Giardia lamblia, also called Giardia duodenalis or Giardia intestinalis, is a protozoan parasite of the small intestine that causes extensive morbidity worldwide. It was first described in the late 17th century by the Dutch microscopist Antonie van Leeuwenhoek 62, and research into its epidemiology, pathogenesis, and treatment has intensified since G. lamblia waterborne outbreaks were reported in Europe and the United States during the 1960s and 1970s 53, 81, 123, 128, 174. Giardia infects approximately 2% of the adults and 6 to 8% of the children in developed countries worldwide and is currently responsible for the largest number of waterborne outbreaks of diarrhea in the United States 54, 139.

Despite the recognition of G. lamblia clinical illness for the last 40 years, the nearly 5,000 people hospitalized with giardiasis annually in the United States 149, and the millions infected worldwide, there have been few reviews of therapy for this infection and no definitive treatment protocols have been published 58, 113, 150, 165, 261. In addition, only a handful of agents have been used in therapy, and the agents which are available may have adverse effects or be contraindicated in certain clinical situations. Also, resistance may play a role in some infections. This paper will review the agents currently used for the treatment of giardiasis. The history, mechanism of action, in vitro and clinical studies, and adverse effects are detailed for each drug class. In addition, special clinical situations are discussed and recommendations for therapy are made.

BACKGROUND

The life cycle of G. lamblia has two forms: the trophozoite (Fig. 1) and the cyst. The cyst is the infectious form and is ingested in contaminated water or food or directly from fecal-oral contact. As few as 10 cysts may establish infection 206. After ingestion, excystation occurs. Excystation is thought to be initiated by contact with acidic gastric contents, followed by a highly coordinated sequence of events leading to the release of one or two trophozoites 27, 109, 210. A parasite-derived protease may be activated during the excystation process 252. The trophozoite infects the duodenum and upper intestine, which have a favorable alkaline pH, and gives rise to the clinical sequelae. As trophozoites pass through the small intestine to the colon, encystation occurs. Encystation can be initiated in vitro by culture of parasites in a reduced concentration of bile salts and cholesterol followed by culture in an increased concentration of bile at an alkaline pH 156. Cyst wall proteins are then transcribed, secreted into encystment-specific vesicles, and transported to the newly forming cell wall over 14 to 16 h 75.

The wide variety of clinical presentations, from severe disease to an asymptomatic carrier state, makes the definitive determination of pathogenesis difficult. However, several theories have been put forward 83, 115. Some of the most likely include the ability of the protozoan to cause direct damage to the intestinal mucosa via adherence with the disk, disaccharidase enzyme reduction following brush border damage, the release from Giardia of cytopathic substances such as thiol proteinases and lectins, and the stimulation of a host immune response with release of cytokines and mucosal inflammation 41, 48, 61, 78, 83, 106, 110, 157, 259. Additionally, it is likely that there are genetic differences between Giardia isolates which may confer virulence 115, 173, 182, 190. The surface of Giardia may also undergo antigenic variation in the human host and thus evade immune detection 181. Given these multiple potential mechanisms, a multifactoral process is likely.

G. lamblia is found primarily in mammals including humans, cats, dogs, beavers, and cattle 40, 74, 77, 257. Transmission of the G. lamblia cyst to humans occurs most commonly following ingestion of contaminated water 139. Transmission via surface water is facilitated by the relative resistance of the cyst to chlorination and its ability to survive in cold water for weeks 59, 122. Transmission by food 22, 152, 187, by direct fecal-oral contact among children in day care 28, 224, 237 or in developing-world settings 96, 159, and by sexual practices which include oral-anal contact 168 represent other common modes of transmission 113. G. lamblia is also seen as a cause of prolonged diarrhea in travelers 37, 66, 125, 136, 205; N. Fiumara, Letter, N. Engl. J. Med. 288:1410-1411, 1973).

Worldwide, the majority of patients infected with G. lamblia are asymptomatic. However, typical clinical symptoms of giardiasis usually begin 1 to 3 weeks after ingestion of cysts and are marked by diarrhea, malaise, flatulence, greasy stools, and abdominal cramps 113, 256. Other symptoms commonly include bloating, weight loss 174, and anorexia. Vomiting and fever are less common, and blood- or mucus-tinged feces are rare. Illness can last several months if untreated and can be characterized by continued exacerbations of diarrheal symptoms. With chronic illness, malabsorption of fat, lactose, vitamin A, and vitamin B12 are reported, and failure of children to thrive has been noted 86, 112, 149, 184, 227.

Giardiasis should be considered in the differential diagnosis of many diarrheal syndromes. A careful history, which notes any risk factors such as recent travel, wilderness exposure, or situations involving poor fecal-oral hygiene, and a physical examination are essential. Infection with G. lamblia can often be distinguished from bacterial and viral infections because of the longer duration of illness, 7 to 10 days by the time of presentation, and the presence of weight loss 113. Parasitic diarrhea with Cryptosporidium or Cyclospora can have similar features in the immunologically normal host and would need to be distinguished by specific diagnostic testing 50, 99.

Several methods exist for detection of the parasite. Demonstration of trophozoites or cysts in the stool, called the ova and parasite (O&P) examination, is the traditional means of diagnosis 167. One stool sample will allow the detection of 60 to 80% of infections, 2 stool samples will allow the detection of 80 to 90%, and three stool samples will allow the detection of over 90% 97, 111. However, in some instances, because of intermittent or low levels of shedding, it is necessary to examine more than three stool samples. The desire for more sensitive and specific, as well as faster and reproducible, diagnostic testing has led to the development of immunoassays. Fecal antigen detection using enzyme-linked immunosorbent assays, nonenzymatic immunoassays, or fluorescein-tagged monoclonal antibodies can be superior diagnostic methods to the O&P examination 7, 89, 90, 161, 262. It is particularly helpful in assessing cure or in screening for Giardia infection. However, when other parasites are in the differential diagnosis, a stool sample for O&P examination should still be ordered. In the unusual patient for whom a diagnosis cannot be made by O&P examination of stool, endoscopy with duodenal fluid sampling and biopsy may be performed 82, 113, 185, 256. An instance in which this may be helpful is the human immunodeficiency virus-infected patient with diarrhea, whose illness has multiple potential etiologies. Culture and sensitivity testing is available only in research settings 120, 138. DNA probes have been generally limited to detection of parasites in water samples 134, 158, and serologic testing is most useful in epidemiologic surveys 118, 119, 170. Figure 2 outlines an approach to the diagnosis and management of suspected cases of giardiasis and is discussed further below (see "Recommendations").