Guidelines for the treatment of dysentery (shigellosis): a systematic review of the evidence

Figures & data

Table 1. 2005 WHO guidelines: antimicrobials for treatment of shigellosis (adapted) [4].

Antimicrobial	Treatment schedule for children	Limitations
1st-line: ciprofloxacin	15 mg/kg orally twice daily for 3 days	Expensive
		Resistance emerging
		Drug interactions
2nd-line: pivmecillinam	20 mg/kg orally 4 times daily for 5 days	Cost
		No paediatric formulation
		Four times daily dosing
		Resistance emerging
OR*: ceftriaxone	50–100 mg/kg intramuscular injection for 2–5 days	Requires parenteral administration
		Generates antimicrobial resistance
OR: (for adults) azithromycin	6–20 mg/kg, orally once daily for 1–5 days	Cost
		Drug interactions
		Resistance emerges rapidly, spreads to other bacteria

* Ceftriaxone is listed as an alternative therapy ‘only for use when local strains of shigella are known to be resistant to ciprofloxacin’.

Table 2. Antimicrobials highlighted as inappropriate for shigellosis in the 2005 WHO guidelines [4].

Antimicrobial	Rationale for not prescribing
Ampicillin	Antimicrobial resistance
Chloramphenicol	Antimicrobial resistance
Co-trimoxazole	Antimicrobial resistance
Tetracyclines	Antimicrobial resistance
Nalidixic acid	Antimicrobial resistance; cross-resistance to ciprofloxacin observed (MIC increased)
Nitrofurans (nitrofurantoin, furazolidone)	Penetrate the intestinal mucosa poorly
Oral aminoglycosides (gentamicin, kanamycin)	Penetrate the intestinal mucosa poorly
1st- and 2nd-generation cephalosporins (cefazolin, cephalotin, cefaclor, cefoxitin)	Penetrate the intestinal mucosa poorly
Amoxicillin	Penetrates the intestinal mucosa poorly

Table 3. Inclusion and exclusion criteria.

Inclusion criteria	Exclusion criteria
• Systematic review, randomised controlled trial or multi-centre study investigating clinical treatment options and outcomes for shigellosis • Paediatric-specific information included • Where resistance patterns were investigated, information on antimicrobial testing methodologies documented	• Published before 2005 • Not pertaining to treatment in humans • Data pertaining to carriage rates only

Figure 1. Search strategy.

Table 4. Current international guidelines for the treatment of shigellosis.

Guideline	Last update	Recommendations
IDSA [30]	2001; update in progress	Based on A-1 level of evidence
		[Where: A = good evidence to support a recommendation for use; and I = Evidence from at least one properly randomised, controlled trial]
		Selective therapy should be instituted for shigellosis
		• TMP-SMZ 160 + 800 mg, respectively (paediatric dose 5 and 25 mg/kg, respectively) bd for 3/7 if susceptible)
		or
		• Fluoroquinolone: e.g. ciprofloxacin bd for 3/7 (paediatric dosing not listed); 300 mg ofloxacin; 400 mg norfloxacin; or 500 mg nalidixic acid 55 mg/kg/day for 5/7 • Ceftriaxone 100 mg/kg/day in 1 or 2 divided doses
Therapeutic Guidelines (Australia) [31]	2014	Selective therapy for:
		• Children < 6 years • Institutionalised populations or food handlers • MSM • Immunosuppressed • Patients with severe disease
		Empirical therapy (while awaiting local sensitivities):
		• Ciprofloxacin 500 mg (12.5 mg/kg up to 500 mg) PO bd for 5 days
		or
		• Norfloxacin 400 mg (10 mg/kg up to 400 mg) PO bd for 5 days
		or
		• TMP-SMZ 160 + 800 mg (4 + 20 mg/kg up to 160 + 800 mg) PO bd for 5 days
		Second-line therapy:
		• Azithromycin 500 mg (10 mg/kg up to 500 mg) PO on day 1, then 250 mg (5 mg/kg up to 250 mg) PO daily for a further 4 days
American Academy of Pediatrics [7]	2015	• Do not treat mild episodes • Selected therapy: for those with severe disease or immunosuppressed
		Empirical therapy (while awaiting culture/susceptibility results): any of (not hierarchical):
		• Ciprofloxacin 15 mg/kg bd for 3 days • Azithromycin 12 mg/kg on day 1; then 6 mg/kg on days 2–4 (total course: 4 days) • Parenteral ceftriaxone (50–75 mg/kg daily) for 2–5 days – for seriously ill patients
		The guidelines also note that oral cephalosporins (cefixime) have been used successfully in treating shigellosis in adults.
BMJ Clinical Evidence [32]	2016	Selective therapy for:
		• Malnourished, immunocompromised or elderly patients; food handlers, health care workers • Severe disease: defined as bloody diarrhoea with cramping while systemically unwell
		Empirical therapy (while awaiting local sensitivities):
		• Ciprofloxacin: 15 mg/kg (max 500 mg) PO bd
		or
		• Norfloxacin: 10 mg/kg (max 400 mg) PO bd
		Second-line therapy:
		• Ceftriaxone: 50–100 mg/kg IM once daily (adults: 1–2 g intramuscularly once daily)
		or
		• Azithromycin: 6–20 mg/kg PO once daily
		All therapies state ‘consult with a specialist for guidance on duration of treatment’
British National Formulary [33]	2016	Ciprofloxacin 20 mg/kg bd (higher dose than 15 mg/kg previously recommended)

Table 5. Common adverse reactions to antibiotics currently indicated to treat shigellosis in children [7,33].

Antibiotic	Life-threatening	Mild adverse effects which may result in discontinuation of treatment	Other	Relevant interactions
Fluoroquinolones:CiprofloxacinNorfloxacinOfloxacin	Hypersensitivity reactions;	Dyspepsia, headache, diarrhoea, vomiting, hypotension	Tendonitis and tendon rupture; peripheral neuropathy.	All fluoroquinolones should be used with caution in patients receiving drugs known to prolong the QT interval
	Prolonged QT syndrome			The toxicity of fluoroquinolones is increased by the concurrent use of systemic steroidal medications
			A 2010 systematic review of ciprofloxacin safety in paediatrics concluded that although musculoskeletal adverse effects occur owing to ciprofloxacin use, these events are reversible [14]
				Fluoroquinolones’ effects are reduced by the co-administration of iron- and zinc-containing products, of importance when zinc-containing products are used to treat diarrhoea in children.
				Fluoroquinolones cause additive toxicity with non-steroidal anti-inflammatory drugs (ibuprofen, meloxicam, naproxen)
Azithromycin	Hypersensitivity reactions;	Dyspepsia, flatulence, headache, disturbance in taste, anorexia	Malaise, paraesthesia	Macrolides use not advised with other drugs which prolong the QT interval, (including anti-malarial medications such as artemether-lumefantrine) owing to the risk of ventricular arrhythmias. However, azithromycin has been identified as a safer macrolide (in terms of its ability to prolong the QT interval) in this class of antibiotics.
	Prolonged QT syndrome
				Plasma concentrations of azithromycin are increased by ritonavir
				Azithromycin in combination with rifabutin results in increased side-effects of rifabutin, including neutropenia
Ceftriaxone	Hypersensitivity reactions	Diarrhoea, headache, abdominal discomfort	Transient cholestatic jaundice owing to biliary sludge formation	Relevant interactions for all cephalosporins:
				Increased risk of nephrotoxicity when co-administered with aminoglycosides
				Enhance anticoagulant effect of coumarins
Cefixime	Hypersensitivity reactions; immune-mediated haemolytic anaemia	Flatulence, headache, abdominal pain, defaecation urgency, nausea, constipation, vomiting	Transient cholestatic jaundice owing to biliary sludge formation	As per ceftriaxone
Pivmecillinam	As with all penicillins: hypersensitivity reactions, serum-sickness-like reactions, anaphylaxis	Diarrhoea, joint pain, rashes, urticaria	Avoid use in acute porphyrias	Contra-indicated for concurrent use with sodium valproate

Table 6. Risk factors for the development of torsades de pointes [34].

Risk factor	Examples
Genetic risk factors	Channelopathies
	CYP3A4 poor metaboliser
Underlying cardiac disease	Bradycardia
	Congestive cardiac failure
	Myocardial ischaemia
	Atrial fibrillation
Electrolyte derangements	Hypokalaemia
	Hypomagnesaemia
	Hypocalcaemia
Organ impairment, altering medication toxicity	Renal insufficiency
	Severe hepatic disease
Use of medication to increase QT liability	Concurrent CYP medications administered

Table

Author	Year	Title	Setting	Population	Method	Findings	Level of evidence
Das et al. [12]	2013	Antibiotics for the treatment of cholera, ahigella and xryptosporidium in children	Systematic review and meta-analysis (international)	Children <16 years	The CHERG standard rules were applied to determine the final effect of treatment with antibiotics on diarrhoea morbidity and mortality	Using clinical failure rates as a proxy for shigella deaths (as there was no data on mortality), the authors propose that treating shigella dysentery with antibiotics results in an 82% (67–99%) reduction in diarrhoea mortality from shigella.	A
				48 papers relevant to Ahigella were included, 47 of which were from developing country settings
					Studies were included if they reported the effect of antibiotics on morbidity and mortality associated with diarrhoea owing to cholera, shigella and cryptosporidiosis in children, as observed by clinical and bacteriological failure and mortality. No studies compared antibiotics with placebo or a control group, so studies with an antibiotic comparison group were also included. Only studies with a confirmed diagnosis of the respective infection and on immunocompetent patients were included
				All studies were hospital-based
						Bacteriological failure: Antibiotics (including ciprofloxacin, pivmecillinam and ceftriaxone) successfully clear shigella pathogens in 96% (88–99%) of cases
						The overall conclusion is that there is strong evidence of effectiveness against serious mortality and morbidity
						All antimicrobials were analysed together
Gu et al. [8]	2012	Comparison of the prevalence and changing resistance to nalidixic acid and ciprofloxacin of Ahigella between Europe–America and Asia–Africa from 1998 to 2009.	Systematic review comparing Africa-Asia region with Europe–America	26,877 specimens from adults and children in LMIC and HIC	SR for articles published during 1998–2011 using search strategy ‘bacterial surveillance’ OR ‘antimicrobial resistance’ OR ‘bacterial resistance’ AND ‘shigella’	The predominant species isolated was S. sonnei, representing 8900 (56.6%) of total isolates, followed by S. flexneri (5749 isolates, 36.5%), S. boydii (601 isolates, 3.8%) and S. dysenteriae (481 isolates, 3.1%)	A
					102 studies met inclusion criteria, LMIC and HIC all included	Quinolone resistance in Asia–Africa:
						• NALIDIXIC ACID: Resistance to nalidixic acid increased gradually from 12.1% (95% CI 4.3–23.2) from 1998–2000, to 64.5% (13.8–99.3) in 2007–2009; a 5.3-fold increase in resistance rates • CIPROFLOXACIN: Resistance to ciprofloxacin increased from 0.6% (0.2–1.3) in 1998–2000 to 29.1% (0.9–74.8) in 2007–2009; a 49-fold increase in resistance over 12 years • Overall rates are much higher than those documented in:
						Quinolone resistance in Europe–America:
						• NALIDIXIC ACID: 1.3% (0.6–2.1) 1998–2000 to 2.1% (1.3–3.0) in 2007–2009 • CIPROFLOXACIN: 0.0% (1998–2000) to 0.6% (0.2–1.2) in 2007–2009 • i.e. SIGNIFICANTLY lower than resistance rate increases in Africa–Asia • S. flexneri showed higher resistance rates than S. sonnei to ciprofloxacin, with a general upward trend in resistance over time internationally • In Asia–Africa, the resistance patterns differed – S. sonnei appeared to be more resistant than S. flexneri to nalidixic acid • Resistance rates to quinolones were much greater in children than in adults, with the respective rates being 33.05% (23.9–42.8) vs 14.3% (8.30–21.7) for nalidixic acid, and 7.5% (4.3–11.5) vs 3.6% (2.2–5.3) for ciprofloxacin
					In all the studies collected, a total of 26,877 isolates were positive for shigella, 15,731 of which had information about prevalence of subtypes
						Owing to widespread use of nalidixic acid as the first-line agent for empirical treatment of infectious diarrhoea, resistance to nalidixic acid in Asian–African countries increased to 64.5% (95% CI 13.8–99.3) in 2007–2009. Thus, this drug should no longer be considered appropriate empirical therapy
						Progressively increasing resistance to ciprofloxacin is still a serious cause of concern and several studies have emphasised that most nalidixic acid-resistant strains exhibit some degree of cross-resistance to ciprofloxacin
Gu et al. [17]	2013	Prevalence and trends of aminoglycoside resistance in shigella worldwide, 1999–2010	Systematic review and meta-analysis evaluating aminoglycoside resistance in shigella, Asia–Africa vs Europe–America	Adults and children	3176 publications were retrieved from MEDLINE and EMBASE reported from 1999 to 2012, 68of which met the inclusion criteria	• The summarised prevalence of gentamicin, kanamycin and amikacin resistance was found to be 3.95% (95% CI 3.59–4.22) (n/N = 937/14,059), 6.88% (6.36–7.43) • (n/N = 1106/8,647) and 1.29% (0.97–1.68) • (n/N = 432/8614), respectively. Importantly, evident heterogeneity was observed (p < 0.001). • The most common drug resistance was observed for kanamycin. Re. kanamycin resistance, the highest drug resistance rate by geographic areas was in Asia with a prevalence of 16.78% (7.58–28.71). • Similarly, the most common resistance was observed for 2005–2007 and S. flexneri with a summarised combined prevalence of 12.05% (11.18–14.21) and 9.25% (7.69–10.96), respectively. • A lower prevalence of gentamicin resistance was found in European–American countries at 0.68% (0.39–1.05). • After analysing the study data on years, we observed a minimal change in the resistance prevalence of gentamicin, from 0.25% (0.04–0.64) to 0.84% (0.08–2.40) in European–American countries, in contrast to data in Asian–African countries, which fluctuated from 6.05% (1.18–14.28) to 20.83% (12.67–30.40). • It is worth noting that the resistance prevalence of gentamicin increased annually in Asian–African countries, while the resistance prevalence decreased year by year in European–American countries: The prevalence of gentamicin resistance in Asian–African countries increased sharply from 14.00% (3.97–28.85) in 2002–2004 to 20.96% (3.37–48.11) in 1999–2001 and to 32.40% (17.87–48.91) in 2005–2007. Data for Asian–African regions from 2008–2010 were not found. • The changes in kanamycin resistance in European–American countries were minimal; in fact, the resistance prevalence decreased annually. • In European–American regions, a lower amikacin resistance was also found during the 12-year study period (decreased from 0.28% (0.00–1.08) to 0.05% (0.04–0.40). The highest resistance of shigella isolates to amikacin was only 0.28% (0.00–1.08). • The prevalence of amikacin resistance remarkably increased from 6.39% (1.40–14.63) to 48.06% (34.57–61.65) in Asian–African countries. • In the paediatric age group, resistance of shigella to gentamicin was higher than in adults [5.93% (3.97–8.23) and 18.34% (9.81–28.76)]. • Kanamycin resistance in the paediatric age group was significantly higher than in the adults which showed 70.72% (33.95–96.25) vs 5.40% (1.87–10.62) for kanamycin. • Similarly, there was greater resistance to amikacin in the paediatric group than in the adult group [8.43% (3.26–15.71) vs 2.23% (0.81–4.35)].	A
Gu et al. [15]	2015	Comparison of resistance to 3rd–generation cephalosporins in shigella between Europe–America and Asia–Africa from 1999–2012	Europe–America and Asia–Africa	Adults and children	A systematic review was conducted to compare resistance to 3rd-generation cephalosporins in shigella strains between Europe–America and Asia–Africa from 1998 to 2012	• In Asia–Africa, the prevalence of resistance of total and different subtypes to ceftriaxone, cefotaxime and ceftazidime increased markedly over the study period, with a total prevalence of resistance up to 14·2% [95% confidence interval (CI) 3·9–29·4], 22·6% (95% CI 4·8–48·6) and 6·2% (95% CI 3·8–9·1) during 2010–2012, respectively. • By contrast, resistance rates to these TGCs in Europe–America remained relatively low – <1% during the 15 years • A noticeable finding was that certain countries in Europe–America and Asia–Africa had a rapid rising trend in the prevalence of resistance of S. sonnei which even outnumbered S. flexneri in some periods • Comparison between countries showed that currently the most serious problem concerning resistance to these TGCs was in Vietnam especially for ceftriaxone, in China especially for cefotaxime and in Iran especially for ceftazidime. • Changes in the prevalent serogroups and resistance patterns in antimicrobial susceptibilities in shigella are posing major difficulties in determining an appropriate drug for the treatment of shigellosis • Based on our meta-analyses, two main recommendations can be given for empirical antibiotic therapy. First, the current situation in Europe–America supports the use of ceftriaxone and cefotaxime for treating shigellosis according to the relatively lower prevalence of resistance to the study drugs (although a mild upward trend should be noticed). To some extent, data suggest that ceftriaxone and cefotaxime may not be appropriate for shigellosis in Asia–Africa.	A
					Only high quality studies were included for analysis (defined as prospective cohort or retrospective consecutive cohort studies where susceptibility tests were conducted according to CLSI guidelines with external quality control). 104 articles met these inclusion criteria
Traa et al. [14]	2010	Antibiotics for the treatment of dysentery in children.	Systematic review	Children aged <16 years	Systematic review investigating the effect of ciprofloxacin, ceftriaxone and pivmecillinam for dysentery in children in developing countries; CHERG Standard Rules were applied	• Treatment with ciprofloxacin, ceftriaxone or pivmecillinam resulted in a clinical failure rate of 0.1% (95% CI – 0.2 to 0.5 – not significant) • Treatment with ciprofloxacin, ceftriaxone or pivmecillinam resulted in a cure rate of >99% while assessing clinical failure, bacteriological failure and bacteriological relapse • Therefore, the antibiotics recommended by WHO are effective in reducing the clinical and bacteriological signs and symptoms of dysentery and thus can be expected to decrease diarrhoea mortality attributable to dysentery • NB: The methods of susceptibility testing were not discussed and treatment benefit was summarised for all therapies together	B
					8 papers were selected for abstraction; 4 reported on bacteriological failure and 5 on bacteriological relapse
					All studies were RCTs judged to be of good quality
			Developing countries
			All studies were conducted in clinical or hospital settings
von Seidlein et al. [9]	2006	A multicentre study of shigella diarrhoea in six Asian countries: disease burden, clinical manifestations, and microbiology	Surveillance of 600,000 persons of all ages	Bangladesh, China, Pakistan, Indonesia, Vietnam and Thailand	Shigella was isolated from 2927 (5%) of 56,958 diarrhoea episodes detected between 2000 and 2004	• The overall incidence of treated shigellosis was 2.1 episodes per 1000 residents per year in all ages and 13.2/1000/y in children under 60 months. • S. flexneri was the most frequently isolated shigella species (1976/2927 [68%]) in all sites except Thailand, where S. sonnei was most frequently detected [124/146, 85%). • The majority of S. flexneri isolates in each site were resistant to amoxicillin and cotrimoxazole. Ciprofloxacin-resistant S. flexneri isolates were identified in China (18/305, 6%), Pakistan (8/242, 3%) and Vietnam (5/282, 2%)	B
					Swabs were inoculated onto MacConkey agar and salmonella-shigella agar and incubated overnight then checked for non-lactose fermenting enteropathogens
					Antimicrobial sensitivity testing against ampicillin, cotrimoxazole, nalidixic acid and ciprofloxacin was performed by disk diffusion following CLS methods, and subject to external laboratory validation
Vinh et al. [18]	2011	A multi-centre randomized trial to assess the efficacy of gatifloxacin vs ciprofloxacin for the treatment of shigellosis in Vietnamese children	Vietnam	494 children <15 years admitted to a paediatric ward with a history of passing bloody or mucoid stools, with or without abdominal pain, tenesmus or fever for <72 hours prior to admission	Randomised, open-label, controlled trial with two parallel arms at two hospitals in southern Vietnam	• We could not demonstrate superiority of gatifloxacin and observed similar clinical failure rates in both groups (gatifloxacin 12.0% and ciprofloxacin 11.0%, p=0.72). • The median (inter-quartile range) time from illness onset to cessation of all symptoms was 95 (66–126) hours for gatifloxacin recipients and 93 (68–120) hours for the ciprofloxacin recipients [HR (95% CI) 0.98 (0.82–1.17), p=0.83]. • Gatifloxacin showed a similar efficacy of both drugs in the treatment of childhood dysentery, including those with a stool culture-confirmed shigella infection. • However, gatifloxacin has a longer half-life than ciprofloxacin and the once-a-day administration may be considered more convenient than the twice-a-day regimen of ciprofloxacin. • Data show similar overall risks of treatment failure in the 2 treatment groups (11% in the ciprofloxacin group vs 12%) • The most commonly isolated shigella species here was S. sonnei • S. dysenteriae causes a considerably more severe syndrome than S. sonnei which is largely associated with the secretion of shiga toxin • These data suggest that whilst there has been a notable increase in MIC to nalidixic acid in shigella in Vietnam over the last 10 years, it may not yet be substantial enough to hinder the bactericidal effect of ciprofloxacin in vivo. • A similar effect of both antimicrobial agents, despite gatifloxacin having greater in vivo activity, supports the theory of a less severe infection which may not in all cases require an antimicrobial for the cessation of symptoms. Alternatively, shigella may respond in an atypical manner to gatifloxacin with respect to other gram-negative organisms, and mutations in the gyrA and parC gene may have a greater effect in reducing the potency of the antimicrobial agent. • We conclude that in Vietnam, where nalidixic acid resistant Shigellae are highly prevalent, ciprofloxacin and gatifloxacin are similarly effective for the treatment of acute shigellosis	B
				EXCLUSION CRITERIA = any prior treatment with a fluoroquinolone during the current bout of disease, or children with a trophozoite or Entamoeba histolytica in their stool on microscopic examination
					The study was designed as a superiority trial and children with dysentery meeting the inclusion criteria were invited to participate
					Participants received either gatifloxacin (10 mg/kg/day) in a single daily dose for 3 days or ciprofloxacin (30 mg/kg/day) in two divided doses for 3 days
					The primary outcome measure was treatment failure; secondary outcome measures were time to the cessation of individual symptoms
					494 patients were randomised to receive either gatifloxacin (n = 249) or ciprofloxacin (n = 245), of 107 of whom had a positive shigella stool culture
Thompson et al. [21]	2016	Clinical implications of reduced susceptibility to fluoroquinolones in paediatric Shigella sonnei and Shigella flexneri infections	Vietnam	490 paediatric patients <15 years admitted to tertiary units in Vietnam	Clinical information and bacterial isolates were derived from a randomised controlled trial comparing gatifloxacin with ciprofloxacin (above, Vinh et al.) for paediatric shigellosis.	• Shigella flexneri patients treated with gatifloxacin had significantly worse outcomes than those treated with ciprofloxacin. • However, the MICs of fluoroquinolones were not significantly associated with poorer outcome. • The presence of S83L and A87T mutations in the gyrA gene significantly increased MICs of fluoroquinolones. • Elevated MICs and the presence of the qnrS gene allowed shigella to replicate efficiently in vitro in high concentrations of ciprofloxacin. • Conclusions: We found that below the CLSI breakpoint, there was no association between MIC and clinical outcome in paediatric shigellosis infections. However, S. flexneri patients had worse clinical outcomes when treated with gatifloxacin in this study regardless of MIC. • Shigella harbouring the qnrS gene are able to replicate efficiently in high concentrations of ciprofloxacin and we hypothesise that such strains possess a competitive advantage against fluoroquinolone-susceptible strains owing to enhanced shedding and transmission. • NOTE: Data collected between 2006 and 2009	C
					Time-kill experiments were performed to evaluate the impact of MIC on in-vitro growth of shigella, and Cox regression modelling was used to compare clinical outcome between treatments and shigella species
					Patients were excluded if they had
					received any fluoroquinolones within the time of this bacterial illness.
					-Stool samples were collected on admission and standard microbiological techniques were employed to identify shigella and salmonella isolates-Antimicrobial susceptibility testing was performed by disc diffusion following methods prescribed by the CLSI-MICs were calculated by Etest as per the manufacturer’s instructions (AB Biodisk, Sweden). -Strains identified as resistant to ceftriaxone were subjected to further phenotypic tests to confirm ESBL production using discs containing only cefotaxime (30 mg) and both cefotaxime and ceftazidime combined with clavulanic acid (10 mg), according to current CLSI guidelines
Christopher et al. [2]	2010	Antibiotic therapy for shigella dysentery	Systematic review (international)	16 RCTs met the inclusion criteria, which totalled 1748 children and adults based on clinical symptoms of dysentery prior to bacteriological confirmation	Of the 16 RCTs included, this was composed of 2 RCTs comparing antibiotics and placebo vs no drug; and 14 RCTs comparing effectiveness of different antibiotic regimens for treatment of shigella	There was insufficient evidence to consider any class of antibiotic superior in efficacy in treating shigella dysentery, but heterogeneity for some comparison limits confidence in the results	C
						There were no statistically significant differences in adverse events between participants taking macrolides, β-lactams or fluoroquinolones, leading the authors to conclude that all antibiotics were safe
						There was inadequate evidence regarding the role of antibiotics in prevention of complications]
						Conclusion: Low- to moderate-quality evidence that antibiotic therapy significantly reduces the number of children with dysentery on follow-up compared with no antibiotic
					All RCTs were low- to moderate-quality evidence: of the 16 trials, 7 were at risk of bias owing to inadequate allocation concealment, and 12 owing to incomplete reporting of outcome data
					Limited data from one 3-armed trial of people with moderately severe illness suggest that antibiotics reduce the episodes of diarrhoea at follow-up
					Many RCTs included in the review were conducted before 1990 and included Abx no longer used owing to high resistance (cotrimoxazole, ampicillin, nalidixic acid)
					Reviewed both developed and developing countries, limiting generalisability of findings to developing country settings

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