Antiamoebic drugs for treating amoebic colitis - The Cochrane Library

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analysed the participants as one group (Misra 1974; Tripathi 1986). • ◦ Thirteen trials recruited and analysed participants with symptoms of intestinal amoebiasis or amoebic colitis together, regardless of whether they presented with dysentery or not. Participant age Participant age ranged from seven months to 80 years; see Appendix 7 for details. Adults only (ie those aged more than 15 years) were recruited in 15 trials, while 10 trials recruited only children. Both adults and children were recruited in the remaining 10 trials. Participant age was not stated in two trials (Kapadia 1968; Batra 1972). Methods used to diagnose amoebic colitis Stool microscopy with direct smear was used as the predominant method for determining the presence of E. histolytica cysts or trophozoites in stools (details in Appendix 8): concentration methods for better detection of cysts (16 trials); flotation technique (two trials); and polyvinyl alcohol fixative for the detection of trophozoites (one trial). One trial used stool culture for E. histolytica in addition to stool microscopy to evaluate parasitological response, but it was not used as an inclusion criterion in the trial (Batra 1972). Only one trial used stool antigen-based ELISA test (Rossignol 2007). Concomitant infection with other intestinal parasites Aside from E. histolytica, concomitant infection with other intestinal parasites was identified in 10 trials: giardiasis (Singh 1977; Prasad 1985; Tripathi 1986; Rossignol 2001); intestinal helminth infection (Pudjiadi 1973; Panggabean 1980; Sitepu 1982); and other intestinal protozoa and helminth infection (Pehrson 1983; Salles 1999; Davila 2002). Three trials explicitly stated that stool bacterial culture was done before enrolment and excluded those found to be positive for pathogenic bacteria (Toppare 1994; Karabay 1999; Rossignol 2007). Concomitant infection with other intestinal pathogens or bacteria was not examined or not mentioned in the remaining trials. Since clinical symptoms may not have been exclusively caused by amoebiasis in those with concomitant intestinal parasites and the effect of concomitant infection on eradication of E. histolytica by antiamoebic drugs is not known, data for E. histolytica infection alone were used in assessment of outcomes except in those trials that did not separate the data for those with single and mixed infections. Separate analysis for clinical outcomes for those with E. histolytica alone and those with concomitant infection with Giardia and E. histolytica was carried out in three trials (Prasad 1985; Rossignol 2001; Davila 2002). Drug comparisons The included trials contained a variety of comparisons and involved over 30 individual drugs and combinations. As shown in Appendix 9, we grouped the trials into the following categories (some trials are included in more than one category): • single agent alternative versus metronidazole (17 trials); • any antiamoebic drug versus placebo (four trials); • combination regimen versus monotherapy (seven trials); • single-dose regimens versus longer regimens (five trials); and • other amoebic drug comparisons (nine trials). More than two interventions were compared in six trials. Three trials compared different doses of the same drugs with standard or control groups: three dosages of quinfamide with placebo in Huggins 1982; two treatment durations of tinidazole with metronidazole in Awal 1979; and four dosages of MK-910 in Batra 1972. Ten different treatment groups were compared with placebo in Donckaster 1964, and three drugs used alone or in three different combinations were compared in Pamba 1990. Two brands of tinidazole and two brands of metronidazole were compared in one trial (Chunge 1989). For trials with more than two intervention groups, we combined multiple treatment arms as appropriate in one group and compared them collectively with the standard or control group. This is the recommended approach to avoid a unit of analysis error by not counting the placebo or control participants more than once in the same meta-analysis (Higgins 2008). For the trial comparing two brands of tinidazole and two brands of metronidazole, the two brands of tinidazole were combined as one group and compared with the two brands of metronidazole in the other group. Duration of follow up The follow-up period varied considerably between trials. Seventeen trials were followed up for about one month. Four trials were followed up only until the end of the treatment period (Kapadia 1968; Batra 1972; Pudjiadi 1973; Asrani 1995). Duration of follow up was less than 15 days in 10 trials (Huggins 1982; Sitepu 1982; Prasad 1985; Chunge 1989; Toppare 1994; Mohammed 1998; Padilla 2000; Rossignol 2001; Davila 2002; Rossignol 2007), while the longest period was 12 months (Nnochiri 1967). Outcome measures Antiamoebic drugs for treating amoebic colitis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. The primary outcomes in this review were clinical failure, parasitological failure, and relapse. Thirty-one trials evaluated both clinical and parasitological outcomes, and six trials evaluated parasitological outcomes only (Donckaster 1964; Nnochiri 1967; Pehrson 1983; Pehrson 1984; Padilla 2000; Davila 2002). The definition of clinical and parasitological cure or failure in the trials varied. Nine trials (Misra 1974; Joshi 1975; Mathur 1976; Misra 1977; Singh 1977; Swami 1977; Misra 1978; Awal 1979; Tripathi 1986) used the definitions set by the WHO Expert Committee on Amoebiasis 9
(WHO 1969) where ’cure’ was defined as symptom-free, ulcers healed, stools negative for E. histolytica, ’probable failure’ was defined as persistent symptoms and rectal ulcerations despite disappearance of E. histolytica in stools or ulcer scrapings, and ’failure’ was defined as positive E. histolytica with or without symptoms and rectal ulcers. For this review, ’probable failure’ was interpreted as clinical failure and ’failure’ was interpreted as parasitological failure based on the definitions given. Data for clinical and parasitological outcomes were presented as dichotomous data in most trials. The duration of time from the start of treatment to resolution of diarrhoea and other clinical symptoms was also presented in seven trials (Batra 1972; Naoemar 1973; Pudjiadi 1973; Toppare 1994; Rossignol 2001; Mansour-Ghanaei 2003; Rossignol 2007), and the duration of time from start of treatment to disappearance of E. histolytica in stools in three trials (Naoemar 1973; Pudjiadi 1973; Karabay 1999). Two trials reported on the number of stools passed during treatment (Botero 1977; Tripathi 1986), and also on days seven and 21 after treatment (Botero 1977), while another reported average daily frequency of stools on admission and at the end of days five and 10 of treatment (Asrani 1995). One trial reported on cumulative daily clearance of E. histolytica from stools during treatment and on days 15, 30, and 60 after the start of treatment (Pamba 1990). One trial assessed clinical and parasitological outcomes jointly as ’cure’ (Prasad 1985). Only dichotomous outcomes were included in the analysis because of inconsistent data in trials also reporting continuous data. Relapse or recurrence was reported in two trials (Naoemar 1973; Botero 1974) and described but not reported in another trial (Pamba 1990). Measurements of clinical and parasitological outcomes were made at different time points. Thirteen trials reported outcomes between the end of treatment to 14 days, and 15 trials reported outcomes from 18 to 30 days after the end of treatment. Outcomes were measured repeatedly in nine trials and reported for two time points in six trials (Donckaster 1964; Nnochiri 1967; Naoemar 1973; Joshi 1975; Soedin 1985; Karabay 1999). Three trials reported results at one time point only because of high drop-out rates during the other follow-up periods (Panggabean 1980; Sitepu 1982; Pamba 1990). Adverse events were reported in 33 trials and were not ascertained in the remaining four trials (Sitepu 1982; Chunge 1989; Karabay 1999; Mansour-Ghanaei 2003). Sixteen trials had incomplete data: 10 reported specific adverse events but not the number of participants who developed any adverse event (Nnochiri 1967; Kapadia 1968; Batra 1972; Botero 1974; Prasad 1985; Pamba 1990; Asrani 1995; Davila 2002; Padilla 2000; Rossignol 2007); two reported only the number of participants with adverse events severe enough to cause discontinuation of drug treatment (Pehrson 1983; Pehrson 1984); four did not report the actual number of participants who developed any adverse event (Rubidge 1970; Pudjiadi 1973; Soedin 1985; Toppare 1994); and one reported of adverse events only for the experimental group (Mohammed 1998). Risk of bias in included studies See Appendix 10 for an overview of the methodological quality assessment. Only one trial reported using appropriate procedures to minimize or eliminate bias in allocation concealment, generation of the allocation sequence, blinding (of the care providers, participants, and outcome assessors), and inclusion of all randomized participants ( Rossignol 2007). Generation of allocation sequence Only six trials reported adequate generation of the allocation sequence: four trials used a random-numbers table (Donckaster 1964; Awal 1979; Sitepu 1982; Mohammed 1998); one trial used computer-generated randomization (Rossignol 2007); and one trial used coin toss (Padilla 2000). The other trials did not describe the method used. Allocation concealment Two trials used identical coded drugs prepared independently at a site remote from the study site and had adequate allocation concealment (Pudjiadi 1973; Rossignol 2007). Two trials had inadequate allocation concealment as communicated by the primary author (Pehrson 1983; Pehrson 1984). The remaining 33 trials did not report on this. Blinding Antiamoebic drugs for treating amoebic colitis (Review) Copyright © 2009 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd. Only seven trials reported blinding of the participants, care providers, and outcome assessors (Nnochiri 1967; Naoemar 1973; Pudjiadi 1973; Prasad 1985; Rossignol 2001; Mansour-Ghanaei 2003; Rossignol 2007). One trial reported blinding of the participants and outcome assessors but not the care providers (Padilla 2000), one trial reported blinding only of the participants and microscopists assessing stool specimens (Chunge 1989), one trial reported blinding only of the care providers (Panggabean 1980), and another reported blinding only of the microscopists assessing stool specimens (Pamba 1990). Seven trials were reported to be ’double-blind’ (Donckaster 1964; Botero 1974; Botero 1977; Huggins 1982; Sitepu 1982; Tripathi 1986; Davila 2002), but they did not describe the procedure for blinding, similarity of the appearance of drugs, or use of placebo. Five trials were also unclear regarding blinding (Kapadia 1968; Misra 1974; Misra 1977; Swami 1977; Misra 1978), and the other 14 were open label. 10
Page 1 and 2: Antiamoebic drugs for treating amoe
Page 3 and 4: Analysis 6.4. Comparison 6 Subgroup
Page 5 and 6: Authors’ conclusions Tinidazole i
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Characteristics of studies awaiting
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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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