Given the increasing prevalence of methicillin resistant Staphylococcus aureus (MRSA), these authors discuss the differences between HA-MRSA and CA-MRSA, what the literature reveals about antibiotic therapy and keys to the diagnostic workup of these patients.
To say that methicillin-resistant Staphylococcus aureus (MRSA) is a growing problem in the healthcare setting is an understatement. Indeed, healthcare providers are diagnosing this organism at an alarming rate in severe infections of both healthy people and the immunocompromised. In 1973, the Centers for Disease Control and Prevention (CDC) reported that MRSA accounted for 2 percent of all Staphylococcus infections. In 2004, it accounted for 63 percent.1
In both the nondiabetic and diabetic populations, Staphylococcus aureus is the most frequently isolated organism in all lower extremity infections. Some studies have noted that Staphylococcus aureus accounts for up to 76 percent of organisms isolated in the foot with 20 percent being MRSA.1,2 It now also has the dubious honor of being the most common isolate in infections that occur after vascular graft placements.3-5
When researchers first discovered MRSA in the early 1960s, it was believed that a single clone was responsible for all MRSA isolates. The landscape has now been vastly complicated by the emergence of at least five new strains of MRSA. While researchers originally saw MRSA as only a nosocomial pathogen, new strains are emerging as community associated MRSA (CA-MRSA).
 The CDC defines CA-MRSA infections as those acquired by: people who have neither been hospitalized nor had a medical procedure in the past year; people who do not have indwelling catheters or medical devices; people with no history of previous MRSA infections or colonization; and those who are diagnosed in an outpatient setting or within 48 hours of initial hospitalization. The CDC also reports that although 25 to 30 percent of the general population is colonized with Staph aureus, 1 percent of the population is colonized with MRSA.1,2
The difference between hospital-acquired MRSA (HA-MRSA) and CA-MRSA lies in their genetic makeup. All strains of MRSA have a mec-A gene, which is responsible for its drug resistance and is located on an element called staphylococcal cassette chromosome (SCCmec). There are five types of SCCmec with different variations of size and genetic makeup. CA-MRSA strains have a type IV SCCmec gene, which induces its resistance to methicillin, beta-lactams and erythromycin. However, the type IV SCCmec gene is susceptible to other drugs such as clindamycin and trimethoprim-sulfamethoxazole.6-9
The CA-MRSA strains also produce Panton-Valentine leukocidin (PVL), a pore-forming exotoxin that researchers have shown is correlated with more febrile days and higher complications of osteomyelitis.7 Genestier, et al., discovered that PVLs targeted and caused cell death in neutrophils and lymphocytes by disrupting the mitochondria. This also induced the release of certain neutrophil factors that cause inflammation and tissue loss.
Researchers have postulated that this mechanism results in the high incidence of CA-MRSA found in skin and soft tissue infections (SST).8 Naimi, et al., reported that 75 percent of CA-MRSA isolates were found in SST infections as opposed to 37 percent of HA-MRSA found in SST infections.6
The HA-MRSA strains tend to be less virulent but are more prevalent. Conservative estimates note that there is at least a 30 percent prevalence of MRSA in hospitals and long-term care facilities. In the intensive care units, the numbers reach at least 60 percent.9-15 Those most at risk tend to have had prolonged hospitalization, previous antimicrobial therapy and previous invasive medical procedures. The CDC identified three groups most at risk for developing HA-MRSA: healthcare workers, hospitalized patients and residents of long-term rehabilitation facilities or nursing homes.2
In the past, the standard of care for treating complicated skin, skin structure and bone infections due to MRSA included a combination of wide debridement and antimicrobial therapy, usually consisting of vancomycin. The problem now is decreasing susceptibility to vancomycin.
To date, the CDC has six confirmed cases of vancomycin-resistant Staphylococcus aureus (VRSA) and 21 confirmed cases of vancomycin-intermediate Staphylococcus aureus (VISA) in the United States. Vancomycin-resistant Staphylococcus aureus is defined as having a minimum inhibitory concentration (MIC) of > 16 µg/mL whereas VISA is defined as having a MIC of 4 to 8 µg/mL.2
In a 2006 study, Wang, et al., analyzed the Staphyloccocus aureus clinical isolates and vancomycin MIC data at one university hospital. Over the course of five years and over 6,000 isolates, the average MIC increased from < 0.5 to 1.0 µg/mL. There was also one confirmed case of VISA in this study.16
The new data on both HA-MRSA and CA-MRSA suggests a colossal barrier for limb preservation. Recent studies have shown that patients with MRSA infections have an increased mortality compared to their non-MRSA counterparts. Nixon, et al., noted that in the orthopedic and trauma wards, MRSA patients had a mortality rate that was 2.7 percent higher than their matched counterparts, resulting in additional surgical and medical intervention, and extended hospital stays.11 Roche, et al., also found that the MRSA patients had triple the length of stay in comparison to non-MRSA patients.12
In addition, patients with diabetes are 40 times more likely to have amputations. The leading cause of amputation in the diabetic population is usually an infected ulcer. Of those diabetic foot infections, Staphylococcus aureus is the most common culprit. With repeated hospitalizations, the likelihood of MRSA being the causative agent in diabetic foot infection increases exponentially.9,10 Tentolouris, et al., discovered that 50 percent of Staphylococcus aureus isolates found in diabetic foot infections were MRSA.17 In their study of diabetic and non-diabetic patients with leg ulcers, Valencia, et al., isolated Staphylococcus aureus 67 percent of the time with MRSA accounting for 75 percent of those isolates. In the same study, Staphylococcus aureus made up 75 percent of the isolates for superficial wounds with MRSA accounting for 44 percent of the subset.18
Vascular surgery patients are also emerging as a subset susceptible to MRSA. Taylor, et al., reported that of the post-op infections in vascular graft patients, 58 percent were due to MRSA. Only four patients of the 772 studied had previous MRSA infections or colonization. Forty percent of the MRSA infected patients required amputations. Researchers also found that the mean hospital stay for MRSA patients was 29.7 days in comparison to 22.7 days for non-MRSA infected patients.4 In their review of 172 patients infected with MRSA after vascular graft surgery, Nasim, et al., noted a 100 percent incidence of lower extremity amputation after an infected infrainguinal bypass graft.5
Coverage of MRSA wounds also proves to be challenging. Dow, et al., found that in the presence of skin grafts or skin substitutes, the bacterial burden that impairs wound healing is lowered to 1.0 x 105 or less colony forming units.19 In a prospective study on infected skin grafts, Unal, et al., found that split thickness skin grafts were more prone to infection related loss than the full thickness grafts. They thought this was due to the proportional lack of dermal components in split thickness skin grafts that increased their susceptibility to infections. The same study also noted that Staphylococcus aureus was the second most common pathogen isolated in the infected skin grafts.20
With all of the daunting data, the question begs to be asked: Is limb salvage a viable option in patients with MRSA? With early detection, a high clinical suspicion and appropriate early therapy — both prophylactic and empiric — we believe physicians can treat MRSA infections in the lower extremity without significant loss of limb or life.
For skin and skin structure infections caused by CA-MRSA, the drugs of choice can include trimethoprim–sulfamethoxazole, tetracycline (doxycycline) or clindamycin. Currently, the pharmacological options in the U.S. for erythromycin-resistant MRSA strains include vancomycin, linezolid, daptomycin, quinupristin-dalfopristin and tigecyline. For VISA and VRSA infections, the drugs of choice are linezolid, daptomycin and quinupristin-dalfopristin.
Again, vancomycin has long been the gold standard pharmacological treatment of MRSA skin, soft tissue and bone infections. Systemic vancomycin levels have been shown to be effective in acute cancellous bone infections. However, the levels are unsatisfactory in cortical bone. With vancomycin treatment, there is an increased risk of nephrotoxicity.
 Researchers have shown that linezolid, a bacteriostatic oxazolidinone, has a 58 percent clinical cure rate in MRSA-infected bone. However, it is not approved for use of more than 28 days of therapy secondary to risks of bone marrow suppression. For complicated skin and skin structure infections, researchers have proven that linezolid is as effective as vancomycin. In one prospective study of 1,200 patients, the clinical cure rate of those treated with linezolid was 94 percent as compared to 90 percent in people treated with vancomycin. The advantage of utilizing linezolid lies in the fact that its oral bioavailability is the same as its parenteral bioavailability. This allows for decreased hospitalization and eliminates the need for central line placement.21-23
Studies have also found that daptomycin, a bactericidal cyclic lipopeptide, is as effective as vancomycin in treating complicated skin and skin structure MRSA infections. In one study of 1,100 people, the clinical cure rate for patients treated with daptomycin was 75 percent in comparison to 69 percent in vancomycin treated patients. In murine models, researchers found daptomycin PMMA beads were as effective as vancomycin PMMA beads in treating chronic osteomyelitis. However, this has not been studied in human subjects.24,25
Yin, et al., found that systemic tigecycline, a bacteriostatic glycylcycline, was as effective as systemic vancomycin in rabbits with osteomyelitis.25 In a study of humans with complicated skin and skin structures infections, researchers also found that tigecycline is as effective as vancomycin. Side effects of tigecycline include mostly gastrointestinal symptoms, including nausea in 25 to 30 percent of patients and vomiting in approximately 20 percent of patients.27
Quinupristin-dalfopristin is currently FDA approved for methicillin susceptible Staphylococcus aureus skin infections but not for MRSA. Researchers have shown the drug has some activity against MRSA and that it is a viable alternative in patients who either cannot tolerate vancomycin or those who initially fail vancomycin therapy. The most common complaint with quinupristin-dalfopristin tends to be generalized myalgias and arthralgias.28
Dalbavancin, a new bactericidal lipoglycopeptide, is an analog of teicoplanin, an anti-MRSA agent not currently available in the U.S. Dalbavancin is still currently under FDA review. Early data has shown that it has promising activity against MRSA in skin and skin structure infections. The advantage of utilizing dalbavancin is its long half life, which allows for once weekly dosing. The most common side effect with dalbavancin is oral candidiasis. Gastrointestinal complaints are mild and include diarrhea and constipation.29,30
Each of these cases should begin with a good history and physical. Treating physicians should answer several important questions.
 Where is the source of the infection? In some cases of CA-MRSA that present to the emergency departments, the source of infection is a lesion or abscess that patients mistakenly attribute to a “spider bite.” In fact, this “spider bite” can be due to shaving, “turf” burns or cuts from wresting mats.
What is the underlying etiology of the skin breakdown? Is it due to peripheral arterial disease, a mechanical source, peripheral neuropathy or a combination? Peripheral arterial disease appears to be highly correlated with MRSA infections.
What is the patient’s recent medical, surgical and social history? Is the patient a young athlete involved in team sports? Is the patient undergoing dialysis? Is the patient a healthcare worker? Before final culture sensitivities return, a good history could help guide initial antimicrobial treatment for CA-MRSA versus HA-MRSA.
What are the final sensitivities of deep wound cultures? Look at the sensitivity data for oxacillin, erythromycin and clindamycin. If the pattern shows that the organism is resistant to oxacillin and erythromycin, but susceptible to clindamycin, it is a clue to order a D-test from the microbiology lab in order to determine inducible resistance to clindamycin. If the D-test is positive, one should not use clindamycin as part of the treatment.
In almost all cases of complicated skin and bone infections, wide debridement and excision of infected, nonviable bone and tissue is indicated. While there is an array of new pharmacological agents available, one should only use these agents as adjunct therapy to surgical debridement. There should also be an extremely high suspicion for CA-MRSA in patients who have little to no medical history of presenting with fulminating infections.
In conclusion, MRSA is on the rise and is taking a devastating toll on lower extremity infections. Increased awareness of its presence as well as the type of strains present could greatly decrease the morbidity of lower-extremity infections.
Dr. Lam is currently the Chief Resident at the Yale-New Haven Hospital/ DVA CT Healthcare Podiatric Surgical Residency Program. She will soon be practicing in Naples, Fla.
Dr. Blume is an Assistant Clinical Professor within the Section of Podiatry in the Department of Orthopedics and Rehabilitation at the Yale University School of Medicine. He is the Director of Limb Preservation at the Yale-New Haven Hospital in New Haven, Ct.
Dr. Palladino is the Director of Research at the North American Center for Limb Preservation in New Haven, Ct.
1. Whitby M, McLaws ML, Berry G. Risk of death from methicillin-resistant Staphylococcus aureus bacteraemia: a meta-analysis. Med J Aus 2001;175:264-7
2. http://www.cdc.gov/ncidod/dhqp/ar_mrsa.html 
3. Bozic KJ, Ries MD. The impact of infection after total hip arthroplasty on hospital and surgeon resource utilization. J Bone Joint Surg [Am] 2005;87-A:1746-51.
4. Taylor MD, Napolitano LM. Methicillin-resistant Staphylococcus aureus infections in vascular surgery: increasing prevalence. Surgical Infections. 5(2):180-7, 2004.
5. Nasim A, Thompson MM, Naylor AR, Bell PR, London NJ. The impact of MRSA on vascular surgery. European Journal of Vascular & Endovascular Surgery. 22(3):211-4, 2001 Sep.
6. Naimi TS, LeDell KH, Como-Sabetti K, Borchardt SM, Boxrud DJ, Etienne J, Johnson SK, Vandenesch F, Fridkin S, O’Boyle C, Danila RN, Lynfield R. Comparison of community- and health care-associated methicillin-resistant Staphylococcus aureus infection. JAMA. 290(22):2976-84, 2003 Dec 10.
7. Bocchini CE, Hulten KG, Mason EO Jr., Gonzalez BE, Hammerman WA, Kaplan SL. Panton-Valentine leukocidin genes are associated with enhanced inflammatory response and local disease in acute hematogenous Staphylococcus aureus osteomyelitis in children. Pediatrics. 117(2):433-40, 2006 Feb.
8. Genestier AL, Michallet MC, Prevost G, Bellot G, Chalabreysse L, Peyrol S, Thivolet F, Etienne J, Lina G, Vallette FM, Vandenesch F, Genestier L. Staphylococcus aureus Panton-Valentine leukocidin directly targets mitochondria and induces Bax-independent apoptosis of human neutrophils. Journal of Clinical Investigation. 115(11):3117-27, 2005 Nov.
9. Fejfarova, V, Jirkovska, A, Skibova J, et al. Pathogen resistance and other risk factors in the frequency of lower limb amputations in patients with the diabetic foot syndrome. Vnitrni Lekarstvi 48, 302–6.
10. Mantey I, Hill RL, Foster AV. et al. Infection of foot ulcers with Staphylococcus aureus associated with increased mortality in diabetic patients. Communicable Disease and Public Health/PHLS. 3, 288–90.
11. Nixon M, Jackson B, Varghese P, Jenkins D, Taylor G. Methicillin-resistant Staphylococcus aureus on orthopaedic wards: incidence, spread, mortality, cost and control. Journal of Bone & Joint Surgery (Br). 88(6):812-7, 2006 Jun.
12. Roche SJ. Fitzgerald D. O'Rourke A. McCabe JP. Methicillin-resistant Staphylococcus aureus in an Irish orthopaedic centre: a five-year analysis. Journal of Bone & Joint Surgery (Br). 88(6):807-11, 2006 Jun.
13. Lipsky BA, Pecoraro RE, Larson SA. et al. Outpatient management of uncomplicated lower-extremity infections in diabetic patients. Archives of Internal Medicine 150, 790–7.
14. Gemmell CG, Edwards DI, Fraise AP, Gould FK, Ridgway GL, Warren RE, Joint Working Party of the British Society for Joint Working Party of the British Society for Antimicrobial Chemotherapy, Hospital Infection Society and Infection Control Nurses Association. Guidelines for the prophylaxis and treatment of methicillin-resistant Staphylococcus aureus (MRSA) infections in the UK. Journal of Antimicrobial Chemotherapy. 57(4):589-608, 2006 Apr.
15. Kollef MH, Micek ST. Methicillin-resistant Staphylococcus aureus: a new community-acquired pathogen? Current Opinion in Infectious Diseases. 19(2):161-8, 2006 Apr.
16. Wang G, Hindler JF, Ward KW, Bruckner DA. Increased vancomycin MICs for Staphylococcus aureus clinical isolates from a university hospital during a 5-year period. [Journal Article] Journal of Clinical Microbiology. 44(11):3883-6, 2006 Nov.
17. Tentolouris N, Petrikkos G, Vallianou N, Zachos C, Daikos GL, Tsapogas P, Markou G, Katsilambros N. Prevalence of methicillin-resistant Staphylococcus aureus in infected and uninfected diabetic foot ulcers. Clinical Microbiology & Infection. 12(2):186-9, 2006 Feb.
18. Valencia IC, Kirsner RS, Kerdel FA. Microbiologic evaluation of skin wounds: alarming trend toward antibiotic resistance in an inpatient dermatology service during a 10-year period.[erratum appears in J Am Acad Dermatol. 2004 Jul;51(1):67]. Journal of the American Academy of Dermatology. 50(6):845-9, 2004 Jun.
19. Dow G, Browne A, Sibbald RG. Infection in chronic wounds: controversies in diagnosis and treatment. Ostomy Wound Management. 45(8):23-7, 29-40; quiz 41-2, 1999
20. Unal S, Ersoz G, Demirkan F, Arslan E, Tutuncu N, Sari A. Analysis of skin-graft loss due to infection: infection-related graft loss. Annals of Plastic Surgery. 55(1):102-6, 2005 Jul.
21. Calhoun JH, Overgaard KA, Stevens CM, Dowling JP, Mader JT. Diabetic foot ulcers and infections: current concepts. Advances in Skin & Wound Care. 15(1):31-42; quiz 44-5, 2002 Jan-Feb.
22. Birmingham MC, Rayner CR, Flavin SM et al. Linezolid for the treatment of multidrug-resistant Gram-positive infections: experience from a compassionate-use program. Clin Infect Dis. 2003 Jan 15;36(2):159-68. Epub 2003 Jan 3.
23. Weigelt J, Itani K, Stevens D, Lau W, Dryden M, Knirsch C, and the Linezolid CSSTI Study Group. 2005. Linezolid versus vancomycin in treatment of complicated skin and soft tissue infections. Antimicrob. Agents Chemother. 49:2260-2266.[
24. Arbeit RD, Maki D, Tally FP, et al. The safety and efficacy of daptomycin for the treatment of complicated skin and skin-structure infections. Clin Infect Dis 2004; 38:1673.
25. Rouse MS, Piper KE, Jacobson M, Jacofsky DJ, Steckelberg JM, Patel R. Daptomycin treatment of Staphylococcus aureus experimental chronic osteomyelitis. Journal of Antimicrobial Chemotherapy. 57(2):301-5, 2006 Feb
26. Yin LY, Lazzarini L, Li F, Stevens CM, Calhoun JH. Comparative evaluation of tigecycline and vancomycin, with and without rifampicin, in the treatment of methicillin-resistant Staphylococcus aureus experimental osteomyelitis in a rabbit model. Journal of Antimicrobial Chemotherapy. 55(6):995-1002, 2005 Jun
27. Van Wart SA, Owen JS, Ludwig EA, Meagher AK, Korth-Bradley JM, Cirincione BB. Population pharmacokinetics of tigecycline in patients with complicated intra-abdominal or skin and skin structure infections. Antimicrobial Agents & Chemotherapy. 50(11):3701-7, 2006 Nov.
28. Drew RH, Perfect JR, Srinath L, et al. Treatment of methicillin-resistant Staphylococcus aureus infections with quinupristin-dalfopristin in patients intolerant of or failing prior therapy. For the Synercid Emergency-Use Study Group. J Antimicrob Chemother 2000; 46:775.
29. Seltzer E, Dorr MB, Goldstein BP, Perry M, Dowell JA, Henkel T; Dalbavancin Skin and Soft-Tissue Infection Study Group. Once-weekly dalbavancin versus standard-of-care antimicrobial regimens for treatment of skin and soft-tissue infections. Clin Infect Dis. 2003;37:1298-303.
30. Scheinfeld N. Dalbavancin: a review for dermatologists. Dermatology Online Journal. 12(4):6, 2006.
For further reading, see “MRSA: Where Do We Go From Here?” in the March 2005 issue of Podiatry Today.
Also check out the archives at www.podiatrytoday.com .
CE Exam #154 Choose the single best answer to the following questions. 1. ____________ is the most frequently isolated organism in all lower extremity infections. a) Pseudomonas aeruginosa b) Staphylococcus aureus c) Group B Streptococcus d) None of the above 2. Which of the following statements is true about community-acquired MRSA (CA-MRSA)? a) CA-MRSA strains tend to be more virulent and more prevalent than HA-MRSA strains. b) CA-MRSA strains have a type IV SCCmec gene, which induces its resistance to clindamycin and beta-lactams. c) CA-MRSA strains produce Panton-Valentine leukicidin (PVL), which has a reported correlation with more febrile days and higher complications of osteomyelitis. d) All of the above 3. People most at risk for healthcare-associated MRSA (HA-MRSA) strains tend to have had … a) prolonged hospitalization b) previous antimicrobial therapy c) previous invasive medical procedures d) any of the above 4. In regard to the length of hospital stay, one study found that MRSA patients had … a) triple the length of stay in comparison to non-MRSA patients b) double the length of stay in comparison to non-MRSA patients c) an average of three weeks more in the hospital than non-MRSA patients d) none of the above 5. In regard to post-op infections in vascular graft patients, one study reported that __ percent were MRSA. a) 42 b) 58 c) 25 d) none of the above 6. According to one study, split thickness skin grafts … a) may lead to an increased risk of HA-MRSA in older patients with diabetes b) are more prone to infection-related loss than full thickness skin grafts c) are less prone to infection-related loss than full thickness skin grafts d) None of the above 7. In regard to skin and skin structure infections caused by CA-MRSA, the drugs of choice may include … a) clindamycin b) tetracycline (doxycycline) c) trimethoprim-sulfamethoxazole d) All of the above 8. Which of the following statements is false about linezolid? a) It is a bacteriostatic oxazolidinone. b) Its oral bioavailability is the same as its parenteral bioavailability. c) It is significantly more effective than vancomycin in treating HA-MRSA. d) all of the above 9. Which of the following statements is true about daptomycin? a) It is a bacteriostatic glycylcycline. b) In one study of 1,100 people, daptomycin had a greater clinical cure rate than vancomycin. c) Daptomycin PMMA beads were just as effective as vancomycin PMMA beads in treating osteomyelitis in humans with diabetes. d) None of the above 10. Which of the following statements is true about dalbavancin? a) It is a bacteriostatic oxazolidinone. b) It is currently FDA-approved for methicillin susceptible Staph aureus but not MRSA. c) Early data has shown that dalbavancin has promising activity against MRSA in skin and skin structure infections. d) All of the above Instructions for Submitting Exams Fill out the enclosed card that appears on the following page or fax the form to the NACCME at (610) 560-0502. Within 60 days, you will be advised that you have passed or failed the exam. A score of 70 percent or above will comprise a passing grade. A certificate will be awarded to participants who successfully complete the exam. Responses will be accepted up to 12 months from the publication date.