Original Article Long-Term Efficacy of Oral Vancomycin Prophylaxis for the Prevention of Clostridium difficile Recurrence Journal of Pharmacy Practice 1-7 ª The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0897190019825994 journals.sagepub.com/home/jpp Emmanuel M. Knight, PharmD, BCPS, BCGP1, Daryl S. Schiller, PharmD, BCPS AQ-ID1, Magda K. Fulman, PharmD, BCPS1, and Rupangi Rastogi, PharmD, BCPS1 Abstract Background: Limited evidence suggests that prophylactic oral vancomycin may be beneficial in preventing Clostridium difficile infection (CDI) recurrence, but long-term efficacy is unknown. Objective: To evaluate the long-term efficacy of oral vancomycin prophylaxis (OVP) in preventing CDI recurrence in subjects who require subsequent antibiotic exposure. Methods: A retrospective cohort study was conducted at a community hospital. A total of 91 subjects with a history of CDI between January 2013 and December 2015 who had a subsequent hospitalization requiring systemic antibiotics within 12 months were evaluated. Thirtytwo subjects who received prophylaxis with oral vancomycin were compared to 59 subjects who did not receive prophylaxis. Results: CDI recurrence within 12 months was significantly lower in subjects receiving OVP compared to those who did not receive OVP (6.3% vs 28.8%; odds ratio [OR]: 0.16; 95% confidence interval [CI]: 0.04-0.77; P ¼ .011) including patients whose previous CDI was an initial episode (3.7% [1/27] vs 28.3% [15/53]; OR: 10.3; 95% CI: 1.28-82.6; P ¼ .009). Conclusion: Use of OVP in subjects with a history of CDI up to 12 months prior to subsequent antibiotic exposure appears to reduce the risk of CDI recurrence for up to 12 months. Keywords Clostridium difficile, vancomycin, prophylaxis, recurrent, infectious diseases Background Clostridium difficile is a spore-forming bacterium that can infect the large bowel and cause severe diarrhea, inflammation, and damage to the colon. Over the years, Clostridium difficile infections (CDIs) have become more frequent and difficult to treat. The recent increase in incidence and severity is due to the emergence of a previously uncommon hypervirulent strain, known as restriction enzyme analysis type BI, North American Pulsed Field type 1 (NAP1), or polymerase chain reaction (PCR) ribotype 027 (BI/ NAP1/027), which is more resistant to antibiotics and produces more toxin.1,2,3This emergent strain is characterized by higher than usual toxin A and B production, the primary virulence factors of CDI, and the presence of a binary toxin.4,5 It has also been associated with outbreaks of severe disease in North America and Europe.5 A recent study estimated that the number of CDI in the United States was 453 000 in 2011. The incidence was estimated to be higher among females, whites, and persons 65 years of age or older.6 The estimated number of first recurrences of CDI was 83 000 in the United States in 2011 with estimated annual health-care costs of US$2.8 billion.6,7 Subjects with a history of a previous CDI are at increased risk for recurrent episodes. Additionally, evidence has shown that exposure to systemic antibiotics is also an independent risk factor for recurrence as they may kill protective gut bacteria allowing C difficile to multiply and cause infection.8,9,10Clindamycin, fluoroquinolones, cephalosporins, and carbapenems carry a particularly higher risk than other antibiotics.11-13 Currently, there are no published guidelines that outline the best way to prevent recurrence in subjects with a past history of CDI who require antibiotic treatment. There have been several recent studies that evaluated treatment and prevention strategies for recurrent CDI. Fidaxomicin, 1 Department of Pharmacy Services, Montefiore Nyack Hospital, Nyack, NY, USA Corresponding Author: Emmanuel M. Knight, Department of Pharmacy Services, Montefiore Nyack Hospital, 160 North Midland Avenue, Nyack, NY 10960, USA. Email: [email protected] 2 a newer macrolide antibiotic, was shown to be effective for treatment and prevention of recurrent CDI.14 Results from 2 randomized controlled trials found that fidaxomicin was similar to vancomycin for the initial cure of CDI (87.6% vs 85.6%, confidence interval [CI]: 0.98-1.07) but was superior to vancomycin for the prevention of recurrent CDI (14.1% vs 26.1%, CI: 0.42-0.71). Bezlotoxumab, another promising option, is a human monoclonal antibody that binds C difficile toxin B and is indicated for adult subjects receiving antibiotics for CDI to prevent future recurrence. Two phase III trials demonstrated a 40% relative reduction in recurrent CDI with bezlotoxumab compared to placebo (16.5% vs 26.6%, P < .0001).15 However, the high costs and accessibility of fidaxomicin and bezlotoxumab are major barriers to their routine use. There has been some evidence from several studies suggesting that fecal microbiota transplantation (FMT) may have a significant effect on reducing recurrent CDI.14,16 Although most of the studies performed were case series and had relatively small sample sizes, collectively, the treatment success rates described in the studies for recurrent CDI have been relatively high. The expert opinion from the recent 2017 update to the Clinical Practice Guidelines for CDI by the Infectious Diseases Society of America (IDSA) and Society for Healthcare Epidemiology of America (SHEA) recommends a trial of FMT for patients with multiple recurrences of CDI who have failed appropriate antibiotic treatments.17-20 Even with the updated FMT recommendations in the IDSA guidelines, the logistics of obtaining fecal microbiota may be a potential barrier for routine use. Additionally, limited evidence also suggests that the use of oral vancomycin as secondary prophylaxis (OVP) may be efficacious in preventing CDI recurrence.21-23 The largest study evaluating OVP for CDI prophylaxis, conducted by Carignan et al, was a retrospective cohort study conducted in 2 tertiary care centers in Canada.22 This study examined whether OVP reduced the risk of recurrence in subjects diagnosed with CDI who received subsequent antibiotics within 90 days. A patient was considered to have experienced a recurrence if within 6 months diarrhea developed and either an additional specimen was positive for the C difficile toxin or the attending physician empirically ordered a second course of treatment against CDI. The median duration of OVP was 7 days (interquartile rang [IQR]: 3-12 days), and a dosage of 125 mg 4 times a day was most common. OVP was found to significantly decrease the risk of recurrence in subjects with recurrent CDI who underwent subsequent antibiotic exposure, but not in those whose CDI was an initial episode. A similar retrospective cohort study was performed at a community teaching hospital in Missouri and showed comparable results.23 In this study, investigators examined 203 subjects, and recurrence was defined as diarrhea in a patient whose stool tested positive for C difficile by PCR within 4 weeks after completion of systemic antibiotics. This study had no prespecified cutoff for previous CDI; however, the mean time from previous CDI to subsequent antibiotic exposure was 6.14 months in the OVP group and 7.61 months in the control group. Journal of Pharmacy Practice XX(X) Of the subjects who received OVP, 41% received 125 mg twice daily and 59% received 250 mg twice daily. This study found that the incidence of CDI within 4 weeks was significantly lower in subjects receiving prophylaxis compared to those without prophylaxis. In light of the findings of these previous studies, OVP may potentially represent a lower cost and more readily available option in subjects at risk for recurrent CDI. However, further investigation is warranted to confirm and expand upon these findings. Objective Study investigators hypothesized that prophylactic oral vancomycin would reduce CDI recurrence in subjects with a history of CDI who required antibiotics. This study aimed to expand upon the findings of previous studies by extending the period for recent history of CDI to 12 months and extending the follow-up for recurrence to 12 months with the goal to determine whether patients with a less recent history of CDI would benefit from OVP, as well as evaluate for long-term efficacy. Methods Study Design and Patient Population This was a retrospective, single-center, cohort study that was conducted by evaluating the medical records of subjects at a 375-bed community acute care hospital. This study was approved by the hospital’s institutional review board and did not require informed consent due to the retrospective nature of the study. Adult subjects aged 18 years with symptoms of loose stool or diarrhea and a positive PCR assay for C difficile between January 1, 2013, and December 31, 2015, were screened. Subjects were included if they were candidates for OVP and were identified as those who had a CDI on an index visit (i-CDI) followed by a subsequent hospitalization within 12 months that required the use of systemic antibiotics. To be included the patients had to receive at least 2 doses of a systemic antibiotic for the treatment of any condition other than a CDI. Subjects were excluded if they received metronidazole at any point during their subsequent hospitalization due to its activity against C difficile or if they had a community-acquired CDI that was identified within 72 hours of admission. Subjects who received OVP were compared to those who did not receive prophylaxis. The decision to start prophylaxis was based on the clinical judgment of the ordering physician, with the majority of the orders placed by infectious disease specialists. Subjects receiving OVP received a dose of 125 to 250 mg 4 times daily typically for the duration of their antibiotic treatment. OVP dosing was at the discretion of the prescribing practitioner since there were no standardized guidelines. Knight et al Study Outcomes and Data Collection The primary outcome of the study was the odds of developing CDI recurrence based on whether or not OVP was used. Recurrence was defined as having symptoms of loose stools or diarrhea and a PCR-positive CDI within 12 months of a subsequent hospitalization requiring systemic antibiotics use. Secondary outcomes included the odds of CDI recurrence in subjects with a more recent history versus older history of CDI. Subjects were classified as having had a recent history of CDI if their i-CDI was 0 to 6 months prior to receiving subsequent antibiotics and were classified as having had an older history of CDI if their i-CDI was 6 to 12 months prior to receiving subsequent antibiotics. Additional secondary outcomes include the time to CDI recurrence and the odds of laboratory-confirmed vancomycin-resistant enterococci (VRE) infections within 12 months in subjects who received OVP. The following information was collected through chart abstraction: patient gender, age, date of i-CDI, severity of i-CDI, date of CDI recurrences, antibiotic treatment details, oral vancomycin dose and duration, proton pump inhibitor (PPI) usage, histamine-2 receptor antagonist usage, probiotics usage, and instances of VRE. For standardization, the total antibiotic daily doses received were calculated based on the Anatomical Therapeutic Chemical/Defined Daily Dose system as outlined by the World Health Organization Collaborating Centre for Drug Statistics Methodology.24 Some additional information collected was directed toward potential risk factors associated with CDI and potential confounders including increasing age, use of gastric acid suppressing medications, duration of antibiotic course, and administration of multiple antibiotics.8,25,26 The severity of i-CDI was determined based on the subject’s white blood cell (WBC) count and serum creatinine level as the IDSA defines an initial episode of CDI as severe if the WBC count is greater than or equal to 15 000 cells/ mm3 or the serum creatinine is greater than 1.5 mg/dL.17 Statistical Analysis Baseline demographics, primary outcomes, and secondary outcomes were analyzed using the Student t test for continuous data and the Pearson Chi-square or Fisher exact test were used for categorical data. Descriptive statistics including mean, median, and IQR were used for analysis and comparison of outcomes. A Kaplan-Meier analysis and a log-rank test were used to evaluate differences in the time to CDI recurrence. Observations were censored with the development of CDI or completion of 52 weeks of follow-up without an event. A value of P < .05 was considered a statistically significant difference. To calculate 80% power with a of .05 and an expected difference in incidence between both groups of 22%, it was determined that a sample size of 90 subjects was needed. The sample size and power analysis is based primarily on the observed differences between instances of CDI in subjects receiving OVP versus control in a similar study by Van Hise et al.23 3 Table 1. Patient Characteristics. Characteristic Male, no. (%) Age (years), mean (SD) Proton pump inhibitor, no. (%) Inpatient Home medication H2RA, no. (%) Inpatient Home medication Inpatient probiotics, no. (%) Time to antibiotic exposure (months), mean (SD) i-CDI episode, no. (%) Initial Recurrent i-CDI severity, no. (%) Initial episode, nonsevere Initial episode, severe OVP dose, no. (%) 250 mg 4 times daily 125 mg 4 times daily OVP No prophylaxis P (n ¼ 32) (n ¼ 59) Value 12 (38) 77.3 (16) 19 (32) 77.7 (13) .39 .46 24 (75) 19 (59) 53 (90) 38 (64) .06 .64 5 (16) 4 (13) 13 (41) 2.9 (3) 2 (3) 5 (8) 16 (27) 4.2 (3) .05 .39 .19 .02 27 (84) 5 (16) 53 (90) 6 (10) .33 .33 10 (37) 17 (63) 30 (57) 23 (43) .09 .09 22 (69) 10 (31) – – – – Abbreviations: H2RA, histamine receptor 2 antagonists; i-CDI, Clostridium difficile infection on index visit; OVP, oral vancomycin prophylaxis; SD, standard deviation. Results A total of 414 subjects with PCR-confirmed i-CDI were screened for inclusion. Of these subjects, 251 were excluded for not having a subsequent hospitalization requiring antibiotic treatment within 12 months of i-CDI, 43 were excluded for receiving metronidazole during their subsequent hospitalization, and 29 were excluded for receiving CDI treatment within the first 72 hours of their subsequent hospitalization. Of the 91 subjects who met the inclusion criteria, 32 subjects received OVP and 59 subjects received no prophylaxis. Table 1 shows the baseline characteristics of these subjects. The majority of iCDI episodes were an initial episode (80 [88%] episodes), while a small number were a recurrent episode (11 [11%] episodes). Most subjects in the OVP group received a dose of 250 mg 4 times daily (22 [69%] subjects), while the remaining subjects received 125 mg 4 times daily (10 [31%] subjects). On average, subjects received OVP for 8.5 (6) days. OVP was started in the majority of subjects within 48 hours of antibiotics being initiated (27 [84%] subjects) and most subjects received OVP, at minimum, until the inpatient antibiotics were discontinued (28 [88%] subjects). There were no statistically significant differences in gender, age, PPI use, or probiotic use. The severity of i-CDI, determined by WBC count and serum creatinine levels, was similar between the 2 groups. Subjects who received OVP had an earlier subsequent antibiotic exposure at baseline than those who did not (2.9  vs 4.2  months; P ¼ .02). Table 2 shows details on the systemic antibiotics that the subjects received. There were no statistically significant differences in the type of antibiotics received between the 2 groups; 4 Journal of Pharmacy Practice XX(X) Table 2. Systemic Antibiotic Details. Antibiotic Detail OVP (n ¼ 32) No Prophylaxis (n ¼ 59) P Value Daily doses received (sum, g) Aminoglycosides Carbapenems Cephalosporins Clindamycin Fluoroquinolones Macrolides Penicillins Vancomycin Antibiotic duration (days), mean (SD) 6.87 72.5 33.25 0 12.7 13.67 111.82 75.02 10.7 (13) 13.25 35.25 120.16 12.33 54.5 18 53.96 68.4 7.2 (6) .48 <.01 .08 .11 .07 .32 <.01 .01 .04 Abbreviations: OVP, oral vancomycin prophylaxis; SD, standard deviation. Figure 2. Clostridium difficile infection (CDI) recurrence based on whether oral vancomycin prophylaxis (OVP) was received in subjects with a more recent history of CDI (RecentHx; 0-6 months prior to receiving subsequent antibiotics) versus an older history of CDI (OlderHx; 6-12 months prior to receiving subsequent antibiotics). Figure 1. Clostridium difficile infection (CDI) recurrence within 12 months based on whether or not the subject received oral vancomycin prophylaxis (OVP). however, differences were seen in the total daily doses of carbapenems, penicillins, and vancomycin that were received between the groups. The OVP group also had a longer mean duration of antibiotic treatment (10.7  vs 7.2  days; P ¼ .04). The odds of developing CDI recurrence were significantly lower in subjects who received OVP (6.3% [2/32] vs 28.8% [17/59]; odds ratio [OR]: 0.16; 95% CI: 0.04-0.77; P ¼ .01; Figure 1), including patients whose i-CDI was an initial episode (3.7% [1/27] vs 28.3% [15/53]; OR: 10.3; 95% CI: 1.2882.6; P ¼ .009). Recurrence in OVP patients receiving 250 mg 4 times daily versus 125 mg 4 times daily was 9.1% (2/22) and 0% (0/10), respectively. For the secondary outcomes, Figure 2 shows a subgroup analysis of subjects whose i-CDI was recent versus older. The odds of recurrence in subjects with a recent history of CDI were 7.4% (2/27) in the OVP group compared to 27.9% (12/43) in the group without OVP. In subjects with an older history of CDI, odds of recurrence were 0% (0/5) in the OVP group compared to 31.3% (5/16) in the group without OVP. Significantly more patients remained CDI-free at Figure 3. Subjects without a Clostridium difficile infection (CDI) recurrence over time based on whether oral vancomycin prophylaxis (OVP) was received. 52 weeks, with recurrences occurring considerably later in the OVP group (median: 49 days, IQR: 42-55 days) compared to the no OVP group (median: 17 days, IQR: 4-153 days, P ¼ .0138; Figure 3). VRE infections occurred in 6.3% (2/32) of subjects in the OVP group and 3.4% (2/59) of subjects in the group without prophylaxis (P ¼ .44). Discussion While there are no current guidelines that outline the best way to prevent CDI recurrences, the 2017 IDSA/SHEA C difficile guidelines provide some input.17 These guidelines mention that it may be prudent to administer low doses of vancomycin if an institution decides to recommend CDI prevention agents, although the long-term benefit is unknown. The update also Knight et al describes factors that may influence the decision to administer secondary prophylaxis, including length of time from previous CDI and number of previous CDI episodes. This study may further guide decision-making as it elaborates on some of the described factors and addresses some potential long-term benefits. Similar to the previous studies, this study showed that subjects with a history of CDI who required subsequent antibiotic exposure were less likely to have a recurrent CDI if they received OVP in conjunction with the antibiotics.22 However, a key strength that differentiates this study from the study performed by Carignan et al is the finding of a treatment effect for OVP following both initial and recurrent CDI episodes. Carignan et al showed a treatment effect only in patients whose i-CDI was a recurrent episode. This study also differs from previous studies in that recurrence was defined as symptoms plus a PCR-confirmed CDI within 12 months of a subsequent hospitalization with systemic antibiotic exposure. The studies conducted by Van Hise et al and Carignan et al defined recurrence of CDI within 4 weeks and 6 months, respectively.22,23 Although there is literature suggesting that the highest risk for CDI is during the first 30 days after antibiotic use, the question of whether OVP provides long-term benefits in preventing recurrence still exists.27 In addition to less overall CDI recurrence, our study found that when subjects who received OVP did have a recurrence, it occurred significantly later than those who did not receive OVP. Although extending the follow-up period for recurrence to 12 months to assess long-term efficacy does leave open the possibility for reinfection with a different strain, a study by Kamboj et al examined relapse versus reinfection in 102 patients and suggests that the number of CDI episodes classified as new infections may be misrepresented.28 That study found that for CDI episodes occurring >8 weeks after the initial episode (range: 56-337 days), the majority were due to the original infecting strain thus representing a relapse and not a new infection. Therefore, patients may still be at risk for recurrence within 12 months of antibiotic exposure. Since there is limited literature evaluating the use of prophylaxis to prevent CDI recurrence, determining which subjects should receive OVP was a secondary aim of the study. The question of whether subjects who had a previous CDI up to 12 months prior to receiving subsequent antibiotics would benefit from OVP was evaluated and a statistically lower number of recurrences were seen in those who received OVP. The largest study to date in this population only assessed subjects whose previous CDI was within 90 days of their subsequent antibiotic exposure.22 Despite the potential benefit of OVP for CDI prophylaxis, development of VRE infections is a concern that should not be overlooked. 29,30 Risk factors for hospital-acquired VRE include previous treatment with antimicrobials, particularly vancomycin, metronidazole, and some others.30,31 This study evaluated the number of VRE infections in subjects receiving OVP and found no significant differences between the 2 5 groups. However, it should be noted that not all patients were tested for VRE. The few subjects in both groups who did develop a subsequent VRE infection did not have any prior documented instances of VRE. To the knowledge of the study investigators, there have been no other studies to date that assessed the risk of developing VRE in patients who received vancomycin as prophylaxis. There were some notable limitations of this study. It was retrospective in nature and only included subjects from a single institution. Since the investigators only had access to medical records at the study hospital, subjects who may have been admitted to other hospitals with CDI recurrences could not be accounted for. There were also some differences in the duration and total daily doses of antibiotics received between the 2 groups. However, since antibiotic duration was longer and more subjects received carbapenems in the OVP group, which are both factors associated with higher risk of CDI, this may help reaffirm the treatment effect of OVP. The OVP group received more total daily doses of penicillins and vancomycin as well, but since these classes are typically less frequently associated with CDI compared to other antibiotics, this likely did not impact the results. Additionally, there was a variation in OVP dosing, although most subjects in the OVP group received 250 mg 4 times daily dosing, some subjects did receive 125 mg 4 times daily. While the updated IDSA guidelines suggest that once-daily dosing may be feasible for prevention, there were no published guidelines during the study period. This may explain why, similar to the studies performed by Carignan et al and Van Hise et al which had similar study periods, OVP doses were higher that what may have been necessary.22-23 However, since the 2 subjects in OVP group who had recurrences both received the 250 mg 4 times daily dosing, it can be assumed that the higher doses did not necessarily provide enhanced reduction over the lower doses, or impact the results. Further studies to determine the optimal dosing of OVP are warranted and there are several currently in the recruitment phase to evaluate once-daily dosing according to the US National Library of Medicine clinical trials registry. The subgroup analysis that was performed comparing subjects with a recent versus older history of CDI was not adequately powered to make any implications as to whether one subgroup benefitted more from OVP over the other. The rationale behind this subgroup analysis was to compare OVP efficacy in patients who had a less recent versus more recent CDI history, since the majority of patients analyzed in previous studies had previous CDI episodes within 6 months of their subsequent antibiotic exposure. Conclusion This study demonstrated that using OVP in subjects with a history of CDI up to 12 months prior to subsequent antibiotic exposure resulted in a significant reduction in the risk of CDI recurrence for up to 12 months. Further studies are needed to 6 prospectively confirm these findings and to assess the effectiveness of lower doses of OVP in preventing CDI recurrence. Authors’ Note A portion of this study was previously presented at Eastern States Residency Conference—a pharmacy residency conference in Hershey, Pennsylvania. Declaration of Conflicting Interests The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. References 1. Ofosu A. Clostridium difficile infection: a review of current and emerging therapies. Ann Gastroenterol. 2016;29(2):147-154. 2. McDonald LC, Killgore GE, Thompson A, et al. An epidemic, toxin gene-variant strain of Clostridium difficile. N Engl J Med. 2005;353(23):2433-2441. 3. Bartlett JG. 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