Giardiasis treatment: an update with a focus on refractory disease : Current Opinion in Infectious Diseases

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Giardiasis treatment: an update with a focus on refractory disease

Mørch, Kristinea,b; Hanevik, Kurta,b

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Current Opinion in Infectious Diseases 33(5):p 355-364, October 2020. | DOI: 10.1097/QCO.0000000000000668
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Giardiasis is a protozoan infection of the small bowel, frequently responsible for traveler’ diarrhea [1,2], and for complications from chronic or repeated infections [3,4].

The infectious cysts can survive for months in the environment, explaining why the infection is closely associated with unsafe water. In low-income and middle-income countries (LMICs), the incidence is very high and in some areas close to 100% of children have had one or more Giardia infections before the age of 2 years [3,5,6]. In high-income countries, Giardia is a frequent cause of waterborne outbreaks [7], as in Bergen, Norway in 2004 where approximately 2500 people were treated for giardiasis [8].

In a nonendemic area, clinical infection in all age groups range from asymptomatic carrier state to severe abdominal pain, diarrhea, vomiting, flatulence, malabsorption, anorexia and weight loss, with a fraction of patients developing postinfectious irritable bowel disease and chronic fatigue [8–11].

Histological findings in over 500 cases of giardiasis found normal appearance of the duodenal mucosa in the majority of cases; only a minority of cases revealed duodenal inflammation and mild villous shortening on light microscopy [12]. However, in previously unexposed adults, protracted infection has been associated with duodenal inflammation [13,14] and increased risk of postinfectious complications [15].

In low-resource settings, Giardia infection is common both in diarrheal and nondiarrheal cases, and is associated with chronic diarrhea [16]. It mainly occurs in children, and a serious manifestation is its contribution to malnutrition and stunting of growth following early or repeated infections [3,17–20]. Two large multicenter studies of diarrhea cause in LMIC reported that Giardia was more prevalent in controls than in diarrheal cases [21,22], leading to speculations about a potential negative association between Giardia and acute infectious diarrhea. However, after adjusting for metronidazole exposure in diarrhea cases in the MAL-ED study [3], a negative association between Giardia and diarrhea was not significant.

A small experimental study among adults challenged with Giardia revealed that establishment of infection was dose dependent and shedding was self-limited in 85% of individuals, but 15% of individuals developed chronic shedding [23]. The mean duration of infection in spontaneously cured cases was almost 3 weeks. It is rational to treat giardiasis both in endemic and nonendemic areas, to prevent complications, chronic disease and spread of the infection.

The first-line treatment of giardiasis is the 5-nitroimidazoles, but there are reports of high incidence of nitroimidazole refractory cases of giardiasis [24,25▪▪]. Although antimicrobial resistance is an increasing problem in giardiasis, in-vitro susceptibility testing methods to help clinicians guide targeted treatment is not available. This review provide an overview of clinical studies of anti-Giardia treatment and suggest choice of treatment in refractory cases, and discuss potential mechanisms and molecular targets for future in-vitro testing of drug resistance. 

Box 1:
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Until a few decades ago, Giardia lamblia was considered an innocent bystander in the microbial gut flora, but after the pathogenicity of the parasite was recognized, different classes of drugs have been used [26▪]. Current therapies, with different availability across countries, include nitroimidazole derivatives (metronidazole, tinidazole, secnidazole and ornidazole), benzimidazoles (albendazole, mebendazole), nitazoxanide, furazolidone, quinacrine, chloroquine and paromomycin.

Current treatment options

Randomized controlled trials (RCTs) of drugs used in first-line treatment of giardiasis are listed in Table 1. Efficacy is evaluated by stool microscopy posttreatment in all the studies. Study designs are heterogeneous regarding study population, dose and duration of treatment, time until follow-up and number of stool samples examined.

Table 1:
Randomized controlled studies evaluating anti-Giardia treatment


5-Nitroimidazoles are the most frequently used first-line drugs. These drugs become activated after entering the parasite, and kill the microorganism by release of reactive, toxic, partially reduced intermediates [67]. Tinidazole, secnidazole and ornidazole have long half-life, and cure rates above 90% are reported when single-dose regimens of 1–2 g in adults and 30 mg/kg (secnidazole), 20–40 mg/kg (ornidazole) and 50 mg/kg (tinidazole) in children, are given (Table 1). These nitroimidazoles are better tolerated than metronidazole. Metronidazole has a shorter half-life, and longer courses are needed to achieve similar efficacy; 250 mg three times daily (tid) for 7 days or 500 mg tid for 5 days in adults, and 5–7 mg/kg tid for 5–7 days in children. Reported side effects are gastrointestinal discomfort, anorexia, metallic taste, disulfiram-like effect, headache, vertigo, insomnia, irritability, neuropathy, seizures, rash, leukopenia, hepatitis and pancreatitis (references in Table 1).


Albendazole and mebendazole are widely used antihelminthic drugs, but treatment efficacy in giardiasis is variable (Table 1). The benzimidazoles exert their function by binding to, and preventing microtubule transport and assembly, and may also induce oxidative stress in the parasite [68].

Albendazole 400 mg in adults, and 10 mg/kg in children, single dose for 5 days, show 83–96% efficacy, while shorter duration is less effective. Efficacy for mebendazole vary greatly (14–95%), both for single-dose treatment and for dosage 200 mg tid up to 7 days. Benzimidazoles are usually well tolerated; reported side effects are nausea, vomiting, diarrhea and abdominal pain.


The oral aminoglycoside paromomycin is the drug of choice for giardiasis in pregnant women, because it is poorly absorbed and has no systemic effect [69]. Paromomycin inhibits the protein synthesis in Giardia[70]. Although this is the only anti-Giardia drug considered completely safe during early pregnancy, few clinical studies of treatment efficacy have been reported (Table 1). In a controlled study from Cuba among 256 children, efficacy was 92% compared with 80% for metronidazole [59], while a small case series from 1962 using 15 mg/kg/day for 5 days reported 40% efficacy [71].


Quinacrine is an effective anti-Giardia drug (Table 1), although its exact mechanism of action in Giardia is not known [72]. Two studies among children treated for 5 days report 100% efficacy. However, quinacrine has bothersome and potentially severe side effects. In a study reporting 77% efficacy, severe vomiting explained most of the treatment failures in small children [55]. In a study from Cuba reporting 84% efficacy, nausea, vomiting, discoloration of skin and headache was significantly more common than in the metronidazole group [52]. Yellow discoloration of skin is a common but harmless and self-limiting side effect [52,54,55], while neuropsychiatric disturbances ranging from restlessness, nightmares and insomnia to seizures and psychoses are rare but feared complications [73–75].


Furazolidone has shown high efficacy in studies of first-line therapy, although no RCTs are reported since 1980s (Table 1). It is a prodrug which release damaging intermediates when its nitro group is reduced [76]. The drug is contraindicated in glucose-6-phosphate-dehydrogenase (G6PD) deficiency and in neonates, due to risk of hemolytic anemia.


Nitazoxanide is the only available drug for Cryptosporidium, and like metronidazole it is also activated by reduction of its nitro group and inhibits metabolic enzymes [77]. In controlled studies of giardiasis, it has shown efficacies between 44 and 91% (Table 1). It may cause some gastrointestinal discomfort but is usually well tolerated.


Chloroquine is effective against nonfalciparum malaria and rheumatic disorders. Its mechanism of action against giardiasis is not known, but it may limit the trophozoite adherence to the intestinal wall. Its effect against Giardia has been investigated in RCTs in Cuba; in a large study among children, efficacy was 86% compared with 91% for tinidazole and 62% for albendazole [66]. Reported side effects were bitter taste and gastrointestinal problems, similar to for tinidazole. Chloroquine may potentially cause prolonged QT time, and hemolytic anemia in G6PD deficiency [78].

Treatment of refractory giardiasis

Drug trials have usually shown efficacy above 90% for the nitroimidazoles (Table 1); however, treatment refractory disease is an increasing problem. In a study from England, nitroimidazole failure increased from 15% (n = 8/53) in 2008 to 40% (n = 35/87) in 2013, and among travelers from India treatment failure occurred in as much as 50% [24].

The association between location of contracting infection and nitroimidazole failure, in four clinical studies, is shown in Table 2. As much as 46% failure was reported after metronidazole 500 mg tid for 5 days in a large cohort from Cuba in 2018 [25▪▪]. Although there are few studies and number of cases are small, treatment failure among European travelers seemed to be more common after travel to Asia than to Africa and Latin America (Table 2).

Table 2:
Prevalence of nitroimidazole failure associated with origin of Giardia infection

A few clinical, mainly small, studies are available providing evidence for treatment efficacy in refractory cases (Table 3). Observational studies show that another class of drug, combination therapy, or repeated courses with increased dose/duration of the same drug is used with varying efficacy.

Table 3:
Clinical studies of treatment in nitroimidazole refractory infections

Quinacrine is effective in almost all cases, but due to availability problems and potentially severe side effects, the drug is normally preferred only when other treatment options fail. Both quinacrine in combination with a 5-nitroimidazole for up to 3 weeks, and quinacrine monotherapy for as short as 3 days, were effective in reported studies (Table 3).

Combination of drugs from different classes also seems to be an effective second-line option. Albendazole in combination with metronidazole was effective in 90% in a small RCT in Italy [81], and 79% effective in a prospective treatment ladder study in Norway [83]. The combination of secnidazole and mebendazole was effective in 89% in a large treatment ladder study in Cuba, while a repeated course of 5-nitroimidazole after initial metronidazole treatment cured only 24–27% [25▪▪].

Albendazole monotherapy seem to be less effective, although number of cases reported are small (Table 3).


Antimicrobial resistance is defined by WHO as ‘the ability of a microorganism (like bacteria, viruses and some parasites) to stop an antimicrobial (such as antibiotics, antivirals and antimalarials) from working against it. As a result, standard treatments become ineffective, infections persist and may spread to others’ [87]. There are no defined molecular resistance mechanisms in Giardia yet, thus the term treatment refractory is better suited to describe treatment failure, as there is no doubt that also the hosts’ combined immune defenses play a role in eradicating the parasite.

Treatment refractory clinical infections have mostly been observed against the 5-nitroimidazole drug metronidazole [24]. To exert its antibiotic function, metronidazole needs to be activated by intracellular reduction of its nitro group, creating hyper-reactive intermediates, disrupting the microorganism by excessive oxidative stress [72]. Four enzymes have been identified in the metabolism of Giardia that seem capable of activating metronidazole by partial reduction into toxic hyper-reactive intermediates; nitroreductase 1 [88], pyruvate : ferredoxin oxidoreductase (PFOR) 1 and 2 [89,90] and the thiol-cycling associated enzyme thioredoxin reductase (TrxR) [89,91]. This partial reduction only occurs under anaerobic or microaerophilic conditions.

Inducing resistance in vitro, by gradually increasing drug concentrations in growth media of a small fraction of Giardia strains that can be cultured, is quite easy. Most research on resistance mechanisms have been performed on such laboratory strains, isolated from infected humans decades ago [92]. Significantly, the drug resistance seen in laboratory-induced strains is reduced or lost if the trophozoites pass through a cyst stage [93]. It is unknown how important this nontransmissible resistance is in clinical practice, but the rapidly increasing resistant infections seen, indicates the presence of new heritable traits conferring metronidazole resistance, or the ability to rapidly develop it. Typing of metronidazole resistant isolates in two studies shows that several subgroups of assemblage A and B isolates are represented among resistant strains [80,94].

Elucidating mechanisms of drug resistance

Methods for determining resistance in Giardia are not easily available. Only a small fraction of clinical isolates will grow in available liquid culture media, with assemblage A more often being successful than assemblage B parasites [95]. Strains will grow at different speeds making measurement of growth inhibition in drug dilutions very difficult to standardize, even for the few isolates that are culturable [96,97].

Compared with bacteria, identifying genetic markers of resistance in an early eukaryote, binucleate, functionally tetraploid organism such as Giardia is challenging. A relatively high degree of genetic diversity is seen in the metronidazole activating genes [89], both between isolates and in the up to four alleles of each gene. This offers Giardia substantial potential for variability to tweak its metabolism and for selection of well adapted variants.

Studies analyzing both genes and gene expression in metronidazole resistant laboratory strains and their metronidazole-susceptible ancestor, find a quite broad and variable adaptive response in the resistant isotypes [98]. There seem to be both posttranscriptional and posttranslational alterations [67,93,99], and Giardia thereby seem to have several ways it may develop tolerance to metronidazole.

A frequent finding in the few existing studies in metronidazole-resistant laboratory strains has been downregulation of nitroreductase 1 [98–100]. One isolate has been shown to harbor a nonsense mutation in transcripts of this gene, inferring that it may have substantially lower levels of this metronidazole-activating enzyme [98]. Results from genetic analysis of the other metronidazole metabolizing enzymes have been less consistent, but indicates a role for nitroreductase 2, PFOR, and TrxR and flavin mononucleotide-dependent oxidoreductases in resistance against metronidazole [67].

In a study examining protein expression in Giardia strains made gradually resistant in vitro against metronidazole and nitazoxanide, no specific trait or marker was identified [101▪]. Rather, it seemed that each of the three resistant strains had found their own strategy for tolerating high level of the drugs.

Thus, we can conclude that despite the carefully designed gene and protein expression studies in cultured isolates we still have very limited knowledge regarding the ways Giardia protects itself from drugs such as metronidazole. However, laboratory-induced resistant strains gathered decades ago may be quite different from the metronidazole refractory isolates now circulating. The rapidly increasing resistance reported [24,25▪▪], suggest that there are genetic changes that helps the parasite overcome the toxic effects of metronidazole, but further research is needed in clinical isolates.


Nitroimidazole failure in up to 50% is reported in giardiasis, both among travelers and in high endemic countries. Repeated courses of nitroimidazole, and monotherapy with a drug with another mode of action, seem to be less effective than combination therapy. A combination of a 5-nitroimidazole and albendazole or mebendazole, and quinacrine as last option, are rational choices in nitroimidazole refractory infections.

Research in drug resistant Giardia laboratory strains have not yet succeeded in identifying mechanisms, or markers, of resistance but show that Giardia strains possess a varied armamentarium of adaptations. Further research into more recent clinical isolates seems necessary to uncover mechanisms for the emerging metronidazole refractory cases.



Financial support and sponsorship

The current work was supported by the Norwegian National Advisory unit on Tropical Infectious Diseases, Haukeland University Hospital, Norway.

Conflicts of interest

There are no conflicts of interest.


Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest


1. Schlagenhauf P, Weld L, Goorhuis A, et al. Travel-associated infection presenting in Europe (2008–12): an analysis of EuroTravNet longitudinal, surveillance data, and evaluation of the effect of the pretravel consultation. Lancet Infect Dis 2015; 15:5564.
2. Pouletty M, De Pontual L, Lopez M, et al. Multiplex PCR reveals a high prevalence of multiple pathogens in traveller's diarrhoea in children. Arch Dis Child 2019; 104:141146.
3. Rogawski ET, Bartelt LA, Platts-Mills JA, et al. Determinants and impact of Giardia infection in the first 2 years of life in the MAL-ED birth cohort. J Pediatric Infect Dis Soc 2017; 6:153160.
4. Lengerich EJ, Addiss DG, Juranek DD. Severe giardiasis in the United States. Clin Infect Dis 1994; 18:760763.
5. Gilman RH, Marquis GS, Miranda E, et al. Rapid reinfection by Giardia lamblia after treatment in a hyperendemic Third World community. Lancet 1988; 1:343345.
6. Roy M, Singha B, Dhar D, Roychoudhury S. Prevalence of Giardia intestinalis with other co-infecting parasites in Barak Valley, Assam, India: a molecular approach. J Parasit Dis 2019; 43:426442.
7. Karanis P, Kourenti C, Smith H. Waterborne transmission of protozoan parasites: a worldwide review of outbreaks and lessons learnt. J Water Health 2007; 5:138.
8. Hanevik K, Wensaas KA, Rortveit G, et al. Irritable bowel syndrome and chronic fatigue 6 years after Giardia infection: a controlled prospective cohort study. Clin Infect Dis 2014; 59:13941400.
9. Nygard K, Schimmer B, Sobstad O, et al. A large community outbreak of waterborne giardiasis-delayed detection in a nonendemic urban area. BMC Public Health 2006; 6:141.
10. Lopez CE, Dykes AC, Juranek DD, et al. Waterborne giardiasis: a communitywide outbreak of disease and a high rate of asymptomatic infection. Am J Epidemiol 1980; 112:495507.
11. Morch K, Hanevik K, Rortveit G, et al. High rate of fatigue and abdominal symptoms 2 years after an outbreak of giardiasis. Trans R Soc Trop Med Hyg 2009; 103:530532.
12. Oberhuber G, Kastner N, Stolte M. Giardiasis: a histologic analysis of 567 cases. Scand J Gastroenterol 1997; 32:4851.
13. Hanevik K, Hausken T, Morken MH, et al. Persisting symptoms and duodenal inflammation related to Giardia duodenalis infection. J Infect 2007; 55:524530.
14. Dizdar V, Hausken T, Laerum OD, et al. Prolonged duodenal mucosal lymphocyte alterations in patients with and without postinfectious functional gastrointestinal disorders after Giardia infection. J Infect Dis 2019; 220:321329.
15. Morch K, Hanevik K, Rortveit G, et al. Severity of Giardia infection associated with postinfectious fatigue and abdominal symptoms two years after. BMC Infect Dis 2009; 9:206.
16. Muhsen K, Levine MM. A systematic review and meta-analysis of the association between Giardia lamblia and endemic pediatric diarrhea in developing countries. Clin Infect Dis 2012; 55: (Suppl 4): S271S293.
17. Celiksoz A, Acioz M, Degerli S, et al. Effects of giardiasis on school success, weight and height indices of primary school children in Turkey. Pediatr Int 2005; 47:567571.
18. Prado MS, Cairncross S, Strina A, et al. Asymptomatic giardiasis and growth in young children; a longitudinal study in Salvador, Brazil. Parasitology 2005; 131 (Pt 1):5156.
19. Nunez FA, Hernandez M, Finlay CM. Longitudinal study of giardiasis in three day care centres of Havana City. Acta Trop 1999; 73:237242.
20. Donowitz JR, Alam M, Kabir M, et al. A prospective longitudinal cohort to investigate the effects of early life giardiasis on growth and all cause diarrhea. Clin Infect Dis 2016; 63:792797.
21. Platts-Mills JA, Babji S, Bodhidatta L, et al. Pathogen-specific burdens of community diarrhoea in developing countries: a multisite birth cohort study (MAL-ED). Lancet Glob Health 2015; 3:e564e575.
22. Kotloff KL, Nataro JP, Blackwelder WC, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case–control study. Lancet 2013; 382:209222.
23. Rendtorff RC. The experimental transmission of human intestinal protozoan parasites. II. Giardia lamblia cysts given in capsules. Am J Hyg 1954; 59:209220.
24. Nabarro LE, Lever RA, Armstrong M, Chiodini PL. Increased incidence of nitroimidazole-refractory giardiasis at the Hospital for Tropical Diseases, London: 2008–2013. Clin Microbiol Infect 2015; 21:791796.
25▪▪. Canete R, Noda AL, Rodriguez M, et al. 5-Nitroimidazole refractory giardiasis is common in Matanzas, Cuba and effectively treated by secnidazole plus high-dose mebendazole or quinacrine: a prospective observational cohort study. Clin Microbiol Infect 2019; 26:1092.E11092.E6.
26▪. Arguello-Garcia R, Leitsch D, Skinner-Adams T, Ortega-Pierres MG. Drug resistance in Giardia: mechanisms and alternative treatments for giardiasis. Adv Parasitol 2020; 107:201282.
27. Jokipii L, Jokipii AM. Comparison of four dosage schedules in the treatment of giardiasis with metronidazole. Infection 1978; 6:9294.
28. Jokipii AM, Jokipii L. Comparative evaluation of two dosages of tinidazole in the treatment of giardiasis. Am J Trop Med Hyg 1978; 27:758761.
29. Nigam P, Kapoor KK, Kumar A, et al. Clinical profile of giardiasis and comparison of its therapeutic response to metronidazole and tinidazole. J Assoc Physicians India 1991; 39:613615.
30. Speelman P. Single-dose tinidazole for the treatment of giardiasis. Antimicrob Agents Chemother 1985; 27:227229.
31. Jokipii L, Jokipii AM. Treatment of giardiasis: comparative evaluation of ornidazole and tinidazole as a single oral dose. Gastroenterology 1982; 83:399404.
32. 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; 90:912.
33. Ozbilgin A, Ertan P, Yereli K, et al. Giardiasis treatment in Turkish children with a single dose of ornidazole. Scand J Infect Dis 2002; 34:918920.
34. Oren B, Schgurensky E, Ephros M, et al. Single-dose ornidazole versus seven-day metronidazole therapy of giardiasis in Kibbutzim children in Israel. Eur J Clin Microbiol Infect Dis 1991; 10:963965.
35. Rastegar-Lari A, Salek-Moghaddam A. Single-dose secnidazole versus 10-day metronidazole therapy of giardiasis in Iranian children. J Trop Pediatr 1996; 42:184185.
36. Cimerman B, Camilo Coura L, C Salle JM, et al. Evaluation of secnidazole gel and tinidazole suspension in the treatment of giardiasis in children. Braz J Infect Dis 1997; 1:241247.
37. Hall A, Nahar Q. Albendazole as a treatment for infections with Giardia duodenalis in children in Bangladesh. Trans R Soc Trop Med Hyg 1993; 87:8486.
38. Dutta AK, Phadke MA, Bagade AC, et al. A randomised multicentre study to compare the safety and efficacy of albendazole and metronidazole in the treatment of giardiasis in children. Indian J Pediatr 1994; 61:689693.
39. Baqai R, Zuberi SJ, Qureshi H, et al. Efficacy of albendazole in giardiasis. East Mediterr Health J 2001; 7:787790.
40. Yereli K, Balcioglu IC, Ertan P, et al. Albendazole as an alternative therapeutic agent for childhood giardiasis in Turkey. Clin Microbiol Infect 2004; 10:527529.
41. Karabay O, Tamer A, Gunduz H, et al. Albendazole versus metronidazole treatment of adult giardiasis: an open randomized clinical study. World J Gastroenterol 2004; 10:12151217.
42. Pengsaa K, Sirivichayakul C, Pojjaroen-anant C, et al. Albendazole treatment for Giardia intestinalis infections in school children. Southeast Asian J Trop Med Public Health 1999; 30:7883.
43. Canete R, Rodriguez P, Mesa L, et al. Albendazole versus metronidazole in the treatment of adult giardiasis: a randomized, double-blind, clinical trial. Curr Med Res Opin 2012; 28:149154.
44. Pengsaa K, Limkittikul K, Pojjaroen-anant C, et al. Single-dose therapy for giardiasis in school-age children. Southeast Asian J Trop Med Public Health 2002; 33:711717.
45. Escobedo AA, Canete R, Gonzalez ME, et al. A randomized trial comparing mebendazole and secnidazole for the treatment of giardiasis. Ann Trop Med Parasitol 2003; 97:499504.
46. Bulut BU, Gulnar SB, Aysev D. Alternative treatment protocols in giardiasis: a pilot study. Scand J Infect Dis 1996; 28:493495.
47. Sadjjadi SM, Alborzi AW, Mostovfi H. Comparative clinical trial of mebendazole and metronidazole in giardiasis of children. J Trop Pediatr 2001; 47:176178.
48. al-Waili NS, al-Waili BH, Saloom KY. Therapeutic use of mebendazole in giardial infections. Trans R Soc Trop Med Hyg 1988; 82:438.
49. Gascon J, Moreno A, Valls ME, et al. Failure of mebendazole treatment in Giardia lamblia infection. Trans R Soc Trop Med Hyg 1989; 83:647.
50. Canete R, Escobedo AA, Gonzalez ME, et al. A randomized, controlled, open-label trial of a single day of mebendazole versus a single dose of tinidazole in the treatment of giardiasis in children. Curr Med Res Opin 2006; 22:21312136.
51. Almirall P, Escobedo AA, Ayala I, et al. Mebendazole compared with secnidazole in the treatment of adult giardiasis: a randomised, no-inferiority, open clinical trial. J Parasitol Res 2011; 2011:636857.
52. Canete R, Escobedo AA, Gonzalez ME, Almirall P. Randomized clinical study of five days apostrophe therapy with mebendazole compared to quinacrine in the treatment of symptomatic giardiasis in children. World J Gastroenterol 2006; 12:63666370.
53. Sabchareon A, Chongsuphajaisiddhi T, Attanath P. Treatment of giardiasis in children with quinacrine, metronidazole, tinidazole and ornidazole. Southeast Asian J Trop Med Public Health 1980; 11:280284.
54. Kavousi S. Giardiasis in infancy and childhood: a prospective study of 160 cases with comparison of quinacrine (Atabrine) and metronidazole (Flagyl). Am J Trop Med Hyg 1979; 28:1923.
55. Craft JC, Murphy T, Nelson JD. Furazolidone and quinacrine. Comparative study of therapy for giardiasis in children. Am J Dis Child 1981; 135:164166.
56. Levi GC, de Avila CA, Amato Neto V. Efficacy of various drugs for treatment of giardiasis. A comparative study. Am J Trop Med Hyg 1977; 26:564565.
57. Murphy TV, Nelson JD. Five v ten days’ therapy with furazolidone for giardiasis. Am J Dis Child 1983; 137:267270.
58. Quiros-Buelna E. Furazolidone and metronidazole for treatment of giardiasis in children. Scand J Gastroenterol Suppl 1989; 169:6569.
59. Nunez FA, Escobedo AA, Finlay CM. Efficacy of various drugs for treatment of Giardia lamblia infection in children. Rev Panam Infectol 2004; 6:1720.
60. Rodriguez-Garcia R, Rodriguez-Guzman LM, Cruz del Castillo AH. Effectiveness and safety of mebendazole compared to nitazoxanide in the treatment of Giardia lamblia in children. Rev Gastroenterol Mex 1999; 64:122126.
61. Escobedo AA, Alvarez G, Gonzalez ME, et al. The treatment of giardiasis in children: single-dose tinidazole compared with 3 days of nitazoxanide. Ann Trop Med Parasitol 2008; 102:199207.
62. Rossignol JF, Ayoub A, Ayers MS. Treatment of diarrhea caused by Giardia intestinalis and Entamoeba histolytica or E. dispar: a randomized, double-blind, placebo-controlled study of nitazoxanide. J Infect Dis 2001; 184:381384.
63. Davila-Gutierrez CE, Vasquez C, Trujillo-Hernandez B, Huerta M. Nitazoxanide compared with quinfamide and mebendazole in the treatment of helminthic infections and intestinal protozoa in children. Am J Trop Med Hyg 2002; 66:251254.
64. Ortiz JJ, Ayoub A, Gargala G, et al. Randomized clinical study of nitazoxanide compared to metronidazole in the treatment of symptomatic giardiasis in children from Northern Peru. Aliment Pharmacol Ther 2001; 15:14091415.
65. Rossignol JF, Lopez-Chegne N, Julcamoro LM, et al. Nitazoxanide for the empiric treatment of pediatric infectious diarrhea. Trans R Soc Trop Med Hyg 2012; 106:167173.
66. Escobedo AA, Nunez FA, Moreira I, et al. Comparison of chloroquine, albendazole and tinidazole in the treatment of children with giardiasis. Ann Trop Med Parasitol 2003; 97:367371.
67. Leitsch D. A review on metronidazole: an old warhorse in antimicrobial chemotherapy. Parasitology 2019; 146:11671178.
68. Martinez-Espinosa R, Arguello-Garcia R, Saavedra E, Ortega-Pierres G. Albendazole induces oxidative stress and DNA damage in the parasitic protozoan Giardia duodenalis. Front Microbiol 2015; 6:800.
69. Kreutner AK, Del Bene VE, Amstey MS. Giardiasis in pregnancy. Am J Obstet Gynecol 1981; 140:895901.
70. Edlind TD. Susceptibility of Giardia lamblia to aminoglycoside protein synthesis inhibitors: correlation with rRNA structure. Antimicrob Agents Chemother 1989; 33:484488.
71. Carter CH, Bayles A, Thompson PE. Effects of paromomycin sulfate in man against Entamoeba histolytica and other intestinal protozoa. Am J Trop Med Hyg 1962; 11:448451.
72. Leitsch D. Drug resistance in the microaerophilic parasite Giardia lamblia. Curr Trop Med Rep 2015; 2:128135.
73. Genel F, Erermis S, Aksu G, et al. Quinacrine-induced psychiatric disturbances in a child with common variable immunodeficiency and chronic giardiasis. Hum Psychopharmacol 2002; 17:357359.
74. Lindenmayer JP, Vargas P. Toxic psychosis following use of quinacrine. J Clin Psychiatry 1981; 42:162164.
75. Weisholtz SJ, McBride PA, Murray HW, Shear MK. Quinacrine-induced psychiatric disturbances. South Med J 1982; 75:359360.
76. Tatsumi K, Yamada H, Yoshimura H, Kawazoe Y. Metabolism of furazolidone by milk xanthine oxidase and rat liver 9000 g supernatant: formation of a unique nitrofuran metabolite and an aminofuran derivative. Arch Biochem Biophys 1981; 208:167174.
77. Muller J, Wastling J, Sanderson S, et al. A novel Giardia lamblia nitroreductase, GlNR1, interacts with nitazoxanide and other thiazolides. Antimicrob Agents Chemother 2007; 51:19791986.
78. Borba MGS, Val FFA, Sampaio VS, et al. Effect of high vs low doses of chloroquine diphosphate as adjunctive therapy for patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection: a randomized clinical trial. JAMA Netw Open 2020; 3:e208857.
79. Munoz Gutierrez J, Aldasoro E, Requena A, et al. Refractory giardiasis in Spanish travellers. Travel Med Infect Dis 2013; 11:126129.
80. Requena-Mendez A, Goni P, Rubio E, et al. The use of quinacrine in nitroimidazole-resistant Giardia duodenalis: an old drug for an emerging problem. J Infect Dis 2017; 215:946953.
81. Cacopardo B, Patamia I, Bonaccorso V, et al. Synergic effect of albendazole plus metronidazole association in the treatment of metronidazole-resistant giardiasis. Clin Ter 1995; 146:761767.
82. Nash TE, Ohl CA, Thomas E, et al. Treatment of patients with refractory giardiasis. Clin Infect Dis 2001; 33:2228.
83. Morch K, Hanevik K, Robertson LJ, et al. Treatment-ladder and genetic characterisation of parasites in refractory giardiasis after an outbreak in Norway. J Infect 2008; 56:268273.
84. Lopez-Velez R, Batlle C, Jimenez C, et al. Short course combination therapy for giardiasis after nitroimidazole failure. Am J Trop Med Hyg 2010; 83:171173.
85. Requena-Mendez A, Goni P, Lobez S, et al. A family cluster of giardiasis with variable treatment responses: refractory giardiasis in a family after a trip to India. Clin Microbiol Infect 2014; 20:O135O138.
86. Meltzer E, Lachish T, Schwartz E. Treatment of giardiasis after nonresponse to nitroimidazole. Emerg Infect Dis 2014; 20:17421744.
87. Hjelt K, Paerregaard A, Krasilnikoff PA. Giardiasis causing chronic diarrhoea in suburban Copenhagen: incidence, physical growth, clinical symptoms and small intestinal abnormality. Acta Paediatr 1992; 81:881886.
88. Pal D, Banerjee S, Cui J, et al. Giardia, Entamoeba, and Trichomonas enzymes activate metronidazole (nitroreductases) and inactivate metronidazole (nitroimidazole reductases). Antimicrob Agents Chemother 2009; 53:458464.
89. Saghaug CS, Klotz C, Kallio JP, et al. Genetic variation in metronidazole metabolism and oxidative stress pathways in clinical Giardia lamblia assemblage A and B isolates. Infect Drug Resist 2019; 12:12211235.
90. Leitsch D, Burgess AG, Dunn LA, et al. Pyruvate:ferredoxin oxidoreductase and thioredoxin reductase are involved in 5-nitroimidazole activation while flavin metabolism is linked to 5-nitroimidazole resistance in Giardia lamblia. J Antimicrob Chemother 2011; 66:17561765.
91. Leitsch D, Muller J, Muller N. Evaluation of Giardia lamblia thioredoxin reductase as drug activating enzyme and as drug target. Int J Parasitol Drugs Drug Resist 2016; 6:148153.
92. Townson SM, Laqua H, Upcroft P, et al. Induction of metronidazole and furazolidone resistance in Giardia. Trans R Soc Trop Med Hyg 1992; 86:521522.
93. Muller J, Ley S, Felger I, et al. Identification of differentially expressed genes in a Giardia lamblia WB C6 clone resistant to nitazoxanide and metronidazole. J Antimicrob Chemother 2008; 62:7282.
94. Lecova L, Weisz F, Tumova P, et al. The first multilocus genotype analysis of Giardia intestinalis in humans in the Czech Republic. Parasitology 2018; 145:15771587.
95. Cruz A, Sousa MI, Azeredo Z, et al. Isolation, excystation and axenization of Giardia lamblia isolates: in vitro susceptibility to metronidazole and albendazole. J Antimicrob Chemother 2003; 51:10171020.
96. Pearce DA, Reynoldson JA, Thompson RC. A comparison of two methods for assessing drug sensitivity in Giardia duodenalis. Appl Parasitol 1996; 37:111116.
97. Leitsch D. Drug susceptibility testing in microaerophilic parasites: cysteine strongly affects the effectivities of metronidazole and auranofin, a novel and promising antimicrobial. Int J Parasitol Drugs Drug Resist 2017; 7:321327.
98. Ansell BR, Baker L, Emery SJ, et al. Transcriptomics indicates active and passive metronidazole resistance mechanisms in three seminal Giardia lines. Front Microbiol 2017; 8:398.
99. Emery SJ, Baker L, Ansell BRE, et al. Differential protein expression and posttranslational modifications in metronidazole-resistant Giardia duodenalis. Gigascience 2018; 7:giy024.
100. Muller J, Muller N. Nitroreductases of bacterial origin in Giardia lamblia: potential role in detoxification of xenobiotics. Microbiologyopen 2019; 8:e904.
101▪. Muller J, Braga S, Heller M, Muller N. Resistance formation to nitro drugs in Giardia lamblia: no common markers identified by comparative proteomics. Int J Parasitol Drugs Drug Resist 2019; 9:112119.

5-nitroimidazoles; albendazole; Giardia; paromomycin; quinacrine

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