A Closer Look At Diabetic Foot Infections

   Diabetic foot infections arising from ulcerations are the largest non-traumatic cause of lower extremity amputations. Contributing factors include peripheral neuropathy and vascular disease, rigid pedal deformities, local trauma and pressure, extensive soft tissue loss, multi-system failure, non-compliance and severe infection.    Over the decades, there have been a number of shifts in the way clinicians approach diabetic foot infections (DFIs). Throughout the ‘60s and into the ‘70s, clinicians felt most DFIs were, like other skin and skin structure infections, caused primarily by the gram-positive aerobic cocci, Staphylococcus aureus and Streptococcus.    In the early ‘80s, some of the emerging literature used more sophisticated culturing modalities and laboratory techniques.1 Researchers were finding multiple organisms, primarily anaerobic gram negative rods, that had not been isolated from these infections in the past. Soon, all DFI were being called “polymicrobial” with mixed flora containing aerobic gram-positive cocci, gram-negative rods and anaerobic cocci and rods. There was an emphasis by clinicians to ensure that all of these isolates were covered by an overly broad-spectrum empiric antibiotic regimen, pending deep culture reports.    A critical look at these studies shows many of them did not represent everyday clinical experience. There was little stratification based on the severity of the infections. Most of the studies examined end-stage, severe, chronic, malodorous, necrotic infections. In fact, the literature actually referred to just this type of severe process as the “diabetic foot.” In some cases, the researchers actually obtained cultures from amputation specimens in the morgue or pathology laboratory. Clinicians did not consider the wide range of clinical presentation of infections in these patients. Unfortunately, this concept of the polymicrobial DFI is still alive today not only in podiatric circles but throughout most of medicine.    Around 1990, the thinking on DFI started changing again. Lipsky and Pecoraro looked at “uncomplicated” infections in the diabetic lower extremity and compared the efficacy of cephalexin with clindamycin.2 The study showed both drugs had similar effects. This was particularly interesting for a number of reasons. It was one of the first times DFI were not all grouped together as a severe, limb threatening process. There could be “uncomplicated” presentations.    More importantly, when they compared the spectrum of activity of each drug, Lipsky and Pecoraro noted that cephalexin has activity against gram positive cocci and some gram negatives but no coverage against anaerobic organisms. Clindamycin shares the activity against the gram positive cocci but adds anaerobic coverage and has no activity against the gram negatives. In terms of coverage, the only organisms these drugs had in common were Staphylococcus and Streptococcus. One could conclude that these gram positive organisms were the primary pathogens despite what other bacteria may have been isolated from these uncomplicated DFIs.

Gram-Positive Cocci: Why It Is An Essential Consideration

   Understanding the importance of gram-positive cocci, in particular Staphylococcus aureus and Group B Streptococcus, is critical in the current antibiotic approach to DFIs. The recent Infectious Diseases Society of America (IDSA) Diabetic Foot Infection Guidelines emphasize the following point:     “Aerobic gram positive cocci (especially Staphylococcus aureus) are the predominant pathogens in diabetic foot infections. Patients who have chronic wounds or who have recently received antibiotic therapy may also be infected with gram negative rods, and those with foot ischemia or gangrene may also have obligate anaerobes.”3    The guidelines specifically note the dated thinking that all DFIs are mixed infections is not evidence based. There is a difference in microbial flora based on the severity of the infection and the presence of comorbidities. Even in the more complicated infections in which a myriad of other organisms may be isolated, their importance as primary pathogens needing antibiotic coverage is debatable. Many represent colonization only.

Assessing The Impact of MRSA

   While the number and types of true pathogens in the majority of DFIs may be limited to Staphylococcus and Streptococcus, it does not mean that the clinician can rest assured that traditional therapies active against these two organisms will be enough.    In the past five years, there has been a seemingly logarithmic growth in the incidence of methicillin resistant Staphylococcus aureus (MRSA) as a pathogen in the diabetic foot. This organism was once associated only with nosocomial infections but now community-acquired strains of MRSA have become common in DFI cases. While it is outside the scope of this feature to review MRSA in detail, it is important to examine the situation in the diabetic foot.    As recently as 1996, Goldstein reported that 20 percent of the staphylococcal isolates from his diabetic foot population in California were methicillin resistant.4 In 1999, Tentolouris showed 40 percent of the staphylococcal isolates in their diabetic foot clinic in the United Kingdom were methicillin resistant.5 In 2003, the same group published a follow-up study entitled “Methicillin resistant Staphylococcus aureus in the diabetic foot clinic: A worsening problem.”6 Although the absolute percentage of MRSA among their staphylococcal isolates only increased to 42.2 percent, the number of patients that actually presented with MRSA doubled. Fortunately, their study found many of these MRSA isolates could be treated effectively with debridement, topical therapy and isolation.    What does this mean in terms of empiric antibiotic therapy? Does one have to include MRSA coverage in the mix? At this point, in most locales, the incidence of MRSA has not reached the level of medical probability. In other words, it is not yet “more likely than not” that MRSA is in the wound, which is the legal definition of medical probability. Therefore, empiric MRSA coverage is probably not warranted for most diabetic foot infections. However, one may consider empiric coverage when treating patients at high risk for MRSA (see “Which Patients Are At High Risk For MRSA?” below).7

Rethinking Empiric Antibiotic Therapy For DFIs

   Despite the overall prevalence of diabetic foot infections, there are surprisingly few large scale, randomized, controlled clinical trials specific to the condition.3 The central premise of most empiric antibiotic therapy for these infections is that there must be a broad spectrum of coverage to handle not only the gram positive cocci but also the gram negative rods and the anaerobic organisms.    However, as we discussed above, this thinking is radically changing in line with the newer theories of pathogenicity. More and more clinicians are appreciating that antibiotic coverage should concentrate on the gram positive cocci and that one should reserve broader spectrum choices only for those patients at risk for a true polymicrobial infection. Even in these more severe infections, in which one may isolate multiple types of organisms, the need for truly broad-spectrum coverage is undergoing re-evaluation. The current thinking has likened the microbial flora of a diabetic infection to a snake in which the gram positive cocci represent the head of the snake and all the rest of the organisms comprise the body. Once one removes the head of the snake, the rest will die. Almost as surely, if one kills the Staphylococcus and Streptococcus, the remaining organisms too will be inconsequential.    Traditional lines of thinking are also changing with regard to oral versus parenteral therapy. Many clinicians have a misconception that intravenous antibiotics are somehow “stronger” or “more potent.” Actually, any number of oral antibiotics have bioavailabilities that are similar regardless of whether the drug is given orally or parenterally. Examples include the quinolones, trimethoprim/sulfa and linezolid. In the case of linezolid, the oral bioavailability is actually greater than the IV form.    With any of these drugs, there is really no reason to give the drug parenterally as the oral medication will work every bit as well. There will also be a significant cost savings in not having to maintain an IV line and there is less risk of complications such as line sepsis. Even in drugs that do not have equivalent bioavailability between oral and parenteral forms, given the proper dosing, a compliant patient and a functioning GI tract, there is no reason why the oral regimen should not be effective. Even in the case of osteomyelitis, which has long been considered a prototypical disease that required long-term IV therapy, oral regimens are finding success and favor.

Mild DFIs: What Are The Best Treatment Options?

   The IDSA Guidelines divide the severity of DFIs into four distinct categories: non-infected, mild infection, moderate infection and severe infection. Non-infected ulcers do not require culturing or antibiotics. Let us take a closer look at the remaining three categories of DFIs.    Mild (uncomplicated) infection. Infected ulcerations with only localized signs of inflammation fall under the category of mild infections. These lesions are infected almost exclusively with the aerobic gram positive cocci Staphylococcus and Streptococcus. In fact, the bacteriology of these lesions is so well accepted that culturing is really not even necessary. Since, by definition, these are localized processes, treatment usually begins with any oral antibiotic with sufficient activity against these two organisms. One would not empirically address MRSA unless the patient presents with risk factors for MRSA (see “Which Patients Are At High Risk For MRSA?” above).    There are some commonly used oral antibiotics for mild diabetic foot infections that are listed below (see “A Guide To Oral Antibiotics For Mild DFIs”). While the list in the sidebar is not exhaustive, one may employ any antibiotic with activity against Staph and Strep. In podiatric medicine, amoxicillin/clavulanic acid is possibly the most commonly used antibiotic for these infections. This again dates back to a time when clinicians considered it necessary to use a drug with broad spectrum, anti-anaerobic activity. Although amoxicillin/clavulanic acid is effective, the drug is expensive and one probably doesn’t need the broad spectrum activity.    Overall, cephalexin is the most commonly used oral antibiotic in podiatry. It has a long safety history and decent activity against the important pathogens. On the downside, most clinicians tend to have patients take the medication three to four times per day, which may affect compliance.    Cefdinir is a cephalosporin that actually has significantly better in vitro activity against Staph and Strep than cephalexin. It also has the advantage of being a twice-a-day drug. In patients with a true allergy to penicillin, oral clindamycin is an excellent choice for these mild infections. Levofloxacin is another option for penicillin- or cephalosporin-sensitive patients.    However, be aware that not all quinolones are equal in this regard. Avoid using ciprofloxacin in cases in which Staph is expected since Staph develops rapid resistance and the drug is far from optimal. Also be aware there is a major issue with quinolone cross-resistance. If a Staphylococcus develops resistance to ciprofloxacin, there is a good chance it is resistant across the class.

Essential Insights On Managing Complicated Infections

   Moderate to severe (complicated) infections. These infections can be limb- or life-threatening. More often than not, hospitalization is required to stabilize the patient not only from an infection standpoint but also metabolically. Urgent surgical incision and drainage is frequently required. As discussed above, these infections tend to grow out a greater variety of organisms. While it may only be necessary to treat the gram positive cocci at this point in time, it is still prudent to begin a broader spectrum course of therapy and narrow it down as the patient responds.    In many hospitals, beta-lactam/beta-lactamase inhibitor compounds, such as piperacillin/tazobactam or ampicillin/sulbactam, are considered first line therapy for complicated diabetic foot infections. These drugs have a spectrum of activity that consists of excellent gram positive and anaerobic coverage with variable activity against the gram negatives. Piperacillin/tazobactam is the better of these compounds in this regard. For the most part, however, the drugs are interchangeable and frequently only one or the other is available on a given formulary.    Recent data shows that ertapenem, a penem class antibiotic, is as effective at one gram per day IV/IM as the four times a day dosing of piperacillin/tazobactam.8 Using the once-a-day therapy facilitates a much lower cost and more convenience for the patient, especially in the outpatient setting. This study, which enrolled close to 600 patients, is the largest single trial to date examining antibiotic therapy of complicated DFIs.    In patients with sensitivity to a beta-lactam drug, the combination of parenteral clindamycin along with an oral quinolone gives empiric, broad-spectrum coverage. Clindamycin will cover the gram-positive organisms and the anaerobes while the quinolone will pick up the gram-negative organisms.    A number of newer generation quinolones also have potential activity against the wide variety of pathogens one finds in these complicated DFIs. Although trovafloxacin was essentially pulled from the market because of toxicities, newer drugs such as moxifloxacin, gatifloxacin and garenoxacin may show promise. Unfortunately, the data is still not overly convincing.    For patients with a documented MRSA or those who are at high risk for MRSA, linezolid is becoming the drug of choice. This is only the third antibiotic to be granted a specific indication for DFIs by the FDA. The pivotal trial that led to the FDA approval compared linezolid (po or IV) to amoxicillin/clavulanic acid (po) and ampicillin/sulbactam (IV).9 The researchers found that linezolid had superior efficacy for cases of infected ulcerations.    More recent data compared linezolid to vancomycin for the treatment of complicated skin and skin structure infections (CSSSIs). In a large trial of 1,200 patients, Weigelt found linezolid to be statistically superior to vancomycin in the treatment of CSSSIs caused by MRSA.10 In a similar but smaller study, Sharpe found that linezolid was not only superior to vancomycin but also noted there were seven amputations in the patients treated with vancomycin and none in the patients treated with linezolid.11

How To Facilitate Clean Wounds And Appropriate Wound Closure

   When treating DFIs, one of the most important factors to consider is the need for early surgical intervention as resulting limb- or life-threatening infections can lead to subsequent amputation. Initial surgery to address the severe infection should precede the need of vascular reconstruction. One should remove all pus, devitalized and infected soft tissue or bone from the wound, thereby converting the defect to a surgically clean acute wound. Keep in mind that one may have to perform this process more than once before the wound is ready for closure.    Ensuring a thorough vascular examination and performing possible reconstruction if necessary are also critical to the healing process of the DFIs. When the patient has intact vascular status, consider a primary wound closure for the non-infected chronic wound. If the wound bed has enough granular tissue and is free from any necrotic and infected soft tissue and/or bone, one may perform a delayed primary closure. When it comes to infected and draining wounds, leave these packed open initially. There are a variety of plastic surgery techniques one may employ to close the wound.    Initial incision planning is very important to facilitate the delayed primary closure process. Aggressive surgical debridement and appropriate adjunctive therapy are also vital to facilitating healing of DFIs. Adjunctive modalities may include negative pressure vacuum therapy, hyperbaric oxygen therapy, local wound care, growth factor stimulators and offloading devices.

Pertinent Pointers On Employing Antibiotic Bone Cement

   The use of antibiotic-loaded bone cement is one surgical modality that may help accelerate healing in DFIs. After performing proper soft tissue and osseous debridement of the infected structures, one can place antibiotic-loaded synthetic spacers between the resected osseous structures. The spacers provide a biological function as they sterilize the affected area by providing a local concentration of antibiotic. The spacers also provide a structural function as they fill the resultant “dead space” and maintain osseous position by preventing periarticular soft tissue contraction that makes subsequent osseous reconstruction more difficult.    To this end, the use of antibiotic-loaded polymethylmethacrylate bone cement (AL-PMMA-BC) has been commonly used since 1970 when Bucholz and Engelbrecht first described its use in infected total hip arthroplasties.12 Since that time, many authors have described the use of AL-PMMA-BC in treating foot and ankle osteomyelitis.13-17 Although no studies have documented an actual cure with this treatment alone, when researchers combined it with parenteral antibiotic therapy, AL-PMMA-BC provided a bactericidal effect in the rat model.18 Since the polymerization process of PMMA-BC is highly exothermic (i.e., the mean heat of reaction is 94º C), the antibiotic one chooses must be heat stable and should exist in a powder form for even distribution throughout the PMMA-BC.19    Fortunately, there are a number of available antibiotics that are heat stable, exist in powdered form and are compatible with PMMA-BC.20 Vancomycin and tobramycin are the most commonly added antibiotics to PMMA-BC. However, with the development of multi-drug resistant bacterial organisms, such as MRSA, vancomycin-resistant Staphylococcus aureus (VRSA) and vancomycin resistant Enterococcus (VRE), one should be very cautious before using antibiotic-loaded bone cement. Surgeons should also be aware of the possibility of severe inflammatory reactions about the implantation site with frequent serous drainage.21-23    The release or elution of antibiotic from PMMA-BC is obviously an important consideration and researchers have identified several factors that directly affect the success of the antibiotic delivery system.19,24-28 Interestingly, some authors have shown the combination of vancomycin and gentamycin decreases the release of vancomycin by more than 50 percent without affecting the release of gentamycin.28 Since there are several commercially available forms of PMMA-BC that are pre-loaded with gentamycin, one should avoid adding vancomycin to these PMMA-BCs and instead add pure PMMA-BC that is devoid of gentamycin. Researchers have shown that vancomycin maintains the MIC of susceptible organisms for up to 12 days while gentamycin has the same effect for up to 30 days and tobramycin for up to 90 days.29,30    Following the soft-tissue and osseous debridement, it is common to leave the AL-PMMA-BC in place for between seven to 10 days. One would subsequently perform a repeat irrigation and debridement with AL-PMMA-BC exchange or a definitive reconstruction if clinical, pathological and systemic signs and symptoms support this approach. It is interesting to note that authors have also shown that AL-PMMA-BC stimulates platelet activation and thereby releases growth factors from the wound that may enhance soft tissue and osseous healing adjacent to the implantation of the modality.31    There is a simple technique to creating rounded beads. Fill a 10 cc syringe with the AL-PMMA-BC while it is still in a semi-solid state. Then dispense the appropriately sized bead onto a heavy gauge suture or monofilament wire to create a chain of beads approximately 6 mm in diameter. Ensure that the beads are evenly spaced every 5 mm. This allows the chain to be malleable and fill the defect evenly.

Final Thoughts

   In recent years, there have been interesting developments in the treatment of DFIs. While ensuring a multidisciplinary approach remains vital to managing these infections and other comorbidities, the understanding of the pathogenic organisms has changed and a number of new antibiotics have recently become available to treat these infections.    In the near future, we believe that more antibiotics will be granted a specific FDA indication for the treatment of DFIs. Indeed, early aggressive surgical debridement and appropriate antibiotic therapy are necessary to successfully treat severe foot infections and permit a quicker recovery. 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. Dr. Zgonis is an Assistant Professor in the Department of Orthopaedics/Podiatry Division of the University of Texas Health Science Center at San Antonio. He is an Adjunct Assistant Professor of Surgery at the College of Podiatric Medicine and Surgery at Des Moines University in Des Moines, Iowa. Dr. Zgonis is an Associate of the American College of Foot and Ankle Surgeons. Dr. Roukis is a Fellow of the American College of Foot and Ankle Surgeons. He practices at the Weil Foot and Ankle Institute in Des Plaines, Ill. For related articles on diabetic foot infections, see “MRSA: Where Do We Go From Here?” in the March 2005 issue, the April 2004 supplement “Treating MRSA Infections,” “Are Your Antibiotic Prescriptions In Line With Evidence-Based Medicine” in the May 2005 issue or check out the archives at www.podiatrytoday.com.
 

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