CRO-OSTEO: Efficacy of Oral Antibiotic Therapy Compared to Intravenous Antibiotic Therapy for Osteomyelitis
Study Details
Study Description
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Midfoot Individuals with an infection on the midfoot are randomized to an intravenous antibacterial agent or an oral antibacterial agent. |
Drug: Intravenous Antibacterial Agent
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.
Other Names:
Drug: Oral Antibacterial Agent
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)
Other Names:
|
| Active Comparator: Hindfoot Individuals with an infection on the hindfoot are randomized to an intravenous antibacterial agent or an oral antibacterial agent. |
Drug: Intravenous Antibacterial Agent
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.
Other Names:
Drug: Oral Antibacterial Agent
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)
Other Names:
|
| Active Comparator: Toe Individuals with an infection on the toe are randomized to an intravenous antibacterial agent or an oral antibacterial agent. |
Drug: Intravenous Antibacterial Agent
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.
Other Names:
Drug: Oral Antibacterial Agent
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)
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Number of Participants With Bone Infection [Six Months]
Six months following completion of treatment, the researchers record evidence of bone infection for each participant. A negative diagnosis is made when there is (i) an absence of infection based on clinical examination and (ii) down-trending of inflammatory markers. Otherwise, a positive diagnosis is made.
Secondary Outcome Measures
- Number of Participants With Ulcer Resolution [Six Months]
Six months following completion of treatment, the researchers record whether each participant's ulcer has resolved.
Eligibility Criteria
Criteria
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)
Exclusion Criteria:
-
Absolute neutrophil count (ANC) < 500
-
Pregnant or lactating patients
-
Patients with organisms resistant to oral therapy
-
Internal hardware
-
Definitive amputations (BKA)
-
Limb ischemia [absent pedal pulses or ankle-brachial index (ABI) < 0.5]
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Loyola University Medical Center | Maywood | Illinois | United States | 60153 |
Sponsors and Collaborators
- Loyola University
Investigators
- Principal Investigator: Michael Pinzur, M.D., Loyola University
Study Documents (Full-Text)
More Information
Publications
- Bouazza N, Pestre V, Jullien V, Curis E, Urien S, Salmon D, Tréluyer JM. Population pharmacokinetics of clindamycin orally and intravenously administered in patients with osteomyelitis. Br J Clin Pharmacol. 2012 Dec;74(6):971-7. doi: 10.1111/j.1365-2125.2012.04292.x.
- Lazzarini L, Lipsky BA, Mader JT. Antibiotic treatment of osteomyelitis: what have we learned from 30 years of clinical trials? Int J Infect Dis. 2005 May;9(3):127-38. Review.
- Lipsky BA, Berendt AR, Cornia PB, Pile JC, Peters EJ, Armstrong DG, Deery HG, Embil JM, Joseph WS, Karchmer AW, Pinzur MS, Senneville E; Infectious Diseases Society of America. 2012 Infectious Diseases Society of America clinical practice guideline for the diagnosis and treatment of diabetic foot infections. Clin Infect Dis. 2012 Jun;54(12):e132-73. doi: 10.1093/cid/cis346.
- Pinzur MS, Gil J, Belmares J. Treatment of osteomyelitis in charcot foot with single-stage resection of infection, correction of deformity, and maintenance with ring fixation. Foot Ankle Int. 2012 Dec;33(12):1069-74. doi: DOI: 10.3113/FAI.2012.1069.
- Spellberg B, Lipsky BA. Systemic antibiotic therapy for chronic osteomyelitis in adults. Clin Infect Dis. 2012 Feb 1;54(3):393-407. doi: 10.1093/cid/cir842. Epub 2011 Dec 12. Review.
- 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. doi: 10.2337/dc12-2712. Review.
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Study Results
Participant Flow
| Recruitment Details | Participants were recruited from March 2014 through February 2017 (36 months) from a tertiary care practice |
|---|---|
| Pre-assignment Detail | Prior to randomization, 16 participants were excluded because they tested positive for organisms that were resistant to oral antibiotic therapy. Additionally, one participant withdrew prior to randomization and one participant was excluded prior to randomization due to a definitive amputation. |
| Arm/Group Title | Oral Antibacterial Agent | Intravenous Antibacterial Agent |
|---|---|---|
| Arm/Group Description | Individuals in this arm were randomized to an oral antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an oral antibacterial agent as determined by their primary healthcare provider. This therapy was 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) | Individuals in this arm were randomized to an intravenous antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy was 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. |
| Period Title: Overall Study | ||
| STARTED | 5 | 7 |
| COMPLETED | 3 | 5 |
| NOT COMPLETED | 2 | 2 |
Baseline Characteristics
| Arm/Group Title | Intravenous Antibacterial Agent | Oral Antibacterial Agent | Total |
|---|---|---|---|
| Arm/Group Description | Individuals in this arm were randomized to an intravenous antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy was 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. | Individuals in this arm were randomized to an oral antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an oral antibacterial agent as determined by their primary healthcare provider. This therapy was 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) | Total of all reporting groups |
| Overall Participants | 7 | 5 | 12 |
| Age (years) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [years] |
56.18
|
45.86
|
54.60
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
0
0%
|
0
0%
|
0
0%
|
| Male |
7
100%
|
5
100%
|
12
100%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
2
28.6%
|
1
20%
|
3
25%
|
| Not Hispanic or Latino |
5
71.4%
|
4
80%
|
9
75%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
1
14.3%
|
2
40%
|
3
25%
|
| White |
4
57.1%
|
3
60%
|
7
58.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
2
28.6%
|
0
0%
|
2
16.7%
|
| Region of Enrollment (participants) [Number] | |||
| United States |
7
100%
|
5
100%
|
12
100%
|
| Comorbid Diabetes (Count of Participants) | |||
| No |
0
0%
|
0
0%
|
0
0%
|
| Yes |
7
100%
|
5
100%
|
12
100%
|
| Comorbid Peripheral Vascular Disease (Count of Participants) | |||
| No |
6
85.7%
|
5
100%
|
11
91.7%
|
| Yes |
1
14.3%
|
0
0%
|
1
8.3%
|
| Comorbid Coronary Artery Disease (Count of Participants) | |||
| No |
6
85.7%
|
4
80%
|
10
83.3%
|
| Yes |
1
14.3%
|
1
20%
|
2
16.7%
|
| Comorbid Chronic Kidney Disease (Count of Participants) | |||
| No |
7
100%
|
4
80%
|
11
91.7%
|
| Yes |
0
0%
|
1
20%
|
1
8.3%
|
| Comorbid Hypertension (Count of Participants) | |||
| No |
2
28.6%
|
2
40%
|
4
33.3%
|
| Yes |
5
71.4%
|
3
60%
|
8
66.7%
|
| Comorbid Heart Disease (Count of Participants) | |||
| No |
7
100%
|
4
80%
|
11
91.7%
|
| Yes |
0
0%
|
1
20%
|
1
8.3%
|
| Comorbid Hyperlipidemia (Count of Participants) | |||
| No |
3
42.9%
|
3
60%
|
6
50%
|
| Yes |
4
57.1%
|
2
40%
|
6
50%
|
| Comorbid Thyroid Disorder (Count of Participants) | |||
| No |
7
100%
|
5
100%
|
12
100%
|
| Yes |
0
0%
|
0
0%
|
0
0%
|
| Comorbid Depression (Count of Participants) | |||
| No |
7
100%
|
5
100%
|
12
100%
|
| Yes |
0
0%
|
0
0%
|
0
0%
|
| Comorbid Cancer (Count of Participants) | |||
| No |
7
100%
|
5
100%
|
12
100%
|
| Yes |
0
0%
|
0
0%
|
0
0%
|
| History of Stroke (Count of Participants) | |||
| No |
7
100%
|
5
100%
|
12
100%
|
| Yes |
0
0%
|
0
0%
|
0
0%
|
| History of Heart Attack (Count of Participants) | |||
| No |
7
100%
|
5
100%
|
12
100%
|
| Yes |
0
0%
|
0
0%
|
0
0%
|
| Comorbid Obesity (Count of Participants) | |||
| No |
6
85.7%
|
5
100%
|
11
91.7%
|
| Yes |
1
14.3%
|
0
0%
|
1
8.3%
|
Outcome Measures
| Title | Number of Participants With Bone Infection |
|---|---|
| Description | Six months following completion of treatment, the researchers record evidence of bone infection for each participant. A negative diagnosis is made when there is (i) an absence of infection based on clinical examination and (ii) down-trending of inflammatory markers. Otherwise, a positive diagnosis is made. |
| Time Frame | Six Months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population comprises all randomized participants who had a six month follow-up appointment. |
| Arm/Group Title | Intravenous Antibacterial Agent | Oral Antibacterial Agent |
|---|---|---|
| Arm/Group Description | Individuals in this arm were randomized to an intravenous antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy was 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. | Individuals in this arm were randomized to an oral antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an oral antibacterial agent as determined by their primary healthcare provider. This therapy was 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) |
| Measure Participants | 5 | 3 |
| Bone Infection Negative |
5
71.4%
|
3
60%
|
| Bone Infection Positive |
0
0%
|
0
0%
|
| Title | Number of Participants With Ulcer Resolution |
|---|---|
| Description | Six months following completion of treatment, the researchers record whether each participant's ulcer has resolved. |
| Time Frame | Six Months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The analysis population comprises all randomized participants who had a six month follow-up appointment. |
| Arm/Group Title | Intravenous Antibacterial Agent | Oral Antibacterial Agent |
|---|---|---|
| Arm/Group Description | Individuals in this arm were randomized to an intravenous antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy was 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. | Individuals in this arm were randomized to an oral antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an oral antibacterial agent as determined by their primary healthcare provider. This therapy was 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) |
| Measure Participants | 5 | 3 |
| Not Resolved |
5
71.4%
|
2
40%
|
| Resolved |
0
0%
|
1
20%
|
Adverse Events
| Time Frame | Adverse event data were collected from March 2014 through February 2017 (36 months) | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | ||||
| Arm/Group Title | Intravenous Antibacterial Agent | Oral Antibacterial Agent | ||
| Arm/Group Description | Individuals in this arm were randomized to an intravenous antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an intravenous antibacterial agent as determined by their primary healthcare provider. This therapy was 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. | Individuals in this arm were randomized to an oral antibacterial agent. They were not assigned to specific medications. Instead, individuals in this arm received an oral antibacterial agent as determined by their primary healthcare provider. This therapy was 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) | ||
All Cause Mortality |
||||
| Intravenous Antibacterial Agent | Oral Antibacterial Agent | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 0/5 (0%) | ||
Serious Adverse Events |
||||
| Intravenous Antibacterial Agent | Oral Antibacterial Agent | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 0/5 (0%) | ||
Other (Not Including Serious) Adverse Events |
||||
| Intravenous Antibacterial Agent | Oral Antibacterial Agent | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/7 (0%) | 1/5 (20%) | ||
| Blood and lymphatic system disorders | ||||
| Hyperkalemia | 0/7 (0%) | 0 | 1/5 (20%) | 1 |
Limitations/Caveats
More Information
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Michael Pinzur, M.D. |
|---|---|
| Organization | Loyola University Medical Center |
| Phone | 708-216-4993 |
| mpinzu1@lumc.edu |
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