Rifaximin for the treatment of irritable bowel syndrome – a drug safety evaluationFrancesca Romana Ponziani, Silvia Pecere, Loris Lopetuso, Franco Scaldaferri, Giovanni Cammarotaand Antonio Gasbarrini
Internal Medicine and Gastroenterology Division, A. Gemelli Hospital Rome, Rome, Italy
ABSTRACTIntroduction: Irritable bowel syndrome is a functional gastrointestinal disorder with a multifactorialetiology. Alterations of intestinal motility and immunity, gut-brain interactions, as well as gut micro-biota dysbiosis contribute to the development of irritable bowel syndrome. Therefore, gut microbiotamodulation by non-absorbable antibiotics is a therapeutic option in patients with IBS.Areas covered: Published articles including patients with irritable bowel syndrome reporting dataabout rifaximin activity and safety have been searched throughout the literature and selected.Expert opinion: The optimal antibiotic molecule should be local-acting, long-acting and safe-acting.Rifaximin is a non-absorbable antibiotic with additional anti-inflammatory and gut microbiota-modulat-ing activity. It is effective in inducing symptoms relief in patients with IBS, even after repeatedtreatment courses. Rifaximin-related side effects in patients with IBS are reported to be mild andinfrequent; microbial resistance is rare and transient, due to the high local concentration of the drugand to the absence of horizontal transmission. Clostridium difficile infection is not usual in patientsreceiving rifaximin in absence of predisposing conditions such as hospitalization and immunosuppres-sion, which are uncommon in patients affected by irritable bowel syndrome. Nevertheless rifaximin is anantibiotic active against Clostridium difficile infection. Rifaximin has limited metabolic interactions and isnot expected to interfere with drug metabolism in patients with normal hepatic function. Theseproperties make rifaximin a safe antibiotic for gut microbiota modulation in patients with IBS.
ARTICLE HISTORYReceived 17 February 2016Accepted 3 May 2016Published online 23 May2016
KEYWORDSIBS; gut microbiota;rifaximin; gut barrier; safety
1. Introduction
Irritable bowel syndrome (IBS) is a relapsing gastrointestinalfunctional condition characterized, according to the Rome IIICriteria, by recurrent abdominal pain or discomfort at least3 days/month in the last 3 months, which improves withdefecation or is associated with a change in frequency orform of stools.[1] These symptoms clearly impact quality oflife with important social costs. IBS prevalence in the generalpopulation ranges from 5% to 15%, being one of the mostcommon gastrointestinal functional disorders.[2] Overall,more females than males are affected by IBS. It can beclassified in diarrhea predominant (IBS-D), constipation pre-dominant (IBS-C), mixed subtype (IBS-M), or unclassified (IBS-U) on the basis of prevalent bowel habit. Its diagnosis isbased on clinical assessment, since there are no specificabnormal radiological or endoscopic findings or reliable bio-marker tests. The pathophysiology of IBS is still not clear.However, many factors have been implicated, such as low-grade immune activation, increased mucosal intestinal per-meability, visceral hypersensitivity,[3] and gut microbiotaderegulation.[4] The clinical efficacy of dietary approachesand pharmacological agents able to modulate the gut micro-biota further supports the hypothesis of a role of dysbiosis inIBS pathogenesis.[5]
2. Gut microbial background in IBS
Gut microbiota alteration participates in the pathogenesis ofdiseases without major signs of intestinal inflammation ordamage, such as IBS. Indeed, subjects with IBS-D may havean abnormal lactulose or glucose hydrogen breath test, sug-gesting the presence of small intestinal bacterial overgrowth(SIBO).[6–8] Symptoms associated with IBS (bloating, abdom-inal pain, and altered bowel habits) are generally similar tothose associated with SIBO.[6,9] Furthermore, studies based onnew molecular biology techniques have highlighted signifi-cant differences in the quality, quantity, and temporal stabilityof the gut microbiota in IBS patients as compared to healthycontrols. A reduced diversity of small bowel microbial popula-tions in patients with IBS compared with healthy controls hasbeen reported.[10] In particular, lower levels of coliform bac-teria, Lactobacilli and Bifidobacteria,[11,12] as well as highernumbers of Clostridium species [12] and Enterobacteriaceaehave been found in fecal samples of IBS patients comparedto controls.[13] As regards IBS subtypes, a decreased numberof Lactobacillus species has been reported in IBS-D subjects,while constipated patients have an increased number ofVeillonella species compared to healthy controls.[14] The gutmicrobiota of IBS patients appears less stable over time com-pared to healthy subjects, as shown by denaturing gradient
CONTACT Loris R. Lopetuso [email protected] Internal Medicine and Gastroenterology Division, A. Gemelli Hospital of Rome, Largo Gemelli, Rome100168, Italy
EXPERT OPINION ON DRUG SAFETY, 2016VOL. 15, NO. 7, 983–991http://dx.doi.org/10.1080/14740338.2016.1186639
gel electrophoresis fingerprint profiles [15]; furthermore, thecomposition of mucosa-adherent microbiota is differentbetween IBS patients and healthy controls, beingEubacterium rectale and Clostridium coccoides the predominantbacterial species, accounting for 48% of the total adherentbacteria in IBS compared to 32% of healthy controls. Finally,the density of bacterial biofilm (a layer of micro-organismsthat form a coat on the surface of the intestine) is significantlylarger in IBS patients.[16] More recent data have reinforcedthese observations, showing that the gut microbiota of IBSpatients also differs from that of healthy controls in otherbacterial species, including Coprococcus spp., Collinsella spp.,and Coprobacillus spp.[17] A higher prevalence of Escherichiacoli, Enterococcus spp., and Klebsiella pneumoniae has alsobeen reported in some clusters of IBS patients,[18] with sig-nificantly higher levels of pathogens in those with SIBO thanin those without. Another study described a marked over-representation of Escherichia/Shigella and Aeromonas spp. inIBS-D subjects, while there was an underrepresentation ofLactococcus, Acinetobacter and Citrobacter.[19] Finally,Kerckhoffs et al.[23] found that Bifidobacterium catenulatumlevels were significantly lower in patients with IBS thanhealthy controls.
IBS can also develop in 10% of cases after an acute infec-tious episode of the gastrointestinal tract, and more than halfof subjects may remain symptomatic for bowel dysfunctioneven 6 years after the acute event.[20,21] In these patients,specific and permanent alterations of the gut microbiota havebeen described.[22] It can be assumed that the increasingavailability of new microbiological techniques will result inincreasing knowledge, which may ultimately explain the effi-cacy of the old therapeutic approaches and help to identifynew ones.
These findings provide further evidence that changes insmall bowel microbial composition may underlie the patho-genesis of IBS for some patients.[23] However, not only gutmicrobiota alteration but also other different mechanismsunderlie IBS pathophysiology and this should not be ignored.Likely, microbiota changes could be crucial only in some sub-sets of patients, while could reflect the immediate conse-quence of different primary triggers in others.
3. Rifaximin treatment for IBS: is there a role for anantibiotic in a non-infectious disease?
Based on the role of the gut microbiota in the pathogenesis ofIBS, non-absorbable antibiotics should be one of the
treatment options for this disease. The ideal antibiotic mole-cule for this clinical setting should have a local effect, shouldbe able to improve symptoms producing negligible sideeffects, and should have a broad-spectrum antimicrobial activ-ity and a low resistance profile.
Rifaximin is the non-absorbable antibiotic approved for theuse in patients with IBS, since 2015. Its efficacy in patients withIBS is due to direct bactericidal properties as well as due toindirect effects on the gut microbiota additional to the pri-mary antibiotic activity (Box 1).
In vitro studies demonstrated that rifaximin is able tomodulate bacterial virulence in enterotoxigenic E. coli iso-lates,[24] and that pretreatment of epithelial cells (HEp-2laryngeal cells, HCT-8 ileocecal cells, A549 epithelial lungcells, and HeLa cervical cells) with rifaximin significantlyreduces the adherence of enteroaggregative E. coli comparedto rifampin, acetone, and doxycycline.[25] In the same study,rifaximin also inhibited Bacillus anthracis and Shigella sonneiinternalization into A549 and HeLa cells more effectively thancontrol antibiotics. Moreover, rifaximin can reduce gut micro-biota-driven inflammation by modulating nuclear factorkappa-light-chain-enhancer of activated B cells activationvia the pregnane X receptor [26–28] and can inhibit bacterialtranslocation.[28]
Interestingly, the administration of rifaximin has been asso-ciated with a positive modulation of the gut microbiota char-acterized by the increase in beneficial bacterial strains. Studiesbased on standard microbiological analyses and others basedon continuous cultures [29,30] demonstrated that while rifax-imin does not affect the overall composition of the gut micro-biota, it increases the abundance of Bifidobacterium,Atopobium and Faecalibacterium prausnitzii, which are impor-tant modulators of intestinal health.[31–33] More recent stu-dies in mice models of hyperalgesia [34] highlighted thattreatment with rifaximin may increase the abundance ofLactobacilli, which are known to improve gut barrier function,to reduce stress-induced visceral pain and to downregulatepro-inflammatory cytokines.[35–39] Finally, pyrosequencing of16S ribosomal RNA obtained from fecal samples of patientsaffected by different gastrointestinal diseases including IBS,confirmed an increase in Lactobacillus and Faecalibacteriumabundance following administration of rifaximin.[40,41]
Taking together all the evidences about the additional prop-erties of the antibiotic rifaximin, it is reasonable to argue that theresulting favorable ‘eubiotic’ modulation of the gut microbiotamay contribute to its success in the clinical setting.
One of the first evidences about the efficacy of rifaximinin patients with IBS came from Pimentel’s group (Table 1).[42] Eighty-seven patients who met the Rome I criteria wererandomized to receive either rifaximin 1200 mg daily orplacebo for 10 days; rifaximin arm obtained a higher rateof global symptoms improvement compared to the placeboone, and this result was maintained for the whole studyduration (10 weeks). Another randomized controlled trialincluding 124 patients affected by IBS reported the ameli-oration of bloating and flatulence in 40.5% of cases follow-ing the administration of rifaximin 800 mg for 10 days,compared to an improvement of only 18.2% in the placebogroup, without any reported adverse event (AE).[43]
Box 1. Drug summary
Drug name (generic) RifaximinPhase (for indication underdiscussion)
III
Indication (specific todiscussion)
Irritable bowel syndrome
Pharmacology description/mechanism of action
Inhibition of RNA transcription by binding tothe β-subunit of bacterial RNA polymerase
Route of administration OralChemical structure C43H51N3O11
Pivotal trial(s) TARGET-1, TARGET-2, TARGET-3
984 F. R. PONZIANI ET AL.
Table1.
Mainfeatures
ofthepu
blishedstud
iesexploringefficacyandsafety
ofrifaximin
inpatientsaffected
byirritablebo
wel
synd
rome(IB
S).
Stud
yDesign
No.
ofpts.
Rifaximin
dose
Efficacy
Follow-up
AEs
Cuocoet
al.[45]
Retrospective
96pts
1200
mg/daily
for14
days
Sign
ificant
improvem
entof
IBS
symptom
safterrifaximin
treatm
ent
4–5Mon
ths
Non
e
Pimentele
tal.
[43]
Dou
ble-blind,
rand
omized,
placebo-controlled
43rifaximin
44placebo
AllIBS
subtypes
400mgtid
for10
days
Averageimprovem
ent:36.4%
rifaximn
grou
pvs.2
1%placebo(p
=0.020);
VASscores
sign
ificantly
better
intherifaximin
grou
pfor
bloatin
g(p
=0.010)
butno
tfor
abdo
minalpain
(p=0.32),diarrhea
(p=0.67),andconstip
ation
(p=0.069)
10Weeks;g
lobal
improvem
entand
VASscores
improvem
entfor
bloatin
gwere
maintaineddu
ring
follow-up
Placebovs.rifaximin:abd
ominalpain
3vs.4,con
stipation2vs.1,nausea2vs.
0,vomiting
1vs.0
,badtaste0vs.2
,fatigue
1vs.1
,straining0vs.1
,urgency
0vs.1
,headache
1vs.0,h
emorrhoid1vs.0
,rash
1vs.0
,gas
1vs.0
,fever1vs.0
.Nostatisticaldiffe
rence
betweengrou
psShararaet
al.[44]
Rand
omized
doub
le-blind
placebo-controlled
37rifaximin
33placebo
400mgbidfor10
days
Symptom
srelief:15/37(40.5%
)rifaximin
grou
pvs.6
/33(18.2%
)placebogrou
p(p
=0.04)
After10
days
follow-up:
symptom
atic
improvem
ent10/37
(27%
)rifaximingrou
pvs.3
/33(9.1%)
placebogrou
p(p
=0.05)
Non
e
Scarpellini
etal.
[46]
Prospective,parallel-g
roup
,rand
omized
80pts,63
with
IBS(allsubtypes)
40pts,of
who
m33
with
IBS(group
1):rifaximin
1600
mg⁄daily
for7days
40pts,of
who
m30
with
IBS(group
2):rifaximin
1200
mg⁄
daily
–14
AEsallo
fmild
intensity;the
most
frequent
were
constip
ation(2
inthegrou
p1and3in
thegrou
p2),d
yspepsia
(2in
thegrou
p1and1in
thegrou
p2)
Yang
etal.[47]
Retrospective
84pts
400mgtid
for10
days
Clinicalrespon
se:5
8(69%
)Rifaximin
retreatm
ent
forsymptom
srecurrence
was
100%
successful
(16/16
pts)
–
Lembo
etal.[48]
PhaseII,do
uble-blind,
placebo-controlled
191rifaximin
197placebo
550mgtwicedaily
for
14days
followed
byan
additio
nal1
4days
ofplaceboin
both
grou
ps
Attheendof
treatm
ent:
glob
alIBSsymptom
simprovem
ent:
53%
rifaximin
vs.4
3%placebo
(p=0.03);
bloatin
gimprovem
ent:50%
rifaximin
vs.4
2%placebo(p
=0.04)
Attheendof
12weeks
follow-up:
glob
alIBSsymptom
simprovem
ent:62%
rifaximin
vs.4
9%placebo(p
<0.05);
bloatin
gimprovem
ent:
59%
rifaximin
vs.
51%
placebo
(p<0.05)
Similarto
placebo
Peralta
etal.[49]
Observatio
nal
97pts
AllIBS
subtypes
1200
mg/daily
for7days
Symptom
sscoreimproved
from
2.3±
0.6to
0.9±0.8(p
=0.003)
onlyin
patientswith
BTno
rmalization
3Weeks
–
(Con
tinued)
EXPERT OPINION ON DRUG SAFETY 985
Table1.
(Con
tinued).
Stud
yDesign
No.
ofpts.
Rifaximin
dose
Efficacy
Follow-up
AEs
Pimentele
tal.
[50]
TARG
ET1ph
ase3,
doub
le-
blind,
placebo-controlled
309rifaximin
vs.3
14placebo
IBS-Cexclud
ed550mgtid
for14
days
Globalsym
ptom
srelief:126/309
(40.8%
)rifaximin
vs.98/314(31.2%
)placebop=(0.01)
10Weeks
Rifaximin
vs.p
lacebo
(pooleddata):
headache
38(6.1%)vs.4
2(6.6%),
upperrespiratory
tractinfection35
(5.6%)vs.3
9(6.2%),abdo
minal
pain
29(4.6%)vs.3
5(5.5%),
nausea
27(4.3%)vs.2
4(3.8%),diarrhea
27(4.3%)vs.2
2(3.5%),
nasoph
aryngitis
19(3%)vs.34
(5.4%),
sinu
sitis
17(2.7%)vs.1
6(2.5%),
vomiting
15(2.4%)9vs.(1.4%
),bron
chitis13
(2.1%)vs.1
7(2.7%),
coug
h13
(2.1%)vs.9
(1.4%),
flatulence10
(1.6%)vs.1
4(2.2%),back
pain
10(1.6%)vs.1
5(2.4%),
pharyngo
laryng
ealp
ain9(1.4%)vs.
15(2.4%),
chestpain
1(0.2%)vs.2
(0.3%),breast
cancer
1(0.2%)vs.1
(0.2%),
cholecystitisor
acutecholecystitis0vs.2
(0.3%),
upperrespiratory
tractinfection35
(5.6%)vs.3
9(6.2%),viral
gastroenteritis7(1.1%)vs.8
(1.3%),
gastroenteritis6(1%)vs.3
(0.5%),
cellulitis3(0.5%)vs.1
(0.2%),
pneumon
ia1(0.2%)vs.5
(0.8%),viral
infection1(0.2%)vs.4
(0.6%)
TARG
ET2ph
ase3,
doub
le-
blind,
placebo-controlled
315rifaximin
vs.3
20placebo
IBS-Cexclud
ed550mgtid
for14
days
Globalsym
ptom
srelief:128/315
(40.6%
)rifaximin
vs.1
03/320
(32.2%
)placebop=(0.03)
10Weeks
DiS
tefano
etal.
[51]
Dou
ble-blind,
rand
omized,
cross-over
24pts
IBS-C
400mgbidfor7days
Redu
ctionof
cumulative
breath
H2excretion,
andof
bloatin
g,abdo
minal
distentio
n,abdo
minal
pain,flatulence,bo
rborygmi
severityon
lyafterrifaximin
administrationin
patients
norm
osensitiveto
colonic
ferm
entatio
n
–Mild
worsening
ofconstip
ationdu
ring
rifaximin
treatm
entin
1pt,
headache
durin
gplaceboin
1pt
Meyratet
al.[52]
Phase
IV,p
rospective
106
200mgqu
idfor14
days
Symptom
simprovem
ent:5.5±2.6vs.
3.4±2.3forbloatin
g(p
<0.001),
2.9±2.4vs.2
.2±1.8fordiarrhea
(p=0.008),5
.0±2.7vs.4
.1±2.2
forflatulence(p
=0.006),
4.8±2.7vs.3
.0±1.5forabdo
minal
pain
(p<0.001),
3.9±2.4vs.2
.4±2.0forredu
ced
overallw
ell-b
eing
(p<0.001)
–Headache3/106(3%),dryskin
1/106
(1%),nausea
with
outvomiting
1/106(1%)
Pimentele
tal.
[53]
Dou
ble-blind,
rand
omized,
placebo-controlled
31pts(16neom
ycin
and
placebo,
15neom
ycin
andrifaximin)
with
C-IBSand
methane
level>
3pp
mon
asing
lebreath
sample
Neomycin
500mgbid
orneom
ycin
500mgbid+
rifaximin
550mgtid
and
placebofor14
days
VASscoreforconstip
ation(com
bined
vs.n
eomycin):28.6
±30.8
vs.
61.2
±24.1
(p=0.0020)
4Weeks
Neomycinvs.neomycin/rifaximn:nausea
10(63%
)vs.7
(47%
),bloatin
gand
distension
9(56%
)vs.7
(47%
),abdo
minal
pain
6(38%
)vs.3
(20%
),constip
ation2(13%
)vs.2
(13%
),diarrhea
2(13%
)vs.1(1%),urgency2
(13%
)vs.0
,tinnitus0vs.1
(1%),
upperrespiratory
tractinfection0vs.
1(1%),malaise
1(1%)vs.0
Abbreviatio
ns:p
t,patient;A
Es,adverse
events;IBS-C,con
stipationIBS;VA
S,visual
analog
scale.
986 F. R. PONZIANI ET AL.
Following these favorable experiences, two randomizedcontrolled trials including patients with non-constipation IBS(TARGET-1 and TARGET-2), were published in 2011; these twostudies demonstrated that rifaximin 550 mg three times dailyfor 2 weeks improved symptoms, bloating, abdominal pain,and stools consistency over the whole study period of10 weeks.[49] A recently published meta-analysis [53] con-cluded that rifaximin produces a therapeutic gain comparableto other treatment options in patients with IBS and is superiorto placebo in inducing global symptoms and bloatingimprovement, but with a similar safety profile. However, thetherapeutic amelioration is small. Only 10% more than pla-cebo and a number needed to treat (NNT) of 10.
Finally, two studies with a small sample size explored theeffects of rifaximin on functional symptoms in patients with C-IBS and increased colonic fermentation, demonstrated bymethane excretion at lactulose breath test.[50,52] Alone orassociated with neomycin, rifaximin improved symptomsseverity, especially constipation, straining, bloating, abdominaldistention and pain, especially when visceral sensitivity wasnot altered.
Rifaximin may also be useful in the eradication of SIBO,which may play a role in the development of symptoms inpatients with IBS. Rifaximin has demonstrated efficacy in redu-cing bacterial abundance in the duodenum and in the ileum inmice models of visceral hyperalgesia,[34,54] and has bacter-icidal effect on duodenal isolates of patients affected by SIBO.[55] The activity of rifaximin in specific tracts of the intestinemay be explained by the high bile acids-dependent solubilityof the molecule.[56] Although clinical data seem to confirmthe beneficial activity of rifaximin in eradicating SIBO inpatients with IBS, producing symptoms amelioration,[44–46,48,51] these data derive from uncontrolled studies, inwhich SIBO diagnosis was not always achieved by glucosebreath test. Another study based on jejunal cultures failed toconfirm a significant difference in SIBO prevalence betweenIBS patients and controls.[57]
4. Rifaximin safety in IBS
The debate about rifaximin safety is focused on two mainconcerns: AEs occurring during treatment, which may be ornot drug-related, and, as like as other antibiotic molecules, therisk of infections sustained by resistant microorganisms andthe development of Clostridium difficile colitis.[58] The issue ofinfective complications has been particularly stressed in IBS,since use of rifaximin in this setting often requires prolongedor repeated therapeutic attempts.
Consistent data about rifaximin safety come from studiesincluding patients with liver disease, Crohn’s disease, andsubjects with traveler’s diarrhea. The most common reportedAEs were ascites, headache, nausea, dizziness, dyspepsia,abdominal discomfort, abdominal distension, diarrhea, consti-pation, and flatulence.[59–67] Although cellulitis, peritonitis,pneumonia, sepsis/septic shock, urinary tract/kidney infection,nasopharyngitis, fever and respiratory tract infections havebeen reported, data about the occurrence of infections incirrhotic patients undergoing treatment with rifaximin arecontrasting.[65,67,68]
As regards Clostridium difficile colitis, two cases have beenreported in patients with cirrhosis and hepatic encephalopa-thy in the registrative trial,[68] while four cases were diag-nosed in patients evaluated during the long-termmaintenance period.[65] One case of Clostridium difficile infec-tion was also reported in patients with Crohn’s disease under-going treatment with rifaximin.[63]
However, it should be noted that the incidence ofClostridium difficile infection mainly depends on the severityof the underling disease, the immune system function and therate of hospitalization, conditions that are infrequent inpatients with IBS, who are usually in good general conditionsand do not require hospitalization. Furthermore, rifaximin hasa strong activity against Clostridium difficile strains, beingtherefore uncommon the emergence of infections in absenceof predisposing conditions.[69]
4.1. Rifaximin safety in patients with IBS
Data from prospective and retrospective published studieshave been encouraging regarding rifaximin safety in IBS.Headache, nausea, abdominal pain, and constipation havebeen the most shared AEs among rifaximin-treatment arms,but, notably, there was no significant difference in AEs inci-dence in respect to the group of comparison (Table 1).[45,50–52]
In two studies no AEs were recorded,[43,44] and only oneepisode of infectious complications (upper respiratory tractinfection) was observed in one patient receiving rifaximin inassociation with neomycin.[52]
Phase II and III trials and the registrative study havedrawn a more detailed picture of safety and tolerability ofrifaximin.[47,49,70] In both treatment phases and duringthe post-treatment follow-up, the incidence of AEs wassimilar to placebo and involved 52.5% of patients beingclassified as treatment-related in only 12.1% of cases.[71]Headache was the most common symptom, while nausea,abdominal pain, diarrhea, and vomiting were the mostcommon gastrointestinal AEs. The incidence of constipationor diarrhea were lower than 2%. Infections were alsoreported, in particular upper respiratory tract infections,urinary tract infections, nasopharyngitis and sinusitis, butnone of the patients on active treatment developedClostridium difficile infection. Overall, data pooling demon-strated that only about 6% of the AEs were severe, amongwhich 1.6% were serious and in only 0.1% were drug-related. AEs caused drug discontinuation in 2% of patients,even if in only 0.8% of cases there was a clear relationshipwith rifaximin assumption. A similar safety profile wasrecorded in the registrative study.[71]
4.2. Rifaximin retreatment and bacterial resistance
IBS is a chronic condition characterized by frequent re-acutiza-tion of symptoms. Retreatment is therefore very common, andmay represent a serious issue when antibiotic therapy is cho-sen, since efficacy is usually decreased by the development ofmicrobial resistance. Lack of clinical efficacy has been reported
EXPERT OPINION ON DRUG SAFETY 987
in more than 70% of cases when antibiotics, such as neomycinhave been used for IBS retreatment.[46]
A recent study [55] analyzed the in vitro bacteriostatic andbactericidal activity of rifaximin on duodenal isolates from 117patients affected by SIBO, 68 also diagnosed with IBS. At thebreakpoint of 32 mcg/mL, 85.4% of E. coli, 43.6% of Klebsiellaspp., 34.8% of Enterobacter spp., 54.5% of otherEnterobacteriaceae, 82.6% of non-Enterobacteriaceae Gramnegatives, 100% of E. faecalis, 100% of E. faecium and 100%of S. aureus were inhibited. Moreover, bactericidal effects weredetected on nine bacterial isolates after 24 h of exposure torifaximin 500 mcg/mL. Taking into account that rifaximin canreach fecal concentrations as high as 8000 mcg/g,[72] with aconsequent very high tissue concentration per minimal inhi-bitory concentrations for tested isolates, this could explain thehigh efficacy of rifaximin even in the case of retreatment.
Nevertheless, rifaximin resistance requires chromosomalmutation and is almost rare,[73] with resistant bacterial strainsdisappearing within 12 weeks after treatment discontinuation.[74] While some studies failed to demonstrate the emergenceof bacterial resistance following administration of rifaximin[75] in patients with inflammatory bowel diseases resistant E.coli strains have been isolated,[76] as well as rifampin-resistantskin Staphylococci have emerged in a small number of healthyvolunteers following rifaximin intake.[77] Rifaximin-resistantorganism have nevertheless been isolated after 800-mg dailytreatment for 5 days; resistance was developed by 30–90% offecal bacterial strains, including Enterobacteriaceae,Enterococcus, Bacteroides, Clostridium, and anaerobic cocci,but it was not sustained since disappeared within monthsafter therapy.[73]
These data may justify the persistence of efficacyobserved even when multiple subsequent administrationsof rifaximin are performed. A retrospective analysis exploredthe efficacy of rifaximin-repeated treatment among 71patients with non-constipated IBS; 48 of them received asecond-, 22 a third-, 7 a fourth-, and 4 a fifth-repeat treat-ment. Rifaximin-treatment attempts were successful in morethan 75% of cases initially non-responders to the first course.The median time between treatments was similar, furtherconfirming that duration of rifaximin effects did not decreaseafter the first treatment.[78] In the TARGET-3,[70] the openlabel study required for rifaximin-treatment approval for IBS,636 patients with recurrent symptoms following administra-tion of rifaximin were randomized to receive a first retreat-ment with rifaximin 550-mg tid or placebo for 2 weeks,followed by a 4-week treatment-free period. The rate ofsymptoms improvement was significantly higher in the rifax-imin group compared to placebo (33% vs. 25%), and this wasalso true in case of a second retreatment (37% vs. 29%). Therate of recurrence prevention and of response duration wassuperior in the rifaximin group (13.2% vs. 7.1% and 17.1% vs.11.7%). Rifaximin retreatment was neither associated withthe emergence of resistant bacterial strains nor with oppor-tunistic infections.
Another study demonstrated that rifaximin re-challenge atdouble dose after initial 1200-mg daily treatment furtherincreased by 53% the rate of symptoms improvement inde-pendently of IBS type.[78]
Therefore, rifaximin-repeated treatment or re-challenge athigher dose represent an alternative option in unresponsivepatients or in case of symptoms recurrence. The infrequentoccurrence of clinical resistance is supported by the rapid lossof mechanisms of resistance among bacterial strains, or itcould be in some cases overcome by the high concentrationsreached by the drug.
Nevertheless, the acquisition of resistant phenotype maysometimes result as an advantage. Indeed, members ofBacteroides spp., Lactobacillus spp., Clostridium/Eubacteriumspp., Bifidobacterium spp. and Atopobium/Collinsella spp.,may become resistant after rifaximin exposure, being able togrow at rifaximin concentrations higher than 1024 mg/L.[79]Thus, the growth of resistant beneficial bacterial may beanother mechanism contributing to rifaximin-positive modula-tion of the gut microbiota, being part of the ‘eubiotic’ effectsof this peculiar antibiotic.
4.3. Considerations about pharmacokinetics
Although derived from rifamycin, a cytochrome P450 (CYP450)enzyme system inducer, rifaximin is not expected to interferewith drug metabolism in patients with normal hepatic func-tion. This has been confirmed by two studies including healthyindividuals on treatment with CYP450 substrates.[80,81] Inparticular, in women receiving estro-progestinic treatment(ethinyl estradiol 0.07 mg daily and norgestimate 0.5 mgdaily), rifaximin 800-mg daily administration did not alterestradiol pharmacokinetics, and similar results were obtainedwith the same rifaximin dose in subjects taking midazolam.However, doses recommended for IBS treatment are highercompared to that used in these two studies; furthermore, liverimpairment may heavily alter rifaximin absorption due to theincreased intestinal permeability, which is a common featureof these patients. Systemic exposure is increased by 10–13folds in Child A and B patients, reaching 20-fold increasedvalues in Child C cirrhosis. Since rifaximin is presumably actinglocally, in case of liver impairment no dose adjustment isrequired by the manufacturer; however, a careful use is advi-sable in this category of patients. P-glycoprotein is alsoinvolved in rifaximin metabolism and in vitro studies reportedan increase in rifaximin Cmax and area under the curve inpresence of P-glycoprotein inhibitors, such as verapamil andcyclosporine; however, the clinical consequences areunknown.
No major safety issues in the elderly have been raised inpublished studies,[68] even if increased sensitivity should notbe overlooked in these category of patients. Even if there areno adequate and well-controlled studies in humans, adminis-tration of rifaximin has demonstrated teratogenic risk in ani-mal models, and the amount of drug excreted in maternalmilk is unknown; the decision on whether to use the drugduring pregnancy or lactation should be taken only if thepotential benefits may justify the risk for the fetus.[83]
Data about use of rifaximin in patients aged 18 years withrenal impairment and in specific races or ethnicities are lack-ing. However, use of rifaximin has been recently demonstratedto be safe in children (10–13 years) with SIBO and IBS.[82]
988 F. R. PONZIANI ET AL.
A final consideration regards generic formulations of rifax-imin. A recent study demonstrated a higher systemic bioavail-ability of the generic drug compared to the branded one,which contains only the polymorph-α.[83] This may obviouslyimpact the incidence of systemic effects of rifaximin, with aconsequent failure of an important feature of this antibiotic.
5. Conclusion
Although the exact mechanisms of action of rifaximin have notbeen completely clarified, this drug has proven to be effective inreducing/resolving intestinal symptoms in patients affected byIBS, as shown by large clinical trials. Additional effects overcom-ing the traditional antibiotic activitymay contribute to the eubio-tic effects of rifaximin on the gut microbiota. Clinical benefits ofrifaximin are paralleled by a high safety profile: metabolic inter-actions and the development of resistant bacterial strains arenearly absent, and drug-related AEs are mild and infrequent.Moreover, properties of rifaximin seem to be maintained evenafter repeated treatment cycles. All these features make rifaximina safe antibiotic for the management of IBS patients.
6. Expert opinion
IBS is a functional gastrointestinal disease with a multifactorialetiology. Several evidences indicate gut microbiota plays arole in IBS pathogenesis. Indeed, an unbalanced microbialcomposition has been observed in IBS patients. For thesereasons, local-acting antibiotics have an important therapeuticrole. Rifaximin is a non-absorbable antibiotic with additionalanti-inflammatory and gut microbiota-modulating activity. It isable to relief symptoms in IBS patients even after repeatedtreatment courses. Clinical benefits of rifaximin are associatedwith high safety profile: metabolic interactions and the devel-opment of resistant bacterial strains are nearly absent, drug-related AEs are mild and infrequent. Future studies will needto clarify the exact mechanisms of rifaximin action in IBS, andin the meanwhile these findings should guide the optimiza-tion of use of rifaximin in these patients. In this scenario, thedevelopment of a ‘long-acting’ molecule may allow to prolongthe beneficial gut microbiota modulation produced by rifax-imin, favoring the maintenance of homeostasis with the endgoal of promoting gut health.
Declaration of interests
The authors have no relevant affiliations or financial involvement with anyorganization or entity with a financial interest in or financial conflict withthe subject matter or materials discussed in the manuscript. This includesemployment, consultancies, honoraria, stock ownership or options, experttestimony, grants or patents received or pending, or royalties.
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