*4.2.1 Biofilms*

Clinicians often neglect the substantial role of bacterial biofilm in various infections, including the diabetic foot [35, 51]. Biofilm-forming bacteria are more refractory to host response and medical treatment and may be responsible for chronicity and complications. The proportion of biofilm-forming bacteria in DFO has been estimated at 30–60% [51]. In a clinical and microbiological study from Turkey [52], the assessed proportion of suspected biofilms among 339 diabetic foot wound isolates occurred in 34%. The multivariate regression analysis revealed two variables to be significant factors associated with biofilm: MDR micro-organism and XDR micro-organism [52]. New strategies are required in the management of wounds with biofilm to effectively destroy and even to prevent its formation.

One antibiotic might be associated with better outcomes in treating DFO biofilms: rifampin [53]. In analogy to implant-related staphylococcal infections, the antibiotic combination with rifampin may reveal a superior outcome. For example, Senneville et al. published a non-randomized observational study in 17 DFO patients treated with ofloxacin-rifampicin and achieved a remission in 88% of the cases [54]. Many other examples, especially from the US and France, are reported. We need the confirmation of the benefit of rifampicin use in DFO in future prospective-randomized trials.

#### **4.3 Duration of antibiotic therapy**

Because of a substantial risk for clinical failures according to every day's clinical experience, many physicians treat DFOs, on purpose, with a very long course of antimicrobial therapy, although guidelines limit the overall antibiotic prescription to 4–6 weeks only [33, 55]. Of note, this official guidance never had advocated a prolonged course. A retrospective evaluation with 1018 episodes of soft tissue infections and DFO failed to determine an optimal duration of systemic antibiotic administration regarding the remission, or failure, of diabetic foot infection [48]. A randomized controlled trial found that 6 weeks, compared with 12 weeks, of targeted antibiotic DFO therapy produced similar results [56]. This opinion is shared by other research groups [57, 58]. Today, a maximal duration of 6 weeks is the standard. If the is no remission after this period, clinicians should consider a new approach, which is surgical in the majority of cases. Maybe, the actual standard of 6 weeks might equally be too long for usual DFO cases. Recently, we published our experience of a randomized, controlled (RCT) pilot trial investigating shorter antibiotic administrations for DFO [55]. In this trial, a systemic antibiotic therapy of 3-weeks gave similar (and statistically non-inferior) incidences of remission and adverse events to a course of 6 weeks [55]. We also started the confirmatory RCT with 400 planned episodes in the Balgrist University Hospital in Zurich [59], by using a streamlined surgical approach, an initial radiological examination by magnetic resonance imaging and stratification between surgical versus totally antibiotic treatment approaches. If we confirm our pilot findings, the clinical implications, especially for improved antibiotic stewardship of in the field of DFO [60] might be substantial. Until further results are present, we agree with recommendations of up to six weeks of antibiotic therapy when residual infected bone is suspected or proven [25, 61–66].

### *4.3.1 Serum inflammatory parameters during the follow-up control of therapy*

Clinicians frequently control serum C-reactive protein (CRP) levels during the therapy of DFO. This routine practice should be abandoned. There is often no immediate benefit. On the contrary, surprisingly high CRP blood levels usually trigger unnecessary exams (X-rays, angiology exams, superficial wound swabs, urinary cultures); even in absence of clinical indications. The worst consequence would be a prolongation of the scheduled antibiotic therapy, only basing on these CRP level. In our prospectively collected database [55], routine serum CRP samples, at different time points during ongoing antimicrobial therapy for (operated) DFO, failed to predict future clinical failures [58].

#### *4.3.2 Duration of antibiotic therapy after surgical resection of DFO*

After a complete surgical resection of all infected and necrotic bone, many experts only warrant a short very duration of antimicrobial therapy (2–5 days) to finish with a remaining soft tissue infection [18, 59, 60]. However, surgeons frequently doubt about the clinical absence of residual bone infection in the proximal amputation stump [63–65]. The IWGDF recommends sampling the marginal, remaining bone for evidence of residual infection; and advocates a up to 6 weeks of a consecutive, targeted antimicrobial therapy if the residual bone samples return with positive microbiological results [33]. This recommendation is cautious. We reported 482 DFO episodes with a median follow-up of two years after presumably curative total amputation [18]. According to this experience, neither the duration of the postsurgical antibiotic use, nor its immediate discontinuation, predicted future clinical failure [18]. Other research groups advocate that 5 days of a post-surgical antibiotic continuation are sufficient for a potential residual bone infection after amputation [64]. The residual cultures may also be false-negative, when receiving antibiotics, or false-positive when the samples are contaminated [33]. For example, colleagues from Basel, Switzerland, suggested that positive cultures, without a visual clinical confirmation of osteomyelitis and without concomitant histological confirmation, might overestimate the true rate of residual osteomyelitis, because of contamination at the time of surgery [66].

#### **4.4 Administration route of antibiotic therapy**

During the last decades, clinicians used a weeks'-long parenteral antibiotic therapy for all severe or moderate cases of DFO, usually with a switch to oral administration the hospitalized patient has been improving [67]. Today, we are living a change of paradigm in daily clinical life and start to consider oral regimens as efficacious as intravenous therapy in chronic DFO [48, 55, 67]. Therapy with oral antibiotic drugs is effective in non-bacteremic mild and moderate DFOs. A review of 93 DFO cases strongly supports the possibility of oral antibiotic regimens right from the start [68]. The same principle applies for other forms and localizations of chronic osteomyelitis [67]. Additional retrospective and prospective studies demonstrated the non-inferiority of oral antibiotic medication for DFO [60]. In our single-center cohort with a defined clinical diabetic foot infection pathway, oral β-lactam therapy did not alter the incidence of remission [67]. Spanish researchers conducted a prospective-randomized trial in DFO patients; with a strictly conservative antibiotic treatment of ninety days versus an approach with surgery plus antibiotics of ninety days. In the conservative arm, oral antibiotics were given very early in the course. Practically, the outcomes were equivalent [61]. The authors of this chapter ignore the existence of a prospective-randomized trial in favor of a long initial parenteral treatment for chronic, non-septic, DFO in adult patients. Finally, topical antibiotics have no place in the treatment of unresected, deep DFO [69].
