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Results
Publication data Of 1356 articles identified, 10 met inclusion criteria. Rifaximin was the most
Submitted 15 April 2013 commonly studied antibiotic (eight studies) with overall breath test normalisa-
First decision 26 May 2013
tion rate of 49.5% (95% confidence interval, CI 44.0–55.1) (44.0%–55.1%) then
Resubmitted 15 August 2013
Accepted 16 August 2013
(46.7%–55.5%), then (4.6%–17.8%). Antibiotic efficacy varied by antibiotic
EV Pub Online 4 September 2013 regimen and dose. Antibiotics were more effective than placebo, with a com-
bined breath test normalisation rate of 51.1% (95% CI 46.7–55.5) for antibiotics
As part of AP&T’s peer-review process, a compared with 9.8% (95% CI 4.6–17.8) for placebo. Meta-analysis of four stud-
technical check of this meta-analysis was ies favoured antibiotics over placebo for breath test normalisation with an odds
performed by Mr M. Siddiqui. ratio of 2.55 (95% CI 1.29–5.04). Clinical response was heterogeneously evalu-
ated among six studies, but tended to correlate with breath test normalisation.
Conclusions
Antibiotics appear to be more effective than placebo for breath test normalisa-
tion in patients with symptoms attributable to SIBO, and breath test normalisa-
tion may correlate with clinical response. Studies were limited by modest
quality, small sample size and heterogeneous design. Additional higher quality
clinical trials of SIBO therapy are warranted.
The mean rate of breath test normalisation was calcu- Breath test normalisation
lated along with the 95% confidence interval (CI) using The pooled rate of breath test normalisation varied
the CI calculator in Stata. widely across different antibiotics and doses (Table 4).
When feasible, meta-analysis was performed to com- Rifaximin monotherapy was evaluated in eight studies
pare breath test normalisation among different treatment with pooled rate of breath test normalisation ranging
regimens. A random-effects model estimated the from 21.7% (95% CI 12.1–34.2) at low doses to 46.1%
weighted average of the breath test normalisation rate (95% CI 35.4–57.0) at high doses to 60.8% (95% CI
ratio between treatment interventions.13 Relative risk 53.2–68.1) at medium doses. For all trials of rifaximin
ratios for normalisation of breath tests with 95% CIs monotherapy combined, the aggregate breath test nor-
were calculated for each analysis, and a forest plot was malisation rate was 49.5% (95% CI 44.0–55.1). Rifaximin
generated to graphically represent the available studies. combined with partially hydrolysed guar gum was used
Due to the small number of studies that were appropri- in one study with a breath test normalisation rate of
ate for meta-analysis, sensitivity analyses were not possi- 85% (95% CI 70.2–94.3). Metronidazole was used in two
ble. A statistically significant result was observed with a studies, with a combined breath test normalisation rate
95% CI not crossing 1.0 and a P value <0.05. Heteroge- of 51.2% (95% CI 40.1–62.1). Ciprofloxacin had the
neity was calculated using Mantel–Haenszel chi-squared highest rate of breath test normalisation (100%, 95% CI
test with a P < 0.10 representing significant heterogene- 76.8–100.0), but this was based on a single study with
ity. Because it was only possible to meta-analyse four rel- only 14 subjects in each treatment arm. For all antibiotic
atively small studies, we did not assess for publication regimens combined, breath test normalisation occurred
bias, because the small sample size made such analysis in 51.1% (95% CI 46.7–5.5). Conversely, only 9.8% (95%
unreliable. All statistical analyses were calculated using CI 4.6–17.8) of placebo-treated subjects among four
STATA 11.0 (Stata Corp, College Station, TX, USA). studies had breath test normalisation.
Collins United DB, RCT Not reported Children with Rifaximin vs. LBT LBT normal 14 60 Light meal the No probiotics
(2011) States chronic placebo days after night before for 60 days
abdominal pain treatment
Chang United DB, RCT 2006–2008 Coeliac patients Rifaximin vs. LBT LBT normal 4 30 Multiple food None
(2011) States with abdominal placebo days after exclusions
symptoms treatment the day before
Furnari Italy OL, RT 2007–2010 Adults with Rifaximin vs. GBT GBT normal 30 10 Boiled rice, No probiotics
(2010) SIBO Rifaximin days after meat and or proton pump
symptoms plus PHGG treatment water the inhibitors for
night before 10 days
Lauritano Italy OL, RT 2005–2007 Adults with Rifaximin vs. GBT GBT normal 30 90 Carbohydrate No laxatives for
(2009) SIBO metronidazole days after restricted 30 days
symptoms treatment the night before
Scarpellini Italy OL, RT 2004–2006 Adults with Rifaximin GBT GBT normal 30 90 Carbohydrate No laxatives
(2007) SIBO (compared days after restricted for 30 days
symptoms multiple doses) treatment the night before
Lauritano Italy OL, RT 2003–2004 Adults with Rifaximin GBT GBT normal 30 30 Carbohydrate No laxatives
(2005) SIBO (compared days after restricted for 30 days
symptoms multiple doses) treatment the night before
Castiglione Italy OL, RT 2000–2002 Adults with Metronidazole vs. LBT GBT normal 7 30 No starch None
(2003) Crohn’s ciprofloxacin followed days after for 48 h
disease by GBT treatment
Pimentel United DB, RCT Not reported Adults meeting Neomycin vs. LBT LBT normal 7 90 No legumes ‘All use
(2003) States Rome I placebo days after or heavy prohibited’
criteria treatment foods the
for IBS night before
Biancone Italy Blinded‡, Not reported Adults with Rifaximin vs. GBT GBT normal 14 Not No specific None
(2000) RT Crohn’s placebo days after reported restrictions
disease treatment
Di Stefano Italy DB, RT Not reported Adults with Rifaximin vs. GBT GBT normal 3 30 Rice, meat and None
(2000) SIBO chlortetracycline days after olive oil the
symptoms treatment evening before
DB, double-blinded; GBT, glucose breath test; IBS, irritable bowel syndrome; LBT, lactulose breath test; OL, open-label; PHGG, partially hydrolysed guar gum; RCT, randomised con-
trolled trial; RT, randomised trial; SIBO, small intestinal bacterial overgrowth.
* These data are meant to be descriptive and do not represent analytical subgroups.
† Unless otherwise stated, subjects were NPO for 12 h before testing.
‡ Unclear whether single- or double-blinded.
to 6.4 for chlortetracycline).21 Castiglione et al. found no ogeneous populations, there was no evidence of statistical
differences in bloating, stool quality or abdominal pain heterogeneity (P = 0.32 for heterogeneity). Treatment of
comparing metronidazole with ciprofloxacin (composite SIBO with any antibiotic was associated with higher rate
score not reported).19 The Chang and Collins studies of breath test normalisation compared with placebo
reported no differences in symptoms for subjects treated (effectiveness ratio 2.55, 95% CI 1.29–5.04, P = 0.03).
with rifaximin vs. placebo, but objective data were not The second meta-analysis included three stud-
reported in either study.14, 22 ies14, 20, 22 comparing rifaximin with placebo (Figure 3).
Four of the studies16–18, 20 reported no data regarding Although these studies included heterogeneous popula-
symptoms. tions, there was no evidence of statistical heterogeneity
(P = 0.41 for heterogeneity). Treatment with rifaximin
Meta-analysis was associated with a higher rate of breath test normali-
Two meta-analyses were possible. The first included four sation compared with placebo, although this was not
studies6, 14, 20, 22 comparing any antibiotic therapy with statistically significant (effectiveness ratio 1.97, 95% CI
placebo (Figure 2). Although these studies included heter- 0.93–4.17, P = 0.08).
Cures in Cures in
Subjects in treatment Subjects in treatment
treatment arm Treatment treatment arm 2, Statistical
Study Treatment arm 1* arm 1, n 1, n (%) arm 2* arm 2, n n (%) significance
Collins Rifaximin 1650 mg/day 49 9 (18.4) Placebo three times 26 3 (11.5) NS
(2011) 910 days daily 910 days
Chang Rifaximin 1200 mg/day 11 2 (18.2)† Placebo three times 16 3 (18.8)† NS
(2011) 910 days daily 910 days
Furnari Rifaximin 1200 37 23 (62.2) Rifaximin 1200 mg/day 40 34 (85.0) P < 0.05
(2010) mg/day 910 days plus PHGG
5 g daily 910 days
Lauritano Rifaximin 1200 mg/day 71 45 (63.4) Metronidazole 250 mg 71 31 (43.7) P < 0.05
(2009) 910 days three times
daily 910 days
Scarpellini Rifaximin 1600 mg/day 40 32 (80.0) Rifaximin 1200 mg/day 40 23 (57.5) P < 0.05
(2007) 97 days 97 days
Lauritano Rifaximin 600 mg/day 30 5 (16.7) Rifaximin 800 mg/day 30 8 (26.7) P < 0.05
(2005) 97 days 97 days for arm 3‡
compared
with arms
1 and 2
Castiglione Metronidazole 250 mg 15 13 (86.7) Ciprofloxacin 500 mg 14 14 (100.0) NS
(2003) three times daily twice daily 910 days
910 days
Pimentel Neomycin 500 mg twice 41 8 (19.5) Placebo twice daily 43 1 (2.3) Not
(2003) daily 910 days 910 days reported
Biancone Rifaximin 1200 mg/day 7 7 (100.0) Placebo three times 7 2 (28.6) P < 0.05
(2000) 97 days daily 97 days
Di Stefano Rifaximin 1200 mg/day 10 7 (70.0) Chlortetracycline 11 3 (27.3) P < 0.05
(2000) 97 days 333 mg
three times
daily 97 days
Quality assessment any apparent conflict of interest. Two studies did not report
Quality of reporting across the studies varied. No studies a funding source, while two studies reported pharmaceuti-
showed evidence of selective outcome reporting, and two cal company funding. See Table S1 for more details.
studies had incomplete outcome data. The protocol for
sequence generation of antibiotic and/or placebo was high DISCUSSION
quality in six studies, but reporting was inadequate to cha- Given the prevalence of SIBO and its potential for signif-
racterise sequence generation in the other four studies. icant consequences when left untreated, we found a sur-
Seven studies had high-quality allocation concealment, prising lack of depth in the literature describing
while three studies did not provide enough information to antibiotic therapy for SIBO. Our extensive literature
classify allocation concealment. Reporting of blinding was search produced only 10 studies describing antibiotic tri-
adequate in 9 of 10 studies; however, only four studies had als for SIBO meeting inclusion criteria. The majority of
high-quality blinding of participant, personnel and out- studies were of modest size, and most were open-label
come. Six studies reported funding that did not indicate randomised trials. Only two antibiotics (metronidazole
Number of Total number Number with breath Per cent with breath 95% confidence
Treatment studies of subjects test normalisation test normalisation interval*
Rifaximin 1600 or 1650 mg/day 2 89 41 46.1 35.4–57.0
Rifaximin 1200 mg/day 6 176 107 60.8 53.2–68.1
Rifaximin 600 or 800 mg/day 1 60 13 21.7 12.1–34.2
Rifaximin monotherapy (all 8 325 161 49.5 44.0–55.1
doses combined)
Rifaximin plus PHGG 1 40 34 85.0 70.2–94.3
Metronidazole 2 86 44 51.2 40.1–62.1
Neomycin 1 41 8 19.5 8.8–34.9
Ciprofloxacin 1 14 14 100.0 76.8–100.0
Chlortetracycline 1 11 3 27.3 6.0–61.0
All antibiotics 10 517 264 51.1 46.7–55.5
Placebo 4 92 9 9.8 4.6–17.8
PHGG, partially hydrolysed guar gum.
* Calculated using the confidence interval function of Stata.
Effectiveness ratio
Study – (95% Cl) % Weight
Figure 2 | Meta-analysis of
.1 1 10
any antibiotic vs. placebo.
Effectiveness ratio
and rifaximin) were evaluated in more than one study. Measurement of symptoms pre- and post-treatment
Only four studies compared antibiotics with placebo, and was even more heterogeneous. Only two studies6, 15
meta-analysis of these studies suggested modest benefit reported symptom data using objective, composite clini-
of antibiotic over placebo. Our findings call attention to cal scores. Unfortunately, the remaining eight studies
several important issues and considerations for SIBO were much more limited, with four studies reporting on
therapy and research moving forward. clinical response in a limited fashion,14, 19, 21, 22 and the
In the meta-analyses, we were unable to reject the null other four reporting no data regarding symptoms and
hypothesis of no statistical heterogeneity, likely due to clinical response.16–18, 20 As SIBO therapy is most fre-
the small number of studies meta-analysed. For the 10 quently driven by a desire to reduce or eliminate bother-
studies included in our overall review, though, there was some symptoms, this is an important gap in the
evident heterogeneity in study design, including popula- literature that should be addressed. Specifically, addi-
tions studied, pre-study restrictions, treatment regimens tional large, randomised, double-blind trials assessing
used, type and timing of breath testing, and assessment both breath test normalisation and objectively measured
of clinical response (Table 2). This limits our ability to symptomatic response are needed.
draw firm conclusions regarding choice of antibiotics for Because case series and observational studies carry sig-
breath test normalisation among patients with SIBO. nificant risk of publication bias, we chose a priori to
Effectiveness ratio
Study – % Weight
(95% Cl)
Figure 3 | Meta-analysis of
.1 1 10
rifaximin vs. placebo.
Effectiveness ratio
include only clinical trials comparing placebo and/or anti- single study included only 14 subjects in each arm.19 Aside
biotics. Given the limited nature of our meta-analysis, we from this small trial, the most effective treatment regimen
chose to calculate pooled rates of breath test normalisa- was rifaximin plus partially hydrolysed guar gum, which
tion for the various treatment regimens, including varying was associated with an 85% breath test normalisation
doses of rifaximin (Table 4). The purpose of this analysis rate.15 Partially hydrolysed guar gum is a prebiotic agent
was to provide summative data that would be more clini- that favours growth of Bifidobacteria and Lactobacillus
cally useful. Rifaximin was the most commonly studied spp., among others.24 Treatment with antibiotics alone
antibiotic, with 8 of 10 studies evaluating monotherapy at does not fully address the microbial dysbiosis associated
varying doses. The overall breath test normalisation rate with SIBO, as antibiotics do not restore normal flora.15
for rifaximin monotherapy was only 49.5% (95% CI 44.0– Accordingly, the addition of pre- or probiotics is an
55.1), but this ranged widely from 16.7% to 100%. This attractive option.25 Probiotics are postulated to enhance
wide range may be attributable to variability in study pop- gut barrier function, decrease inflammatory response, sta-
ulations, dosing strategies and timing of post-treatment bilise gut flora and potentially modulate visceral hypersen-
breath testing. In meta-analysis (Figure 3), rifaximin had sitivity.26 Their use has been best described among
an effectiveness ratio of 1.97 compared with placebo, but patients with irritable bowel syndrome and Clostridium
this was not statistically significant (95% CI 0.93–4.17, difficile infection27–30 and our understanding of these ther-
P = 0.08). The lack of statistical significance likely relates apies in SIBO remains limited. Prebiotics, in contrast, alter
to relatively small numbers of subjects (67 subjects gut microbiota indirectly by favouring growth of certain
received rifaximin and 49 received placebo among all bacterial species via provision of metabolites. The thera-
three studies combined), and it is possible that a true ben- peutic profile of prebiotics is less well defined and avail-
efit for rifaximin exists compared with placebo. able data are generally of poor quality.31 As noted above,
Other antibiotics were notably less studied, with met- the Furnari15 study was the only study meeting inclusion
ronidazole being most common after rifaximin, and still criteria that included a prebiotic, and none of the studies
limited to only two studies. As rifaximin is costly and meeting inclusion criteria included a probiotic arm. In our
may be unavailable to many patients, more thorough overall search of the literature, only one other fully
investigation of alternate antibiotic choices is warranted, reviewed article included a probiotic arm.32 In this small
ideally double-blind studies comparing other antibiotics study (which did not meet inclusion criteria), the adminis-
with rifaximin. Such data would be useful not only for tration of oral Lactobacillus spp. did not reduce symptoms
primary treatment of SIBO but also to inform therapeu- or result in breath test normalisation among patients with
tic choices for patients with recurrent or refractory SIBO, SIBO.32 The role of microbiome-related therapy for SIBO
which are not uncommon clinical entities.10, 23 is intuitive. As techniques to study the human microbiome
Numerically, the most effective antibiotic was ciproflox- advance, this will become an increasingly important area
acin, with a 100% breath test normalisation rate, but the for further attention and research.
We chose to assess breath test normalisation as our pri- In summary, we identified 10 studies comparing antibi-
mary outcome of interest due to its ubiquity in SIBO trials otic therapies for SIBO. Antibiotic therapy appears to be
and the aforementioned lack of standardisation in symp- superior to placebo for the eradication of SIBO, but the
tom reporting. Proximal intestinal aspirates were previ- small number of heterogeneously designed studies pre-
ously accepted as the gold standard for diagnosing SIBO, vented more detailed meta-analyses of different treatment
but methodological considerations (such as obtaining a regimens. Future studies of SIBO should address the short-
representative sample, culturing fastidious bacteria, and comings of these studies. Trials involving larger patient
differentiating culprit strains from contamination or non- populations, comparing a greater diversity of antibiotics
pathogenic strains) limits the utility of this test, particu- with one another and with placebo, are needed. The use of
larly if repeat testing after treatment is desired.3 Indirect objective measures of clinical response among patients
tests for SIBO, such as breath test analysis, are therefore being treated for SIBO is critical, as is longer term fol-
appealing.3 The sensitivity and specificity of breath testing low-up assessing durability of response and risk of relapse
varies, but glucose breath testing (sensitivity 63%, specific- among patients successfully treated.
ity 82%, diagnostic accuracy 72%) is thought to be more
accurate than lactulose breath testing (sensitivity 52%, AUTHORSHIP
specificity 86%, diagnostic accuracy 55%).2 Guarantor of the article: Dr. J. L. Sewell.
The transition from an abnormal breath test to a normal Author contributions: Drs. Sewell, Day and Somsouk had
breath test provides biological evidence of a treatment’s full access to all the data in the study and take responsibil-
effectiveness in eradicating bacteria in the small intestine, ity for the integrity of the data and the accuracy of the data
which is necessary to ‘cure’ SIBO. The two studies docu- analysis. Sewell, Day and Somsouk contributed to the
menting clinical response by breath test normalisation6, 15 study concept and design. Sewell contributed to the acqui-
clearly demonstrate that breath test normalisation is highly sition of data. Sewell, Day, Somsouk and Shah performed
associated with reduction in symptoms attributable to the analysis and interpretation of data. Sewell and Shah
SIBO. This is further supported by the four studies report- drafted the manuscript. Day, Somsouk and Sewell per-
ing limited clinical response data. The one study identify- formed the critical revision of manuscript for important
ing differences in breath test normalisation between intellectual content. Sewell, Day and Somsouk performed
treatment arms21 found analogous differences in clinical the statistical analysis. Sewell, Day and Somsouk contrib-
response, whereas the three studies without differences in uted to the study supervision. We thank Gloria Won,
breath test normalisation between treatment arms14, 19, 22 MLIS, for her assistant with the literature search. All
failed to find differences in clinical response. These data authors approved the final version of the manuscript.
suggest that breath test normalisation may correlate with
symptomatic response. Repeat breath testing among ACKNOWLEDGEMENTS
patients who have been treated for SIBO, yet remain symp- Declaration of personal interests: None.
tomatic, may, therefore, have utility in clinical practice, as Declaration of funding interests: MS is supported by the NIH
it may help clarify whether persistent SIBO is the source of K23 CA157929 award. The funder played no role in the
ongoing symptoms, or if other aetiologies, such as irritable design, execution, interpretation or manuscript preparation.
bowel syndrome, should be considered. There are strong MS has received research grant support from Salix Pharma-
data supporting a robust association between SIBO and ceuticals, Inc. for previous research. Salix Pharmaceuticals,
irritable bowel syndrome, with two meta-analyses identify- Inc. was not involved in the present study in any way.
ing a 3.5- to 9.6-fold increased odds of SIBO in patients
with irritable bowel syndrome.33, 34 That rifaximin has SUPPORTING INFORMATION
been shown to be an effective therapy for irritable bowel Additional Supporting Information may be found in the
syndrome patients without constipation further supports online version of this article:
the role of SIBO in irritable bowel syndrome.35 Table S1. Assessment of quality.
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