Oral vs IV Antibiotics for Infected Broken Bones

(POvIV2 Trial)

Recruiting at 10 trial locations

Overseen By Karen Trochez

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Major Extremity Trauma Research Consortium

Must be taking: Antibiotics

Disqualifiers: Amputation risk, Investigational therapy, Incarceration, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 5

Duration: 6 weeks

250 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a Phase III clinical randomized control trial to investigate differences between patient with an infected nonunion treated by PO vs. IV antibiotics. The study population will be 250 patients, 18 years or older, being treated for infected nonunion after internal fixation of a fracture with a segmental defect less than one centimeter. Patients will be randomly assigned to either the treatment (group 1) PO antibiotics for 6 weeks or the control group (group 2) IV antibiotics for 6 weeks. The primary hypothesis is that the effectiveness of oral antibiotic therapy is equivalent to traditional intravenous antibiotic therapy for the treatment of infected nonunion after fracture internal fixation, when such therapy is combined with appropriate surgical management. Clinical effectiveness will be measured as the primary outcome as the number of secondary re-admissions related to injury and secondary outcomes of treatment failure (re-infection, nonunion, antibiotic complications) within the first one year of follow-up, as defined by specified criteria and determined by a blinded data assessment panel. In addition, treatment compliance, the cost of treatment, the number of surgeries required, the type and incidence of complications, and the duration of hospitalization will be measured.

Will I have to stop taking my current medications?

The trial information does not specify whether you need to stop taking your current medications. It is best to discuss this with the trial coordinators or your doctor.

What data supports the effectiveness of oral versus intravenous antibiotics for treating infected broken bones?

Research shows that oral antibiotics can be as effective as intravenous antibiotics for bone and joint infections, with similar cure rates observed in conditions like osteomyelitis (a bone infection). This suggests that oral antibiotics might work just as well for treating infected broken bones. ^{1 2 3 4 5}

Is it safe to use oral antibiotics instead of intravenous antibiotics for treating infections?

Research suggests that oral antibiotics can be a safe alternative to intravenous antibiotics for certain infections, as they have been shown to achieve safe levels in the body and are generally well-tolerated. Studies indicate that oral antibiotics may have fewer complications compared to intravenous ones, and they are considered safe for use in stable patients. ^{4 6 7 8 9}

How do oral and intravenous antibiotics differ for treating infected broken bones?

This treatment is unique because it compares oral antibiotics, which are taken by mouth, to intravenous antibiotics, which are given through a vein, for treating infected broken bones. Research suggests that oral antibiotics can be just as effective as intravenous ones, offering a more convenient option without compromising outcomes. ^{1 2 4 5 10}

Research Team

William Obremskey, MD

Principal Investigator

Vanderbilt Medical Center

Renan Castillo, PhD

Principal Investigator

Johns Hopkins Bloomberg School of Public Health

Eligibility Criteria

This trial is for adults over 18 with infected nonunion fractures after internal fixation, which haven't healed properly despite previous surgery. Participants must need at least 6 weeks of antibiotics and meet specific infection criteria. Those not fitting this description or having other conditions that could interfere with the study are excluded.

Inclusion Criteria

My broken bone hasn't healed properly after surgery and it's been over 3 months.

I have an infection confirmed by a doctor and am on antibiotics for 6+ weeks.

Exclusion Criteria

Patients with a high risk of amputation based on the initial managing physician

Incarcerated or institutionalized patients

Patients with a prior history of chronic infection at the index site before fracture fixation

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive either oral (PO) or intravenous (IV) antibiotics for 6 weeks post hospitalization for infected nonunion

6 weeks

Visits at 2 weeks and 6 weeks for laboratory evaluation and clinical follow-up

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments for re-hospitalization, treatment failure, infection, nonunion, and amputation

12 months

Follow-up visits at 3 months, 6 months, and 12 months

Treatment Details

Interventions

• IV antibiotics
• PO antibiotics

Trial Overview The trial compares oral (PO) versus intravenous (IV) antibiotics in treating infected nonunion fractures after surgical bone repair. It aims to determine if taking pills is as effective as IV treatment when combined with proper surgery. Outcomes include re-admission rates, treatment failure, complications within a year, and overall costs.

Participant Groups

Group I: Standard of Care Intravenous (IV) antibiotics Active Control 1 Intervention

An intervention in this study includes randomization of patients with an infected nonunion to intravenous (IV) antibiotics for up to 6 weeks post hospitalization. No medications will be provided by the study. Study participants will be prescribed their IV antibiotics by their treating physician and the specific type will depend on their infection diagnosis. Medications will be obtained using health insurance and/or resources available at the treating facility therefore the mode of antibiotics utilized as standard of care will vary across participating sites. Sites will follow their standard of care delivery for antibiotics and the study will defer to this standard.

Group II: Standard of Care PO (oral) antibiotics Active Control 1 Intervention

An intervention in this study includes randomization of patients with an infected nonunion to standard of care PO (oral) antibiotics for up to 6 weeks post hospitalization. No medications will be provided by the study. Study participants will be prescribed their oral antibiotics by their treating physician and the specific type will depend on their infection diagnosis. Medications will be obtained using health insurance and/or resources available at the treating facility therefore the mode of antibiotics utilized as standard of care will vary across participating sites. Sites will follow their standard of care delivery for antibiotics and the study will defer to this standard.

Who Is Running the Clinical Trial?

Major Extremity Trauma Research Consortium

Lead Sponsor

Trials

32

Recruited

27,400+

United States Department of Defense

Collaborator

Trials

940

Recruited

339,000+

Findings from Research

A study involving 1054 adults with bone and joint infections found that oral antibiotics are just as effective as intravenous antibiotics for the first 6 weeks of treatment, with a treatment failure rate of 14.62% for IV therapy compared to 13.16% for oral therapy, meeting the non-inferiority criterion.

Oral therapy was associated with fewer complications, particularly fewer IV catheter-related issues, and was more cost-effective, saving approximately £2740 per patient without compromising quality of life.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT. Scarborough, M., Li, HK., Rombach, I., et al.[2021]

In a study of 1054 adults with complex orthopedic infections, oral antibiotic therapy was found to be noninferior to intravenous therapy, with a treatment failure rate of 13.2% for oral antibiotics compared to 14.6% for intravenous antibiotics, indicating similar effectiveness.

The incidence of serious adverse events was comparable between the two groups, but catheter complications were significantly more common in the intravenous group (9.4% vs. 1.0%), suggesting that oral antibiotics may offer a safer alternative.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral versus Intravenous Antibiotics for Bone and Joint Infection. Li, HK., Rombach, I., Zambellas, R., et al.[2022]

A quality improvement initiative at a large children's hospital successfully increased the discharge rate of patients with acute osteomyelitis on oral antibiotics from virtually 0% to a maximum of 9 cases, achieving a goal of at least 70%.

The intervention demonstrated that treatment failures and complications remained low, with no significant differences in hospital length of stay or charges, indicating that oral antibiotics are a safe and effective alternative to intravenous therapy for this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral antibiotics at discharge for children with acute osteomyelitis: a rapid cycle improvement project. Brady, PW., Brinkman, WB., Simmons, JM., et al.[2021]

In a study of 95 children treated for acute osteomyelitis, the university hospital had a higher rate of intravenous antibiotic use at discharge (95%) compared to the county hospital (65%), indicating a potential difference in treatment practices.

Despite the higher use of intravenous antibiotics at the university hospital, the recurrence and complication rates were not significantly different from the county hospital, suggesting that oral antibiotics may be a viable alternative and warrant further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous versus oral outpatient antibiotic therapy for pediatric acute osteomyelitis. Liu, RW., Abaza, H., Mehta, P., et al.[2021]

In a study of 58 children with febrile neutropenia, there was no significant difference in treatment outcomes between oral antibiotic therapy (ciprofloxacin and amoxicillin-clavulanate) and intravenous therapy (cefepime), with treatment failure rates of 51.2% and 45.8%, respectively.

Both treatment groups had similar lengths of hospital stays, averaging around 7 to 8 days, indicating that oral therapy may not be less effective than intravenous therapy, but further research is needed to establish oral therapy as a standard treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral vs. intravenous empirical antimicrobial therapy in febrile neutropenic patients receiving childhood cancer chemotherapy. Cagol, AR., Castro Junior, CG., Martins, MC., et al.[2020]

Current guidelines recommend 4-6 weeks of IV antibiotics for infective endocarditis (IE), but recent evidence suggests that oral antibiotics can achieve safe and effective serum levels, challenging the need for prolonged IV therapy.

The largest randomized controlled trial, the POET trial, found that oral therapy is non-inferior to prolonged IV therapy in stable patients with left-sided IE, supporting a potential shift towards oral antibiotics as a viable treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Oral antibiotics for infective endocarditis: a clinical review. Brown, E., Gould, FK.[2021]

A set of 16 measurable conditions for safely switching from intravenous to oral antibiotics in hospitalized adults was developed through a rigorous expert panel process, ensuring clinical relevance and safety.

Key criteria include stable blood pressure, absence of severe infections or gastrointestinal issues, and the ability to achieve adequate drug concentrations orally, which can enhance clinical decision-making and improve patient outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Development of operationalized intravenous to oral antibiotic switch criteria. Akhloufi, H., Hulscher, M., Melles, DC., et al.[2022]

A systematic review of five studies involving 580 patients found that sequential IV/PO antibiotic therapy does not increase the risk of complications compared to continuous IV antibiotics, indicating it is a safe alternative.

The study shows that using sequential IV/PO antibiotics is noninferior to IV-only therapy in preventing postoperative abscesses, wound infections, and readmissions, suggesting it could be a cost-effective treatment option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous versus intravenous/oral antibiotics for perforated appendicitis in pediatric patients: a systematic review and meta-analysis. Wang, C., Li, Y., Ji, Y.[2020]

A systematic review of 10 studies found no significant difference in the overall rate of adverse events between oral and intravenous antimicrobial therapies, suggesting that both routes are similarly safe.

Injection site reactions were more common with intravenous therapy, but no serious drug-related adverse events were reported, indicating that both methods are generally well-tolerated.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of adverse events between oral and intravenous formulations of antimicrobial agents: a systematic review of the evidence from randomized trials. Kouranos, VD., Karageorgopoulos, DE., Peppas, G., et al.[2018]

In a study of 328 patients with bone and joint infections, implementing the OVIVA trial findings allowed 66.1% of patients to switch to effective oral antibiotics, demonstrating that oral therapy is a viable alternative to intravenous treatment in real-world settings.

Postimplementation, patients experienced a 4-day reduction in hospital stay and a significant cost savings of £2764.28 per patient, while the rate of adverse drug reactions requiring treatment changes increased from 21.0% to 37.1%.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clinical Experience of Implementing Oral Versus Intravenous Antibiotics (OVIVA) in a Specialist Orthopedic Hospital. Azamgarhi, T., Shah, A., Warren, S.[2021]

References

1. England pubmed.ncbi.nlm.nih.gov

Oral versus intravenous antibiotics for bone and joint infections: the OVIVA non-inferiority RCT. [2021]

2. United States pubmed.ncbi.nlm.nih.gov

Oral versus Intravenous Antibiotics for Bone and Joint Infection. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Oral antibiotics at discharge for children with acute osteomyelitis: a rapid cycle improvement project. [2021]

4. United States pubmed.ncbi.nlm.nih.gov

Intravenous versus oral outpatient antibiotic therapy for pediatric acute osteomyelitis. [2021]

5. Brazil pubmed.ncbi.nlm.nih.gov

Oral vs. intravenous empirical antimicrobial therapy in febrile neutropenic patients receiving childhood cancer chemotherapy. [2020]

6. England pubmed.ncbi.nlm.nih.gov

Oral antibiotics for infective endocarditis: a clinical review. [2021]

7. England pubmed.ncbi.nlm.nih.gov

Development of operationalized intravenous to oral antibiotic switch criteria. [2022]

8. England pubmed.ncbi.nlm.nih.gov

Intravenous versus intravenous/oral antibiotics for perforated appendicitis in pediatric patients: a systematic review and meta-analysis. [2020]

9. England pubmed.ncbi.nlm.nih.gov

Comparison of adverse events between oral and intravenous formulations of antimicrobial agents: a systematic review of the evidence from randomized trials. [2018]

10. United States pubmed.ncbi.nlm.nih.gov

Clinical Experience of Implementing Oral Versus Intravenous Antibiotics (OVIVA) in a Specialist Orthopedic Hospital. [2021]