Antiamoebic drugs for treating amoebic colitis - The Cochrane Library

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We constructed a funnel plot for the one outcome measure with a sufficient number of trials and examined it visually for possible bias or heterogeneity: any antiamoebic drug versus metronidazole and measuring parasitological failure 15 to 60 days after the end of treatment (13 trials, Figure 4). This included nine trials that compared tinidazole with metronidazole. The funnel plot is asymmetrical due to the absence of smaller trials at the base and fewer trials to the right of the overall estimate. Although this may indicate the presence of publication bias, asymmetry in the funnel plot may also indicate inadequate methodological quality of the trials. Heterogeneity in the trials as a result of differences in study population, interventions, outcome measurements, trial design, and quality also have to be considered. Figure 4. Funnel plot. Alternative drug vs metronidazole: parasitological failure 15 to 60 days after end of treatment. D I S C U S S I O N Effectiveness of antiamoebic drugs This systematic review examined the effectiveness of various antiamoebic drugs for treating amebic colitis by measuring improvements in both clinical and parasitological outcomes. The rapid relief of diarrhoea and other gastrointestinal symptoms associated Antiamoebic drugs for treating amoebic colitis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. with intestinal amoebiasis is an important concern of the individual with disease, while eradication of the parasite is important to prevent further invasion with damage to the intestinal mucosa and possible extraintestinal spread. The purpose of the review was to determine the best drug and treatment regimen required for effective treatment of amoebic colitis. Tinidazole versus metronidazole Metronidazole, the current recommended first-line drug for treating amoebic colitis, is a tissue amoebicide predominantly but 17
with some activity against cysts in the bowel lumen. Among the other nitroimidazole drugs, only tinidazole had a sufficient number of trials to be able to draw any meaningful conclusions in the pooled results. The pooled results show that tinidazole demonstrated greater resolution of clinical symptoms, but there was inconclusive evidence of its advantage over metronidazole in eradication of E. histolytica in the stools. The comparable parasitological response could be attributed to similar activities of drugs belonging to the nitroimidazole drug class. In one trial, the poor eradication of parasites with tinidazole was attributed to its greater absorption and higher blood and tissue concentrations, possibly resulting in inadequate levels in the bowel lumen (Pehrson 1984). Lower concentrations of tinidazole could also be explained by the suboptimal dosing interval used in some trials (Misra 1974; Joshi 1975; Mathur 1976; Pehrson 1984). Tinidazole is better given as a single dose than divided doses because of its longer half life of approximately 12 to 14 hours resulting in longer concentrations in the body (Monro 1974; Looke 1987). In contrast, metronidazole has a shorter half life of about six to eight hours and is better if given in divided doses. Also, longer courses may lead to its re-excretion through the bile resulting in higher concentrations within the bowel lumen (Knight 1980; Tracy 2001). This is supported by the summary report of nine trials conducted in India where tinidazole given once daily was more effective compared with divided doses, and was also more effective than metronidazole given once daily (Bakshi 1978). The incidence of mild to moderate gastrointestinal complaints was noted to be greater in those given metronidazole compared with tinidazole, particularly when it was given as a single dose. Again, this is similar to the summary report of Bakshi 1978, where the number of gastrointestinal adverse effects were greater in those given single-dose metronidazole compared with divided doses and compared with single daily administration of tinidazole. In both groups, the most frequently reported adverse effects were mild gastrointestinal side effects such as nausea, decreased appetite, vomiting, and metallic or bitter taste. The calculation of the risk difference for clinical failure in those given tinidazole and those given metronidazole would give an absolute change in risk of 0.16 that is attributable to tinidazole. The inverse of the risk difference for clinical failure gave a number needed to treat to benefit (NNTB) of 6.25. Thus, we will need to treat seven people with tinidazole to reduce clinical failure in one more individual. However, this could not be applied to the parasitological failure because there appears to be no significant difference in eradication of E. histolytica in those given tinidazole compared with metronidazole. Relapse can only be evaluated if stools are examined several times after the end of treatment. Data for relapse were only reported in two trials comparing ornidazole with metronidazole, with an increased risk in the ornidazole group compared with metronidazole; however, the available data were too few to draw any conclusions regarding the result. Antiamoebic drugs for treating amoebic colitis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The funnel plot constructed from the trials comparing any antiamoebic drug versus metronidazole and measuring parasitological failure demonstrated asymmetry. Selection bias may arise when small studies reporting greater treatment benefit for the experimental drugs are more likely to be published (publication bias) and found (language and citation). Asymmetry could also result from poor methodological quality of the trials since greater treatment effect of the experimental drugs was seen in the smaller studies. Heterogeneity in treatment regimens used could also explain the asymmetry in the funnel plot. There was a trend favouring the experimental drugs in three trials (Singh 1977; Swami 1977; Awal 1979) where metronidazole was given at a dose of 2 g once daily for two or three days; a much lower dose compared to the recommended dose of 500 to 750 mg thrice daily in adults or 30 to 50 mg/kg/day in children for at least five days. This could account for the higher parasitological failure in those on metronidazole. When metronidazole was given at a dose of 2.4 g for five days, it was significantly more effective compared to tinidazole (Pehrson 1984). The presence of asymmetry in the funnel plot could lessen confidence in the results. Antiamoebic drugs versus placebo Antiamoebic drugs were shown to be more effective in reducing clinical symptoms of amoebic colitis and in eradicating E. histolytica in the stools compared with placebo. The significant heterogeneity in the pooled results could be attributed to factors such as differences in participant characteristics or the varied antiamoebic drugs used. Twelve different antiamoebic drugs were used and all, except for dehydroemetine, are more active for parasites found in the bowel lumen with no activity against invasive tissue forms. Since none of the participants were diagnosed as having amoebic dysentery, the significant response in those given these luminal drugs may result from the activity of these drugs against cysts in those with nondysenteric amoebic colitis or unspecified intestinal amoebiasis. The disappearance of parasites in 50 out of 133 (38%) individuals while on placebo may result from spontaneous eradication of E. histolytica or infection with nonpathogenic amoeba. Several studies have shown that up to 90% of individuals with untreated E. histolytica infection spontaneously clear their infection within one year (Gathiram 1985; Haque 2001; Blessman 2003b; Haque 2002). It may have been possible that E. histolytica was misidentified in the trials utilizing stool microscopy as the only means for diagnosis. Use of placebo as a comparison drug for individuals with symptomatic amoebic colitis may draw objections. Even in those with asymptomatic infection, approximately 3% to 10% of untreated individuals may still develop symptoms of invasive amoebiasis ( Gathiram 1985; Haque 2001; Blessman 2003b; Haque 2002). For this reason, it is generally recommended that antiamoebic treatment be given to all individuals with definite E. histolytica, even 18
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Page 3 and 4: Analysis 6.4. Comparison 6 Subgroup
Page 5 and 6: Authors’ conclusions Tinidazole i
Page 7 and 8: parasite RNA and DNA (Haque 1995; H
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Page 33 and 34: Dans 2006 Dans L, Martinez E. Amoeb
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Page 37 and 38: Awal 1979 (Continued) Participants
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2 Parasitological failure: 1 to 14
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2.3 Chlorhydroxyquinoline vs diiodo
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Comparison 9. Subgroup analyses: an
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(... Continued) Study or subgroup A
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Analysis 1.4. Comparison 1 Alternat
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Analysis 1.6. Comparison 1 Alternat
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Analysis 2.2. Comparison 2 Any anti
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Analysis 3.2. Comparison 3 Combinat
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Analysis 5.1. Comparison 5 Other an
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Analysis 6.1. Comparison 6 Subgroup
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(... Continued) Study or subgroup A
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(Continued) 24 - - chloroquine oxyt
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(Continued) Department of Medicine,
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(Continued) Africa Egypt Rossignol
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(Continued) Stool microscopy plus s
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(Continued) 6. Not used, but mentio
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(Continued) Padilla 2000 Adequate U
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(Continued) Misra 1974 Malaise: tin
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(Continued) Pehrson 1984 ticipants)
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(Continued) ; metronidazole (4 part
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(Continued) Panidazole Botero 1977
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(Continued) Appendix 12. Adverse ev
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(Continued) Rossignol 2001 Rossigno
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(Continued) Secnidazole vs quinfami
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(Continued) idazole was encountered
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(Continued) Combinationtinidazole a
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(Continued) H I S T O R Y Protocol
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Sensitivity analyses We intended to
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