This article is more than 5 years old. Information may no longer be current.
Montezuma’s revenge: A new treatment option
Click Here to Manage Email Alerts
One of the most disappointing situations you can encounter while traveling is the dreaded travelers’ diarrhea. Travelers’ diarrhea is the most common travel-related illness that can disrupt vacations and business plans when visiting low-income countries. The rate of travelers’ diarrhea has been reported to be as high as 70%, depending on the time of year and destination, but most recent data suggest that rates have decreased overall and are in the range of 10% to 40%. The highest risk for infection is within the first few weeks while abroad, and it somewhat decreases thereafter. The definition of classic travelers’ diarrhea is three or more diarrheal stools per day, along with at least one other clinical sign, such as abdominal cramps, fever, nausea or vomiting. Approximately 10% of those suffering from this illness will require medical care, and up to 3% may require hospitalization. On average, the duration of illness in those that go untreated is approximately 4 to 5 days.
Patients with travelers’ diarrhea acquire the pathogen via fecal-oral transmission from contaminated food or water, or even from person-to-person contact. Diarrheagenic Escherichia coli, such as enterotoxigenic E. coli (ETEC) and enteroaggregative E. coli (EAEC) are the most common causes. Other organisms that can be implicated are Salmonella, Campylobacter, Shigella, norovirus, rotavirus and others, depending upon the region being visited.
Management of travelers’ diarrhea starts with proper hydration and mitigating symptoms by using loperamide or bismuth subsalicylate. Antibiotic therapy is not recommended for patients with mild travelers’ diarrhea that is tolerable, not distressing, and does not interfere with planned activities. Antibiotic treatment can be considered for those with moderate travelers’ diarrhea and should be given to all patients with severe symptoms. The most commonly used antibiotics include fluoroquinolones and azithromycin. However, nonabsorbable antibiotics such as rifaximin, and the newly approved rifamycin SV, can also be used. Nonabsorbable antibiotics may have some advantages such as delivering high concentrations of active drug to the site of infection, avoidance of drug-drug interactions and decreasing the incidence of systemic side effects. Aemcolo (rifamycin SV MMX, Cosmo Pharmaceuticals) is the newest nonabsorbable antibiotic, approved by the FDA in November for the treatment of travelers’ diarrhea due to noninvasive strains of E. coli.
Rifamycin SV-MMX pharmacology
Rifamycin SV is a semisynthetic antibiotic belonging to the same class as rifaximin, the ansamycins. It is a broad-spectrum antibiotic with activity against gram-positive and gram-negative bacteria, as well as mycobacteria. It has bactericidal activity through the inhibition of protein synthesis by binding to the beta subunit of the bacterial DNA-dependent RNA polymerase.
Rifamycin SV MMX (RIF-MMX) tablets are formulated using a multimatrix structure (MMX) to deliver high antibiotic concentrations into the colon. The tablets are manufactured as a double matrix system with rifamycin SV dispersed in a lipophilic matrix, which is embedded in a hydrophilic matrix. This double matrix decreases the rate of drug dissolution because of the partially hydrophobic environment. The tablets are also coated with a pH-dependent film that will disintegrate when the pH is 7 or higher. This allows the tablet to pass through the stomach unaltered until it reaches the cecum, where the coating begins to disintegrate and the tablet swells up and forms a viscous gel mass. This gel mass slows the release of rifamycin SV into the colonic lumen, allowing for maximum local concentrations in the colon to optimize its antimicrobial effects. Less than 1% of rifamycin SV is absorbed after oral administration of RIF-MMX.
The current approved dosage of RIF-MMX for treatment of travelers’ diarrhea is 388 mg (two tablets) twice daily for 3 days, which can be taken with or without food. Because the tablets are enteric coated, they should be taken whole and not split, crushed or chewed.
Clinical evidence supporting RIF-MMX
The safety and efficacy of RIF-MMX was compared with placebo in adult travelers to Mexico or Guatemala suffering from travelers’ diarrhea. The primary endpoint was the duration between the administration of the first dose of the study drug and time to last unformed stool (TLUS) within a 5-day observation period. RIF-MMX was given as a dose of 400 mg twice per day orally for 3 days. Compared with placebo, TLUS was significantly shorter with RIF-MMX (68 hours vs. 46 hours). Antimicrobial susceptibility testing was conducted on bacterial pathogens that were isolated before and after treatment. It is important to note that one-third of the diarrheagenic E. coli and invasive pathogens continued to grow after the RIF-MMX treatment course due to the development of resistance. The investigators saw the minimum inhibitory concentrations (MICs) for ETEC, EAEC, diffusely adherent E. coli and Campylobacter species all increase significantly, which raises concerns despite the fact that it was not associated with clinical failure of RIF-MMX treatment.
In a randomized, double-blind, phase 3 study, the efficacy and safety of RIF-MMX was compared with ciprofloxacin for the treatment of travelers’ diarrhea in India and Latin America (Ecuador and Guatemala). Patients were treated for 3 days with either RIF-MMX 400 mg twice daily or ciprofloxacin 500 mg twice daily. The primary endpoint was TLUS after clinical cure was declared. The median TLUS in the RIF-MMX group was 42.8 hours vs. 36.8 hours in the ciprofloxacin group, which indicated that RIF-MMX was noninferior to ciprofloxacin. This study also evaluated extended-spectrum beta-lactamase (ESBL)-producing E. coli colonization rates before and after treatment with each study drug. Although the rates of ESBL E. coli colonization were similar at baseline, those in the ciprofloxacin group saw a significant increase in ESBL E. coli colonization at the end of the treatment period. In contrast, those in the RIF-MMX group did not see an increase in ESBL E. coli acquisition. Fluoroquinolones are well known to disrupt the gut microbiome, so this might be an advantage of RIF-MMX.
Safety
The most common side effects associated with oral RIF-MMX in clinical trials include aggravated diarrhea, headache and constipation. There are no known significant drug-drug interactions because there is minimal drug absorption. However, rifamycin has been shown to strongly inhibit members of the organic anion transporting polypeptide family after IV administration. This may play a role in the bioavailability of oral drugs such as HMG-CoA reductase inhibitors, angiotensin II receptor blockers, loop diuretics, protease inhibitors, antihistamines, as well as others, but the significance of this unknown.
RIF-MMX’s place in therapy
Consensus guidelines for prevention and treatment of travelers’ diarrhea were published before the FDA approval of RIF-MMX, so these guidelines do not address its use for this condition. Published data on RIF-MMX highlight some concerns with its routine use over other available antibiotics. First, although the median TLUS of RIF-MMX was similar to ciprofloxacin, research has shown a lower median TLUS for a single dose of azithromycin plus loperamide (11 hours) vs. a single dose of azithromycin alone (34 hours). Additionally, the median TLUS was 32.5 hours with rifaximin 200 mg twice daily for 3 days among travelers to Mexico. Although we do not have direct head-to-head trials between RIF-MMX and azithromycin or rifaximin, the outcomes for RIF-MMX are underwhelming given the longer TLUS in those treated with RIF-MMX compared with past trials for other antibiotic regimens. Secondly, the development of resistance, or “MIC creep,” after RIF-MMX treatment is concerning because the incidence of antibiotic-resistant diarrheagenic E. coli and Campylobacter species are increasing worldwide. Lastly, there are limited efficacy data for pathogens other than for diarrheagenic E. coli. However, like rifaximin, RIF-MMX is considered to be a nonabsorbable antibiotic and should result in fewer systemic side effects and drug-drug interactions than azithromycin and fluoroquinolones.
Despite the fact that RIF-MMX appears to be a safe and effective antibiotic for travelers’ diarrhea, its routine use should be reserved for those unable to be treated with azithromycin until more clinical evidence is available to help further refine its role in the treatment of this illness. More data are needed to address the concerns of the development of resistance as well as treatment of diarrhea caused by more invasive pathogens.
- References:
- Di Stefano AFD, et al. Antimicrob Agents Chemother. 2011;doi:10.1128/AAC.01504-10.
- DuPont HL, et al. Clin Gastroenterol Hepatol. 2007;doi:10.1016/j.cgh.2007.02.004.
- DuPont HL, et al. J Travel Med. 2014;doi:10.1111/jtm.12168.
- Ericsson CD, et al. J Travel Med. 2007;doi:10.1111/j.1708-8305.2007.00144.
- Lin SW, et al. Expert Opin Pharmacother. 2017;doi:1080/14656566.2017.1353079.
- Riddle MS, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix693.
- Riddle MS, et al. J Travel Med. 2017;doi:10.1093/jtm/tax026.
- Shane AL, et al. Clin Infect Dis. 2017;doi:10.1093/cid/cix669.
- Steffen R, et al. J Travel Med. 2018;doi:10.1093/jtm/tay116.
- Steffen R, et al. JAMA. 2015;doi:10.1001/jama.2014.17006.
- For more information:
- Jeff Brock, PharmD, MBA, BCPS-AQ ID, is an infectious disease pharmacy specialist at Mercy Medical Center in Des Moines, Iowa. He can be reached at: jbrock@mercydesmoines.org.
Disclosure: Brock reports no relevant financial disclosures.