Expert Opinion on Pharmacotherapy

ISSN: 1465-6566 (Print) 1744-7666 (Online) Journal homepage: http://www.tandfonline.com/loi/ieop20

Rifamycin SV MMX for the treatment of traveler’s

diarrhea

Shu-Wen Lin, Chun-Jung Lin & Jyh-Chin Yang

To cite this article: Shu-Wen Lin, Chun-Jung Lin & Jyh-Chin Yang (2017): Rifamycin SV
MMX for the treatment of traveler’s diarrhea, Expert Opinion on Pharmacotherapy, DOI:
10.1080/14656566.2017.1353079

To link to this article: http://dx.doi.org/10.1080/14656566.2017.1353079

Accepted author version posted online: 11

Jul 2017.

Submit your article to this journal

View related articles

View Crossmark data

Full Terms & Conditions of access and use can be found at

http://www.tandfonline.com/action/journalInformation?journalCode=ieop20

Download by: [Cornell University Library] Date: 12 July 2017, At: 08:42
 Publisher: Taylor & Francis

Journal: Expert Opinion on Pharmacotherapy

DOI: 10.1080/14656566.2017.1353079

Rifamycin SV MMX for the treatment of traveler’s diarrhea

Shu-Wen Lin, Pharm.D., M.S.1,2,3, Chun-Jung Lin, Ph.D.1,2, Jyh-Chin Yang, M.D.,

t
ip
Ph.D.4*

cr
us
1
Graduate Institute of Clinical Pharmacy, College of Medicine, National Taiwan

University, Taipei, Taiwan

an
2
School of Pharmacy, College of Medicine, National Taiwan University, Taipei,

Taiwan
M

Departments of 3Pharmacy and 4Internal Medicine, Hospital and College of Medicine,

National Taiwan University, Taipei, Taiwan

ed
pt

* Corresponding author
Jyh-Chin Yang, M.D., Ph.D.
ce

Departments of Internal Medicine, National Taiwan University Hospital and National

Taiwan University College of Medicine, Taipei, Taiwan
Address: No.7, Zhongshan S. Rd., Zhongzheng Dist., Taipei City 10002, Taiwan
Ac

E-mail: jcyang47@ntu.edu.tw; Phone: +886-2-23123456 ext. 65055

Funding
This paper was not funded

Declaration of Interest
The authors have no relevant affiliations or financial involvement with any
organization or entity with a financial interest in or financial conflict with the subject
 matter or materials discussed in the manuscript. This includes employment,
consultancies, honoraria, stock ownership or options, expert testimony, grants or
patents received or pending, or royalties.

Abstract

Introduction: Rifamycin SV MMX®, a non-absorbable rifamycin antibiotic

t
ip
formulated using the multi-matrix system, was designed to exhibit its

cr
pharmacological action on the distal small intestine and colon. Its clinical efficacy and

us
safety profile in the treatment of traveler’s diarrhea were evaluated in several clinical

studies.
an
Areas covered in this review: This review summarizes all available evidence
M

regarding clinical trials of the efficacy and safety profile of rifamycin SV MMX for
ed

the treatment of traveler’s diarrhea.

Expert opinion: Rifamycin SV MMX demonstrated an excellent pharmacokinetic

pt

profile with decreased systemic toxicity similar to rifaximin. In phase II and phase III
ce

clinical trials, concerns have been raised regarding the medicine’s efficacy in terms of
Ac

the time to last unformed stool and cure rate compared to current recommended

antibiotics in the treatment of acute diarrhea caused by diarrheagenic Escherichia coli

and invasive pathogens. The significance of the increase in MICs after the use of

rifamycin SV MMX warrants further examination.

 Key words: infectious diarrhea, non-absorbable antibiotics, rifamycin SV MMX,

traveler’s diarrhea

t
ip
cr
us
an
M
ed
pt
ce
Ac
 1. Background

1.1. Traveler’s diarrhea

The GeoSentinel network reports that acute diarrhea is the most common condition

for which international travelers seek medical care after arrival in their country of

t
residence [1]. People who suffer from traveler’s diarrhea may experience the loss of

ip
business or vacation days. Medical care is required for approximately 10% of them

cr
and up to 3% need hospitalization [2, 3]. The highest incidence rates of traveler’s

us
diarrhea occur in individuals traveling from highly industrialized countries to regions
an
in Africa and South, Central and West Asia [4]. On the other hand, travelers to North
M
America, Northeast Asia, and Australia are considered to be at the lowest risk for

traveler’s diarrhea [5]. Most studies have defined traveler’s diarrhea as the passage of
ed

three or more uniformed stools, plus at least one sign or symptom of enteric infections
pt

after completion of travel, usually in developing countries [4, 5].

ce

Most patients with traveler’s diarrhea acquire the pathogen via fecal-oral

transmission from contaminated water, food, or through person-to-person contact [6,

Ac

7]. Globally, the most common culprits in food- and water-borne infection are bacteria,

including Escherichia coli, Salmonella spp., Campylobacter jejuni, and Shigella spp.

[4, 5]. Various forms of diarrheagenic E. coli, primarily enterotoxigenic E. coli (ETEC)

and enteroaggregative E. coli (EAEC), with geographical variations, are responsible

 for 50% to 80% of cases of traveler’s diarrhea [5, 8]. They exhibit various

pathogeneses and sites of infection ranging from the small intestine to the colon [9].

Meanwhile, Campylobacter spp., followed by Salmonella spp. and Shigella spp.

remain the major causes of traveler’s diarrhea in Southeast Asia [4, 5]. After ingestion,

t
these bacteria tend to invade the distal small bowel and colon (the main site of

ip
infection), where they multiply intracellularly and damage the intestinal epithelium

cr
[9]. They may cause various degrees of gastrointestinal (GI) symptoms, such as

us
nausea, vomiting, and abdominal cramps associated with watery or bloody diarrhea
an
and fever (dysentery) [6, 7]. Norovirus, which accounts for 12-17% of cases of
M
traveler’s diarrhea, and parasites such as Giardia, Entamoeba histolytica and

Cryptosporidium are also identified as causative agents [10-12]. However, about 20–
ed

50% of cases have no definable cause [10, 13, 8, 14].

pt

Approximately 90% of traveler’s diarrhea is self-limited to five days or fewer,

ce

but 5–10% of travelers may develop febrile and dysenteric symptoms and 1–2% have

prolonged diarrhea lasting over two 2 weeks. Some travelers even develop
Ac

post-infection irritable bowel syndrome (IBS) [10, 13, 15, 16]. The severity of

diarrhea and the risk of dehydration are usually higher in young children than in adult

travelers, and this results in the need for hydration with intravenous fluids and

hospitalization in 10.4% of pediatric patients [17, 18].

 1.2. Treatment options

In addition to proactive prevention of traveler’s diarrhea, empirical self-treatment has

been recommended upon the initiation of diarrhea symptoms [4, 19]. Strategies

t
include fluid replacement, anti-diarrheal medications such as loperamide, and early

ip
antibiotic treatment [4]. Children and people with comorbidities such as

cr
insulin-dependent diabetes mellitus, renal insufficiency or heart failure are most

us
vulnerable to dehydration [4, 17, 20]. Therefore, travelers and/or family members
an
should be aware of the effectiveness of WHO-formulated oral rehydration salts or
M
other commercially available packaged products [21, 22]. Loperamide or bismuth

subsalicylate agents, used alone, are safe and effective against mild traveler’s diarrhea
ed

[23, 24]. However, bismuth, with its antimicrobial, antisecretory, and adsorbent
pt

properties, exhibited slower onset of action and less effectiveness compared to

ce

loperamide [24]. For moderate or severe sickness, loperamide, when used as an

adjunct therapy with antibiotics, increases the probability of curing the illness and
Ac

decreases its duration compared to antibiotic therapy when used alone [23].

American College of Gastroenterology Clinical Guideline recommends no

routine use of antibiotics for community-acquired diarrhea; traveler’s diarrhea is an

exception since bacterial infection is its most common etiology [25]. An early
 systematic review indicated that antibiotic therapy may effectively shorten the disease

course of traveler’s diarrhea and reduce the overall severity of the illness [26].

Currently the most commonly used antibiotics in the treatment of traveler’s diarrhea

include systemically absorbed fluoroquinolones and azithromycin as well as

t
non-absorbable rifaximin [27, 5].

ip
Previous studies indicated that fluoroquinolones, such as ciprofloxacin or

cr
levofloxacin, used empirically for one to three days, could minimize the severity of

us
the disease and significantly decrease the duration of time to last unformed stool
an
(TLUS) [19, 26]. However, concerns regarding the use of fluoroquinolones include
M
the potential for increasing resistance of ETEC and Campylobacter, adverse events

(AEs) of tendinitis and tendon rupture, drug-drug or drug-food interactions,

ed

photosensitivity, hypersensitivity, and a predisposition to Clostridium difficile colitis

pt

[4, 10, 28-30]. Azithromycin is currently recommended for febrile or dysenteric

ce

traveler's diarrhea or as an alternative treatment if fluoroquinolones or rifaximin fails.

The combination of azithromycin and loperamide has been demonstrated to be

Ac

effective and safe, since the vast majority of individuals receiving combination

therapy demonstrated its benefits in the first 24-48 hours of therapy [23]. Other

concerns include the increasing resistance of Gram-negative pathogens, AEs of QTc

prolongation, and drug-drug interactions (since macrolides are inhibitors of

 cytochrome P450 enzyme systems). [10, 31]. Rifaximin was approved in the United

States for the treatment of afebrile forms of traveler's diarrhea caused by non-invasive

strains of E. coli in patients older than 12 years of age and for the treatment of

infectious diarrhea in Europe [25, 32]. A couple of studies have demonstrated minimal

t
potential for the development of bacterial resistance after up to two weeks of use in

ip
travelers [33, 34]. Another study found that rifaximin may select stable, highly resistant

cr
mutants in a single step even though it has a low level of resistance selection in EAEC

us
and ETEC [35]. The mechanisms of resistance were proposed either as mutations in the
an
rpoB gene, overexpression of Phe-Arg-β-naphthylamide (PAβN)-inhibitable efflux
M
pump, or a combination of the two [36, 37]. In addition, the transferable arr-2 gene in

plasmids also played a role in rifaximin resistance in multidrug resistant E. coli isolated
ed

from travelers returning to the UK [38]. Currently it is recommended in the treatment

pt

of traveler’s diarrhea with mild to moderate severity without febrile and dysenteric
ce

symptoms, given that it is not quite effective against Salmonella, Shigella, and

Campylobacter spp. [39].

Ac

The use of prophylactic antibiotics has been evaluated with regard to the high

incidence of bacterial pathogens causing traveler's diarrhea. It is recommended for use

in prudently selected populations of travelers, for instance, persons with underlying

severe renal/hepatic/heart disease, insulin-dependent diabetes, and GI disorders

 (including IBS, gastrectomy, achlorhydria and ileostomies) or who take

glucocorticoids or immunosuppressants. Prophylactic agents, including

fluoroquinolones, rifaximin, and bismuth subsalicylate agents, have also been studied

in clinical trials [40-42]. In general, prophylaxis regimens should provide protection

t
for at least 75% of travelers and minimize the cost, potential drug interactions and

ip
AEs of antibiotics (such as photosensitivity in the tropical areas, hypersensitivity, C.

cr
difficile colitis, vaginal candidiasis, and toxicities in pregnant women and pediatrics)

us
[10, 39, 43].
an
1.3. The development of rifamycin SV MMX®
M

1.3.1. Mechanism of action and chemistry

ed

Rifaximin is an orally non-absorbable derivative of rifamycin SV (Figure 1). They

pt

both belong to the rifamycins, a family of fermentation products from the

ce

Gram-positive bacterium Amycolatopsis mediterranei (originally classified as

Streptomyces mediterranei). The mechanism of action was identified against the

Ac

DNA-dependent RNA polymerase of bacteria and eukaryotic cells [13, 25, 44-45].

The broad-spectrum, semisynthetic rifamycin SV (C37H47NO12, CAS registry number

6998-60-3) was derived from rifamycin B, the main product in the presence of

diethylbarbituric acid, and introduced into clinical setting as an intravenous regimen

 for tuberculosis in 1962 [44, 46]. It is basically insoluble in water with the Log P

(octanol/water partition coefficient) = 5, and very soluble in ethanol, methanol,

acetone, and ethyl acetate [47]. Rifampin, which is commonly used in the treatment of

tuberculosis, was a 3-(4-methylpiperazinoiminomethyl) derivative of rifamycin SV

t
[44]. Compared to rifampin, rifamycin CV is a less lipophilic and anionic compound

ip
with pKa = 1.8 [48].

cr
us
1.3.2. Spectrum of activity
an
Rifamycin SV is active against Gram-positive and Gram-negative pathogens, and
M
mycobacteria. The MIC50/MIC90 are 0.03/256 μg/mL against C. difficile and

32-64/64-128 μg/mL against E. coli, with slightly more potent activity against
ed

enterohemorrhagic E. coli and EAEC. Various MIC50 and MIC90 values are
pt

documented against invasive pathogens, ranging from 2 to 128 μg/mL and 2 to 256
ce

μg/mL (with the greatest potency against Vibrio parahaemolyticus and least against

Campylobacter spp.), respectively [15, 49, 50]. The distributions of MIC50 and MIC90
Ac

values of rifamycin SV against selected enteric pathogens are listed in Table 1.

Cross-resistance is not observed between rifamycin SV and other antimicrobial agents

[46]. However, in the light of evidence of the prior use of rifaximin as a risk factor for

resistant E. coli in patients with IBD [37], the selection pressure and cross resistance
 between rifaximin and rifamycin CV needs close monitoring and further investigation.

1.3.3. MMX formulation

Due to poor oral absorption, rifamycin SV has been used through parenteral

t
administration for the treatment of tuberculosis or topical application for severe skin

ip
infections [25, 44]. The increasing interest in oral administration of rifamycin SV for

cr
the treatment of GI infections has led to the discovery of new dosage formulations for

us
clinical applications. Accordingly, an oral modified-release formulation of rifamycin
an
SV created using the patented technology of the multi-matrix structure (MMX;
M
Cosmo Technologies Ltd., Dublin, Ireland) was developed to deliver the active

ingredient to the distal small bowel and colon without interfering with the normal
ed

flora in the upper GI tract [48]. The MMX system has been successfully used to
pt

deliver mesalazine (5-aminosalicylic acid, 5-ASA) and budesonide to the colon in

ce

healthy volunteers [51-52]. After single-dose administration of 153Sm-labelled

budesonide MMX tablets in 12 healthy males, 95.9 ± 4.2 % of the dose was
Ac

systemically absorbed during passage throughout the whole colon. Ten out of 12 study

subjects had initial tablet disintegration in the colon whereas the remaining two

subjects had disintegration in the small intestine/ileum region [52]. Rifamycin SV

MMX likely exhibits a similar mode of action, but supporting evidence and further
 studies are needed.

1.3.4. Biopharmaceutics, pharmacokinetics and metabolism

In rifamycin SV MMX, the active ingredient is dispersed in the lipophilic matrix that

t
is surrounded in a hydrophilic matrix. The lipophilic matrix protects the active

ip
ingredient from dissolution in the intestinal aqueous fluids before it arrives in the

cr
cecum. In addition, the gastro-resistant polymer film surrounding the core does not

us
disintegrate at a pH of lower than 7. The film gradually transforms to a viscous gel
an
mass within the distal ileum and the rectosigmoid. Rifamycin SV then disaggregates
M
and releases in proximity to the mucosa during its movement to the rectum [46, 48].

The bioavailability of rifamycin SV-MMX is less than 0.1%, and the plasma
ed

concentrations are mostly undetectable (< 2 ng/mL) in healthy volunteers taking a

pt

single dose of 400 mg. Approximately 18.6% (74.60 ± 115.99 mg), 50.01% (200.04 ±
ce

134.72 mg), and 21% (84.15 ± 98.10 mg) of the administered dose were recovered in

feces during the first 24 hours, 24 to 48 hours, and 48 to 72 hours post-dose,

Ac

respectively. [48]. Although both rifaximin and rifamycin SV MMX act on the GI

tract, rifaximin primarily delivers to deliver to the small intestine due to its selective

solubility in bile in the proximal small intestine [53, 54]. In contrast, rifamycin SV

MMX is more concentrated on distal small intestine and colon [49].

 Rifamycin SV is mainly metabolized in hepatocytes and intestinal microsomes to

25-deacetyl metabolite with a significant first-pass effect [48, 55]. The parent drug

and metabolite are then excreted into bile with negligible urinary excretion in humans

[48, 55]. Since rifampin, the derivative of rifamycin SV, rifabutin and rifaximin (but

t
not rifapentine) cause an autoinduction of metabolism in the liver and intestine and

ip
increase biliary secretion, the potential and risk of drug-drug interaction should be

cr
considered for rifamycin SV [56].

us
After a single 250 mg dose of rifamycin SV given intravenously in 24 healthy
an
volunteers, the maximal plasma concentration (Cmax), time to Cmax,
M
area-under-the-concentration-versus-time-curve, half-life, mean residence time (MRT),

clearance, and volume of distribution were measured or calculated, respectively as

ed

36.03 ± 8.57 mg/L, 5 ± 0 mins, 11.84 ± 4.00 mg/L • hr, 3.04 ± 0.73 hrs, 0.49 ± 0.06
pt

hrs, 23.29 ± 7.25 L/hr, and 101.79 ± 40.34 L [48]. In an early study, the protein binding
ce

was reported to be about 80–95%, with one to two hours of half-life [57].

The minimal GI absorption of rifamycin SV may prevent dosing adjustment in

Ac

special populations as well as drug interactions occurred in the process of distribution,

metabolism and excretion. However, in vitro and animal studies have shown that

rifamycin SV strongly inhibits the ubiquitous transporter organic anion transporting

polypeptide (OATP) family, namely OATP1A2, OATP1B1, OATP1B3, OATP2,

 OATP2B1, OATP8, OATP-A, OATP-B, and OATP-C, at peak serum concentration of

25 to 50 μmol/L (approximately 17.43 to 34.85 mg/L based on the molecular weight

of 697.31 80 daltons) after intravenous administration [43, 58-61]. The OATP-B

family is expressed in the liver as well as in other tissues including the intestines,

t
placenta, kidneys, and lungs. OATP 1A2, 3A1, and 4A1 have also been detected in

ip
human intestines. Among them, OATP2B1 (SLC21A9) is considered the dominant

cr
OATP in the GI tract. It may play an important role in the bioavailability of other oral

us
drugs, of which substrates of OATP2B1 include HMG-CoA reductase inhibitors
an
(statins), angiotensin II receptor blockers (olmesartan), endothelin antagonists used to
M
treat diabetes (atrasentan), loop diuretics (torsemide), protease inhibitors used to treat

human immunodeficiency viral infections (lopinavir), cancer chemotherapy (SN-38),

ed

anti-histamine agents (fexofenadine), and immunosuppressants (tacrolimus) [59, 62].

pt

Acute elevation of bilirubin concentrations in serum was reported since rifamycin SV

ce

inhibits the activity of OATP-C which is the main transporter in the uptake of

unconjugated bilirubin into the human liver [61].

Ac

1.3.5. Pharmacodynamics

Current evidence suggests that Cmax correlates with the bactericidal activity of

rifampin against mycobacterium. The inconsistence of the magnitude among rifampin,

 rifabutin, and rifapentine might results from issues of the extent of protein binding,

intracellular concentration, combination therapy, etc [63]. As of June 2017, the

pharmacodynamical model of rifamycin SV against pathogens in traveler’s diarrhea is

not available in the literature.

t
ip
1.3.6. Clinical use and development

cr
Phase III clinical trials of rifamycin SV MMX® in treating traveler’s diarrhea

us
have been completed in Europe and America. The new drug application (NDA) is
an
currently being prepared by the manufacturer; it will be filed for the indication of the
M
treatment of traveler’s diarrhea in both the EU and the United States [64]. Phase II

and phase III clinical trials are being undertaken in the treatment of traveler's diarrhea
ed

(in comparison to ciprofloxacin), C. difficile infection, acute uncomplicated

pt

diverticulitis, infectious diarrhea, inflammatory bowel diseases, and hepatic

ce

encephalopathy. The regimen of using a higher dose (600 mg) three times daily is also

currently under investigation [65].

Ac

2. Efficacy and safety of rifamycin SV MMX in published clinical trials

 2.1. Efficacy

Di Stefano et al completed a phase II clinical trial to compare the efficacy and safety

of rifamycin SV with rifaximin in the treatment of infectious diarrhea (“Study 1”)

[46]. This multicenter, double blinded, double dummy, randomized, parallel-group

t
study was conducted in South Africa. Both rifamycin SV MMX and rifaximin were

ip
given in an oral dosing regimen of 200 mg four times daily for three days. Among

cr
those who completed the dosing schedule, the successful responses were 47.8% (22

us
out of 46 patients) and 50.9% (27 out of 53 patients) in the rifamycin SV group and
an
the rifaximin group, respectively. No significant differences were observed in the rate
M
of therapeutic success including TLUS (67.5 hours vs 65.5 hours) and success rates

(47.8% vs. 50.9%). The power in statistical analysis was not reported. Eight patients
ed

in the rifamycin SV group and 13 patients in the rifaximin group stopped receiving
pt

antibiotics due to AEs or major protocol violations. It was not clear whether the rest of
ce

the patients discontinued treatments due to the need to take rescue medications for

diarrhea or for other reasons. In addition, it was not clear whether any restrictions
Ac

were given for taking loperamide or other anti-diarrheal medications in the study. The

study’s overall discontinuation rate (50.5%) was much higher than that of other

clinical trials [12]. C. jejuni were identified both before and after treatment with

rifamycin SV MMX and rifaximin, which was consistent with the elevated MIC
 values compared with other pathogens.

In a randomized and double-blinded phase III clinical trial (“Study 2”), the

efficacy and safety of rifamycin SV MMX were compared to placebo in adult

travelers to Mexico or Guatemala who suffered from acute traveler’s diarrhea [12].

t
Rifamycin SV MMX was given at a relatively convenient dosing regimen of 400 mg

ip
twice a day orally for three days. A total of 264 patients were randomized in a 3:1

cr
ratio to receive rifamycin SV (n = 199) or a placebo (n = 65). The primary endpoint

us
was the duration between the administration of the first dose of the study drug and
an
TLUS within the observation period of five days. Patients who received rifamycin SV
M
MMX showed significantly shorter median TLUS compared with the placebo (46 vs.

68 hours, p-value 0.0008). The results showed a trend of higher cure rate (81.4%) in
ed

patients receiving rifamycin SV MMX than in patients receiving the placebo (56.9%).
pt

The pathogen eradication rates based on stool specimen were insignificantly higher in
ce

the rifamycin SV group than in the placebo group (67.0% vs. 54.8%, p = 0.0836). One

third of diarrheagenic E. coli and invasive pathogens continued to grow after the
Ac

rifamycin SV MMX treatment course [12]. This phenomenon, however, was not

associated with the diminished efficacy of rifamycin SV in terms of TLUS and the

clinical cure rate. The treatment responses in patients with invasive pathogens didn’t

seem inferior to those in patients with diarrheagenic E. coli. An additional

 nonbacterial mechanism of action such as anti-inflammatory and/or

immunomodulatory activities might explain how clinical efficacy was maintained in

the presence of resistant pathogens. [25]. An in vitro study discovered a significant

reduction of virulence factors of ETEC, EAEC and Shigella sonnei isolates following

t
exposure to rifaximin, and this could be considered a possible mechanism for

ip
rifamycin SV MMX [66]. Subgroup analysis indicated TLUS was significantly

cr
shorter in the rifamycin SV MMX patients with EAEC, ETEC, or diffusely adherent E.

us
coli (p = 0.0035) compared with the placebo. It was not significantly different in those
an
with invasive bacterial infections such as Shigella spp., C. jejuni, Salmonella spp.,
M
Yersinia enterocolitica, Aeromonas spp., Plesiomonas spp. and Vibrio spp., most

likely due to the small sample size. In patients who received rifamycin SV MMX, the
ed

cure rate seemed quite similar between those who acquired E. coli (80.4%) and those
pt

who acquired invasive bacteria (70%), whereas a noticeable difference was observed
ce

in terms of TLUS (49.3 hours vs. 18.5 hours, respectively). The percentage of

microbiological eradication was high in average (75-100%) in invasive pathogens

Ac

with the exception of Cryptosporidium parvum (25%) and norovirus (50%) [12], in

which the percentage was consistent with the distribution of common pathogens in the

intestine [9].

Study 2 used a similar design, including the primary outcomes and definitions,
 origin of the travelers, study location (continent, country), and the constancy of

investigators, compared to previous studies that evaluated different antibiotic

regimens between 1998 and 2007 [54, 67-71]. However, TLUS in patients treated

with rifamycin SV MMX was much longer in patients who received rifaximin on the

t
same dosing regimen in 2001 [67] (46 hours vs. 25.7 hours; Table 2). Rifaximin

ip
maintained a similar TLUS, failure rate, and microbiological cure rate across several

cr
clinical trials treating traveler’s diarrhea. The longer TLUS was observed in rifamycin

us
SV MMX users in comparison with TLUS in the studies of single dose of
an
levofloxacin (21.5 hours) [69] and azithromycin (11 to 34 hours in different study
M
arms) [70, 71], and ciprofloxacin 500 mg twice a day for three days (25 hours) [67].

The treatment failure rate was also higher in patients receiving rifamycin SV MMX in
ed

Study 2 compared with patients treated with single dose of azithromycin and
pt

adjunctive loperamide (18.6% vs. 4%) [71]. The apparently reduced efficacy of
ce

rifamycin SV MMX compared to non-absorbable rifaximin and systemic absorbed

antibiotics may raise concerns among clinicians.

Ac

2.2. Resistance
 In patients with traveler’s diarrhea treated unsuccessfully, both diarrheagenic E. coli

and invasive pathogens acquired resistance to antibiotics after the completion of the

three-day rifamycin SV MMX treatment in Study 2 [12]. The MIC50 and MIC90

values were elevated 8- to 125-folds in ETEC, EAEC, diffusely adherent E. coli, and

t
Campylobacter spp. (details in Table 1). Even though the creep of MICs was not

ip
associated with lower efficacy, it raised concerns regarding the use of rifamycin SV

cr
MMX for the treatment or prophylaxis of traveler’s diarrhea [12]. Farrell et al.

us
revealed that rifamycin SV showed the ability to induce stable resistance in a
an
mutational passaging study. It remains unknown whether the mechanism of resistance
M
is due to genetic mutation in the rpoB gene or is associated with the efflux pump seen

in rifaximin treatment [49]. The transferable arr-2 gene in the plasmids of multidrug
ed

resistant E. coli isolates was also worrisome [38].

pt
ce

2.3. Safety

Early studies indicated that hepatotoxicity was associated with intravenous

Ac

administration of rifamycin SV [57]. The proposed mechanism was the depletion of

glutathione and the generation of reactive oxygen in liver microsomes [57]. The oral

form of rifamycin provided an improved safety profile in recent clinical trials [12, 46,

48]. The following AEs were considered to have a causal relationship to the treatment
 in Study 1: diarrhea and aggravated diarrhea, constipation, increased alanine

aminotransferase, dry mouth, abdominal distension/cramps/tenderness in the

rifamycin SV group, and headache, general itching, constipation, abdominal spasm

and hearing loss in the rifaximin group. In Study 2, the overall AEs appeared to be

t
more frequent with the placebo (38.5%) than with rifamycin SV (29.6%). The most

ip
common events were aggravated diarrhea, headache and constipation [12]. Common

cr
AEs with the frequency ≥ 2% from the two clinical trials were summarized in Table 3

us
[12, 46].
an
M
3. Conclusions

The broad-spectrum and non-absorbable rifamycin SV is active against diarrheagenic

ed

E. coli, C. difficile, and invasive pathogens except for Campylobacter spp. The oral
pt

modified-release formulation, MMX, can selectively deliver rifamycins SV to the

ce

distal small bowel and colon without interfering with microbiota in the upper GI tract.

The results of various phase II and phase III clinical trials have demonstrated that the
Ac

efficacy of rifaximin SV MMX is superior to placebo and is not significantly different

from rifaximin in the treatment of traveler’s diarrhea and infectious diarrhea.

Although rifaxmin SV MMX seems to be effective and well tolerated, its TLUS is

longer than those of currently available regimens. The creep of MICs after treatment
 also raises concerns since the antibiotic resistances of diarrheagenic E. coli and

Campylobacter spp. are increasing throughout the world. Further studies of rifamycin

SV MMX are warranted in order to determine its role in the treatment of GI

infections.

t
ip
cr
4. Expert opinions

us
The unique MMX formulation provides the benefit of delivering the active ingredient
an
to the targeted distal small intestine and colon [9, 48, 49]. However, while it is known
M
that rifaximin achieves a luminal concentration of 8,000 μg/gram of feces [49],

information on rifamycin SV concentrations in each section of the intestine is not

ed

readily available in the literatures. The comparisons between drug exposure and MICs,
pt

and the differences among pathogens and geographical regions are also not yet clear.
ce

The non-absorbable property of rifamycin SV decreases systemic toxicity and

potentially avoids drug interactions resulting from CYP450 isoenzymes at anticipated

Ac

clinical plasma concentration. However, the potential to inhibit OATPs in the

absorption of several commonly used medications for the control of chronic diseases

warrants further examinations.

 Compared to current recommended antibiotics in the treatment of infectious

diarrhea, the high discontinuation rate and long TLUS observed in clinical trials may

also raise concerns regarding the clinical application of rifamycin SV MMX.

However, this may be due to the selected patient populations, the altered prevalent

t
pathogens and resistant patterns over times. Even though rifamycin SV MMX tended

ip
to prolong response time, the treatment failure rate (18.6%) [12] was quite similar to

cr
that of studies which compared rifaximin or rifamycin SV MMX with other

us
antibiotics or placebo. Among these previous studies, the failure rate of rifaximin
an
alone was reported at 11% to 25% [13, 50, 68, 69]; it was 23% for rifaximin with
M
loperamide [69], 29% for trimethoprim-sulfamethoxazole [50], and 12% for

ciprofloxacin [68]. Diarrheagenic E. coli demonstrated a more profound increase of

ed

MIC after a three-day treatment of rifamycin SV MMX compared with invasive

pt

pathogens. In addition, the treatment responses in patients with invasive pathogens

ce

didn’t seem inferior to those in patients with diarrheagenic E. coli in Study 2. More

clinical and microbiological evidence are needed to evaluate whether the diarrhea
Ac

caused by invasive pathogens could be treated by rifamycin SV MMX [32].

Given the nature of traveler’s diarrhea, the use of non-absorbable antibiotics

might justify the potential systemic side effects. With the rapid pace of globalization

and the challenges of increasing resistance of enteric pathogens, the prudent use of
 rifamycin SV MMX in the treatment and prophylaxis of infectious diarrhea should be

taken into consideration with more clinical evidence regarding efficacy, safety, and

impacts on resistance made available.

t
ip
cr
us
an
M
ed
pt
ce
Ac
 Reference

1. Harvey K, Esposito DH, Han P, et al. Surveillance for travel-related

disease--GeoSentinel Surveillance System, United States, 1997-2011. MMWR
Surveill Summ. 2013; 62:1–23.
2. von Sonnenburg F, Tornieporth N, Waiyaki P, Lowe B, et al. Risk and aetiology of
diarrhoea at various tourist destinations. Lancet. 2000;356:133–134.
3. Piyaphanee W, Kusolsuk T, Kittitrakul C, Suttithum W, et al. Incidence and impact
of travelers' diarrhea among foreign backpackers in Southeast Asia: a result from

t
ip
Khao San road, Bangkok. J Travel Med. 2011;18:109–114.
4. Giddings SL, Stevens AM, Leung DT. Traveler’s diarrhea. Med Clin North Am

cr
2016;100: 317–330.
5. Paredes-Paredes M, Flores-Figueroa J, Dupont HL. Advances in the treatment of

us
travelers’ diarrhea. Curr Gastroenterol Rep 2011;13:402-7.
6. Riddle MS, DuPont HL, Connor BA. ACG clinical guideline: diagnosis, treatment,
and prevention of acute diarrheal infections in adults. Am J Gastroenterol
an
2016;111:602–22.
7. Semrad CE. Approach to the Patient with Diarrhea and Malabsorption. In:
Goldman L, Schafer A. Goldman-Cecil Medicine, Chapter 140, 918-35. 25th ed.
M
Elsevier. 2015.
8. Jiang ZD, DuPont HL, Brown EL, Nandy RK, et al. Microbial etiology of travelers’
diarrhea in Mexico, Guatemala, and India: importance of Enterotoxigenic
ed

Bacteroides fragilis and Arcobacter Species. J Clin Microbiol 2010;48:1417-19.

9. Croxen MA, Law RJ, Scholz R, Keeney KM, et al. Recent advances in
understanding enteric pathogenic Escherichia coli. Clin Microbiol Rev 2013;
pt

26:822–80.
10. Haines CF and Sears CL. Infectious Enteritis and Proctocolitis. In: Feldman M.
ce

Sleisenger and Fordtran's Gastrointestinal and Liver Disease, Chapter 110,

1896-929.10th ed. Elsevier. 2015.
Ac

11. Koo HL, Ajami NJ, Jiang ZD, et al. Noroviruses as a cause of diarrhea in travelers
to Guatemala, India, and Mexico. J Clin Microbiol. 2010;48:1673–6.
12. DuPont HL, Petersen A, Zhao J, Mundt A, et al. Targeting of rifamycin SV to the
colon for treatment of travelers’ diarrhea: a randomized, double-blind,
placebo-controlled phase 3 study. J Travel Med 2014;21:369-76.
13. Stephen R, Sack DA, Riopel L, Jiang ZD, et al. Therapy of travelers’ diarrhea with
rifaximin on various continents. Am J Gastroenterol 2003;98:1073–8.
 14. Shah N, DuPont HL, Ramsey DJ. Global etiology of travelers' diarrhea:
systematic review from 1973 to the present. Am J Trop Med Hyg. 2009;80(4):
609–614.
15. Ross AG, Olds GR, Cripps AW, Farrer JJ, et al: Enteropathogens and chronic
illness in returning travelers. N Engl J Med 2013;368:1817-25.
16. DuPont HL, Jiang ZD, Okhuysen PC, Ericsson CD, et al. A randomized,
double-blind, placebo-controlled trial of rifaximin to prevent travelers’ diarrhea.
Ann Intern Med. 2005;142:805-12.
17. Leuthard D, Berger C, Staubli G, Nadal D, et al. Management of children with

t
ip
travel-related illness evaluated in a pediatric emergency room. The Pediatric
Infectious Disease Journal 2015;34:1279-82.

cr
18. Stauffer WM, Konop RJ, Kamat D. Traveling with infants and young children.
Part III: travelers’ diarrhea. J Travel Med. 2002;9:141–150.

us
19. Al-Abri SS, Beeching NJ, Nye FJ. Traveller’s diarrhoea. Lancet Infect Dis
2005;5:349–60.
20. Hagmann SH, Han PV, Stauffer WM, et al. Travel-associated disease among US
an
residents visiting US GeoSentinel clinics after return from international travel.
Fam Pract. 2014;31:678–687.
21. Fox TG, Manaloor JJ, Christenson JC. Travel-related infections in children.
M
Pediatr Clin North Am. 2013;60:507–527.
22. Doan S and Steele RW. Advice for families traveling to developing countries with
young children. Clin Pediatr (Phila). 2013;52:803–811.
ed

23. Riddle MS, Arnold S, Tribble DR. Effect of adjunctive loperamide in combination
with antibiotics on treatment outcomes in traveler's diarrhea: a systematic review
and meta-analysis. Clin Infect Dis. 2008;47:1007-14.
pt

24. Ericsson CD. Nonantimicrobial agents in the prevention and treatment of

traveler's diarrhea. Clin Infect Dis. 2005;41(Suppl 8):S557–563.
ce

25. Rosette C, Buendia-Laysa F Jr, Patkar S, Moro L, et al. Anti-inflammatory and

immunomodulatory activities of rifamycin SV. Int J Antimicrob Agents.
Ac

2013;42:182-6.
26. de Bruyn G, Hahn S, Borwick A. Antibiotic treatment for travelers’ diarrhoea.
Cochrane Database Syst Rev 2000;3:CD002242.
27. Hill DR and Beeching NJ. Travelers’ diarrhea. Curr Opin Infect Dis 2010;23:481–
7.
28. Guerrant RL, van Gilder T, Steiner TS, Thielman NM, et al. Practice Guidelines
for the Management of Infectious Diarrhea. Clin Infect Dis 2001;32:331–50.
29. Corrao G, Zambon A, Bertù L, Mauri A, et al. Evidence of tendinitis provoked by
fluoroquinolone treatment: a case-control study. Drug Saf. 2006;29: 889-896.
 30. Tsai WC, Yang YM. Fluoroquinolone-associated Tendinopathy. Chang Gung Med
J 2011;34:461-7.
31. FDA Drug Safety Communication: azithromycin (Zithromax or Zmax) and the
risk of potentially fatal heart Available at:
https://www.fda.gov/drugs/drugsafety/ucm341822.htm [Last accessed 24 February
2017]
32. Adachi JA and Dupont HL. Rifaximin: a novel nonabsorbed rifamycin for
gastrointestinal disorders. Clin Infect Dis 2006;42:541–7.
33. DuPont HL, Jiang ZD, Okhuysen PC, et al. A randomized, double blind,

t
ip
placebo-controlled trial of rifaximin to prevent travelers’ diarrhea. Ann Intern Med.
2005;142:805–12.

cr
34. DuPont HL, Jiang Z-D. Influence of rifaximin treatment on the susceptibility of
intestinal gram-negative flora and enterococci. Clin Microbiol Infect.

us
2004;10:1009–1011.
35. Ruiz J, Mensa L, Pons MJ, Vila J, et al. Development of Escherichia coli
rifaximin-resistant mutants: frequency of selection and stability. Antimicrob
an
Chemother. 2008;61:1016-9.
36. Pons MJ, Mensa L, Gascón J, Ruiz J. Fitness and molecular mechanisms of
resistance to rifaximin in in vitro selected Escherichia coli mutants. Microb Drug
M
Resist. 2012;18: 376-379.
37. Kothary W, Scheri EJ, Bosworth B, Jiang ZD, et al. Rifaximin resistance in
Escherichia coli associated with inflammatory bowel disease correlates with prior
ed

rifaximin use, mutations in rpoB, and activity of

Phe-Arg-β-naphthylamide-inhibitable efflux pumps. Antimicrob. Agents
Chemother. 2013;57:811-817.
pt

38. Hopkins KL, Mushtaq S, Richardson JF, Doumith M, et al. In vitro activity of
rifaximin against clinical isolates of Escherichia coli and other enteropathogenic
ce

bacteria isolated from travellers returning to the UK. Int J Antimicrob Agents.
2014;43:431-7.
Ac

39. Bobak DA and Guerrant RL. Nausea, Vomiting, and Noninflammatory Diarrhea.
In: Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases,
Chapter 100, 1253-1262. 8th ed. Elsevier. 2015.
40. Hu Y, Ren J, Zhan M, Li W, et al. Efficacy of rifaximin in prevention of travelers '
diarrhea : a meta-analysis of randomized, double-blind, placebo-controlled trials.
Centre for Reviews and Dissemination. J Travel Med, 2012;19:352-6.
41. Alajbegovic S , Sanders JW, Atherly DE, Riddle MS. Effectiveness of rifaximin
and fluoroquinolones in preventing travelers ' diarrhea (TD): a systematic review
 and meta-analysis. Centre for Reviews and Dissemination. Systematic Reviews,
2012;1:39.
42. Rao G , Aliwalas M G , Slaymaker E, Brown B. Bismuth revisited: an effective
way to prevent travelers' diarrhea. Centre for Reviews and Dissemination. J Travel
Med, 2004;11:239-42.
43. UCSF-FDA Transporter. Available at:
http://dbts.ucsf.edu/fdatransportal/compounds/rifamycin-sv/ [Last accessed 27
February 2017].
44. Riva S and Silvestri LG. Rifamycins: a general view. Annu. Rev. Microbiol.

t
ip
1972.26:199-224.
45. Scarpignato C and Pelosini I. Rifaximin, a poorly absorbed antibiotic:

cr
pharmacology and clinical potential. Chemotherapy 2005;51 (Suppl 1):36-66.
46. Di Stefano AFD, Binelli D, Labuschagne W, Mojapelo M, et al. Efficacy of the

us
treatment of infectious diarrhoea with non-absorbable rifamycin SV formulated as
MMC modified release tablet vs. rifaximin. Anti-Infective Agents
2013,11:192-203.
an
47. Moffat AC, Osselton MD, Widdop B, Watts J, editors. Clarke's Analysis of Drugs
and Poisons. Accessed 6/20/2017 via ClinicalKey search engine, Pharmaceutical
Press.
M
48. Di Stefano AFD, Rusca A, Loprete L, Dröge MJ, et al. Systemic absorption of
rifamycin SV MMX administered as modified-release tablets in healthy volunteers.
Antimicrob Agents Chemother. 2011;55:2122-8.
ed

49. Farrell DJ, Putnam SD, Biedenbach DJ, Moro L, et al. In vitro activity and
single-step mutational analysis of rifamycin sv tested against enteropathogens
associated with traveler’s diarrhea and Clostridium difficile. Antimicrob Agents
pt

Chemother 2011;55:992–6.
50. DuPont HL, Ericsson CD, Mathewson JJ, Palazzini E, et al. Rifaximin: a
ce

nonabsorbed antimicrobial in the therapy of travelers’ diarrhea. Digestion

1998;59:708–14.
Ac

51. Brunner M, Assandri R, Kletter K, Tschurlovits M, et al. Gastrointestinal transit

and 5-ASA release from a new mesalazine extended-release formulation. Aliment.
Pharmacol. Ther 2003;17:395–402.
52. Brunner M, Ziegler S, Di Stefano AFD, Dehghanyar P, et al. Gastrointestinal
transit, release and plasma pharmacokinetics of a new oral budesonide formulation.
Br. J. Clin. Pharmacol 2006;61:31–8.
53. Floss HG and Yu TW. Rifamycin-mode of action, resistance, and biosynthesis.
Chem Rev 2005;105:621–632.
 54. Riddle MS, Connor BA, Tribble DR. Targeted therapy in travelers’ diarrhea: what
is the role for the non-absorbable? J Travel Med 2014;21: 365-8.
55. Fattinger K, Cattori V, Hagenbuch B, Meier PJ, et al. Rifamycin SV and
rifampicin exhibit differential inhibition of the hepatic rat organic anion
transporting polypeptides, Oatp1 and Oatp2. Hepatol 2000;32:82-6.
56. Maslow MJ and Portal-Celhay C. Rifamycins. In: Mandell, Douglas, and
Bennett's Principles and Practice of Infectious Diseases, Updated Edition, Chapter
315, 3459-65. 8th ed. Elsevier. 2015.
57. Aristoff PA, Garcia GA, Kirchhoff PD, Showalter H. Rifamycins - obstacles and

t
ip
opportunities. Tuberculosis (Edinb). 2010;90:94-118.
58. Hirano M, Maeda K, Shitara Y, Sugiyama Y. Drug-drug interaction between

cr
pitavastatin and various drugs via OATP1B1. Drug Metabolism and Disposition
2006,34:1229-36.

us
59. Vavricka SR, Montfoot JV, Ha HR, Meier PJ, et al. Interactions of rifamycin SV
and rifampicin with organic anion uptake systems of human liver. Hepatol
2002;36:164-172.
an
60. Reaxys database. [Accessed 6/20/2017.]
61. Vavricka SR, Montfoort JV, Ha HR, Meier PJ, et al. Interactions of rifamycin SV
and rifampicin with organic anion uptake systems of human liver. Hepatol
M
2002;36:164-72.
62. Kovacsics D, Patik I, Özvegy-Laczka C. The role of organic anion transporting
polypeptides in drug absorption, distribution, excretion and drug-drug interactions.
ed

Expert Opin Drug Metab Toxicol 2017;13:409-24.

63. Burman WJ, Gallicano K, Peloquin C. Comparative pharmacokinetics and
pharmacodynamics of the rifamycin antibacterials. Clin Pharmacokinet
pt

2001;40:327-41.
64. Cosmo Pharmaceuticals official website. Available at:
ce

http://www.cosmopharma.com/activities/product-pipeline/rifamycin-sv-mmx [Last
accessed 7 March 2017].
Ac

65. U.S. National Institutes of Health. Available at: ClinicalTrials.gov [Last accessed
7 March 2017].
66. Jiang ZD, Ke S, DuPont HL. Rifaximin-induced alteration of virulence of
diarrhoea-producing Escherichia coli and Shigella sonnei. Antimicrob Agents.
2010;35:278-81.
67. DuPont HL, Jiang ZD, Ericsson CD, Adachi JA, et al. Rifaximin versus
ciprofloxacin for the treatment of traveler’s diarrhea: a randomized, double-blind
clinical trial. Clin Infect Dis 2001;33:1807–15.
 68. Dupont HL, Jiang ZD, Belkind-Gerson J, Okhuysen PC, et al. Treatment of
travelers’ diarrhea: randomized trial comparing rifaximin, rifaximin plus
loperamide, and loperamide alone. Clin Gastroenterol Hepatol 2007;5:451–6.
69. Adachi JA, Ericsson CD, Jiang ZD, DuPont MW, et al. Azithromycin found to be
comparable to levofloxacin for the treatment of US travelers with acute diarrhea
acquired in Mexico. Clin Infect Dis 2003;37:1165–71.
70. Ericsson CD, DuPont HL, Okhuysen PC, Jiang ZD, et al. Loperamide plus
azithromycinmore effectively treats travelers’ diarrhea in Mexico than
azithromycin alone. J Travel Med 2007;14:312–9.

t
ip
71. Infante RM, Ericsson CD, Jiang ZD, Ke S, et al. Enteroaggregative Escherichia
coli diarrhea in travelers: response to rifaximin therapy. Clin Gastroenterol

cr
Hepatol 2004;2:135–8.
72. Taylor DN, Bourgeois AL, Ericsson CD, Steffen R, et al. A randomized,

us
double-blind, multicenter study of rifaximin compared with placebo and with
ciprofloxacin in the treatment of travelers’ diarrhea. Am J Trop Med Hyg
2006;74:1060–6.
an
M

Figure Legend:
Figure 1. Chemical structure of rifamycin SV. The formula is C37H47NO12 and its molecular weight is
ed

697.80 daltons [60, 61].

pt
ce
Ac
 Figure 1. Chemical structure of rifamycin SV. The formula is C37H47NO12 and its molecular weight is
697.78 daltons [69]. (Please see separated attachment in ChemDraw format)

List of abbreviation
GI: Gastrointestinal
IBS: Irritable bowel syndrome

t
ETEC: Enterotoxigenic E. coli

ip
EAEC: Enteroaggregative E. coli
TLUS: Time to last unformed stool

cr
AEs: Adverse events
MMX: Multi-matrix structure

us
OATP: Organic anion transporting polypeptide
NDA: New drug application an
In Table 2:
CIP: ciprofloxacin
RIF-MMX: Rifamycin SV MMX
M
RFX: Rifaximin
TMP-SMX: Trimethoprim-sulfamethoxazole
LOP: Loperamide
ed

bid: Two times a day

tid: Three time a day
pt
ce
Ac
 Table 1. MIC50 and MIC90 of rifamycin SV MMX® against selected enteric pathogens [12, 49]
Organism Rifamycin SV MIC (μg/mL)
(No. of isolates tested) MIC50 MIC90 Range
E. coli (443) [49] 32-64 64-128 2- >512
E. coli (178, pre-treatment) [12] 16 32-128 4-1024
E. coli (63, post-treatment) [12] 512-1024 1024 16-1024
Enterohemorrhagic (105) [49] 32 64 8-256

t
Enterotoxigenic (201) [49] 64 128 2- >512

ip
Enterotoxigenic (100, pre-treatment) [12] 16 32-128 4-1024
Enterotoxigenic (33, post-treatment) [12] 1024 1024 16-1024

cr
Enteroaggregative (92) [49] 32 128 4-256
Enteroaggregative (48, pre-treatment) [12] 16 64 8-1024

us
Enteroaggregative (13, post-treatment) [12] 512 1024 16-1024
Enteropathogenic (45) [49] 64 128 16-128
Diffusely adherent (30, pre-treatment) [12] 16 64 8-64
an
Diffusely adherent (7, post-treatment) [12] 1024 1024 16-1024
Salmonella spp. (102) [49] 128 256 16-256
Salmonella spp. (2, pre-treatment) [12] 64 64 16-64
M
Salmonella spp. (0, post-treatment) [12] -- -- --
Shigella spp. (2, pre-treatment) [12] 32 32 16-32
Shigella spp. (0, post-treatment) [12] -- -- --
ed

Campylobacter spp. (102) [49] >512 >512 >512

Campylobacter spp. (4, pre-treatment) [12] 64 64 16-64
pt

Campylobacter spp. (1, post-treatment) [12] 1024 1024 1024

Aeromonas hydrophila (101) [49] 4 16 2-512
Plesiomonas shigelloides (16) [49] 8 8 4-8
ce

Plesiomonas spp. (2, pre-treatment) [12] 8 8 8

Plesiomonas spp. (0, post-treatment) [12] -- -- --
Ac

Vibrio parahaemolyticus (42) [49] 2 2 2-4

Vibrio spp. (1, pre-treatment) [12] 64 64 64
Vibrio spp. (0, post-treatment) [12] -- -- --
C. difficile* (30) [49] 0.03 256 ≤ 0.015-512
*including 1 hypervirulent NAP1 strain
Table 2. Controlled clinical trials of rifaximin and rifamycin SV MMX® in the treatment of traveler’s diarrhea
Year(s) of Location Study n Age range Drug/regimen ETEC TLUS, Treatment Microbiological
study arm mean±SD preva-len hours failure, % cure,a %

t
(range) ce, % (median)

rip
DuPont 2010-2012 Mexico, RIF-MM 199 28.0±11.4 400 mg bid x 3 days 46 46 18.6 67
[12] Jamaica X

c
Placebo 65 28.9±12.7 bid x 3 days 42 68 43.1 55

us
b
DuPont [50] 1996 Mexico RFX 18 23.9 200 mg tid x 5 days 39 26.3 (3 RFX 100
RFX 18 25.8 400 mg tid x 5 days 17 40.5 combined: 60

an
RFX 19 24.0 600 mg tid x 5 days 11 35 11%) 50
TMP-S 18 24.4 160/800 mg bid x 5 days 33 47 29 100

M
MX
DuPont [67] 1997-1998 Mexico, RFX (187) 26.3±9.5 400 mg bid x 3 days 39 25.7 13 74

d
Jamaica (18-57)
CIP
te 25.6±9.2
(18-59)
500 mg bid x 3 days 38 25 12 88
ep
b
Stephen [13] 1999-2000 Mexico, RFX 116 29.0±1.1 200 mg tid x 3 days NA 32.5 16 NA
Guatemala, (18-72)
c

Kenya 114 29.9±1.0 400 mg tid x 3 days NA 32.9 16.7 NA

Ac

(18-66)
Placebo 119 28.3±0.9 NA 60 34.9 NA
(16-69)
Infante [71] Published in Mexico, RFXb 55 tourists or 200 mg or 400 mg tid x 3 55 22 54.5 NA
2004 Guatemala, college days (EAEC)
(focusing on Kenya students

t
EAEC) Placebo 39 (age not tid x 3 days 33 72 33 NA

rip
mentioned) (EAEC)
DuPont [68] 2004-2005 Mexico RFX (310) 26.1 200 mg bid x 3 days 36 32.5 23 76

c
with (18-60)

us
LOP
RFX 25.5 200 mg bid x 3 days 38 27.3 25 68

an
without (18-76)
LOP

M
Taylor [72] 2002-2003 Mexico, RFX 197 Overall: 200 mg tid x 3 days NA 32.0 14.7 61.6
Guatemala, 33 (18-80)

d
India, Peru
CIP
te
101 500 mg bid (+ placebo
daily) x 3 days
NA 28.8 6.9 80.7
ep
Placebo 101 tid x 3 days NA 65.5 26.7 51.7
NOTE. The constancy of investigators, study location (continent, country) and design including the primary outcomes and definitions, origin of the travelers, and prevalent
c

pathogens and resistant patterns may differ among the studies.

Ac

ETEC, enterotoxigenic E. coli; EAEC, enteroaggregative E. coli; NA, not available; CIP, ciprofloxacin; RIF-MMX, rifamycin SV MMX®; RFX, rifaximin; TLUS, time to last
unformed stool; TMP-SMX, trimethoprim-sulfamethoxazole; LOP, loperamide; bid, two times a day; tid, three time a day.
a Defined as eradication in post-treatment samples of pathogens found in pretreatment samples.
b P <0.05 comparing between study drug(s) with active comparator or placebo.
 Table 3. Adverse events experienced by ≥ 2% in phase II and phase III clinical trial of rifamycin
SV MMX® in the treatment of GI infections
Adverse event Rifaximin Rifamycin SV MMX® Placebo
200 mg qid 200 mg qid 400 mg bid (N=65)
(N=58) (N=57) (N=199)
Overall 25 (43.1) 29 (50.9)
Headache 12 (20.7) 14 (24.6) 17 (8.5) 6 (9.2)
Constipation 4 (6.9) 4 (7.0) 7 (3.5) 1 (1.5)

t
Nausea 1 (1.7) 3 (5.3) -- --

ip
Aggravated diarrhea 4 (6.9) 3 (5.3) 20 (10.0) 11 (16.9)
Abdominal pain 2 (3.4) 1 (1.8) -- --

cr
Amoebic dysentery 0 (0%) 2 (3.1)
Worsening GI infections 0 (0%) 2 (3.1)

us
NOTE. Data are no. (%) of adverse events. From [46] and [12].
an
M
ed
pt
ce
Ac

1
 Drug Summary Box

Drug name (generic) Rifamycin SV

Phase (for indication under
discussion)
Indication (specific to
discussion)
Pharmacology
description/mechanism of
Phase III
Traveler’s diarrhea, C. difficile infection, acute uncomplicated diverticulitis, infectious
diarrhea, inflammatory bowel diseases, and hepatic encephalopathy.
The mechanism of action is against the DNA-dependent RNA polymerase of bacteria and
eukaryotic cells. The broad-spectrum, semisynthetic rifamycin SV is actively against

t
action Gram-positive and Gram-negative pathogens, and mycobacteria.

ip
Route of administration Oral

cr
Chemical structure

us
an
M
Pivotal trial(s) 1. DuPont HL, Petersen A, Zhao J, Mundt A, et al. Targeting of rifamycin SV to the colon for
treatment of travelers’ diarrhea: a randomized, double-blind, placebo-controlled phase 3 study.
J Travel Med 2014;21:369-76.
ed
pt
ce
Ac