The Utility of Levofloxacin-Rifampin in the Therapy of Prosthetic Joint Infection

Condition(s) targeted: Staphylococcal Infection; Staphylococcus Aureus Prosthetic Joint Infection

Phase: N/A

Status: Recruiting

Sponsored by: Mayo Clinic

Official(s) and/or principal investigator(s):
Elie F. Berbari, M.D., Principal Investigator, Affiliation: Mayo Clinic

Prosthetic joint infection is a devastating complication of total joint arthroplasty ultimately leading to the failure of the total joint arthroplasty function and possibly death. Optimal treatment requires the resection of the infected total joint arthroplasty followed by prolonged parenteral antimicrobial therapy. This procedure is followed by reimplantation of a new total joint arthroplasty at a later date. Surgical debridement and retention of the infected total joint arthroplasty offers a more conservative surgical approach and has been proven to be cost-effective in selected groups of patients. Traditional medical therapy for staphylococcal infection would require an initial parenteral antimicrobial followed by chronic oral non-rifampin containing antimicrobial suppression regimen for the life of the total joint arthroplasty. With this strategy the success rate is close to 30%. Recently, several prospective studies of patients with THA, TKA and fracture fixation device infections conducted in Europe showed that the success rate with a 3-6 month course of a quinolone-rifampin combination is effective in 70% to 100% of cases. The proposed study will be a prospective open label observational cohort that will evaluate the outcome of Patients with S. aureus PJI treated with a medical regimen that includes oral levofloxacin- rifampin and debridement and retention of components. This medical regimen was approved for use by the Orthopedic Infectious Diseases focus group, Mayo Clinic, Rochester. 15 patients will be enrolled over a one-year period and followed up to minimum of 1 additional year. The outcome of this group will be compared to a historical group that is treated with traditional therapy.

Official title: Prolonged Oral Levofloxacin-Rifampin for Staphylococcus Aureus Prosthetic Joint Infection (PJI) Treated With Debridement And Retention Of Components: A Prospective Observational Cohort Study. Mayo PJI Study Group (MPSG)*

Study design: Longitudinal, Defined Population, Prospective Study

Detailed description:

- Specific Aims The risk of a prosthetic joint infection (PJI) following the estimated

540,000 total hip (THA) and total knee arthroplasties (TKA) performed in the United States each year is 0. 5-4%. PJI may lead to total joint arthroplasty removal or loss of function, and is associated with a mortality rate of 3 to 18 percent (1,2,3,4,5,6,7,8,9,10,11). Treatment often requires removal of the infected total joint arthroplasty and prolonged intravenous antimicrobial therapy. The cost of each episode is estimated to be in excess of $50,000 (12). Previous investigators including ourselves have evaluated the success rate of a conservative surgical approach using debridement and retention of components followed by chronic antimicrobial suppression using a non rifampin containing regimen. The reported success rate using this strategy has been between 30 to 50%. Several characteristics of patients with PJI such as acute onset of symptoms, early postoperative infection, and infection other than with S. aureus have been identified as predictors of good outcome. Rifampin is an antimicrobial agent that has several pharmacologic and intrinsic properties that would allow it to kill bacteria that are present in the sessile form. This form of bacteria is typically present in biofilms on the surface of prosthetic joints. Emergence of resistance with the use of rifampin monotherapy has led investigators to combine rifampin with a other antimicrobials including quinolones. Cohort studies performed in Europe looking at the efficacy of a rifampin-quinolone combinations have shown that the success rate of staphylococcal implant infection treated with debridement and retention of components is between 80% to 100%. Thus, the purpose of this study is to determine if in staphylococcal PJI treated with debridement and retention of components a levofloxacin-rifampin combination is more effective than the traditional therapy that would use prolonged non-rifampin containing oral regimen.

Objectives 1. To calculate the cumulative probability of success in-patients with Staphylococcus aureus PJI treated with debridement and retention of components followed by a prolonged course of Levofloxacin-Rifampin and chronic oral antimicrobial suppression. 2. To compare the efficacy of Levofloxacin-Rifampin (current cohort) vs traditional antimicrobial therapy (historical cohort from the preceding year) in patients with Staphylococcus aureus prosthetic joint infection treated with debridement and retention of components. 3. To examine the safety of Levofloxacin-Rifampin therapy in patients with Staphylococcus aureus prosthetic joint infection treated with debridement and retention of components.

II. Preliminary Studies A recent analysis of 29 THA infection and 36 TKA infection treated at Mayo between December 2001 and July 2002 revealed that 12/36 and 6/29 were treated with retention of components. 44/65 of these episodes were due to S. aureus or SCN (unpublished data). Furthermore, 38 of these 44 staphylococcal isolates causing PJI seen at our institution were sensitive to all tested quinolones (ciprofloxacin, levofloxacin, gatifloxacin) and 42/44 were sensitive to Rifampin. Therefore assuming that 68% of our PJI episodes are staphylococcal and assuming that 28% of our PJI episodes are débrided and retained, then 19 episodes of PJI would be eligible for enrollment in this study per year. Assuming a 20 % refusal rate or not meeting the eligibility criteria then one can enroll close to 15 patients in the first year.

III. Research Design and Methods

a. Study Design or Overview This study is a prospective cohort observational study that will evaluate the outcome of patients with S. aureus PJI treated with debridement and retention of components followed by levofloxacin-rifampin combination according to recently approved guidelines by the orthopedic infectious diseases service at the Mayo Clinic in Rochester, MN (Appendix I). The outcome of this cohort will be compared to a historical cohort between 2000-2004. Prior to the adoption of the newer practice guidelines, the patients were typically treated using a non-quinolones non rifampin regimen (Table I). Patients will be enrolled over a 1-year period with an additional 1-year of prospective follow-up.

Inclusion criteria 1. Male or female inpatients or outpatients, age 18 years or older with a S. aureus total hip or total knee arthroplasty infection (see case definition below) treated with debridement and retention of any component(s). 2. Patients enrollment must occur within one week of the first surgical debridement 3. Patients must meet the following case definition of prosthetic joint infection: A. 2 positive cultures from a joint aspirate or deep intraoperative culture or B. One positive culture from a joint aspirate or deep intraoperative culture plus either purulence observed at the time of intraoperative inspection or acute inflammation present on histopathologic examination 5. The organism isolated from a joint aspirate or deep intraoperative cultures must be susceptible to ciprofloxacin, levofloxacin, moxifloxacin and Rifampin and the appropriate parenteral antimicrobial therapy (see table I).

6. Consent must be obtained prior to study entry from all patients or their legal guardians. b. 3 Exclusion Criteria 1. Less than 2 years of expected life survival. 2. Intraoperative signs of implant loosening. 3. Being on an effective antimicrobial treatment of more than 1 week after the initial surgical debridement. 4. Patients who are thought to have co-existing medical conditions that would preclude evaluation of a therapeutic response or impair the patient’s ability to take oral medication in tablet or capsule form. 5. Patients with significant renal dysfunction (creatinine clearance * 10 mL/min) or those who are suspected to have acutely deteriorating renal function at the time of enrollment. 6. Patients with significant hepatic dysfunction (AST /ALT * 3x or total bilirubin * 2x the upper limit of normal) or a history of cirrhosis or chronic hepatitis. 7. Patients who have been previously enrolled in the study. 8. Inability to comply with treatment arm and follow up visits.

c- Sample Size Several primary and secondary endpoints will be used to evaluate the relative efficacy of our current guidelines vs historical controls in the treatment of S. aureus prosthetic joint infection treated with debridement and retention. For the purpose of sample size calculation the time free of clinical failure evaluated at one year will be considered the primary outcome variable. Based on the study performed by Zimmerli et al patients treated with the rifampin arm had a 100% success rate while the patients treated with the ciprofloxacin-placebo arm had a 58% success rate. These calculations are based on an alpha of 0. 05 and a beta of 0. 2. Therefore assuming a 5% failure rate in the rifampin-levofloxacin arm and 40-50% failure rate the traditional arm at a minimum of 1 year of follow-up respectively, one would need sample sizes of 18 or 14 in each group.

d- Data Analysis Distribution of covariates in both groups will be checked to confirm the comparability of the two groups. The groups will be compared by the chi-square test or Fisher's exact test for categorical. A separate analysis that includes only those patients who complete a full course of antimicrobial therapy will also be performed.

The probabilities of clinical failure and their standard errors will be estimated by the techniques of survival analysis. A comparison of the overall efficacy between the two groups at 6 months, 1 year and end of study will be made using the log rank test or the Peto-Peto Wilcoxon test. Comparative analyses adjusted for covariates by the appropriate regression methods (i. e. Cox's proportional hazards model) will also be performed. Subgroups of special interest will also be analyzed (i. e. patients with TKA infection, diabetes mellitus, rheumatoid arthritis, etc.). Other outcome variable comparisons between treatment groups (), where follow-up is complete, will be performed using the chi-square test or Fisher's exact test for categorical variables and by the Student's T test or the Wilcoxon rank-sum test for continuous variables. When multiple comparison procedures are required one way analysis of variance methods and Kruskal-Wallis test will be employed. Comparative analyses adjusted for covariates by the appropriate regression methods (i. e. a logistic or linear regression models) will also be performed.

e- Feasibility and Time Frame Based on our conservative estimates approximately 15 patients with Staphylococcus aureus PJI are treated yearly at Mayo with debridement and retention of components. Allowing a one year follow up period after enrollment and based on these conservative estimates we will need a maximum of two years to finish the study. An additional 3-month period is needed for data analysis and manuscript preparation.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

Criteria:

A maximum of 15 adult participants with total hip or total knee arthroplasty are approved for enrollment in this protocol at Mayo Clinic Rochester.

Mayo Clinic, Rochester, Minnesota 55905, United States; Recruiting
Dori Greene, Phone: 507-255-6482, Email: Greene.dori@mayo.edu
Elie F Berbari, MD, Principal Investigator

Starting date: September 2005
Last updated: January 18, 2006