Conditions: Osteomyelitis
Keywords: Osteomyelitis Diabetes Foot Infection
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 30
Healthy volunteers: no

Brief summary:
The Infectious Diseases Society of America (IDSA) 2012 guidelines for the diagnosis and treatment of diabetic foot infections state that for the treatment of diabetic foot osteomyelitis "No data support the superiority of any specific antibiotic agent or treatment strategy, route, or duration of therapy." Traditionally, osteomyelitis has been treated with a long course of intravenous antibiotics, generally six weeks. Oral antibiotics with high bioavailability and adequate bone penetration have been shown in published studies to be effective for the treatment of osteomyelitis.

The investigators propose to conduct a prospective, single-center, randomized, open trial at Loyola University Medical Center (LUMC) comparing the efficacy of oral antibiotic therapy to intravenous (IV) antibiotic therapy for the treatment of diabetic foot osteomyelitis. The investigators hypothesize that oral antibiotic therapy is equivalent to IV antibiotic therapy. Bone/tissue cultures are obtained for all patients for clinical purposes and are sent to pathology for histologic examination and to the clinical microbiology laboratory for culture and susceptibility. Patients will receive six weeks of IV or oral antibiotic therapy depending upon their randomization group. Primary outcomes at six months clinical follow-up will include: (i) no evidence of bone infection and (ii) resolution of ulcer.

Detailed description:
Currently, available literature is not adequate to determine the best agent, route, or duration of antibiotic therapy for the treatment of chronic osteomyelitis. The standard of therapy has been to treat patients with a parenteral antibiotic for four to six weeks. In a recent literature review by Spellberg et al. it was concluded that oral and parenteral antibiotic therapy have similar cure rates for the treatment of chronic osteomyelitis. Oral antibiotic therapy is associated with a lower risk to the patient due to avoiding the need of a central IV line. Additionally, oral therapy costs less than a course of IV antibiotics. Oral antibiotics with high bioavailability and good bone penetration include, fluoroquinolones, linezolid, trimethoprim/sulfamethoxazole (2 tabs bid), clindamycin and metronidazole. These antibiotics have been shown in recent studies to obtain levels in the bone that exceed the minimum inhibitory concentration (MIC) levels of the targeted organisms. According to the IDSA 2012 guidelines for the treatment of diabetic foot infections, the diagnosis of osteomyelitis can be made via plain radiographs or MRI imaging (more sensitive). A bone scan can be considered if an MRI cannot be done. The preferred method of diagnosis is by bone culture and histology. The guidelines also recommend surgical debridement to healthy tissue for diabetic foot infections followed by antibiotic therapy.

The Purpose of this study is to compare the efficacy of oral antibiotic therapy with intravenous antibiotic therapy for the treatment of diabetic foot osteomyelitis following surgical debridement. They hypothesis is that oral antibiotic therapy is equivalent to intravenous antibiotic therapy for the treatment of diabetic foot osteomyelitis.

Arms:
arm 1: Individuals with an infection on the midfoot are randomized to an intravenous antibacterial agent or an oral antibacterial agent. arm 2: Individuals with an infection on the hindfoot are randomized to an intravenous antibacterial agent or an oral antibacterial agent. arm 3: Individuals with an infection on the toe are randomized to an intravenous antibacterial agent or an oral antibacterial agent.

Interventions: intervention 1: Intravenous Antibacterial Agent intervention 2: Oral Antibacterial Agent
Intervention descriptions: intervention 1: Individuals in this arm receive an intravenous antibacterial agent. They are not assigned to specific medications. Individuals in this arm will receive an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy is usually one of the following intravenous medications: (i) piperacillin/tazobactam (Zosyn), (ii) cefepime, (iii) metronidazole, (iv) aztreonam, (v) vancomycin, (vi) daptomycin, (vii) linezolid (Zyvox), and/or (viii) meropenem. intervention 2: Individuals in this arm receive an oral antibacterial agent. They are not assigned to specific medications. Individuals in this arm will receive an oral antibacterial agent as determined by their primary healthcare provider. This therapy is usually one of the following oral medications: (i) sulfamethoxazole/trimethoprim (SMX-TMP), (ii) clindamycin (Clindesse), (iii) linezolid (Zyvox), (iv) moxifloxacin (Avelox), (v) ciprofloxacin (Cetraxal), and/or (vi) metronidazole (Flagyl)

Protocol document:
Prot_SAP_000.pdf: 
Page 1 of 10 
 
 
Protocol 
 
Annual Review III Date:  February 2, 2017 
 
Protocol Title: Efficacy of Oral Antibiotic Therapy compared to Intravenous Antibiotic 
Therapy for the Treatment of Diabetic Foot Osteomyelitis (CRO-OSTEOMYELITIS) 
Protocol Version:  1.70 (Amendment 9) 
Protocol Date:  11/18/2015 
Principal Investigator: Michael Pinzur MD 
Research Team: Michael Pinzur, Paul O’ Keefe, Tammy Rhoda, Laurie Labuszewski 
PharmD, Katherine Dux, DPM, Tonya Crawford PharmD, Jorge Parada MD, Stephanie 
Kliethermes, PhD, William Adams, MA, Francis J. Rottier, DPM, Casey J. Holmes, 
Louise Lie, Nina Patel, DO, Infectious Diseases Fellow, Adam Schiff, MD 
 
I. 
Abstract 
 
The Infectious Diseases Society of America (IDSA) 2012 guidelines for the 
diagnosis and treatment of diabetic foot infections state that for the treatment 
of diabetic foot osteomyelitis “No data support the superiority of any specific 
antibiotic agent or treatment strategy, route, or duration of therapy.” [1] 
Traditionally, osteomyelitis has been treated with a long course of intravenous 
antibiotics, generally 6 weeks.  Oral antibiotics with high bioavailability and 
adequate bone penetration have been shown in published studies to be 
effective for the treatment of osteomyelitis.[2] 
 
We propose to conduct a prospective, single-center, randomized, open trial at 
Loyola University Medical Center (LUMC) comparing the efficacy of oral 
antibiotic therapy to intravenous (IV) antibiotic therapy for the treatment of 
diabetic foot osteomyelitis. We hypothesize that oral antibiotic therapy is 
equivalent to IV antibiotic therapy.  
 
Bone/tissue cultures are obtained for all patients for clinical purposes and are 
sent to pathology for histologic examination and to the clinical microbiology 
laboratory for culture and susceptibility.  
 
Patients will receive six weeks of IV or oral antibiotic therapy depending upon 
their randomization group.  Primary outcomes at six months clinical follow-up 
will be no evidence of bone infection and resolution of ulcer.  
 
 
II. 
Background and Significance/Preliminary Studies 
 
Currently available literature is not adequate to determine the best agent, 
route, or duration of antibiotic therapy for the treatment of chronic 
osteomyelitis [1,2,3]  The standard of therapy has been to treat patients with a 


Page 2 of 10 
 
parenteral antibiotic for 4 to 6 weeks.  In a recent literature review by 
Spellberg et al. it was concluded that oral and parenteral antibiotic therapy 
have similar cure rates for the treatment of chronic osteomyelitis.[2] Oral 
antibiotic therapy is associated with a lower risk to the patient due to avoiding 
the need of a central IV line.  Additionally, oral therapy costs less than a 
course of IV antibiotics.  Oral antibiotics with high bioavailability and good 
bone penetration include, fluoroquinoles, linezolid, 
trimethoprim/sulfamethoxazole (2 tabs bid), clindamycin and metronidazole.  
These antibiotics have been shown in recent studies to obtain levels in the 
bone that exceed MIC’s of the targeted organisms. [2]   
 
According to the IDSA 2012 guidelines for the treatment of diabetic foot infections, 
the diagnosis of osteomyelitis can be made via plain radiographs or MRI imaging 
(more sensitive).  A bone scan can be considered if an MRI cannot be done.  The 
preferred method of diagnosis is by bone culture and histology.  The guidelines also 
recommend surgical debridement to healthy tissue for diabetic foot infections 
followed by antibiotic therapy. [1] 
 
III. 
Study Aims 
 
1. The Purpose of this study is to compare the efficacy of oral antibiotic therapy 
with IV antibiotic therapy for the treatment of diabetic foot osteomyelitis 
following surgical debridement. 
 
Hypotheses: Oral Antibiotic Therapy is equivalent to IV Antibiotic Therapy 
for the Treatment of Diabetic Foot Osteomyelitis. 
 
Outcomes will be assessed at six months: 
i. 
No evidence of bone infection. (absence of infection based on 
clinical examination and down-trending of inflammatory markers) 
ii. 
Resolution of ulcer. 
 
2. To biobank bone/tissue specimens obtained from all patients who participate 
in the study for future research purposes. 
 
IV. 
Administrative Organization 
This will be a prospective, single-center study at Loyola University Medical 
Center (LUMC). The Clinical Research Office (CRO) at Loyola will assist 
with the project. 
 
V. 
Study Design 
A prospective, randomized, single-center, open trial at Loyola University 
Medical Center will be conducted in adult diabetic patients with osteomyelitis 
involving the foot.  Patients will be randomized into three groups: 
1. Toe osteomyelitis (phlanges) 
2. Midfoot osteomyelitis: infection distal to the tarsal-metatarsal joint up to 
the metatarsal-phalangeal joint. 


Page 3 of 10 
 
3. Hindfoot osteomyelitis: infection distal to the ankle up to the tarsal- 
metatarsal joint.   
 
Patients in each group will be randomized to receive either oral antibiotic 
therapy or IV antibiotic therapy for a minimum of 6 weeks. 
 
Outcomes: 
 
1. No evidence of bone infection at 6 months. (Clinical absence of infection) 
2. Resolution of ulceration at 6 months. 
 
VI. 
Study Procedures 
 
A.  Inclusion Criteria 
18 years of age and older 
Diagnosis of Diabetes Mellitus (Per past medical history documented in the 
patient medical record) 
Foot osteomyelitis (distal to ankle) 
Surgical debridement (in operating room) 
 
      B.    Exclusion Criteria 
                  Absolute neutrophil count (ANC) < 500 
                  Pregnant or lactating patients 
                  Patients with organisms resistant to oral therapy (In the IV and oral groups) 
                  Internal hardware  
                  Definitive amputations (BKA) 
 
 
      Limb ischemia (absent pedal pulses or ABI < 0.5) 
                   
Bone/tissue specimens are obtained for all patients for clinical purposes. These 
specimens are sent to pathology for histologic examination and to the clinical 
microbiology laboratory for culture and susceptibility.  Ulcers and wounds will be 
measured at all clinical appointments.  
Any remaining specimens beyond what is needed for clinical purposes (if any) 
will be stored as defined in the IRB approved Clinical Research Office 
Biospecimen Repository (LU# 204853).  
 
Until cultures results are available, patients will receive IV antibiotics (i.e., 
usually for the first 3 to 5 days).  Once the culture results are known, the patient 
will be assigned an antibiotic regimen (IV or oral) depending on the 
randomization group and based upon the organisms isolated and their 
susceptibilities.  Antibiotic therapy will be administered for a minimum of six 
weeks. 
 
Patients will be followed by the Infectious Diseases service and either the 
Orthopedics or Podiatry service in the hospital.  After discharge, the patients are 
seen clinically every 2 weeks by either the Orthopedics, Podiatry, or Infectious 


Page 4 of 10 
 
Diseases service.  At specific follow-up appointments, we will collect laboratory 
relevant laboratory data: 
Table 1. Laboratory test monitoring schedule. 
 
Laboratory Test 
Oral antibiotic group 
IV antibiotic group 
CBC w/ dif 
Baseline & weeks 3 & 6 Baseline & weekly 
BUN 
Baseline & weeks 3 & 6 Baseline & weekly 
Creatinine 
Baseline & weeks 3 & 6 Baseline & weekly 
ESR 
Baseline & weeks 3 & 6 Baseline & weeks 3 & 6 
CRP 
Baseline & weeks 3 & 6 Baseline & weeks 3 & 6 
CK 
N/A 
Baseline & weekly 
Vancomycin 
concentration 
N/A 
Weekly  
Albumin 
Baseline 
Baseline 
HgA1c 
Baseline 
Baseline 
N/A-not applicable 
 
EMPIRIC IV THERAPY: 
 
Initial IV therapies for patients before the availability of their culture and 
susceptibility data include: 
 
1.  piperacillin/tazobactam (Zosyn) OR 
 
       PCN ALLERGY with rash: cefepime + metronidazole ̽ OR 
                   
       SEVERE PCN ALLERGY: aztreonam + vancomycin + metronidazole ̽ 
 
2.  If patient has a history of  MRSA (methicillin resistant staphylococcus 
aureus) infection or colonization then add vancomycin OR 
 
VANCOMYCIN ALLERGY/INTOLERANCE : daptomycin or linezolid* 
 
3.  If history of ESBL (extended spectrum beta-lactamase producing organism): 
Use meropenem instead of piperacillin/tazobactam or cefepime + 
metronidazole (meropenem cannot be used in patients with severe PCN 
allergies without desensitization). 
 
((̽ linezolid and metronidazole will be given orally in all patients (empiric, IV and 
oral groups) unless oral administration is not feasible)).  
 


Page 5 of 10 
 
When culture and susceptibility data are available, therapy will be altered to 
as narrow spectrum coverage as possible in both study groups.   
 
ORAL THERAPY OPTIONS:   
 
Once culture and susceptibility data are available, patients randomized to the oral 
therapy group will be converted from IV therapy to one or more of the oral 
antibiotic choices included in table 2.  
 
Table 2.  Oral antibiotic options 
Oral Antibiotic 
Dose 
Organisms covered 
SMX-TMP 
2 double strength tablets 
(DS) every 12 hours* 
[2] 
MSSA, MRSA, 
susceptible gram negative 
bacilli 
clindamycin 
600mg every 8 hours [4] 
MSSA, MRSA, 
Streptococcus,  anaerobes 
linezolid 
600mg every 12 hours 
MSSA, MRSA, 
Streptococcus, VRE 
moxifloxacin 
400mg every 24 hours 
Streptococcus, gram 
negative bacilli except 
pseudomonas 
ciprofloxacin 
750mg every 12 hours* 
[2]  
pseudomonas and other 
gram negative bacilli  
metronidazole 
500mg every 8 hours 
anaerobes 
MSSA- methicillin sensitive staphylococcus aureus, MRSA- methicillin resistant staphylococcus 
aureus, VRE- vancomycin resistant enterococcus. 
 *dose adjustment required for renal dysfunction 
 
          C.   Recruitment procedures 
 
Participants will be approached in the hospital or in the outpatient clinics by a 
qualified member of the research team and informed consent will be obtained 
in a private consult room prior to surgery by the PI or a research team member  
 
           D. Screening procedures 
 
All ordered tests and procedures in the study protocol are part of standard care.   


Page 6 of 10 
 
Patients who do not meet inclusion criteria for the study or who do not agree to 
participate in the study will continue to be treated with appropriate, routine 
clinical care.  
 
E.  Randomization procedures 
 
This is an open study.  The randomization table will be generated by Stephanie 
 
Kliethermes, PhD, who is the principle biostatistician for this trial using SAS 
 
version 9.2) 
 
F.  Study Intervention 
 
This is an open study.  The antibiotics used in this study are routinely used in 
clinical practice.  The oral antibiotics to be used in the study were chosen 
because they have a high oral bioavailability and have been shown in the 
medical literature to have adequate bone concentrations when given orally to 
treat osteomyelitis. 
 
Patients receiving IV antibiotics will continue to receive such clinical therapy 
as described by their healthcare provider, via a central line under the care of a 
home care agency, nursing home, rehabilitation center or infusion center 
consistent with current clinical practice. Laboratory studies will be monitored 
with dosage modifications as necessary (see Table 1).   
  
G. Study Assessments and Activities 
 
Bone/tissue specimens are obtained for all patients for clinical purposes.  
These specimens will be sent to pathology for histologic examination and to 
the clinical microbiology laboratory for culture and susceptibility.  Any 
extraneous bone/tissue that would routinely be discarded will be collected and 
stored for Dr. Katherine Radek’s study (LU#202919) and used for research 
activities stated in the approved protocol.  The CRO will act as the honest 
broker and following signing of a usage agreement to release the biological 
specimens, the de-identified bone/tissue samples will be retrieved and relevant 
phenotype information will be provided in a de-identified manner.  Data will 
be collected prospectively, pooled, statistically analyzed and formatted for 
presentation at regional or national meetings and/or publication in peer 
reviewed surgical/medical journals for research purposes only. 
Debridement will be accomplished with either sharp debridement and/or 
pulsed ultrasound.  Surgery will be considered adequate when all purulent or 
dysvascular tissue has been removed and margins are clinically viable ( ie. 
excision of all infected tissues).  If the final surgery is performed at the level 
of infection, the wound (s) will be initially managed with open treatment.  
Secondary wound closure vs. healing by secondary intention will be decided 
by the operating surgeon.  If the surgery is performed proximal to the level of 
infection, i.e. amputation, the wound will be primary closed. [1,5]   


Page 7 of 10 
 
 
Diabetic foot wounds will be classified according to the Wagner system.  
Ulcers and wounds will be measured to determine size and depth at baseline 
and at follow up visits.   Baseline measurements will be obtained post-
debridement and measurements will be obtained at each follow-up visit until 
closure of the wound is obtained. 
 
Laboratory tests will be completed at baseline and then weekly for patients on 
IV antibiotics and oral linezolid (CBCw/ dif, BUN & creatinine).  Patients on 
oral antibiotics (other than linezolid) will get the same laboratory tests at 
baseline and at weeks 3 and 6. A baseline ESR and CRP will be obtained on 
all patients and repeated at weeks 3 and 6.  Albumin and Hg A1c will be 
collected for all patients at baseline.  Patients receiving daptomycin will have 
creatinine kinase (CK) tested once weekly in addition to other labs as above.  
Vancomycin concentrations will be obtained at least once weekly.  All 
laboratory screenings are considered routine clinical care. 
 
Patients will be followed by the Infectious Diseases service and either the 
Orthopedics or Podiatry service in the hospital.  After discharge the patients 
will be seen every 2 weeks by either the Orthopedics, Podiatry, or Infectious 
Diseases service.  This is considered routine clinical care. 
 
Additional variables that will be collected in this study include the results of 
the following tests: X-ray, CT scan, MRI, bone scan, and white blood cell 
scan, pathology reports, surgical reports and culture results.  These 
assessments will have been ordered by the patient’s healthcare provider and 
are considered routine clinical care. 
 
 
VII. 
Safety Monitoring Plan 
 
Because the therapy agents, regardless of their route of administration, are 
considered routine clinical care, adverse reactions will be managed on an 
individual basis by the patient’s healthcare providers.   
 
If an antibiotic needs to be changed due to intolerance or toxicity in a patient 
randomized to the oral antibiotic group, the patient will remain in the study if 
another oral antibiotic is substituted by his/her healthcare provider.  If a 
patient in the oral antibiotic group requires a change to an IV antibiotic, then 
the patient will be considered to have failed oral therapy 
 
 
VIII. Power Analysis / Analysis Plan 
 


Page 8 of 10 
 
Formula based Sample Size Calculations (no adjustment for infection 
group) 
 
As the assumed proportion of individuals experiencing bone infection after 6 
months increases, the sample size decreases.  This is because the probability is 
shifting further away from 50%.  Assuming a non-inferiority margin of 10% 
results in lower sample size needs than assuming a non-inferiority margin of 
5%.   
  
Proportion without Bone Infection 
60% 
70% 
80% 
90% 
Non-inferiority margin 
5% 10% 
5% 10% 
5% 10% 
5% 10% 
α=0.05 
2376 
594 2078 
520 1584 
396 
892 
224 
α =0.01 
3878 
964 3374 
844 2570 
644 1446 
362 
 
Simulation based Sample Size Calculations (adjusting for infection group) 
These calculations assume an equal number of patients are enrolled in each of 
the three groups (toe, midfoot, hindfoot) and that there is no difference in the 
proportion of individuals who experience bone infection in any group.  The 
sample sizes are slightly larger than those in the first table because we are now 
accounting for the stratification by group.   
 
 
Proportion without Bone Infection 
60% 
70% 
80% 
90% 
Non-inferiority margin 
5% 10% 
5% 10% 
5% 10% 
5% 10% 
α =0.05 
2394 
604 2102 
533 1606 
400 
898 
231 
α =0.01 
3896 
990 3418 
857 2619 
659 1454 
378 
 
Based on the power analysis above, the goal sample size will be 224 
patients with α=0.05, a non-inferiority margin of 10% and a 90% cure rate 
(90% without bone infection after 6 months).  We will request to consent 
up to 300 people to account for individuals who are excluded due to 
abnormal laboratory values and would not be able to continue with their 
participation. 
 
IX. 
Literature Cited 
 
1. Lipsky B, Berendt A, Cornia P, et al. 2012 Infectious Diseases Society of America 
Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot 
Infections. CID 2012;54(12):1679-84. 
 
2. Spellberg B and Lipsky B. Systemic Antibiotic Therapy for Chronic Osteomyelitis 
in Adults. CID 2012;54(#):393-407 
 
3. Lazzarini L, Lipsky B, Mader J. Antibiotic Treatment of Osteomyeleitis: What 
Have we Learned from 30 years of Clinical Trials. Int J Infect Dis 2005;9:127-138 


Page 9 of 10 
 
 
4. Bouazza N, Pestre V, Jullien V, et al.  Population pharmacokinetics of 
Clindamycin Orally and Intravenously Administered in Patients with Osteomyelitis. 
Br J Clin Pharmacol 2012;74(6):971-77. 
  
5. Wukich DK, Armstrong DG, Attinger CE, Boulton AJ, Burns PR, Frykberg RG,    
Hellman R, Kim PJ, Lipsky BA, Pile JC, Pinzur MS, Siminerio L. Inpatient 
management of diabetic foot disorders: a clinical guide. Diabetes Care. 2013 
Sep;36(9):2862-71. 
 
6. Pinzur M, Fil J, Belmares J. et al.  Treatment of Osteomyelitis in Charcot Foot with 
Single-Stage Resection of Infection, Correction of Deformity, and Maintenance with 
Ring Fixation.  Foot Ankle Int.2012;33(12)1069-74. 
 
 
X. 
Summary of Amendments 
 
1. Protocol 1.00  1.10: (dated 3/21/14 – WAdams) (Amendment 1) 
 
1. Added research team members Anilrudh Venugopal, Michael 
Pinzur, Paul O’ Keefe, and Tammy Rhoda 
 
2. Protocol 1.10  1.20: (dated 7/14/14 – WAdams) (Amendment 2) 
 
1. Removed research team member Anilrudh Venugopal 
2. Removed exclusion criterion:  “Bone biopsy histology negative for 
inflammation” 
3. Removed exclusion criterion:  “Negative bone/tissue cultures and 
no evidence of infection demonstrated on microscopic 
examination” 
4. Minor changes to the ICD that do not affect meaning or 
interpretation. 
 
3. Protocol 1.20  1.30:  (dated 7/14/14 – WAdams) (Amendment 3) 
 
1. Removed inclusion criterion:  Bone biopsy with histologic 
evidence of acute or chronic inflammation 
 
4. Protocol 1.30  1.40: (dated 8/19/14 – DMartin) (Amendment 4) 
 
1. Added research activities which include sharing patient specimens 
Under Study Assessments  
 
5. Protocol 1.40:  did not change version (dated 10/06/14 – TRhoda) 
(Amendment 5) 
 


Page 10 of 10 
 
1. Added Research Team Member: Francis J. Rottier, DPM 
 
6. Protocol 1.30  1.40: (Should have been 1.40  1.50) (dated 10/27/14 
– DMartin) (Amendment 6) 
 
1. Added an additional specific aim and study procedure to include 
banking left over materials for future research purposes in the 
CRO-BIOREPOSITORY  
2. Added Research Team Members: Casey J. Holmes, Louise Lie 
 
7.  Protocol 1.40  1.50:  (dated 7/2/2015 – TRhoda) (Amendment 7) 
 
1. Added Research Team Members:  Adam Schiff, MD and Nina 
Patel, DO, Infectious Diseases Fellow 
 
8.  Protocol 1.50  1.60:  (dated 7/13/2015 – TRhoda) (Amendment 8) 
 
1. Amendment 7 – No Action Due to Adam Schiff due for Citi 
Training Refresher Modules.  Remove him from Protocol and add 
Research Team Member:  Nina Patel, DO, Infectious Diseases 
Fellow 
9. Protocol 1.60  1.70:  (dated 11/18/2015 – TRhoda) (Amendment 9) 
 
1. Amendment 9– Add Research Team Member Adam Schiff - 
Completed Citi Training Refresher Modules.