The effectiveness of systemic antibiotics for osteomyelitis of the foot in adults with diabetes mellitus: a systematic review protocol

Infection of the foot in people with diabetes mellitus can lead to significant morbidity and mortality [1‐5]. The contribution of hyperglycaemia, peripheral neuropathy, vascular insufficiency or trauma in a patient with diabetes mellitus can lead to the development of diabetic foot ulcer (DFU) which may become the point of entry for pathogens [6‐8]. It is estimated the lifetime risk of a person with diabetes developing a DFU is as high as 25% and infection complicates these in 40–80% [9]. Diabetic foot osteomyelitis (DFO) is the consequence of a soft tissue infection that progresses into bone by breaching the cortex and invading the medullary cavity [10, 11]. It is estimated 20% of infected DFU will result in DFO [9]. Infected DFU in this patient group is associated with the use of prolonged antibiotic therapy, hospitalisation and surgery [9]. Increased healthcare costs, adverse drug reactions and antibiotic resistance are associated with overuse of antibiotics [12].

The Infectious Disease Society of America (IDSA) and International Working Group on the Diabetic Foot (IWGDF) classify diabetic foot infection (DFI) and DFO based on clinical presentation [13, 14]. These clinical signs may include inflammation, purulent or non-purulent secretions, malodour and a positive probe-to-bone (PTB) [11, 13, 14]. These guidelines highlight the most appropriate diagnostic processes and treatment interventions that include antibiotic therapy for DFO. Although many antibiotics are used to treat DFO, the most appropriate practice has not been established [15]. Furthermore, it has been suggested that comparison of studies treating DFO is difficult due to differing diagnostic criteria and treatment regimens [16]. It has not been established whether the optimal treatment of DFO is surgical intervention in conjunction with appropriate antibiotics or by systemic antibiotic pharmacotherapy alone [17]. Some authors have suggested that surgical debridement is crucial in the treatment of DFO [8], whilst other studies have shown antibiotic pharmacotherapy alone to be sufficient when treating DFO [18].

The most common pathogens involved in DFO are aerobic gram positive staphylococcus aureus and streptococcus species [5, 8, 10, 16, 19, 20]. Gram negative pathogens including the Enterobacteriaceae family including Escherichia coli, Klebsiella pneumoniae, Morganella morganii and Proteus mirabilis have also been reported [8, 20]. Pseudomonas is regarded as a rare invader in non-humid climate countries and although infrequently isolated on wound swabs it is usually a coloniser and not a cause for diabetic foot infections [21, 22]. Anaerobes are reported to be more likely involved in necrotic wounds and gangrene [1].

A prolonged course of oral antimicrobial therapy may contribute to the evolution of antimicrobial-resistant bacteria and antibiotic related complications such as Clostridium difficile colitis [16, 23, 24]. The prevalence of antibiotic resistant and multiple drug resistance organisms (MDRO) and organisms isolated from people with diabetes has been reported to be increasing [1, 10]. A surgical approach and use of synthetic orthobiological agents combined with a reduced duration of systemic antibiotics for the management of DFO has been proposed to reduce these risks as well as achieving optimum concentrations of antibiotic at the site of infection [8, 25, 26]. The successful treatment of DFO with antibiotic therapy alone without surgery has been reported to be associated with microbiological assessment of bone samples [27]. The treatment choice for a presenting DFO is based on multiple factors but it is often the treating clinician who must weigh up the risks and benefits given the patients co-morbidities.

The diagnosis of DFO is recommended as above by IDSA and IWGDF guidance clinical, but in all cases microbiological samples should be taken to identify the pathogen involved to support targeted therapy [4, 5, 10, 11]. Microbiological samples include deep tissue and bone for culture and antibiotic sensitivity testing. Tissue samples are more specific for bacterial identification than superficial wound swabs alone [20]. Blood samples should also be taken for serum biomedical markers and haematological testing that may support a clinical diagnosis of infection [1, 5, 11, 28]. Diagnosis should also be supported by radiologic investigations [10, 29]. With technological advances, sophisticated imaging modalities such as contrast Magnetic Resonance Imaging (MRI), positive emission tomography (PET)/computed tomography (CT) and single-photon emission computed tomography (SPECT)/CT may also be considered subject to their availability. The use of radiolabelled autologous white blood cells (WBC) and anti-granulocyte antibodies (anti-G-mAb) is also a recognised practice in the identification of DFO [30]. A combination of diagnostic interventions are considered to be an appropriate approach to diagnose DFO [10].

Antibiotic regimens are initially empirical and may be based on the severity of presenting infection and local antibiotic policies, with targeted narrow spectrum agents introduced after positive culture and sensitivity results are available [5]. The aim of antibiotic therapy is to achieve high concentration of antibiotics at the site of infection [9]. In addition to data suggesting successful treatment of DFO with systemic antibiotics [16, 18], a more recent trial suggests there is no clinical outcome difference between oral and intravenous antibiotic therapy when treating osteomyelitis, although not all participants in this trial had diabetes [31]. Furthermore, the incidence of concurrent peripheral arterial disease (PAD) or critical limb threatening ischaemia (CLTI) remains unknown in this trial which may have caused discrepancies in optimum delivery or concentration of antibiotics to bone regardless of systemic antibiotic mode of delivery. There is no proven laboratory test or imaging modality to determine when antibiotic therapy should be discontinued [5]. The duration of antibiotic therapy is not consistent for treating DFO and studies have reported on similar outcomes when comparing 3 and 6 weeks or 6 weeks short term and 12 weeks long term antibiotic therapy [32, 33]. The optimum duration of antibiotic therapy for DFO is therefore not well defined [11].

There is existing evidence to hypothesise systemic antibiotic therapy treats DFO [16, 18, 34, 35]. However, some fail to treat DFO with reported worsening infection requiring surgical debridement or amputation [27, 36, 37]. Therefore, investigation is required to identify the most effective systemic antibiotic treatment for DFO.

A recently published systematic review has analysed the effectiveness of all interventions in the management of infection of the diabetic foot [3]. However, this systematic review did not specifically identify the outcome measures for DFO with systemic antibiotics [3]. A second systematic review by the same authors on the diagnosis of DFI does however provide some guidance for clinicians on clinical and inflammatory markers for the diagnosis of osteomyelitis [28]. The systematic review does not however identify the single or combined diagnostic investigations that should be considered to monitor progress or complete resolution when treating DFI or DFO with systemic antibiotics.

It is evident there remains uncertainty about the most appropriate antibiotic therapy for the management of DFO. The challenge is not to identify the most effective antibiotic but to establish the antibiotic intervention and practice that is most effective for the eradication of DFO and preservation of limb. A systematic review is therefore required to establish this.

We present a systematic review protocol that will review the effectiveness of systemic antibiotic therapy for DFO and identify outcomes used to determine the effectiveness. The systematic review will aim to identify the role of systemic antibiotics when treating DFO. To our knowledge there is no published systematic review addressing our proposed question.

Details of this protocol are registered on the International Prospective Register of Systematic Reviews (PROSPERO) registry. The planned start date is from the inception of databases to the 30^th April 2022.

Multiple studies have reported on the management of DFO with systemic antibiotics [16, 18, 32‐34, 42]. This systematic review protocol will synthesise the existing evidence on the effectiveness of systemic antibiotic therapy for treating DFO. The study will identify the diagnostic imaging, laboratory investigations and clinical measures currently used to determine the effectiveness of systemic antibiotic therapy. The findings will summarise existing research and standards in practice for treating DFO with systemic antibiotic therapy. The study may discover if guidelines are required to standardise practice when treating DFO with systemic antibiotic therapy. To the best of our knowledge, this systematic review will be the first to evaluate the effectiveness of systemic antibiotic therapy when treating DFO in adults with diabetes mellitus. The systematic review will not provide specific information on the most single appropriate antibiotic drug or regime for treating DFO. The findings will compliment scientific evidence in support or against systemic antibiotic therapy in the management of DFO worldwide.