In a person with diabetes and a foot infection, is any particular antibiotic regimen (specific agent [s], route, duration) better than any other for treating soft tissue or bone infection?

Recommendation 10

Treat a person with a diabetes-related foot infection with an antibiotic agent that has been shown to be effective in a published randomised controlled trial and is appropriate for the individual patient. Some agents to consider include penicillins, cephalosporins, carbapenems, metronidazole (in combination with other antibiotic [s]), clindamycin, linezolid, daptomycin, fluoroquinolones, or vancomycin, but not tigecycline. (Strong; high).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a high quality of evidence and a strong (strength of) recommendation for the recommendation. Although evidence is based on good quality randomised controlled trials (RCTs), it was noted that the majority of these demonstrated that agents were non-inferior to each other, raising the possibility that other agents that have not been tested in RCTs may be similarly effective (i.e. agents such as cotrimoxazole and doxycycline which are commonly used for diabetes-related foot infections in Australia). The recommendation was considered compatible and applicable to the Australian context, where there is appropriate expertise and resources available to use these antibiotics in most primary, secondary and tertiary healthcare settings. The recommendation was consistent with existing Australian antibiotic guidelines [33].

Implementation considerations

The panel noted that multiple additional factors are important in determining the appropriate antibiotic to use for a patient, similar to those described in Recommendation 11, including severity of infection, route of administration, adverse drug reactions, current and prior microbiological results, local antibiotic resistance patterns, appropriate antimicrobial stewardship, antibiotic restrictions, cost and access. Specifically, some antibiotics will only be available in tertiary settings, and even then, more restricted antibiotics such as daptomycin may not be widely accessible.

Subgroup considerations Geographically remote people

The panel noted that the use of intravenous antibiotics may be difficult in some rural and remote locations, requiring patient transfer to a tertiary centre.

Aboriginal and Torres Strait islander peoples

Similar to people in geographically remote locations it was noted that some Aboriginal and Torres Strait Islander Peoples may be located in remote areas restricting access to intravenous antibiotics.

Monitoring considerations

The panel recommends that individual services should collaborate with their local antimicrobial stewardship team to evaluate their local antibiotic usage and compare it to similar services and centres where possible.

Future research considerations

The panel noted there is a need for studies comparing regularly used empiric antibiotic regimens (rather than new antibiotics) in order to identify the best empiric regimen for different severity infections.

Recommendation 11

Select an antibiotic agent for treating a diabetes-related foot infection based on: the likely or proven causative pathogen(s) and their antibiotic susceptibilities; the clinical severity of the infection; published evidence of efficacy of the agent for diabetes-related foot infections; risk of adverse events, including collateral damage to the commensal flora; likelihood of drug interactions; agent availability; and, financial costs. (Strong; moderate).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a moderate quality of evidence and a strong (strength of) recommendation for the recommendation. The recommendation was considered compatible with most patients’ values, applicable to the Australian context and feasible in most Australian locations. It was noted that the list of considerations in the recommendation is not exhaustive and there are many additional patient-related considerations including patient acceptance of antibiotic frequency or administration type, patient adherence to a regimen, and patient preference to be treated in the outpatient setting or on country where possible. In addition, there should be a preference for narrower spectrum antibiotics where possible from an antimicrobial stewardship perspective. Conversely, at times it may be appropriate to use broader spectrum antibiotics if there is a history of recent infection or colonisation with multidrug resistant organisms or if local antimicrobial susceptibility profiles demonstrate an increased risk of such organisms.

Implementation considerations

As described in the Summary justification, the panel identified a number of additional implementation considerations, many of which are patient-related. These are described in additional detail in the Subgroup considerations below.

Subgroup considerations Geographically remote people

The panel noted that people in geographically remote locations may have a greater preference to be treated in the outpatient setting to avoid travel away from home. This led to variation in the importance that they place on the use of some antibiotics over others. For example, they may prefer to trial oral antibiotics rather than intravenous antibiotics.

Aboriginal and Torres Strait islander peoples

The panel noted that Aboriginal and Torres Strait Islander Peoples may have a greater preference to be treated in the outpatient setting with oral antibiotics or prefer to use intravenous antibiotics through outpatient parenteral services if available to enable them to stay on country or avoid inpatient hospital admissions. There should also be consideration of language barriers as described in Recommendation 2.

Other subgroup considerations

The panel noted that an increased preference to be treated in the outpatient setting with oral antibiotics or use intravenous antibiotics through outpatient parenteral services may exist for many other patient groups, including carers and those with dependants. In addition, broader spectrum antibiotics may be commenced if patients have a history of recent infection or colonisation with multidrug resistant organisms (such as methicillin-resistant Staphylococcus aureus (MRSA)) or if local antimicrobial susceptibility profiles demonstrate an increased risk of multidrug resistant organisms. Risk factors for MRSA infection in the Australian context have been described [34].

Future research considerations

The panel noted that qualitative studies to explore and rank the factors most important for patients would assist clinicians in understanding patients’ preferences and providing the most balanced options when discussing treatment with patients. In addition, preferences could be assessed for specific patient subgroups such as those in geographically remote locations or Aboriginal and Torres Strait Islander Peoples.

Recommendation 12

Administer antibiotic therapy initially by the parenteral route to any patient with a severe (grade 4) skin and soft tissue diabetes-related foot infection. Switch to oral therapy if the patient is clinically improving and has no contraindications to oral therapy and if there is an appropriate oral agent available. (Strong; very low).

Decision: Adopted

Rationale: The panel decided to adapt this recommendation after full assessment based on having differences in judgements to IWGDF for quality of evidence (Table 2) and due to a lack of clarity around the population it referred to. The changes made to the original IWGDF recommendation included downgrading the quality of evidence from low to “very low” and including the phrase “skin and soft tissue” to define the relevant population of patients with diabetes-related foot infection (Table 3).

Summary justification

Although the panel downgraded the quality of evidence to very low, they agreed with the IWGDF that diabetes-related foot infections were an important health problem in Australia, and that the balance of effects favoured the use of initial intravenous antibiotics for severe (grade 4) skin and soft tissue diabetes-related foot infections. It was noted that a switch to oral therapy when the patient was clinically improving was appropriate for severe (grade 4) skin and soft tissue infections. Furthermore, it was noted that in the IWGDF guidelines this recommendation was intended to relate to people with skin and soft tissue infections, sitting under a sub-heading stating this, however, this was not clear when the recommendation was read outside the context of the overall IWGDF guideline document. The panel were unsure whether the critical outcome of clinical cure of infection would be consistently valued above all other outcomes by all patients (for example some patients may prefer avoidance of amputation and long term antibiotic suppression). They noted that the recommendation was likely acceptable and feasible in the Australian setting. Detailed justifications from the panel’s full assessment are provided in Supplementary Table S1.

Subgroup considerations Geographically remote people

Individuals in geographically remote populations may require initial intramuscular administration of antibiotics or once off intravenous antibiotics before transfer to a larger facility. As such, treatment may be unable to be undertaken in a remote location. For the majority of individuals, the potential for clinical cure facilitated through such a transfer would likely outweigh the potential suboptimal care in a less equipped environment and the need for transfer.

Aboriginal and Torres Strait islander peoples

Aboriginal and Torres Strait Islander Peoples living in remote locations are likely to require similar considerations to people living in geographically remote locations.

Future research considerations

One of the key research priorities identified by IWGDF was whether oral antibiotic therapy alone is as effective as parenteral treatment for diabetes-related foot infections, including diabetes-related foot osteomyelitis. The panel noted a need for studies to evaluate whether all patients with severe (grade 4) infections require initial parenteral antibiotic therapy. Furthermore, they identified a need for studies to explore the duration of initial parenteral antibiotics that is needed prior to oral switch for patients with severe (grade 4) diabetes-related foot infections and the factors that influence this decision.

Recommendation 13

Treat patients with a mild (grade 2) diabetes-related foot infection, and most with a moderate (grade 3) diabetes-related foot infection, with oral antibiotic therapy, either at presentation or when clearly improving with initial intravenous therapy. (Weak; low).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a low quality of evidence and a weak (strength of) recommendation for the recommendation. The recommendation was considered compatible with patients’ values, applicable to the Australian context and feasible in most Australian locations.

Future research considerations

IWGDF highlighted a need to further understand whether complete oral therapy is as effective as parenteral treatment for diabetes-related foot infections. The panel agreed that studies are needed to compare the use of complete oral therapy with initial intravenous therapy in infections of moderate (grade 3) severity and that they should assess patient outcomes.

Recommendation 14

We suggest not using any currently available topical antimicrobial agent for treating a mild (grade 2) diabetes-related foot infection. (Weak; moderate).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that when specifically considering the use of topical antibiotic agents for mild bacterial infection there was a moderate quality of evidence and a weak (strength of) recommendation against using currently available topical antimicrobial agents given a lack of evidence demonstrating efficacy of these agents, and their potential to increase the risk of antimicrobial resistance. The panel also noted that the use of anti-septic agents is considered separately in recommendation 27b. The recommendation was considered compatible with most patients’ values, and applicable and feasible in the Australian setting.

Future research considerations

The panel noted that topical antimicrobial agents remain an important area of future research which have the potential to alter the treatment pathways of diabetes-related foot infections if efficacious and safe agents are identified.

Recommendation 15a

Administer antibiotic therapy to a patient with a skin or soft tissue diabetes-related foot infection for a duration of 1 to 2 weeks. (Strong; high).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a high quality of evidence and a strong (strength of) recommendation for the recommendation. The recommendation was consistent with existing Australian antibiotic guidelines [33], and considered compatible with patients’ values, applicable to the Australian context and feasible in primary, secondary and tertiary healthcare settings in Australia.

Monitoring considerations

The panel recommends that services record the duration of antibiotic treatment provided to patients to enable an audit of treatment duration by infection severity compared with the guidelines.

Future research considerations

The IWGDF identified a need for further studies to determine the optimal duration of treatment for skin and soft tissue infections. The panel noted that such studies should be categorised by infection severity and infecting microorganisms and should consider additional confounders such as severe peripheral artery disease.

Recommendation 15b

Consider continuing treatment, perhaps for up to 3 to 4 weeks, if the infection is improving but is extensive and is resolving slower than expected or if the patient has severe peripheral artery disease. (Weak; low).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a low quality of evidence and a weak (strength of) recommendation for the recommendation. The recommendation was noted to be pragmatic and generally consistent with existing Australian antibiotic guidelines [33]. It was considered compatible with patients’ values, applicable to the Australian context and feasible in primary, secondary and tertiary healthcare settings in Australia.

Monitoring considerations

See Recommendation 15a.

Future research considerations

See Recommendation 15a.

Recommendation 15c

If evidence of infection has not resolved after 4 weeks of apparently appropriate therapy, re-evaluate the patient, and reconsider the need for further diagnostic studies or alternative treatments. (Strong; low).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a low quality of evidence but a strong (strength of) recommendation for the recommendation. The recommendation was noted to be pragmatic and generally consistent with existing Australian practice. It was considered compatible with patients’ values, applicable to the Australian context and feasible in primary, secondary and tertiary healthcare settings in Australia.

Monitoring considerations

See Recommendation 15a.

Future research considerations

See Recommendation 15a.

Recommendation 16

For patients who have not recently received antibiotic therapy and have an acute infection, consider targeting empiric antibiotic therapy at just aerobic Gram positive pathogens (beta-haemolytic streptococci and Staphylococcus aureus) in cases of a mild (grade 2) diabetes-related foot infection. (Weak; low).

Decision: Adopted

Rationale: The panel decided to adapt this recommendation after full assessment based on having differences in judgements to IWGDF for balance of effects and the population impacted (Table 2). The changes made to the original IWGDF recommendation included downgrading the balance of effects from strong to “weak”, extending the recommendation to all locations in Australia by excluding the need for patients to reside in a temperate climate area and narrowing the population by adding the phrase “and have an acute infection” (Table 3).

Summary justification

The panel agreed with the IWGDF that diabetes-related foot infections were an important health problem in Australia, that the use of empiric narrower spectrum antibiotics had more desirable benefits than undesirable benefits, and that the quality of the evidence supporting this was low. However, the panel felt the balance of effects was weak, consistent with a conditional recommendation for narrower spectrum antibiotics in the described circumstances and consistent with the use of the word consider in the recommendation. The panel also noted that although the recommendation was likely acceptable and feasible in the Australian setting, Australian practice and guidelines [33] do not distinguish use of narrow spectrum antibiotics by climate and there is no local evidence to support such a distinction. However, both local guidelines [33] and studies [35] support use of narrower spectrum agents in acute infections. The panel noted that the definition of acute infection in the published literature has varied from less than 2 to 6 weeks and suggest that, in concordance with local guidelines [33], duration of infective symptoms of less than 4 weeks could be considered acute while noting broader therapy may be required for those with a duration of ulceration of greater than 6 weeks [35] and in those with recent antibiotic exposure [36]. Detailed justifications are described in Supplementary Table S2.

Subgroup considerations

The panel noted that there is no evidence from the Australian context to suggest individuals living in tropical regions with acute infections cannot be treated with narrow spectrum antibiotics and current practice in Australia is to treat such individuals with narrow spectrum antibiotics. They also noted that in patients known to be colonised with MRSA or in areas with a high prevalence, prescribers should consider empiric coverage of MRSA. Many tropical regions of Australia are also remote and increased rates of MRSA may exist in some of these remote populations. Similarly, many Aboriginal and Torres Strait Islanders live in tropical regions of Australia and there is an increased rate of MRSA in some Aboriginal and Torres Strait Islander populations [5].

Future research considerations

The panel identified a need for further studies to investigate whether a difference in patient outcomes exists between patients treated with narrow compared with broad spectrum antibiotics in patients with acute infections. They also highlighted the need for further studies comparing pathogens in acute infections between temperate and tropical regions of Australia.

Recommendation 17

For patients who have been treated with antibiotic therapy within a few weeks, have a chronic infection, have a severely ischaemic affected limb, or a moderate (grade 3) or severe (grade 4) infection, we suggest selecting an empiric antibiotic regimen that covers Gram positive pathogens, commonly isolated Gram negative pathogens, and possibly obligate anaerobes in cases of moderate (grade 3) to severe (grade 4) diabetes-related foot infections. Then, reconsider the antibiotic regimen based on both the clinical response and culture and sensitivity results. (Weak; low).

Decision: Adopted

Rationale: The panel decided to adapt this recommendation after full assessment based on having differences in judgements to IWGDF for the population impacted in the Australian setting (Table 2). This was achieved by extending the recommendation to all locations in Australia by excluding the need for patients to reside in a tropical/subtropical climate and including patients with chronic infections by adding the phrase “who have a chronic infection” (Table 3).

Summary justification

The panel agreed with the IWGDF that diabetes-related foot infections were an important health problem in Australia, that the use of empiric narrower spectrum antibiotics had more desirable benefits than undesirable benefits, that the quality of the evidence supporting this was low and the balance of effects was weak. The panel also noted that although the recommendation was likely acceptable and feasible in the Australian setting, similar to Recommendation 16, Australian practice and guidelines [33] do not distinguish use of antibiotic spectrum by climate and there is no local evidence to support such a distinction. However, both local guidelines [33] and studies [35] support use of broader spectrum agents in chronic infections and in the presence of chronic ulceration. As described in Recommendation 16, the panel noted that the definition of acute infection and thus chronic infection varies in the published literature and suggest that, in concordance with local guidelines [33], duration of infective symptoms of four or more weeks could be considered chronic while noting broader therapy may also be required for those with a duration of ulceration of greater than 6 weeks [35]. Detailed justifications are described in Supplementary Table S3.

Subgroup considerations

See Recommendation 16.

Future research considerations

See Recommendation 16.

Recommendation 18

Empiric treatment aimed at Pseudomonas aeruginosa is not usually necessary but consider it if P. aeruginosa has been isolated from cultures of the affected site within the previous few weeks, or in tropical/subtropical climates (at least for moderate [grade 3] or severe [grade 4] infection). (Weak; low).

Decision: Adopted

Rationale: The panel decided to adapt this recommendation after full assessment based on minor differences in judgements to IWGDF for the population impacted in the Australian setting (Table 2). This was achieved by extending the recommendation to all locations in Australia by excluding the phrase “in temperate climates” (Table 3).

Summary justification

The panel agreed with the IWGDF that diabetes-related foot infections were an important health problem in Australia, that the use of empiric antibiotic treatment to cover P. aeruginosa in certain circumstances had more desirable benefits than undesirable benefits, that the quality of the evidence supporting this was low and the balance of effects was weak. The panel also noted that although the recommendation was likely acceptable and feasible in the Australian setting, P. aeruginosa can be a pathogen in temperate as well as tropical regions [35]. Detailed justifications are described in Supplementary Table S4.

Implementation considerations

The panel noted that in Australia, many clinicians obtain cultures via superficial swabs. Thus, increased weight should be given to treatment covering P. aeruginosa if it has been previously isolated from tissue samples from the affected site compared with superficial swabs.

Future research considerations

The panel identified a number of potential areas for future research that related to this recommendation including:

1.

Studies to investigate differences in the prevalence of P. aeruginosa in diabetes-related foot infections in temperate and tropical regions of Australia and how this differs by severity of infection.

2.

Studies to investigate differences in outcomes of diabetes-related foot infections treated with empiric P. aeruginosa coverage versus those that are not.

3.

Studies to investigate differences in outcomes of diabetes-related foot infections that culture P. aeruginosa and are treated with antibiotics that target this bacteria versus those that do not.

Recommendation 19

Do not treat clinically uninfected foot ulcers with systemic or local antibiotic therapy with the goal of reducing the risk of infection or promoting ulcer healing. (Strong; low).

Decision: Adopted

Rationale: The panel decided to adopt the recommendation unchanged following screening as judgements were consistent with the IWGDF and the recommendation was considered acceptable and applicable in the Australian setting (Table 1).

Summary justification

The panel agreed with the IWGDF that there was a low quality of evidence but a strong (strength of) recommendation for the recommendation. The recommendation was considered to be consistent with antimicrobial stewardship principles. It was considered compatible with patients’ values, applicable to the Australian context and feasible in primary, secondary and tertiary healthcare settings in Australia.