Antibiotic therapy for Shigella dysentery

Prince RH Christopher; Kirubah V David; Sushil M John; Venkatesan Sankarapandian

doi:10.1002/14651858.CD006784.pub4

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Figure 1

Methodological quality summary: review authors' judgments about each methodological quality item for each included study.

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Figure 2

Methodological quality graph: review authors' judgments about each methodological quality item presented as percentages across all included studies.

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Analysis 1.1

Comparison 1 Antibiotic versus no drug or placebo, Outcome 1 Diarrhoea on follow up.

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Analysis 1.2

Comparison 1 Antibiotic versus no drug or placebo, Outcome 2 Time to cessation of fever (in days).

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Analysis 1.3

Comparison 1 Antibiotic versus no drug or placebo, Outcome 3 Time to cessation of diarrhoea (in days).

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Analysis 1.4

Comparison 1 Antibiotic versus no drug or placebo, Outcome 4 Time to cessation of blood in stools (in days).

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Analysis 1.5

Comparison 1 Antibiotic versus no drug or placebo, Outcome 5 Other adverse events.

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Analysis 2.1

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 1 Diarrhoea on follow up.

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Analysis 2.2

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 2 Fever at follow up.

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Analysis 2.3

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 3 Relapse.

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Analysis 2.4

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 4 Bacteriological failure.

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Analysis 2.5

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 5 Development of severe complications.

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Analysis 2.6

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 6 Serious adverse events.

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Analysis 2.7

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 7 Adverse events leading to discontinuation of treatment.

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Analysis 2.8

Comparison 2 Fluoroquinolones versus beta‐lactams, Outcome 8 Other adverse events.

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Analysis 3.1

Comparison 3 Fluoroquinolones versus macrolides, Outcome 1 Diarrhoea on follow up.

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Analysis 3.2

Comparison 3 Fluoroquinolones versus macrolides, Outcome 2 Fever at follow up.

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Analysis 3.3

Comparison 3 Fluoroquinolones versus macrolides, Outcome 3 Time to cessation of blood in stools.

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Analysis 3.4

Comparison 3 Fluoroquinolones versus macrolides, Outcome 4 Bacteriological failure.

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Analysis 3.5

Comparison 3 Fluoroquinolones versus macrolides, Outcome 5 Other adverse events.

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Analysis 4.1

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 1 Diarrhoea on follow up.

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Analysis 4.2

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 2 Bacteriological failure.

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Analysis 4.3

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 3 Time to cessation of diarrhoea (hours).

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Analysis 4.4

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 4 Time to cessation of fever (hours).

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Analysis 4.5

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 5 Time to cessation of visible blood in stools.

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Analysis 4.6

Comparison 4 Cotrimoxazole versus beta‐lactams, Outcome 6 Other adverse events.

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Analysis 5.1

Comparison 5 Cotrimoxazole versus fluoroquinolones (norfloxacin), Outcome 1 Bacteriological failure.

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Analysis 5.2

Comparison 5 Cotrimoxazole versus fluoroquinolones (norfloxacin), Outcome 2 Other adverse events.

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Analysis 6.1

Comparison 6 Cotrimoxazole versus furazolidone, Outcome 1 Diarrhoea on follow up.

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Analysis 7.1

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 1 Diarrhoea at follow up.

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Analysis 7.2

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 2 Fever at follow up.

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Analysis 7.3

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 3 Bacteriological relapse.

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Analysis 7.4

Comparison 7 Oral gentamicin versus nalidixic acid, Outcome 4 Bacteriological failure.

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Analysis 8.1

Comparison 8 Sulphonamides versus tetracycline, Outcome 1 Diarrhoea at follow up.

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Analysis 8.2

Comparison 8 Sulphonamides versus tetracycline, Outcome 2 Bacteriological failure.

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Table 5. Suggestions for a trial of antibiotic for Shigella dysentery

Methods

Participants

Interventions

Outcomes

Notes

Allocation:
Centralized sequence generation with table of random numbers or computer generated lists

Stratified by severity of illness

Sequence concealed until interventions are assigned

Blinding:
Those recruiting and assigning participants, those administering the intervention, and those assessing the outcomes, must all be blind to the allocated group; the administered drugs have to be identical or a double dummy technique has to be used. Liquid medications have to be in similar looking bottles, identical in shape and weight; the medications must themselves be similar in colour and flavour.

Duration:
Minimum of 4 weeks after completion of therapy to assess relapse

Entry criteria can be clinical dysentery, i.e. acute onset frequent loose stools with blood or mucus or both lasting for less than 72 hours and at least 3 stools per day. Other features, such as fever and tenesmus at presentation, have to be recorded but need not be necessary for inclusion into study.

If it is possible to presumptively or decisively detect Shigella in stool before inclusion into study, it should be done. Real‐time PCR is a rapid but expensive method to diagnose Shigella early (Legros 2004).

Sample size:
(See Table 6). Age group: trials should be separately done for adults and children (less than 15 years of age) or at least presented separately if they are in the same trial. In children, infants must be a separate group.

Setting: in‐ or out‐patients. The number of participants, if hospitalized for standardization of administration of the interventions, have to be reported separately from those hospitalized due to complications.

Sex: men and women.

Special groups (those who have higher risk of complications:

Malnourished children
HIV positive individuals
Adults more than 50 years of age
Infants

Exclusion criteria:
Allergy to the drug studied; history of antibiotic use for this episode of illness in the previous 48 hours; pregnant and lactating women; clinical presence of another infection needing antimicrobials

Any antibiotic studied for efficacy and safety
Any other antibiotic that is the standard for the treatment of Shigella dysentery at that period of time in that country

Others: placebos or probiotics to be studied only on those with no risk of complications and those who have mild illness

Primary outcomes:

Number of patients with diarrhoea on follow up.
Clinical relapse
Adverse effects of antibiotics
1. Life threatening adverse effects of the drug
2. Those that require discontinuation of the drug
3. MIld adverse events that need extra therapy but not discontinuation of the drug
Duration of fever
Duration of blood in stools

Secondary outcomes:

Removed from study due to clinical worsening
Fever on follow up
Abdominal pain on follow up
Bacteriological cure
Bacteriological relapse
Duration of diarrhoea
Duration of abdominal pain
Number of days of hospitalisation

Once patients are randomized into the treatment groups, they should not be removed until final analysis. The trial author(s) must publish the outcome findings of the whole group first and then present data for those positive for Shigella by stool or rectal swab culture or PCR and those negative for Shigella. The data have to be presented according to the severity of illness the patients presented with.

Antibiotic sensitivity patterns have to be reported for all antibiotics studied and in all groups

Response to treatment stratified by in vitro antibiotic sensitivity also needs to be reported

Drop‐outs:
The patients who drop out after randomization due to loss of follow up, withdrawal from protocol or consent withdrawal etc have to be reported and accounted in the final analysis (intention‐to‐treat analysis).

Table 5. Suggestions for a trial of antibiotic for Shigella dysentery

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Table 6. Sample size suggestions for trial of antibiotics in Shigella dysentery

SAMPLE SIZES	Antibiotic versus no drug or placebo (placebo response at 45%) or Antibiotic versus another antibiotic
1 sided α	10% difference: 310 20% difference: 75 25% difference: 50 30% difference: 30 40% difference: 15
2 sided α	10% difference: 390 20% difference: 95 25% difference: 60 30% difference: 40 40% difference: 20
1. The sample size required to detect the assumed difference in improvement or worsening with 80% power and 5% significance level using the outcome of 'diarrhoea at follow up' from this review using StatCalc 2006. 2. The sample size mentioned is for each arm of the study.

Table 6. Sample size suggestions for trial of antibiotics in Shigella dysentery

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Summary of findings for the main comparison. Antibiotic versus no drug or placebo for Shigella dysentery

Antibiotic versus no drug or placebo for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Mexico and Bangladesh Intervention: Antibiotic versus no drug or placebo
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Antibiotic versus no drug or placebo
Diarrhoea on follow up ‐ Furazolidone versus no drug clinical criteria Follow‐up: 6 days	58 per 100	12 per 100 (5 to 28)	RR 0.21 (0.09 to 0.48)	73 (1 study)	⊕⊝⊝⊝ very low^1,2,3	Antibiotic sensitivity of Shigella isolates not reported; Trial done in 1989
Diarrhoea on follow up ‐ Cotrimoxazole versus no drug clinical criteria Follow‐up: 6 days	58 per 100	17 per 100 (9 to 34)	RR 0.3 (0.15 to 0.59)	76 (1 study)	⊕⊝⊝⊝ very low^1,2,4	Same trial as above; had three arms
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	The two trials for this comparison were too short in follow up duration (6‐7 days) to estimate relapses and none were reported.
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	None of the two trials for this comparison reported serious adverse events
Other adverse events clinical criteria Follow‐up: 7 days	0 per 100	0 per 100 (0 to 0)	RR 1.43 (0.06 to 34.13)	94 (1 study)	⊕⊝⊝⊝ very low^5,6,7	Data from a three armed trial; only one non‐serious adverse event in the antibiotic arms and none in placebo arm
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Very serious limitations: The method of randomization was not described and there were baseline imbalances in duration of diarrhoea. Allocation concealment and blinding were not reported and this increases the risk of bias in the detection and reporting of some adverse events, though not for other primary outcomes that were objectively ascertained. ² Serious indirectness: The single trial included only children and hence the evidence for effectiveness of antibiotics over no antibiotics in adults is uncertain. Though the trial did not exclude participants who were malnourished, it is unclear if any participant was malnourished. ³ No imprecision: Both limits of the point estimate of the trial indicated benefit with furazolidine over not receiving an antibiotic ⁴ No imprecision: Both limits of the point estimate showed appreciable benefit with cotrimoxazole over not receiving an antibiotic ⁵ Very serious limitations: Allocation was not concealed and there were baseline imbalances in antibiotic sensitivity to those allocated to ceftriaxone (100%) and ampicillin (80%) ⁶ Serious indirectness: The trial randomized only adults. The antibiotics assessed were ceftriaxone and ampicillin. ⁷ Very serious imprecision: The 95% CI of the point estimate of the trial includes appreciable risk of adverse events for antibiotics over placebo with no significant differences between interventions.

Summary of findings for the main comparison. Antibiotic versus no drug or placebo for Shigella dysentery

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Summary of findings 2. Fluoroquinolones versus beta‐lactams for Shigella dysentery

Fluoroquinolones versus beta‐lactams for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Bangladesh (4 trials), Israel (1 trial), USA (1 trial) Intervention: Fluoroquinolones versus beta‐lactams
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Fluoroquinolones versus beta‐lactams
Diarrhoea on follow up ‐ All trials clinical criteria Follow‐up: 5 to 180 days	251 per 1000	259 per 1000 (113 to 595)	RR 1.03 (0.45 to 2.37)	686 (6 studies)	⊕⊝⊝⊝ very low^1,2,3,4	One trial from 1973; four trials in the 1990s; only one trial after 2000. The fluoroquinolones evaluated were nalidixic acid, and ciprofloxacin and the beta‐lactams evaluated were ampicillin, (intra‐muscular) ceftriaxone and pivmecillinam.
Relapse ‐ All trials clinical criteria Follow‐up: 5 to 180 days	70 per 1000	64 per 1000 (8 to 529)	RR 0.91 (0.11 to 7.55)	357 (3 studies)	⊕⊝⊝⊝ very low^5,6,7,8	One trial from 1973, one from 1990 and one from 2000. Only two reported relapse.
Serious adverse events clinical criteria Follow‐up: 16 to 21 days	0 per 100	0 per 100 (0 to 0)	RR 10.9 (0.61 to 194.82)	221 (1 study)	⊕⊝⊝⊝ very low^9,10,11	Only seen in 4.5% of those allocated to fluoroquinolones and not in those given beta‐lactams
Adverse events leading to discontinuation of treatment	62 per 1000	64 per 1000 (17 to 245)	RR 1.02 (0.27 to 3.89)	127 (1 study)	⊕⊝⊝⊝ very low^12,13,14
Other adverse events clinical criteria Follow‐up: 5 to 180 days	177 per 1000	182 per 1000 (136 to 246)	RR 1.03 (0.77 to 1.39)	570 (4 studies)	⊕⊝⊝⊝ very low^15,16,17,18
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ No serious limitations: Four of the six trials in this comparison had limitations in reporting outcomes for some participants but a sensitivity analysis did not appreciably alter the results ² Serious inconsistency: I squared for the pooled data from six trials was 83% but could be partially explained by subgroup analyses of adults and children and by culture‐confirmed versus unconfirmed diagnosis of Shigella dysentery and resultant sensitivity patterns. The one trial in adults showed that a fluoroquinolone (ciprofloxacin) was superior (no imprecision) to a beta‐lactam (ampicillin) when sensitivity of the Shigella isolates was 100% for the former and 43% for the latter . Homogenous data (I squared 0%) from two trials in children showed that beta‐lactams (ampicillin and intra‐muscular ceftriaxone) were superior to fluoroquinolones (nalidixic acid and ciprofloxacin) when >90% of participants had culture‐confirmed Shigella dysentery with 100% sensitivity to the antibiotic used (no imprecision). ³ No serious indirectness: The six trials included children and adults and only two excluded severely malnourished children. The fluoroquinolones used included nalidixic acid and ciprofloxacin and the macrolides used included ampicillin, ceftriaxone and pivmecillinam. ⁴ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with both interventions. ⁵ No serious limitations: One of the three trials for this comparison had limitations in reporting the method of randomization and allocation concealment but exclusion of this trial in sensitivity analysis did not alter results. ⁶ Serious inconsistency: The I squared for the pooled data was 63% and could not explained by subgroup analyses. ⁷ Serious indirectness: The trials that reported this outcome only included children; hence the effects of antibiotics in preventing relapses in adults is unclear. ⁸ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with both interventions ⁹ No serious limitations: There were imbalances in those excluded from analysis in the single trial but randomization, allocation concealment and blinding were free of the risk of bias and follow up included 91% of participants ¹⁰ Serious indirectness: The trial included only infants and children and the applicability of the results for this outcome in adults is uncertain. ¹¹ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ceftriaxone and ciprofloxacin. ¹² Serious limitations: This outcome was reported only for 75% of randomized participants with culture‐confirmed Shigella dysentery. ¹³ Serious indirectness: The trial that reported this outcome included only adults ¹⁴ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ampicillin and ciprofloxacin in this single trial. ¹⁵ Serious limitations: Three of the four trials that reported this outcome reported on less than 85% of those randomised. ¹⁶ No inconsistency: I squared was 0% ¹⁷ No serious indirectness: The four trials included adults and children and two did not specifically exclude malnourished children. ¹⁸ Very serious imprecision: The 95% CI of the pooled estimate indicated appreciable harm and non‐appreciable benefit with beta‐lactams (ampicillin, ceftriaxone and pivmecillinam) over fluoroquinolones (ciprofloxacin and nalidixic acid)

Summary of findings 2. Fluoroquinolones versus beta‐lactams for Shigella dysentery

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Summary of findings 3. Fluoroquinolones versus macrolides for Shigella dysentery

Fluoroquinolones versus macrolides for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Bangladesh and Kenya Intervention: Fluoroquinolones versus macrolides
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Fluoroquinolones versus macrolides
Diarrhoea on follow up clinical criteria Follow‐up: 6 to 10 days	105 per 1000	63 per 1000 (25 to 156)	RR 0.6 (0.24 to 1.49)	189 (2 studies)	⊕⊝⊝⊝ very low^1,2,3,4	One trial reported that none of the participants had diarrhoea on day 10 and in the other 16/76 had diarrhoea on the sixth day
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Duration of follow up in both trials were too short (6 to 10 days) to assess relapse and none were reported.
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	None of the two trials reported that any participant developed serious adverse events
Other adverse events clinical criteria Follow‐up: 6 days	Study population		RR 1.33 (0.32 to 5.56)	76 (1 study)	⊕⊝⊝⊝ very low^5,6,7
	79 per 1000	105 per 1000 (25 to 439)
	Medium risk population
	79 per 1000	105 per 1000 (25 to 439)
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Serious limitations: One of the two included trials had limitations in allocation concealment and both reported outcomes for less than 90% of those randomized (82% and 87%) ² No serious inconsistency: One of the trials had no participants with this outcome and hence risk ratios were estimated for only one trial. ³ Serious indirectness: Both trials randomized only adults. Effects of fluoroquinolones over macrolides in children, especially those who are malnourished are unclear. Antibiotics used were azithromycin and ciprofloxacin in both trials. ⁴ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ciprofloxacin and azithromycin. ⁵ Very serious limitation: The trial reported this outcome only for 82% of randomized participants. ⁶ Serious indirectness: The trial included only adults. The antibiotics studied were ciprofloxacin and azithromycin. ⁷ Very serious imprecision:The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with ciprofloxacin and azithromycin.

Summary of findings 3. Fluoroquinolones versus macrolides for Shigella dysentery

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Summary of findings 4. Cotrimoxazole versus beta‐lactams for Shigella dysentery

Cotrimoxazole versus beta‐lactams for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Guatemala and USA Intervention: Cotrimoxazole versus beta‐lactams
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Cotrimoxazole versus beta‐lactams
Diarrhoea on follow up clinical criteria Follow‐up: 11 to 21 days	227 per 1000	134 per 1000 (52 to 338)	RR 0.59 (0.23 to 1.49)	89 (2 studies)	⊕⊝⊝⊝ very low^1,2,3,4	One trial was reported in 1976 and the other in 1993. The antibiotics compared with cotrimoxazole were ampicillin and pivmecillinam respectively.
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	The two trials followed participants for 11 to 21 days but did not report any relapses in this time.
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No serious adverse events leading to death or hospitalization were reported in either trial.
Other adverse events clinical criteria Follow‐up: 11 to 21 days	136 per 1000	110 per 1000 (37 to 333)	RR 0.81 (0.27 to 2.45)	89 (2 studies)	⊕⊝⊝⊝ very low^1,2,3,5
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Serious limitations: Inadequate allocation concealment in one trial and inadequate outcome data reporting (for 39% of randomized participants whose cultures were negative for Shigella) in the other ² No inconsistency: I squared was 0% and the direction of effect favoured cotrimoxazole in both trials. ³ Serious indirectness: Both trials included only infants and children. The antibiotics compared were cotrimoxazole versus ampicillin and pivmecillinam. ⁴ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole and ampicillin and pivmecillinam. ⁵ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with beta‐lactams and cotrimoxazole.

Summary of findings 4. Cotrimoxazole versus beta‐lactams for Shigella dysentery

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Summary of findings 5. Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery

Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Peru Intervention: Cotrimoxazole versus fluoroquinolones (norfloxacin)
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Cotrimoxazole versus fluoroquinolones (norfloxacin)
Diarrhoea on follow up ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Outcome assessed as number of days to last unformed stool. Data not available for proportions with diarrhoea on follow up.
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	The trial followed up participants for 14 days. Relapses were not reported in this time.
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No participant is reported to have developed serious adverse events leading to death or hospitalisation.
Other adverse events clinical criteria Follow‐up: 2 weeks	0 per 1000	0 per 1000 (0 to 0)	RR 2.82 (0.12 to 66.62)	62 (1 study)	⊕⊝⊝⊝ very low^1,2,3
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Very serious limitations: Inadequate allocation concealment and blinding and very inadequate outcome data reporting (for only 32% of 174 randomized). Baseline imbalance in antibiotic sensitivity (100% sensitivity in norfloxacin arm and 84% in the cotrimoxazole arm). ² Serious indirectness: The trial included only adults. ³ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole and norfloxacin.

Summary of findings 5. Cotrimoxazole versus fluoroquinolones (norfloxacin) for Shigella dysentery

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Summary of findings 6. Cotrimoxazole versus furazolidone for Shigella dysentery

Cotrimoxazole versus furazolidone for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Mexico Intervention: Cotrimoxazole versus furazolidone
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Cotrimoxazole versus furazolidone
Diarrhoea on follow up clinical criteria Follow‐up: 6 days	173 per 1000	123 per 1000 (47 to 318)	RR 0.71 (0.27 to 1.84)	101 (1 study)	⊕⊝⊝⊝ very low^1,2,3	Trial reported in 1989; antimicrobial sensitivity to Shigella isolates not reported
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Follow up duration too short (6 days) in the sole trial for this comparison
Serious adverse events	Medium risk population		RR 0 (0 to 0)	0 (0)	See comment	No participant is reported to have developed serious adverse events leading to death or hospitalization.

Other adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No adverse effects reported; unclear if formally evaluated
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Very serious limitations: Risk of bias likely due to inadequate allocation concealment and blinding. Baseline imbalances in participant characteristics (significantly fewer days of diarrhoea in those allocated to furazolidone‐ P =0.02). ² Serious indirectness: The single trial included only infants and children. ³ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with cotrimoxazole over furazolidone.

Summary of findings 6. Cotrimoxazole versus furazolidone for Shigella dysentery

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Summary of findings 7. Oral gentamicin versus nalidixic acid for Shigella dysentery

Oral gentamicin versus nalidixic acid for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Bangladesh Intervention: Oral gentamicin versus nalidixic acid
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Oral gentamicin versus nalidixic acid
Diarrhoea at follow up clinical criteria Follow‐up: 5 days	308 per 1000	527 per 1000 (302 to 915)	RR 1.71 (0.98 to 2.97)	79 (1 study)	⊕⊝⊝⊝ very low^1,2,3	Data from a single trial reported in 1994. Antimicrobial sensitivity for Shigella isolates was 100% in those allocated to oral gentamicin and 70% to those allocated to nalidixic acid.
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Follow up duration too short (5 days) to assess.
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No participant is reported to have developed serious adverse events
Other adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No adverse effects reported; unclear if systematically assessed.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Very serious limitations: Though randomization, allocation and blinding were adequate, data were reported only for 87% randomized and there were baseline imbalances in antibiotic sensitivity (100% sensitive in gentamicin arm and 70% in nalidixic acid arm). ² Serious indirectness: The trial randomized only infants and children and specifically excluded those severely malnourished. ³ Serious imprecision: The 95% CI for the point estimate from the trial includes appreciable and non‐appreciable benefit for nalidixic acid over oral gentamicin.

Summary of findings 7. Oral gentamicin versus nalidixic acid for Shigella dysentery

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Summary of findings 8. Sulphonamides versus tetracycline for Shigella dysentery

Sulphonamides versus tetracycline for Shigella dysentery
Patient or population: patients with Shigella dysentery Settings: Sri Lanka Intervention: Sulphonamides versus tetracycline
Outcomes	*Illustrative comparative risks (95% CI)**		Relative effect (95% CI)	No of Participants (studies)	Quality of the evidence (GRADE)	Comments
	Assumed risk	Corresponding risk
	Control	Sulphonamides versus tetracycline
Diarrhoea at follow up clinical criteria Follow‐up: 8 days	0 per 1000	0 per 1000 (0 to 0)	RR 7.68 (0.46 to 128.12)	60 (1 study)	⊕⊝⊝⊝ very low^1,2,3	Trial reported in 1961. Antimicrobial sensitivity not reported
Relapse ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Duration of follow up too short (8 days) to assess relapse
Serious adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	No participant is reported to have developed serious adverse events.
Other adverse events ‐ not reported	See comment	See comment	Not estimable	‐	See comment	Not reported or pre‐stated as an outcome; unclear if assessed.
The basis for the assumed risk* (e.g. the median control group risk across studies) is provided in footnotes. The corresponding risk (and its 95% confidence interval) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). CI: Confidence interval; RR: Risk ratio;
GRADE Working Group grades of evidence High quality: Further research is very unlikely to change our confidence in the estimate of effect. Moderate quality: Further research is likely to have an important impact on our confidence in the estimate of effect and may change the estimate. Low quality: Further research is very likely to have an important impact on our confidence in the estimate of effect and is likely to change the estimate. Very low quality: We are very uncertain about the estimate.
¹ Very serious limitations: Risk of bias likely due to inadequate allocation concealment and blinding and unclear reporting of numbers randomized and numbers analysed. ² Unclear indirectness: Unclear from report if trial included adults and children; malnourished participants were not specifically excluded. ³ Very serious imprecision: The 95% CI of the pooled estimate includes appreciable benefit and appreciable harm with tetracycline and sulphonamides.

Summary of findings 8. Sulphonamides versus tetracycline for Shigella dysentery

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Table 1. Known adverse effects of antibiotics used to treat Shigella dysentery^

Antibiotic	Life threatening	Discontinuation^^	Other
Tetracycline	Anaphylaxis	Oesophageal irritation, antibiotic‐associated colitis, headache and visual disturbances	In children under 12 years of age causes dental hypoplasia and staining, benign intracranial hypertension
Chloramphenicol	Blood disorders, peripheral and optic neuritis, erythema multiforme	Dyspepsia	—
Ampicillin	Hypersensitivity reactions	Diarrhoea	—
Co‐trimoxazole or trimethoprim ‐ sulphamethoxazole	Stevens‐Johnson syndrome	Diarrhoea, rash	—
Fluoroquinolones	Hypersensitivity	Dyspepsia, headache, hypotension	Pruritis, tachycardia
Norfloxacin	—	Dyspepsia, headache, hypotension	Euphoria, tinnitus, polyneuropathy
Ciprofloxacin	—	Dyspepsia, headache, hypotension	Hot flushes, sweating, tenosynovitis
Ofloxacin	—	Dyspepsia, headache, hypotension	Anxiety, unsteady gait
Azithromycin	Hypersensitivity	Dyspepsia, flatulence, headache	—
Ceftriaxone	Hypersensitivity reactions	Diarrhoea, headache, abdominal discomfort	—
Nalidixic acid	—	Same as in fluoroquinolones	Toxic psychosis, increased intracranial tension, cranial nerve palsy
Rifaximin	Allergic reactions	Allergic reactions	—
Cefixime	Hypersensitivity reactions	Flatulence, headache, abdominal pain, defecation urgency, nausea, constipation, pyrexia, vomiting	—
Pivmecillinam	—	Same as ampicillin, dyspepsia	—
^Source: BNF 2007. ^^Can result in discontinuation of treatment.

Table 1. Known adverse effects of antibiotics used to treat Shigella dysentery^

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Table 2. Detailed search strategies

Search set	CIDG SR^	CENTRAL	MEDLINE^^	EMBASE^^	LILACS^^
1	Shigell*	Shigell*	Shigell*	Shigell$	Shigell*
2	Dysentery	DYSENTERY, BACILLARY	DYSENTERY, BACILLARY	SHIGELLOSIS	Dysentery
3	1 or 2	1 or 2	1 or 2	DYSENTERY	1 or 2
4	antibiotic*	ANTI‐BACTERIAL AGENTS/THERAPEUTIC USE	ANTI‐BACTERIAL AGENTS/THERAPEUTIC USE	1 or 2 or 3	antibiotic*
5	tetracycline*	ANTI‐INFECTIVE AGENTS/THERAPEUTIC USE	ANTI‐INFECTIVE AGENTS/THERAPEUTIC USE	tetracycline$	tetracycline*
6	chloramphenicol	antibiotic*	antibiotic*	chloramphenicol	chloramphenicol
7	ampicillin*	tetracycline*	tetracycline*	ampicillin	ampicillin
8	co‐trimoxazole	chloramphenicol	chloramphenicol	co‐trimoxazole	co‐trimoxazole
9	fluoroquinolone*	ampicillin	ampicillin	fluoroquinolone$	fluoroquinolone*
10	quinolone*	co‐trimoxazole	co‐trimoxazole	quinolone$	quinolone*
11	norfloxacin	fluoroquinolone*	fluoroquinolone*	norfloxacin	norfloxacin
12	ciprofloxacin	quinolone*	quinolone*	ciprofloxacin	ciprofloxacin
13	ofloxacin	norfloxacin	norfloxacin	ofloxacin	ofloxacin
14	azithromycin	ciprofloxacin	ciprofloxacin	azithromycin	azithromycin
15	ceftriaxone	ofloxacin	ofloxacin	ceftriaxone	ceftriaxone
16	nalidixic acid	azithromycin	azithromycin	nalidixic acid	nalidixic acid
17	pivmecillinam	ceftriaxone	ceftriaxone	rifaximin	rifaximin
18	4‐17/or	nalidixic acid	nalidixic acid	cefixime	cefixime
19	3 and 18	rifaximin	rifaximin	trimethoprim‐sulfamethoxazole	trimethoprim‐sulfamethoxazole
20	—	cefixime	cefixime	antibiotic$	pivmecillinam
21	—	trimethoprim‐sulfamethoxazole	trimethoprim‐sulfamethoxazole	pivmecillinam	4‐20/or
22	—	pivmecillinam	pivmecillinam	5‐21/or	3 and 21
23	—	4‐22/or	4‐22/or	Limit 22 to human	—
24	—	3 and 23	3 and 23	—	—
25	—	—	Limit 24 to human	—	—
^Cochrane Infectious Diseases Group Specialized Register. ^^Search terms used in combination with the search strategy for retrieving trials developed by The Cochrane Collaboration (Higgins 2006); upper case: MeSH or EMTREE heading; lower case: free text term.

Table 2. Detailed search strategies

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Table 3. Search strategy: proceedings, organizations, and pharmaceutical companies

Type	Detail
Conference proceeding	‐ Commonwealth Congress on Diarrhoea and Malnutrition: 8th, Dhaka, Bangladesh, 6 to 8 February 2006 (searched on 12 April 2007) ‐ Asian Conference on Diarrhoeal Diseases and Nutrition: 10th, Dhaka, Bangladesh, 7 to 9 December 2003 (searched on 13 April 2007) ‐ Annual Scientific Conference: 10th Dhaka, Bangladesh, 11 to 13 June 2002 (searched on 13 April 2007) ‐ Annual Meeting of Infectious Disease Society of America: 44th, Toronto, Ontario, Canada, 12 to 15 October 2006; 43rd, San Francisco, California, 6 to 9 October 2005; 42nd, Boston, Massachusetts, USA, 30 September to 3 October 2004 (searched on 18 March 2008) ‐ Interscience Conference on Antimicrobial Agents and Chemotherapy: 46th, San Francisco, California, 27 to 30 September 2006; 45th, Washington DC, USA, 16 to 19 December 2005; 44th, Washington DC, USA, 30 October to 2 November, 2004 (searched on 18 March 2008) ‐ European Congress of Clinical Microbiology and Infectious Diseases: 16th, Nice, France, 1 to 4 April 2006; 15th, 2 to 5 April 2005 (searched on 18 March 2008) ‐ International Congress on Infectious Diseases: 12th, Lisbon, Portugal, 15 to 18 June 2006; 11th, Cancun, Mexico, 4 to 7 March 2004 (searched on 18 March 2008) ‐ Annual Meeting of The European Society for Paediatric Infectious Disease: 24th, Basel, Switzerland, 3 to 5 May 2006 (searched on 18 March 2008) ‐ Western Pacific Congress of Chemotherapy and Infectious Diseases: 10th, Fukuoka, Japan, 3 to 6 December 2006 (searched on 18 March 2008) ‐ European Congress of Chemotherapy and Infection: 8th, Budapest, Hungary, 25 to 28 October 2006 (searched on 18 March 2008)
Organizations	‐ Liverpool School of Tropical Medicine (contacted on 11 April 2007) ‐ World Health Organization (contacted on 17 March 2008) ‐ American Society of Tropical Medicine and Hygiene (contacted on 15 April 2007) ‐ International Society of Tropical Pediatrics (contacted on 15 April 2007) ‐ South East Asian Ministers Education Organization (SEAMEO) TROPMED Network (contacted on 17 March 2008) ‐ International Center for Diarrhoeal Disease Research in Bangladesh (contacted on 21 April 2007)
Pharmaceutical companies	‐ Goldshield Pharmaceuticals Ltd (tetracycline, Deteclo; chloramphenicol, Chloromycetin) ‐ contacted on 17 March 2008 ‐ Chemidex (ampicillin, Penbritin) ‐ contacted on 17 March 2008 ‐ GlaxoSmithKline (co‐trimoxazole, Septrin) ‐ contacted on 17 March 2008 ‐ Merck Sharp & Dohme Ltd (norfloxacin, Utinor) ‐ contacted on 17 March 2008 ‐ Bayer (ciprofloxacin, Ciproxin) ‐ contacted on 20 April 2007 ‐ Aventis Pharma (ofloxacin, Tarivid) ‐ contacted on 15 April 2007 ‐ Pfizer (azithromycin, Zithromax) ‐ contacted on 17 March 2008 ‐ Roche (ceftriaxone, Rocephin) ‐ contacted on 20 April 2007 ‐ Rosemont Pharmaceuticals Ltd (nalidixic acid, Uriben) ‐ contacted on 13 April 2007 ‐ Salix Pharmaceuticals (rifaximin, Xifaxan) ‐ contacted on 17 March 2008 ‐ Rhone‐Poulenc Rorer (cefixime, Suprax) ‐ contacted on 17 March 2008 ‐ LEO pharma (pivmecillinam, Selexid) ‐ contacted on 17 March 2008

Table 3. Search strategy: proceedings, organizations, and pharmaceutical companies

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Table 4. Sensitivity patterns of the Shigella isolates reported in included trials

Study ID	Group 1	Group 2	Group 3
Alam 1994	Pivmecillinam group: All were sensitive to pivmecillinam Nalidixic acid sensitivity not reported	Nalidixic acid group: All were sensitive to pivmecillinam 26/37, 45%, were sensitive to nalidixic acid	Nil
Bennish 1990	Ciprofloxacin group: All were sensitive to ciprofloxacin; 34/60, 56.6%, were sensitive to ampicillin	Ampicillin group: All were sensitive to ciprofloxacin; 26/61, 42.6%, were sensitive to ampicillin.	Nil
Bibile 1961	This is a 4‐armed trial with sulphadimidine, sulpha methoxy pyridazine, Strepto triad, and tetracycline in each group respectively Sensitivity patterns not reported for any group	—	—
Dutta 1995	Furazolidone and nalidixic acid Sensitivity patterns not reported for any group	—	—
Gotuzzo 1989	Cotrimoxazole group: 27/32, 84%, were sensitive to cotrimoxazole; all were sensitive to norfloxacin	Norfloxacin group: 26/30, 86%, were sensitive to cotrimoxazole; all were sensitive to norfloxacin	Nil
Haltalin 1973	Nalidixic acid group: All were sensitive to nalidixic acid; ampicillin sensitivity not reported.	Ampicillin group: All were sensitive to ampicillin; nalidixic acid sensitivity not reported	Nil
Islam 1994	Nalidixic acid group: 26/37, 70%, were sensitive to nalidixic acid; all were sensitive to gentamicin	Oral gentamicin: Nalidixic acid sensitivity not reported; all were sensitive to gentamicin	Nil
Kabir 1986	Ceftriaxone group: All were sensitive to ceftriaxone; all were sensitive to ampicillin	Ampicillin group: All were sensitive to ceftriaxone; 24/30, 80%, were sensitive to ampicillin	Placebo: All were sensitive to ceftriaxone; 28/30, 93%, were sensitive to ampicillin
Khan 1997a	Azithromycin group: All were sensitive to both antibiotics	Ciprofloxacin group: All were sensitive to both antibiotics	Nil
Leibovitz 2000	Ciprofloxacin group: All were sensitive to both antibiotics	Ceftriaxone group: All were sensitive to both antibiotics	Nil
Nelson 1976a	Cotrimoxazole group: All were sensitive to cotrimoxazole; 9/14, 64%, were sensitive to ampicillin	Ampicillin group: All were sensitive to cotrimoxazole 10/14, 71%, were sensitive to ampicillin	Nil
Prado 1993	Cotrimoxazole group; 24/30, 80%, were sensitive to cotrimoxazole; 25/30, 83.3%, were sensitive to pivmecillinam	Pivmecillinam group: 23/29, 79.3%, were sensitive to cotrimoxazole; 26/29, 89.7%, were sensitive to pivmecillinam	Nil
Rodriguez 1989	3‐armed trial with furazolidone, cotrimoxazole and a control (no antimicrobials) respectively Sensitivity patterns not reported for any group	—	Nil
Salam 1988	Nalidixic acid group: All were sensitive to nalidixic acid; ampicillin sensitivity not reported	Ampicillin group: All were sensitive to nalidixic acid; 25/40, 62.5%, were sensitive to ampicillin	Nil
Salam 1998	Ciprofloxacin group: All were sensitive to ciprofloxacin; 58/60, 96.7%, were sensitive to pivmecillinam	Pivmecillinam group: All were sensitive to ciprofloxacin; 57/60, 95%, were sensitive to pivmecillinam	Nil
Shanks 1999	Azithromycin and ciprofloxacin Sensitivity patterns not reported for any group	—	Nil
Sensitivity patterns not reported by 4 trials (Bibile 1961; Rodriguez 1989; Dutta 1995; Shanks 1999).

Table 4. Sensitivity patterns of the Shigella isolates reported in included trials

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Comparison 1. Antibiotic versus no drug or placebo

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea on follow up Show forest plot	1		Risk Ratio (M‐H, Fixed, 95% CI)	Subtotals only

1.1 Furazolidone versus no drug	1	73	Risk Ratio (M‐H, Fixed, 95% CI)	0.21 [0.09, 0.48]
1.2 Cotrimoxazole versus no drug	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.30 [0.15, 0.59]
2 Time to cessation of fever (in days) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

2.1 Ceftriaxone (IV) versus placebo	1	64	Mean Difference (IV, Fixed, 95% CI)	‐1.20 [‐2.20, ‐0.20]
2.2 Ampicillin (IV) versus placebo	1	60	Mean Difference (IV, Fixed, 95% CI)	‐1.50 [‐2.41, ‐0.59]
3 Time to cessation of diarrhoea (in days) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

3.1 Ceftriaxone (IV) versus placebo	1	64	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.41, 0.81]
3.2 Ampicillin (IV) versus placebo	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.37, 0.77]
4 Time to cessation of blood in stools (in days) Show forest plot	1		Mean Difference (IV, Fixed, 95% CI)	Subtotals only

4.1 Ceftriaxone (IV) versus placebo	1	64	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.43, 0.83]
4.2 Ampicillin (IV) versus placebo	1	60	Mean Difference (IV, Fixed, 95% CI)	‐0.30 [‐1.41, 0.81]
5 Other adverse events Show forest plot	1	94	Risk Ratio (M‐H, Fixed, 95% CI)	1.43 [0.06, 34.13]

Comparison 1. Antibiotic versus no drug or placebo

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Comparison 2. Fluoroquinolones versus beta‐lactams

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea on follow up Show forest plot	6		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

1.1 All trials	6	686	Risk Ratio (M‐H, Random, 95% CI)	1.03 [0.45, 2.37]
1.2 Adults (subgroup)	1	127	Risk Ratio (M‐H, Random, 95% CI)	0.14 [0.04, 0.44]
1.3 Children (subgroup)	5	559	Risk Ratio (M‐H, Random, 95% CI)	1.46 [0.64, 3.34]
1.4 Confirmed Shigella > 90% (subgroup)	2	257	Risk Ratio (M‐H, Random, 95% CI)	4.68 [1.74, 12.59]
1.5 Confirmed Shigella < 90% (subgroup)	4	429	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.29, 1.42]
2 Fever at follow up Show forest plot	2	191	Risk Ratio (M‐H, Random, 95% CI)	0.87 [0.25, 3.06]

3 Relapse Show forest plot	3		Risk Ratio (M‐H, Random, 95% CI)	Subtotals only

3.1 All trials	3	357	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.11, 7.55]
3.2 Confirmed Shigella > 90% (subgroup)	2	237	Risk Ratio (M‐H, Random, 95% CI)	0.91 [0.11, 7.55]
3.3 Confirmed Shigella < 90% (subgroup)	1	120	Risk Ratio (M‐H, Random, 95% CI)	0.0 [0.0, 0.0]
4 Bacteriological failure Show forest plot	5	1350	Risk Ratio (M‐H, Random, 95% CI)	0.74 [0.50, 1.11]

4.1 All trials	5	450	Risk Ratio (M‐H, Random, 95% CI)	0.73 [0.33, 1.62]
4.2 Adults (subgroup)	1	127	Risk Ratio (M‐H, Random, 95% CI)	0.28 [0.08, 0.95]
4.3 Children (subgroup)	4	323	Risk Ratio (M‐H, Random, 95% CI)	0.95 [0.43, 2.09]
4.4 Confirmed Shigella > 90% (subgroup)	1	36	Risk Ratio (M‐H, Random, 95% CI)	5.56 [0.29, 108.16]
4.5 Confirmed Shigella < 90% (subgroup)	4	414	Risk Ratio (M‐H, Random, 95% CI)	0.65 [0.29, 1.43]
5 Development of severe complications Show forest plot	2	90	Risk Ratio (M‐H, Fixed, 95% CI)	0.89 [0.28, 2.85]

6 Serious adverse events Show forest plot	1	221	Risk Ratio (M‐H, Fixed, 95% CI)	10.90 [0.61, 194.82]

7 Adverse events leading to discontinuation of treatment Show forest plot	1	127	Risk Ratio (M‐H, Fixed, 95% CI)	1.02 [0.27, 3.89]

8 Other adverse events Show forest plot	4	570	Risk Ratio (M‐H, Fixed, 95% CI)	1.03 [0.77, 1.39]

Comparison 2. Fluoroquinolones versus beta‐lactams

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Comparison 3. Fluoroquinolones versus macrolides

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea on follow up Show forest plot	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.6 [0.24, 1.49]

2 Fever at follow up Show forest plot	2	189	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.08, 1.35]

3 Time to cessation of blood in stools Show forest plot	1	113	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐0.68, 0.28]

4 Bacteriological failure Show forest plot	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	0.33 [0.07, 1.55]

5 Other adverse events Show forest plot	1	76	Risk Ratio (M‐H, Fixed, 95% CI)	1.33 [0.32, 5.56]

Comparison 3. Fluoroquinolones versus macrolides

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Comparison 4. Cotrimoxazole versus beta‐lactams

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea on follow up Show forest plot	2	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.59 [0.23, 1.49]

2 Bacteriological failure Show forest plot	1	28	Risk Ratio (M‐H, Fixed, 95% CI)	0.75 [0.20, 2.75]

3 Time to cessation of diarrhoea (hours) Show forest plot	1	61	Mean Difference (IV, Fixed, 95% CI)	‐0.20 [‐15.10, 14.70]

4 Time to cessation of fever (hours) Show forest plot	1	61	Mean Difference (IV, Fixed, 95% CI)	5.90 [‐5.30, 17.10]

5 Time to cessation of visible blood in stools Show forest plot	1	61	Mean Difference (IV, Fixed, 95% CI)	2.80 [‐12.71, 18.31]

6 Other adverse events Show forest plot	2	89	Risk Ratio (M‐H, Fixed, 95% CI)	0.81 [0.27, 2.45]

Comparison 4. Cotrimoxazole versus beta‐lactams

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Comparison 5. Cotrimoxazole versus fluoroquinolones (norfloxacin)

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Bacteriological failure Show forest plot	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	1.69 [0.64, 4.47]

2 Other adverse events Show forest plot	1	62	Risk Ratio (M‐H, Fixed, 95% CI)	2.82 [0.12, 66.62]

Comparison 5. Cotrimoxazole versus fluoroquinolones (norfloxacin)

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Comparison 6. Cotrimoxazole versus furazolidone

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea on follow up Show forest plot	1	101	Risk Ratio (M‐H, Fixed, 95% CI)	0.71 [0.27, 1.84]

Comparison 6. Cotrimoxazole versus furazolidone

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Comparison 7. Oral gentamicin versus nalidixic acid

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea at follow up Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.71 [0.98, 2.97]

2 Fever at follow up Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	2.37 [1.11, 5.07]

3 Bacteriological relapse Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	1.95 [0.64, 5.95]

4 Bacteriological failure Show forest plot	1	79	Risk Ratio (M‐H, Fixed, 95% CI)	2.1 [1.29, 3.42]

Comparison 7. Oral gentamicin versus nalidixic acid

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Comparison 8. Sulphonamides versus tetracycline

Outcome or subgroup title	No. of studies	No. of participants	Statistical method	Effect size
1 Diarrhoea at follow up Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	7.68 [0.46, 128.12]

2 Bacteriological failure Show forest plot	1	60	Risk Ratio (M‐H, Fixed, 95% CI)	11.78 [0.73, 190.30]

Comparison 8. Sulphonamides versus tetracycline

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