Rifamycin SV MMX®: A Review in the Treatment of Traveller’s Diarrhoea
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Rifamycin SV MMX® (Aemcolo™; Relafalk™) is a novel oral formulation of the antibacterial rifamycin SV that uses MultiMatrix (MMX®) technology to enable colonic delivery. Specifically, the active ingredient (rifamycin SV) is released throughout the colon, where it acts locally in the intestinal lumen; systemic absorption is minimal. Rifamycin SV MMX® exhibits antibacterial activity against a broad spectrum of clinically relevant enteropathogens and is available in the EU and the USA for the treatment of adults with traveller’s diarrhoea. In two multinational, phase III studies, rifamycin SV MMX® (400 mg twice daily for 3 days) effectively shortened the duration of non-dysenteric traveller’s diarrhoea in adults, being significantly more effective than placebo and noninferior to ciprofloxacin in reducing median time to last unformed stool. As expected (given its poor systemic absorption), rifamycin SV MMX® was well tolerated in this patient population, with the overall incidence of treatment-emergent adverse events generally similar to those of placebo and ciprofloxacin. Current evidence indicates that twice-daily rifamycin SV MMX® is an effective and well tolerated treatment option for shortening the duration of non-dysenteric traveller’s diarrhoea in adults.
Rifamycin SV MMX®: clinical considerations in the treatment of traveller’s diarrhoea
Novel oral formulation of rifamycin SV that uses MMX® colonic delivery technology
Exhibits antibacterial activity against many of the bacterial enteropathogens frequently associated with traveller’s diarrhoea (including non-invasive strains of Escherichia coli), but not against Campylobacter spp.
Shortens the duration of non-dysenteric traveller’s diarrhoea and is well tolerated
Acute diarrhoea is the most common illness affecting travellers from developed countries visiting developing tropical and semitropical regions [1, 2, 3]. Known as traveller’s diarrhoea, it results from the ingestion of faecally contaminated food and drink, with most cases caused by bacterial enteropathogens [most commonly enterotoxigenic Escherichia coli (ETEC), enteroaggregative E. coli (EAEC), diffusely adherent E. coli, Salmonella spp. and Campylobacter jejuni] .
While traveller’s diarrhoea is usually a benign, self-limited illness (lasting up to 5 days), there can be long-term complications (e.g. post-infectious irritable bowel syndrome) [1, 2]. Antibacterials shorten the duration of symptoms (from an average of 50–93 to 16–30 h), with the choice of antibacterial depending, among other criteria, on the region visited and the tolerability profile of the agent . The potential safety issues associated with systemic (i.e. absorbable) antibacterials prefaces a possible role for novel antibacterials in the management of traveller’s diarrhoea . Using MultiMatrix (MMX®) technology, an oral formulation of the semisynthetic antibacterial rifamycin SV [hereafter referred to as rifamycin SV MMX® (Aemcolo™; Relafalk™)] has been developed to provide colonic release of rifamycin SV [6, 7]. This article discusses pharmacological, therapeutic efficacy and tolerability data relevant to the use of rifamycin SV MMX® for the treatment of traveller’s diarrhoea in adults.
2 Antibacterial Activity of Rifamycin SV MMX®
Rifamycin SV is a semisynthetic antibacterial belonging to the ansamycin class . It exerts its antibacterial activity by irreversibly binding to the bacterial DNA-dependent RNA polymerase β-subunit, thereby inhibiting bacterial RNA synthesis [7, 8]. As rifamycin SV is poorly absorbed from the gastrointestinal tract (GIT) (Sect. 3), it acts locally in the intestinal lumen .
In vitro, rifamycin SV exhibited antibacterial activity against many of the bacterial enteropathogens frequently associated with traveller’s diarrhoea, including non-invasive strains of E. coli; however, it showed no activity against Campylobacter spp. [8, 9] (see Sect. 7).
The development of resistance to rifamycin SV likely involves a mutation in the rpoB gene encoding bacterial RNA polymerase or a stable deregulated efflux pump . Strains of E. coli have demonstrated a spontaneous mutation frequency (independent of the rifamycin SV concentration) for rifamycin SV of 10−6 to 10−10 at 4–16 × minimum inhibitory concentration (MIC) and, both in vitro and clinically, exposure to rifamycin SV has been associated with MIC increases . In addition, cross-resistance has been observed between rifamycin SV and other ansamycins . In clinical studies in patients with traveller’s diarrhoea receiving rifamycin SV MMX®, there was a very low incidence of resistant bacterial subpopulations .
3 Pharmacokinetic Properties of Rifamycin SV MMX®
A gastro-resistant polymer coating that dissolves at a pH of ≥ 7.0 (thereby delaying release of the active ingredient during transit through the GIT until the caecum is reached).
A rifamycin SV-containing MultiMatrix system (i.e. rifamycin SV microparticles dispersed in a lipophilic matrix, which is itself disseminated throughout a hydrophilic matrix) [permitting the release of rifamycin SV throughout the colon].
Colonic delivery using MMX® technology was validated in two pharmacoscintigraphic studies evaluating mesalamine and budesonide .
The estimated mean absolute bioavailability of rifamycin SV [administered as a single oral dose of rifamycin SV MMX® 400 mg (two 200 mg tablets)] was 0.04% under fasting conditions in 24 healthy volunteers . Quantifiable (> 2.00 ng/mL) rifamycin SV plasma concentrations were reported infrequently and were randomly distributed following single (400 mg; administered under both fasting and fed conditions to 24 healthy volunteers) and multiple (400 mg twice daily for 3 days administered to 12 healthy volunteers) doses of rifamycin SV MMX®. Indeed, plasma concentrations were never > 10 ng/mL following multiple doses .
In vitro, plasma protein binding was approximately 80% and CYP-based metabolism was not seen . Most (87%) of the single rifamycin SV MMX® 400 mg dose administered under fasting conditions to 20 healthy volunteers was excreted unchanged in the faeces over an 84-h period . Urinary excretion of rifamycin SV is negligible; quantifiable (> 2.00 ng/mL) urinary rifamycin SV concentrations were rare following a single (400 mg) dose, but were found more generally following multiple doses (400 mg twice daily for 3 days) of rifamycin SV MMX® .
As rifamycin SV undergoes minimal systemic absorption, it acts locally in the intestinal lumen , potentially limiting the requirement for dose adjustments in special patient populations and preventing drug interactions.
4 Therapeutic Efficacy of Rifamycin SV MMX®
Two randomized, double-blind, multinational, phase III studies in adults with non-dysenteric traveller’s diarrhoea compared the therapeutic efficacy of rifamycin SV MMX® with placebo (NCT01142089)  and ciprofloxacin (NCT01208922; ERASE) . Patients had travelled from an industrialized country (within 30 days prior to randomization  or within the previous 4 weeks ) to Ecuador, Guatemala, India and/or Mexico. They were experiencing symptoms of acute (moderate to severe ) diarrhoea, which was defined as the passage of ≥ 3 unformed (i.e. watery or soft) stools within 24 h prior to randomization, a duration of illness of ≤ 72 h, and ≥ 1 symptom of enteric infection (abdominal pain, defecation urgency, flatulence, nausea, rectal tenesmus or vomiting). Patients with a fever of > 38 °C and those with grossly bloody stools were among those excluded [13, 14].
Patients received rifamycin SV MMX® 400 mg (i.e. two 200 mg tablets) or a comparator [placebo  or ciprofloxacin 500 mg (i.e. one 500 mg capsule) ], administered orally twice daily (in the morning and evening) for 3 days. Medication compliance was confirmed in 88.4 and 89.2% of patients receiving rifamycin SV MMX® and placebo in the placebo-controlled study . Where reported, patients in whom the diarrhoea and/or symptoms of enteric infection worsened or failed to improve were eligible to receive rescue therapy .
Baseline patient demographics and disease characteristics were similar between the treatment groups in both studies [13, 14]. At baseline, ≥ 1 pathogen was identified in the stool samples of 66.8 and 73.8% of patients in the rifamycin SV MMX® and placebo groups (n = 199 and 65) in the placebo-controlled study  and 63.3 and 61.2% of patients in the rifamycin SV MMX® and ciprofloxacin groups (n = 420 and 415) in ERASE . Diarrhoeagenic E. coli strains were the most frequently identified pathogen class in 56.3 and 56.9% of patients in the rifamycin SV MMX® and placebo groups in the placebo-controlled study  and in 37.9 and 38.1% of patients in the rifamycin SV MMX® and ciprofloxacin groups in ERASE . Prior to treatment in the placebo-controlled study, rifamycin SV MMX® demonstrated in vitro activity against each bacteria isolated, with MICs required to inhibit the growth of 90% of isolates (MIC90) values ranging from 4 to 128 μg/mL .
The primary endpoint was time to the last unformed stool (TLUS), defined as the interval between the first dose of the study medication and passage of the last unformed stool, following which clinical cure was declared [13, 14]. Patients receiving rescue therapy [13, 14] and those who terminated the study early due to a lack of efficacy or without clinical cure  were considered to have a TLUS of 120 h. ERASE was designed to assess the noninferiority of rifamycin SV MMX® versus ciprofloxacin in terms of TLUS . Analyses were conducted in the intent-to-treat (ITT) [13, 14] and per-protocol  populations.
4.1 Versus Placebo
Efficacy of rifamycin SV MMX® in adults with non-dysenteric traveller’s diarrhoea in two multinational, phase III studies
Treatment (no. of pts)
Median TLUSa (h)
Clinical cure rateb (% of ITT pts)
Treatment failure ratec (% of ITT pts)
Need for rescue therapy (% of ITT pts)
DuPont et al. 
RIF SV MMX® (199)
Steffen et al. (ERASE) 
RIF SV MMX® (384/420)d
The beneficial effects of rifamycin SV MMX® therapy on median TLUS and clinical cure rates in patients with baseline diarrhoeagenic E. coli were consistent with those in the overall population . In this patient subgroup, median TLUS was significantly shorter with rifamycin SV MMX® (n = 112) than placebo (n = 37) [49.3 vs. 68.3 h; p = 0.0035], with 80.4 and 54.1% of patients achieving a clinical cure. Clinical cure rates with rifamycin SV MMX® and placebo therapy were 70.0 and 60.0% in patients with baseline invasive bacteria (e.g. Campylobacter jejuni, Shigella spp.) [n = 10 and 5] and 83.3 and 70.6% in patients with no identifiable pathogen at baseline (n = 66 and 17) .
Rifamycin SV MMX® also demonstrated significant advantages over placebo in the proportions of patients failing treatment or requiring rescue therapy  (Table 1). Moreover, significantly more rifamycin SV MMX® than placebo recipients reported no signs or symptoms of enteric infection during the 48–72-h interval after the first dose of study medication (40.0 vs. 19.4%; p= 0.003) .
Overall microbiological eradication rates did not significantly differ between rifamycin SV MMX® and placebo (67.0 and 54.8% of 185 and 62 pathogens), according to an analysis of pre- and post-treatment (assessed 96–120 h after the first dose of study medication) stool samples . Moreover, there was no significant difference between rifamycin SV MMX® and placebo in terms of diarrhoeagenic E. coli (67.1 and 57.1% of 161 and 49 pathogens) and invasive bacteria (66.7 and 46.2% of 24 and 13 pathogens) eradication rates . A lack of correlation has been previously noted between the persistence of an initial causal enteropathogen and prolonged traveller’s diarrhoea . Although those bacterial isolates present following therapy with rifamycin SV MMX® demonstrated reduced susceptibility to rifamycin SV [MIC50 and MIC90 values increased from 512 to 1024 μg/mL for each bacterial type], such reductions in susceptibility did not affect the clinical outcome . Indeed, compared with the overall population of rifamycin SV MMX®-treated recipients (see Table 1), the subgroup of patients with rifamycin SV MICs of ≥ 512 μg/mL (n = 32) did not have a longer median TLUS (45.9 h) or a lower clinical cure rate (84.4%) .
4.2 Versus Ciprofloxacin
The efficacy of rifamycin SV MMX® was noninferior to that of ciprofloxacin in ERASE, as the between-group difference in the primary endpoint did not exceed the maximally acceptable difference of 8.5 h in the per-protocol population  (Table 1). An ITT population analysis demonstrated that the results of the primary analysis were robust (Table 1). According to subgroup analyses, median TLUS did not significantly differ between the treatment groups in patients with a 0 to < 24 h, 24 to < 48 h, 48–72 h or > 72 h duration of disease symptoms, those who visited India or Latin America, and those with or without blood and/or mucus in their stools. Among the baseline pathogen status subgroups, only in patients positive for potentially invasive bacteria was a statistically significant between-group difference in median TLUS, favouring ciprofloxacin (n = 23) over rifamycin SV MMX® (n = 22), seen [56.2 vs. 35.3 h; hazard ratio (HR) 0.370 (95% CI 0.187, 0.732); p = 0.0031]. It is worth noting that median TLUS was associated with the duration of disease symptoms prior to therapy commencement, being significantly shorter in patients whose treatment commenced 0 to < 24 h after the onset of symptoms than in those whose treatment commenced 24 to < 48 h [HR 0.475 (95% CI 0.401, 0.563); p < 0.0001] and 48 to < 72 h [HR 0.355 (95% CI 0.278, 0.453); p < 0.0001] after the onset of symptoms, according to a subgroup analysis using a Cox regression model. This effect was independent of the treatment arm .
The proportions of patients achieving clinical cure, failing treatment or requiring rescue therapy did not significantly differ between the rifamycin SV MMX® and ciprofloxacin groups  (Table 1). Moreover, the number of unformed stools was rapidly (within 3 days) reduced and the gastrointestinal symptoms of the enteric infection resolved [by ≈ 60% in 4 days (data from a graph)] in a similar manner with both therapies .
Overall microbiological eradication rates did not significantly differ between rifamycin SV MMX® and ciprofloxacin (49.2% of 266 and 49.6% of 254 patients), according to an analysis of pre- and post-treatment (assessed 96–120 h after the first dose of study medication) stool samples . Moreover, microbiological eradication was pathogen species independent, with rates not significantly differing between the respective treatment groups across the diarrhoeagenic E. coli (48.4 and 50.6% of 159 and 158 pathogens) and potentially invasive bacteria (50.5 and 47.9% of 107 and 96 pathogens) and the individual strains [e.g. EAEC (59.8 and 67.3% of 112 and 98 pathogens)]. At 96–120 h after the first dose of study medication, MIC50 and MIC90 values had increased from baseline for rifamycin SV MMX® in the rifamycin SV MMX® group and for ciprofloxacin in the ciprofloxacin group . However, it is worth noting that the increases in MIC values for rifamycin SV MMX® in ERASE  are still mostly below the high intraluminal and faecal concentrations of rifamycin SV MMX® (administered orally as a single 400 mg dose under fasting conditions) reported in a study in healthy volunteers (specific concentrations not reported; faecal elimination rates of 3107, 8335, 3506 and 104 μg/h at 0–24 h, 24–48 h, 48–72 h and 72–84 h post dose, respectively) [see Sect. 3 for study details] .
5 Tolerability of Rifamycin SV MMX®
Rifamycin SV MMX® was well tolerated in adults with non-dysenteric traveller’s diarrhoea [13, 14]. According to the EU summary of product characteristics, common (≥ 1/100 to < 1/10) adverse reactions reported in clinical studies in adults with traveller’s diarrhoea that were considered at least possibly related to rifamycin SV MMX® were diarrhoea and headache .
In the placebo-controlled study, the incidence of treatment-emergent adverse events (TEAEs) did not significantly differ between the rifamycin SV MMX® (n = 199) and placebo (n = 65) groups (29.6 vs. 38.5% of patients) , with most TEAEs considered to be unrelated to the study medication. Constipation was the most frequently reported TEAE (occurring in ≥ 2% of patients in either treatment group and more frequently in the rifamycin SV MMX® group than the placebo group) [3.5 vs. 1.5% of patients in the respective groups]. Most TEAEs in this study were mild or moderate in severity; severe TEAEs occurred in 4.5% of rifamycin SV MMX® recipients and 6.2% of placebo recipients and treatment discontinuation because of TEAEs occurred in 0.5 and 13.8% of patients. Serious AEs were reported in three patients (abdominal pain and vomiting, and neuroblastoma each in one rifamycin SV MMX® recipient, and Clostridium difficile colitis in one placebo recipient), with none considered related to the study medication . In the rifamycin SV MMX® (n = 420) and ciprofloxacin (n = 415) groups of ERASE, the incidences of TEAEs (14.8 vs. 14.9% of patients) and adverse drug reactions (8.1 vs. 7.5%) were generally similar . The most frequently reported (occurring in ≥ 2% of rifamycin SV MMX® recipients and more frequently in the rifamycin SV MMX® group than the ciprofloxacin group) adverse reaction was headache (3.3 vs. 1.9%) . One rifamycin SV MMX® recipient discontinued treatment after 1 day’s therapy because of a ‘worsening of diarrhoea’ . This AE was moderate in severity, but was not considered to be related to the study medication or serious. In fact, no serious AEs or deaths were reported in ERASE .
Antibacterial use during travel is an independent risk factor for extended spectrum β-lactamase-producing (ESBL) Enterobacteriaceae acquisition . According to a post hoc analysis of ERASE, ESBL E. coli colonisation rates did not significantly differ between the rifamycin SV MMX® and ciprofloxacin groups at baseline . However, at 96–120 h after the first dose of study medication, these rates significantly increased from baseline with ciprofloxacin (p = 0.0319), but not with rifamycin SV MMX®, therapy. Moreover, among patients who were ESBL E. coli-negative at baseline, the risk of acquiring ESBL E. coli was significantly higher in patients receiving ciprofloxacin (n = 259) than in those receiving rifamycin SV MMX® (n = 263) [17.4 vs. 10.3%; odds ratio 1.84 (95% CI 1.10, 3.07); p = 0.0197] .
6 Dosage and Administration of Rifamycin SV MMX®
Rifamycin SV MMX® is approved in the EU under the Decentralized Procedure , with Germany, the United Kingdom, Spain, Denmark, Greece, Finland, Hungary, Norway, Portugal, Poland, Sweden and Bulgaria as Member States, for the treatment of adults with traveller’s diarrhoea accompanied by symptoms like nausea, vomiting, gas/flatulence, rectal tenesmus, faecal urgency, and abdominal pain or cramps without clinical signs of invasive enteritis such as fever, blood, occult blood or leucocytes in the stools . It is also approved in the USA for the treatment of adults with traveller’s diarrhoea caused by non-invasive strains of E. coli .
The recommended dosage of rifamycin SV MMX® is 400 mg (i.e. two 200 mg tablets) twice daily for 3 days [10, 11]. Rifamycin SV MMX® should be swallowed whole with a glass of water and can be administered with or without food [10, 11]. In the EU , rifamycin SV MMX® should not be used in patients with clinical signs of invasive enteritis such as fever or bloody stool, and is contraindicated in patients with GIT obstructions, GIT perforations or severe intestinal ulcerative lesions. In the USA, it is not recommended in patients with diarrhoea complicated by fever or bloody stool, or due to pathogens other than non-invasive strains of E. coli . Local prescribing information should be consulted for detailed information regarding other contraindications, use in special patient populations, potential drug interactions, and warnings and precautions.
7 Current Status of Rifamycin SV MMX® in the Treatment of Traveller’s Diarrhoea
The management of traveller’s diarrhoea is dependent upon diarrhoeal severity . Although recent guidelines from an international expert panel  do not recommend the use of antibacterials in patients with mild traveller’s diarrhoea (i.e. diarrhoea that is tolerable/not distressing and that does not impede planned activities), they concluded that antibacterials may be used in those with moderate diarrhoea (i.e. diarrhoea that is distressing or impedes planned activities) and should be used in those with severe diarrhoea (i.e. diarrhoea that is incapacitating or completely precludes planned activities, and which includes the passage of grossly bloody stools). Providing loperamide and an antibacterial to most, if not all, travellers for the self-treatment of traveller’s diarrhoea is also endorsed by the expert panel, although it is worth noting that antibacterial selection for self-treatment may be complicated by the possible inconsistent presentation of the signs and symptoms caused by invasive enteropathogens .
Several parameters should be taken into account when selecting an antibacterial for the treatment of traveller’s diarrhoea [1, 4]. These include the likelihood of therapeutic efficacy, the tolerability profile of the agent, and the probable pathogen(s) and resistance patterns in the region visited . Using azithromycin or a fluoroquinolone for the treatment of moderate traveller’s diarrhoea is strongly recommended by the expert panel, although potential tolerability issues (i.e. reduced intestinal microbiota diversity and musculoskeletal consequences) and the development of widespread resistance to fluoroquinolones, particularly in Campylobacter spp. (which are a common cause of traveller’s diarrhoea in Southeast and South Asia), temper the fluoroquinolone recommendation. Consequently, azithromycin should be the first-line option in patients with moderate diarrhoea arising from travel to Southeast and South Asia (or other regions if Campylobacter or fluoroquinolone-resistant ETEC is the suspected enteropathogen), and is preferred for the treatment of severe traveller’s diarrhoea. Azithromycin and fluoroquinolones are generally well tolerated, with most adverse events (AEs) minimal (azithromycin) or mild and transient (fluoroquinolones) . However, they are systemically absorbed, which is of concern not only because of the potential for systemic AEs (e.g. Achilles tendon rupture, CNS AEs and an increased risk of C. difficile infection with fluoroquinolone use), but also because of the potential for interference with other health conditions or concomitant medications [4, 5].
While the poorly absorbed rifamycin derivative rifaximin may be considered for the treatment of moderate traveller’s diarrhoea, the international expert panel guidelines recommend against its use in cases suspected to be associated with invasive enteropathogens (e.g. Campylobacter, Salmonella and Shigella spp.) and in those arising from travel to regions where invasive enteropathogens are common (e.g. Southeast and South Asia) . The guidelines also recommend rifaximin as an alternative for the treatment of severe non-dysenteric traveller’s diarrhoea , but this agent may need to be prescribed for self-treatment alongside another antibacterial (e.g. azithromycin) in order to ensure invasive enteropathogens are covered.
Rifamycin SV MMX® is an oral formulation of the semisynthetic antibacterial rifamycin SV developed using MMX® colonic delivery technology (Sect. 1). Release of the active ingredient is delayed during transit through the GIT until the caecum is reached, whereupon it acts locally in the intestinal lumen of the colon, exhibiting antibacterial activity against many of the bacterial enteropathogens frequently associated with traveller’s diarrhoea, including non-invasive strains of E. coli, but not Campylobacter spp. (Sects. 2 and 3). Investigation into the high MIC values and lack of efficacy with rifamycin SV MMX® against Campylobacter spp. would be of interest. Rifamycin SV undergoes minimal systemic absorption, reducing the potential for systemic AEs and potentially limiting the requirement for dose adjustments in special patient populations and preventing drug interactions (Sect. 3).
Results from two multinational, phase III studies have demonstrated the efficacy of rifamycin SV MMX® in shortening the duration of non-dysenteric traveller’s diarrhoea in adults (Sect. 4). In these studies, rifamycin SV MMX® (400 mg twice daily for 3 days) significantly reduced median TLUS compared with placebo (Sect. 4.1) and was noninferior to ciprofloxacin (500 mg twice daily for 3 days) in terms of this primary endpoint (Sect. 4.2).
As expected for a poorly absorbed antibacterial, rifamycin SV MMX® was well tolerated in this patient population, with the overall incidence of TEAEs generally similar to those of placebo and ciprofloxacin (Sect. 5). Diarrhoea and headache were the most common adverse reactions that were considered at least possibly related to rifamycin SV MMX® (Sect. 5).
In conclusion, current evidence indicates that rifamycin SV MMX® is an effective and well tolerated treatment option for shortening the duration of non-dysenteric traveller’s diarrhoea in adults.
Data Selection Rifamycin SV MMX®: 67 records identified
Excluded during initial screening (e.g. press releases; news reports; not relevant drug/indication; preclinical study; reviews; case reports; not randomized trial)
Excluded during writing (e.g. reviews; duplicate data; small patient number; nonrandomized/phase I/II trials)
Cited efficacy/tolerability articles
Cited articles not efficacy/tolerability
Search Strategy: EMBASE, MEDLINE and PubMed from 1946 to present. Clinical trial registries/databases and websites were also searched for relevant data. Key words were Rifamycin SV-MMX, Aemcolo, Relafalk, traveller’s diarrhoea. Records were limited to those in English language. Searches last updated 27 May 2019
During the peer review process, the manufacturer of rifamycin SV MMX® was also offered an opportunity to review this article. Changes resulting from comments received were made on the basis of scientific and editorial merit.
Compliance with Ethical Standards
The preparation of this review was not supported by any external funding.
Conflict of interest
Sheridan Hoy is a salaried employee of Adis International Ltd/Springer Nature, is responsible for the article content and declares no relevant conflicts of interest.
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