ORI GI NAL PAPER

Rifaximin versus Other Antibiotics in the Primary Treatment

and Retreatment of Bacterial Overgrowth in IBS
Janet Yang Hyo-Rang Lee Kimberly Low
Soumya Chatterjee Mark Pimentel
Received: 13 November 2006 / Accepted: 5 April 2007 / Published online: 23 May 2007
Springer Science+Business Media, LLC 2007
Abstract
Purpose Previous studies demonstrate improvement in
IBS after antibiotic therapy, with the greatest efcacy seen
with the antibiotic, rifaximin. The purpose of this study
was to compare the efcacy of rifaximin in both the
treatment and retreatment of IBS.
Methods A retrospective chart review was conducted on
Rome I-positive IBS patients. Charts were reviewed to
evaluate all antibiotic treatments (rifaximin, neomycin,
doxycycline, amoxicillin/clavulanate, and ciprooxacin),
even those predating 1 July 2004. Data collection included
symptoms, breath test results (pre- and post-treatment),
antibiotics used, and clinical response to individual anti-
biotic treatments before and after rifaximin availability in
the USA.
Results Out of 98 eligible charts, 84 patients received one
course of rifaximin. Fifty of these (60%) had a follow-up
breath test. Among these, 31 (62%) were clinical
responders and 19 (38%) were nonresponders. Of 31
responders, 25 (81%) had a normal follow-up breath test
compared with only 3 of the 19 nonresponders (16%)
(P < 0.001). Of participants given rifaximin, 69% (58 out
of 84) had a clinical response compared with only 38% (9
out of 24) with neomycin (P < 0.01) and 44% (27 out of
61) with all non-rifaximin antibiotics (P < 0.01).
Rifaximin was used as retreatment on 16 occasions, and all
patients improved.
Conclusions Rifaximin is more effective than other
antibiotics in the treatment and retreatment of IBS.
Keywords Rifaximin Irritable bowel syndrome
Small intestinal bacterial overgrowth Lactulose breath test
Introduction
Irritable bowel syndrome (IBS) is a common disorder
associated with bloating, altered bowel habits, and
abdominal pain [1]. Although it has been reported to affect
1520% of the general population [2, 3], its etiology
remains unknown. There have been several hypotheses
characterizing IBS, including altered gut motility [4],
peripheral [5] and central [6] sensory dysfunction, and an
abnormal response to stress [7]. However, there has been
no single diagnostic test associated with IBS. Conse-
quently, clinical criteria, such as the Rome criteria, have
been developed to aid in diagnosing and categorizing this
syndrome [1, 8, 9].
It has been noted that the symptoms of IBS are similar to
those of small intestinal bacterial overgrowth (SIBO) [10],
a condition caused by colonization of the small bowel with
bacteria that normally reside in the colon. Accordingly, we
have demonstrated in two recent studies that abnormal
lactulose breath tests (LBTs) are more prevalent in IBS
sufferers compared with controls [11, 12]. We have also
shown that antibiotic treatment in IBS sufferers leads to
symptomatic improvement [11, 12]. Moreover, normali-
zation of the LBT after antibiotic treatment correlates with
the degree of clinical improvement [12], suggesting that
the LBT is useful in evaluating SIBO after treatment. More
recent literature using glucose breath testing [13, 14] and
small bowel culture [15] conrm the concept that the small
J. Yang H.-R. Lee K. Low S. Chatterjee
M. Pimentel (&)
GI Motility Program, GI Motility Laboratory, Cedars-Sinai
Burns and Allen Research Institute, Cedars-Sinai Medical
Center, 8730 Alden Drive, Suite 225E, Los Angeles, CA 90048,
USA
e-mail: pimentelm@cshs.org
1 3
Dig Dis Sci (2008) 53:169174
DOI 10.1007/s10620-007-9839-8
bowel of IBS patients contains more bacteria. All of these
studies support the association between SIBO and IBS.
The current standard of treatment for SIBO is empiric
therapy with broad spectrum antibiotics [16, 17]. Tetracy-
clines are commonly used, though there have been few
controlled studies describing the most appropriate choice
or duration of antibiotic therapy [18]. Moreover, conven-
tional antibiotics often suffer from poor efcacy, with only
3040% of SIBO eradication reported with the use of
noroxacin and amoxicillin/clavulanic acid [19]. High
rates of SIBO recurrence are another problem. For exam-
ple, while Attar et al. was able to show in a clinical trial
that both amoxicillin/clavulanic acid and noroxacin were
effective in treating SIBO, it was also noted that diarrhea
quickly recurred after withdrawal of the antibiotic [19].
Data such as these have led to the use of rotating courses of
antibiotics. Multiple antibiotic retreatment courses are
concerning because they increase the likelihood of bacte-
rial resistance and future treatment failure.
Rifaximin has recently become an antibiotic of interest
in the treatment of IBS and SIBO since it has a broad
spectrum of coverage without the associated bacterial
resistance of other antibiotics [20]. As a synthetic,
nonabsorbable derivative of rifamycin, it has virtually no
systemic absorption, minimizing adverse side effects while
maintaining good luminal antibacterial activity [20]. In a
double-blind, randomized, controlled trial comparing the
effects of a 7-day course of rifaximin (1,200 mg/day) and
chlortetracycline (1 g/day), Di Stefano et al. demonstrated
eradication of SIBO in 70% of patients treated with rif-
aximin compared with 27% of patients treated with
chlortetracycline, based on normalization of a glucose
breath test [18]. Furthermore, two recent controlled trials
have now demonstrated that rifaximin is superior to pla-
cebo in IBS global improvement as well [21, 22]. Although
rifaximin appears effective, studies on retreatment are
lacking.
The objective of this study was to determine the efcacy
of rifaximin both in eradicating SIBO in IBS sufferers and
in improving symptoms. We also aimed to compare the
efcacy of rifaximin to other antibiotics in initial and
recurrent treatments of SIBO.
Materials andmethods
Patient population
A retrospective chart review was conducted on consecutive
Rome I-positive IBS patients seen at the GI Motility Pro-
gram (Cedars-Sinai Medical Center) between 1 July 2004,
and 31 October 2005. This interval was chosen as the time
period of FDA approval of rifaximin for travelers diarrhea.
Only patients with a positive LBT in addition to at least
one follow-up visit were included. An abnormal breath test
was one in which the hydrogen or methane values rose to
more than 20 ppm at or before 90 min of ingestion of 10 g
of lactulose. Furthermore, patients were included if they
had at least one treatment for their IBS based on breath test
and at least one follow-up documenting the outcome of that
treatment. In general, our approach for all patients was to
treat the IBS patient and positive breath test with antibiotic
followed by nightly tegaserod to prevent recurrence.
Patients with inammatory bowel disease or other GI
disorders were excluded.
Data extraction
During data extractions, note was made of any previous
gastrointestinal surgery or any known GI disorder besides
IBS. The number of visits to the center for follow-up was
also documented. Patient charts were reviewed to evaluate
all prior antibiotic treatments, even those predating 1 July
2004. The breath test hydrogen and methane levels during
the 180 min of conventional recording were documented.
The overall clinical response in bowel function to each
antibiotic was noted if available in review. Specically, the
review determined to nd out if the patient was satised
with their improvement. In most cases, the motility pro-
gram recorded a percent overall improvement in symptoms
in follow-up and, if documented, this too was recorded. In
all cases, treatment was recorded categorically as
improvement or no improvement.
Data analysis
The percent improvement in IBS overall was noted for
10 days of rifaximin 400 mg tid. This was compared with
other previously used antibiotics. The number of partici-
pants with improvement of greater than 50% was used, as
well as the categorical notation of improvement or no
improvement. If data were available, the response to a
specic symptom was noted. These included bloating,
diarrhea, constipation, and abdominal pain. The clinical
response to rifaximin was then compared between subjects
with and without normalization of their respective abnor-
mality on LBT after antibiotic treatment. This included a
subanalysis to evaluate the success of rifaximin in treating
breath tests in which methane gas was present.
The clinical response to rifaximin was further compared
with responses of the same participant to prior antibiotic
use. Among participants in whom a single antibiotic had
been used on more than one occasion, the ability of the
subsequent use to improve symptoms or normalize the
170 Dig Dis Sci (2008) 53:169174
1 3
breath test was compared between rifaximin and other
antibiotics. This was to evaluate antibiotic resistance and
success of retreatment.
Statistical analysis
When comparing the proportion of clinical responders
among rifaximin-treated IBS patients with those who had
received other antibiotics, a Fishers exact test was used.
Signicance was set at P < 0.05.
Results
Study patients
After inclusion and exclusion criteria were applied, 98
participant charts were eligible and summarized. Of these,
84 patients received at least one course of rifaximin. The
median duration of patient time in clinical treatment was
11 months (range 136 months).
Response to rifaximin
Of the 84 participants who received rifaximin, 1,200 mg
per day, 58 (69%) had a clinical response to therapy. Of
these 84 patients, 50 had a follow-up LBT. Among these,
31 (62%) were clinical responders to rifaximin and 19
(38%) were nonresponders (Table 1). Normalization of the
LBT was predictive of clinical response, since 25 of the 31
clinical responders to rifaximin (81%) normalized their
breath test after treatment. This is in contrast to LBT
normalization occurring in only 3 of the 19 participants
(16%) who did not have a clinical response to rifaximin
(P < 0.001).
Among the 84 participants who received rifaximin, 7
had an abnormal breath test with methane production as
well as a follow-up breath test. In these 7 methane pro-
ducers, 4 (57%) were clinical responders, and 3 of these 4
methane-positive responders had a normal follow-up breath
test. None of the three treatment failures normalized their
breath tests (P = 0.11). In cases in which a follow-up
breath test was not conducted in this study, 68% had a
clinical response.
Rifaximin versus other antibiotics
In contrast to the 69% clinical response seen with rifaximin
treatment, a response was seen in only 27 of the 61 patients
(44%) who in the past had received any antibiotic besides
rifaximin (P < 0.01 when compared with rifaximin;
Table 2). Since neomycin has been studied in IBS [12], we
specically looked at the effect of neomycin on clinical
response. Prior to rifaximin, 24 participants had received
neomycin, with only 9 (38%) realizing a clinical
improvement. This was signicantly lower than that seen
with rifaximin (P < 0.01). Of the 20 patients who did not
respond to one or more previous trials of pre-rifaximin
antibiotics, 75% (15 out of 20) still had clinical improve-
ment with subsequent rifaximin.
Treatment of symptom recurrence with antibiotics
For cases of recurrence, 24 participants received retreat-
ment with an antibiotic. Rifaximin was used as retreatment
on 16 occasions, and all 16 had clinical improvement.
Rifaximin was used a third time in 4 cases, and again, all
patients responded. In contrast, retreatment was only 25%
effective (2 out of 8) when retreating with doxycycline,
augmentin, and neomycin (P < 0.0001 when compared
with rifaximin).
Discussion
In this retrospective chart review, we found that rifaximin
was superior to conventional antibiotics in producing a
clinical response among IBS patients with an abnormal
LBT. More importantly, IBS sufferers who responded to
antibiotic therapy and later had a relapse of symptoms
requiring retreatment universally responded to rifaximin on
subsequent occasions. This was not the case for other
antibiotics as they were rarely successful in achieving
another clinical response, suggesting bacterial resistance
developed after a single course of a non-rifaximin antibi-
otic. This is the rst study to demonstrate the success of a
single agent in the treatment and retreatment of IBS
symptoms in the context of an abnormal breath test.
The link between SIBO and IBS is supported by their
similar clinical presentations. Bloating, for example, is an
established feature of bacterial overgrowth, caused by the
fermentation of nutrients by small bowel bacteria. IBS
sufferers also experience bloating, with studies demon-
strating excessive hydrogen and methane gas production in
these individuals [12]. Bacterial overgrowth may be the
underlying etiology of this excessive gas. The LBT has
been used to determine the presence of bacterial over-
Table 1 Relationship between clinical response to rifaximin and
follow-up breath tests
Normal follow-up
breath test
Abnormal
breath test
Responders (n=31) 25 6
Nonresponders (n=19) 3 16
P < 0.001
Dig Dis Sci (2008) 53:169174 171
1 3
growth, and we recently reported in two studies that
abnormal LBTs are more prevalent in IBS sufferers [11,
12] compared with 20% in controls. We also showed that
antibiotic treatment leads to symptomatic improvement in
IBS sufferers, with an accordant normalization of the post-
treatment LBT. This suggests that the LBT can be used as
an indicator of bacterial overgrowth eradication in IBS
sufferers [12]. There are now a number of LBT studies
demonstrating an association between breath test ndings
and IBS [1114, 23].
More specic tests for bacterial overgrowth now cor-
roborate the suggestion that a subset of IBS patients may
have bacterial overgrowth. Glucose breath testing is be-
lieved to be a more specic tool in identifying bacterial
overgrowth. In two studies, glucose breath testing was
noted to be abnormal in almost 40% of IBS sufferers
compared with only 5% of healthy individuals [13, 14].
More specically, culture studies of the most proximal
small bowel demonstrated >10
6
coliforms in aspirates of
IBS sufferers 12% of the time [24, 25]. Even more recently,
mean coliform counts were found to be elevated in IBS
compared with controls [15].
Despite these data, the most important factor curtailing
the application of antibiotic therapy in IBS is the lack of
efcacy of conventional antibiotics. Since bacterial over-
growth may occur from a wide range of aerobic and
anaerobic ora, the most effective treatment includes drugs
with broad spectrum antibacterial activity [26]. However,
few controlled studies have evaluated the choice and
duration of therapy in bacterial overgrowth. Antibiotics
such as tetracyclines and uoroquinolones have been
shown to improve symptoms, but their widespread use has
been controversial because of high recurrence rates after
antibiotic withdrawal [19] as well as the increased risk of
bacterial resistance [12]. We showed in a recent study that
neomycin was more effective than placebo in producing a
clinical response [12]. Among the participants treated with
neomycin, LBT normalization correlated with a greater
clinical response; however, normalization was seen in only
20% of the cases [12]. These studies suggest that the cur-
rent, conventional antibiotics are not adequate in eradi-
cating bacterial overgrowth. This, with the additional
concern regarding systemic toxicity of traditional therapy,
has prompted the search for other antibiotics that speci-
cally target gut ora.
Rifaximin is a nonabsorbed (<0.4% systemic absorp-
tion) oral antibiotic. As a rifamycin derivative, it has
antibacterial activity through the inhibition of bacterial
RNA synthesis [27] and is active against Gram-positive
and Gram-negative bacteria, including both aerobes and
anaerobes [28]. In particular, it is effective against anaer-
obes such as bacteroides, lactobacilli, and clostridia, the
bacteria frequently responsible for gut alterations in SIBO
patients [27, 28]. As it is poorly water-soluble and mini-
mally absorbed, it is also associated with less systemic
toxicity. Although currently approved for clinical use in the
treatment of travelers diarrhea due to E. coli [29], it is
already demonstrating utility in multiple intestinal, bacte-
rially-related disorders such as hepatic encephalopathy
[30]. Importantly, rifaximin does not appear to lead to
bacterial resistance and has a low incidence of side effects
[31]. The restricted use of nonabsorbed oral antibiotics
only for enteric infections should also reduce the devel-
opment of widespread resistance [32].
A 1,200-mg daily dose of rifaximin for at least 10 days
has been shown to be more clinically effective in the short-
term treatment of SIBO compared with the more traditional
tetracycline antibiotics. Di Stefano et al. reported normal-
ization of the glucose breath test in 70% of participants
treated with rifaximin as opposed to only 27% treated with
chlortetracycline [18]. No side effects were seen, support-
ing rifaximin as a safe antibiotic for bacterial overgrowth
treatment [18]. Lauritano et al. subsequently studied dif-
ferent dosages of rifaximin and concluded that a 7-day
course of 1,200 mg/day was a good regimen to treat SIBO
both in terms of efcacy and tolerability [33]. In a double
blind study by Sharara et al., rifaximin improved clinical
symptoms in patients with functional bloating and in the
subset with IBS [21]. In this study, breath test normaliza-
tion was not as apparent although clinical improvement
was seen to correlate with an improvement in breath test
measurements. In a follow-up to this, a double blind trial of
rifaximin in IBS has produced lasting clinical improvement
for 10 weeks beyond the initial 10 days of therapy [22].
The current study substantiates the results of these ear-
lier studies by Di Stefano et al. [18] and Lauritano et al.
[33], showing that rifaximin has superior efcacy in
treating SIBO in IBS patients compared with other anti-
biotics. The majority of IBS patients treated with rifaximin
for the rst time experienced greater clinical improvement
Table 2 Comparison of rifaximin and other antibiotics in IBS symptom response rates
Condition (n of participants) Response (%) No response (%) P value when compared with rifaximin
Initial treatment with rifaximin (84) 58 (69) 26 (31)
Initial treatment with neomycin (24) 9 (38) 15 (62) <0.01
Initial treatment with other nonrifaximin antibiotics (61) 27 (44) 34 (56) <0.01
172 Dig Dis Sci (2008) 53:169174
1 3
(69%) than those treated with neomycin (38%) or other
conventional antibiotics (44%). Among those who
responded to rifaximin, 81% had a normal follow-up LBT.
In contrast, only 16% of the rifaximin nonresponders
normalized their breath tests. The high rate of breath test
normalization in clinical responders was not seen in our
previous study with neomycin [12], suggesting that
rifaximin is more effective in SIBO eradication. It also
conrmed that breath test normalization was predictive of
improvement in IBS symptoms [11, 12].
Although the above description of the current study
supports previous data, the study goes further to suggest
that rifaximin works better than other antibiotics at
retreating cases of recurrence. Not only did patients treated
with rifaximin for the rst time respond, but 75% of those
who became refractory to previous antibiotics improved on
a trial of rifaximin. Moreover, retreatment with rifaximin
for recurrence of symptoms after initial success with
rifaximin was almost universally successful as well. In
contrast, retreatment was only 25% successful with
neomycin, augmentin, or doxycycline. The reason for this
may be that rifaximin does not develop the bacterial
resistance typical of other antibiotics.
One limitation of this study is that it was not a pro-
spective study. Another potential criticism involves the
small percentage of patients returning for follow-up LBTs.
This can be refuted by the fact that the majority of these
patients did experience symptomatic improvement.
We have demonstrated in this study that rifaximin is
superior to other antibiotics in improving IBS symptoms
among those with abnormal LBTs. Rifaximin is often
successful even with failure of previous antibiotics.
Furthermore, we have shown that clinical responses are
greatest when the follow-up breath tests have normalized.
This substantiates the results of our previous study [12],
suggesting again that the LBT can be used to assess
treatment outcomes in IBS patients with SIBO. The
majority of patients who fail to respond to other antibiotics
still respond to rifaximin, both in initial and retreatment
regimens. Unlike conventional antibiotics, retreatment with
rifaximin is universally efcacious, suggesting a lack of
bacterial resistance development.
Acknowledgements This study was funded through an unrestricted
investigator grant with Salix Pharmaceuticals.
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