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Rifampin for Prosthetic Joint Infections: Lessons Learned Over 20 Years at a VA Medical Center
Orthopedic implants are frequently used to repair fractures and replace joints. The number of total joint replacements is high, with > 1 million total hip (THA) and total knee (TKA) arthroplasties performed in the United States each year.1 While most joint arthroplasties are successful and significantly improve patient quality of life, a small proportion become infected.2 Prosthetic joint infection (PJI) causes substantial morbidity and mortality, particularly among older patients, and is difficult and costly to treat.3
The historic gold standard treatment for PJI is a 2-stage replacement, wherein the prosthesis is removed in one procedure and a new prosthesis is implanted in a second procedure after an extended course of antibiotics. This approach requires the patient to undergo 2 major procedures and spend considerable time without a functioning prosthesis, contributing to immobility and deconditioning. This option is difficult for frail or older patients and is associated with high medical costs.4
In 1998, a novel method of treatment known as debridement, antibiotics, and implant retention (DAIR) was evaluated in a small, randomized controlled trial.5 This study used a unique antimicrobial approach: the administration of ciprofloxacin plus either rifampin or placebo for 3 to 6 months, combined with a single surgical debridement. Eliminating a second surgical procedure and largely relying on oral antimicrobials reduces surgical risks and decreases costs.4 Current guidelines endorse DAIR with rifampin and a second antibiotic for patients diagnosed with PJI within about 30 days of prosthesis implantation who have a well-fixed implant without evidence of a sinus tract.6 Clinical trial data demonstrate that this approach is > 90% effective in patients with a well-fixed prosthesis and acute staphylococcal PJI.3,7
Thus far, clinical trials examining this approach have been small and did not include veterans who are typically older and have more comorbidities.8 The Minneapolis Veterans Affairs Health Care System (MVAHCS) infectious disease section has implemented the rifampin-based DAIR approach for orthopedic device-related infections since this approach was first described in 1998 but has not systematically evaluated its effectiveness or whether there are areas for improvement.
METHODS
We conducted a retrospective analysis of patients who underwent DAIR combined with a rifampin-containing regimen at the MVAHCS from January 1, 2001, through June 30, 2021. Inclusion required a diagnosis of orthopedic device-related infection and treatment with DAIR followed by antimicrobial therapy that included rifampin for 1 to 6 months. PJI was defined by meeting ≥ 1 of the following criteria: (1) isolation of the same microorganism from ≥ 2 cultures from joint aspirates or intraoperative tissue specimens; (2) purulence surrounding the prosthesis at the time of surgery; (3) acute inflammation consistent with infection on histopathological examination or periprosthetic tissue; or (4) presence of a sinus tract communicating with the prosthesis.
All cases of orthopedic device infection managed with DAIR and rifampin were included, regardless of implant stability, age of the implant at the time of symptom onset, presence of a sinus tract, or infecting microorganism. Exclusion criteria included patients who started or finished PJI treatment at another facility, were lost to follow-up, discontinued rifampin, died within 1 year of completing antibiotic therapy due to reasons unrelated to treatment failure, received rifampin for < 50% of their antimicrobial treatment course, had complete hardware removal, or had < 1 year between the completion of antimicrobial therapy and the time of data collection.
Management of DAIR procedures at the MVAHCS involves evaluating the fixation of the prosthesis, tissue sampling for microbiological analysis, and thorough debridement of infected tissue. Following debridement, a course of IV antibiotics is administered before initiating oral antibiotic therapy. To protect against resistance, rifampin is combined with another antibiotic typically from the fluoroquinolone, tetracycline, or cephalosporin class. Current guidelines suggest 3 and 6 months of oral antibiotics for prosthetic hip and knee infections, respectively.6
Treatment Outcomes
The primary outcome was treatment success, defined as meeting all of the following: (1) lack of clinical signs and symptoms of infection; (2) absence of radiological signs of loosening or infection within 1 year after the conclusion of treatment; and (3) absence of additional PJI treatment interventions for the prosthesis of concern within 1 year after completing the original antibiotic treatment.
Treatment failure was defined as meeting any of the following: (1) recurrence of PJI (original strain or different microorganism) within 1 year after the completion of antibiotic therapy; (2) death attributed to PJI anytime after the initial debridement; (3) removal of the prosthetic joint within 1 year after the completion of antibiotic therapy; or (4) long-term antibiotic use to suppress the PJI after the completion of the initial antibiotic therapy.
Statistical Analysis
Descriptive statistics were used to define the baseline characteristics of patients receiving rifampin therapy for orthopedic implant infections at the MVAHCS. Variables analyzed were age, sex, race and ethnicity, type of implant, age of implant, duration of symptoms, comorbidities (diabetes and rheumatoid arthritis), and presence of chronic infection. Patients were classified as having a chronic infection if they received previous infection treatment (antibiotics or surgery) for the orthopedic device in question. We created this category because patients with persistent infection after a medical or surgical attempt at treatment are likely to have a higher probability of treatment failure compared with those with no prior therapy. Charlson Comorbidity Index was calculated using clinical information present at the onset of infection.9 Fisher exact test was used to assess differences between categorical variables, and an independent t test was used to assess differences in continuous variables. P < .05 indicated statistical significance.
To assess the ability of a rifampin-based regimen to achieve a cure of PJI, we grouped participants into 2 categories: those with an intent to cure strategy and those without intent to cure based on documentation in the electronic health record (EHR). Participants who were prescribed rifampin with the documented goal of prosthesis retention with no further suppressive antibiotics were included in the intent-to-cure group, the primary focus of this study. Those excluded from the intent-to-cure group were given rifampin and another antibiotic, but there was a documented plan of either ongoing chronic suppression or eventual explantation; these participants were placed in the without-intent-to-cure group. Analysis of treatment success and failure was limited to the intent-to-cure group, whereas both groups were included for assessment of adverse effects (AEs) and treatment duration. This project was reviewed by the MVAHCS Institutional Review Board and determined to be a quality improvement initiative and to not meet the definition of research, and as such did not require review; it was reviewed and approved by the MVAHCS Research and Development Committee.
RESULTS
A total of 538 patients were identified who simultaneously received rifampin and another oral antibiotic between January 1, 2000, and June 30, 2021.
Forty-two participants (54%) had Staphylococcus aureus and 31 participants (40%) had coagulase-negative staphylococci infections, while 11 gram-negative organisms (14%) and 6 gram-positive anaerobic cocci (8%) infections were noted. Cutibacterium acnes and Streptococcus agalactiae were each found in 3 participants (4% of), and diphtheroids (not further identified) was found on 2 participants (3%). Candida albicans was identified in a single participant (1%), along with coagulase-negative staphylococci, and 2 participants (3%) had no identified organisms. There were multiple organisms isolated from 20 patients (26%).
Fifty participants had clear documentation in their EHR that cure of infection was the goal, meeting the criteria for the intent-to-cure group. The remaining 28 participants were placed in the without-intent-to-cure group. Success and failure rates were only measured in the intent-to-cure group, as by definition the without-intent-to-cure group patients would meet the criteria for failure (removal of prosthesis or long-term antibiotic use). The without-intent-to-cure group had a higher median age than the intent-to-cure group (69 years vs 64 years, P = .24) and a higher proportion of male participants (96% vs 80%, P = .09). The median (IQR) implant age of 11 months (1.0-50.5) in the without-intent-to-cure group was also higher than the median implant age of 1 month (0.6-22.0) in the primary group (P = .22). In the without-intent-to-cure group, 19 participants (68%) had a chronic infection, compared with 11 (22%) in the intent-to-cure group (P < .001).
The mean (SD) Charlson Comorbidity Index in the without-intent-to-cure group was 2.5 (1.3) compared with 1.9 (1.4) in the intent-to-cure group (P = .09). There was no significant difference in the type of implant or microbiology of the infecting organism between the 2 groups, although it should be noted that in the intent-to-cure group, 48 patients (96%) had Staphylococcus aureus or coagulase-negative staphylococci isolated.
The median (IQR) dosage of rifampin was 600 mg (300-900). The secondary oral antibiotics used most often were 36 fluoroquinolones (46%) followed by 20 tetracyclines (26%), 6 cephalosporins (8%), and 6 penicillins (8%). Additionally, 6 participants (8%) received IV vancomycin, and 1 participant (1%) was given an oral antifungal in addition to a fluoroquinolone because cultures revealed bacterial and fungal growth. The median (IQR) duration of antimicrobial therapy was 3 months (1.4-3.0). The mean (SD) duration of antimicrobial therapy was 3.6 (2.4) months for TKA infections and 2.4 (0.9) months for THA infections.
Clinical Outcome
Forty-one intent-to-cure group participants (82%) experienced treatment success. We further subdivided the intent-to-cure group by implant age. Participants whose implant was < 2 months old had a success rate of 93%, whereas patients whose implant was older had a success rate of 65% (P = .02).
Secondary Outcomes
The median (IQR) duration of antimicrobial treatment was 3 months (1.4-3.0) for the 38 patients with TKA-related infections and 3 months (1.4-6.0) for the 29 patients with THA infections. AEs were recorded in 24 (31%) of all study participants. Of those with AEs, the average number reported per patient was 1.6. Diarrhea, gastric upset, and nausea were each reported 7 times, accounting for 87% of all recorded AEs. Five participants reported having a rash while on antibiotics, and 2 experienced dysgeusia. One participant reported developing a yeast infection and another experienced vaginitis.
DISCUSSION
Among patients with orthopedic implant infections treated with intent to cure using a rifampin-containing antibiotic regimen at the MVAHCS, 82% had clinical success. Although this is lower than the success rates reported in clinical trials, this is not entirely unexpected.5,7 In most clinical trials studying DAIR and rifampin for PJI, patients are excluded if they do not have an acute staphylococcal infection in the setting of a well-fixed prosthesis without evidence of a sinus tract. Such exclusion criteria were not present in our retrospective study, which was designed to evaluate the real-world practice patterns at this facility. The population at the US Department of Veterans Affairs (VA) is older, more frail, and with more comorbid conditions than populations in prior studies. It is possible that patients with characteristics that would have caused them to be excluded from a clinical trial would be less likely to receive rifampin therapy with the intent to cure. This is suggested by the significantly higher prevalence of chronic infections (68%) in the without-intent-to-cure group compared with 22% in the intent-to-cure group. However, there were reasonably high proportions of participants included in the intent-to-cure group who did have conditions that would have led to their exclusion from prior trials, such as chronic infection (22%) and implant age ≥ 2 months (40%).
When evaluating participants by the age of their implant, treatment success rose to 93% for patients with implants < 2 months old compared with 65% for patients with older implants. This suggests that participants with a newer implant or more recent infection have a greater likelihood of successful treatment, which is consistent with the results of previous clinical trials.5,10 Considering how difficult multiple surgeries can be for older adult patients with comorbidities, we suggest that DAIR with a rifampin-containing regimen be considered as the primary treatment option for early PJIs at the MVAHCS. We also note inconsistent adherence to IDSA treatment guidelines on rifampin therapy, in that patients without intent to cure were prescribed a regimen including rifampin. This may reflect appropriate variability in the care of individual patients but may also offer an opportunity to change processes to improve care.
Limitations
Our analysis has limitations. As with any retrospective study evaluating the efficacy of a specific antibiotic, we were not able to attribute specific outcomes to the antibiotic of interest. Since the choice of antibiotics was left to the treating health care practitioner, therapy was not standardized, and because this was a retrospective study, causal relationships could not be inferred. Our analysis was also limited by the lack of intent to cure in 28 participants (36%), which could be an indication of practitioner bias in therapy selection or characteristic differences between the 2 groups. We looked for signs of infection failure 1 year after the completion of antimicrobial therapy, but longer follow-up could have led to higher rates of failure. Also, while participants’ infections were considered cured if they never sought further medical care for the infection at the MVAHCS, it is possible that patients could have sought care at another facility. We note that 9 patients were excluded because they were unable to complete a treatment course due to rifampin AEs, meaning that the success rates reported here reflect the success that may be expected if a patient can tolerate and complete a rifampin-based regimen. This study was conducted in a single VA hospital and may not be generalizable to nonveterans or veterans seeking care at other facilities.
Conclusions
DAIR followed by a short course of IV antibiotics and an oral regimen including rifampin and another antimicrobial is a reasonable option for veterans with acute staphylococcal orthopedic device infections at the MVAHCS. Patients with a well-placed prosthesis and an acute infection seem especially well suited for this treatment, and treatment with intent to cure should be pursued in patients who meet the criteria for rifampin therapy.
Acknowledgments
We thank Erik Stensgard, PharmD, for assistance in compiling the list of patients receiving rifampin and another antimicrobial.
1. Maradit Kremers H, Larson DR, Crowson CS, et al. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am. 2015;97(17):1386-1397. doi:10.2106/JBJS.N.01141
2. Kapadia BH, Berg RA, Daley JA, Fritz J, Bhave A, Mont MA. Periprosthetic joint infection. Lancet. 2016;387(10016):386-394. doi:10.1016/S0140-6736(14)61798-0
3. Zhan C, Kaczmarek R, Loyo-Berrios N, Sangl J, Bright RA. Incidence and short-term outcomes of primary and revision hip replacement in the United States. J Bone Joint Surg Am. 2007;89(3):526-533. doi:10.2106/JBJS.F.00952
4. Fisman DN, Reilly DT, Karchmer AW, Goldie SJ. Clinical effectiveness and cost-effectiveness of 2 management strategies for infected total hip arthroplasty in the elderly. Clin Infect Dis. 2001;32(3):419-430. doi:10.1086/318502
5. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279(19):1537-1541. doi:10.1001/jama.279.19.1537
6. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25. doi:10.1093/cid/cis803
7. Lora-Tamayo J, Euba G, Cobo J, et al. Short- versus long-duration levofloxacin plus rifampicin for acute staphylococcal prosthetic joint infection managed with implant retention: a randomised clinical trial. Int J Antimicrob Agents. 2016;48(3):310-316. doi:10.1016/j.ijantimicag.2016.05.021
8. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi:10.1001/archinte.160.21.3252
9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
10. Vilchez F, Martínez-Pastor JC, García-Ramiro S, et al. Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement. Clin Microbiol Infect. 2011;17(3):439-444. doi:10.1111/j.1469-0691.2010.03244.x
Orthopedic implants are frequently used to repair fractures and replace joints. The number of total joint replacements is high, with > 1 million total hip (THA) and total knee (TKA) arthroplasties performed in the United States each year.1 While most joint arthroplasties are successful and significantly improve patient quality of life, a small proportion become infected.2 Prosthetic joint infection (PJI) causes substantial morbidity and mortality, particularly among older patients, and is difficult and costly to treat.3
The historic gold standard treatment for PJI is a 2-stage replacement, wherein the prosthesis is removed in one procedure and a new prosthesis is implanted in a second procedure after an extended course of antibiotics. This approach requires the patient to undergo 2 major procedures and spend considerable time without a functioning prosthesis, contributing to immobility and deconditioning. This option is difficult for frail or older patients and is associated with high medical costs.4
In 1998, a novel method of treatment known as debridement, antibiotics, and implant retention (DAIR) was evaluated in a small, randomized controlled trial.5 This study used a unique antimicrobial approach: the administration of ciprofloxacin plus either rifampin or placebo for 3 to 6 months, combined with a single surgical debridement. Eliminating a second surgical procedure and largely relying on oral antimicrobials reduces surgical risks and decreases costs.4 Current guidelines endorse DAIR with rifampin and a second antibiotic for patients diagnosed with PJI within about 30 days of prosthesis implantation who have a well-fixed implant without evidence of a sinus tract.6 Clinical trial data demonstrate that this approach is > 90% effective in patients with a well-fixed prosthesis and acute staphylococcal PJI.3,7
Thus far, clinical trials examining this approach have been small and did not include veterans who are typically older and have more comorbidities.8 The Minneapolis Veterans Affairs Health Care System (MVAHCS) infectious disease section has implemented the rifampin-based DAIR approach for orthopedic device-related infections since this approach was first described in 1998 but has not systematically evaluated its effectiveness or whether there are areas for improvement.
METHODS
We conducted a retrospective analysis of patients who underwent DAIR combined with a rifampin-containing regimen at the MVAHCS from January 1, 2001, through June 30, 2021. Inclusion required a diagnosis of orthopedic device-related infection and treatment with DAIR followed by antimicrobial therapy that included rifampin for 1 to 6 months. PJI was defined by meeting ≥ 1 of the following criteria: (1) isolation of the same microorganism from ≥ 2 cultures from joint aspirates or intraoperative tissue specimens; (2) purulence surrounding the prosthesis at the time of surgery; (3) acute inflammation consistent with infection on histopathological examination or periprosthetic tissue; or (4) presence of a sinus tract communicating with the prosthesis.
All cases of orthopedic device infection managed with DAIR and rifampin were included, regardless of implant stability, age of the implant at the time of symptom onset, presence of a sinus tract, or infecting microorganism. Exclusion criteria included patients who started or finished PJI treatment at another facility, were lost to follow-up, discontinued rifampin, died within 1 year of completing antibiotic therapy due to reasons unrelated to treatment failure, received rifampin for < 50% of their antimicrobial treatment course, had complete hardware removal, or had < 1 year between the completion of antimicrobial therapy and the time of data collection.
Management of DAIR procedures at the MVAHCS involves evaluating the fixation of the prosthesis, tissue sampling for microbiological analysis, and thorough debridement of infected tissue. Following debridement, a course of IV antibiotics is administered before initiating oral antibiotic therapy. To protect against resistance, rifampin is combined with another antibiotic typically from the fluoroquinolone, tetracycline, or cephalosporin class. Current guidelines suggest 3 and 6 months of oral antibiotics for prosthetic hip and knee infections, respectively.6
Treatment Outcomes
The primary outcome was treatment success, defined as meeting all of the following: (1) lack of clinical signs and symptoms of infection; (2) absence of radiological signs of loosening or infection within 1 year after the conclusion of treatment; and (3) absence of additional PJI treatment interventions for the prosthesis of concern within 1 year after completing the original antibiotic treatment.
Treatment failure was defined as meeting any of the following: (1) recurrence of PJI (original strain or different microorganism) within 1 year after the completion of antibiotic therapy; (2) death attributed to PJI anytime after the initial debridement; (3) removal of the prosthetic joint within 1 year after the completion of antibiotic therapy; or (4) long-term antibiotic use to suppress the PJI after the completion of the initial antibiotic therapy.
Statistical Analysis
Descriptive statistics were used to define the baseline characteristics of patients receiving rifampin therapy for orthopedic implant infections at the MVAHCS. Variables analyzed were age, sex, race and ethnicity, type of implant, age of implant, duration of symptoms, comorbidities (diabetes and rheumatoid arthritis), and presence of chronic infection. Patients were classified as having a chronic infection if they received previous infection treatment (antibiotics or surgery) for the orthopedic device in question. We created this category because patients with persistent infection after a medical or surgical attempt at treatment are likely to have a higher probability of treatment failure compared with those with no prior therapy. Charlson Comorbidity Index was calculated using clinical information present at the onset of infection.9 Fisher exact test was used to assess differences between categorical variables, and an independent t test was used to assess differences in continuous variables. P < .05 indicated statistical significance.
To assess the ability of a rifampin-based regimen to achieve a cure of PJI, we grouped participants into 2 categories: those with an intent to cure strategy and those without intent to cure based on documentation in the electronic health record (EHR). Participants who were prescribed rifampin with the documented goal of prosthesis retention with no further suppressive antibiotics were included in the intent-to-cure group, the primary focus of this study. Those excluded from the intent-to-cure group were given rifampin and another antibiotic, but there was a documented plan of either ongoing chronic suppression or eventual explantation; these participants were placed in the without-intent-to-cure group. Analysis of treatment success and failure was limited to the intent-to-cure group, whereas both groups were included for assessment of adverse effects (AEs) and treatment duration. This project was reviewed by the MVAHCS Institutional Review Board and determined to be a quality improvement initiative and to not meet the definition of research, and as such did not require review; it was reviewed and approved by the MVAHCS Research and Development Committee.
RESULTS
A total of 538 patients were identified who simultaneously received rifampin and another oral antibiotic between January 1, 2000, and June 30, 2021.
Forty-two participants (54%) had Staphylococcus aureus and 31 participants (40%) had coagulase-negative staphylococci infections, while 11 gram-negative organisms (14%) and 6 gram-positive anaerobic cocci (8%) infections were noted. Cutibacterium acnes and Streptococcus agalactiae were each found in 3 participants (4% of), and diphtheroids (not further identified) was found on 2 participants (3%). Candida albicans was identified in a single participant (1%), along with coagulase-negative staphylococci, and 2 participants (3%) had no identified organisms. There were multiple organisms isolated from 20 patients (26%).
Fifty participants had clear documentation in their EHR that cure of infection was the goal, meeting the criteria for the intent-to-cure group. The remaining 28 participants were placed in the without-intent-to-cure group. Success and failure rates were only measured in the intent-to-cure group, as by definition the without-intent-to-cure group patients would meet the criteria for failure (removal of prosthesis or long-term antibiotic use). The without-intent-to-cure group had a higher median age than the intent-to-cure group (69 years vs 64 years, P = .24) and a higher proportion of male participants (96% vs 80%, P = .09). The median (IQR) implant age of 11 months (1.0-50.5) in the without-intent-to-cure group was also higher than the median implant age of 1 month (0.6-22.0) in the primary group (P = .22). In the without-intent-to-cure group, 19 participants (68%) had a chronic infection, compared with 11 (22%) in the intent-to-cure group (P < .001).
The mean (SD) Charlson Comorbidity Index in the without-intent-to-cure group was 2.5 (1.3) compared with 1.9 (1.4) in the intent-to-cure group (P = .09). There was no significant difference in the type of implant or microbiology of the infecting organism between the 2 groups, although it should be noted that in the intent-to-cure group, 48 patients (96%) had Staphylococcus aureus or coagulase-negative staphylococci isolated.
The median (IQR) dosage of rifampin was 600 mg (300-900). The secondary oral antibiotics used most often were 36 fluoroquinolones (46%) followed by 20 tetracyclines (26%), 6 cephalosporins (8%), and 6 penicillins (8%). Additionally, 6 participants (8%) received IV vancomycin, and 1 participant (1%) was given an oral antifungal in addition to a fluoroquinolone because cultures revealed bacterial and fungal growth. The median (IQR) duration of antimicrobial therapy was 3 months (1.4-3.0). The mean (SD) duration of antimicrobial therapy was 3.6 (2.4) months for TKA infections and 2.4 (0.9) months for THA infections.
Clinical Outcome
Forty-one intent-to-cure group participants (82%) experienced treatment success. We further subdivided the intent-to-cure group by implant age. Participants whose implant was < 2 months old had a success rate of 93%, whereas patients whose implant was older had a success rate of 65% (P = .02).
Secondary Outcomes
The median (IQR) duration of antimicrobial treatment was 3 months (1.4-3.0) for the 38 patients with TKA-related infections and 3 months (1.4-6.0) for the 29 patients with THA infections. AEs were recorded in 24 (31%) of all study participants. Of those with AEs, the average number reported per patient was 1.6. Diarrhea, gastric upset, and nausea were each reported 7 times, accounting for 87% of all recorded AEs. Five participants reported having a rash while on antibiotics, and 2 experienced dysgeusia. One participant reported developing a yeast infection and another experienced vaginitis.
DISCUSSION
Among patients with orthopedic implant infections treated with intent to cure using a rifampin-containing antibiotic regimen at the MVAHCS, 82% had clinical success. Although this is lower than the success rates reported in clinical trials, this is not entirely unexpected.5,7 In most clinical trials studying DAIR and rifampin for PJI, patients are excluded if they do not have an acute staphylococcal infection in the setting of a well-fixed prosthesis without evidence of a sinus tract. Such exclusion criteria were not present in our retrospective study, which was designed to evaluate the real-world practice patterns at this facility. The population at the US Department of Veterans Affairs (VA) is older, more frail, and with more comorbid conditions than populations in prior studies. It is possible that patients with characteristics that would have caused them to be excluded from a clinical trial would be less likely to receive rifampin therapy with the intent to cure. This is suggested by the significantly higher prevalence of chronic infections (68%) in the without-intent-to-cure group compared with 22% in the intent-to-cure group. However, there were reasonably high proportions of participants included in the intent-to-cure group who did have conditions that would have led to their exclusion from prior trials, such as chronic infection (22%) and implant age ≥ 2 months (40%).
When evaluating participants by the age of their implant, treatment success rose to 93% for patients with implants < 2 months old compared with 65% for patients with older implants. This suggests that participants with a newer implant or more recent infection have a greater likelihood of successful treatment, which is consistent with the results of previous clinical trials.5,10 Considering how difficult multiple surgeries can be for older adult patients with comorbidities, we suggest that DAIR with a rifampin-containing regimen be considered as the primary treatment option for early PJIs at the MVAHCS. We also note inconsistent adherence to IDSA treatment guidelines on rifampin therapy, in that patients without intent to cure were prescribed a regimen including rifampin. This may reflect appropriate variability in the care of individual patients but may also offer an opportunity to change processes to improve care.
Limitations
Our analysis has limitations. As with any retrospective study evaluating the efficacy of a specific antibiotic, we were not able to attribute specific outcomes to the antibiotic of interest. Since the choice of antibiotics was left to the treating health care practitioner, therapy was not standardized, and because this was a retrospective study, causal relationships could not be inferred. Our analysis was also limited by the lack of intent to cure in 28 participants (36%), which could be an indication of practitioner bias in therapy selection or characteristic differences between the 2 groups. We looked for signs of infection failure 1 year after the completion of antimicrobial therapy, but longer follow-up could have led to higher rates of failure. Also, while participants’ infections were considered cured if they never sought further medical care for the infection at the MVAHCS, it is possible that patients could have sought care at another facility. We note that 9 patients were excluded because they were unable to complete a treatment course due to rifampin AEs, meaning that the success rates reported here reflect the success that may be expected if a patient can tolerate and complete a rifampin-based regimen. This study was conducted in a single VA hospital and may not be generalizable to nonveterans or veterans seeking care at other facilities.
Conclusions
DAIR followed by a short course of IV antibiotics and an oral regimen including rifampin and another antimicrobial is a reasonable option for veterans with acute staphylococcal orthopedic device infections at the MVAHCS. Patients with a well-placed prosthesis and an acute infection seem especially well suited for this treatment, and treatment with intent to cure should be pursued in patients who meet the criteria for rifampin therapy.
Acknowledgments
We thank Erik Stensgard, PharmD, for assistance in compiling the list of patients receiving rifampin and another antimicrobial.
Orthopedic implants are frequently used to repair fractures and replace joints. The number of total joint replacements is high, with > 1 million total hip (THA) and total knee (TKA) arthroplasties performed in the United States each year.1 While most joint arthroplasties are successful and significantly improve patient quality of life, a small proportion become infected.2 Prosthetic joint infection (PJI) causes substantial morbidity and mortality, particularly among older patients, and is difficult and costly to treat.3
The historic gold standard treatment for PJI is a 2-stage replacement, wherein the prosthesis is removed in one procedure and a new prosthesis is implanted in a second procedure after an extended course of antibiotics. This approach requires the patient to undergo 2 major procedures and spend considerable time without a functioning prosthesis, contributing to immobility and deconditioning. This option is difficult for frail or older patients and is associated with high medical costs.4
In 1998, a novel method of treatment known as debridement, antibiotics, and implant retention (DAIR) was evaluated in a small, randomized controlled trial.5 This study used a unique antimicrobial approach: the administration of ciprofloxacin plus either rifampin or placebo for 3 to 6 months, combined with a single surgical debridement. Eliminating a second surgical procedure and largely relying on oral antimicrobials reduces surgical risks and decreases costs.4 Current guidelines endorse DAIR with rifampin and a second antibiotic for patients diagnosed with PJI within about 30 days of prosthesis implantation who have a well-fixed implant without evidence of a sinus tract.6 Clinical trial data demonstrate that this approach is > 90% effective in patients with a well-fixed prosthesis and acute staphylococcal PJI.3,7
Thus far, clinical trials examining this approach have been small and did not include veterans who are typically older and have more comorbidities.8 The Minneapolis Veterans Affairs Health Care System (MVAHCS) infectious disease section has implemented the rifampin-based DAIR approach for orthopedic device-related infections since this approach was first described in 1998 but has not systematically evaluated its effectiveness or whether there are areas for improvement.
METHODS
We conducted a retrospective analysis of patients who underwent DAIR combined with a rifampin-containing regimen at the MVAHCS from January 1, 2001, through June 30, 2021. Inclusion required a diagnosis of orthopedic device-related infection and treatment with DAIR followed by antimicrobial therapy that included rifampin for 1 to 6 months. PJI was defined by meeting ≥ 1 of the following criteria: (1) isolation of the same microorganism from ≥ 2 cultures from joint aspirates or intraoperative tissue specimens; (2) purulence surrounding the prosthesis at the time of surgery; (3) acute inflammation consistent with infection on histopathological examination or periprosthetic tissue; or (4) presence of a sinus tract communicating with the prosthesis.
All cases of orthopedic device infection managed with DAIR and rifampin were included, regardless of implant stability, age of the implant at the time of symptom onset, presence of a sinus tract, or infecting microorganism. Exclusion criteria included patients who started or finished PJI treatment at another facility, were lost to follow-up, discontinued rifampin, died within 1 year of completing antibiotic therapy due to reasons unrelated to treatment failure, received rifampin for < 50% of their antimicrobial treatment course, had complete hardware removal, or had < 1 year between the completion of antimicrobial therapy and the time of data collection.
Management of DAIR procedures at the MVAHCS involves evaluating the fixation of the prosthesis, tissue sampling for microbiological analysis, and thorough debridement of infected tissue. Following debridement, a course of IV antibiotics is administered before initiating oral antibiotic therapy. To protect against resistance, rifampin is combined with another antibiotic typically from the fluoroquinolone, tetracycline, or cephalosporin class. Current guidelines suggest 3 and 6 months of oral antibiotics for prosthetic hip and knee infections, respectively.6
Treatment Outcomes
The primary outcome was treatment success, defined as meeting all of the following: (1) lack of clinical signs and symptoms of infection; (2) absence of radiological signs of loosening or infection within 1 year after the conclusion of treatment; and (3) absence of additional PJI treatment interventions for the prosthesis of concern within 1 year after completing the original antibiotic treatment.
Treatment failure was defined as meeting any of the following: (1) recurrence of PJI (original strain or different microorganism) within 1 year after the completion of antibiotic therapy; (2) death attributed to PJI anytime after the initial debridement; (3) removal of the prosthetic joint within 1 year after the completion of antibiotic therapy; or (4) long-term antibiotic use to suppress the PJI after the completion of the initial antibiotic therapy.
Statistical Analysis
Descriptive statistics were used to define the baseline characteristics of patients receiving rifampin therapy for orthopedic implant infections at the MVAHCS. Variables analyzed were age, sex, race and ethnicity, type of implant, age of implant, duration of symptoms, comorbidities (diabetes and rheumatoid arthritis), and presence of chronic infection. Patients were classified as having a chronic infection if they received previous infection treatment (antibiotics or surgery) for the orthopedic device in question. We created this category because patients with persistent infection after a medical or surgical attempt at treatment are likely to have a higher probability of treatment failure compared with those with no prior therapy. Charlson Comorbidity Index was calculated using clinical information present at the onset of infection.9 Fisher exact test was used to assess differences between categorical variables, and an independent t test was used to assess differences in continuous variables. P < .05 indicated statistical significance.
To assess the ability of a rifampin-based regimen to achieve a cure of PJI, we grouped participants into 2 categories: those with an intent to cure strategy and those without intent to cure based on documentation in the electronic health record (EHR). Participants who were prescribed rifampin with the documented goal of prosthesis retention with no further suppressive antibiotics were included in the intent-to-cure group, the primary focus of this study. Those excluded from the intent-to-cure group were given rifampin and another antibiotic, but there was a documented plan of either ongoing chronic suppression or eventual explantation; these participants were placed in the without-intent-to-cure group. Analysis of treatment success and failure was limited to the intent-to-cure group, whereas both groups were included for assessment of adverse effects (AEs) and treatment duration. This project was reviewed by the MVAHCS Institutional Review Board and determined to be a quality improvement initiative and to not meet the definition of research, and as such did not require review; it was reviewed and approved by the MVAHCS Research and Development Committee.
RESULTS
A total of 538 patients were identified who simultaneously received rifampin and another oral antibiotic between January 1, 2000, and June 30, 2021.
Forty-two participants (54%) had Staphylococcus aureus and 31 participants (40%) had coagulase-negative staphylococci infections, while 11 gram-negative organisms (14%) and 6 gram-positive anaerobic cocci (8%) infections were noted. Cutibacterium acnes and Streptococcus agalactiae were each found in 3 participants (4% of), and diphtheroids (not further identified) was found on 2 participants (3%). Candida albicans was identified in a single participant (1%), along with coagulase-negative staphylococci, and 2 participants (3%) had no identified organisms. There were multiple organisms isolated from 20 patients (26%).
Fifty participants had clear documentation in their EHR that cure of infection was the goal, meeting the criteria for the intent-to-cure group. The remaining 28 participants were placed in the without-intent-to-cure group. Success and failure rates were only measured in the intent-to-cure group, as by definition the without-intent-to-cure group patients would meet the criteria for failure (removal of prosthesis or long-term antibiotic use). The without-intent-to-cure group had a higher median age than the intent-to-cure group (69 years vs 64 years, P = .24) and a higher proportion of male participants (96% vs 80%, P = .09). The median (IQR) implant age of 11 months (1.0-50.5) in the without-intent-to-cure group was also higher than the median implant age of 1 month (0.6-22.0) in the primary group (P = .22). In the without-intent-to-cure group, 19 participants (68%) had a chronic infection, compared with 11 (22%) in the intent-to-cure group (P < .001).
The mean (SD) Charlson Comorbidity Index in the without-intent-to-cure group was 2.5 (1.3) compared with 1.9 (1.4) in the intent-to-cure group (P = .09). There was no significant difference in the type of implant or microbiology of the infecting organism between the 2 groups, although it should be noted that in the intent-to-cure group, 48 patients (96%) had Staphylococcus aureus or coagulase-negative staphylococci isolated.
The median (IQR) dosage of rifampin was 600 mg (300-900). The secondary oral antibiotics used most often were 36 fluoroquinolones (46%) followed by 20 tetracyclines (26%), 6 cephalosporins (8%), and 6 penicillins (8%). Additionally, 6 participants (8%) received IV vancomycin, and 1 participant (1%) was given an oral antifungal in addition to a fluoroquinolone because cultures revealed bacterial and fungal growth. The median (IQR) duration of antimicrobial therapy was 3 months (1.4-3.0). The mean (SD) duration of antimicrobial therapy was 3.6 (2.4) months for TKA infections and 2.4 (0.9) months for THA infections.
Clinical Outcome
Forty-one intent-to-cure group participants (82%) experienced treatment success. We further subdivided the intent-to-cure group by implant age. Participants whose implant was < 2 months old had a success rate of 93%, whereas patients whose implant was older had a success rate of 65% (P = .02).
Secondary Outcomes
The median (IQR) duration of antimicrobial treatment was 3 months (1.4-3.0) for the 38 patients with TKA-related infections and 3 months (1.4-6.0) for the 29 patients with THA infections. AEs were recorded in 24 (31%) of all study participants. Of those with AEs, the average number reported per patient was 1.6. Diarrhea, gastric upset, and nausea were each reported 7 times, accounting for 87% of all recorded AEs. Five participants reported having a rash while on antibiotics, and 2 experienced dysgeusia. One participant reported developing a yeast infection and another experienced vaginitis.
DISCUSSION
Among patients with orthopedic implant infections treated with intent to cure using a rifampin-containing antibiotic regimen at the MVAHCS, 82% had clinical success. Although this is lower than the success rates reported in clinical trials, this is not entirely unexpected.5,7 In most clinical trials studying DAIR and rifampin for PJI, patients are excluded if they do not have an acute staphylococcal infection in the setting of a well-fixed prosthesis without evidence of a sinus tract. Such exclusion criteria were not present in our retrospective study, which was designed to evaluate the real-world practice patterns at this facility. The population at the US Department of Veterans Affairs (VA) is older, more frail, and with more comorbid conditions than populations in prior studies. It is possible that patients with characteristics that would have caused them to be excluded from a clinical trial would be less likely to receive rifampin therapy with the intent to cure. This is suggested by the significantly higher prevalence of chronic infections (68%) in the without-intent-to-cure group compared with 22% in the intent-to-cure group. However, there were reasonably high proportions of participants included in the intent-to-cure group who did have conditions that would have led to their exclusion from prior trials, such as chronic infection (22%) and implant age ≥ 2 months (40%).
When evaluating participants by the age of their implant, treatment success rose to 93% for patients with implants < 2 months old compared with 65% for patients with older implants. This suggests that participants with a newer implant or more recent infection have a greater likelihood of successful treatment, which is consistent with the results of previous clinical trials.5,10 Considering how difficult multiple surgeries can be for older adult patients with comorbidities, we suggest that DAIR with a rifampin-containing regimen be considered as the primary treatment option for early PJIs at the MVAHCS. We also note inconsistent adherence to IDSA treatment guidelines on rifampin therapy, in that patients without intent to cure were prescribed a regimen including rifampin. This may reflect appropriate variability in the care of individual patients but may also offer an opportunity to change processes to improve care.
Limitations
Our analysis has limitations. As with any retrospective study evaluating the efficacy of a specific antibiotic, we were not able to attribute specific outcomes to the antibiotic of interest. Since the choice of antibiotics was left to the treating health care practitioner, therapy was not standardized, and because this was a retrospective study, causal relationships could not be inferred. Our analysis was also limited by the lack of intent to cure in 28 participants (36%), which could be an indication of practitioner bias in therapy selection or characteristic differences between the 2 groups. We looked for signs of infection failure 1 year after the completion of antimicrobial therapy, but longer follow-up could have led to higher rates of failure. Also, while participants’ infections were considered cured if they never sought further medical care for the infection at the MVAHCS, it is possible that patients could have sought care at another facility. We note that 9 patients were excluded because they were unable to complete a treatment course due to rifampin AEs, meaning that the success rates reported here reflect the success that may be expected if a patient can tolerate and complete a rifampin-based regimen. This study was conducted in a single VA hospital and may not be generalizable to nonveterans or veterans seeking care at other facilities.
Conclusions
DAIR followed by a short course of IV antibiotics and an oral regimen including rifampin and another antimicrobial is a reasonable option for veterans with acute staphylococcal orthopedic device infections at the MVAHCS. Patients with a well-placed prosthesis and an acute infection seem especially well suited for this treatment, and treatment with intent to cure should be pursued in patients who meet the criteria for rifampin therapy.
Acknowledgments
We thank Erik Stensgard, PharmD, for assistance in compiling the list of patients receiving rifampin and another antimicrobial.
1. Maradit Kremers H, Larson DR, Crowson CS, et al. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am. 2015;97(17):1386-1397. doi:10.2106/JBJS.N.01141
2. Kapadia BH, Berg RA, Daley JA, Fritz J, Bhave A, Mont MA. Periprosthetic joint infection. Lancet. 2016;387(10016):386-394. doi:10.1016/S0140-6736(14)61798-0
3. Zhan C, Kaczmarek R, Loyo-Berrios N, Sangl J, Bright RA. Incidence and short-term outcomes of primary and revision hip replacement in the United States. J Bone Joint Surg Am. 2007;89(3):526-533. doi:10.2106/JBJS.F.00952
4. Fisman DN, Reilly DT, Karchmer AW, Goldie SJ. Clinical effectiveness and cost-effectiveness of 2 management strategies for infected total hip arthroplasty in the elderly. Clin Infect Dis. 2001;32(3):419-430. doi:10.1086/318502
5. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279(19):1537-1541. doi:10.1001/jama.279.19.1537
6. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25. doi:10.1093/cid/cis803
7. Lora-Tamayo J, Euba G, Cobo J, et al. Short- versus long-duration levofloxacin plus rifampicin for acute staphylococcal prosthetic joint infection managed with implant retention: a randomised clinical trial. Int J Antimicrob Agents. 2016;48(3):310-316. doi:10.1016/j.ijantimicag.2016.05.021
8. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi:10.1001/archinte.160.21.3252
9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
10. Vilchez F, Martínez-Pastor JC, García-Ramiro S, et al. Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement. Clin Microbiol Infect. 2011;17(3):439-444. doi:10.1111/j.1469-0691.2010.03244.x
1. Maradit Kremers H, Larson DR, Crowson CS, et al. Prevalence of total hip and knee replacement in the United States. J Bone Joint Surg Am. 2015;97(17):1386-1397. doi:10.2106/JBJS.N.01141
2. Kapadia BH, Berg RA, Daley JA, Fritz J, Bhave A, Mont MA. Periprosthetic joint infection. Lancet. 2016;387(10016):386-394. doi:10.1016/S0140-6736(14)61798-0
3. Zhan C, Kaczmarek R, Loyo-Berrios N, Sangl J, Bright RA. Incidence and short-term outcomes of primary and revision hip replacement in the United States. J Bone Joint Surg Am. 2007;89(3):526-533. doi:10.2106/JBJS.F.00952
4. Fisman DN, Reilly DT, Karchmer AW, Goldie SJ. Clinical effectiveness and cost-effectiveness of 2 management strategies for infected total hip arthroplasty in the elderly. Clin Infect Dis. 2001;32(3):419-430. doi:10.1086/318502
5. Zimmerli W, Widmer AF, Blatter M, Frei R, Ochsner PE. Role of rifampin for treatment of orthopedic implant-related staphylococcal infections: a randomized controlled trial. Foreign-Body Infection (FBI) Study Group. JAMA. 1998;279(19):1537-1541. doi:10.1001/jama.279.19.1537
6. Osmon DR, Berbari EF, Berendt AR, et al. Diagnosis and management of prosthetic joint infection: clinical practice guidelines by the Infectious Diseases Society of America. Clin Infect Dis. 2013;56(1):e1-e25. doi:10.1093/cid/cis803
7. Lora-Tamayo J, Euba G, Cobo J, et al. Short- versus long-duration levofloxacin plus rifampicin for acute staphylococcal prosthetic joint infection managed with implant retention: a randomised clinical trial. Int J Antimicrob Agents. 2016;48(3):310-316. doi:10.1016/j.ijantimicag.2016.05.021
8. Agha Z, Lofgren RP, VanRuiswyk JV, Layde PM. Are patients at Veterans Affairs medical centers sicker? A comparative analysis of health status and medical resource use. Arch Intern Med. 2000;160(21):3252-3257. doi:10.1001/archinte.160.21.3252
9. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. doi:10.1016/0021-9681(87)90171-8
10. Vilchez F, Martínez-Pastor JC, García-Ramiro S, et al. Outcome and predictors of treatment failure in early post-surgical prosthetic joint infections due to Staphylococcus aureus treated with debridement. Clin Microbiol Infect. 2011;17(3):439-444. doi:10.1111/j.1469-0691.2010.03244.x
Patient Knowledge and Attitudes About Fecal Microbiota Therapy for Clostridium difficile Infection
Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.4,6,7
Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.8 This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.9
A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.10 However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.
Methods
In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).
Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.
Results
Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.
The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.
Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).
Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).
Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.
Discussion
Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.
When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.10 Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.
Strengths/Limitations
Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.
Conclusion
This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.
1. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile Infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
2. Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54(47):1201-1205.
3. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.
4. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013. Updated July 17, 2014. Accessed November 16.2016.
6. Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
7. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289.
8. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6):403-410.
9. Drekonja DM, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection--a systematic review. Ann Intern Med. 2015;162(9):630-638.
10. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012;55(12):1652-1658.
Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.4,6,7
Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.8 This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.9
A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.10 However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.
Methods
In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).
Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.
Results
Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.
The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.
Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).
Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).
Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.
Discussion
Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.
When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.10 Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.
Strengths/Limitations
Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.
Conclusion
This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.
Clostridium difficile (C difficile) infection (CDI) is a leading cause of infectious diarrhea among hospitalized patients and, increasingly, in ambulatory patients.1,2 The high prevalence of CDI and the high recurrence rates (15%-30%) led the CDC to categorize C difficile as an "urgent" threat (the highest category) in its 2013 Antimicrobial Resistance Threat Report.3-5 The Infectious Diseases Society of America guideline recommended treatment for CDI is vancomycin or metronidazole; more recent studies also support fidaxomicin use.4,6,7
Patients experiencing recurrent CDI are at risk for further recurrences, such that after the third CDI episode, the risk of subsequent recurrences exceeds 50%.8 This recurrence rate has stimulated research into other treatments, including fecal microbiota transplantation (FMT). A recent systematic review of FMT reports that 85% of patients have resolution of symptoms without recurrence after FMT, although this is based on data from case series and 2 small randomized clinical trials.9
A commonly cited barrier to FMT is patient acceptance. In response to this concern, a previous survey demonstrated that 81% of respondents would opt for FMT to treat a hypothetical case of recurrent CDI.10 However, the surveyed population did not have CDI, and the 48% response rate is concerning, since those with a favorable opinion of FMT might be more willing to complete a survey than would other patients. Accordingly, the authors systematically surveyed hospitalized veterans with active CDI to assess their knowledge, attitudes, and opinions about FMT as a treatment for CDI.
Methods
In-person patient interviews were conducted by one of the study authors at the Minneapolis VA Health Care System (MVAHCS), consisting of 13 to 18 questions. Questions addressed any prior CDI episodes and knowledge of the following: CDI, recurrence risk, and FMT; preferred route and location of FMT administration; concerns regarding FMT; likelihood of agreeing to undergo FMT (if available); and likelihood of enrollment in a hypothetical study comparing FMT to standard antibiotic treatment. The survey was developed internally and was not validated. Questions used the Likert-scale (Survey).
Patients with CDI were identified by monitoring for positive C difficile polymerase chain reaction (PCR) stool tests and then screened for inclusion by medical record review. Inclusion criteria were (1) MVAHCS hospitalization; and (2) written informed consent. Exclusion criteria were the inability to communicate or participate in an interview. Patient responses regarding their likelihood of agreeing to FMT for CDI treatment under different circumstances were compared using Wilcoxon rank sum test. These circumstances included FMT for their current episode of CDI, FMT for a subsequent episode, and FMT if recommended by their physician. Possible concerns regarding FMT also were solicited, including infection risk, effectiveness, and procedural aesthetics. The MVAHCS institutional review board approved the study.
Results
Stool PCR tests for CDI were monitored for 158 days from 2013 to 2014 (based on availability of study staff), yielding 106 positive results. Of those, 31 (29%) were from outpatients and not addressed further. Of the 75 positive CDI tests from 66 hospitalized patients (9 patients had duplicate tests), 18 of 66 (27%) were not able to provide consent and were excluded, leaving 48 eligible patients. Six (13%) were missed for logistic reasons (patient at a test or procedure, discharged before approached, etc), leaving 42 patients who were approached for participation. Among these, 34 (81%) consented to participate in the survey. Two subjects (6%) found the topic so unappealing that they terminated the interview.
The majority of enrolled subjects were men (32/34, 94%), with a mean age of 65.3 years (range, 31-89). Eleven subjects (32%) reported a prior CDI episode, with 10 reporting 1 such episode, and the other 2 episodes. Those with prior CDI reported the effect of CDI on their overall quality of life as 5.1 (1 = no limitation, 10 = severe limitation). Respondents were fairly accurate regarding the risk of recurrence after an initial episode of CDI, with the average expectedrecurrence rate estimated at 33%. In contrast, their estimation of the risk of recurrence after a second CDI episode was lower (28%), although the risk of recurrent episodes increases with each CDI recurrence.
Regarding FMT, 5 subjects indicated awareness of the procedure: 2 learning of it from a news source, 1 from family, 1 from a health care provider, and 1 was unsure of the source. After subjects received a description of FMT, their opinions regarding the procedure were elicited. When asked which route of delivery they would prefer if they were to undergo FMT, the 33 subjects who provided a response indicated a strong preference for either enema (15, 45%) or colonoscopy (10, 30%), compared with just 4 (12%) indicating no preference, 2 (6%) choosing nasogastric tube administration, and 2 (6%) indicating that they would not undergo FMT by any route (P < .001).
Regarding the location of FMT administration (hospital setting vs self-administered at home), 31 of 33 respondents (94%) indicated they would prefer FMT to occur in the hospital vs 2 (6%) preferring self-administration at home (P < .001). The preferred source of donor stool was more evenly distributed, with 14 of 32 respondents (44%) indicating a preference for an anonymous donor, 11 preferring a family member (34%), and 7 (21%) with no preference (P = .21).
Subjects were asked about concerns regarding FMT, and asked to rate each on a 5-point Likert scale (1 = not at all concerning; 5 = overwhelming concern). Concerns regarding risk of infection and effectiveness received an average score of 2.74 and 2.72, respectively, whereas concern regarding the aesthetics, or "yuck factor" was slightly lower (2.1: P = NS for all comparisons). Subjects also were asked to rate the likelihood of undergoing FMT, if it were available, for their current episode of CDI, a subsequent episode of CDI, or if their physician recommended undergoing FMT (10 point scale: 1 = not at all likely; 10 = certainly agree to FMT). The mean scores (SD) for agreeing to FMT for the current or a subsequent episode were 4.8 (SD 2.7) and 5.6 (SD 3.0); P = .12, but increased to 7.1 (SD 3.23) if FMT were recommended by their physician (P < .001 for FMT if physician recommended vs FMT for current episode; P = .001 for FMT if physician recommended vs FMT for a subsequent episode). Finally, subjects were asked about the likelihood of enrolling in a study comparing FMT to standard antimicrobial treatment, with answers ranging from 1 (almost certainly would not enroll) to 5 (almost certainly would enroll). Among the 32 respondents to this question, 17 (53%) answered either "probably would enroll" or "almost certainly would enroll," with a mean score of 3.2.
Discussion
Overall, VA patients with a current episode of CDI were not aware of FMT, with just 15% knowing about the procedure. However, after learning about FMT, patients expressed clear opinions regarding the route and setting of FMT administration, with enema or colonoscopy being the preferred routes, and a hospital the preferred setting. In contrast, subjects expressed ambivalence with regard to the source of donor stool, with no clear preference for stool from an anonymous donor vs from a family member.
When asked about concerns regarding FMT, none of the presented options (risk of infection, uncertain effectiveness, or procedural aesthetics) emerged as significantly more important than did others, although the oft-cited concern regarding FMT aesthetics engendered the lowest overall level of concern. In terms of FMT acceptance, 4 subjects (12%) were opposed to the procedure, indicating that they were not at all likely to agree to FMT for all scenarios (defined as a score of 1 or 2 on the 10-point Likert scale) or by terminating the survey because of the questions. However, 15 (44%) indicated that they would certainly agree to FMT (defined as a score of 9 or 10 on the 10-point Likert scale) if their physician recommended it. Physician recommendation for FMT resulted in the highest overall likelihood of agreeing to FMT, a finding in agreement with a previous survey of FMT for CDI.10 Most subjects indicated likely enrollment in a potential study comparing FMT with standard antimicrobial therapy.
Strengths/Limitations
Study strengths included surveying patients with current CDI, such that patients had personal experience with the disease in question. Use of in-person interviews also resulted in a robust response rate of 81% and allowed subjects to clarify any unclear questions with study personnel. Weaknesses included a relatively small sample size, underrepresentation of women, and lack of detail regarding respondent characteristics. Additionally, capsule delivery of FMT was not assessed since this method of delivery had not been published at the time of survey administration.
Conclusion
This survey of VA patients with CDI suggests that aesthetic concerns are not a critical deterrent for this population, and interest in FMT for the treatment of recurrent CDI exists. Physician recommendation to undergo FMT seems to be the most influential factor affecting the likelihood of agreeing to undergo FMT. These results support the feasibility of conducting clinical trials of FMT in the VA system.
1. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile Infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
2. Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54(47):1201-1205.
3. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.
4. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013. Updated July 17, 2014. Accessed November 16.2016.
6. Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
7. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289.
8. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6):403-410.
9. Drekonja DM, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection--a systematic review. Ann Intern Med. 2015;162(9):630-638.
10. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012;55(12):1652-1658.
1. Miller BA, Chen LF, Sexton DJ, Anderson DJ. Comparison of the burdens of hospital-onset, healthcare facility-associated Clostridium difficile Infection and of healthcare-associated infection due to methicillin-resistant Staphylococcus aureus in community hospitals. Infect Control Hosp Epidemiol. 2011;32(4):387-390.
2. Centers for Disease Control and Prevention. Severe Clostridium difficile-associated disease in populations previously at low risk--four states, 2005. MMWR Morb Mortal Wkly Rep. 2005;54(47):1201-1205.
3. Johnson S, Louie TJ, Gerding DN, et al; Polymer Alternative for CDI Treatment (PACT) investigators. Vancomycin, metronidazole, or tolevamer for Clostridium difficile infection: results from two multinational, randomized, controlled trials. Clin Infect Dis. 2014;59(3):345-354.
4. Louie TJ, Miller MA, Mullane KM, et al; OPT-80-003 Clinical Study Group. Fidaxomicin versus vancomycin for Clostridium difficile infection. N Engl J Med. 2011;364(5):422-431.
5. Centers for Disease Control and Prevention. Antibiotic resistance threats in the United States, 2013. http://www.cdc.gov/drugresistance/threat-report-2013. Updated July 17, 2014. Accessed November 16.2016.
6. Cohen SH, Gerding DN, Johnson S, et al; Society for Healthcare Epidemiology of America; Infectious Diseases Society of America. Clinical practice guidelines for Clostridium difficile infection in adults: 2010 update by the society for healthcare epidemiology of America (SHEA) and the Infectious Diseases Society of America (IDSA). Infect Control Hosp Epidemiol. 2010;31(5):431-455.
7. Cornely OA, Crook DW, Esposito R, et al; OPT-80-004 Clinical Study Group. Fidaxomicin versus vancomycin for infection with Clostridium difficile in Europe, Canada, and the USA: a double-blind, non-inferiority, randomised controlled trial. Lancet Infect Dis. 2012;12(4):281-289.
8. Johnson S. Recurrent Clostridium difficile infection: a review of risk factors, treatments, and outcomes. J Infect. 2009;58(6):403-410.
9. Drekonja DM, Reich J, Gezahegn S, et al. Fecal microbiota transplantation for Clostridium difficile infection--a systematic review. Ann Intern Med. 2015;162(9):630-638.
10. Zipursky JS, Sidorsky TI, Freedman CA, Sidorsky MN, Kirkland KB. Patient attitudes toward the use of fecal microbiota transplantation in the treatment of recurrent Clostridium difficile infection. Clin Infect Dis. 2012;55(12):1652-1658.