Important aspects during management of diabetic foot infection

Abstract

Diabetic foot is a complex disease. One of its most important complications is infection with risk of limb loss. In severe cases it is also a life-threatening condition. Several guidelines are available in order to achieve the implementation of some standard of care strategies. However, these consensus documents do not address all controversial issues arising during diabetic foot infection. The present article aims to review some of these controversial aspects.

BACKGROUND

Diabetic foot is a complex and heterogeneous disease. One of its most important complications is infection with risk of limb loss. In severe cases it is also a life-threatening condition [1].

Management of these types of infections is not easy since many different specialities are involved on it. In addition, perception, knowledge and awareness of this condition is quite heterogeneous between different physicians. Several guidelines are available in order to achieve the implementation of some standard of care strategies [2,3]. However, these consensus documents do not address all controversial issues arising during diabetic foot infection attention. When to treat resistant bacteria empirically, the duration of this treatment and which is the best dose to achieve high concentrations at the site of infection are aspects that guidelines do not always explain. Some comorbidities play also an important role in the management of prognosis of diabetic foot infections. The present article aims to review some of these controversial aspects:

CHOICE OF EMPIRICAL ANTIBIOTIC

Regarding medical treatment of infection, the choice of an empirical antibiotic is quite difficult, especially in moderate or severe infections, where polymicrobial involvement is frequent. In this clinical scenario, early administration of correct antibiotics improves prognosis and results in lower amputation and mortality rates. On one hand, delay on antibiotic treatment can lead to adverse outcomes, which means that there is often no time to wait until results of cultures are available. But on the other hand, bad evolution and lack of improvement could be the consequence of an incorrect empirical choice.

Mild infection. In general terms, mild infections (less than two centimetres of redness of skin with depth affecting only subcutaneous tissue) of acute lesions with a course of no longer than two weeks and without prior antibiotic are usually caused by gram-positive bacteria and do not need coverage against gram negative bacteria, anaerobes or resistant micro-organisms. However, this is only a general approach [2,3]. It is necessary to take into account that some patients are at high risk of methicillin-resistant Staphylococcus aureus (MRSA) infections despite having non-complicated disease. So, prior MRSA infections or colonization by this microorganism, nasal carriers, peripheral vasculopathy and chronic kidney disease (most of all in dialyzed patients) are risk factors for being infected by this virulent bacterium and are described in medical literature. It is important to rule out these circumstances for the correct treatment of mild infections because when they are present, coverage against MRSA should be, at least, considered [4-6].

At this point it is important to notice that correct evaluation of both vascular status and infection depth is mandatory. For example, small cellulitis areas are sometimes present in deep lesions including osteomyelitis so that they seem to be less severe infections than they really are. That is why this evaluation should be done by trained professionals. When physicians have doubts about these facts prompt referral to specialized diabetic foot units is recommended. This shows that correct diabetic foot infection management requires a complex and multidisciplinary approach. In addition, it is important to mention that sharp debridement at site of infection and revascularization when needed is as important as the correct choice of antibiotic, making teamwork crucial to achieve successful outcomes [1,2].

Moderate and severe infection. Moderate diabetic infections have cellulitis areas that are usually bigger than 2 cm and affect deeper structures beyond subcutaneous tissue such as fascia, muscle, joints or bone. In this scenario, wider antibiotic coverage should be considered including gram negative bacteria and anaerobes. However, multidrug resistant bacteria are not always responsible [2,3].

Severe infection with systemic toxicity signs or sepsis, is a life-threatening condition and needs to be treated covering resistant gram-positive and resistant gram-negative bacteria. In these cases, in which broad spectrum antibiotics are prescribed, it is also mandatory to obtain tissue samples correctly in order to switch to a narrow spectrum antibiotic when possible. Swab samples do not offer reliable results and should not be taken.

Following Basetti, M et al. [7] in general population, host factors in general population for multidrug resistant gram-negative infections are older age (more than 70), diabetes mellitus, chronic obstructive pulmonary disease, malignancy, immunosuppression (including neutropenia and corticosteroid use) Charlson comorbidity index greater than 3, indwelling devices, need of haemodialysis, recent surgery or exposure to antibiotics within previous three months. Poor hygiene, recent hospital stay or transfer from another healthcare facility and prior colonization are also epidemiological factors that must be taken into account when assessing treatment for gram-negative bacteria. Probably, the presence of only one of these risk characteristics is not enough to support treatment against resistant Gram-negative bacteria. However, when some of them are present at the same time, wide spectrum antibiotics need to be considered.

Regarding specifically diabetic foot syndrome population, enterobacteria producing extended-spectrum beta-lactamases (ESBL) play an important role. In addition to the risk factors mentioned above, previous treatment with cephalosporines and presence of osteomyelitis are also risk factors for infection [4].

Importance of Osteomyelitis in diabetic foot infection. As mentioned above, ruling out bone infection in diabetic foot patients is always necessary. Long-time non-healing ulcers usually fail to respond to several antibiotic schemes. When this happens, many different causes could be responsible. Wrong local management, need of revascularization, low antibiotic dosages, bad treatment adherence or the failing of discharge strategies are possible causes. However, when ulcers do not heal or infection does not improve despite an apparently correct treatment, it is crucial to rule out diabetic foot osteomyelitis. Bone penetration of antibiotics is a difficult issue and higher doses could be needed. Bone removal, when possible, is another option that helps to improve infections. When not possible, longer antibiotic courses are needed (as long as six weeks). As it has been explained before, osteomyelitis is an independent risk factor for multi-drug resistant bacteria such as MRSA or ESBL enterobacteria. For all those reasons the classical diabetic foot infection classification [2] (Table 1) is presently very much discussed. Although severe infection with systemic toxicity is always a reason for concern, it seems that the presence of osteomyelitis has important prognosis implications, and a new classification [8] has been proposed by Lavery et al (Table 2).

Table 1.

Classical diabetic foot infection classification by IWGDF in 2019 update [2]

Definition	Grade
No signs of infection.	1
- Infection limited to skin or superficial subcutaneous tissues without local complication or systemic signs AND - Erythema does not extend > 2 cm around the wound.	2
Infection with no systemic manifestations - Erythema extending > 2 cm form the wound margin AND/OR - Infection deeper than skin and subcutaneous tissues (deep tissue abscess, lymphangitis, tendon, muscle, joint and/or bone involvement)	3 (add “O” if infection involves bone)
Any foot infection with associated systemic signs as manifested by 2 or more of the following: - Temperature > 38 ºC or <36ºC - Heart rate > 90 beats/min - Respiratory rate > 20 breaths/minute or PaCO2 < 32 mmHg - White blood cell count >12.000/mm3or < 4000/mm3or > 10% immature (band forms)	4 (add “O” if infection involves bone)

IWGDF: international working group of diabetic foot

Table 2.

Revised IDSA diabetic foot classification by Lavery et al [8]

Definition	Grade
Diabetic foot ulceration without any manifestation of infection	No infection
Infection limited to skin or superficial subcutaneous tissue without local complication or systemic illness with 2 or more of the following signs: - Local swelling or induration - Erythema (extending <2 cm around the wound) - Local tenderness or pain - Local warmth - Purulent discharge	Mild soft tissue infection
Either systemically stable or unstable patients with 1 or more of the following: - Erythema extending > 2 cm from ulceration - Lymphangitis - Spread beneath fascia - Deep tissue abscess - Gangrene - Can involve muscle tendon and joint but not bone This category includes patients with moderate or severe soft tissue infection. Severe infection is defined by 2 or more of the following: - Temperature > 38 ºC or <36ºC - Heart rate > 90 beats/min - Respiratory rate > 20 breaths/minute or PaCO2 < 32 mmHg - White blood cell count >12.000/mm3 or < 4000/mm3 or > 10% immature (band forms)	Moderate/severe soft tissue infection
Any bone infection of the foot This category includes patients with moderate or severe bone infection. Severe infection is defined by 2 or more of the following: - Temperature > 38 ºC or <36ºC - Heart rate > 90 beats/min - Respiratory rate > 20 breaths/minute or PaCO2 < 32 mmHg - White blood cell count >12.000/mm3or < 4000/mm3or > 10% immature (band forms)	Moderate/severe diabetic foot osteomyelitis

IDSA: infectious disease society of America.

One meta-analysis published in 2019 by Pinar Sen et al showed [9] the importance of osteomyelitis as an independent risk factor for amputation. In pooled OR analysis, the presence of gangrene/necrosis (OR: 9.9, 95% CI, 6.243 -15.699; P < 0.001), presence of osteomyelitis (OR: 4.5, 95% CI, 2.277-8.885; P < 0.001), and length of hospitalization (SMD: 0.70, 95% CI, 0.45-0.95; P < 0.001) were the main associations with an increased risk of lower extremity amputations in patients with diabetic foot infections. Results showed also that the risk of amputation increased 1.7 -fold with an IWGDF grade 3 classification and 2.5-fold with an IWGDF grade 4 classification (95% CI, 1.398 -2.061; P < 0.001 and 95% CI, 1.647 -3.823; P < 0.001, respectively)

This study showed that diagnosis of diabetic foot infection is not only based on clinical suspicion and bacterial-isolation. Correct depth assessment and identification of affected structures are obligatory actions to be done before performing any therapeutic strategy. It is particularly important to rule out the presence of gangrene/necrosis and osteomyelitis since they seem to be the most important predictors of amputation.

Bone cultures still remain as an essential procedure in order to diagnose diabetic foot osteomyelitis [10] In addition, in patients with chronic osteomyelitis, which are often overtreated, cultures could be less reliable and bone biopsy should be considered [11].

DURATION OF TREATMENT

Although guidelines make some recommendations about this issue, the decision of stopping antibiotics should be made on the basis of clinical evolution. For example, for mild infections, 1-2 weeks antibiotic courses are recommended [2]. Whether 7 or 14 days of antibiotic treatment are required should be assessed individually taking into account the improvement or absence of infection signs, the possibility of removing infected tissue with sharp debridement, side effects, vascular status, etc. Again, it is particularly important to rule out osteomyelitis because removal of infected bone can reduce dramatically the duration of antibiotic treatment. In cases where bone removal is not possible or surgery is not indicated (Table 3) six weeks of medical therapy alone are recommended [12,13]. However, this medical approach is not preferred since long antibiotic courses are associated with higher risk of side effects such as renal failure, Clostridioides difficile infection, candidiasis, bone marrow toxicity, etc. One prospective, randomized non-inferiority pilot trial suggests that 3 weeks of medical treatment could be enough. However, in this study surgical debridement was performed before medical treatment [14].

Table 3.

Clinical situations in which nonsurgical treatment could be considered in patients with diabetic foot osteomyelitis [13]

Clinical situation
Infection confined to the forefoot
Adequate limb perfusion
No tissue necrosis
Contraindication to surgery AND/OR high surgical risk
Patient preference to avoid surgery

In addition, in cases of infection that do not improve despite apparently correct medical treatment, just prolonging the same antibiotic scheme seems not to be a good option. Checking treatment adherence and antibiotic dose in order to achieve high concentrations at infection site, revising cultures results, evaluating dressing and offloading devices, assessing vascular status and ruling out bone involvement taking samples are essential aspects to be regarded in order to achieve success during management and avoid amputations, which is the most important objective of diabetic foot infection management.

COMORBIDITIES

Some comorbidities have demonstrated to have prognostic implications in diabetic foot infections [15-21]. Chronic kidney disease, haemodialysis, heart failure, ischaemic heart disease, malnutrition and poor glycaemic control are conditions which are frequently present in diabetic foot patients and have shown to increase the risk of adverse outcomes such as mortality after amputation, amputation risk or delay of the healing process.

If these comorbidities are not detected, treated and controlled, diabetic foot infection will have more systemic repercussion and prognosis will worsen. This shows again the need of a multidisciplinary, collaborative and communicative approach between different specialties involved on diabetic foot management. Nurses, vascular surgeons, podiatrists, orthopaedic surgeons, internal medicine, endocrinology, microbiology and infectious diseases specialists are professionals that contribute to improve diabetic foot infection management and it seems difficult that they can achieve their objectives separately. The objective of successful diabetic foot infection management can only be achieved by efficient teamwork.

CONFLICT OF INTEREST

Authors declare no conflict of interest