions should consider “high risk patients” to be: patients who are at increased risk for MRSA by way of previous MRSA infection; those who have had exposure to previous courses of antibiotics; those who have recently hospitalized or had a nursing home stay; or patients in close contact with an MRSA or immunocompromised patient.       Finally, it goes without saying, that obtaining better specimens for cultures is the most important step in knowing if we truly are dealing with a MRSA infection.       Dr. Pupp is a Fellow of the American College of Foot and Ankle Surgeons. He is the Clinical Director of the Kern Foot and Ankle Clinic at Southeast Michigan Surgical Hospital in Warren, Mich.       Dr. Kachan is a second-year surgical resident at Southeast Michigan Surgical Hospital in Warren, Mich. References 1. Rennie RP, Jones RN, Mutrick AH. Occurrence and antimicrobial susceptibility patterns of pathogens isolated from skin and soft tissue. Diagn Microbiol Infect Dis. 2003;45:287-293. 2. NNIS. Centers for Disease Control and Prevention (CDC). National Nosocomial Infections Surveillance (NNIS) System Report, data summary from January 1992 through June 2004, issued October 2004. Am J Infect Control. 2004;32:470-485. 3. Bacquero F. Gram-positive resistance: challenge for the development of new antibiotics. 1997:1-4. 4. Kowalski TJ, Berbari EF, Osmon DR. Epidemiology, treatment, and prevention of community-acquired methicillin-resistant Staphylococcus aureus infection. Mayo Clin Proc. 2005;80:1201-1208. 5. Tentolouris N, Jude EB, Smirnof I, et al. Methicillin-resistant Staphylococcus aureus: an increasing problem in a diabetic foot clinic. Diabet Med. 1999;16:767-771. 6. Centers for Disease Control and Prevention. National Nosocomial Infections Surveillance system report: data from 1974-2004. Atlanta (GA); 2004. 7. Moran GJ, et al. Results of multivariate logistic-regression analyses to identify potential Risk Factors for MRSA Infections. N Engl J Med. 2006;355:666-674. 8. Rubin RJ. et al. The economic impact of Staphylococcus infection in New York Hospitals. Emerging Infectious Diseases. 1999; 5: 9-17. 9. Wagner A, Reike H, Angelkort B. Highly resistant pathogens, especially methicillin-resistant Staphylococcus aureus, in diabetic patients with foot infections. Dtsch Med Worchenschr. 2001;126:1353-1356. 10. Dang CN, Prasad YD, Boulton AJ, Jude EB. Methicillin-resistant Staphylococcus aureus in the diabetic foot clinic: a worsening problem. Diabet Med. 2003;20:159-161. 11. Fejfarova V, Jirkovska A, Skibova J, et al. Pathogen resistance and other risk factors in the frequency of lower limb amputations in patients with diabetic foot syndrome. Vnitr Lek. 2002;48:302-336. 12. Graffunder EM, Venezia RA. Risk factors associated with nosocomial methicillin-resistant Staphylococcus aureus (MRSA) infection including previous use of antimicrobials. J Antimicrob Chemother. 2002;49:999-1005. 13. Weber SG, Gold HS, Hooper DC, et al. Fluoroquinolones and the risk for methicillin-resistant Staphylococcus aureus in hospitalized patients. Emerg Infect Dis. 2005;9:1415-1422. 14. Eneroth M, Apelqvist J, Stenstrom A. Clinical characteristics and outcome in 223 diabetic patients with deep foot infections. Foot Ankle Int. 1997;18:716-722. 15. Salgado CD, Farr BM, Calfee DP. Community-acquired methicillin-resistant Staphylococcus aureus: a meta-analysis of prevalence and risk factors. Clin Infect Dis. 2003;36:131-9. 16. Lipsky BA, Berendt AR, et al. Diagnosis and treatment of diabetic foot infections. Clinical Infectious Diseases. 2004;39:885-910. 17. Lipsky BA, Pecoraro RE, Larson SA, Ahroni JH. Outpatient management of uncomplicated lower extremity infections in diabetic patients. Arch Intern Med. 1990;150:790-797. 18. Sapico Fl, Witte JL, Canawati HN, et al. The infected foot of the diabetic patient; quantitative microbiology and analysis of clinical features. Rev Infect Dis. 1984;6:171-176. 19. Wheat LJ, Allen SD, Henry M, et al. Diabetic foot infections. Bacteriologic analysis. Arch Intern Med. 1986;146:1935-1940. 20. Lipsky BA, et al. Treating foot infections in diabetic patients: a randomized, multicenter, open-label trial of linezolid versus ampicillin-sulbactam/amoxicillin-clavulanate. Clin Infect Dis. 2004;38:17-24. 21. Stevens DI, et al. Oral linezolid versus intravenous vancomycin in the treatment of MRSA. Clin Infect Dis 2002;34:1481-1490. 22. Engemann JJ, Carmeli Y. Cosgrove SE, et al. Adverse clinical and economic outcomes attributable to methicillin resistance among patients with Staphylococcus aureus surgical site infections. Clin Inf Dis. 2003;36:592-8.       For further reading, see “How To Choose Appropriate Antibiotics For Diabetic Foot Infections” in the July 2006 issue of Podiatry Today, “MRSA: Where Do We Go From Here?” in the March 2005 issue or “A Closer Look At Diabetic Foot Infections” in the July 2005 issue. Not necessarily. By Warren S. Joseph, DPM, FIDSA. The author says the current evidence does not support routine coverage of MRSA in the bulk of uncomplicated skin and skin structure infections of the lower extremity.       It is a well-appreciated fact of life that the methicillin-resistant Staph aureus (MRSA) we are currently facing is not “your father’s MRSA.” As recently as eight years ago, MRSA was considered a relatively rare nosocomial pathogen that was predominately a concern among patients from long-term care facilities, those who had been hospitalized in the past or those on multiple courses of antibiotic therapy. Now MRSA is in the community and prevalence rates for most city and suburban hospitals range from 60 to 70 percent of all Staphylococcus.       Furthermore, what used to be a single genetic type of organism has morphed into at least five different genotypes that can roughly be divided into two major categories: healthcare-associated MRSA (HA-MRSA) and community-acquired MRSA (CA-MRSA).             Community-acquired MRSA is of particular concern. Due to various virulence factors including the production of the Panton-Valentine leukocidin (although the importance of PVL as a determinant of virulence has recently come into question), this organism is a more dangerous pathogen than our previous incarnations of MRSA. It can infect young, healthy patients and can rapidly become life threatening. This is the organism that has graced the front pages of USA Today and has been featured in such respectable print and broadcast magazines as Time and 20/20 with stories entitled “Superbugs Spread Fear Far and Wide.”1,2       With all of this fear mongering and increased recognition of how this “superbug” is, in fact, spreading, the question arises: Do we really need to treat it? It may be sacrilege to say but based on the scientific medical evidence, the answer to this question is a resounding “not necessarily.”       This position does not discount the importance of MRSA as a pathogen in major systemic infections or even more severe skin and skin structure infections. In those cases, one should treat MRSA and treat it aggressively. There are fantastic, effective antibiotics (excluding vancomycin) that clinicians can use to treat MRSA but that is outside the scope of this discussion. However, for the bulk of uncomplicated skin and skin structure infections of the lower extremity, the medical evidence — on which we are supposed to be making our treatment decisions — does not support routine coverage of MRSA.       Please note that any concerns based on the scare of medicolegal issues are not taken into account in this discussion. Medical treatment is supposed to be based on published medical evidence, not the fear of being sued. This may or may not be a factor for individual readers of this article. Therefore, in the interest of making this a scientific discourse, I will only outline the evidence-based medicine, not fear and conjecture.

A Closer Look At The Literature On MRSA

      In the New England Journal of Medicine, Scott Fridkin, MD, et. al., published what has become one of the first carefully performed studies to look at this question. In studying the incidence of MRSA in Baltimore, Atlanta and Minnesota, the investigators found “Among patients with skin or soft tissue infections (SSSI), therapy to which the infecting strain was resistant did not appear to be associated with adverse patient-reported outcomes.”3 In other words, it did not matter if the MRSA patients were treated with antibiotics that were ineffective against MRSA. The outcomes were the same.       Physicians around the United States are seeing more and more of what has become known in the vernacular as “spider bites,” especially in younger patients. This term has become pathognomatic for an MRSA abscess. Lee, et. al., looked at children with MRSA abscesses and found that “incision and drainage without adjunctive antibiotic therapy was effective management of CA-MRSA skin and soft tissue abscesses with a diameter of <5 cm in immunocompetent children.”4       A study of MRSA in the emergency department was recently published in the New England Journal of Medicine.5 The authors found that 59 percent of patients with SSSI had MRSA. In the study abstract, the authors concluded that clinicians should modify empiric therapy to cover that organism. However, that conclusion flies in the face of their data, not discussed in the abstract, which shows that “There were no significant differences in outcome … between patients in whom the infecting MRSA isolate was resistant and those in whom the isolate was susceptible to the prescribed antibiotic.”       At this point, the reader may ask: This is all well and good but how does it impact my treatment of the feet? A number of studies have specifically looked at MRSA in foot infections, particularly diabetic feet. Dang, et. al., from Boulton’s group in the United Kingdom, found that the amount of MRSA in their diabetic foot infections doubled between the study they published in 1998 and this one published in 2003.6       That being said, they also noted that “MRSA was eradicated by regular debridement, topical treatment and isolation … .” This led them to conclude that “In the absence of systemic infection, MRSA infected foot ulcers can be successfully treated in the outpatient setting without the use of MRSA-specific drugs … .”       In the largest study to date on the treatment of moderate to severe diabetic foot infections, Lipsky, et. al., compared the use of ertapenem to piperacillin/tazobactam.7 Neither of these drugs have activity against MRSA. Out of the 445 evaluable patients, approximately 20 percent grew MRSA. Despite this being a large, multicenter study, conducted in 89 sites around the U.S., this percentage is significantly lower than that published in other examinations of SSSI. Furthermore, of those that grew MRSA, “Clinical response rates for patients with MRSA … were similar irrespective of whether the patient received concomitant vancomycin therapy … .”7

Final Notes

      In the past two to three years, other studies, too many to enumerate in this brief “Counterpoint” editorial, have also come to the same conclusion: The routine use of anti-MRSA coverage is not always necessary for the treatment of MRSA SSSI.       Certainly, one should ensure appropriate coverage of MRSA when there is reason to believe or cultures reveal that it is the primary pathogen, especially in a more severe infection in a sick patient. However, the routine use of potent anti-MRSA antibiotics for the sake of a “CYA” mentality runs counter to what the medical evidence clearly demonstrates.       Furthermore, the standard dogma of infectious diseases is that overuse of inappropriate antibiotics leads to resistance. Who is to say that MRSA is “as resistant as it gets”? In fact, vancomycin intermediate and vancomycin-resistant Staphylococcus aureus (VISA/VRSA) have already been reported. There have also been reports of Staphylococcus aureus strains that are resistant or have developed a tolerance to the newer anti-MRSA antibiotics including linezolid and daptomycin.       Only through the rational use of appropriate antibiotic therapy based on clear medical evidence, and not popular press fear mongering, can we minimize future resistance issues and ensure proper therapy for our patients.       Dr. Joseph is a Consultant in lower extremity infectious diseases and is a Fellow of the Infectious Diseases Society of America. He is an Attending Podiatrist at the Coatesville Veterans Affairs Medical Center in Coatesville, Pa. References 1. Superbugs spread fear far and wide. USA Today, May 11, 2006. 2. Surviving the New Killer Bug. Time, June 26, 2006. 3. Fridikin SK, Hageman MHS, Morrison MPH, Sanza LT, et al. Methicillin Resistant Staphylococcus aureus Disease in Three Communities. N Engl J Med 2005; 352:1436-44. 4. Lee MC, Rios AM, Fonseca-Aten M, Mejias A, et al. Management and outcome of children with skin and soft tissue abscesses caused by community acquired methicillin resistant Staphylococcus aureus. Pediatr Infect Dis J, 2004;23:123-7. 5. Moran GJ, Krishnadasan A, Gorwitz RJ, Fosheim GE, et al. Methicillin resistant S. aureus infections among patients in the emergency department. N Engl J Med, 2006 Aug 17;355(7):666-74. 6. Dang CN, Prasad YDM, Boulton AJM, Jude EB. Methicillin resistant Staphylococcus aureus in the diabetic foot clinic: A worsening problem. Diabetic Medicine 2003, 20:159-161. 7. Lipsky BA, Armstrong DG, Citron DM, Tice AD, et al. Ertapenem versus piperacillin/tazobactam for diabetic foot infections (SIDESTEP): prospective, randomized, controlled, double-blinded, multicentre trial. Lancet 2005 Nov 11, 366:1695-1703.       For further reading, see “A Guide To Emerging Antibiotics For Diabetic Foot Infections” in the December 2005 issue.