An Update On Antibiotic Resistance And DFUs

The injudicious use of antibiotics appears to be fueling the rise of antibiotic resistance in the treatment of diabetic foot ulcers (DFUs). This author examines critical factors that contribute to resistant strains as well as keys to effective antibiotic selection and treatment of infection in this patient population.

As early as the emergence of the first antibiotic, Sir Alexander Fleming himself recognized the future potential for the development of antibiotic resistance.¹ Today, over 70 years later, there is a rising concern that antibiotic resistance has reached pandemic proportions. Although there are multiple reasons for the rise of antibiotic resistance, a major factor remains the continued overuse and dependence on antibiotic therapy.

The rising concern surrounding antibiotic resistance has certainly impacted the management of diabetic foot ulcerations (DFUs). The cost of the management of DFUs has become a serious financial burden in society today, averaging upward of $10,000 per patient in 2008.² However, this cost increases exponentially when these patients have an infection and/or amputation.

Of further concern is the continued steady increase in the number of people diagnosed with diabetes worldwide, totaling over 366 million people in 2011 with a predicted rise to over 500 million by 2030.3 Up to 25 percent of this population has a risk of sustaining a DFU and approximately half of these patients will develop an associated infection.³

It is therefore imperative to take every appropriate precaution to optimize the health of this population of patients in an effort to recognize, address and manage all associated comorbidities. In addition to striving for optimal glycemic control, clinicians need to assess for and address neuropathy, peripheral vascular disease, pedal deformities and major organ function. For these reasons, the overall care of the patient with diabetes has come to rely heavily upon a more comprehensive, multidisciplinary approach to care.^2,3

A Closer Look At Predisposing Factors To DFU Infection
Diabetic foot ulcers are multifactorial in nature and there are often several issues that ultimately increase the risk for infection in the patient with diabetes. Patients with DFUs most commonly have progressive peripheral neuropathy, resulting in the absence of protective sensation. The skin integrity is further compromised when loss of protective sensation is coupled with foot deformity. This combination results in a greater focus of pressure predisposing the foot to repetitive microtrauma or pressure, and ultimately skin breakdown. This compromise leads to foot ulceration, producing the ultimate nidus for infection. In the absence of early diagnosis, appropriate wound care and offloading, infection becomes inevitable.

Another complicating factor in the presence of DFU is the patient’s level of glycemic control. Researchers have shown that hyperglycemic states in ranges of less than 200 mg/dL reduce the normal functions of the cellular components in the wound healing cascade.³ This compromise in cellular function results in a decrease in bacterial clearance due to impaired neutrophil function and a delay in appropriate cellular apoptosis. This compromise in the cellular components of wound healing predisposes the patient with diabetes not only to a delay in overall healing but to a greater risk of infection as well.

What Factors Contribute To Antibiotic Resistance?
Several factors have been associated with the development of resistant bacterial pathogens ranging from continued exposure to antibiotics and antibiotic use in food producing animals to repetitive exposure to antibiotics, hospital exposure and overprescribing of antibiotics on the part of the medical provider.^3,4 When it comes to patients with diabetes, there is aggressive management for potential infections due to the increased risk of infection and the fear of the consequences in regard to amputation should infection persist or worsen.  

In specific regard to DFUs, one of the key inherent factors that promotes the propagation of bacterial resistance is chronicity.⁵ Often, patients with DFUs have prolonged periods of offloading, wound care, debridement and advanced wound care regimens before full healing occurs. During this drawn-out process, it is not uncommon for physicians to implement intermittent periods of antibiotic regimens for the presence of infection, the suspicion of infection or simply an effort to deter infection. In scenarios that involve prophylaxis against infection or if one has not confirmed the appropriate signs of infection, not only can exposure to the antibiotic be a risk for infection in itself but this repetitive increase in antibiotic exposure contributes to the potential for the development of resistant bacterial strains.

A second concern is the potential for incorrect antibiotic selection when prescribing a regimen for a patient with a chronic DFU.^2,6 Unless one obtains appropriate cultures, antibiotic choice often focuses on a suspected causative organism. Clinicians should obtain cultures either from deep soft tissue specimens or curettage of the wound bed given the demonstrated inaccuracy of superficial swab cultures.⁷ Unfortunately, this often does not happen in the clinical setting. However, if one does obtain cultures, narrowing the antibiotic selection is recommended based on final identification of the causative organism(s) and the susceptibilities.⁷

A Guide To The Resistant Organisms In Diabetic Foot Ulcers
When it comes to managing DFUs and infection, there is an understanding that the majority of DFUs are chronic and all chronic wounds are contaminated with bacteria. It is also important to understand that wound healing can indeed occur in the presence of bacteria. It is not until there is disruption in the bacterial continuum, in which colonization progresses to infection, that one should implement antibiotics.
Microbial flora within a wound change over time and in early wounds, the host’s normal flora, Staphylococcus aureus and Group B Strep tend to predominate. As wounds become more chronic, anaerobes such as Proteus, E. coli and Klebsiella present within the wound flora. Ultimately, as wounds regress and increase in tissue destruction or depth, a more polymicrobial infection ensues.^5,8

When one understands the predominance of organisms within a DFU based on chronicity and progression through the bacterial continuum, and the factors contributing to antibiotic resistance, it is no surprise that methicillin-resistant strains of S. aureus (MRSA) are the most commonly isolated resistant bacterial strains in DFUs.⁵ Although there is documented presence of Gram-negative multi-resistant organisms and other resistant strains are coming into the forefront, MRSA remains the most prevalent organism. It is often the excessive use of antibiotics that contributes to the prevalence of MRSA.

In their review of the prevalence of MRSA in infected diabetic foot wounds, Cervantes-Garcia and colleagues found that approximately one-third of cases of S. aureus isolates were MRSA.⁵ Wounds with these strains also demonstrated up to a threefold increase in healing time in comparison to those wounds infected with methicillin sensitive strains. The authors’ work emphasizes the importance of understanding the pathophysiology of DFU progression and the role of infectious agents in light of the increased mortality and morbidity observed in the presence of resistant organisms.

Making The Diagnosis Of Infection
There is often uncertainty in making a definitive diagnosis of infection when confronting a chronic DFU. It is not uncommon for patients with diabetes to lack the expected immune response in the presence of a chronic wound. This uncertainty can at times translate into the prescribed treatment plan, which can include unnecessary antibiotic management. However, upon initial evaluation and periodically during the course of management of the patient, one must remain cognizant of the classic markers of infection: rubor, pain, erythema, purulence, and erythema along with any observed changes in wound tissue integrity.

The Infectious Diseases Society of America (IDSA) established a foundation for both a classification system for diabetic foot infections, and an effective and universal treatment algorithm.⁷ The guidelines classify infections as Grade I to Grade 4 and based on the extent of infection, the range includes uninfected, mild, moderate and severe. This system provides for distinct clinical markers defining each category, leaving no room for ambiguity in regard to diagnosis.

The guidelines also aid in answering key questions that often arise in the management of diabetic foot infections in an effort to provide a guided approach to starting antibiotics, changing antibiotic regimens and ultimately considerations for hospitalization for patients with the most severe infections.⁷ Utilizing such an intricate system has provided a solid validation of determining foot risk, which demonstrates the increase in amputation risk associated with an increase in infection severity as well as the need for hospitalization in such cases.⁹ The IDSA guidelines have also afforded the practitioner a solid foundation and justification of treatment course when practitioners adhere to these established guidelines in regard to patient care and decision making.

Key Components To Guidelines For Antibiotic Management
The fear of a missed diagnosis of infection and the philosophy of prophylaxis to prevent infection risks in patients with DFU are some of the concerns practitioners face confronting the management of chronic DFUs.⁷ Further compounding these concerns are the pressures from both patients and family members who question the absence of antibiotics in the treatment plan, and request prescriptions of antibiotics. These pressures and demands can ultimately result in the inappropriate use of antibiotics, ultimately impacting the risk for development of bacterial resistance.   

It is important to assess the severity of the infection as this will ultimately determine the need for antibiotics and the appropriate antibiotic regimen.⁷ Severity will also determine the necessary route of administration and timing for any necessary surgical debridement. Recognizing the correlations between wound depth and severity, and how they translate into causative bacteria in the presence of infection will further guide antibiotic decision making.

Superficial, previously untreated DFUs are often predominantly aerobic with Gram-positive bacteria, S. aureus and/or beta-hemolytic Strep.⁷ As wounds progress to more chronic stages and deeper wounds, the concern for polymicrobial invasion is of the highest priority. This includes aerobic Gram positive and negative bacterial strains in conjunction with anaerobic organisms.

When a wound is more chronic and is demonstrating significantly prolonged healing times of greater than two to three months, one must be suspicious of resistant strains such as MRSA.⁷ One should suspect resistant bacterial pathogens in patients who have been previously hospitalized despite the universally implemented precautions against MRSA and in patients who have been previously treated with antibiotics without successful healing or eradication of infection. Regardless of infection, severity and chronicity, one must always display an increased vigilance in regard to antibiotic therapy in order to minimize bacterial resistance.

In Conclusion
The patient with diabetes often has several comorbidities and risk factors linked to the disease process itself. When pedal comorbidities including neuropathy, deformity and vascular disease are present, there is a substantial increase in both morbidity and mortality in an already high-risk population. Accordingly, we do not take the management of diabetic foot ulcers lightly and in an era of emerging wound therapies, grafts, skin substitutes and advanced wound care products, management is often aggressive and involves a multidisciplinary team approach.²  

Despite this effort to incorporate multiple expert opinions in the care of the patient, there seems to be a continued discrepancy with the role of prescribing antibiotics in the management of DFUs despite the presence or absence of infection. One must look at this dilemma critically in regard to the long-term role of antibiotic therapy given the continued emergence of antibiotic resistance.

It is crucial that providers follow well established guidelines and protocol for the prescribing of antibiotics when facing the management of diabetic foot ulcerations, infections and more so with chronic ulcerations demonstrating delayed healing.⁷ Physicians must employ due diligence in the diagnosis, management and use of antibiotic therapy in an effort to deter the future dominance of bacterial pathogens.

Dr. Hadi is a faculty member with the Louis Stokes Cleveland Veterans Administration Medical Center. She is a Fellow of the American College of Foot and Ankle Surgeons.

References

1.     Whiteman H. Antibiotic resistance: how has it become a global threat to public health? Medical News Today. Available at https://www.medicalnewstoday.com/articles/282357.php . Published September 10, 2014.
2.     Abbas M, Uckay I, Lipsky BA. In diabetic foot infections antibiotics are to treat infection, not to heal wounds. Expert Opin Pharmacother. 2015;16(6):821-832.
3.     Boyanova L, Mitov I. Antibiotic resistance rates in causative agents of infections in diabetic patients: rising concerns. Expert Rev Anti Infect Ther. 2013; 11(4):411-420.
4.     Davies J, Davies D. Origins and evolution of antibiotic resistance. Microbiol Mol Biol Rev. 2010; 74(3):417-433.
5.     Cervantes-Garcia E, Garcia-Gonzalez R, Resendiz-Albor A, Salazar-Schettino PM. Infections of diabetic foot ulcers with methicillin-resistant Staphylococcus aureus. Int J Low Extrem Wounds. 2015; 14(1):44-49.
6.     Kingsley A. The wound infection continuum and its application to clinical practice. Ostomy Wound Manage. 2003;49(7A Suppl):1-7.
7.     Lipsky BA, Berendt AR, Cornia PB, et al. 2012 Infectious Disease Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012:54(12):e132-73.   
8.     Bader MS. Diabetic foot infection. Am Fam Physician. 2008; 78(1):71-79
9.     Lavery L, Armstrong DG, Murdoch DP, et al. Validation of the Infectious Diseases Society of America’s Diabetic Foot Infection Classification System. Clin Infect Dis. 2007; 44(4):562-565.
10.     Maragakis LL, Perencevich EN, Cosgrove SE. Clinical and economic burden of antimicrobial resistance. Expert Rev Anti Infect Ther. 2008; 6(5):751-763.

For further reading, see “Keys To Addressing MRSA In The Diabetic Foot” in the March 2013 issue of Podiatry Today, “Point-Counterpoint: Should You Cover MRSA?” in the March 2007 issue, or the DPM Blog “Addressing The Rising Concern Of Antibiotic Resistance With Surgical Prophylaxis” at https://tinyurl.com/q4682ha .

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