Download (direct link):
With the ability to culture Giardia, sensitivity testing can be performed on trophozoites. However, the methods are not standardized and there are wide variations in results. There is also heterogeneity within a Giardia isolate when individual clones are tested (Boreham et al., 1987; Majewska et al., 1991). Finally, there has not been a consistent correlation between in vitro sensitivity or resistance and the clinical sensitivity or resistance (Smith et al., 1982; McIntyre et al., 1986; Upcroft et al., 1990; Majewska et al., 1991).
Testing methods have included macrodilution (Gordts et al., 1985b), incorporation of tritiated thymidine (Boreham et al., 1985; McIntyre et al., 1986; Boreham et al., 1987; Inge and Farthing,
1987), growth inhibition (Smith et al., 1982; Inge and Farthing, 1987; Crouch et al., 1990; Edlind et al., 1990; Majewska et al., 1991), enzyme activity (Kang et al., 1998), adherence (Crouch et al., 1990; Meloni et al., 1990; Farbey et al., 1995), motility (Andrews et al., 1994) and morphologic changes (Meloni et al., 1990; Andrews et al., 1994).
In vitro studies have usually demonstrated that drugs of the nitroimidazole class are most active. Although the benzimidazoles, albendazole and mebendazole, are more active than the nitro-imidazoles in some assays (Edlind et al., 1990; Meloni et al., 1990), in patients the nitro-imidazoles remain the most effective agents, demonstrating again the discordance in in vitro testing. Azithromycin has shown in vitro activity but was not able to clear parasites in an animal model (Boreham and Upcroft, 1991).
Efforts are being made to establish structure-function activity by correlating binding sites with drug affinity and, therefore, effectiveness (Edlind et al., 1990). Resistance can be induced in vitro, but the clinical correlates of this have not been
established (Upcroft et al., 1990, 1996a; Upcroft and Upcroft, 1998). Drug resistance to the nitro-imidazoles appears to be caused by decreased activity of the parasite pyruvate-ferredoxin oxidoreductase, with decreased reduction and activation of the drug (Townson et al., 1996).
Treatment of the infected individual is the main focus in management of giardiasis (Table 10.3) Most information on therapy derives from clinical experience. Therapeutic agents come primarily from the nitroimidazole family of drugs and, while other effective classes exist, development of new drugs for treatment has been relatively limited. Thus, one chooses an agent based on past experience and drug availability (Lerman and Walker, 1982; Davidson, 1984; Wolfe, 1992; Hill, 1993; Farthing, 1996; Zaat et al., 1997; Medical Letter, 1998; Gardner and Hill, 2001).
In the USA the manufacture of quinacrine was discontinued in 1992, leaving metronidazole, a nitroimidazole, as the standard of therapy. Agents of the nitroimidazole class have extensive experience throughout the world as safe and effective therapy for giardiasis in all age groups (Jokipii and Jokipii, 1978; Speelman, 1985; Kuzmicki and Jeske, 1994; Bulut et al., 1996).
It is likely that these agents work by serving as terminal electron acceptors from Giardia ferre-doxin, after which they become activated and then inhibit parasite DNA synthesis (Townson et al., 1994). Although metronidazole is the only nitroimidazole available in the USA, tinidazole and ornidazole are available in other countries. This class has success rates of 85-100% depending upon the drug, the duration of therapy and the follow-up interval.
Metronidazole is most commonly given in a 57 day course, whereas tinidazole is effective when given in a single dose (2 g for adults) (Speelman, 1985). Shorter course and high-dose regimens have been employed for metronidazole, but these may be less well tolerated (Jokipii and Jokipii, 1978). The most common side effects are nausea, headache and dizziness, and the drugs may leave a metallic taste in the mouth. They are rarely associated with a reversible neutropenia. Nitroimidazoles should not be taken with alcohol because they can precipitate a disulfiram-like reaction by interfering with the hepatic degradation of acetaldehyde, a breakdown product of ethanol (Table 10.4) (Goldman, 1980).
Quinacrine, although no longer produced in the USA, may be obtained through alternative sources (see Table 10.3). It may be helpful to use in difficult to treat cases as either an alternative agent or in combination with metronidazole. The drug has an excellent efficacy of
Table 10.3 Treatment of giardiasis
Metronidazole* 250 mg t.i.d. x 5-7 days 5 mg/kg t.i.d. x 5-7 days
Tinidazolet 2g x 1 dose 50 mg/kg x 1 dose (max. 2 g)
Quinacrine* 100 mg t.i.d. x 5-7 days 2mg/kg t.i.d. x7 days
Furazolidone4 100 mg q.i.d. x 7-10 days 2mg/kg q.i.d. x 10 days
Paromomycin* 25-30 mg/kg/day in 3 doses x 5-10 days
Albendazole* 400 mg q.d. x 5 days
*Not a US Food and Drug Administration-approved indication.