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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 [3] vs 4.2 [3] 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 [13] vs 7.2 [6] 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.
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