 |
|
|
|
|
Giardia lamblia (Giardiasis)
Jeanine F.J.B. Nellen, MD Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center - University of Amsterdam. Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel.: +31 20 5664380, Fax: +31 20 6972286, e-mail: fsmit@xs4all.nl; f.j.nellen@amc.uva.nl
Joost O.M. Zaat, MD PhD General Practice Huisartsenmaatschap Landauer, Landauerstraat 200, 1441 XP Purmerend, The Netherlands Tel.: +31 29 9644011, Fax: +31 29 9460216, e-mail: j.zaat@chello.nl
Peter Speelman, MD PhD Professor of Medicine, University of Amsterdam Chief, Div. of Infectious Diseases, Tropical Medicine and AIDS Academic Medical Center Department of Internal Medicine, Division of Infectious Diseases, Tropical Medicine and AIDS, Academic Medical Center - University of Amsterdam. Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands Tel.: +31 20 5664380, Fax: +31 20 6972286, e-mail: p.speelman@amc.uva.nl
GENERAL DESCRIPTION Giardia is a binucleate flagellated protozoan parasite first seen in 1681 by Antoni van Leeuwenhoek, inventor of the microscope, in his own diarrheal stool. Lambl, in 1859, described the genus Giardia more extensively and the human variant was named after him. Parasitology Guided Medline Search Classification of the genus Giardia places it in the phylum Sarcomastigophora, the class Zoomastigophorea, the order Diplomonadida and the family Hexamitidae. It is thought to be one of the most primitive eukaryotes due to its small-subunit rRNA, which differs markedly from other protozoans (41,1). Sequence analysis of the gene encoding for the rRNA shows that it is more related to archebacteria than other eukaryotes (115). It is therefore proposed to be one of the missing links between prokaryotes and eukaryotes. Recent evidence doubts this ancestral lineage (59). The traditional way of classifying Giardia was morphologic, by light microscopy, and host of origin. Based on light microscopy more than one species has been described. Giardia has been found in humans and various mammals (domestic animals as cats, dogs and sheep and in wild animals as beavers and gerbils). Giardia lamblia is also called Giardia intestinalis or Giardia duodenalis. Giardia agilis infects amphibians, Giardia muris infects rodents, birds and reptiles. The life cycle of Giardia consists of two stages: the trophozoite and the cyst. The trophozoite is the free-living stage. It is 9-21 mm long and 5-15 mm wide. It has the shape of a pear when seen from ventral or dorsal. It has a convex dorsal surface and a concave ventral surface. On the ventral side is a disklike structure present which is called the sucking, striated, ventral or adhesive disk. On stained preparations trophozoites characteristically look like a human face with big eyes (41, 100). The trophozoite divides by binary fission in the crypts of the duodenum and upper jejunum; there is no evidence of sexual reproduction. Genetic diversity is explained by clonal divergence (41, 74). The trophozoite can encyst. It then forms oval shaped cysts with a wall of N -acetylgalactosamine. The cysts are 8-12 mm long, 7-10 mm wide with a wall of 0.3 mm thick. Encystation begins in the small intestines and is enhanced by multiple factors, as there are neutral pH, bile salts and cholesterol starvation. Excystation takes place in the duodenum after cyst exposure to gastric acid (low pH) and pancreatic enzymes (chymotrypsin and trypsin). Excystation can also take place at a neutral pH as has been seen in patients with achlorhydria. Epidemiology Guided Medline Search Giardia lamblia is a cause of diarrhea throughout the world and the most commonly isolated intestinal parasite (41, 45, 61, 100). Giardia infections are seen in temperate and tropical regions worldwide. Figures about prevalence and incidence differ per place depending on the population sampled. Prevalence is higher in the developing world and in rural areas. Prevalence rates in the industrialized world are estimated to vary from 2 to 5 %; in the developing world from 20 to 30% (117, 41). Data are mainly based on laboratory based surveillance studies. These data usually provide information about symptomatic infections. Seroprevalence studies did show past or present infection in 40 % of Peruvian children by the age of 6 months (88)! In hyperendemic regions reinfection occurs frequently: up to 98 % within 6 months is reported (52). Most people are infected during childhood. In the USA highest incidence rates of are found in two age groups: 0-5 year and 31-40 year. Most cases are reported during late summer and early fall. Infection (symptomatic or asymptomatic) requires oral ingestion of the cysts. Up to 10 cysts may be enough to cause infection. Contaminated water is the most common cause of infection. Human or animal faeces easily contaminate water. Cysts can survive in surface water for prolonged periods. Person-to-person transmission, sexual transmission and transmission through contaminated foods are also common ways of infection. Clinical Manifestations Guided Medline Search After ingestion of Giardia lamblia cysts several outcomes are possible, depending on Giardia isolate and host defense mechanisms (105, 93, 123):1 ) spontaneous clearance of parasites with no symptoms and no immune response (no infection) in 35-70%, 2) asymptomatic carrier state in 5-15%, 3) self-limiting disease in 25-50%, 4) chronic disease in a small number of patients. The incubation period ranges from 3-25 days (median 7 to 10 days). It may take some time before cysts are excreted in the stools, so symptoms may be present with negative stools. Giardiasis has no distinctive symptoms compared with other causes of diarrhea. The most common symptoms are diarrhea, abdominal cramps, bloating and flatulence. The onset of diarrhea can be acute and accompanied by nausea, anorexia and malaise. Initially diarrhea can be watery and profuse; later stools can become more loose and greasy with the smell of sulfur. Stools may float due to the formation of gas. Giardia stools do not contain blood, mucus or pus. Belching can have a sulfuric smell. Fever and vomiting are absent in most cases. Also profound malaise and fatigue are reported. In a minority of patients the duration of diarrhea may be prolonged with accompanying weight loss. Symptoms can wax and wane and periods of constipation can occur. Generally weight loss is due to malabsorption. Children can present with impairment in growth and development (failure to thrive). Nutritional deficiency is documented for fat-soluble vitamins, vitamin B12, folate, protein and d-xylose (SOLOMONS). Due to disaccharidase deficiency lactose malabsorption develops in 20-40% of cases (26, 62). Extraintestinal manifestations described include uveitits, arthritis, aphtous ulcerations, biliary tract disease and urticaria (62). Physical findings in patients are nonspecific. Pathogenesis Guided Medline Search Although much progress has been made many aspects of the pathogenesis of infection with Giardia lamblia are still not known. The mechanism by which diarrhea and malabsorption are caused is still not fully understood, as is the reason how infection can cause such a wide spectrum of clinical symptoms. After cysts have been ingested, they excyst in the proximal small intestine to become trophozoites. It is thought that trophozoite colonization and multiplication can cause intestinal disease; 35-70 % of persons who have ingested Giardia cysts do not get infected; they do not have any symptoms and spontaneously clear the infection. In the small intestine attachment of the trophozoite to the brushborder of the enterocyt takes place. Suggested mechanisms of attachment are via the disk by sucking or clasping and by a specific receptor-ligand binding in which lectin of Giardia binds to a specific receptor of the enterocyt, or a combination of both. Giardia generally doesn invade the mucosa. Clinical disease is possibly caused by direct damage to the enterocyt due to the attachment. Other postulated mechanism for causing clinical disease described in literature are by production of a toxin, bacterial overgrowth, deconjugation of bile salts, deficiency of disaccharidase due to disruption of the brushborder or inflammatory infiltration with shortening of the villi. These mechanisms of pathogenesis remain to be proven. There is some evidence for most of the mechanisms in some patients but not in every patient. Toxin production has never been found. At pathological-anatomical level villous blunting and lymphocytic infiltration may be seen which is not correlated with severity of the disease. Sporadically invasion of Giardia in the mucosa has been observed. One study reported no significant changes at all in enterocytes of Giardia infected patients compared to normal duodenal biopsies (96).
SUSCEPTIBILITY IN VITRO AND IN VIVO Guided Medline Search In Vitro and In Vivo Isolation, culture and susceptibility testing of Giardia are possible but difficult. So far these are not used in clinical practice due to lack of standardization, variable results and discrepancy in in vivo and in vitro results. More than one system for screening drug resistance has been described since 1980, including growth inhibition, inhibition of adhesion, radioisotopic (incorporation of [3H]thymidine) and colorimetric methods, serum killing and vitaldye exclusion, each with its own deficiency. Crouch provided in vitro data about anti-Giardia properties of 23 chemotherapeutic agents (29). He used a growth inhibition assay and an adherence inhibition assay. Tinidazole, metronidazole and furazolidone were found to have effects on both growth and adherence. Mepacrine had effects on growth only. Mefloquine, doxycycline and rifampicine had significant effects as well. Mefloquine and doxycycline inhibited both growth as adherence; rifampicine inhibited growth. These agents warrant consideration for clinical assessment. Sodium-Fusidate: High concentrations of ox bile inhibit growth of Giardia, whereas low concentrations enhance growth (42). Sodium-fusidate, a bile salt-like compound, proved moderately effective in vitro. It can be used in pregnancy without risk for teratogenicity. Its clinical efficacy remains to be established. Chloroquine and Pyrimethamine: These two drugs are active against Giardia in vitro (54). In 25 isolates of human origin more than 50 % were highly susceptible for both (MIC < 1.0 μg/ml). In vivo activity can be achieved with 600 mg chloroquine a day (79). Tricyclic Depressants: The antidepressant drugs such as imipramine and chlorimipramine can alter the energy metabolism in mammalian mitochondria. Chlorimipramine suppresses growth of Giardia in vitro (133). The mechanism may be disruption of membrane ATPase in Giardia. Synthesis of a novel analogue of imipramine, which can bind selectively to an active site of the parasite, may produce a useful chemotherapeutic compound. Ivermectin: The antigiardial activity of ivermectin in a rat model was effective in a rat model at a dose of 200 μg/kg (134). Pentamidine Analogs: There aromatic diamidines have antiprotozal activity. 38 pentamidine analogs demonstrated antigiardial activity in a [3H]thymidine incorporation assay (14). The most potent antigiardial pentamidine analog was 1,3-di (4-amidino-2-methoxyphenoxy) propane with an IC50 of 0.51 +13 mM. This is an IC50 comparable to quinacrine and tinidazole. The mechanism of action of these compounds is probably through DNA binding. Other Antibiotics: Tetracyclines are protein synthesis inhibitors targeted to rRNA, as also Giardia contains (37). Because (especially the lipophilic) tetracyclines are effective in treating malaria, hypothesized was that they were effective against other protozoa as well. Edlind tested 6 different tetracyclines and found that tetracyclines had antigiardial activity. Increasing lipophilicity correlated with decreasing MIC for Giardia lamblia. For example, doxycycline had a 90 % inhibitory concentration of 22 μg/ml. However, the lipophilicity makes them more readily absorbed from the gut and therefore less appropriate for treating an intestinal infection. Clinical data are not available. Azithromycin was more active in vitro than metronidazole but it was unable to eliminate trophozoites in a mouse model. Differences in in vivo and in vitro activity of macrolide antibiotics against protozoa have been reported before. Biothionol, Dichlorophene and Hexachlorophene: (halogenated bisphenol and related compounds) are known to be effective in some helmintic infections and has antigiardial activity in vitro (120). The surface of a trophozoite is completely covered with variant-specific surface proteins. These proteins contain one or more zinc-finger motifs. Nash tested 34 zinc-finger-active drugs (94); 29 compounds inhibited growth of Giardia lamblia. The most active compound was disulfaram which was cidal at a concentration of 1.23 +0.32 mM. In a mouse model in vivo activity was demonstrated by parasitological cure or decreased parasite burden. Geranium Nivem: This Mexican herb is used by Indians as antipyreticum. An extract prepared from its roots inhibited growth of axenically grown trophozoites of Giardia lamblia (23). Resistance In Vitro Giardia strains resistant to antiparasitic drugs exist (16). There is evidence that resistant strains do occur (16). Giardia isolates from different geographic locations show marked differences in drug sensitivity. Different strains of Giardia showed differences in susceptibility for metronidazole measured as IC50 (inhibitory concentration 50%): over a 16.000 fold variation was found using an adhesion assay (40). For albendazole a 9-fold difference was found. Published IC50 values for metronidazole cover a wide range. It is not known if this is the result of different experimental conditions or reflects clinically significant differences in activity (40). Drug resistance can readily be induced in vitro by growing Giardia at sub-lethal drug dosage or intermittent drug doses (20). It has been described for metronidazole, furazolidone, (41, 126) quinacrine (128) and albendazole. Therapeutic failure commonly occurs. In 10 children with giardiasis, the 2 children refractory to therapy with furazolidone were infected by Giardia strains that were relatively inactive in vitro for furazolidone. Giardia strains from patients who fail antiparasitic drug therapy does not necessarily show decreased drug sensitivity in vitro to the drug , so the correlation between in vivo and in vitro results is variable (128, 113).
ANTIPARASITIC THERAPY Smart search Drug of Choice Guided Medline Search Symptomatic patients with Giardia lamblia should be treated as well as asymptomatic carriers in non-endemic areas. Treating an asymptomatic patient in a highly endemic area is probably of no use, since high recurrence rates are documented (52). Treatment of asymptomatic well-nourished children in these areas remains controversial. Malnourished children probably benefit from treatment.
Since randomized, placebo controlled, double blind, clinical trials, comparing
the different treatment options are lacking, it is not easy to make clear
recommendations. Endpoints of clinical outcome (duration of diarrhea and
complaints) have not been well studied. Most studies use different dosing
schedules and compare different treatment options. Zaat, et al., recently
published an extensive systematic review of all randomized trials on the
treatment of giardiasis (135). They reviewed reports in
the Cochrane Infectious Disease Group Trial registers, the Cochrane Controlled
trial Register, Medline and Embase, Current Contents and reference lists of
articles (136). Placebo controlled trials were rare and
nearly all studies had serious methodological flaws. The authors included
thirty-four randomized and quasi-randomized trials. Compared with placebo,
drug therapy was associated with an improved cure rate.
Treatment Options and Dosing Schedules (Table 1)
Tinidazole:
Tinidazole, a nitroimidazole, acts by interfering with DNA synthesis. It has
the advantage of treatment as a single dose, which favors compliance.
Oral
absorption is good; Tmax is within 2 hours. The drug is cleared renally.
Side
effects are few and less common than with Tinidazole has not been approved in the US (Fasigyn is not available in the US) because it is thought to be teratogenic. It has mutagenic properties in bacteria and is carcinogenic in mice. It has no mutagenic properties in human lymphocytes and bone marrow of mice. It crosses the placenta and is excreted into breast milk. Although there is no direct evidence of teratogenicity in humans, the drug should be avoided in pregnancy. The standard dose for adults is 2 g as a single oral dose, for children 50-75 mg/kg as a single dose (max, 2 g). It is also available as a syrup. In symptomatic (9,50,65,73) and asymptomatic patients (95, 119,116), the standard dose of tinidazole have been compared to other single dose therapies. Parasitological cure did not differ between tinidazole and other single dose therapies, but clinical cure was better among the tinidazole-treated patients. Speelman et al., found that tinidazole, given as a single oral dose, was more effective than metronidazole as a single dose. A single dose of tinidazole was as effective as a 3-day course of metronidazole. Nigam et al., gave 50 mg/kg tinidazole or metronidazole as a single dose in 75 patients: efficacy of tinidazole was 97.5 % and for metronidazole 54 %. In only one trial information was provided about diarrhea at the end of the follow-up period (50); 7/38 cases in the tinidazole treated group had diarrhea versus 21/37 patients in the metronidazole treated group. There was no difference in side effects between tinidazole and other short courses. Gupta gave 20 symptomatic patients tinidazole: 10 patients a single dose of 2 g, 10 patients 150 mg bid for 7 days (57). All patients were cured. In conclusion, tinidazole is the treatment of choice because of its use as a single dose, relatively few side effects and high efficacy. It is not available in the US and should not be used during the first trimester of pregnancy or during lactation.
Metronidazole:
Standard dose is 250 mg tid for 5 to 7 days; for children 5 mg/kg tid for 5-7
days. Parenteral administration is also possible. A suspension can be made by
crushing metronidazole tablets, using a drop of glycerin as lubricant, and
suspending it in cherry syrup NF (79). The duration of
therapy should not exceed 10 days because of potential carcinogenicity. Dosage
should be decreased in case of hepatic dysfunction. There exists drug
interaction with lithium resulting in increased plasma concentrations of
lithium. Side effects are not uncommon but are relatively mild. They include a
metallic taste, nausea and vomiting. Metabolites can color urine dark brown.
Metronidazole also has a disulfaram-like effect. Patients should be warned not
to take alcohol while on metronidazole and for 72 hours thereafter.
Metronidazole had more side effects than
Many trials have studied the effect of a long course of metronidazole on parasitological cure. Eight trials used a negative stool specimen as a measure of cure in symptomatic and asymptomatic persons (18, 36, 49, 58, 77, 100a, 107). Bulut gave 15 children (mean age 9.9 +1.7 years) a dose of 15 mg/kg once daily for 7 days and found a cure rate of 92.6 %. Gascon has treated 11 adult patients with 250 mg metronidazole tid for 7 days: 10/11 were parasitological cleared (90.9 %). Hall prescribed 125 mg tid for 5 days for 230 children between 5 and 10 years old and found a cure rate of 97.4 %. Ten other trials studied symptomatic patients only (4, 11, 25, 47, 56, 66, 68, 89, 104, 131). Al-Waili prescribed metronidazole 200 mg tid for 5 days for 21 children (age 3-13) and 86% patients were cured. Misra prescribed metronidazole 400 mg qid for 5 days or 7.5 mg/kg tid for 31 children and 100% were cured. Although metronidazole had a higher cure rate in all patients, it should be noted that the comparator treatment in various trials often did not contain regular treatment of optimal doses. In the only trial, which used clinical cure as outcome, there was no difference between metronidazole and furazolidone (47). In conclusion, metronidazole 250 mg tid in a 5-7 day course is recommended for treatment of giardiasis because of its high efficacy. Its disadvantage is the duration of the therapy and the three times a day schedule. Furthermore it is not FDA approved for giardiasis.
Albendazole:
Standard dose in adults is 400 mg for five days. It can be used in children above the age of 6 years at a dosage of 7.5 mg/kg bid, although it is used in younger children in the studies mentioned in the table. It is available as syrup. Side effects are stomach discomfort, nausea, vomiting, headache and dizziness. Following prolonged use, 15 % of patients develop a reversible increase in hepatic transaminases. The efficacy of different doses of albendazole was surveyed in symptomatic and asymptomatic patients (103). Adults receiving 400 mg for five days were all cured (15/15). A single dose of 400 mg or 400 mg on two consecutive days gave cure rates of 23.5 and 47.4 % respectively in children.
There are 5 studies described by Zaat concerning the effects of albendazole (36,
58, 89, 107). Hall
et al. studied albendazole at 4 different dosages in comparison to
Mebendazole: Mebendazole is another benzimidazole with mechanism of action similar to albendazole. Its absorption is very poor (2-10%). Tmax is reached after 1 hour. It is teratogenic and embryotoxic in animals and should be avoided in pregnancy. Side effects are diarrhea, abdominal pain, headache and dizziness. The dosage in adults is usually 200-400 mg per day for 5 to 10 days. The usual dosage for children is 15 mg/kg per day for 5 to 7 days. It is available as a syrup.
Clinical reports on mebendazole are variable. Mebendazole 600mg daily resulted
in 95% (38/40) cure (4). In a small, randomized study in
children, efficacy of mebendazole was similar to that of
In conclusion, mebendazole can be used for treatment of giardiasis in children
with variable efficacy.
Furazolidone: Furazolidone is a nitrofuran and the only FDA approved drug, which is
available at present time (66,47). Its
mechanism of action is not exactly known. Furazolidone inhibits many bacterial
enzyme systems through DNA binding. It is readily absorbed in the
gastrointestinal tract and metabolized in tissues, leading to low serum and
urine concentrations (48, 71). There are
no data about use in pregnancy. Like A five-day course cured only 20 % of children (92). Furazolidone is probably less active than metronidazole and quinacrine (11, 47). Bassily found a cure rate of 80 % for furazolidone, 95 % for metronidazole, 100 % for quinacrine and 0 % in the placebo group. He treated 20 patients in each group. In conclusion, Furazolidone is the only available FDA approved treatment for giardiasis. It has a lower efficacy then metronidazole and tinidazole. Quinacrine: Quinacrine, a yellow acridine dye, is an antimalarial agent in which mechanism of action is not precisely known. It intercalates with Giardia lamblia DNA and causes inhibition of nucleic acid synthesis. In vitro quinacrine reduces cyst viability and excystation rates (48). It is rapidly absorbed from the gastrointestinal tract and widely distributed in tissues. The standard dosage for adults is 100 mg tid for 5-7 days. For children, a dosage of 2 mg/kg tid for 5-7 days has been recommended. It crosses the placenta and is not useful in pregnancy. There is a possible link with spina bifida and renal agenesis. Carcinogenicity has never been proved. The most common side effects are nausea, vomiting and abdominal cramping. It has a bitter taste, which makes it difficult to use in children. Yellow discoloration of the skin, urine and sclerae may occur; the discoloration occurs in 4-5 % of those taking quinacrine and begins a week after starting therapy and can last for 4 months! Rare side effects include toxic psychosis, hemolysis in glucose-6-phosphate dihydrogenase-deficient patients and exfoliative dermatitis (92).
Quinacrine is highly effective and is considered by some the agent of choice,
despite its considerable side effects (11,68).
Bassily (see furazolidone) found a cure rate of 100 % in 20 Egyptian patients.
He gave adults 3 dd 100 mg quinacrine for 5 days. In a comparative trial of
160 children (4.5 m -13 y), quinacrine in a dosage of 8 mg/kg body weight
divided in three doses for five days was compared to Paromomycin: Paromomycin is an older non-absorbable oral aminoglycoside that has in vitro-activity against Giardia lamblia (1). Aminoglycosides inhibit protein synthesis in bacteria through binding to rRNA, causing misreading of mRNA codons. Paromomycin is poorly absorbed from the intestinal tract and concentrated in stool. It shares the toxicity of the other aminoglycosides, oto- and nephrotoxicity, when given systemically. In vitro paromomycin shows activity against Giardia lamblia, but the activity is less then the nitroimidazoles, quinacrine and furazolidone (54). Older studies describe the in vivo effect of paromomycin in giardiasis (24,34,124). Although there are few recent clinical data, the drug is frequently recommended for treatment of giardiasis during pregnancy because of its limited absorption when given orally (1,108). Recommended dosage is 30 mg/kg/day in three doses for 10 days in adults and children (70). In conclusion, paromomycin may be useful in pregnancy especially in the first trimester when other options are contraindicated. Conclusions
In summary, antiparasitic drug therapy for giardiasis is superior to placebo. Single dose therapy with tinidazole is the drug of choice since it gives the
highest clinical cure rates and has relatively few adverse effects. However,
this drug is not available in the United States. Alternatively,
Specific Situations Treatment Failure: Treatment failure occurs in up to 20% of patients and has been reported for all antiparasitic drugs (41). It is important to confirm treatment failure by stool specimens or duodenal aspirates before starting another antiparasitic agent because symptoms of giardiasis can persist weeks after eradication due to lactase deficiency.
Options vary for treatment failures. Some authors recommend repeat therapy of
longer courses or higher doses. Use of a single agent in a different class to
avoid potential cross-resistance is another option. If tinidazole 2 g single
dose proves ineffective, we recommend
Reinfection from infected family members should also be considered. Household pets (cats, dogs and guinea pigs) can be infected with Giardia lamblia (human genotype) so they are a possible source of infection (122). This mode of transmission needs to be proven. When reinfection is likely, the original agent can be re-prescribed. Family members and sometimes pets should then be treated as well. Avoidance of dairy products can be tried if lactase deficiency is suspected.
Combination
Therapy: Some case reports mention combination therapy. Quinacrine and
Immunocompromised Hosts Primary Immunodeficiencies: Prevalence of Giardia cysts in the stools of hypogammagobulinemic patients is higher than in immunocompetent hosts. No significant differences are reported between the two types of hypogammaglobulinaemia. Therefore the development of symptomatic giardiasis is not associated with failure of one specific arm of the immune system.
X-Linked
Infantile Agammaglobulinemia: A pure B cell deficiency with low levels of all immunoglobulins and normal T cell function is seen. Giardiasis is rare in
these patients (5,132), but three cases
of symptomatic giardiasis in this disease have been reported (82).
All three cases improved clinically with long or repeated courses of
Common
Variable Late-Onset Hypogammaglobulinemia: In this disease, IgA and IgG are
low; T cell dysfunction can also occur. Diarrhea seems to occur in about one
third of the adults and is due to giardiasis (5). Webster
found giardiasis in 50 % of patients with symptomatic diarrhea. Ten patients
were treated with The effect of gamma globulin supplementation alone has not been studied. The immunoglobulin deficiency alone is not enough to explain the high frequency of giardiasis; most patients with giardiasis have normal immunoglobulins and giardiasis is very rare in children with the X-linked and the variable hypogammaglobulinaemia. The low gastric acidity occurring at adult age in this disease is postulated to be responsible. Selective T-cell Defects (Di-George Syndrome): There are very few patients with this disease and giardiasis has never been reported in these patients. This is remarkable because nude mice, which have a severe T-cell deficiency, are very prone to giardiasis. Severe Combined Immunodeficiency: Diarrhea and malabsorption do occur frequently, however chest infections are the major problem. Nowadays children with this disease are treated as soon as the diagnosis is made, with bone marrow transplantation or enzyme replacement. Giardiasis has not been reported in these patients.
HIV/AIDS
(114, 63): Although giardiasis does
occur more often in homosexual men, chronic giardiasis does not occur more
often in HIV/AIDS. There seems no relation between giardiasis and the degree
of immunodeficiency in HIV. This is remarkable because in a mouse model of
giardiasis, CD4+ T cells are necessary for elimination of the parasite. Janoff
showed significant lower levels of antibody response (IgG, IgA and IgM) in
patients with AIDS and acute giardiasis than in heterosexual subjects with
giardiasis (63). He concluded that patients with AIDS do not suffer from
chronic giardiasis because of the available effective specific therapy. When
an infection occurs, it can be difficult to cure. It is not clear if
recalcitrance to therapy occurs more in AIDS patients than in the normal
population. Recommendations for treatment of giardiasis in HIV is a 5 to 7 day
course of Pregnancy and Lactation: Asymptomatic infection during pregnancy should not be treated (31,48,55). In the first trimester of pregnancy, treatment of giardiasis is indicated in cases of dehydration or inadequate nutritional status. Whenever possible, treatment should be postponed until the second or third trimester or after pregnancy. Paromomycin is frequently recommended in pregnancy and considered safe because of its poor absorption from the intestine and therefore low serum concentrations. The effects on the fetus of serum concentrations are not known. Clinical data are limited. Kreutner describes the successful use of paromomycin in two severe symptomatic cases of giardiasis early in pregnancy (70). The dosage advised is 30 mg/kg divided in three doses for 10 days.
Paromomycin is considered safe during lactation although there are no clinical data. Drug levels must be low in breast milk and absorption is probably also poor in the baby. Metronidazole is excreted in breast milk and gives it an unpleasant metallic taste. Therefore discontinuation of breastfeeding is recommended when taking a course of metronidazole. One can try a single course of 2 g metronidazole and start breast feeding again after 24 hours. For tinidazole the same advice can be given. There is evidence that breast milk is cytotoxic to Giardia. It provides protection to infection in suckling infants (91). Alternative Therapy Secnidazole (Sentyl), Nimorazole (Naxogin) and Ornidazole (Tiberal): These 5-nitroimidazoles closely related to metronidazole and available in some countries outside the USA. Their efficacy is comparable to tinidazole and metronidazole (12, 65, 72, 119, 48). Secnidazole can be used as a single dose 30/mg/kg in children en 2 g in adults. Ornidazole can be used in adults as a single dose of 1.5-2 g or in children in a dosage of 40-50 mg/kg. In adults a course of 250 mg a day for 10 days can be given. Nimorazole should be used in 250 mg bid in adults. In children aged 1-5 year 125 mg bid can be given; aged 6-10 125 tid is advised. All should be avoided in pregnancy and during lactation. Nitazoxanide: (21, 35) is a 5-nitrothiazole compound effective against protozoa, nematodes, cestodes, trematodes, anaerobic bacteria and some aerobic bacteria. It is partially absorbed from the intestine with a Tmax of its metabolite at 2-6 hours. Side effects are nausea and headache. Usual dosage is 500 mg bid in adults for 3-7 days. Single dose regimens, 2-3 g in adults, are used in treatment of Taenia saginata and Hymenolepis nana with high cure rates. Nitazoxide is not FDA approved. Nitazoxide 500 mg bid for 7 days was administered to 18 patients with cryptosporidial diarrhea. Three patients were coinfected with Giardia lamblia and Giardia was eradicated in all three (35). 87 patients with giardiasis 500 mg were treated with nitazoxide bid for 3 days (children > 12 year 200 mg), a parasitological cure rate of 71% was seen (21). Its efficacy against both protozoa and helminthes with minimal side effects makes nitazoxanide a promising antigiardial agent. Clarithromycin: In a multicenter double blind trial of HIV-infected patients randomized to clarithromycin 500 mg bid or placebo for mycobacterium avium complex. Giardia lamblia was found in 0.9 % (3 patients) in the clarithromycin group versus 2.9 % (10 patients) in the placebo group. The difference was significant (Pierce 1996, unpublished data). Bacitracin: Bacitracin is a peptide antibiotic that is amoebicidal and has in vivo activity (125) and in vitro activity against Giardia (51). Zinc has been shown to form a complex with bacitracin enhancing stability and bactericidal activity. In a randomized prospective clinical trial, bacitracin (120.000 U bid x 10 d), bacitracin zinc (120.000 U bid x 10 d), neomycin (120.000 U bid x 10 d) and bacitracin zinc with neomycin (60.000 U each bid x 10 d) were evaluated (6). 84 patients with about 20 patients in each group were treated. Cure rates at day 25 were 94.7 % for bacitracin zinc, 87.4 % for bacitracin, 86.4 % for neomycin and 87.5 % for bacitracin zinc and neomycin. Side effects were diarrhea, constipation and nausea. Disadvantages were the duration of the therapy and potential nephrotoxicity. Synergistic activity of these drugs could not be demonstrated clinically. Pippali Rasayani: This is an Indian herbal medicine, prepared from Piper longum and Butea monosperma. It is used in the ayurvedic system of medicine. 1 g Pippali rasayani p.o. tid was given for 15 days in 25 symptomatic patients (111). At day 15, parasitological cure was found in 23 patients. Agarwal found a cure rate of 98 % in mice infected with Giardia lamblia trophozoites (2). Piper longum fruit powder was tested in vitro and in a mouse model by Tripathi and found to have antigiardial properties in both (127). Bee-glue propolisina for 5 days was compared with tinidazole 1.5 gram a day for 5 days in a Cuban study (9). In adults the high concentration of propolisina (40%) seemed more effective than tinidazole. Cure rates at day 5 after treatment were 60% versus 40 %. D-propranolol (Acranil): a weak beta-blocker, inhibits sperm motility in vitro. It inhibited motility and growth of Giardia lamblia in vitro. It was effective in treating a therapy resistant patient in combination with metronidazole whereas metronidazole alone failed (102).
ADJUNCTIVE THERAPY Guided Medline Search A lactase free diet can be tried during treatment and shortly after, because deficiency of disaccharidases can occur due to damage to the brush border. Antidiarrheal drugs may be used but are usually not necessary. Oral rehydration solution or intravenous fluid administration is advised for volume depletion.
ENDPOINTS FOR MONITORING THERAPY Guided Medline Search Resolution of symptoms and/or parasitological cure are the endpoints of therapy.When resolution of symptoms is achieved in individual patients, repeat stool specimens are not required. In our opinion, one should keep in mind the possibility of drug resistance in a patient with a documented treatment failure. In non-endemic areas one can treat asymptomatic carriers to prevent symptomatic cases. Carriers of Giardia who work in day care centers or elderly homes or who work in the preparation of food should have documentation of parasitologic cure by stool specimens. When there is reason to think of cross-infection in a family, all carriers in the family (think also of pets) should be treated till parasitological cure is documented.
VACCINES Guided Medline Search Vaccines for humans are not available, but a commercial Giardia vaccine is available in the USA for dogs and cats in preventing clinical symptoms and reduction of cyst shedding. It protected dogs and cats from infection when orally challenged with Giardia lamblia derived from a symptomatic human source (98). A safety study in 817 dogs showed only mild injection-side reactions in 3 %, but no systemic reaction.
PREVENTION Guided Medline Search Smart search General Thorough hand washing after using the toilet, playing with pets, changing diapers and preparing food is important. Drinking untreated water should be avoided. Food that is to be eaten raw should be washed thoroughly. When traveling in endemic areas, uncooked food should be avoided. Water can be made Giardia free by boiling it for 1 minute or by using a filter with an absolute pore size of at least 1 mm. Chlorination or iodination are less effective. Antiparasitic Agent Prophylaxis There is no antiparasitic agent available as prophylaxis.
CAVEATS Randomized placebo controlled trials with standardization of symptoms are indicated. Metronidazole, tinidazole and albendazole should be compared using objective endpoints for cure.
TABLES AND FIGURES Table 1. Antiparasitic
Agents for Giardiasis Table 2. Trials on Treatment of Giardiasis
REFERENCES 1. Adam RD. The biology of Giardia spp. Microbiological Reviews 1991; 55:706-732. [PubMed] 2. Agarwal AK, Singh M, Gupta N, Saxena R, Puri A, Verma AK, Saxena RP, Dubey CB, Saxena KC. Management of giardiasis by an immunomodulatory herbal drug Pippali rasayana. J Ethnopharmacol 1994; 44:143-146.[PubMed] 3. al Karawi M, Salam I, Mohamed AE. Combined oral and endoscopic mepacrine therapy in a case of persistent chronic symptomatic giardiasis. Trans R Soc Trop Med Hyg 1988; 82:581.[PubMed] 4. Al-Waili NS, Hasan NU. Mebendazole in Giardial infections: a comparative study with metronidazole. J Infect Dis 1992;165:1170-1171.[PubMed] 5. Ament ME, Rubin CE. Relation of giardiasis to abnormal intestinal structure and function in gastrointestinal immunodeficiency syndromes. Gastroenterology 1972; 62: 216-226. [PubMed] 6. Andrews BJ, Panitescu D, Jipa GH, Vasile-Bugarin AC, Vasiliu RP, Ronnevig JR. Chemotherapy for giardiasis: randomized clinical trial with bacitracin, bacitracin zinc, and a combination of bacitracin zinc with neomycin. Am J Trop Med Hyg 1995: 52: 318-321. [PubMed] 7. Awadalla HN, El-Gowhary SH, Sadaka HA, Khalifa AM. Aminosidine sulphate in experimental giardiasis. J Egypt Soc Parasitol 1995; 25: 53-61.[PubMed] 8. Babb RR. Giardiasis. Taming this pervasive parasitic infection. Postgrad Med 1995; 98: 155-158.[PubMed] 9. Bakshi JS, Ghiara JM, Nanivadekar AS. How does tinidazole compare with metronidazole? Drugs 1978; 15 (suppl 1): 33-42.[PubMed] 10.Baruch AC, Isaac-Renton J, Adam RD. The molecular epidemiology of Giardia lamblia: a sequence-based approach. J Infect Dis 1996; 174: 233-236.[PubMed] 11. Bassily S, Farid Z, Mikhail JW, Kent DC, Lehman JS. The treatment of Giardia lamblia infection with mepacrine, metronidazole and furazolidone. J Trop Med Hyg 1970; 73: 15-8.[PubMed] 12. Bassily S, Farid Z, el Masry NA, Mikhail EM. Treatment of intestinal E. histolytica and G. lamblia with metronidazole, tinidazole and ornidazole: a comparative study. J Trop Med Hyg 1987; 90: 9-12.[PubMed] 13. Beard CM, Noller KL, Oallon WM, Kurland LT, Dockerty MB. Lack of evidence for cancer due to use of metronidazole. N Eng J Med 1979; 301: 519-522.[PubMed] 14. Bell CA, Cory M, Fairley TA, Hall JE, Tidwell RR. Structure-activity relationships of pentamidine analogs against Giardia lamblia and correlation of antigiardial activity with DNA-binding affinity. Antimicrob Agents Chemother 1991; 35: 1099-1107. [PubMed] 15. Berget A, Weber T. Metronidazole and pregnancy. Ugeskr Laeger 1972; 134: 2085-2089.[PubMed] 16. Boreham PF. Australia contribution to the chemotherapy of parasites. Int J Parasitol 1995; 25: 1009-1022.[PubMed] 17. Boreham PF, Upcroft JA. The activity of azithromycin against stocks of Giardia intestinalis in vitro and in vivo. Trans R Soc Trop Med Hyg 1991; 85: 620-62.[PubMed] 18. Bulut BU, Gulnar SB, Aysev D. Alternative treatment protocols in giardiasis: a pilot study. Scan J Infect Dis 1996; 28: 493-495.[PubMed] 19. Burtin P, Taffio A, Ariburnu O, Einarson TR, Koren G. Safety of metronidazole in pregnancy: a meta-analysis. Am J Obstet Gynaecol 1995; 172: 525-529.[PubMed] 20. Butcher PD, Cevallos AM, Carnaby S, Alstead EM, Swarbrick ET, Farthing MJ. Phenotypic and genotypic variation in Giardia lamblia isolates during chronic infection. Gut 1994; 35: 51-54.[PubMed] 21. Cabello RR, Guerrero LR, del Rocio Munoz Garcia M, Cruz AG. Nitazoxide for the treatment of intestinal protozoan and helminthic infections in Mexico. Trans R Soc Trop Med Hyg 1997; 91: 701-703[PubMed] 22. Cacopardo B, Patamia I, Bonaccorso V, Paola O, Bonforte S, Brancati G. Efficacia sinergica dellssociazione albenazolo-metronidazol nella giardiasi refrattaria a monoterapia con metronidazolo. Clin Ter 1995; 146: 761-767.[PubMed] 23. Calzada F, Cerda-Garcia-Rojas CM, Meckes M, Cedillo-Rivera R, Bye R, Mata R. Geranins A and B, new antiprotozoal A-type proanthocyanidins from Geranium niveum. J Nat Prod 1999; 62: 705-709.[PubMed] 24. Carter CH, Bayles A, Thompson PE. The effects of paromomycin sulfate in man against Entamoeba histolytica and other intestinal protozoa. Am J Trop Med Hyg 1962; 11: 448-451.[PubMed] 25. Chacon RA, Wang Chio M, Cob Sosa CE. Eficacia de la furazolidone, metronidazol y secnidazol en el tratamiento de la giardiasis en ninos. Compend Invest Clin Latinoam 1991;11:41-44.[PubMed] 26. Chenu P, Gottrand F, Turck D, Dutoit E. Intestinal disaccharidase activity in Giardiasis. J Pediatr Gastroenterol Nutr 1992; 14:356.[PubMed] 27. Cimerman B, Boruchovski H, Cury FM, Bichued LM, Ieri A. Comparison between secnidazole and metronidazole in treatment of giardiasis. Arq Bras Med 1988; 62: 291-4.[PubMed] 28. Cooperstock M, DuPont HL, Corrado ML, Fekety R, Murray DM. Evaluation of new anti-infective drugs for the treatment of diarrhea by Giardia Lamblia. Clin Infect Dis 1992; 15: S244-S248.[PubMed] 29. Crouch AA, Seow WK, Whitman LM, Thong YH. Sensitivity in vitro of Giardia intestinalis to dyadic combinations of azithromycin, doxycyclin, mefloquine, tinidazole and furazolidone. Trans R Soc Trop Med Hyg 1990; 84: 246-248.[PubMed] 30. Crouch AA, Seow WK, Thong YH. Effect of twenty-three chemotherapeutic agents on the adherence and growth of Giardia lamblia in vitro. Trans R Soc Med Hyg 1986; 80: 893-896.[PubMed] 31. D'Alauro F, Lee RV, Pao-In K, Khairallah M. Khairallah. Intestinal parasites and pregnancy. Obstet Gynaecol 1985; 66: 639-643.[PubMed] 32. Davidson RA. Issues in clinical parasitology: the treatment of giardiasis. Am J Gastroenterol 1984; 79: 256-261.[PubMed] 33. Di Rosa S, Affronti M, Scardavi M, Vassallo L, Occhino C, Savalli F, Rini GB. The treatment of Giardia with albendazole. J Chemother 1989; 1: 948.[PubMed] 34. Dobon JF, Cedrato AE, Colom NM. The use of paramomycin in intestinal amoebiasis and giardiasis. El Dia Medico. July 11, 1963, p. 1012.[PubMed] 35. Doumbo O, Rossignol JF, Pichard E, Traore HA, Dembele M, Diakite M, Traore F, Diallo DA. Nitazoxanide in the treatment of cryptosporidial diarrhea and other intestinal parasitic infections associated with acquired immunodeficiency syndrome in tropical Africa. Am J Trop Med Hyg 1997; 56: 637-639.[PubMed] 36. Dutta AK, Phadke M, Bagade AC, Joshi V, Gazder A, Biswas TK. A randomized multicenter study to compare the safety and efficacy of albendazole and metronidazole in the treatment of giardiasis in children. Indian J Pediatr 1994; 61: 264-266.[PubMed] 37. Edlind DE. Tetracyclines as antiparasitic agents: lipophilic derivates are highly active against Giardia lamblia in vitro. Antimicrob Agents Chemother. 1989; 33: 2144-2145. [PubMed] 38. Edlind TD, Hang TL, Chakraborty PR. Activity of antihelmintic benzimidazoles against Giardia lamblia in vitro. J Infect Dis 1990; 162: 1408-1411.[PubMed] 39. Elliott ME, Klaus BD, North DS, Martin HP. Furazolidone-induced mood disorder during the treatment of refractory giardiasis in a patient with AIDS. Clin Infect Dis 1998; 26: 1015.[PubMed] 40. Farbey MD.Reynoldson JA, Thompson RC. In vitro drug susceptibility of 29 isolates of Giardia duodenalis from humans as assessed by adhesion assay. Int J Parasitol 1995; 25: 593-599.[PubMed] 41. Farthing MJ. Giardiasis. Gastroenterol Clin N Am 1996; 25: 493-515.[PubMed] 42. Farthing MJ, Inge PM. Antigiardial activity of the bile salt-like antibiotic sodium fusidate. J Antimicrob Chemother 1986; 17: 165-171.[PubMed] 43. Farthing MJ, Inge PM, Pearson RM. Effect of D-propanolol on growth and motility of flagellate protozoa. J Antimicrob Chem 1987; 20: 519-522.[PubMed] 44. Faubert G. Immune response to Giardia duodenalis. Clin Microbiol Rev 2000; 13: 35-54.[PubMed] 45. Flanagan PA. Giardia - diagnosis, clinical course and epidemiology. A review. Epidemiol Infect. 1992; 109: 1-22.[PubMed] 46. Freeman CD, Klutman NE, Lamp KC. Metronidazole. Drugs 1997; 54: 697-708. [PubMed] 47. Garg BK. Furazolidone and metronidazole in the treatment of Giardiasis. Indian J Pediatr 1972; 39: 264-6.[PubMed] 48. Gardner TB, Hill DR. Treatment of giardiasis. Clin Microbiol Rev 2001; 14: 114-128. [PubMed] 49. Gascon J, Abos R, Valls ME, Corachan M. Mebendazole and metronidazole in giardial infections. Trans R Soc Trop Med Hyg 1990; 84: 694.[PubMed] 50. Gazder AJ, Banerjee M. Single-dose treatment of giardiasis in children; a comparison of tinidazole and metronidazole. Current Med Res Opin 1977; 5: 164-8.[PubMed] 51. Gillin FD, Diamond LS. Inhibition of clonal growth of Giardia lamblia and Entamoeba histolytica by metronidazole, quinacrine, and other antimicrobial agents. J Antimicrob Chemother 1988; 8: 305-316.[PubMed] 52. Gilman RH, Marquis GS, Miranda E, Vestegui M, Martinez H. Rapid reinfection by Giardia lamblia after treatment in a hyperendemic third world community. Lancet 1988; 343-345.[PubMed] 53. Goka AK, Rolstn DD, Mathan VI, Farthing MJ. The relative merits of fecal and duodenal juice microscopy in the diagnosis of giardiasis. Trans R Soc Trop Med Hyg 1990; 84: 66-67.[PubMed] 54. Gordts B, Hemelhof W, Asselman C, Butzler JP. In vitro susceptibilities of 25 Giardia lamblia isolates of human origin to six commonly used antiprotozoal agents. Antimicrob Agents Chemother. 1985 Sep; 28(3): 378-80.[PubMed] 55. Grandien M, Sterner G, Kalin M, Engardt L. Management of pregnant women with diarrhea at term of healthy carriers of infectious agents in stools at delivery. Scan J Infect Dis, Suppl. 1990; 71: 9-18.[PubMed] 56. Guerreiro NM, Herrera PM, de Escalona L, de Kolster CE, de Yanes VG, de Febres O, Naveda O, de Naveda M. Giardia lamblia: comparison of two diagnostic methods and evaluation of response to treatment with metronidazole. G.E.N. 1991:45-105-110. [PubMed] 57. Gupta JP, Jain AK, Nanivadekar AS. Efficacy of tinidazole in giardiasis in parasitologic, biochemical and gut transit studies. Indian J Gastroenterol 1989; 8; 103-4.[PubMed] 58.Hall A, Nahar Q. Albendazole as a treatment for infections with Giardia duodenalis in children in Bangladesh. Trans R Soc Trop Med Hyg 1993; 87: 84-86.[PubMed] 59. Hashimoto T, Sanchez LB, Shirakura T, Muller M, Hasegawa M. Secondary absence of mitochondria in Giardia Lamblia and Trichomonas vaginalis revealed by valyl-tRNA synthetase phylogeny. Proc Natl Acad Sci USA 1998; 95: 6860-6865.[PubMed] 60. Heinonen OP, Slone D, Shapiro S. Birth defects and drugs in pregnancy. Publishing Science Group, Littleton, Mass 1977: 296-302.[PubMed] 61. Heresi G, Cleary TG. Giardia. Pediatr Rev 1997; 7: 243-247.[PubMed] 62. Hill DR. Giardiasis; issues in diagnosis and management. Infect Dis Clin North Am 1993; 7: 503-525.[PubMed] 63. Janoff EN, Smith PD, Blaser MJ. Acute antibody responses to Giardia lamblia are depressed in patients with AIDS. J Infect Dis 1988; 157: 798-804.[PubMed] 64. Jones EG, Brown WR. Serum and intestinal fluid immunoglobulins in patients with giardiasis. Am J Dig Dis 1974; 19: 791-797.[PubMed] 65. Jokipii L, Jokipii AM. Treatment of giardiasis: comparative evaluation of ornidazole and tinidazole as a single oral dose. Gastroenterology 1982; 83:399-404.[PubMed] 66. Kalayci AG, Cetinkaya F, Gunaydin M, Gurses N. Comparison of mebendazole with metronidazole and furazolidone in the treatment of giardiasis in children. Ann Saudi Med 1995; 15; 655-6.[PubMed] 67. Kang EW, Clinch K, Furnaux RH, Harvey JE, Schofield PJ, Gero AM. A novel and simple colorimetric method for screening Giardia intestinalis and anti-giardial activity in vitro. Parasitology 1998; 117: 229-234.[PubMed] 68. Kavousi S. Giardiasis in infancy and childhood; a prospective study of 160 cases with comparison of quinacrine and metronidazole. Am J Trop Med Hyg 1979; 28: 19-23.[PubMed] 69. Kollaritsch H, Jeschko E, Wiedermann G. Albendazole is highly effective against cutaneous larva migrans but not against Giardia infection. Trans R Soc Trop Med Hyg 1993; 87: 689.[PubMed] 70. Kreutner AK, Del Bene VE, Amstey MS. Giardiasis in pregnancy. Am J Obstet Gynecol 1981; 140:895-899.[PubMed] 71. Kucers A, Crowe SM, Grayson ML, Hoy JF. Nitrofurans. In:The use of antibiotics. A clinical review of antibacterial, antifungal and antiviral drugs. 5th ed. Butterworth-Heinemann, Oxford, United Kingdom; 1997. p. 922-923.[PubMed] 72. Kuzmicki R, Jeske J. Observations of the efficacy of ornidazole in treatment of Giardiasis. Wiad Parazitol 1994; 40: 65-68.[PubMed] 73. Kyronseppa H, Pettersson T. Treatment of giardiasis: relative efficacy of metronidazole as compared to tinidazole. Scand J Infect Dis 1981; 13: 311-12.[PubMed] 74. Lanzer M, Fischer K, LeBlancq SM. Parasitism and chromosome dynamics in protozoan parasites: is there a connection? Molec Biochem Parasitol 1995;70:1-8. [PubMed] 75. Laughon BE, Druckman DA, Vernon A, Quinn TC, Polk BF, Modlin JF, Yolken RH, Bartlet JG. Prevalence of enteric pathogens in homosexual men with and without acquired immunodeficiency syndrome. Gastroenterology 1988; 94: 984-993.[PubMed] 76. Leary P, Jones C, Douglas F. Metronidazole suspension in the outpatient treatment of giardiasis. J Trop Pediatr 1974; 20: 198-200.[PubMed] 77. Leite EV, Goncalves AL, da Costa DG, da Costa Filho RL, Podkameni N. Comparison between ornidazole and metronidazole: double blind clinical therapeutical trial in intestinal giardiasis. Rev Inst Med Trop Sao Paulo 1976;18:28-35.[PubMed] 78. Leonhardt U, Ebert R, Bommer W, Schauer A.Diagnostische und therapeutische probleme bei infektionen mit lamblien. Dtsche Med Wochenschr 1992; 117: 96-100. [PubMed] 79. Lerman SJ, Walker RA. Treatment of giardiasis: literature review and recommendations. Clin Pediatr 1982; 21: 409-414.[PubMed] 80. Levi GC, Avila CA, Neto VA. Efficacy of various drugs for treatment of giardiasis. Am J Trop Med Hyg 1977:26: 564-565.[PubMed] 81. Liu LX, Weller PF. Antiparasitic drugs. N Eng J Med 1996; 334: 1178-84.[PubMed] 82. LoGalbo PR, Sampson HA, Buckley RH. Symptomatic giardiasis in three patients with X-linked agammaglobulinaemia. J Pediatr 1974; 101: 78-80.[PubMed] 83. Mank TG, Zaat JO, Blotkamp J, Polderman AM. Comparison of fresh versus sodium acetate acetic acid formalin preserved stool specimens for diagnosis of intestinal protozoal infections. Eur J Clin Microbiol Infect Dis 1995; 14: 1076-1082.[PubMed] 84. Mank TG, Zaat JO, Deelder AM, van Eijk JT, Polderman AM Sensitivity of microscopy versus enzyme immunoassay in the laboratory diagnosis of giardiasis. Eur J Clin Microbiol Infect Dis 1997; 16: 615-619.[PubMed] 85. Mank TG, Zaat JO, Polderman AM. Onderschatting van darmprotozoa als oorzaak van diarree in de huisartsenpaktijk. Ned Tijdschr Geneeskd 1995; 139: 324-327.[PubMed] 86. McIntyre P, Boreham PF, Phillips RE, Shepherd RW. Chemotherapy in giardiasis: clinical responses and in vitro drug sensitivity of human isolates in axenic culture. J Pediatr 1986; 108: 1005-1009.[PubMed] 87. Meloni PB, Thompson RC, Reynoldson JA, Seville P. Albendazole: a more effective antigiardial agent in vitro than metronidazole or tinidazole. Trans R Soc Trop Med Hyg. 1990; 84: 375-379.[PubMed] 88. Miotti PG, Gilman RH, Santosham M, Ryder RW. Age-related rate of seropositivity of antibody to Giardia lamblia in four diverse populations. J Clin Microbiol 1986; 24: 972-975.[PubMed] 89. Misra PK, Kumar A, Agarwal V, Jagota SC. A comparative clinical trial of albendazole versus metronidazole in children with giardiasis. Indian Pediatr 1995; 32:291-4.[PubMed] 81. Liu LX, Weller PF. Antiparasitic drugs. N Eng J Med 1996; 334: 1178-84.[PubMed] 82. LoGalbo PR, Sampson HA, Buckley RH. Symptomatic giardiasis in three patients with X-linked agammaglobulinaemia. J Pediatr 1982; 101: 78-80.[PubMed] 83. Mank TG, Zaat JO, Blotkamp J, Polderman AM. Comparison of fresh versus sodium acetate acetic acid formalin preserved stool specimens for diagnosis of intestinal protozoal infections. Eur J Clin Microbiol Infect Dis 1995; 14: 1076-1082.[PubMed] 84. Mank TG, Zaat JO, Deelder JTM, Eijk van JTM, Polderman AM. Sensitivity of microscopy versus enzyme immunoassay in the laboratory diagnosis of giardiasis. Eur J Clin Microbiol Infect Dis 1997; 16: 615-619.[PubMed] 85. Mank ThG, Zaat JOM, Polderman AM. Onderschatting van darmprotozoa als oorzaak van diarree in de huisartsenpaktijk. Ned Tijdschr Geneeskd 1995; 139: 324-327.[PubMed] 86. McIntyre P, Boreham PF, Philips RE, Shepherd RW. Chemotherapy in giardiasis: clinical responses and in vitro drug sensitivity of human isolates in axenic culture. J Pediatr 1986; 108: 1005-1009.[PubMed] 87. Meloni BP, Thompson RC, Reynoldson JA, Seville P. Albendazole: a more effective antigiardial agent in vitro than metronidazole or tinidazole. Trans R Soc Trop Med Hyg. 1990; 84: 375-379.[PubMed] 88. Miotti PG, Gilman RH, Santosham M, Ryder RW. Age-related rate of seropositivity of antibody to Giardia lamblia in four diverse populations. J Clin Microbiol 1986; 24: 972-975.[PubMed] 89. Misra PK, Kumar A, Agarwal V, Jagota SC. A comparative clinical trial of albendazole versus metronidazole in children with giardiasis. Indian Pediatr 1995; 32:291-4.[PubMed] 90. Miyares C, Hollands I, Castaneda C, Gonzalez T, Fragoso T, Curras R, Soria C. Clinical trial with a preparation based on propolis "ropolisnia" in human giardiasis. Acta Gastroenterol Latinoam 1988;18:195-201.[PubMed] 91. Morrow AL, Reves RR, West MS, Guerrero ML, Ruiz-Palacios, Pickering LK. Protection against infection with Giardia lamblia by breastfeeding in a cohort of Mexican infants. J Pediatr 1992; 363-370.[PubMed] 92. Murphy T, Nelson JD. Five versus ten days' therapy with furazolidone for giardiasis. Amer J Dis Child1983; 137: 267-70.[PubMed] 93. Nash TE, Herrington DA, Losonsky GA, Levine MM. Experimental human infections with Giardia lamblia. J Infect Dis 1987; 156: 974-984.[PubMed] 94. Nash T, Rice WG. Efficacies of zinc-finger-active drugs against Giardia lamblia. Antimicrob Agents Chemother 1998; 42: 1488-1492.[PubMed] 95. Nigam P, Kapoor KK, Kumar A, Sarkari NB, Gupta AK. Clinical profile of giardiasis and comparison of its therapeutic response to metronidazole and tinidazole. J Assoc Physicians India 1991;39:613-615.[PubMed] 96. Oberhuber G, Stolte M. Giardiasis: analysis of histological changes in biopsy specimens of 80 patients. J Clin Pathol 1990; 43: 641-643.[PubMed] 97. Okhuysen PC, Dupont HL, Flores Lopez JF, Perez Castell J, Mathewson JJ. A comparative study of furazolidone and placebo in addition to oral rehydration in the treatment of acute infantile diarrhea. Scan J Gastroenterol 1989; 169 (suppl): 39-46.[PubMed] 98. Olson ME, Ceri H, Morck DW. Giardia vaccination. Parasitol Today 2000; 16: 213-217.[PubMed] 99. Oren B, Schgurensky E, Ephros M, Tamir I, Raz R. Single-dose ornidazole versus seven day metronidazole therapy of giardiasis in Kibbutzim children in Israel. Eur J Clin Microbiol Infect Dis 1991; 10: 963-5.[PubMed] 100. Ortega YR, Adam RD. Giardia: overview and update. Clin Infect Dis 1997; 25: 545-549.[PubMed] 100a Palomino 1970 (email Dr. Nellen) 101. Phillips SC, Mildvan D, William DC, Gelb AM, White MC. Sexual transmission of enteric protozoa and helminthes in a veneral-disease-clinic population. N Eng J Med 1981; 305: 603-606..[PubMed] 102. Popovic OS, Milovic V. Propranolol and metronidazole for the treatment of metronidazole resistant giardiasis. J Clin Gastroenterol 1990; 12: 604-605.[PubMed] 103. Pungpak S, Singhasivanon V. Albendazole treatment for Giardia. Ann Trop Med Parasitol 1996; 5: 563-565.[PubMed] 104. Quiros Buelna E. Furazolidone and metronidazole for treatment of giardiasis in children. Scan J Gastroenterol (suppl) 1989; 169: 65-9.[PubMed] 105. Rendtorff RC, Holt CJ. The experimental transmission of human intestinal protozoan parasites. II. Giardia lamblia cysts in capsules. Am J Hyg 1954; 59: 209-220.[PubMed] 106. Reynoldson JA, Thompson RCA, Horton RJ. Albendazole as a future antigiardial agent. Parasitol today. 1992; 8: 412-414.[PubMed] 107. Romero- Cabello R, Robert L, Munoz-Garcia R, Tanaka J. Estudio aleatorio para comparar seguridad y eficacia of albendazole and metronidazole en el tratamiento de giardiasis an ninos. Rev Latinoam Microbiol 1995; 37: 315-323.[PubMed] 108. Rotblatt MD. Giardiasis and amoebiasis in pregnancy. Drug Intell Clin Pharmacol 1983; 17: 187-188.[PubMed] 109. Rousham EK. An increase in Giardia duodenalis infection among children receiving periodic antihelminthic treatment in Bangladesh. J Trop Ped 1994; 40: 329-333.[PubMed] 110. Rowedder A, Meier R, Wegmann W, Gyr K. Kombinierte orale und endoscopische Mepakrine-therapie bei therapieresistenter symptomatischer giardiasis. Schweiz Med Wochenschr 1991; 121: 1383-1386.[PubMed] 111. Saxena KC, Dubey CB, Agrawal AK, Trpathi DM Sahai R, Gupta N, Saxena RP, Puri A. Sing M, Misra RN. Management of giardiasis by a herbal drug Pippali Rasayana: a clinical study. J Ethnopharmacol 1997; 56: 233-236.[PubMed] 112. Shepherd RW, Boreham PFL. Recent advances in the diagnosis and management of giardiasis. Scan J Gastroenterol 1989; 169: 60-64.[PubMed] 113. Smith PD, Gillin FD, Spira WM, Nash TE. Chronic giardiasis: studies on drug sensitivity, toxin production, and host immune response. Gastroenterology 1982; 83: 797-803.[PubMed] 114. Smith PD, Lane HC, Gill VJ, Manischewitz JF, Quinnan GV, Fauci AS, Masur H. Intestinal infections in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1988; 108: 328-333.[PubMed] 115. Sogin ML, Gunderson JH, Elwood HJ, Alonso RA, Pettie DA. Phylogenetic meaning of the kingdom concept: an unusual ribosomal RNA from Giardia Lamblia. Science 1989; 243: 75-77.[PubMed] 116. Speelman P. Single -dose Tinidazole for the treatment of giardiasis. Antimicrob Agents Chemother 1985; 27: 227-229.[PubMed] 117. Speelman P, Ljungstrom I. Protozoal enteric infections among expatriates in Bangladesh. Am J Trop Med Hyg 1986; 35: 1140-1145.[PubMed] 118. Sullivan PB, Marsh MN, Philips MB, Dewit O, Neale G, Cevallos AM, Yamson, Farthing MJG. Prevalence and treatment of giardiasis in chronic diarrhea and malnutrition. Arch Dis Childhood 1990; 65: 304-306.[PubMed] 119. Suntornpoch V, Chavalittamrong B. Treatment of giardiasis in children with tinidazole, ornidazole and metronidazole. Southeast Asian J Trop Med Public Health 1981; 12: 231-5.[PubMed] 120. Takeuchi T, Kobayashi S, Tanabe M, Fujiwara T. In vitro inhibition of Giardia lamblia and Trichomonas vaginalis growth by Biothionol, dichlorophene and hexachlorophene. Antimicrob Agents Chem 1985; 27: 65-70.[PubMed] 121. Taylor GD, Wenman WM, Tyrell DLJ. Combined metronidazole and quinacrine hydrochloride therapy for chronic giardiasis. CMAJ 1987; 136: 1179-1180.[PubMed] 122. Thompson RC. Giardiasis as a re-emerging infectious disease and its zoonotic potential. Int J Parasitol 2000; 30: 1259-1267.[PubMed] 123. Thompson RC, Meloni BP. Molecular variation in Giardia and its implications. Acta Trop 1993; 53: 167-184.[PubMed] 124. Thompson PE, Bayles A, Herbst SF, Olszewski B. Meisenhelder J. Antimebic and antitrichomonal studies on the antibiotic paramomycin in vitro and in experimental animals. Antibiot Chemother 1959;9:618. [PubMed] 125. Tobie JE, Most H, Reardon LV, Bozicevich J. Laboratory results on the efficacy of teramycin, aueomycin and bacitracin in the treatment of asymptomatic amoebiasis. Am J Trop Med 1951; 31: 414-419. [PubMed] 126. Townson SM, Laqua H, Upcroft PF, Boreham PF, Upcroft JA. Induction of metronidazole and furazolidone resistance in Giardia. Trans R Soc Trop Med Hyg 1992; 86: 521-522.[PubMed] 127. Tripathi DM, Gupta N, Lakshmi V, Saxena KC< Agrawal AK. Antigiardial and immunostimulatory effect of Piper longum on giardiasis due to Giardia lamblia. Phytother Res 1999; 13: 561-565.[PubMed] 128. Upcroft JA, Upcroft P, Boreham PF. Drug resistance in Giardia intestinalis. Int J Parasitol 1990; 20: 489-496.[PubMed] 129. Vesy CJ, Peterson WL. Review article: the management of giardiasis. Aliment Pharmacol Ther 1999; 13: 843-50.[PubMed] 130. Venkatesan P. Albendazole. J Antimicrob Chemother 1998; 41: 145-147.[PubMed] 131. Vinaychandran Nair K, Sharma MP, Mithal S, Tandon BN. Successes of metronidazole and furazolidone in the treatment of giardiasis. J Indian Med Assoc 1979; 72: 162-5.[PubMed] 132. Webster AD. Giardiasis and immunodeficiency diseases. Trans R Soc Trop Med Hyg 1980; 74: 440-448.[PubMed] 133. Weinbach EC, Costa JL, Wieder SC. Antidepressant drugs suppress growth of the human pathogenic protozoan Giardia lamblia. Res Communn Chem Pathol Pharmacol 1985; 47: 145-148.[PubMed] 134. Youssef MY, Essa MM, Sadaka HA, Eissa Mm, Rizk AM. Effect of ivermectin on combined intestinal protozoal infection (giardiasis and cryptosporidiosis). J Egypt Soc Parasitol 1996;26:543-53.[PubMed] 135. Zaat JO, Mank TG, Assendelft WJ. A systemic review on the treatment of giardiasis. Trop Med Int Health 1997; 2: 63-82.[PubMed] 136. Zaat JO, Mank TG, Assendelft WJ. Drugs for treating giardiasis. The Cochrane Database Syst Rev 1999; 2.[PubMed] 137. Zinneman HH, Kaplan AP. The association of giardiasis with reduced intestinal secretory immunoglobulins. Dig Dis 1972; 17: 793-797.[PubMed] |
|