Section 1. Antimicrobials versus placebo/ no treatment
A total of 23 trials included a comparison of antimicrobials versus placebo/no treatment, contributing to one or more of the outcomes detailed below. The last trial was completed in 1994.
On average, antimicrobials reduced the duration of diarrhoea by about one and a half days compared to placebo or no treatment (MD -36.77 hours, 95% CI -43.51 to -30.03, 18 trials, 1479 participants, Analysis 1.1). However, there were statistically significant subgroup differences in the magnitude of the effect (P < 0.00001). Tetracycline, the most studied antibiotic, shortened the duration of diarrhoea by almost two days (MD -47.38 hours, 95% CI -52.36 to -42.41, I2 = 0%, 11 trials, 665 participants); doxycycline shortened the duration by just over one day (MD -25.44 hours, 95% CI -38.90 to -11.99, I2 = 50%, three trials, 91 participants); and norfloxacin shortened the duration by less than half a day (MD -10.80 hours, 95% CI -14.13 to -7.48, I² = 0%, three trials, 123 participants).
Thirteen trials reported stool volume as total litres excreted, while four studies reported it as mL/kg body weight. The results were highly skewed in most trials.
Overall, the mean stool volume was 50% lower in those treated with antibiotics compared to placebo/no treatment (ROM 0.50, 95% CI 0.45 to 0.56, 17 trials, 1716 participants, Analysis 1.2). As with diarrhoea duration, there were statistically significant sub-group differences between antibiotics (P = 0.01). Tetracycline was again the most studied antibiotic and reduced stool volume by 56% (ROM 0.44, 95% CI 0.39 to 0.50, I2 =0%, 12 trials, 771 participants). Large effects were also seen with norfloxacin (two trials), ciprofloxacin (one trial), doxycycline (three trials), chloramphenicol (three trials), furazolidone (five trials), and ampicillin (one trial).
No deaths were reported in all trials, although only six trials explicitly stated that no deaths occurred (Analysis 1.3).
Clinical failure was variably assessed between 48 to 96 hours after enrolment to the study or from starting to take the study drugs.
Overall, clinical failure was significantly lower with antimicrobial treatment (RR 0.21, 95% CI 0.13 to 0.34, 10 trials, 1023 patients, Analysis 1.4). Tetracycline reduced the risk of clinical failure by 90% (RR 0.10, 95% CI 0.05 to 0.22, I2 = 46%, six trials, 431 participants), and statistically significant effects were also seen with fleroxacin (one trial), trimethoprim-sulfamethoxazole (TMP-SMX; two trials), chloramphenicol (two trials), and sulfometoxine (one trial).
Eight trials reported total hydration fluid requirement as litres, while three trials reported it as mL/kg body weight.
Overall, the total volume of hydration fluid required was 40% lower in patients given antibiotics (ROM 0.60, 95% CI 0.53 to 0.68, 11 trials, 1201 participants, Analysis 1.5). The effect was slightly greater than the pooled total with tetracycline (ROM 0.50, 95% CI 0.43 to 0.58, I2 =19%, eight trials, 604 participants), and lower for doxycycline (ROM 0.76, 95% CI 0.57 to 1.02, I2 = 37%, two trials, 66 participants) and norfloxacin (ROM 0.72, 95% CI 0.60 to 0.86, I2 = 57%, two trials, 98 participants ). Beneficial effects were also seen with chloramphenicol (two trials) and amoxicillin (one trial).
Pathogen excretion duration
The mean duration of pathogen excretion was significantly shorter in patients given antibiotics (MD -2.74 days, 95% CI -3.07 to -2.40, 11 trials, 1009 participants, Analysis 1.6). Tetracycline was the most studied antibiotic and reduced the duration of excretion by three days (MD -3.05 days, 95% CI -3.43 to -2.67, I2 = 60%, 11 trials, 616 participants). Large beneficial effects were also seen with TMP-SMX (one trial), chloramphenicol (two trials), and furazolamide (three trials). All studies monitored stools for pathogen excretion daily.
As for clinical failure, microbiological failure was variably assessed at 48 to 96 hours after enrolment to study or from start of the study drugs.
Overall, bacteriological failure was significantly lower with antimicrobial therapy (RR 0.25, 95% CI 0.16 to 0.39, 15 trials, 1147 patients, Analysis 1.7), but with significant subgroup differences (P < 0.00001) and significant heterogeneity within some subgroups. Considerable heterogeneity was present in the analysis of tetracycline, but all studies pointed in the same direction (RR 0.28, 95% CI 0.13 to 0.64, I2 = 86%, seven trials, 320 participants), with large reductions seen in small trials of doxycycline (two trials), norfloxacin (three trials), fleroxacin (one trial), ciprofloxacin (one trial), and erythromycin (three trials).
Risk of bias
We evaluated the possible influence of poor study design on the observed effects of antimicrobial treatment by conducting a sensitivity analysis against the risk of selection bias. For duration of diarrhoea (Analysis 2.1), stool volume (Analysis 2.2), hydration requirements (Analysis 2.4), clinical failure (Analysis 2.3), and bacteriological failure (Analysis 2.6), the largest effects were observed in trials at high risk of selection bias and the smallest effects in trials at low risk of bias. Nevertheless, when the analysis was restricted to those to studies at low risk of bias, the benefits of antibiotics remained both statistically and clinically significant.
Conversion of medians to means
When excluding trials reporting results in medians (which we converted into means), the results remained almost identical to the main analysis (data not shown).
For stool volume, the time interval for stool output assessment was eight hours in 16 studies, six hours in six studies, 24 hours or more in four studies, and not reported in 13 studies. Heterogeneity dropped significantly in the group of trials with exact time intervals of eight hours (MD -42.21 hours, 95% CI -47.64 to -36.78, I² = 45%, nine trials, 1038 patients, Analysis 3.1).
For clinical and bacteriological failure, there were no significant differences in effects between trials assessing failure at 48, 72 or 96 hours (Analysis 3.2; Analysis 3.3).
Age of participants
No statistically significant subgroup differences were seen (data not shown).
No statistically significant subgroup differences were seen (data not shown).
Level of dehydration at baseline
The effect of antimicrobials was smaller in trials where all patients were severely dehydrated at baseline compared to studies with broader inclusion criteria (range 0 to 88% severely dehydrated) for duration of diarrhoea (test for subgroup differences P = 0.005, Analysis 4.1), stool volume (P = 0.07, Analysis 4.2), and hydration requirements (P = 0.04, Analysis 4.4). There were no subgroup differences for clinical failure (P = 0.77, Analysis 4.3).
Restriction of the analysis of bacteriological failure to studies reporting that all cholera isolates were susceptible to the administered antimicrobials resulted in similar results to the overall analysis (RR of 0.13, 95% CI 0.06 to 0.27, Analysis 5.1).
Small study effects
The funnel plots for most outcomes in the comparison of antimicrobial versus placebo/no treatment did not show a small study effect; only in the clinical and microbiological failure analyses did small studies tend to show a larger effect, but these analyses included only a small proportion of existing studies.
Assessment of quality of evidence
This comparison is summarized in Summary of findings for the main comparison. The evidence for the large effect of antibiotics on the duration of diarrhoea, total stool volume, fluid requirement, and pathogen excretion duration was judged to be of moderate quality, meaning we have reasonable confidence in these results. We downgraded the quality of evidence from high to moderate because the effects appear to be exaggerated in trials at high risk of selection bias. We did not downgrade for inconsistency, as much of the observed heterogeneity was explained by differences between antibiotic classes and differences in the timing of outcome measurements. We also did not downgrade for indirectness despite many of the trials being old. We consider the observed effects applicable to effective antibiotics today.
Section 2. Comparison between different antimicrobials
Direct comparisons are addressed, followed by indirect comparisons where relevant. Funnel plots were not drawn for all head-to-head comparisons because of the paucity of trials in most comparisons.
Azithromycin versus ciprofloxacin
Two trials have directly compared single doses of azithromycin (effective duration of four days) and ciprofloxacin (effective duration of 12 hours) among children (Kaushik 2010 IND) and adults (Saha 2006 BGD).
Compared to ciprofloxacin, treatment with azithromycin reduced the mean duration of diarrhoea by over a day (MD -32.43 hours, 95% CI -62.90 to -1.95, two trials, 375 participants, Analysis 6.1), reduced stool volume by about two-thirds (ROM 0.35, 95% CI 0.28 to 0.44, one trial, 195 participants, Analysis 6.2), reduced hydration requirements by about a third (ROM 0.66, 95% CI 0.52 to 0.83, two trials, 375 participants, Analysis 6.3), and reduced bacteriological failure at 48 to 72 hours by over three-quarters (RR 0.23, 95% CI 0.16 to 0.34, two trials, 375 participants, Analysis 6.5).
This comparison is summarized in Summary of findings 2. The quality of the evidence for a reduction in diarrhoea duration was judged to be moderate. We downgraded the evidence because the trial that demonstrated the largest effect had baseline imbalances favouring azithromycin (Saha 2006 BGD). The effects on stool volume and bacteriological failure were further downgraded to low quality due to concerns about indirectness and inconsistency, respectively.
Azithromycin versus erythromycin
One trial directly compared single dose azithromycin (effective duration of four days) with three days of erythromycin (Khan 2002 BGD), and one trial compared a three-day regimen of both drugs (Bhattacharya 2003 IND).
Compared to erythromycin, azithromycin reduced the duration of diarrhoea by half a day (MD 12.05 hours, 95% CI -22.02 to -2.08, two trials, 179 participants, Analysis 7.1), and reduced the total stool volume by a third (ROM 0.69, 95% CI 0.56 to 0.85, two trials, 172 participants, Analysis 7.2). Hydration requirements were lower with azithromycin, but this did not reach statistical significance (two trials, 172 participants, Analysis 7.3), and no differences were observed for clinical failure (Analysis 7.4) or bacteriological failure (Analysis 7.5).
This comparison is summarized in Summary of findings 3. The quality of evidence for the reduction in diarrhoea duration and stool volume was judged to be of moderate quality.
Tetracycline versus doxycycline
Three trials directly compared tetracycline with doxycycline. In two trials tetracycline was given four times daily for four days (De 1976 IND; Rahaman 1976 BGD), and in one trial tetracycline was given four times daily for two days (Alam 1990 BGD). All trials administered a total dose of 300 mg of doxycycline, spread over three days (Rahaman 1976 BGD), two days (De 1976 IND) or given as a single dose (Alam 1990 BGD).
Overall, no consistent clinically important differences were observed for diarrhoea duration, stool volume, or hydration requirements (three trials, 230 participants, Analysis 8.1; Analysis 8.2,Analysis 8.4), or for duration of pathogen excretion (two trials, 66 participants, Analysis 8.5). Only a few patients with bacteriological failure were reported, but this reached statistical significance in favour of tetracycline (RR 0.20, 95% CI 0.06 to 0.68, two trials, 198 participants, Analysis 8.6).
This comparison is summarized in Summary of findings 4. The evidence of no difference between antimicrobials was downgraded to low quality due to concerns about the risk of bias of the studies and their age, with the most recent study being 25 years old.
This direct evidence is in contrast to the indirect evidence comparing tetracycline (10 trials) and doxycycline (three trials) with placebo/no treatment. In this analysis, diarrhoea duration was almost a day shorter in the trials using tetracycline compared with the trials using doxycycline (MD 21.94 hours, 95% CI -36.29 to -7.59, Analysis 1.1), while the stool volume reduction was significantly higher with tetracycline (ROM 0.44, 95% CI 0.39 to 0.50) compared to doxycycline (ROM 0.64, 95% CI 0.51 to 0.81, Analysis 1.2, P = 0.004 for subgroup difference).
Tetracycline versus quinolones
Three trials compared tetracycline with quinolones. The three trials compared tetracycline 500 mg four times daily for three days with: ciprofloxacin 1 g single dose (Khan 1995a BGD); ciprofloxacin 250 mg once daily for three days (Gotuzzo 1995 PER); and norfloxacin 400 mg twice daily for three days (Moolasarat 1998 THA).
There were no statistically significant differences in the duration of diarrhoea (three trials, 259 participants, Analysis 9.1), stool volume (two trials, 234 participants, Analysis 9.2), clinical failure (one trial, 202 participants, Analysis 9.4), hydration requirements (two trials, 234 participants, Analysis 9.5), duration of pathogen excretion (one trial, 25 participants, Analysis 9.6), or bacteriological failure (two trials, 234 participants, Analysis 9.7).
This evidence of no difference was judged to be of low to moderate quality (see Summary of findings 5).
In indirect comparisons, tetracycline appeared to have a larger effect on diarrhoea duration than norfloxacin, compared to placebo/no treatment (P < 0.002 for subgroup difference, Analysis 1.1). Statsitically significant subgroup differences in favour of tetracycline were also seen for stool volume (P=0.004, Analysis 1.2) and hydration requirements (P=0.003, Analysis 1.5).
Tetracycline versus TMP-SMX
Three trials compared tetracycline (500 mg four times daily for three days) versus TMP-SMX (twice daily for three days) (Francis 1971 NGA; Gharagozoloo 1970 IRN; Grados 1996 PER).
Compared to TMP-SMX, diarrhoea duration was slightly shorter in those treated with tetracycline (MD -6.44 hours, 95% CI -10.93 to -1.96, two trials, 152 participants, Analysis 10.1); stool volume was not reported. Clinical failure was also lower with tetracycline (RR 0.56, 95% CI 0.34 to 0.92, two trials, 152 participants, Analysis 10.2). In one small trial, pathogen excretion was reduced by a day with tetracycline (MD -1.1 days, 95% CI -1.74 to -0.46, one trial, 45 participants, Analysis 10.3), but there was no difference in bacteriological failure across all three trials (three trials, 173 participants, Analysis 10.4).
In indirect comparisons, tetracycline was associated with a greater reduction in diarrhoea duration (MD -47.38 hours tetracycline vs -30.76 hours TMP-SMX, test for subgroup differences P=0.09, Analysis 1.1) and a greater reduction in clinical failure (RR 0.10 tetracycline vs 0.33 TMP-SMX, test for subgroup differences P = 0.02 , Analysis 1.4).
Tetracycline versus other antibiotics
Tetracycline has also been directly compared to: chloramphenicol (three trials); furazolidone (four trials); ampicillin (two trials); erythromycin (two trials); and sulphadoxine (two trials).
Tetracycline was more effective than chloramphenicol for all outcomes examined, without statistically significant differences (Analysis 11.1; Analysis 11.2; Analysis 11.4; Analysis 11.3), except for pathogen excretion duration where the difference of about one day was statistically significant (Analysis 11.5).
Tetracycline was also more effective than furazolidone for most outcomes examined, with these differences statistically significant for diarrhoea duration (mean difference -16.00 hours, 95% CI -31.26 to -0.74, Analysis 12.1), stool volume (Analysis 12.2), hydration requirements (Analysis 12.5), and clinical failure (Analysis 12.4). There was no difference in deaths (Analysis 12.3).
For the remaining comparisons (versus ampicillin, erythromycin and sulphadoxine), diarrhoea duration was not reported. Consistent clinical differences were not detected (data not shown), except for an advantage of tetracycline in hydration requirements in comparison to ampicillin or erythromycin (ROM 0.43, 95% CI 0.25 to 0.73, Roy 1998 BGD) and in bacteriological failure in comparison to sulphadoxine (RR 0.14, 95% CI 0.02 to 0.96, Mihindukulasurya 1976 LKA).
Doxycycline versus quinolones
Four trials were included overall, with three of the trials having a similar treatment duration (single dose) (Dutta 1996 IND; Khan 1995a BGD; Khan 1996 BGD) and one trial having a longer duration (Usubutun 1997 TUR). Ciprofloxacin was examined in three trials and norfloxacin in one trial (Dutta 1996 IND).
There was no clinically or statistically significant difference in diarrhoea duration (Analysis 13.1), stool volume (Analysis 13.2) or deaths (Analysis 13.3). Hydration requirements were lower with quinolones, although there was only a small magnitude of effect based mostly on the results of a single trial (Analysis 13.4). Bacteriological failure occurred more frequently with doxycycline (RR 5.84, 95% CI 2.70 to 12.65, Analysis 13.5).
The quality of the evidence was rated low to moderate for the main outcomes (Summary of findings 6).
For indirect comparisons, no differences between doxycycline and quinolones were observed.
Erythromycin versus ciprofloxacin
Three trials compared erythromycin with ciprofloxacin (Khan 1995a BGD; Khan 1995b BGD; Saha 2005 BGD) and found no statistically significant differences (data not shown).
TMP-SMX versus other antibiotics
Two trials compared TMP-SMX with erythromycin (Burans 1989 SOM; Kabir 1996 BGD) and found no statistically significant differences (Analysis 14.1; Analysis 14.2; Analysis 14.3).
A single trial compared TMP-SMX with norfloxacin (Lolekha 1988 THA), but reported only diarrhoea duration; it found no significant difference between the drugs (data not shown).
Section 3. Short versus long duration of treatment (mean difference < 0 and risk ratio < 1 in favour of short duration)
Only the few trials (eight) comparing the same antimicrobial or antimicrobial class were included in this comparison. We divided the trials into subgroups according to the effective duration of treatment in the long treatment arm (24, 48, 72, or 96 hours). The duration of treatment in the short treatment arm was always shorter than 24 hours. This comparison is summarized in Summary of findings 7.
For clinical outcomes; one trial found that three days of norfloxacin (400 mg twice daily) was superior to a single dose (800 mg), but the remaining trials found no statistically significant benefits with longer durations; diarrhoea duration (seven trials, Analysis 15.1), stool volume (eight trials, Analysis 15.2), hydration requirements (six trials, Analysis 15.3), clinical failure (two trials, Analysis 15.5).
In three trials comparing long and short durations of tetracycline, doxycycline and furazolidine respectively, there was a consistent reduction in the duration of pathogen excretion (MD 0.40 days, 95% CI 0.11 to 0.69, three trials, Analysis 15.4). There were also more bacteriological failures with shorter treatment (RR 1.53, 95% CI 1.01 to 2.32, Analysis 15.6), although the trials were generally at high risk of bias, and underpowered to detect these effects so provide only low quality evidence of this effect.
Section 4. Low versus high dose of treatment
The identified comparisons are detailed in Table 5. As antimicrobials and schedules were different, the studies could not be combined. No differences were detected in any trials for any comparisons, except for a comparison between single-dose doxycycline 200 mg versus 300 mg for adults (and 4 mg/kg versus 6 mg/kg for children). In this case, an advantage was found with the high dose for diarrhoea duration (two trials) and pathogen excretion duration (one trial, data not shown).
Table 5. Dose comparison
|Study||Antimicrobial||Low dose||High dose||Duration||Population|
| Pierce 1968 IND||furazolidone||200 mg||400 mg||72 hours||Adults|
| Alam 1990 BGD||doxycycline ||200 mg||300 mg||Single dose||Adults|
| De 1976 IND||doxycycline ||Adults: 200 mg; Children: 4 mg/kg||Adults: 300 mg; Children: 6 mg/kg||Single dose||Adults and children|
| Karchmer 1970 PAK||tetracycline||10 mg/kg/day in 4 doses||31-62 mg/kg/day in 4 doses||7 days||Children|
| Islam 1987 BGD||tetracycline||1 g||2 g||Single dose||Adults|