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Therapeutic Options for Diabetic Foot Infections
A Review with an Emphasis on Tissue Penetration Characteristics
Foot complications are common in diabetic patients; foot ulcers are among the more serious consequences. These ulcers frequently become infected, and if not treated promptly and appropriately, diabetic foot infections can lead to septic gangrene and amputation. Foot infections may be classified as mild, moderate, or severe; this largely determines the approach to therapy. Staphylococcus aureus is the most common pathogen in these infections, and the increasing incidence of methicillin-resistant S aureus during the past two decades has further complicated antibiotic treatment. Chronic infections are often polymicrobial. Physiologic changes, and local and systemic inflammation, can affect the plasma and tissue pharmacokinetics of antimicrobial agents in diabetic patients, leading to impaired target-site penetration. Knowledge of the serum and tissue concentrations of antibiotics in diabetic patients is, therefore, important for choosing the optimal drug and dose. This article reviews the commonly used therapeutic options for treatment, including many newer antibiotics developed to target multidrug-resistant gram-positive bacteria, and includes available data relating specifically to the tissue penetration of these agents. (J Am Podiatr Med Assoc 100(1): 52–63, 2010)
Antibiotic Tissue Penetration in Diabetic Foot Infections
A Review of the Microdialysis Literature and Needs for Future Research
Although many antimicrobial agents display good in vitro activity against the pathogens frequently implicated in diabetic foot infections, effective treatment can be complicated by reduced tissue penetration in this population secondary to peripheral arterial disease and emerging antimicrobial resistance, which can result in clinical failure. Improved characterization of antibiotic tissue pharmacokinetics and penetration ratios in diabetic foot infections is needed. Microdialysis offers advantages over the skin blister and tissue homogenate studies historically used to define antibiotic penetration in skin and soft-tissue infections by defining antibiotic penetration into the interstitial fluid over the entire concentration versus time profile. However, only a select number of agents currently recommended for treating diabetic foot infections have been evaluated using these methods, which are described herein. Better characterization of the tissue penetration of antibiotic agents is needed for the development of methods for maximizing the pharmacodynamic profile of these agents to ultimately improve treatment outcomes for patients with diabetic foot infections.
Vancomycin is a common treatment option for skin and skin structure infections caused by methicillin-resistant Staphylococcus aureus (MRSA). Given the increasing prevalence of MRSA, vancomycin is widely used as empirical therapy. In patients with lower-limb infections, antimicrobial penetration is often reduced because of decreased vascular perfusion. In this study, we evaluated the tissue concentrations of vancomycin in hospitalized patients with lower-limb infections.
An in vivo microdialysis catheter was inserted near the margin of the wound and was perfused with lactated Ringer's solution. Tissue and serum samples were obtained after steady state for one dosing interval. Tissue concentrations were corrected for percentage of in vivo recovery using the retrodialysis technique.
Nine patients were enrolled (mean ± SD: age, 54 ± 19 years; weight, 105.6 ± 31.5 kg). Patients received a mean of 12.8 mg/kg of vancomycin every 12 hours (n = 7), every 8 hours (n = 1), or every 24 hours (n = 1). Mean ± SD steady-state trough vancomycin concentrations in serum and tissue were 11.1 ± 3.3 and 6.0 ± 2.6 μg/mL. The mean ± SD 24-hour free drug areas under the curve for serum and wound were 283.7 ± 89.4 and 232.8 ± 75.7 μg*h/mL, respectively. The mean ± SD tissue penetration ratio was 0.8 ± 0.2.
These data suggest that against MRSA with minimum inhibitory concentrations of 1 μg/mL or less, vancomycin achieved blood pharmacodynamic targets required for the likelihood of success. Reduced concentrations may contribute to poor outcomes and the development of resistance. As other literature suggests, alternative agents may be needed when the pathogen of interest has a minimum inhibitory concentration greater than 1 μg/mL.