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

Abstract Background: Shigella remains the primary cause of diarrhoea in paediatric patients worldwide and accounts for up to 40,000 deaths per year. Current guidelines for the treatment of shigellosis are based on data which are over a decade old. In an era of increasing antimicrobial resistance, an updated review of the appropriate empirical therapy for shigellosis in children is necessary, taking into account susceptibility patterns, cost and the risk of adverse events. Methods: A systematic review of the current published literature on the treatment of shigella dysentery was undertaken in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Results: The initial search produced 131 results, of which nine studies met the inclusion criteria. The quality of the studies was assessed as per the Grading of Recommendations Assessment, Development and Evaluation (GRADE) guidelines. International guidelines were also reviewed. There is a lack of current research regarding the clinical treatment of shigellosis in paediatric and adult patients, despite rising antimicrobial resistance worldwide. In particular, there is a lack of studies assessing the non-susceptibility of community-acquired strains, with almost all published research pertaining to microbiological data from hospital-based settings. Discussion: Current WHO guidelines support the use of fluoroquinolones (first-line), β-lactams (second-line) and cephalosporins (second-line) which accords with currently available evidence and other international guidelines, and there is no strong evidence for changing this guidance. Azithromycin is appropriate as a second-line therapy in regions where the rate of non-susceptibility of ciprofloxacin is known to be high, and research suggests that, from a cardiac point of view, azithromycin is safer than other macrolide antibiotics. Cefixime is also a reasonable alternative, although its use must be weighed against the risk of dissemination of extended-spectrum β-lactamase-producing organisms.


Introduction
Shigella is a Gram-negative, non-motile bacillus belonging to the enterobacteriacae family of which four species exist: S. dysenteriae, S. flexneri, S. boydii and S. sonnei (designated as serogroups A, B, C and D, respectively) with multiple serotypes. Of the estimated 165 million shigella diarrhoeal episodes every year, 99% of cases occur in low-and middle-income countries (LMIC), mainly (69%) in children [1]. Shigella has recently been identified as the leading pathogen causing childhood diarrhoea worldwide, and has been estimated to be responsible for 1.1 million deaths per year, 61% of which are children <5 years of age [2,3].
Because of overcrowding and poor sanitation, shigellosis occurs predominantly in LMIC. Infants, non-breast fed or malnourished children and adults >50 years have a more severe illness and a greater risk of death [4]. Acquired immunity to shigella is serotype-specific. While S. boydii and S. sonnei usually cause a relatively mild illness (watery or bloody diarrhoea only), S. flexneri and S. dysenteriae are chiefly responsible for endemic and epidemic shigellosis, respectively, in developing countries, with high transmission rates and significant case fatality. S. dysenteriae (Type 1, also known as Shiga bacillus) is capable of causing a more severe and prolonged illness owing to the production of a potent cytotoxin (Shiga) which is associated with the development of haemolytic-uraemic syndrome [5]. Other complications of shigellosis include sepsis, rectal prolapse, arthralgia, intestinal perforation, toxic megacolon, electrolyte imbalance, seizures and leukaemoid reactions [1,2].
The species distribution of shigella infection varies globally. While S. sonnei is the predominant species worldwide, S. flexneri is more prominent in low-income settings in Africa and Asia [1,4] while the less virulent S. sonnei predominates in higher-income settings [5,6].
guidelines also listed antimicrobials which should not be used to treat shigellosis owing to their poor mucosal penetration or increasing antimicrobial resistance ( Table  2). The more recently published 2013 WHO Pocketbook of Hospital Care for Children included a chapter on the treatment of shigella dysentery, with recommendations which were the same as in the 2005 guidelines [10].
Current guidelines are therefore based on evidence which is increasingly outdated. In view of changing patterns of resistance to antimicrobials worldwide, this systematic review was undertaken to evaluate the current international literature on the treatment of shigellosis in children.

Methods
A systematic search for systematic reviews, meta-analyses, multi-centre studies and randomised controlled trials of antibiotic therapy was undertaken using the MeSH search terms 'Shigella' , 'dysentery' , 'antibiotics' and 'antimicrobials' . The databases EMBASE, Cochrane database of systematic review and Pubmed were searched. To ensure accurate and up-to-date information on antimicrobial non-susceptibility patterns, the search was limited to trials in humans published since 2005. Inclusion and exclusion criteria are listed in Table 3.
Initially, the search was restricted to studies in the paediatric population but published research in this age group was limited and the search was, therefore, expanded to include all ages. International clinical practice guidelines were also reviewed, including the Infectious Diseases Society of America (IDSA), BMJ Clinical Evidence, the American Academy of Pediatrics and Therapeutic Guidelines (Australia).

Results
The initial search produced 131 results (Figure 1), 28 of which qualified for full-text review. Ultimately, nine studies met the inclusion criteria and were abstracted as detailed in Appendix 1. The quality of the studies was assessed as per the Grading of Recommendations Transmission occurs via a number of mechanisms -the faecal/oral route, person-to-person contact, household flies, infected water, or inanimate objects following exposure to as few as 10-100 organisms [3,6]. Once infected, all shigella species multiply and cause acute bloody diarrhoea by invading the colonic epithelium where pro-inflammatory cytokines are released, and the subsequent inflammatory reaction (recruiting a number of polymorphonuclear cells) destroys the epithelial cells which line the gut mucosa, allowing for further direct invasion by shigella.
The resultant infectious diarrhoea causes a loss of water and electrolytes with a clinical picture of abdominal cramping, fever, and bloody/mucoid stools. Stool microscopy -a cheap, rapid and simple diagnostic test -demonstrates numerous polymorphonuclear cells on methylene blue stain; however, microbiological culture is required to differentiate between shigella and other causes of colitis [7]. Multiplex polymerase chain reaction (PCR) platforms for the detection of shigella are commercially available but in most health-care settings their availability is limited.
With effective antibiotic therapy, clinical improvement occurs within 48 h, resulting in a decreased risk of serious complications and death, shorter duration of symptoms, and the elimination of shigella from the stool. This results in diminished transmission of infection by decreasing the duration of faecal carriage from approximately 4 weeks to 3 days, conferring significant public health benefits [8,9]. Current guidelines for treating shigella were published by WHO in 2005 and they recommend ciprofloxacin as the first-line treatment (Table 1) [4]. The guidelines also noted that pivmecillinam (amdinocillin pivoxil) and ceftriaxone were 'the only antimicrobials that are usually effective for the treatment of multi-resistant strains of Shigella in all age groups' , yet their usage is limited by their high cost and formulation (four times daily dosing for pivmecillinam, and parenteral administration for ceftriaxone). Pivmecillinam and ceftriaxone were therefore only listed for use when local strains of shigella are known to be resistant to ciprofloxacin. Azithromycin was included as a second-line therapy for adults. The 2005  [11].

Characteristics of included studies
Of the papers eligible for inclusion, six studies were systematic reviews and meta-analyses (conducted across an international setting). One, a multi-centre study, evaluated 600,000 cases of shigella diarrhoea in six Asian countries. Two papers were based on data collated from a multi-centre randomised trial in Vietnam.
Four papers were classified as high-quality evidence, three as moderate-quality evidence and the two papers based on data investigating a multi-centre trial in Vietnam were classified as low-quality evidence.
Two systematic reviews exclusively assessed paediatric antimicrobial response, while the remainder included adults and children in their population. The papers based on a multi-centre trial in Vietnam investigated clinical outcomes in children < 16 years.
Evidence for current WHO recommendations: ciprofloxacin, pivmecillinam and ceftriaxone A systematic review in 2013 [12] used CHERG standard rules [13] to analyse 48 high-quality randomised controlled trials in children aged <16 years mainly in lowand middle-income countries (LMIC), seven of which were ultimately eligible for inclusion. It demonstrated that current WHO guidelines for treatment with either ciprofloxacin, pivmecillinam or ceftriaxone reduced clinical failure rates (which the authors postulated were a proxy for shigella deaths) by 82% (95% CI 67-99%). It was reported that ciprofloxacin, pivmecillinam or ceftriaxone successfully cleared shigella pathogens in 96% of cases (95% CI 88-99%). The authors concluded that there is strong evidence that current antimicrobial guidelines are effective in preventing serious mortality and morbidity. Of note, 98% of the trials reviewed were undertaken in LMIC which increases the generalisability and applicability of the findings. However, all studies were hospital-based which limits the information available on resistance patterns for shigella infections typically treated within the community.
Another systematic review in 2010 [14] assessed ciprofloxacin, pivmecillinam or ceftriaxone for children in LMIC (limited to hospital-based settings) using CHERG rules to document clinical failure rates of 0.1% (95% CI-0.2-0.5%). It concluded that the antimicrobial antibiotics currently recommended by WHO are effective from both a clinical and bacteriological point of view.
The same authors conducted a review which compared resistance to third-generation cephalosporins (ceftriaxone, cefotaxime and ceftazidime) between 1999 and 2012 [15]: it found markedly increased resistance in   (gatifloxacin 12% vs 11% for ciprofloxacin, p = 0.72), with gatifloxacin showing similar efficacy in the treatment of paediatric dysentery [2]. However, while gatifloxacin might be more convenient than ciprofloxacin owing to its longer half-life (allowing administration once daily rather than twice daily as required for ciprofloxacin), retrospective review of clinical outcomes in patients treated with gatifloxacin revealed significantly poorer clinical outcomes than in those treated with ciprofloxacin, regardless of isolate minimum inhibitory concentrations (MIC). Overall, no association between MIC and clinical outcome in paediatric shigellosis was found [17].
Macrolides. Azithromycin, a macrolide antibiotic, is listed as an alternative second-line therapy for adults in current WHO guidelines as well as in most international guidelines (for both paediatric and adult patients). To date, no trials comparing the efficacy of azithromycin vs ciprofloxacin in children have been published. In the late 1990s, azithromycin was found to be as effective as ciprofloxacin in adults in Kenya and Bangladesh [18]. In Tanzanian adults in 2004-2005, 90% of shigella strains isolated were S. flexneri and all were reported to be sensitive in vitro to ciprofloxacin, nalidixic acid and cefuroxime, while 98% were sensitive to azithromycin. By 2010/2011 in Dhaka, Bangladesh, in vitro susceptibilities to ciprofloxacin, pevmecillinam, azithromycin and ceftriaxone were 65, 50, 74 and 95%, respectively [19]. More recently, however, increasing reports of azithromycin-resistant strains of shigella spp. have been documented, including by the Centers for Disease Control and Prevention (CDC) [20][21][22][23][24].
Oral cephalosporins. Cefixime is an oral thirdgeneration cephalosporin which inhibits bacterial cell wall synthesis by binding to one or more of the penicillinbinding proteins (PBPs), inhibiting cell wall synthesis. It is widely distributed throughout the body and reaches therapeutic concentration levels in most tissues and body fluids, with a time to peak serum concentration of 2-6 h and a half-life of 3-4 h [25]. Cefixime has been demonstrated to be effective (at 8 mg/kg/day in two divided doses) for shigellosis in adults and paediatric patients [26][27][28][29], although one study documented inferior efficacy to that of azithromycin [27]. Short (2day) courses have been found to be as effective as 5-day courses [27,29]. Cefixime may be useful for paediatric patients when cephalosporin is necessary owing to high resistance to fluoroquinolones and β-lactams, and it can be taken orally. Cefixime is affordable and the suspension can be stored at room temperature [28]. Updated clinical trials to investigate this therapy as an alternative treatment option are urgently needed because previous randomised controlled trials investigating its efficacy are over a decade old.

Evidence for alternative antibiotic treatment options
In view of the research above documenting increasing resistance to ciprofloxacin and ceftriaxone, the international literature was reviewed for alternative antimicrobials that might be used for shigella dysentery. Previously effective agents (including nalidixic acid, amoxicillin and co-trimoxazole) have been removed from the WHO guidelines on dysentery because of extensive resistance, a decision which continues to be supported in view of the evidence above.
A 2010 Cochrane review [2] investigated antibiotic therapy for shigella dysentery but found no superior efficacy when comparing fluoroquinolones, β-lactams or macrolides. The authors noted that the current practice of presumptively treating shigella dysentery with antibiotics should continue because of the public health benefits conferred, but that no specific antibiotic, or antibiotic class, is universally effective for shigella. However, this study included several randomised controlled trials of low-to moderate-quality (many of which were conducted before 1990) and probably do not reflect current resistance patterns.

Aminoglycosides.
A 2013 systematic review [16] which assessed worldwide patterns of aminoglycoside resistance in shigella (between 1999 and 2010) documented increasing levels of in vitro gentamicin resistance in the Asia-Africa region which reached 32.4% (95% CI 17.87-48.91%) in 2005-2007. Resistance to gentamicin, kanamycin and amikacin was higher in children than in adults. The 2010 Cochrane review outlined above further supported the ineffectiveness of aminoglycosides which tend to have poor absorption when administered orally, further limiting their usefulness.
Fluoroquinolones. Gatifloxacin, a fourth-generation fluoroquinolone, was investigated as an alternative therapy in a multi-centre randomised trial assessing the efficacy of gatifloxacin vs ciprofloxacin for shigellosis in Vietnamese children between 2006 and 2008 [17]. No superiority to gatifloxacin was found in terms of clinical failure rates which were similar in both groups repolarisation are clinically unnoticeable, although these antimicrobials may serve to amplify the risk of torsades de pointes (TdP), a potentially fatal polymorphic ventricular tachyarrhythmia which may present as sudden death (owing to ventricular tachycardia), syncope, palpitations, seizures or asymptomatically if the duration is short and it terminates spontaneously [35]. Of note, the current literature identifies this risk as requiring the presence of other risk factors, as highlighted in Table 6. The main reported risk factor for TdP is co-administration of other medications which are substrates and/or inhibitors of cytochrome P450 (CYP) enzymes, and the possibility of metabolic instability resulting from synergistic interactions with this enzyme. This risk is enhanced by individual allelic variations in CYP3A4, the most important enzyme in human drug metabolism. CYP3A4 is responsible for the biotransformation of approximately 60% of all oxidised drugs and allelic variations can result in patients being poor metabolisers of CYP3A4-inducing medications, resulting in reduced clearance of drug substrates and increasing exposure to the effects of toxicity [36].
Existing evidence suggests that the individual risk of cardiac arrhythmias secondary to these antimicrobials is minimal; yet, when combined with a genetic propensity to poor metabolism of CYP3A4-inducing medications and co-administration with other CYP potentiators, the risk may be magnified. How this might affect clinical practice, however, remains unclear. Another important risk factor to consider is the possibility of acute renal failure in the setting of severe dehydration secondary to shigellosis which could result in decreased clearance and enhanced toxic effects, increasing prolongation of the QT interval in a clinical setting.
Prolonged QT syndrome and azithromycin. As discussed, the predominantly reported risk of macrolideassociated TdP is the co-administration of other CYP3A4 inhibitors, resulting in increased drug toxicity. However, azithromycin has been identified as distinguishable from other macrolides as a group in terms of its cardiac toxicity as it minimally inhibits CYP3A4, resulting in a lack of appreciable interaction with other CYP3A4 substrates, and is classified as one of the safer macrolide antibiotics from a cardiac perspective [35,37]. In recent years, however, increasing attention has been paid to azithromycin's risks following a documented increased risk of cardiac death in a cohort of 347,795 patients aged 30-74 years taking azithromycin [38]. The study found that patients taking 5 days of azithromycin, in comparison with taking no antibiotics, had a statistically significantly increased risk of cardiac death (hazard ratio 2.88, 95% CI 1.25-2.75, p < 0.0001) as well as of death from any cause (HR 1.85, 95% CI 1.25-2.75, p = 0.002). However, the risk was found to be most pronounced in patients with a high baseline risk of cardiovascular No other antimicrobial agents were investigated in the research which met this review's inclusion criteria.

Synopsis of international guidelines
Four evidence-based international guidelines were reviewed (listed in order of most recently updated): the Infectious Diseases Society of America (IDSA) [30], Therapeutic Guidelines (Australia) [31], the American Academy of Pediatrics (AAP) [7] and BMJ Clinical Evidence [32]. Their recommendations are summarised in Table 4. Apart from the IDSA guidelines which are currently under review (last published in 2001), in line with the 2005 WHO guidelines [4], most international guidelines currently recommend fluoroquinolones as first-line therapy.
Of note, comparison of international guidelines reveals differing dosage ranges for ciprofloxacin, from 12.5 mg/kg [31] to 20 mg/kg (BNF) [33], and the WHO 2005 guidelines list 15 mg/kg as the currently recommended dosage [4]. Ciprofloxacin has high oral bio-availability (approximately 70%) which is not influenced by the concurrent administration of feeds, and no substantial loss by first-pass metabolism. Maximum serum concentrations are attained 1 or 2 h after oral dosing, and its half-life is approximately 4 h in patients with normal renal function [32]. References supporting the efficacy of a higher dose range (20 mg/kg, above the currently recommended 15 mg/kg) were not found in the literature, and, owing to the associated risk of adverse events when combined with other CYP3A4 inhibitors (discussed below), there is no current evidence base to suggest that a higher dose of ciprofloxacin than currently recommended is warranted in shigellosis. Furthermore, higher minimum inhibitory concentrations (MIC) of fluoroquinolones requiring increased ciprofloxacin concentrations have not been found to be significantly associated with poorer clinical outcomes [30].

Review of harms and toxicity -summary of evidence on safety
Adverse events. A 2010 systematic review of 1748 paediatric and adult patients [2] found no statistically significant differences in adverse events between patients taking fluoroquinolones, macrolides (including azithromycin) or β-lactams for shigellosis, concluding that all classes of currently available antibiotics for shigellosis are safe. The side effects of therapies currently recommended for shigellosis and those which may be considered in the future are highlighted in Table 5.
Possible cardiac side effects. Previous case reports of fluoroquinolones and macrolides have been associated with prolongation of the QT interval [34,35]. Independently, mild delays in ventricular Fluoroquinolone use and polyneuropathy. In 2013, the FDA issued a communiqué to specifically address the risk of peripheral neuropathy (PN) for all oral fluoroquinolones [41], mainly in response to case reports of this adverse event [42], in the absence of large epidemiological studies. The neurotoxic mechanism is thought to be through the inhibition of GABAreceptors which occurs within days of use and may be permanent. Between 1997 and 2012, the FDA's AERS recorded 539 reports (1% of all submitted events for fluoroquinolones) pertaining to peripheral neuropathy. A review of these reports found that the majority of affected patients were female with a median age of 48 years (range 9-100) [43]. This evidence was further investigated by a 2014 pharmaco-epidemiological study which quantified the risk and demonstrated a relative risk of developing peripheral neuropathy with fluoroquinolone use of 2.07 (95% CI 1.56-2.74) [44]. With regard to ciprofloxacin specifically, the increased disease, and there was evidence of confounding by factors associated with both azithromycin use and risk of cardiovascular disease -namely a history of smoking, high body mass index, poor diet and low physical activity. At present, published case reports of an increased risk of sudden cardiac deaths in patients taking azithromycin are limited to adults [39,40].
Prolonged QT syndrome and fluoroquinolones. As with macrolides, there is interclass variability in the QT prolongation effect of fluoroquinolones. Ciprofloxacin's inhibition of CYP1A2 has been described as 'relatively inconsequential' [35] and the US Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) supports the notion of several causes of fluoroquinolone-associated TdP, usually in the context of co-administration with another QT-prolonging drugs, underlying cardiac disease, renal impairment and electrolyte anomaly. 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) [ • 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]. explain why shigella resistance patterns vary worldwide -as the distribution of integrons varies according to the species and resistance phenotype (with. S. sonnei and S. boydii strains containing a single class 2 integron, while S. flexneri and S. dysenteriae carry a class 1 integron, often in combination with a class 2 integron which increases the propensity of dissemination of MDR strains of shigella) [53]. This underpins the importance of any antimicrobial resistance programme including surveillance to document changes in prevalent species in regions worldwide.
Resistance to fluoroquinolones. The primary target of fluoroquinolones is the DNA gyrase, a type II topoisomerase essential for DNA replication and transcription. Mutations in the gyrA gene have been shown to increase the MICs of fluoroquinolones for shigella spp. and other enterobacteriaceae, while plasmid-mediated quinolone resistance genes can also be acquired [54]. Of concern, complete ciprofloxacin resistance (MIC ≥ 4 mg/L) has recently been reported in domestic and imported S. sonnei isolates in the USA, Vietnam and elsewhere [55][56][57], and patients infected with fluoroquinolone-resistant shigella have a longer duration of diarrhoea than those with fluoroquinolonesusceptible strains [26]. Ciprofloxacin resistance must continue to be closely monitored and non-susceptibility should be reported when data are available.
Resistance to cephalosporins. Cephalosporin resistance is also of concern, arising from the production of plasmid-mediated β-lactamase [58]. Resistance to thirdgeneration cephalosporins owing to the production of extended-spectrum β-lactamases (ESBLs) which confer resistance to all β-lactamases (except cephamycins and carbapenems) is increasingly prevalent and has been documented in recent laboratory analyses in Asia [59,60]. ESBL resistance in shigella spp. needs to be closely monitored in view of the necessity of treatment with expensive carbapenems, one of the last options for treating multi-resistant Gram-negative organisms, and there has been a considerable increase in the prevalence of ESBL resistance, including in shigella [53,59,60]. Thus, previous reports of the efficacy of ceftriaxone and cefixime might not reflect today's susceptibility patterns; the use of these agents rapidly induces ESBLs and resistance to other antibiotic classes.

Discussion
Shigella, a Gram-negative enterobacteriaceae, is responsible for 165 million diarrhoeal episodes each year, 99% of which occur in LMIC, and 69% in the paediatric population. With effective antibiotic therapy, there is clinical improvement within 48 h, diminishing the risk of mortality and decreasing transmission by eliminating shigella from the stool. The WHO 2005 Guidelines for the Control of Shigellosis, Including Epidemics due to risk was quantified as RR 1.93 (95% CI 1.32-2.82), a small but appreciable increase. However, the research was based on a cohort of men with a mean age of 68 years, and it is difficult to extrapolate these data to the paediatric population. Because of the risk of permanent peripheral neuropathy resulting from fluoroquinolone use, the FDA's most recent advice warns against the use of fluoroquinolone except when no other treatment is available [41]; yet, in the setting of global shigella spp. non-susceptibility, the public health benefits of treatment outweigh the small yet statistically significant risk of this adverse event.
Co-administration of azithromycin with artemisinin-based antimalarial drugs. Co-administration of macrolides or quinolones with other QT-prolonging agents could present a clinical problem, yet nearly all data examining the risk are for adults (often with pre-existing cardiac risks), and genetic differences between populations may limit interpretation. Azithromycin is a weak antimalarial that has been used in combination with several other anti-malarials or co-administered to treat non-malarial infections. Current evidence evaluating the cardiac risk of azithromycin co-adminsitered with chloroquine [45][46][47], artesunate/arthmeter [48,49] or piperaquine [50,51] does not identify an increased risk of cardiac instability in paediatric patients.

Antimicrobial resistance patterns
Evidence suggests that antibiotic resistance is an increasing challenge in the therapeutic management of shigellosis, as recognised by the WHO prioritising ciprofloxacin-resistant shigella as a target of current international focus on antimicrobial resistance [52]. There are several mechanisms by which this may occur. In shigella spp., antimicrobial resistance is often owing to classes 1 and 2 integrons which contain resistance gene cassettes which are mobile and transferrable from one bacterium to another, providing a flexible way for bacteria to adapt to the environmental pressure caused by antibiotics. This may account for the dissemination of resistant genes and the emergence of multidrug-resistant strains, and compare the efficacy of ciprofloxacin, azithromycin and cefixime as the first-line treatment of shigellosis in children, including the assessment of MICs in relation to treatment outcomes and addressing the risks of exacerbating resistance in other intestinal bacteria, especially ESBL-producing enterobacteriaceae.
In conclusion, current WHO guidelines supporting the use of fluoroquinolones (first-line), β-lactams (second-line) and cephalosporins (second-line) accord with currently available evidence and other international guidelines, and there is no strong evidence to change this guidance. Azithromycin may be considered as an appropriate second-line therapy in regions with known high rates of ciprofloxacin non-susceptibility. Cefixime is also a reasonable alternative, although its use must be balanced against the risk of increasing antimicrobial resistance and the spread of ESBL.
Shigella Dysenteriae Type 1 listed the fluoroquinolone ciprofloxacin (15 mg/kg orally twice daily for 3 days) as first-line treatment for shigellosis in children, and (more expensive and less available) pivmecillinam (amdinocillin pivoxil) and (parenteral) ceftriaxone were listed as second-line therapy when local strains were known to be resistant to ciprofloxacin. The macrolide azithromycin was listed as a second-line therapy for adults.
There is a lack of current research on the clinical treatment of shigellosis in paediatric or adult patients, despite rising antimicrobial non-susceptibility rates worldwide. In particular, there is a lack of research assessing the non-susceptibility of community-acquired strains; almost all published research pertains to microbiological data from hospital-based settings. Research investigating non-susceptibility of community-acquired shigellosis is urgently required. A large proportion of the current evidence is based on in vitro studies which do not necessarily correspond with clinical outcomes, and studies of clinical efficacy do not evaluate individual drugs.
A number of international guidelines currently list azithromycin as a first-and second-line therapy for shigellosis in children. While there are no published trials comparing the efficacy of azithromycin with that of ciprofloxacin for shigellosis in children, previous trials in adults have demonstrated similar efficacy and higher in vitro susceptibility; however, reports of azithromycin-resistant strains are increasing. In areas where ciprofloxacin-resistance is evident, azithromycin is an appropriate second-line alternative therapy owing to its oral administration and affordability. Safety concerns (the risk of polyneuropathy in ciprofloxacin use and prolonged QT syndrome secondary to azithromycin) are based mainly on retrospective studies in adults and results cannot necessarily be extrapolated to the paediatric population, although care should be taken when co-administering with other CYP450 inducing medications.
Prior research has investigated the antibiotics currently recommended by WHO together rather than assessing individual therapies. Research investigating non-susceptibility of ahigellosis -particularly community-acquired strains -is urgently required, and in vitro non-susceptibility studies need to be correlated with clinical outcomes. Further randomised controlled trials adhering to CONSORT guidelines are required to guide future treatment options for shigellosis, especially in populations at risk of high case fatality (such as malnourished or HIV-positive children). The efficacy of oral cephalosporins (cefixime) for shigellosis should be a priority for research as it is affordable and easily administered compared with (the currently recommended) parenteral ceftriaxone. Specifically, a large randomised controlled trial in children in the Asia-Africa region should • 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).
• 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 • the changes in kanamycin resistance in european-american countries were minimal; in fact, the resistance prevalence decreased annually.
• Kanamycin resistance in the paediatric age group was significantly higher than in the adults which showed 70.72% (33. • 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