As diabetic infections continue to evolve and become more resistant to antibiotics, having a comprehensive treatment plan for methicillin resistant Staphylococcus aureus (MRSA) is crucial. These authors present a guide to current antibiotic options and offer two illuminating case studies of patients with diabetes and MRSA.
Since the first published reports of methicillin-resistant Staphylococcus aureus (MRSA) in the early 1960s, MRSA has seen a steady increase in prevalence and growing antibiotic resistance. The superbug reached endemic proportions in hospitals worldwide by 1990 after being a major problem in Europe in the 1970s.
This species of Staphylococcus has seen division into two distinct organisms, healthcare-associated MRSA (HA-MRSA) and community-associated MRSA (CA-MRSA). Resistance continues to be a factor with both HA-MRSA and CA-MRSA, with some strains showing resistance to even vancomycin and linezolid (Zyvox, Pfizer). The Centers for Disease Control and Prevention (CDC), in a review of cases from 2005 to 2008, reported a decline in healthcare-associated MRSA (HA-MRSA) by almost 30 percent.1 Despite this trending decline in healthcare-associated infections, CA-MRSA strains progress without a decline in sight.
This transition has not only had a greater impact on the general population but clinicians are seeing an increasing impact on the diabetic population, especially in regard to those with diabetic foot ulcers, wounds and infections.
In a 2003 study, Dang and colleagues studied the prevalence of pathogenic organisms in foot ulcers in patients with diabetes and compared the results with a similar study three years earlier.2 Their findings demonstrated a twofold increase in the prevalence of MRSA in diabetic foot infections within a three-year span. Further study by Yates and co-workers concluded that wound/ulcer chronicity and chronic renal disease each independently predispose patients to MRSA infections.3 The researchers also found that prior hospitalization and chronicity of wounds were both associated with the increased presence of polymicrobial infection, often involving gram-negative organisms.
For these reasons, in order to optimize initial antibiotic regimens, clinicians should raise their index of suspicion for MRSA in populations presenting with chronic ulcers, chronic wounds, a prior history of MRSA and positive carrier traits such as nasal swabs that are positive for MRSA.
Aerobic, gram-positive cocci, especially Staphylococcus aureus, have been the predominant pathogenic organisms in diabetic foot infections. Indeed, the prevalence of MRSA and its growing resistance to antibiotic treatment regimens should be warning signs in regard to appropriate antibiotic selection when dealing with these types of infections. It is also important to remember that more severe diabetic foot infections are most often polymicrobial. Accordingly, coverage of only MRSA would be inadequate. Given the current data and the known risk indicators for MRSA, one can implement a guided approach to antibiotic selection prior to and after cultures.
Wound cultures have been a primary indicator of bacterial presence or bioburden. The Infectious Diseases Society of America (IDSA) recommends obtaining cultures from a deep soft tissue specimen for more appropriate and accurate isolation of the infectious organism.4 Prior to final culture results, the initial management of the diabetic foot infection is often dictated by the severity of the infection, especially in the presence of an ulcer or wound. The severity of infection can range from skin and soft tissue infections, abscess and cellulitis to osteomyelitis and necrotizing infections. When necessary, one should always recognize the importance of adequate surgical debridement in conjunction with initiating an appropriate antibiotic regimen. Clinicians may tailor this regimen upon final confirmation of the pathogenic organisms with appropriate soft tissue cultures.
By following the guidelines established by the IDSA in identifying and categorizing diabetic foot infections, one has a strong foundation for approaching empiric therapy and antibiotic selection. The guidelines define infections as uninfected, mild, moderate and severe.4 The guideline authors further define each category with distinct clinical manifestations and appropriate management options (see “A Guide To The IDSA Diabetic Foot Infection Classification” below at left).
Uninfected wounds. There are no signs of infection. There is a healthy wound or ulcer in the absence of erythema, warmth, purulence/discharge, swelling or pain. Monitor these patients with aggressive wound hygiene, appropriate offloading and follow-up care.
The progression to infected wounds is defined by the presence of at least two of the following items: local swelling or induration; erythema; local tenderness or pain; local warmth and purulent discharge (thick, opaque to white sanguineous drainage).
Mild infections. These ulcers or wounds demonstrate clinical signs of infection that only affect the skin and subcutaneous tissue. There is an absence of deep tissue involvement and systemic signs of infection. The presence of peri-ulcer erythema is confined to a width of 0.5 to 2.0 cm. It is important in these types of wounds and suspected infections to rule out other sources of skin inflammation.
Moderate infections. These infections involve wider parameters in regard to depth of tissue involvement and surrounding erythema. These infections are associated with deep tissue involvement beyond the subcutaneous tissue. They are often at risk for osteomyelitis and deep abscess formation. However, systemic inflammatory response syndrome signs are not present in patients with moderate infections.
Severe infections. These infections incorporate the above findings with the presence of two or more manifestations of systemic inflammatory response signs. These manifestations include:
• a body temperature less than 36°C (96.8°F) or greater than 38°C (100.4°F);
• a heart rate greater than 90 beats per minute;
• tachypnea >20 breaths per minute or an arterial CO2 partial pressure less than 4.3 kPa (32 mmHg);
• a white blood cell count < 4,000 cells/mm³ or > 12,000 cells/mm³ (12 x 109 cells/L); or the presence of greater than 10 percent immature neutrophils (band forms).4
When it comes to patients with confirmed MRSA or at-risk hospitalized patients who have a previous history of MRSA infections, it is important to ensure appropriate bacterial coverage with the initial antibiotic regimen. In the absence of risk factors and during a period of pending cultures, it is best to initiate broad spectrum coverage and include MRSA coverage in the initial antibiotic regimen. Upon confirmation of final cultures, one may tailor the antibiotic regimen to a more focused selection or, when necessary, combination therapy.
The IDSA also provides recommendations and therapeutic guidelines for antibiotic selection. In patients with first time infections and no prior antibiotic treatment, it is appropriate to cover for methicillin susceptible S. aureus (MSSA) as opposed to MRSA. The consensus is to avoid using antibiotics in uninfected wounds in an attempt to reduce the risk of colonization and infection with resistant bacteria. Always initiate anti-MRSA therapy in high-risk patients with a history of MRSA, chronic wounds or ulcers, severely immunocompromised states, etc.
Where vancomycin was at one time the mainstay for management of MRSA, there has been increasing concern for resistance to the drug. This is a precise reminder of the rapid virulence of S. aureus. Despite a decline in the development of newer antibiotics, there are currently a number of antibiotic options for the treatment of MRSA and a variety of oral options. It is critical to remember, however, that these antibiotics come with risks. Close monitoring of renal and/or hepatic function is often crucial and one must appropriately adjust the dosing.
Trimethoprim/sulfamethoxazole (Bactrim, Roche). This is a dihydrofolate reductase inhibitor with a bactericidal, synergistic effect. It is contraindicated in patients with hepatic impairment and requires adjustment for renal dosing with CrCl of 15 to 30 mL/min. Indicated for CA-MRSA, trimethoprim/sulfamethoxazole is effective in deep infections and soft tissue infections with noted purulence. There is a concern for increasing resistance to trimethoprim/sulfamethoxazole. Therefore, cautious use and prescribing of the antibiotic is recommended. It is contraindicated in patients with folate deficiency, glucose-6-phosphate dehydrogenase deficiency, a history of anemia or thrombocytopenia. Exercise caution and make appropriate dosing adjustments when using this in elderly patients with renal insufficiency.
Doxycycline (Vibramycin, Pfizer). There has been growing use of doxycycline for CA-MRSA and it offers convenient twice per day dosing at 100 mg. There is no required renal adjustment to dosing but one must use caution with the drug and ensure monitoring in patients with hepatic impairment. Multiple reports have demonstrated successful outcomes with the use of doxycycline in SSTI.5 To date, research has shown doxycycline to be an effective monotherapy option in MRSA-associated SSTI.
Clindamycin (Cleocin, Pfizer). While clindamycin is effective in some MRSA infections, there has been increasing resistance in both the outpatient and hospital settings. It is critical to note that resistance to clindamycin is inducible but inked to macrolide resistance. Therefore, one should avoid clindamycin in patients with erythromycin isolates despite clindamycin sensitivity.
Clindamycin has bacteriostatic properties and does not require renal or hepatic adjustment in dosing. The manufacturer notes that possible side effects include diarrhea (noted in up to 20 percent of those taking the medication) and a risk of C. difficile. Clindamycin has excellent tissue, bone and abscess penetration. Further testing with the D-zone test is recommended for the detection of resistance although this would result in a one- to two-day delay in final confirmation.
Linezolid (Zyvox, Pfizer). Linezolid is an oxazolidinone drug that also inhibits the initiation of protein synthesis at the 50S ribosome. It has a specific indication for diabetic foot infections (skin and soft tissue infections) and is effective in targeting both MRSA and vancomycin resistant Enterococcus (VRE). It does not require renal adjustment with dosing and the dosage is 600 mg q12h. It is available as both an oral and parenteral agent with equal bioavailability. Accordingly, oral dosing is more desirable.
Use caution in all patients as there are associated risks of hematologic toxicity, thrombocytopenia and anemia. Therefore, monitoring of the complete blood cell count is required in patients on prolonged therapy.
Vancomycin. While vancomycin is commonly perceived as the “gold standard” antibiotic and is often a first-line therapy for at-risk patients with MRSA, there have been reports of increased resistance or decreased efficacy.6 This resistance is often described as a “creeping resistance” given that isolates are still susceptible but require higher concentrations of vancomycin (therefore demonstrating higher minimum inhibitory concentrations). Vancomycin is a glycopeptide, bactericidal antibiotic and requires slow infusion over two hours. One must monitor peaks and troughs, and dose accordingly. Renal function is a concern and clinicians must carefully assess this when considering vancomycin. Tissue penetration is variable depending upon the extent of the inflammatory process present and the presence/absence of bone involvement.
Quinupristin/dalfopristin (Synercid, Pfizer). Both of these drug components have a synergistic effect in protein synthesis at the 50S ribosomal subunit. While both components are bacteriostatic, the combination of the two demonstrates bactericidal properties to the bacterial wall. There are no renal or hepatic adjustments with the dosing of Synercid but one should still monitor patients with these comorbid risks.
Clinicians commonly use this drug for vancomycin-resistant Staph aureus (VRSA) and as a combination agent for severe MRSA infections. Risks of the medication include arthralgia, myalgia and nausea. Cautious use and prescribing of this agent are recommended in an attempt to avoid the future risks of resistance.
Tigecycline (Tygacil, Pfizer). Tigecycline, a glycylcycline bacteriostatic agent, demonstrates excellent soft tissue penetration and researchers have shown it to be effective against many resistant organisms, including MRSA.7 One advantage is its efficacy against gram-negative bacteria, giving clinicians a broad spectrum coverage option. Researchers have shown tigecycline to be equivalent to vancomycin in battling skin and soft tissue infections.7
However, clinicians should use caution in regard to monitoring sensitivities in the presence of polymicrobial infections involving Pseudomonas. There is no required renal or hepatic adjustment in adults but again, monitoring in high-risk populations is recommended.
Daptomycin (Cubicin, Cubist Pharmaceuticals). Daptomycin is a lipopetide that acts by disrupting cell membrane function via calcium dependent binding. It is bacteriostatic and concentration dependent. There is required renal adjustment to dosing with CrCl levels <30 mL/min. Risks include muscle weakness or pain, and one should monitor patients. Researchers have noted that dosing of greater than 4 mg/kg/day is associated with increased levels of creatine phosphokinase.8 Daptomycin is approved by the FDA for SSTI and is active against MRSA and VRE.
A 59-year-old African-American male with a history of diabetes for 15 years presented to the clinic with a recurrence of an ulcer to the plantar aspect of his left foot at the level of the fifth metatarsal base. He has had the ulcer on and off for the past year as the ulcer would heal fully but then recur. For the last month, the patient had been self-treating the wound with antibiotic ointment (bacitracin) that he had left over from previous prescriptions. He has not had any pain in the area but is concerned that the ulcer is worse than before as it is “blowing out” of the top and side as well. The patient did notice a creamy discharge when it blew out but that has ceased since then.
The patient’s past medical history is positive for type 2 diabetes, hypertension and peripheral vascular disease. He has a history of a partial hallux amputation on the left foot and partial second and third toe amputations on the right foot, which were well healed. The patient also had a femoral to popliteal bypass on the right extremity. He is married and denies tobacco and alcohol use. The patient cares for his wife, who is also a below-knee amputee and has diabetes. His last HgA1c was 7.2 and he monitors his blood glucose levels regularly. He denies fever and chills.
Upon examination, the patient has palpable dorsalis pedis and posterior tibial pulses on the right and decreased posterior tibial and dorsalis pedis pulses on the left (1+). He has palpable popliteal bilateral with absent pedal and lower extremity hair growth. Protective sensation is absent to both feet proximal to the ankle with the Semmes Weinstein monofilament. Nails are intact bilaterally. He has a 1.5 cm ulceration to the plantar left fifth metatarsal base, which probes to the bone and tracks laterally to exit the ulcer site at the lateral fifth metatarsal base. There are surrounding macerated tissue margins to the ulcer sites. Seropurulent drainage is present. We irrigated the wound and took deep soft tissue cultures. Radiographs of the left foot did not demonstrate any osseous involvement and cortices were intact.
Cultures were positive for MSSA. We reviewed the case with the infectious disease team and followed recommendations for the initiation of therapy with dicloxacillin (Diclocil, Bristol-Myers Squibb). Treatment also included aggressive offloading and wound care management with Iodosorb (Smith and Nephew) dressings daily with aggressive irrigation of the wound tract. The patient refused incision and drainage with operative debridement due to needing to care for his wife and father.
Due to the death of his father and his mother-in-law within the same two-week period, the patient was absent to follow up in the clinic for one month. Upon his return, he had a full blown abscess and fluctuance encompassing the entire fifth metatarsal region. The patient had a new onset of pain to his foot at the fifth metatarsal and along the peroneals just distal to the lateral malleolus. He had nausea and complained of not being able to keep his food down. The patient was febrile with a 101º temperature and had an elevated white blood cell count of 16, findings that were concerning for systemic inflammatory response syndrome.
We hospitalized the patient and started him on vancomycin and piperacillin/tazobactam (Zosyn, Pfizer) due to concern for MRSA and polymicrobial infection, given the wound’s chronicity and progression to a severe diabetic foot infection.
After two days on an intravenous antibiotic, the patient developed a localized fluctuant abscess in the region of the fifth metatarsal base extending dorsal and lateral. He then went to the operating room for a formal incision and drainage.
Intraoperative findings were consistent with thick purulent drainage. The fifth metatarsal was gray and fragmented along the midshaft to the level of the base. The peroneus brevis tendon was shredded from the insertion to the distal lateral malleolus and there was hemorrhagic tissue along the sheath of the longus tendon proximal to the lateral malleolus. We resected the respective portion of the brevis and debrided the sheath of the longus.
The cuboid had a dorsal erosion and cartilage was intact. The intraoperative biopsy and culture were consistent with osteomyelitis and new cultures revealed E. coli, Proteus and MRSA. Once the patient was stable postoperatively, the patient was discharged. He remained on the same antibiotic coverage (vancomycin 1,500 mg q12h and Zosyn 3 gm q8h) per the infectious disease team via PICC line placement and home nursing assistance. Due to the severity of his infection and required revascularization, antibiotic use continued for seven weeks without evidence of toxicity. Serial radiographs were without evidence of progressed osseous changes to the cuboid with full granulation of the wound.
Therefore, we decided to discontinue the antibiotics after consulting with the infectious disease team. The wound continued to improve and the patient progressed to weightbearing activities with prescription shoe gear and bracing.
A 57-year-old female with a history of diabetes for 12 years presented with complaints of pain, redness and swelling of her left foot for a one-week duration. She noticed the foot starting to blister on top and presented to the clinic. The patient denies any trauma or puncture, and states she wears socks around the house. She does have numbness to her feet and does not always feel well. The patient has had a history of a “sore” to the foot before but it healed after she put an antibiotic ointment on it. She tried the same ointment with this episode but the foot has not responded. The patient noted that she soaks the foot in warm, soapy water and applies the antibiotic ointment each day. She admits her blood glucose levels fluctuate and are usually more on the high end, around 200 mg/dL.
In addition to having diabetes for 12 years, she has hypertension and has been on dialysis for three years. The remainder of her social and past medical history is non-contributory.
On examination, the patient has palpable posterior tibial, dorsalis pedis and popliteal pulses bilaterally. She has absent protective sensation per Semmes Weinstein monofilament testing. There is a hemorrhagic bullous lesion encompassing the dorsal forefoot, extending from the base of her toes two through five and extending to the midshaft of the metatarsals. There is erythema encompassing the dorsal and lateral left foot to the level of the heel. Plantar to the distal fourth interspace, she has a hemorrhagic hyperkeratotic lesion communicating with the dorsal bulla via the webspace and there is a 2 mm pinpoint opening. There is plantar erythema extending across the metatarsophalangeal joints with tenderness to palpation at these levels. The tenderness is greatest to the fourth and fifth metatarsal heads, and fourth interspace.
The patient’s vital signs were stable, she was afebrile and the white blood cell count was elevated at 12. The patient went to the hospital. Given the severity of the infection and past history of ulceration with renal compromise, the patient started on vancomycin and received an incision and drainage. There was full thickness necrosis of the dorsal skin margins. This resulted in significant skin loss. There was no radiographic or intraoperative osseous involvement. Cultures were consistent with MRSA. Once the patient was stable and the white blood cell count trended down within normal range, she was discharged from the hospital. We prescribed doxycycline 100 mg PO bid for two weeks and employed an aggressive wound care regimen and VAC therapy (KCI) to healing.
The morbidity and mortality associated with MRSA infections is an alarming indicator of the urgency in addressing these infections in the diabetic population. Patients with diabetes whose MRSA infections resulted in amputation demonstrated a five times greater mortality rate in comparison to patients with non-MRSA infections.9
Additionally, researchers demonstrated that MRSA-related amputations have a higher stump infection rate of 24 percent.9 Re-infection rates with MRSA are also more frequent.
Therefore, even upon completion of therapy and appropriate management (whether it is surgical debridement, wound care or both), it is important to alert patients of colonization, the risk of carrier-states and long-term morbidity and mortality. Despite the subtle decline in HA-MRSA reported by the CDC, it is important to remember the unyielding state of CA-MRSA and its presence and contribution to healthcare-associated infections.10
The introduction of MRSA is not uncommon in the diabetic population and has become more prevalent today. Risk factors in this population go beyond the immunocompromised state of the patient with diabetes and also require a strong understanding of ulcer chronicity, prior hospitalization and chronic renal disease as associated risk factors for MRSA.
Dr. Hadi is the Director of the PAVE Program with the VA Puget Sound Healthcare System in Seattle and is a Fellow of the American College of Foot and Ankle Surgeons.
Dr. Garr is a first-year resident with the VA Puget Sound Healthcare System in Seattle.
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10. Centers for Disease Control and Prevention: MRSA Statistics. Available at http://www.cdc.gov/mrsa/statistics/index.html  .