Acta Tropica 153 (2016) 120127

Contents lists available at ScienceDirect

Acta Tropica
journal homepage: www.elsevier.com/locate/actatropica

A meta-analysis of the efcacy of albendazole compared with

tinidazole as treatments for Giardia infections in children
Angel A. Escobedo a,b,c, , Javier Ballesteros d , Eduardo Gonzlez-Fraile e , Pedro Almirall c,f
a

Academic Paediatric Hospital Pedro Borrs, Calle F No. 616 esquina 27, Plaza, La Habana CP 10400, Cuba
Working Group on Zoonoses, International Society for Chemotherapy, Aberdeen, United Kingdom
Committee on Clinical Parasitology, Panamerican Association of Infectology
d
University of the Basque Country, UPV/EHU and CIBERSAM, Medical SchoolDepartment of Neuroscience, Barrio Sarriena S/N, Leioa, Spain
e
Institute of Psychiatric Research, Ega
na 10, 48010 Bilbao, Spain
f
Municipal Centre of Hygiene, Epidemiology and Microbiology Plaza, Calle 8 No. 406 esquina a 19, Plaza, La Habana CP 10400, Cuba
b
c

a r t i c l e

i n f o

Article history:
Received 4 July 2015
Received in revised form
17 September 2015
Accepted 27 September 2015
Available online 22 October 2015
Keywords:
Giardia infection
Giardiasis
Children
Systematic review
Meta-analysis

a b s t r a c t
Metronidazole is frequently used against Giardia infection; however, it has been associated with signicant failure rates in clearing parasites from the gut; additionally, as it should be taken for 5 to 10 days, it is
associated with poor compliance, probably due to side effects. Other drugs, including tinidazole (TNZ) and
albendazole (ABZ) have been included in the antigiardial armamentarium. Our aim was to assess the efcacy of ABZ compared with TNZ in Giardia infections in children. A systematic review and a meta-analysis
were carried out. PubMed, Medline, EMBASE, CENTRAL, and LILACS were searched electronically until
February 2015. Also relevant journals and references of studies included therein were hand-searched
for randomised controlled trials (RCTs). The meta-analysis was limited to RCTs evaluating the use of ABZ
compared with TNZ in children with Giardia infection. The assessed outcome was parasitological efcacy.
Prediction intervals (PI) were computed to better express uncertainties in the effect estimates. Five RCTs
including 403 children were included. Overall, TNZ signicantly outperformed ABZ without differences
between subgroups dened by ABZ dosages [relative risk, (RR) 1.61 (95% CI): (1.401.85); P < 0.0001].
The 95% prediction interval range is 1.282.02. There was no signicant heterogeneity (I2 = 0%; Q-test of
heterogeneity P = 0.4507. The number-needed-to-treat, the average number of patients who need to be
treated with TNZ to gain one additional good outcome as compared with ABZ was 4, 95% CI: 35. Our
results show that TNZ outperforms ABZ in the treatment of Giardia infections in children from developing
countries.
2015 Elsevier B.V. All rights reserved.

Contents
1.
2.

3.

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
2.1.
Search strategy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
2.2.
Inclusion and exclusion criteria . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121
2.3.
Study selection and data extraction process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2.4.
Outcome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2.5.
Evaluation of study quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
2.6.
Analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
Results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.1.
Study selection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122
3.2.
Study characteristics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 122

Corresponding author at: Academic Paediatric Hospital Pedro Borrs, Calle F

No. 616 esquina 27, Havana 10400, Cuba.
E-mail address: escobedo@infomed.sld.cu (A.A. Escobedo).
http://dx.doi.org/10.1016/j.actatropica.2015.09.023
0001-706X/ 2015 Elsevier B.V. All rights reserved.

A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

121

3.3.
Parasitological examination . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.4.
Meta-analytical results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124
3.5.
Sensitivity results . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4.
Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
4.1.
Limitations of study . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
5.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125
Conict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Authors contributions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
Appendix A.
Supplementary data . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126

1. Introduction
Giardia lamblia, a common single-celled intestinal parasite of
humans and animals, continues to be a signicant public health
problem, mainly in developing countries. Infection with this protozoan parasite occurs primarily by oral inoculation of faecally
excreted infective cysts either by person-to-person contact (including any form of sexual contact with proximity to faeces) or by
ingestion of contaminated food or water. Although most of the
persons who carry this protozoan remain symptomless, it has also
been increasingly implicated in the aetiology of a range of different
intestinal and extra-intestinal manifestations, including acute to
persistent and severe diarrhoea (with or without dehydration and
malabsorption), abdominal cramps, atulence, bloating, and nausea and, in the early childhood, the failure to thrive syndrome
(Escobedo et al., 2010).
Giardiasis, the disease this protozoan causes, occurs worldwide,
as research on its therapy, too. During the last years, research on giardiasis has been growing (Escobedo et al., 2015), maybe as a result
of its re-emergence in industrialized countries and the fact that it
was included in the World Health Organization (WHO) Neglected
Diseases Initiative from 2004 (Savioli et al., 2006). However, the
number of drugs available against this infection has not varied
substantially during the last decades. Five-nitroimidazole (5-NI)
compounds, mainly metronidazole (MTZ), have been the mainstay
of pharmacological treatment for patients with Giardia infection.
Their introduction in the antigiardial armamentarium constituted
a signicant improvement in giardiasis therapy. The long duration
of treatment with MTZ and its side effect prole (metallic taste,
headache, anorexia, nausea, vomiting) have been important disadvantages to its use. The other 5-NI compounds, including tinidazole
(TNZ), ornidazole and secnidazole, are effective when given as
a single dose and are associated with fewer side effects, which
reects their better acceptance. However, there is an increasing
number of treatment failures reported in the literature (McIntyre
et al., 1986; Lo Line Mei et al., 1987; Taylor et al., 1987; Al Karawi
et al., 1988; Rowedder et al., 1991; Elliott et al., 1998; Abboud
et al., 2001; Nash et al., 2001; Mrch et al., 2008; Kampitak, 2010;
Tejman-Yarden et al., 2013; Requena-Mndez et al., 2014; Meltzer
et al., 2014; Navarro et al., 2015). The interpretation and implications of these studies are still being debated, but they have led to
an increased awareness of Giardia resistance as a current clinical
problem. In addition to resistance, other potential causes of treatment failures include patient compliance (Shepherd and Boreham,
1989), poor quality of medicines, which includes spurious/falsely
labeled/falsied/counterfeit medicines, chemical and/or physicochemical instability, inappropriate storage and transport, and poor
quality control during manufacturing and importing medicines
(Heyman and Williams, 2011), reinfection, inadequate drug levels, immunosuppression, resistance to the drug, sequestration in
the gallbladder or pancreatic ducts, and unknown reasons (Nash
et al., 2001; Robertson et al., 2010). Consequently, newer and older

drugs have been proposed as alternatives for the treatment of this

intestinal infection (Escobedo and Cimerman, 2007).
G. lamblia has been reported to be highly susceptible to albendazole (ABZ) in vitro (Edlind et al., 1990; Meloni et al., 1990). In
addition, clinical experience has also demonstrated therapeutic
benets for the use of ABZ in this infection (Hall and Anwar, 1991;
Karabay et al., 2004; Yereli et al., 2004) and according to the results
of a meta-analysis, published in 2010, ABZ was found to be as effective as MTZ in the treatment of giardiasis in humans (RR 0.97; 95%
CI, 0.93, 1.01) (Solaymani-Mohammadi et al., 2010). Nowadays, this
drug is considered as an alternative in Giardia infection treatment.
Meta-analysis is a valuable analytical tool for summarizing
results from different, but comparable, individual studies (Paul and
Leibovici, 2014; Murad et al., 2014). To our knowledge, 4 previous
systematic reviews and/or meta-analyses (Solaymani-Mohammadi
et al., 2010; Zaat et al., 1997; Granados et al., 2012; Pasupuleti
et al., 2014) have evaluated the efcacy of antigiardial drugs in the
treatment of Giardia infection. None compared the efcacy of ABZ
with TNZ. Herein, we report the results of a meta-analysis of randomized clinical trials (RCTs) comparing the efcacy of ABZ vs TNZ
for the treatment of Giardia infection in children. This could serve
the needs of clinicians and public health professionals from both
industrialised and developing nations.
2. Methods
This meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analysis
(PRISMA) statement (Moher et al., 2015).
2.1. Search strategy
PubMed, Medline, and EMBASE through Ovid, CENTRAL and
LILACS were searched without language restriction from the earliest date up to 5 February 2015. Appropriate search terms are
recorded in the data supplement 1. Also relevant journals and references of studies included therein were hand-searched for RCTs
comparing ABZ with TNZ in terms of efcacy. Where necessary we
contacted with study investigators for clarication of methods.
2.2. Inclusion and exclusion criteria
We search for published RCTs comparing the efcacy of ABZ
with TNZ for treating Giardia infection in children. Eligible studies
were (i) original RCTs comparing the efcacy of ABZ with TNZ, (ii)
previously untreated patient population, (iii) entire study available
for the review, (iv) included participants aged <18 years, (v) study
population of patients with parasitologically-demonstrated Giardia
and measured parasitological cure (dened as a negative Giardia in
faecal specimens at the follow-up) within 21 days of treatment. We
excluded studies if efcacy data (parasitological cure rates) were
not available or extractable.

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A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

2.3. Study selection and data extraction process

A spreadsheet recorded data on: study design, randomization
method, and participant numbers by treatment arm and sex, presence of signs and/or symptoms at diagnosis, diagnostic method
used to assess parasitological cure, follow-up times, and parasitological cure frequencies. Data from included studies were
abstracted by two authors (A. A. E. and P. A.), whereas other author
(J. B.) checked the data extracted. Any discrepancy was resolved by
discussion between the authors, until a consensus was reached to
ensure that accurate data were obtained.

2.4. Outcome
The outcome measure was parasitological cured (dened as
above) at the end of the treatment in at least two consecutive faecal
microscopic examination performed at the last follow-up.

2.5. Evaluation of study quality

The assessment of the internal validity of the clinical trials was
performed using the risk of bias tool of the Cochrane Cooperation (Higgins et al., 2011), and the overall quality of the evidence
gathered was assessed by the GRADE guidelines (Balshem et al.,
2011). The quality of parasitological diagnostic methods was separately assessed by the scoring system utilised by Zaat et al., (1997)
and Solaymani-Mohammadi et al., (2010). This method evaluates
whether techniques are sufciently described and adequate.

2.6. Analysis
Meta-analysis was used to calculate the pooled estimates of the
treatment efcacy, comparing TNZ vs ABZ. We used the I2 index to
estimate the proportion of total variability in point estimates that
could be attributed to between-trials heterogeneity, rather than
by a chance (Higgins et al., 2003). The relative risk (RR) was the
effect size to analyze with values >1 meaning TNZ was better than
ABZ. Individual effect sizes were combined by the MantelHaenszel
method using a random effects model and a predictive RR estimate
was obtained (Higgins et al., 2009).
Sensitivity analysis was performed to assess the consistency
of the overall ndings on the magnitude of the effect when trials
were removed one at the time from the full analysis set. This
would also allow us to check the impact of excluding the trial that
utilised the most insensitive parasitological methods, i.e. direct faecal microscopy with brine otation technique employed (Chan del
Pino et al., 1999). The latter method, unlike the ether sedimentation
method used in the rest of studies, is just a concentration technique
for the diagnosis of intestinal helminth infections, not for intestinal protozoa (Garca and Bruckner, 1993). A sensitivity analysis was
also performed with the two articles with follow-up longer than 14
days (Chan del Pino et al., 1999; Mendoza et al., 2003), considering
that faecal specimens at least in endemic countries should be
obtained during the rst 12 days after completion of therapy (the
number of days needed for a Giardia infection to become patent)
(Jokipii and Jokipii, 1977).
A small study bias analysis was planned only in case we retrieved
an appropriate number of studies for the meta-analysis (about 10).
All analyses were performed with the R package (R Core Team,
2014) using the meta library (Schwarzer, 2014).

Fig. 1. Flow chart of study selection.

3. Results
3.1. Study selection
The review process is shown in Fig. 1 and the selected papers
meeting the inclusion criteria are summarised it Table 1.
3.2. Study characteristics
Our search identied 5 RCTs which compared ABZ with TNZ, representing a total of 423 children with Giardia infection included for
the current review (Chan del Pino et al., 1999; Mendoza et al., 2003;
Pengsaa et al., 1999, 2002; Escobedo et al., 2003). Trials were published between 1999 and 2003. One trial was conducted in Peru;
two were conducted in Thailand and the other two in Cuba, all
of them are countries where Giardia infection is endemic. At the
last follow-up visit, 220 and 203 children were evaluated for ABZ
and TNZ, respectively. All studies were open label trials with random allocation of children to ABZ or TNZ. TNZ was prescribed at
a single 50 mg/kg dose. However, the dosages of ABZ ranged from

Table 1
Characteristics of the randomised controlled trials included in the meta-analysis.
Author, year (country)

Study design

No. of randomised participants Age (y) Sex(M/F) Disease

characteristics

Chan del Pino (1999)

(Peru)

Open-label, RCT
5 parallel arms

79

313

NS

Symptomatica

Diagnostic test

Antigiardial drug
regimens
(No. of
participants)

Direct wet mount

and brine otation
techniques

ABZ, 400 mg/d for 5 11/17 (64.7%)

days (17)

Efcacy

Follow-up

Day 7, 14 and 21

TNZ, 50 mg s.d. (15) 13/15

(86.6%)
Open-label, RCT
2 parallel arms

131

315

71/73

Symptomatic and
asymptomatic

Direct smear in
0.9% saline and
ether
sedimentation
method

ABZ, 400 mg/d for 3 31/68 (45.6%)

days (68)

TNZ, 50 mg (max.
2 g) s.d. (63)
Pengsaa (2002)
(Thailand)

Mendoza (2003)
(Cuba)

Open-label, RCT
3 parallel arms

Open-label, RCT
2 parallel arms

84

92

715

25

NS

47/45

Symptomatic

Symptomatic and
asymptomatic

Direct smears and ABZ, 800 mg s.d.

iodine stained after (26)
ethersedimentation
concentration
TNZ, 50 mg (max.
2 g) s.d. (27)
Direct wet mount
and after formol
ether
sedimentation

Escobedo (2003)
(Cuba)

Open-label, RCT
3 parallel arms

165

215

58/57

Symptomatic

49/63 (77.8%)
13/26 (50%)

ABZ, 400 mg/d for 5

Direct wet mount
and after formol
days (60)
ether
sedimentation
technique methods
TNZ, 50 mg (max.
2 g) s.d. (55)

Day 7 and 14 after

treatment

25/27 (92.6%)

ABZ, 400 mg/d for 5 17/49

days (49)
(34.6)

TNZ, 50 mg (max.
2 g) s.d. (43)

Day 7 and 14 after

treatment

Day 7, 14 and 21
after treatment

A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

Pengsaa (1999)
(Thailand)

31/43
(72.0%)
37/60
(62.0%)

Day 7 and 10 after

treatment

50/55
(91.0%)

As children were included after a screening may be some of them could be asymptomatic.

123

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A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

Table 2
Parasitological quality of included studies.
Study

Chan del Pino et al. (1999)

Pengsaa et al. (1999)
Pengsaa et al. (2002)
Mendoza et al. (2003)
Escobedo et al. (2003)
b

Parasitological examination
Description

Adequate

Repeated

Interobserver variation

Totalb

2
2
2
2
2

0
3
3
3
3

3
3
3
3
3

0
0
0
0
0

5
8
8
8
8

Range 015; 15 indicates optimal laboratory technique.

Fig. 2. Forest plot showing the effects of albendazole and tinidazole in giardiasis in children.

800 mg given as a single dose (Pengsaa et al., 2002) to 400 mg/d

for 5 consecutive days (Chan del Pino et al., 1999; Mendoza et al.,
2003; Escobedo et al., 2003). In 2 studies, children included have
both symptomatic and asymptomatic Giardia infections (Pengsaa
et al., 1999; Mendoza et al., 2003); other 2 studies included only
symptomatic children (Pengsaa et al., 2002; Escobedo et al., 2003);
the other study also included symptomatic children; however,
according to the test used to include children after a parasitological
screening, it is possible that some children could be asymptomatic
(Chan del Pino et al., 1999). Follow-up periods ranged from 7 to 21
days (Chan del Pino et al., 1999; Mendoza et al., 2003; Pengsaa et al.,
1999, 2002; Escobedo et al., 2003). Loss of follow-up did not occur in
3 studies (Mendoza et al., 2003; Pengsaa et al., 2002; Escobedo et al.,
2003), whereas 2 studies reported withdrawals and/or dropouts
(Chan del Pino et al., 1999; Pengsaa et al., 1999) (Table 1).
3.3. Parasitological examination
In all studies, the absence of detectable Giardia trophozoites
and/or cysts in the faecal microscopy during the follow-up period
was required to declare the children cured. The mean score on our
parasitological quality index was 7.4 (range 58) out of a maximum of 15, indicating a modest quality (Table 2). Four trials scored
8 points, mainly due to the relatively great weight of the item
repeated examinations at follow-up. Inter-observer variation was

not described in any trial. In 4 studies, the diagnosis of Giardia infection was based on direct faecal microscopy in combination with
ether concentration technique (Mendoza et al., 2003; Pengsaa et al.,
1999, 2002; Escobedo et al., 2003), and the remaining study (Chan
del Pino et al., 1999) used direct faecal microscopy in combination with brine otation technique, which is not specic for the
diagnosis of intestinal protozoa.
3.4. Meta-analytical results
In all ABZ dosage subgroups, TNZ signicantly outperformed
ABZ (see forest plot in Fig. 2). The overall RR estimate was 1.61
(95% CI: 1.40, 1.85) P < 0.0001. The 95% prediction interval range
for the RR was 1.282.02. There was no signicant heterogeneity
(I2 = 0%; Q-test of heterogeneity P = 0.4507).
The results did not vary by different dosages of ABZ (Qtest = 0.65, d.f = 2, P = 0.72). For 400 mg once a day for 5 days, the
RR was 1.55 (95% CI: 1.241.94), for 400 mg for 3 days the RR was
1.70 (95% CI: 1.272.28) and for 800 mg the RR was 1.85 (95% CI,
1.242.76).
We also evaluated the results on the risk difference (RD) scale
and its inverse, the number-needed-to-treat (NNT) to obtain one
more success with TNZ than the comparative arm. The RD of 0.33
(95% CI: 0.250.41) translates to a 33% higher efcacy for TNZ, with
a NNT of 4 (95% CI: 35). To put these estimates in perspective, if we

A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

Table 3
Inuential analysis (random effects model).

125

the rst option is the best, due to its advantages in terms of the
frequency of cure and the simplicity of the dosing regimen.

Study omitted [Ref.]

RR

95% CI

P value

Chan del Pino et al. (1999)

Escobedo et al. (2003)
Mendoza et al. (2003)
Pengsaa et al. (1999)
Pengsaa et al. (2002)
Pooled estimate

1.65
1.71
1.56
1.60
1.58
1.61

[1.42; 1.91]
[1.42; 2.06]
[1.34; 1.81]
[1.33; 1.91]
[1.35; 1.84]
[1.40; 1.85]

<0.0001
<0.0001
<0.0001
<0.0001
<0.0001
<0.0001

assume a 49.5% of parasitological cure for ABZ (109 children cured

over 203 tested), the treatment with TNZ would increase the cure
rate by 302 more subjects per 1000 children treated.
3.5. Sensitivity results
The sensitivity analysis did not nd evidence of any inuential
study (Table 3). We performed also a sensitivity analysis by deleting
the studies of Chan del Pino et al., (1999) and Mendoza et al., (2003)
that report longer follow-ups (21 days), without noting appreciable
changes in the pooled results (RR = 1.63; 95% CI: 1.37, 1.96).
4. Discussion
To our knowledge, this is the rst systematic review and
meta-analysis to compare ABZ with TNZ; and has been done without language restrictions, to avoid possible tower of babel bias
(Gregoire et al., 1995). The methodological quality of the included
studies is moderate, mainly because all trials were open label with
risk of performance bias due to the lack of blinding of participants
and personnel to the treatment arms.
Our results suggest the superiority of TNZ over ABZ against Giardia infections. This nding was quite unexpected because, even
though 5-NI drugs have been the cornerstone of Giardia infections
therapy for years, two previous meta-analyses, the rst including 8 RCTs (n = 900) (Solaymani-Mohammadi et al., 2010) and the
second including 19 RCTs (n = 1817) (Granados et al., 2012), concluded that the efcacies of ABZ and the main 5-NI reference MTZ
were similar. However TNZ has demonstrated to possess an in vitro
advantage over MTZ (Jokipii and Jokipii, 1980; Gordts et al., 1985).
In addition, TNZ is, in terms of parasitological cure, more effective than- (Gazder and Banerjee, 1978; Jokipii and Jokipii, 1979;
Sabchareon et al., 1980; Kyronseppa and Petersson, 1981) or comparable to MTZ (Bassily et al., 1987; Chan del Pino et al., 1999) in
the treatment of giardiasis. TNZ has fewer side-effects, and better compliance than MTZ (Escobedo and Cimerman, 2007). In fact,
TNZ has been used in cases where treatment with MTZ has previously failed. Although, cross-resistance between MTZ and TNZ has
been also reported (Upcroft and Upcroft, 1993; Upcroft, 1998). A
recent systematic review by Pasupuleti et al., (2014), including 30
RCTs (n = 3930), published up to 2014, that evaluated the efcacy
of 5-NI drugs, found that TNZ was the most effective single-dose
therapy compared with other short therapies, having at the same
time, relatively fewer harmful effects.
ABZ has the broadest spectrum of activity of the benzimidazoles released to date and has been widely used in human clinical
medicine as a safe drug (Venkatesan, 1998). Due to its broad
activity against many parasites, including Ascaris lumbricoides and
the hookworms (Necator americanus and Ancylostoma duodenale),
Strongyloides stercoralis, Enterobius vermicularis, microsporidia,
adult and larval forms of some cestode infections, and Giardia
(Venkatesan, 1998), ABZ has increasingly been deployed in mass
drug administration programs, which require a single drug administration to all subjects without previous diagnosis (WHO, 2006),
and in the treatment of polyparasitism. However, in Giardia infections, it seems that in places where both TNZ and ABZ are available,

4.1. Limitations of study

Our results should be viewed within the context of their limitations and the characteristics of the research in this eld. We have
found a small number of RCTs. Although the literature search was
extensive, publication bias is possible, and if present our results
could overestimate the reported efcacy of TNZ versus ABZ. Also,
all included studies were open-label without blinding the interventions to patients and clinicians which could have been resulted in
biased estimates of efcacy regardless of the direction (TNZ better or worse than ABZ). This limitation is difcult to circumvent
in studies that compare drugs with different time schedules and
dosages. According to the risk of bias, all studies included in the
meta-analysis presented high risk on performance bias due to lack
of blinding of participants and personnel. However the blinding of
outcome assessment and its objective characteristics (presence of
cysts/parasites on faecal samples) made detection bias unlikely.
Endemic giardiasis most commonly affects children and since
this was our population of interest we cannot make recommendations specic to adults, and besides that the disease presentation
in children differ from adults in both severity and complications,
i.e. poor cognitive function and failure to thrive in early childhood
(Berkman et al., 2002). Additionally, giardiasis is mostly managed
in community and outpatient settings; hospitalised patients represent the more severe end of the clinical spectrum of giardiasis
and this meta-analysis did not include any article with hospitalised
cases.
Any meta-analysis is or could be as good as the studies
that it includes and thus their main limitations come from the several risk of bias present in the combined studies. Whereas blinding
interventions is an issue in this meta-analysis, blinding the outcome assessment, attrition bias and selective reporting are not.
However it is worth to note that most studies included in this
meta-analysis did not present enough information to appropriately
assess the possibility of selection bias due to inappropriate random
sequence generation or allocation concealment. This lack of information regarding does not necessarily imply studies were biased,
just that unfortunately authors do not get accustomed to explain
randomization and concealing procedures in detail.
It should be taken into account that, being children who live in
endemic countries, some positive cases after the treatment period
could not be exactly truly indicative of treatment failures, but the
result of re-infections, a frequent phenomenon in endemic areas
(Berkman et al., 2002; Gilman et al., 1988; Sullivan et al., 1989;
et al., 1999; Saffar et al., 2005).
Nnez
The applicability of the results should also be viewed with caution, as information on the efcacy of these drugs in industrialised
countries is lacking. No studies from North America or European
countries were found.
5. Conclusions
This study has shown TNZ presents higher efcacy than ABZ
for the treatment of Giardia infections in children from developing
countries. The consistency and precision of results, the direct relevance of the main outcome, and the unlikely presence of publication
bias, resulted in a GRADE level of high quality of evidence.
The prediction interval (PI) of the meta-analysis gave us a range
of effects to be expected in a prospective study (RR: 1.282.02).
PI incorporates heterogeneity from two sources of variation: the
within-study random error, and the between-studies variability. It
provides a condence region in which about 95% of times the true

126

A.A. Escobedo et al. / Acta Tropica 153 (2016) 120127

study effect is expected to lie. Its clinical relevance and application

has been recently discussed (Graham and Moran, 2012).
We currently lack, and need, well-designed multicentric G. lamblia trials in children; particularly in industrialized nations where
the prevalence of its infection and associated disease burden is
increasing. The search for new agents to treat G. lamblia infections
is relevant and must continue. Although our results show ABZ efcacy is lower than TNZ in children from developing countries, ABZ
is an option when no other antigiardial drug is available (or locally
approved for the indication), or when patients are intolerant to 5NI. Also, the anti-helmintic effects of ABZ should not be forgotten,
mainly where infections co-occur with Giardia and other sensitive
agents.
Conict of interest
The authors declare that they have no competing interests.
Authors contributions
AAE and JB conceived the study. EGF developed the search algorithms. The four authors collected the data. AAE and JB analysed
and interpreted the data. The four authors wrote the initial draft of
the manuscript, checked for accuracy, commented on the draft and
approved the nal version.
Acknowledgement
JB is supported through a University of the Basque Country
research grant (GIU14/27).
Appendix A. Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.actatropica.2015.
09.023.
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