Three new antimicrobials available for diarrhea

October 2004

The last six months has seen three new agents approved by the FDA for the treatment of diarrheal diseases. This is remarkable with the growing trend in the lack of new antimicrobial drug development. However, it should be noted that two of these agents, rifaximin (Xifaxan, Salix Pharmaceuticals) and tinidazole (Tindamax, Presutti Labs), have been widely used in Europe and other parts of the world for many years and are just now becoming available in the United States. This article will give a short introduction to each of these new medications.

Rifaximin

The FDA approved rifaximin on May 25, 2004, for the treatment of traveler’s diarrhea. Although new in the United States, rifaximin has been available in Europe for 17 years with an excellent record for use. More than 500 million doses have been prescribed with no major adverse effects reported. Most adverse effects are gastrointestinal in nature and are probably due to the underlying diarrhea rather than to the medication. Rifaximin is a nonabsorbable semisynthetic derivative of rifampin. It has a broad spectrum of activity that includes many aerobic and anaerobic gram-positive and gram-negative bacteria; no significant resistance has been documented.

Rifaximin has virtually no absorption following oral administration, with a bioavailability of 0.4%. Eighty percent to 90% of the dose is concentrated in the gut, with approximately 97% eliminated as unchanged drug in the feces. Since rifaximin is so closely related to rifampin, clinicians should be concerned about drug-drug interactions. However, no clinically significant drug interactions have been found. This is most likely related to the lack of systemic absorption of rifaximin. Studies with concurrent use of oral contraceptives or midazolam have shown no effect on the levels of the oral contraceptives, midazolam or rifaximin.

One study compared two doses of rifaximin (1,200 mg/day, 600 mg/day) with placebo for the treatment of traveler’s diarrhea (Steffen et al). Patients began therapy after having three or more loose stools in the 24 hours prior to enrollment. The primary efficacy endpoint was time to last unformed stool. There was no difference between the rifaximin groups, but both treatments were superior to placebo. This study was carried out in three different countries (Guatemala, Kenya, Mexico), giving the results worldwide application.

Rifaximin is used in a dose of 200 mg orally three times a day for three days. It should be used with caution in patients with diarrhea complicated by fever or gross blood in the stools.

Tinidazole

Tinidazole is a second-generation nitroimidazole that was approved by the FDA on May 17, 2004, for the treatment of trichomoniasis, giardiasis and amebiasis. Tinidazole has been available in Europe for more than 25 years with proven safety and efficacy.

Tinidazole, like metronidazole, has in vitro activity against a wide spectrum of protozoa and anaerobic bacteria. Tinidazole is more potent than metronidazole against Trichomonas vaginalis. It also has activity against Giardia species and Entamoeba histolytica. Tinidazole has in vitro activity against a variety of anaerobic bacteria such as Bacteroides fragilis, other Bacteroides species, Prevotella, Clostridium species including C. difficile, Peptococcus and Peptostreptococcus to name a few. Tinidazole has also been extensively studied in Europe for the treatment of Helicobacter pylori.

Tinidazole has a favorable pharmacokinetics profile. It is rapidly and completely absorbed following oral administration. Taking tinidazole with food delays the absorption but not the extent of absorption; therefore, it may be taken without regard to meals. The half-life of tinidazole is approximately 12 to 14 hours, which is twice as long as metronidazole’s. Tinidazole concentrations are also higher when compared to metronidazole for up to 48 hours after a single 2-g dose.

Tinidazole is a lipophilic agent that is widely distributed throughout the body, including the central nervous system. It is significantly metabolized prior to elimination through the kidneys and liver. Tinidazole’s dose does not need adjustment for renal insufficiency.

The safety profile of tinidazole has been well delineated and is similar to metronidazole’s, with the exception of a low incidence of gastrointestinal adverse effects. When compared with equivalent doses, tinidazole had statistically significantly fewer gastrointestinal adverse effects than metronidazole did. Overall, the rate of adverse effects is low, and they are usually self-limiting.

Tinidazole has been extensively studied, with more than 20 clinical trials for each of its indications. For trichomoniasis, tinidazole has produced a greater than 90% cure rate in both men and women after a single 2-g dose. A single 2-g dose of tinidazole has also shown excellent results for giardiasis. A recent Cochrane review concluded that single-dose tinidazole had better cure rates when compared with other single-dose therapies. Intestinal amebiasis has a 90% response rate after three days of tinidazole.

For trichomoniasis and giardiasis, the dose of tinidazole is 2 g as a single dose for adults and 50 mg/kg as a single dose for children (maximum of 2 g). Intestinal amebiasis is treated with 2 g per day for three days for adults and 50 mg/kg/day up to 2 g for children. Hepatic amebiasis uses the same doses for five days. If a patient is unable to swallow the tablets, an extemporaneous oral suspension may be compounded; the formula for this may be found in the package insert. It is likely that additional indications for tinidazole will be coming in the future for treatment of anaerobic infections and H. pylori.

Nitazoxanide

Nitazoxanide (Alinia, Romark) was approved by the FDA for the treatment of giardiasis and Cryptosporidium in children on Nov. 22, 2002, and just recently for giardiasis in adults. This is the first agent approved for treatment of cryptosporidiosis. Nitazoxanide is one of the few agents that have had pediatric indications and an oral suspension prior to gaining approval for adults.

Nitazoxanide is a prodrug that is converted tizoxanide. The mechanism of action is interference with the pyruvate:ferredoxin oxidoreductase enzyme-dependent electron transfer reaction, which is an essential process in anaerobic energy metabolism. Nitazoxanide has a broad range of activity against common intestinal parasites other than Giardia and Cryptosporidium, including E. histolytica, Ascaris lumbricoides, Ancylostoma duodenale, Trichuris trichiura and Fasciola hepatica, to name a few. Nitazoxanide also has activity against H. pylori, C. difficile and T. vaginalis (Bailey et al).

Nitazoxanide is rapidly converted to tizoxanide following oral administration. Tizoxanide undergoes conjugation primarily by glucuronidation. It is then eliminated in the urine, bile and feces. Tizoxanide is highly protein-bound, so caution should be used when using it in conjugation with other highly protein-bound drugs such as warfarin. No other information regarding drug-drug interactions is available.

The safety and efficacy of nitazoxanide has been studied in both controlled and open-label clinical trials. There was an 85% cure of giardiasis following a three-day course of therapy with minimal adverse effects. There was also a greater than 80% cure of Cryptosporidium in immunocompetent individuals following a three-day course of therapy. Use of nitazoxanide for Cryptosporidium in immunocompromised patients remains controversial, as the studies have given mixed results. However, the current agents that are used to treat Cryptosporidium in immunocompromised patients also have mixed results; thus, nitazoxanide is another option that could be tried (Bailey et al).

In clinical trials, nitazoxanide was well tolerated with few reported adverse effects. Most adverse effects were gastrointestinal in nature and may have actually represented the primary disease state rather than an effect of the drug.

Nitazoxanide doses range from 100 mg to 500 mg orally every 12 hours depending on the indication and age of the patient. Clinicians should refer to the package insert for complete prescribing information.

Rifaximin, tinidazole and nitazoxanide are newly approved agents for the treatment of diarrhea in adult patients. These agents are safe and effective with few adverse effects. They are welcome additions to the antimicrobial armamentarium.

For more information:

• Xifaxan package insert. Raleigh, N.C.: Salix Pharmaceuticals Inc.; June 2004.
• Steffen R, Sack DA, Riopel L et al. Therapy of traveler’s diarrhea with rifaximin on various continents. Am J Gastroenterol. 2003;98:1073-1078.
• Tindamax package insert. Rolling Meadows, Ill.: Presutti Laboratories; May 2004.
• Alinia package insert. Tampa, Fla.: Romark Pharmaceuticals; July 2004.
• Bailey JM, Erramouspe J. Nitazoxanide treatment for giardiasis and cryptosporidiosis in children. Ann Pharmacother. 2004;38:634-640.

• Marianne Billeter, PharmD, BCPS, is Clinical Pharmacology Specialist, Infectious Diseases, at Ochsner Clinic Foundation, New Orleans.