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The impact of the length of total and intravenous systemic antibiotic therapy for the remission of diabetic foot infections

Open AccessPublished:March 28, 2022DOI:https://doi.org/10.1016/j.ijid.2022.03.049

      Highlights

      • No benefit for antibiotic therapy >6 weeks in diabetic foot infections
      • No benefit for intravenous antibiotic therapy >14 days in diabetic foot infections
      • The minority of re-amputations is due to microbiological failure

      Abstract

      Objective

      We investigated the impact of the total length of systemic antibiotic therapy (ABT) and its initial intravenous (IV) part on clinical failure (CF) and microbiological failure (MF) in diabetic foot infections (DFIs).

      Methods

      In this single-center, retrospective, unmatched case-control study, we included DFI episodes treated with a combined surgical-antibiotic approach.

      Results

      We included 721 DFI episodes, 537 with osteomyelitis (DFO). CF occurred in 191 (26.5%) and MF in 42 (5.8%) episodes. Multivariate Cox regression analysis showed that a short ABT of 8–21 days (hazard ratio [HR] 0.4; 95% CI 0.2–0.7) was inversely associated with CF. This was also applicable for IV ABT with relatively short durations of 2–7 days (HR 0.5; 95% CI 0.3–0.8) or 8–14 days (HR 0.6; 95% CI 0.4–0.9). We failed to detect a minimal threshold of total or IV ABT predictive for CF or MF.

      Conclusions

      Compared with total ABT of more than 84 days and IV therapy of more than 14 days, shorter total and IV ABT yielded no enhanced risk of CF or MF. Considering the “bias by indication” that is inherent to retrospective DFI studies, the best study design concerning the duration of ABT would be a stratified, prospective randomized trial, which is currently under way in our medical center.

      Keywords

      Introduction

      Diabetic foot infection (DFI) is a frequent complication of diabetes and is associated with prolonged hospital stays (
      • Henke PK
      • Blackburn SA
      • Wainess RW
      • Cowan J
      • Terando A
      • Proctor M
      • et al.
      Osteomyelitis of the foot and toe in adults is a surgical disease: Conservative management worsens lower extremity salvage.
      ;
      • Lindbloom BJ
      • James ER
      • McGarvey WC.
      Osteomyelitis of the Foot and Ankle.
      ), a high risk of amputation (
      • Hartemann-Heurtier A
      • Senneville E.
      Diabetic foot osteomyelitis.
      ;
      • Shank CF
      • Feibel JB.
      Osteomyelitis in the Diabetic Foot: Diagnosis and Management.
      ), and long-term antibiotic therapy (ABT) (
      • Ahluwalia R
      • Lázaro-Martínez JL
      • Reichert I
      • Maffulli N.
      Advances in pharmacotherapy for diabetic foot osteomyelitis.
      ;
      • Gariani K
      • Pham T-T
      • Kressmann B
      • Jornayvaz FR
      • Gastaldi G
      • Stafylakis D
      • et al.
      Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.
      ). Diabetes and DFI prevalence is increasing worldwide and so are the related costs (
      • van Asten SAV
      • Mithani M
      • Peters EJG
      • La Fontaine J
      • Kim PJ
      • Lavery LA
      Complications during the treatment of diabetic foot osteomyelitis.
      ;
      • Bus SA
      • Lavery LA
      • Monteiro-Soares M
      • Rasmussen A
      • Raspovic A
      • Sacco ICN
      • et al.
      IWGDF guideline on the prevention of foot ulcers in persons with diabetes.
      ;
      • Raspovic KM
      • Wukich DK.
      Self-reported quality of life and diabetic foot infections.
      ). In addition to adequate debridement, surgery, and off-loading, systemic ABT is one of the cornerstones of therapy (
      • Uçkay I
      • Gariani K
      • Pataky Z
      • Lipsky BA.
      Diabetic foot infections: state-of-the-art.
      ). DFI is probably one of the most frequent causes for inadequately prolonged ABT worldwide (
      • Lipsky BA.
      Diabetic foot infections: Current treatment and delaying the ‘post-antibiotic era.’ Diabetes.
      ). Although there are clear guidelines available (
      • Lipsky BA
      • Senneville É
      • Abbas ZG
      • Aragón-Sánchez J
      • Diggle M
      • Embil JM
      • et al.
      Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
      ), the evidence for an optimal treatment duration and the appropriate route of administration is still weak (
      • Ahluwalia R
      • Lázaro-Martínez JL
      • Reichert I
      • Maffulli N.
      Advances in pharmacotherapy for diabetic foot osteomyelitis.
      ;
      • Ertuğrul B
      • Uçkay I
      • Schöni M
      • Peter-Riesch B
      • Lipsky BA.
      Management of diabetic foot infections in the light of recent literature and new international guidelines.
      ;
      • Lipsky BA.
      Diabetic foot infections: Current treatment and delaying the ‘post-antibiotic era.’ Diabetes.
      ). Adverse events occur in up to 30% of all DFI regimens, and resistance against antibiotic agents is increasing (
      • van Asten SAV
      • Mithani M
      • Peters EJG
      • La Fontaine J
      • Kim PJ
      • Lavery LA
      Complications during the treatment of diabetic foot osteomyelitis.
      ;
      • Senneville E
      • Robineau O.
      Treatment options for diabetic foot osteomyelitis.
      ). Frequent adverse events are diarrhea (68%), nausea and inappetence (10%), renal function deterioration (9%), cutaneous rash (9%), hepatitis (5%), cholestasis (3%), mycosis (3%), leukopenia (2%), pruritus (2%), or headaches (2%) (
      • Schindler M
      • Bernard L
      • Belaieff W
      • Gamulin A
      • Racloz G
      • Emonet S
      • et al.
      Epidemiology of adverse events and Clostridium difficile-associated diarrhea during long-term antibiotic therapy for osteoarticular infections.
      ). At the same time, recent studies indicate that oral ABT is as effective as intravenous (IV) therapy for most bone and joint infections (
      • Ertuğrul B
      • Uçkay I
      • Schöni M
      • Peter-Riesch B
      • Lipsky BA.
      Management of diabetic foot infections in the light of recent literature and new international guidelines.
      ;
      • Li HK
      • Rombach I
      • Zambellas R
      • Sarah Walker A
      • McNally MA
      • Atkins BL
      • et al.
      Oral versus intravenous antibiotics for bone and joint infection.
      ), whereas oral regimens remain with shorter hospital stays and fewer complications than IV therapies (
      • van Asten SAV
      • Mithani M
      • Peters EJG
      • La Fontaine J
      • Kim PJ
      • Lavery LA
      Complications during the treatment of diabetic foot osteomyelitis.
      ;
      • Li HK
      • Rombach I
      • Zambellas R
      • Sarah Walker A
      • McNally MA
      • Atkins BL
      • et al.
      Oral versus intravenous antibiotics for bone and joint infection.
      ;
      • Schindler M
      • Bernard L
      • Belaieff W
      • Gamulin A
      • Racloz G
      • Emonet S
      • et al.
      Epidemiology of adverse events and Clostridium difficile-associated diarrhea during long-term antibiotic therapy for osteoarticular infections.
      ). Peripheral venous catheters may account for at least 6.3% of all preventable bloodstream infections (
      • Jefferson J
      • Mermel LA.
      Coordination of Infection Control Activities at the Healthcare System Level: Survey Results.
      ). Another DFI study computed that the median ABT cost reaches $969 (AUD), of which the bulk of 95.3% would only be attributed for its IV part (
      • Commons RJ
      • Robinson CH
      • Gawler D
      • Davis JS
      • Price RN.
      High burden of diabetic foot infections in the top end of Australia: An emerging health crisis (DEFINE study).
      ).
      To avoid adverse events and possible developments of antibiotic resistance and to optimize the cost-effective treatment of DFI, the duration of total and IV ABTs should be kept as short as possible. Currently, the best approach to improve antibiotic stewardship seems to be the “individualized reduction of unnecessary or inappropriate antibiotic use” (
      • Uçkay I
      • Berli M
      • Sendi P
      • Lipsky BA.
      Principles and practice of antibiotic stewardship in the management of diabetic foot infections.
      ). Gariani et al published a retrospective study (
      • Gariani K
      • Lebowitz D
      • von Dach E
      • Kressmann B
      • Lipsky BA
      • Uçkay I
      Remission in diabetic foot infections: Duration of antibiotic therapy and other possible associated factors.
      ) as well as a small prospective pilot trial in diabetic foot osteomyelitis (DFO) (
      • Gariani K
      • Pham T-T
      • Kressmann B
      • Jornayvaz FR
      • Gastaldi G
      • Stafylakis D
      • et al.
      Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.
      ) to determine the most appropriate duration of ABT in DFI and DFO. In the retrospective study, they found no threshold for the optimal duration of ABT to prevent treatment failures. The DFO pilot trial showed no benefit in ABT exceeding 3 weeks. Recent expert opinions and the newest International Working Group on Diabetic Foot Infections (IWGDF) guidelines conclude that ABT duration still remains one of the main controversies in the management of DFI (
      • Ertuğrul B
      • Uçkay I
      • Schöni M
      • Peter-Riesch B
      • Lipsky BA.
      Management of diabetic foot infections in the light of recent literature and new international guidelines.
      ;
      • Lipsky BA
      • Senneville É
      • Abbas ZG
      • Aragón-Sánchez J
      • Diggle M
      • Embil JM
      • et al.
      Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
      ;
      • Uçkay I
      • Berli M
      • Sendi P
      • Lipsky BA.
      Principles and practice of antibiotic stewardship in the management of diabetic foot infections.
      ).
      In this study, we investigated whether the length of total ABT and/or its IV part are associated with an enhanced risk of CF and recurrences after the therapy of DFI. These local data will serve as a guidance to larger and streamlined randomized controlled trials.

      Methods

      The Balgrist University Hospital is a tertiary referral center for orthopedic surgery with a specialized clinical and academic research unit for the diabetic foot. For this study, we analyzed all DFI episodes treated with a combined surgical-antibiotic approach from January 1, 2000, to March 31, 2020. The exclusion criteria were strictly conservative treatments without any surgical debridement, a postoperative follow-up of less than 6 months, major amputations, age <18 years, and insufficient documentation in the medical files. The study was approved by the local ethical committee in Zürich, Switzerland.
      Primary outcomes were clinical failure (CF) and microbiological failure (MF) within 1 year after therapy, further stratified by the respective presence of osteomyelitis (DFO), gangrene, and primary versus revision surgeries. We defined CF as any clinical failure needing revision surgery, such as ischemia (
      • Bus SA
      • Lavery LA
      • Monteiro-Soares M
      • Rasmussen A
      • Raspovic A
      • Sacco ICN
      • et al.
      IWGDF guideline on the prevention of foot ulcers in persons with diabetes.
      ), whereas MFs were true microbiological recurrences with at least 50% of pathogens being identical with the bacteria of the index infection. We diagnosed DFO intraoperatively by the presence of bacteria in bone samples and preoperatively using x-ray examination or magnetic resonance imaging (MRI). If MRI was not possible for any reason, we replaced it with computed tomography or skeletal scintigraphy. The duration and the choice of the postoperative systemic antibiotic agents was based on the discretion of the treating surgeon and the infectious diseases consultant.

      Statistical analyses

      For crude group comparisons with categorical parametric variables, we used the Student t test or the chi-square test, as appropriate. Regarding nonparametric continuous variables, we used the Mann-Whitney U test. For survival data, we performed a log-rank analysis and plotted the corresponding Kaplan-Meier survival curves. The total duration of postdebridement ABT was computed as categorical and continuous data. We arbitrarily stratified the length of total ABT arbitrarily into 5 usual durations (0–7, 8–21, 22–42, 43–84, and >84 days) and the initial IV ABT into 4 categories (0–1, 2–7, 8–14, and >14 days).
      We added a multivariate Cox regression analysis with the primary outcome “CF” to adjust for the large case-mix that is inherent to the DFI population. Therefore, reference was set at >84 days for total ABT and >14 days for IV ABT. For both outcomes (CF or MF), the final models consisted of the following variables: age, sex, chronic renal insufficiency, coronary artery disease, peripheral artery disease, bypass and/or angioplasty, diabetes type, nicotine abuse, prior amputations, postoperative total ABT, and the duration of IV therapy. In an ulterior step, we repeated the analyses for the strata DFO, gangrene, primary surgery, and revision surgery separately. Finally, we visually investigated a possible minimal duration level by plotting the risk of recurrences against the administered ABT durations and used SPSS software (Version 26, IBM Corp., Armonk, NY) by setting the significance level (2-tailed) at α = 0.05.

      Results

      Study population

      We included 721 DFI episodes in 331 different patients (79 women, 23.9%), with 570 (79.1%) primary episodes and 151 (20.9%) already revised episodes (Table 1). The mean active follow-up (physical medical controls) was 4.0 years (SD 3.5 years, range 0 days–20.1 years) after the end of index therapy. One patient died on the day of surgery because of a cardiac event and was excluded from the analyses. The mean passive follow-up (indication of problems by the patient) was 6.6 years (SD 5.3 years, range 0 days–20.5 years). During the follow-ups, 29.7% of the patients died after a mean interval of 4.1 (SD 3.6) years after therapy. The mean age at surgery was 66 (SD 11.5) years and the mean body mass index (BMI) 30.03 kg/m2. Diabetes mellitus type II was present in 611 episodes (84.7%) and 69.6% received insulin treatment. Clinical polyneuropathy was present in 92.5% and Charcot neuroarthropathy in 12.1%. We noted peripheral artery disease in 526 episodes (73%), 108 (15%) of them at stages III and IV. Overall, 128 patients (17.8%) yielded a glomerular filtration rate ≤45 mL/min, and 48 patients (6.7%) were on dialysis. Other comorbidities included coronary artery disease (n = 325, 45.1%) and chronic immunosuppressive therapy (n = 50, 6.9%) and a history of organ transplantation (n = 17, 2.4%). In 332 episodes (46%), the patients revealed a history of contralateral minor or major amputation of the lower extremities.
      Table 1Study population.
      All episodes (n = 721)New episodes (n = 570)Revision episodes (n = 151)p-value
      Age (years), mean (SD)66.0 (11.5)66.0 (12.0)65.0 (11.0)ns
      Sex (%)

       Female

       Male


      146 (20.2%)

      575 (79.8%)


      125 (21.9%)

      445 (78.1%)


      21 (13.9%)

      130 (86.1%)
      0.029
      Body mass index (kg/m2), mean (SD)30.0 (5.9)29.8 (5.9)30.8 (6.0)ns
      Side (%)

       Left

       Right


      358 (49.7%)

      363 (50.3%)


      275 (48.2%)

      295 (51.8%)


      83 (55.0%)

      68 (45.0%)
      ns
      Diabetes (%)

       Type 1

       Type 2

       Others


      106 (14.7%)

      611 (84.7%)

      4 (0.6%)


      81 (14.2%)

      486 (85.3%)

      3 (0.5%)


      25 (16.6%)

      125 (82.8%)

      1 (0.7%)
      ns
      Insulin treatment in type 2 diabetes, n (%)425 (69.6%)326 (67.1%)99 (79.2%)0.009
      Duration of diabetes (years), mean (SD)20.0 (12.5)20 (12)22 (13)ns
      Neuropathy, n (%)667 (92.5%)525 (92.1%)142 (94.0%)ns
      Charcot neuroarthropathy, n (%)87 (12.1%)74 (13.0%)13 (8.6)ns
      PAD (%)526 (73.0%)411 (72.1%)115 (76.2%)ns
      PAD stage III or IV (Fontaine)108 (15.0%)81 (14.2%)27 (17.9%)ns
      Prior PTA, n (%)380 (52.7%)292 (51.2%)88 (58.3%)ns
      Prior bypass surgery, n (%)25 (3.5%)19 (3.3%)6 (4.0%)ns
      Coronary artery disease, n (%)325 (45.1%)245 (43.0%)80 (53.0%)0.028
      Advanced kidney disease, n (%)

       Dialysis

       Kidney transplantation

       Glomerular filtration rate ≤ 45 mL/min
      184 (25.5%)

      48 (6.7%)

      12 (1.7%)

      128 (17.8%)
      141 (24.7%)

      39 (6.8%)

      9 (1.6%)

      97 (17.0%)
      43 (28.5%)

      9 (6.0%)

      3 (2.0%)

      31 (20.5%)
      ns

      ns

      ns

      0.029
      Immunosuppressants, n (%)50 (6.9%)37 (6.5%)13 (8.6%)ns
      Prior organ transplantation, n (%)17 (2.4%)14 (2.5%)3 (2.0%)ns
      Smoking history (%)424 (58.8%)327 (57.7%)97 (64.2%)ns
      Ongoing nicotine abuse (% of smoker)154 (36.3%)120 (36.7%)34 (35.1%)ns
      Alcohol abuse, n (%)178 (24.7%)133 (23.5%)45 (29.8%)ns
      Already amputation on the other side, n (%)

       Minor amputation

       Major amputation
      332 (46.0%)

      306 (42.4%)

      26 (3.6%)
      245 (43.0%)

      225 (39.5%)

      20 (3.5%)
      87 (57.6%)

      81 (53.6%)

      6 (4.0%)
      0.005

      0.002

      ns
      Clinical failure, n (%)191 (26.5%)138 (24.2%)53 (35.1%)0.007
      Microbiological failure, n (%)42 (5.8%)31 (5.4%)11 (7.3%)ns
      Revision (general) during FU, n (%)407 (56.4%)321 (56.3%)86 (57%)ns
      Time to revision (months), mean (SD)17.4 (28.5)18.9 (30.5)11.5 (17.9)0.032
      Major amputation during FU, n (%)125 (17.3%)92 (16.1%)33 (21.9%)ns
      Death for any reason during FU, n (%)214 (29.7%)171 (30.0%)43 (28.5%)ns
      Time-to-death (months), mean (SD)49.4 (43.8)51.9 (44.7)39.6 (39.1)ns
      FU (months), mean (SD)47.6 (41.9)48.8 (43.2)42.9 (36.3)ns
      Statistical significance is indicated in bold.
      BMI = body mass index; eGFR = estimated glomerular filtration rate; FU = follow-up; ns = not significant; PAD = peripheral artery disease; PTA = percutaneous transluminal angioplasty; SD = standard deviation.

      Infections

      We diagnosed DFO in 537 episodes (74.5%), gangrene in 14.1%, soft-tissue DFIs in 5.4%, chronic infected wounds in 5.9%, and open-toe arthritis in 0.1%. The anatomic location was the forefoot in 620 (86.0%), midfoot in 58 (8.0%), and hindfoot in 23 (3.2%) episodes. Intraoperative tissue samples revealed a polymicrobial infection in 263 episodes (36.5%) with 1.8 pathogens per sample (range, 1–6 pathogens). In 193 episodes (26.8%), at least 1 Gram-negative pathogen was involved. In total, 249 of the 883 pathogens (28.2%) were Gram-negative. Strikingly, gangrenes were significantly more associated with Gram-negative infections compared with OM (43.9% vs 25.2%). The most frequent microorganisms are listed in Table 2. In 69 episodes (9.6%), we failed to identify the causative pathogens.
      Table 2Pathogen groups.
      All episodes

      (n = 721)
      Osteomyelitis (n = 537)Gangrene (n = 102)p-valueNew episodes (n = 570)Revision episodes (n = 151)p-value
      Coagulase-negative staphylococci219 (25.9%)185 (28.1%)17 (15.2%)0.000176 (25.3%)43 (28.5%)ns
      Staphylococcus aureus184 (21.7%)151 (22.9%)18 (16.1%)0.028155 (22.3%)29 (19.2%)0.045
      Enterococci83 (9.8%)67 (10.2%)10 (8.9%)ns67 (9.6%)16 (10.6%)ns
      Streptococci51 (6.0%)42 (6.4%)5 (4.5%)ns47 (6.8%)4 (2.6%)0.017
      Pseudomonas aeruginosa43 (5.1%)33 (5.0%)7 (6.3%)ns38 (5.5%)5 (3.3%)ns
      Enterobacter sp.40 (4.7%)33 (5.0%)7 (6.3%)ns36 (5.2%)4 (2.6%)ns
      Escherichia coli27 (3.2%)18 (2.7%)6 (5.4%)ns22 (3.2%)5 (3.3%)ns
      Klebsiella sp.21 (2.5%)14 (2.1%)4 (3.6%)ns17 (2.4%)4 (2.6%)ns
      Statistical significance is indicated in bold.
      ns = not significant.

      Treatment

      We did not use local antiseptics or topical antibiotics. The surgeons performed a partial minor amputation in 566 episodes (78.5%), an internal partial foot amputation in 119 episodes (16.5%), soft-tissue debridement in 20 episodes (2.8%), and an internal resection of infected bone with stabilization using an external Ilizarov ring fixation in 16 episodes (2.2%). We administered postoperative ABT in all episodes, of which 533 (73.9%) were IV at the start. The mean duration of IV therapy was 13 days (SD 17). The mean duration of total ABT was 36 days (SD 37) (Tables 3 and 4). We used 34 different regimens, of which the most common single agents were ciprofloxacin (n = 331), amoxicillin/clavulanic acid (320), clindamycin (250), piperacillin/tazobactam (220), vancomycin (99), co-trimoxazole (71), and levofloxacin (47). Of note, when comparing Gram-negative to Gram-positive DFI, no significant difference was found with regard to the duration of total ABT.
      Table 3Durations of antibiotic therapy in new episodes and revisions.
      All episodes (n = 721)New episodes (n = 570)Revision episodes (n = 151)p-value
      Duration of intravenous therapy (days), mean (SD)13 (17)12 (16)16 (18)0.021
      Categorized information about duration of intravenous antibiotic therapy

       No intravenous therapy

       ≤24 hours

       2–7 days

       8–14 days

       >14 days

       Duration not documented


      182 (25.2%)

      20 (2.8%)

      228 (31.6%)

      149 (20.7%)

      120 (16.6%)

      22 (3.1%)


      156 (27.4%)

      15 (2.6%)

      188 (33.0%)

      112 (19.6%)

      83 (14.6%)

      16 (2.8%)


      26 (17.2%)

      5 (3.3%)

      40 (26.5%)

      37 (24.5%)

      37 (24.5%)

      6 (4.0%)


      0.010

      ns

      0.009

      ns

      0.020

      ns
      Duration of overall postoperative antibiotic therapy (days), mean (SD)36 (37)34 (36)43 (39)0.010
      Categorized information about duration of overall postoperative antibiotic therapy

       ≤7 days

       8–21 days

       22–42 days

       4–84 days

       >84 days


      61 (8.5%)

      290 (40.2%)

      194 (26.9%)

      112 (15.5%)

      64 (8.9%)


      53 (9.3%)

      243 (42.6%)

      147 (25.8%)

      82 (14.4%)

      45 (7.9%)


      8 (5.3%)

      47 (31.1%)

      47 (31.1%)

      30 (19.9%)

      19 (12.6%)


      ns

      0.010

      ns

      ns

      ns
      Statistical significance is indicated in bold.
      ns = not significant; SD = standard deviation.
      Table 4Durations of antibiotic therapy for osteomyelitis vs gangrene.
      All episodes

      (n = 721)
      Osteomyelitis (n = 537)Gangrene (n = 102)p-value
      Duration of intravenous therapy (days), mean (SD)13 (17)12 (16)16 (20)ns
      Categorized information about duration of intravenous antibiotic therapy

       No intravenous therapy

       ≤24 hours

       2–7 days

       8–14 days

       >14 days

       Duration not documented


      182 (25.2%)

      20 (2.8%)

      228 (31.6%)

      149 (20.7%)

      120 (16.6%)

      22 (3.1%)


      125 (23.3%)

      12 (2.2%)

      188 (35.0%)

      109 (20.3%)

      88 (16.4%)

      15 (2.8%)


      34 (33.3%)

      3 (2.9%)

      23 (22.6%)

      16 (15.7%)

      19 (18.6%)

      7 (6.9%)


      0.031

      ns

      ns

      ns

      ns

      ns
      Duration of overall postoperative antibiotic therapy (days), mean (SD)36 (37)34 (33)38 (41)ns
      Categorized information about duration of overall postoperative antibiotic therapy

       ≤7 days

       8–21 days

       22–42 days

       43–84 days

       >84 days


      61 (8.5%)

      290 (40.2%)

      194 (26.9%)

      112 (15.5%)

      64 (8.9%)


      38 (7.1%)

      231 (43.0%)

      149 (27.7%)

      80 (14.9%)

      39 (7.3%)


      14 (13.7%)

      36 (35.3%)

      27 (26.5%)

      15 (14.7%)

      10 (9.8%)


      0.024

      ns

      ns

      ns

      ns
      Statistical significance is indicated in bold.
      ns = not significant; SD = standard deviation.

      Outcomes

      We witnessed CF in 191 episodes (26.5%) and MF in 42 episodes (5.8%). Hence, we saw 5 times more (ischemic) treatment failures than true infection recurrences. The mean durations of total and IV ABT were not different between the episodes with and without CF (Table 5). The same applies for the outcome of MF. The plotting of the overall failure risk against the ABT duration failed to define a minimal threshold. Revision surgery was necessary in 407 episodes (56.4%) with an average of 2 revisions per patient (range, 1–13 surgeries) and a major amputation in 64 episodes (15.3%). The mean time delay to revision was 17.4 months and to major amputation, 34.5 months.
      Table 5Duration of antibiotic therapy for clinical and microbiological failure.
      Clinical failureMicrobiological failure
      YesNop-valueYesNop-value
      Duration of intravenous therapy (days), mean (SD)

      17 (18)


      11 (16)


      ns


      13(11)


      13 (17)


      ns
      Categorized information about duration of intravenous antibiotic therapy, n (%)

       No intravenous therapy

       ≤24 hours

       2–7 days

       8–14 days

       >14 days

       Duration not documented


      5 (1.0)

      48 (9.3)

      37 (7.2)

      58 (11.2)


      15 (2.9)

      180 (34.8)

      112 (21.7)

      62 (12.0)


      ns

      0.001

      ns

      0.000


      0

      18 (3.5)

      10 (1.9)

      10 (1.9)


      20 (3.9)

      210 (40.6)

      139 (26.9)

      110 (21.3)


      ns

      ns

      ns

      Duration of overall postoperative antibiotic therapy (days), mean (SD)47 (45)32 (33)ns36 (32)36 (37)ns
      Categorized information about duration of overall postoperative antibiotic therapy

       ≤7 days

       8–21 days

       22–42 days

       43–84 days

       >84 days


      12 (1.7)

      55 (7.6)

      47 (6.5)

      51 (7.1)

      26 (3.6)


      49 (6.8)

      235 (32.6)

      147 (20.4)

      61 (8.5)

      38 (5.3)


      ns

      0.000

      ns

      0.000

      0.007


      2 (0.3)

      17 (2.4)

      13 (1.8)

      7 (1.0)

      3 (0.4)


      59 (8.2)

      273 (37.9)

      181 (25.1)

      105 (14.6)

      61 (8.5)


      ns

      ns

      ns

      ns

      ns
      SD = standard deviation.

      Stratified outcomes

      Among the 537 DFO episodes, CF occurred in 124 (23.1%) and MF in 35 (6.5%) episodes. In cases with superinfected gangrene, CF occurred statistically significantly more often with 38.2% (p = 0.001) (Figure 1). MF was seen in 3.9% in this group. Overall, revision surgery was needed in 298 episodes with DFO (55.5%) versus revision surgery in 58 episodes with gangrene (56.9%). Comparing the groups with DFO and gangrene, there was no significant difference in time to CF (mean 2.8 vs 2.9 months, p = 0.920), time to revision (18.7 vs 14.1 months, p = 0.269), and time to major amputation (34.1 vs 14.9 months, p = 0.056). However, the time to MF was significantly shorter in DFO (2.6 vs 5.8 months, p = 0.045). In new DFI episodes, CF was observed in 138 (24.2%) and MF in 31 (5.4%) episodes. In revisions, CF occurred in 53 (35.1%) and MF in 11 (7.3%) episodes. Comparing new and revision episodes, there was no difference in time to CF and time to MF.
      Figure 1
      Figure 1Kaplan-Meier survival curves regarding remission.
      CF = clinical failure.

      Multivariate results

      Short ABT durations such as the groups of 8–21 days (hazard ratio [HR] 0.4, 95% CI 0.2–0.7) or 22–42 days (HR 0.5, 95% CI 0.3–0.9) were inversely associated with CF. Regarding the initial IV part, short prescriptions such as 2–7 days (HR 0.5, 95% CI 0.3–0.8) or 8–14 days (HR 0.6, 95% CI 0.4–0.9) were also negatively associated. In contrast, a previous contralateral minor amputation (HR 1.5, 95% CI 1.1–2.1) and a history of revascularization (HR 1.5, 95% CI 1.0–2.1) were clear risks associated with CF (Tables 6 and b). In DFOs, a contralateral minor (HR 1.8, 95% CI 1.2–2.8) or a major (HR 3.1, 95% CI 1.3–7.3) amputation was a significant risk factor for CF. Equally, we confirmed an inverse association with CF regarding the total ABT of 8–21 days (HR 0.3, 95% CI 0.2–0.7). In new episodes, the clinical need for revascularization (HR 1.7, 95% CI 1.1–2.5) was a significant risk, whereas, again, a short ABT of 8–21 days (HR 0.5, 95% CI 0.2–1.0), or short IV administrations of 2–7 days (HR 0.4, 95% CI 0.3–0.8) or 8–14 days (HR 0.5, 95% CI 0.3–0.8) still were inversely associated with CF.
      Table 6aEnd point clinical failure–OM vs gangrene.
      All episodes

      Univariate analysis, HR (95% CI)
      All episodes

      Multivariate analysis, HR (95% CI)
      Osteomyelitis

      Univariate analysis, HR (95% CI)
      Osteomyelitis

      Multivariate analysis, HR (95% CI)
      Gangrene

      Univariate analysis, HR (95% CI)
      Gangrene

      Multivariate analysis, HR (95% CI)
      Age0.995 (0.98–1.01)1.01 (0.99–1.02)0.996 (0.98–1.01)1.01 (0.98–1.03)0.997 (0.97–1.02)1.03 (0.98–1.1)
      Female sex0.7 (0.5–1.1)0.8 (0.5–1.3)0.5 (0.3–0.9)0.4 (0.2–0.9)1.1 (0.5–2.3)2.4 (0.6–9.0)
      Advanced kidney disease1.3 (0.9–1.7)0.9 (0.6–1.4)1.3 (0.9–1.9)0.9 (0.5–1.4)0.9 (0.5–1.7)0.6 (0.3–1.5)
      Coronary artery disease1.5 (1.1–2.0)1.1 (0.8–1.6)1.6 (1.1–2.3)1.3 (0.9–2.0)1.5 (0.8–2.8)0.9 (0.3–2.6)
      Bypass and/or PTA1.3 (1.004–1.8)1.5 (1.04–2.1)1.5 (1.02–2.1)1.2 (0.8–1.9)1.2 (0.6–2.4)2.5 (0.8–7.4)
      Diabetes type 20.8 (0.5–1.1)0.7 (0.4–1.01)0.7 (0.5–1.1)0.8 (0.5–1.2)0.6 (0.3–1.3)0.5 (0.2–1.4)
      Nicotine abuse1.3 (0.9–1.7)1.1 (0.8–1.6)1.1 (0.8–1.6)0.9 (0.6–1.4)1.2 (0.6–2.4)1.5 (0.5–4.1)
      Prior contralateral minor amputation1.6 (1.2–2.1)1.5 (1.1–2.1)1.6 (1.1–2.3)1.8 (1.2–2.8)2.4 (1.3–4.6)2.5 (1.1–5.5)
      Prior contralateral major amputation1.8 (0.9–3.5)1.8 (0.8–3.8)2.2 (0.95–5.1)3.1 (1.3–7.4)1.1 (0.3–4.9)2.1 (0.3–17.2)
      PAD1.4 (1.01–2.0)1.1 (0.6–1.9)1.4 (0.92–2.1)0.9 (0.4–1.9)2.4 (0.3–17.8)1.9 (0.1–33.4)
      Overall postoperative antibiotic therapy

      ≤7 days

      8–21 days

      22–42 days

      43–84 days

      >84 days


      0.5 (0.2–0.9)

      0.4 (0.3–0.7)

      0.6 (0.3–0.9)

      1.3 (0.8–2.0)

      reference


      0.8 (0.4–1.8)

      0.4 (0.2–0.8)

      0.5 (0.3–0.9)

      0.96 (0.6–1.7)

      reference


      0.6 (0.2–1.4)

      0.4 (0.2–0.8)

      0.5 (0.4–0.9)

      1.3 (0.7–2.5)

      reference


      0.7 (0.3–1.9)

      0.3 (0.2–0.7)

      0.5 (0.2–1.04)

      1.3 (0.6–2.9)

      reference


      0.1 (0.02–0.6)

      0.2 (0.09–0.6)

      0.4 (0.2–1.04)

      0.6 (0.2–1.7)

      reference


      0.3 (0.04–2.9)

      0.4 (0.1–2.6)

      0.4 (0.1–1.7)

      0.5 (0.1–2.6)

      reference
      Intravenous antibiotic therapy

      ≤24 hours

      2–7 days

      8–14 days

      >14 days


      0.4 (0.2–0.98)

      0.3 (0.2–0.5)

      0.4 (0.3–0.6)

      reference


      0.4 (0.2–1.1)

      0.5 (0.3–0.8)

      0.6 (0.3–0.9)

      reference


      0.3 (0.1–1.4)

      0.4 (0.3–0.6)

      0.4 (0.2–0.7)

      reference


      0.4 (0.1–1.9)

      0.8 (0.4–1.5)

      0.7 (0.4–1.2)

      reference


      n.d.

      0.3 (0.1–0.7)

      0.4 (0.1–0.9)

      reference


      n.d.

      0.3 (0.1–0.8)

      0.4 (0.1–1.01)

      reference
      Statistical significance is indicated in bold.
      ns = not significant; OM = osteomyelitis; PAD = peripheral artery disease; PTA = percutaneous transluminal angioplasty; SD = standard deviation.
      Table 6bEnd point clinical failure–new vs revision episodes.
      All episodes

      Univariate analysis, HR (95% CI)
      All episodes

      Multivariate analysis, HR (95% CI)
      New episodes

      Univariate analysis, HR (95% CI)
      New episodes

      Multivariate analysis, HR (95% CI)
      Revisions

      Univariate analysis, HR (95% CI)
      Revisions

      Multivariate analysis, HR (95% CI)
      Age0.995 (0.98–1.01)1.005 (0.99–1.02)1.002 (0.99–1.02)1.01 (0.99–1.03)0.98 (0.950.999)0.97 (0.90.995)
      Female sex0.7 (0.5–1.1)0.8 (0.5–1.3)0.8 (0.5–1.3)0.9 (0.5–1.5)0.5 (0.2–1.3)0.6 (0.1–2.8)
      Advanced kidney disease1.3 (0.9–1.7)0.9 (0.6–1.4)1.3 (0.9–1.9)1.1 (0.7–1.7)0.98 (0.5–1.8)0.6 (0.3–1.3)
      Coronary artery disease1.5 (1.12.0)1.1 (0.8–1.6)1.5 (1.052.04)1.04 (0.7–1.6)1.4 (0.8–2.4)1.4 (0.7–2.6)
      Bypass and/or PTA1.3 (1.0041.8)1.5 (1.042.1)1.3 (0.9–1.9)1.7 (1.12.5)1.2 (0.7–2.2)0.99 (0.3–3.3)
      Diabetes type 20.8 (0.5–1.1)0.7 (0.4–1.01)0.8 (0.5–1.3)0.6 (0.4–1.1)0.7 (0.3–1.2)0.6 (0.2–1.3)
      Nicotine abuse1.3 (0.9–1.7)1.1 (0.8–1.6)1.2 (0.8–1.6)0.99 (0.6–1.5)1.6 (0.9–2.9)1.5 (0.7–3.4)
      Prior contralateral minor amputation1.6 (1.22.1)1.5 (1.12.1)1.3 (0.9–1.9)1.3 (0.9–2.0)2.4 (1.34.3)2.3 (1.24.4)
      Prior contralateral major amputation1.8 (0.9–3.5)1.8 (0.8–3.8)1.8 (0.8–3.8)1.9 (0.8–4.5)1.7 (0.4–7.3)2.2 (0.5–9.9)
      PAD1.4 (1.012.0)1.1 (0.6–1.9)1.5 (0.98–2.2)1.2 (0.6–2.3)1.2 (0.6–2.3)1.2 (0.5–2.9)
      Overall postoperative antibiotic therapy

      ≤7 days

      8–21 days

      22–42 days

      43–84 days

      >84 days


      0.5 (0.2–0.9)

      0.4 (0.3–0.7)

      0.6

      (0.3–0.9)

      1.3

      (0.8–2.0)

      reference


      0.8 (0.4–1.8)

      0.4

      (0.2–0.8)

      0.5

      (0.3–0.9)

      0.96

      (0.6–1.7)

      reference


      0.4 (0.2–0.9)

      0.4

      (0.2–0.7)

      0.5

      (0.3–0.9)

      1.2

      (0.7–2.1)

      reference


      0.8 (0.3–2.2)

      0.5

      (0.2–0.96)

      0.6

      (0.3–1.3)

      1.003

      (0.4–2.0)

      reference


      1.01 (0.3–3.8)

      0.8

      (0.3–1.8)

      0.7

      (0.3–1.6)

      1.5

      (0.7–3.6)

      reference


      0.9 (0.2–3.4)

      0.5

      (0.2–1.3)

      0.5

      (0.2–1.4)

      1.2

      (0.5–3.1)

      reference
      Intravenous antibiotic therapy

      ≤24 hours

      2–7 days

      8–14 days

      >14 days


      0.4 (0.2–0.99)

      0.3 (0.2–0.5)

      0.4 (0.3–0.6)

      reference


      0.4 (0.2–1.1)

      0.5 (0.3–0.8)

      0.6 (0.4–0.9)

      reference


      0.4 (0.2–1.2)

      0.3 (0.2–0.5)

      0.4 (0.2–0.6)

      reference


      0.5 (0.1–1.5)

      0.4 (0.3–0.8)

      0.5 (0.3–0.8)

      reference


      0.3 (0.04–2.2)

      0.5 (0.3–1.1)

      0.6 (0.3–1.2)

      reference


      0.2 (0.03–1.7)

      0.5 (0.2–1.3)

      0.9 (0.4–2.1)

      reference
      Statistical significance is indicated in bold.
      ns = not significant; PAD = peripheral artery disease; PTA = percutaneous transluminal angioplasty; SD = standard deviation.
      We found no associations between the tested variables and MF in all regression analyses. Gram-negative DFI was not associated with MF in nonrevised DFIs (Gram-negatives vs Gram-positives: MF 6.9% vs 7.6%). This held equally true when only analyzing OM alone (MF 8.6% for Gram-negative OM vs 7.85 failure risk for Gram-positive OM).

      Discussion

      In this large, retrospective DFI cohort study, we found no minimal thresholds and no optimal durations concerning the total systemic ABT or the IV ABT in relation to clinical failures and microbiological recurrences. This lack of association concerned all strata: the overall study population, DFO episodes, and revision surgeries for DFI. Statistically speaking, the shorter the duration of ABT, the less the occurrence of failures, indicating a major “confounding by indication” that is inherent to many retrospective studies with a large case-mix (
      • Jeffcoate WJ
      • Bus SA
      • Game FL
      • Hinchliffe RJ
      • Price PE
      • Schaper NC.
      Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality.
      ). It is probable that the surgeons prolonged the duration of ABT for episodes with unsatisfactory evolutions without finally being able to reverse the risk of failure. The low number of MF (true microbiological recurrences: n = 42, 5.8%) compared with CF (mostly ischemic failures: n = 191, 26.5%) supports the fact that the ABT was sufficient for the index infection in most episodes. This is conclusive, with further data showing that only a small proportion of stump complications are caused by infections.(
      • Dunkel N
      • Uçkay I
      • Belaieff W
      • Assal M
      • Corni V
      • Lacraz A
      • et al.
      Wound dehiscence and stump infection after lower limb amputation: risk factors and association with antibiotic use.
      ;
      • Uçkay I
      • Agostinho A
      • Belaieff W
      • Toutous-Trellu L
      • Scherer-Pietramaggiori S
      • Andres A
      • et al.
      Noninfectious wound complications in clean surgery: Epidemiology, risk factors, and association with antibiotic use.
      ).

      Duration and route of application of ABT

      Various studies and guidelines show no benefit for ABT lasting longer than 6 weeks for DFO; or 2 weeks for soft-tissue DFIs (
      • Gariani K
      • Lebowitz D
      • von Dach E
      • Kressmann B
      • Lipsky BA
      • Uçkay I
      Remission in diabetic foot infections: Duration of antibiotic therapy and other possible associated factors.
      ;
      • Lipsky BA
      • Senneville É
      • Abbas ZG
      • Aragón-Sánchez J
      • Diggle M
      • Embil JM
      • et al.
      Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
      ;
      • Tone A
      • Nguyen S
      • Devemy F
      • Topolinski H
      • Valette M
      • Cazaubiel M
      • et al.
      Six-week versus twelve-week antibiotic therapy for nonsurgically treated diabetic foot osteomyelitis: A multicenter open-label controlled randomized study.
      ). The currently largest study concerning ABT durations in DFI (
      • Gariani K
      • Lebowitz D
      • von Dach E
      • Kressmann B
      • Lipsky BA
      • Uçkay I
      Remission in diabetic foot infections: Duration of antibiotic therapy and other possible associated factors.
      ) equally found no threshold for the total duration of ABT or its IV part. Gariani et al. recently released an randomised controlled (RC) prospective pilot trial comparing 3 versus 6 weeks of ABT with a similar incidence for remission (
      • Gariani K
      • Pham T-T
      • Kressmann B
      • Jornayvaz FR
      • Gastaldi G
      • Stafylakis D
      • et al.
      Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.
      ). We confirm these results. Likewise, different IV durations cannot influence outcomes regardless of the stratum or the outcome analyzed. If the pathogen is sensitive to a specific antibiotic agent, oral ABT is not inferior to IV application for long-term treatment (
      • Alves C
      • Juliana Casqueiro
      • Janine Casqueiro
      Infections in patients with diabetes mellitus: A review of pathogenesis.
      ;
      • Whisstock C
      • Volpe A
      • Ninkovic S
      • Marin M
      • Meloni M
      • Bruseghin M
      • et al.
      Multidisciplinary Approach for the Management and Treatment of Diabetic Foot Infections with a Resorbable, Gentamicin-Loaded Bone Graft Substitute.
      ). On the basis of available literature, the new IWGDF guidelines (
      • Lipsky BA
      • Senneville É
      • Abbas ZG
      • Aragón-Sánchez J
      • Diggle M
      • Embil JM
      • et al.
      Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
      ) support that in mild DFIs and most episodes with a moderate DFI, we can safely perform an oral ABT right from the start. In severe DFIs, the ABT is given by the parenteral route, with a switch to oral therapy after 5–7 days if the patient is improving and has no contraindications to oral regimens (
      • Lipsky BA
      • Senneville É
      • Abbas ZG
      • Aragón-Sánchez J
      • Diggle M
      • Embil JM
      • et al.
      Guidelines on the diagnosis and treatment of foot infection in persons with diabetes (IWGDF 2019 update).
      ).
      Indeed, in the entire field of orthopedic infection, (
      • Li HK
      • Rombach I
      • Zambellas R
      • Sarah Walker A
      • McNally MA
      • Atkins BL
      • et al.
      Oral versus intravenous antibiotics for bone and joint infection.
      ) demonstrated the noninferiority of oral ABT (after 1 week IV ABT) compared with the 6-week IV regimens. In addition, an early switch to oral therapy was associated with a shorter hospitalization owing to reduced side effects. Another promising new approach, which is currently evolving, is the local application of antibiotic agents for disruption of biofilms and prevention of recurrence. These include polymethylmethacrylate blocks, bone cement, collagen sponges, and calcium sulfate formulations (
      • Gauland C.
      Managing Lower-Extremity Osteomyelitis Locally with Surgical Debridement and Synthetic Calcium Sulfate Antibiotic Tablets.
      ;
      • Hutting KH
      • aan de Stegge WB
      • van Netten JJ
      • ten Cate WA
      • Smeets L
      • Welten GMJM
      • et al.
      Surgical Treatment of Diabetic Foot Ulcers Complicated by Osteomyelitis with Gentamicin-Loaded Calcium Sulphate-Hydroxyapatite Biocomposite.
      ;
      • Jogia RM
      • Modha DE
      • Nisal K
      • Berrington R
      • Kong MF.
      Use of highly purified synthetic calcium sulfate impregnated with antibiotics for the management of diabetic foot ulcers complicated by osteomyelitis.
      ;
      • Krause FG
      • DeVries G
      • Meakin C
      • Kalla TP
      • Younger AS.
      Outcome of Transmetatarsal Amputations in Diabetics Using Antibiotic Beads.
      ;
      • Varga M
      • Sixta B
      • Bem R
      • Matia I
      • Jirkovska A
      • Adamec M.
      Application of gentamicin-collagen sponge shortened wound healing time after minor amputations in diabetic patients - A prospective, randomised trial.
      ). Use of these agents may reduce the need for IV ABT even further (
      • Ferguson J
      • Diefenbeck M
      • McNally M.
      Ceramic Biocomposites as Biodegradable Antibiotic Carriers in the Treatment of Bone Infections.
      ;
      • McNally MA
      • Ferguson JY
      • Lau ACK
      • Diefenbeck M
      • Scarborough M
      • Ramsden AJ
      • et al.
      Single-stage treatment of chronic osteomyelitis with a new absorbable, gentamicin-loaded, calcium sulphate/hydroxyapatite biocomposite: A prospective series of 100 cases.
      ;
      • Varga M
      • Sixta B
      • Bem R
      • Matia I
      • Jirkovska A
      • Adamec M.
      Application of gentamicin-collagen sponge shortened wound healing time after minor amputations in diabetic patients - A prospective, randomised trial.
      ).

      Limitations

      Our study has several limitations. First, it has a retrospective design with a substantial “confounding by indication.” It is conceivable that DFI episodes with poor evolution during therapy received a prolonged ABT. Second, the study population is heterogeneous. Stratification according to different surgical factors that are known to influence the outcome should be implemented in future studies, such as adequate disruption of bacterial biofilm, resection to clear bone margins (wide or marginal), or protocolized debridement to mention a few (
      • Ahluwalia R
      • Vainieri E
      • Tam J
      • Sait S
      • Sinha A
      • Manu CA
      • et al.
      Surgical Diabetic Foot Debridement: Improving Training and Practice Utilizing the Traffic Light Principle.
      ;
      • Johnson MJ
      • Shumway N
      • Bivins M
      • Bessesen MT.
      Outcomes of Limb-Sparing Surgery for Osteomyelitis in the Diabetic Foot: Importance of the Histopathologic Margin.
      ;
      • Senneville E
      • Robineau O.
      Treatment options for diabetic foot osteomyelitis.
      ;
      • Simpson AH
      • Deakin M
      • Latham JM.
      Chronic osteomyelitis. The effect of the extent of surgical resection on infection-free survival.
      ) as well as various patient-related factors, such as peripheral artery disease, diabetes, and malnutrition (
      • Abbas M
      • Uçkay I
      • Lipsky BA.
      In diabetic foot infections antibiotics are to treat infection, not to heal wounds.
      ;
      • Uckay I
      • Jornayvaz FR
      • Lebowitz D
      • Gastaldi G
      • Gariani K LB
      An Overview on Diabetic Foot Infections, including Issues Related to Associated Pain, Hyperglycemia and Limb Ischemia.
      ;
      • Uçkay I
      • Gariani K
      • Pataky Z
      • Lipsky BA.
      Diabetic foot infections: state-of-the-art.
      ). Third, because of heterogeneity of pathogens and antibiotic agents, no targeted analysis on the role of these specific pathogens or antibiotic agents was possible. Of note, we recorded a total of 81 different microbiological constellations and 34 different antibiotic regimens, especially among the Gram-negative pathogens. Fourth, our geographical localization might play a role, limiting the generatability of our findings. Gram-negative DFI is a challenge for clinicians, especially in Southern Europe and subtropical regions, such as Southern Asia (
      • Uçkay I
      • Gariani K
      • Pataky Z
      • Lipsky BA.
      Diabetic foot infections: state-of-the-art.
      ) for several reasons. The proportion of (nonfermenting) Gram-negative rods in DFI is more predominant in these arid countries (up to 60%) compared with temperate areas such as Northern America or Central Europe, for which the exact reasons remain unknown. In addition, the Gram-negative rods are much more antibiotic resistant and emerging than the usual Gram-positive bacteria, for which many oral antimicrobial agents remain available. For example,
      • Saltoglu N
      • Ergonul O
      • Tulek N
      • Yemisen M
      • Kadanali A
      • Karagoz G
      • et al.
      Turkish Society of Clinical Microbiology and Infectious Diseases, Diabetic Foot Infections Study Group. Influence of multidrug resistant organisms on the outcome of diabetic foot infection.
      found that most Gram-negative DFI involved Pseudomonas spp. with a high proportion of multidrug-resistant microorganisms, leading to a prolonged IV therapy because of the nonavailability of oral agents rather than because of the clinical virulence of the infection. If there is a high proportion of multidrug resistance, the CF and MF failures risk may also increase because of that resistance (
      • Saltoglu N
      • Ergonul O
      • Tulek N
      • Yemisen M
      • Kadanali A
      • Karagoz G
      • et al.
      Turkish Society of Clinical Microbiology and Infectious Diseases, Diabetic Foot Infections Study Group. Influence of multidrug resistant organisms on the outcome of diabetic foot infection.
      ). In temperate areas and resource-rich countries where the resistance problem might be less predominant, the duration of the ABT is less driven by the clinical picture. Unsurprisingly, the total duration of our ABT did not differ between Gram-negative and Gram-positive foot infection. Likewise, the outcomes of MF were similar between both pathogen groups, suggesting that there might be no genuine difference in terms of clinical virulence between Gram-negative and Gram-positive germs. This can obviously change when the Gram-negatives are becoming multidrug resistant, which is not yet the case in our region. In such a case, the ABT would also rely more on IV administrations because of the nonavailability of performant oral agents. Of note, the proportion of P. aeruginosa among all causative DFI pathogens in our region ranges between 6% and 12% (
      • Uçkay I
      • Holy D
      • Schöni M
      • Waibel FWA
      • Trache T
      • Burkhard J
      • Böni T
      • Lipsky BA
      • Berli MC.
      How good are clinicians in predicting the presence of Pseudomonas spp. in diabetic foot infections? A prospective clinical evaluation.
      ). Curative resection and remission are to date difficult to prove with consistence. Current studies have shown good results for routine intraoperative biopsies and percutaneous biopsies of the residual bone stump (
      • Costerton JW
      • Post JC
      • Ehrlich GD
      • Hu FZ
      • Kreft R
      • Nistico L
      • et al.
      New methods for the detection of orthopedic and other biofilm infections.
      ;
      • Elamurugan TP
      • Jagdish S
      • Kate V
      • Chandra Parija S.
      Role of bone biopsy specimen culture in the management of diabetic foot osteomyelitis.
      ;
      • Kosmopoulou OA
      • Dumont IJ.
      Feasibility of Percutaneous Bone Biopsy as Part of the Management of Diabetic Foot Osteomyelitis in a 100% Neuropathic, Grade 3 IDSA/IWGDF Population on an Outpatient Basis.
      ;
      • Kowalski TJ
      • Matsuda M
      • Sorenson MD
      • Gundrum JD
      • Agger WA.
      The Effect of Residual Osteomyelitis at the Resection Margin in Patients with Surgically Treated Diabetic Foot Infection.
      ;
      • Senneville E
      • Melliez H
      • Beltrand E
      • Legout L
      • Valette M
      • Cazaubiel M
      • et al.
      Culture of percutaneous bone biopsy specimens for diagnosis of diabetic foot osteomyelitis: Concordance with ulcer swab cultures.
      ). In case of confirmed curative resection, recent studies even suggest to limit postoperative ABT to 0–5 days (
      • Rossel A
      • Lebowitz D
      • Gariani K
      • Abbas M
      • Kressmann B
      • Assal M
      • et al.
      Stopping antibiotics after surgical amputation in diabetic foot and ankle infections—A daily practice cohort.
      ;
      • Saltoglu N
      • Dalkiran A
      • Tetiker T
      • Bayram H
      • Tasova Y
      • Dalay C
      • et al.
      Piperacillin/tazobactam versus imipenem/cilastatin for severe diabetic foot infections: a prospective, randomized clinical trial in a university hospital.
      ). This also holds true for the guidelines for the management of simple soft-tissue infections, which suggest a maximum of 2–5 days (
      • Uçkay I
      • Berli M
      • Sendi P
      • Lipsky BA.
      Principles and practice of antibiotic stewardship in the management of diabetic foot infections.
      ).

      Conclusion

      Our study retrospectively demonstrates that in a specialized surgical diabetic foot unit for adult patients with DFI and DFO, relatively short postoperative regimens of total ABT (eg, for less than 6 weeks) do not yield an enhanced risk of CFs or MFs. The same applies for IV administrations of 2–14 days compared with more than 14 days. We were also unable to define optimal minimal threshold of ABT durations. Given the presence of substantial “confounding by indication,” the best study design for our study questions would be stratified prospective randomized trials (
      • Gariani K
      • Pham T-T
      • Kressmann B
      • Jornayvaz FR
      • Gastaldi G
      • Stafylakis D
      • et al.
      Three Weeks Versus Six Weeks of Antibiotic Therapy for Diabetic Foot Osteomyelitis: A Prospective, Randomized, Noninferiority Pilot Trial.
      ;
      • Jeffcoate WJ
      • Bus SA
      • Game FL
      • Hinchliffe RJ
      • Price PE
      • Schaper NC.
      Reporting standards of studies and papers on the prevention and management of foot ulcers in diabetes: required details and markers of good quality.
      ), which are currently under way (
      • Waibel F
      • Berli M
      • Catanzaro S
      • Sairanen K
      • Schöni M
      • Böni T
      • et al.
      Optimization of the antibiotic management of diabetic foot infections: Protocol for two randomized controlled trials.
      ).

      Disclosures

      All authors declare no conflict of interest.

      Funding

      None.

      Acknowledgments

      We are indebted to the Unit for Clinical Applied Research (UCAR) for their invaluable support. We thank the teams of our Diabetic Foot Clinic and the Technical Orthopedic Unit for help.

      Authors’ contributions

      FH, FW, ML, EW and MS performed the data acquisition. MS, EW and IU performed the statistical analysis. FH, FW, ML, IU, EW and MS have contributed to analysis and interpretation of the data. All authors contributed by either drafting or critical revision of the manuscript. All authors have read and approved the final submitted manuscript.

      Ethical approval statement

      We further confirm that any aspect of the work covered in this manuscript that has involved human patients has been conducted with the ethical approval of all relevant bodies and that such approvals are acknowledged within the manuscript. IRB approval was obtained. Written consent to publish potentially identifying information, such as details of the case and photographs, was obtained from the patients or their legal guardians.

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