Intestinal infection with G. lamblia is a common problem in summer

July 2003

Intestinal infection with Giardia lamblia, also known as Giardia intestinalis, is among the most common protozoal illnesses in the United States. Infection may be spread in the summer months by contaminated water, such as public swimming pools. While several pharmaceutical agents have activity toward G. lamblia, only a select few are commercially available in the United States, and, until just recently, none have been commercially available in liquid dosage forms. Nitazoxanide, (Alinia, Romark Pharmaceuticals) became available in March of this year and is available as an oral suspension. This month’s column will review the treatment of giardiasis.

G. lamblia is a flagellate protozoan and exists in trophozoite (active, motile, feeding stage) and cyst forms. Infection results from ingestion of the cyst form. Ingestion may occur directly through fecal-oral means from an infected individual — the most common means of transmission — or indirectly through a contaminated water source, such as natural water sources contaminated by fecal matter from infected wildlife. Public water supplies may also become contaminated with G. lamblia cysts, for the cysts are relatively hardy, as they can remain viable for as long as three months in moist environments, and they are able to resist chlorination levels that are able to kill coliform bacteria. Infection with as few as 10 cysts can result in clinical disease. Outbreaks may also occur in day care settings. Once ingested, excystation occurs, which is stimulated by exposure to gastric acidity. One cyst may release between one or two trophozoites. The trophozoite form then infects the duodenum and upper intestine, attaching to mucosal surfaces near the base of the villi. The biliary tract may also become infected. As trophozoites pass through the small intestinal tract to the colon, encystation occurs, resulting in cyst formation, and contamination of passed fecal material. Incubation periods are typically one to four weeks and infected individuals can remain infectious for months.

Infection with G. lamblia may be asymptomatic or symptomatic, with asymptomatic infection occurring relatively commonly. Symptomatic infection may result in watery diarrhea or production of large, relatively formed, greasy stools, and abdominal pain. Protracted, intermittent disease may also occur, resulting in anorexia, abdominal distension, weight loss and failure to thrive. Malabsorption of fat and lactose may occur, potentially resulting in growth retardation and anemia. In some areas chronic disease may occur as commonly as acute illness. Chronic symptomatic disease is more likely to occur in persons with humoral immunodeficiencies. A diagnosis of giardiasis should be considered in an individual with unexplained diarrhea lasting seven days or more. Diagnosis is by microscopic examination of fecal material for cysts.

Treatment

Although several medications have been assessed as potentially useful in the therapy of giardiasis, only a few have been evaluated in children or are available commercially. Prior to the availability of Alinia, no product was commercially available in a liquid formulation.

Metronidazole has traditionally been recommended as the treatment of choice for giardiasis, although this may change with the recent approval of Alinia. Even though metronidazole is often recommended, several limitations of its use exist. Metronidazole is not available in liquid formulation, although a recipe for compounding a 50 mg/ml suspension in cherry syrup can be commonly found. Metronidazole is not formally approved by the FDA for treatment of giardiasis, although it is quite effective at doses of 15-30 mg/kg/day, divided every 8 hours, for five to seven days. Efficacy rates of 90% or more should be expected with treatment. Adverse effects of metronidazole may limit its use, including nausea or vomiting, a metallic aftertaste, or a disulfiram-like reaction when given with alcohol or alcohol-containing products (eg, digoxin elixir). Metronidazole’s use is further limited somewhat by its potential mutagenic effects, which have been shown in bacteria only, and not humans. Metronidazole is classified as pregnancy category B, although its use in pregnancy remains controversial. The manufacturer and the CDC consider metronidazole’s use contraindicated during the first trimester of pregnancy when used in the therapy of trichomoniasis.

Other treatments that may be considered include albendazole (Albenza, GlaxoSmithKline), quinacrine, or paromomycin (Humatin, Parke-Davis). Limitations of using albendazole may include some studies documenting efficacy rates below those expected with metronidazole therapy. Albendazole is not commercially available as a liquid dosage form, although a recipe for a liquid formation can be found. Although quinacrine can effectively treat giardiasis, it is not commercially available, and is only available by special pharmaceutical compounding through a select, small number of pharmacies. Significant adverse effects further limit quinacrine’s use, including a bitter taste and vomiting. Paromomycin is an aminoglycoside and thus is poorly absorbed when given orally. Studies of its use in the treatment of giardiasis are limited, although paromomycin has been recommended as a therapy for the pregnant patient, because it is poorly absorbed orally.

Alinia (nitazoxanide)

Alinia is the only pharmaceutical agent officially approved by the FDA for the treatment of giardiasis. This approval was based upon a controlled, randomized, unblinded, trial of 110 children (2-11 years of age) in Peru. A three-day therapy of Alinia was compared to a five-day therapy of metronidazole. The primary end point was the clinical response after seven days of follow-up. In the intent-to-treat analysis, 85% of children receiving nitazoxanide and 80% of children receiving metronidazole responded well to therapy (statistically non-significant). By a per protocol analysis, where only those children receiving all study medication were assessed, 90% and 83% of children receiving nitazoxanide and metronidazole, respectively, responded well to therapy.

Alinia is dosed at 100 mg twice daily and 200 mg twice daily for children 12-47 months of age, and 4-11 years of age, respectively. Dosing regimens are for three days, which provides another advantage over metronidazole, with typical regimens of five to seven days. Alinia is available as a pink, strawberry-flavored suspension. It may be two or three-fold more expensive than Flagyl, and up to five to ten-fold more expensive than generically available metronidazole. Tizoxanide, the active metabolite of nitazoxanide, is highly protein bound, and thus it may result in clinically significant drug interactions with other highly protein-bound drugs.

Summary and conclusions

Alinia is equally effective as metronidazole, but compares favorably to it by having a shorter duration of therapy and commercial availability as a liquid preparation. It may be substantially more expensive than metronidazole. The vast majority of children should respond to a single course of either drug. Children who do not respond may be offered another course of therapy. Children with symptom persistence after two treatment courses should be evaluated for continued re-infection, lactose intolerance resulting from giardiasis, or potentially drug resistance. Such resistance, while possible, is poorly defined.

For more information:

• Gardner TB. Treatment of giardiasis. Clinical Microbiology Reviews 2001;14:114-28
• Ortiz JJ. Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from northern Peru. Alimentary Pharmacology and Therapeutics 2001;15:1409-15.
• Nitazoxanide (Alinia) – a new antiprotozoal agent. The Medical Letter 2003;45:29-31.