Shigella infection: Treatment and prevention in children

INTRODUCTION — Shigella infections are a major cause of pediatric morbidity and mortality worldwide.

Shigella infection is characterized by high fever (>38.5°C [101.3°F]), abdominal cramps, diarrhea, tenesmus, and polymorphonuclear leukocytes on a methylene blue stain of the stool; extraintestinal manifestations and complications also occur (table 1) [1,2]. Definitive diagnosis requires a stool culture or a polymerase chain reaction assay. The characteristic small-volume, bloody/mucous stools are present in approximately one-half of the children with shigellosis [1]. Neonates [3] and children with underlying immune deficiency (including human immunodeficiency virus [HIV] infection) [4,5] or malnutrition [6,7] are at increased risk of bacteremia and other complications of shigellosis. (See "Shigella infection: Epidemiology, clinical manifestations, and diagnosis".)

The treatment of and prevention of Shigella infection in children will be reviewed here. The microbiology, epidemiology, pathogenesis, clinical manifestations, and diagnosis of Shigella infection in children are discussed separately, as is the treatment of Shigella in adults. (See "Shigella infection: Epidemiology, clinical manifestations, and diagnosis" and "Shigella infection: Treatment and prevention in adults".)

NATURAL HISTORY — Infection with Shigella generally is self-limited; the average duration of gastrointestinal symptoms in untreated Shigella gastroenteritis is approximately seven days [8]. In the absence of specific antibiotic treatment, children with Shigella gastroenteritis shed the organism for up to four weeks; children with immune deficiency shed for much longer periods, even if their symptoms have resolved [1,4,5].

SUPPORTIVE THERAPY — Correction of fluid and electrolyte losses is the mainstay of treatment of acute gastroenteritis in children, no matter the cause [1]. Oral rehydration is preferred when feasible [9], but intravenous fluids may be necessary. Fluid repletion in children is discussed separately. (See "Oral rehydration therapy" and "Treatment of hypovolemia (dehydration) in children in resource-abundant settings".)

Early restoration of oral intake, especially protein, is important to prevent malnutrition, particularly in resource-limited countries [10-12]. In addition, the administration of vitamin A or zinc, or the ingestion of unripe, mature green banana fruit, may hasten resolution of symptoms in malnourished children in resource-limited countries [13-17]. (See "Approach to the child with acute diarrhea in resource-limited settings", section on 'Vitamins and minerals'.)

Intestinal antimotility drugs (eg, paregoric, diphenoxylate, loperamide) should be avoided in children with suspected shigellosis [18]. These drugs may prolong the duration of fever, diarrhea, and excretion of the organism [19].

ANTIBIOTIC RESISTANCE — Antibiotic susceptibility testing is essential for management of patients with suspected Shigella infection. Antimicrobial resistance is relatively high and patterns of resistance vary geographically [20-23].

●In the United States – In the United States, antimicrobial resistance is an increasing problem. Among the 3079 Shigella isolates tested by the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria by whole genome sequencing during 2022, the following results were reported [23]:

•Ceftriaxone – 10.9 percent resistant

•Ciprofloxacin – 54.3 percent had decreased susceptibility

•Azithromycin – 32.1 percent resistant

•Ampicillin – 67.8 percent resistant

•Trimethoprim-sulfamethoxazole – 63.3 percent resistant

•Nalidixic acid – 31.8 percent resistant

In 2022, 89.1 percent of isolates tested by whole genome sequencing were resistant to ≥3 Clinical and Laboratory Standards Institute antimicrobial classes [23], and 5 percent were extensively drug resistant (ie, resistant to azithromycin, ciprofloxacin, ceftriaxone, trimethoprim-sulfamethoxazole, and ampicillin (compared with 0 percent in 2015) [24]. Only 5 percent of patients with XDR Shigella isolates were children.

Risk factors for drug-resistant Shigella include international travel to or adoption from Asia or Africa [23,25-27] and treatment with cephalosporins for Shigella or Salmonella infection [28]. In addition, antibiotic-resistant Shigella infections have been observed more frequently among men who have sex with men, people with HIV infection, and people experiencing homelessness [24,29,30].

Decreased susceptibility to azithromycin and/or other antibiotics has also been detected in several Shigella sonnei and Shigella flexneri outbreaks and sporadic cases throughout the United States, predominantly among men who have sex with men and people experiencing homelessness [24,29,31-35]. Scattered infections with extremely drug-resistant isolates that are ciprofloxacin-resistant and have decreased susceptibility to azithromycin have also been reported [36,37].

Species-, state-, and antibiotic-specific resistance information is available from NARMS Now, an interactive tool provided by the Centers for Disease Control and Prevention [23].

●In other regions

•Europe – In Europe, resistance to nalidixic acid, ceftriaxone, and azithromycin has been reported [38,39] but is uncommon. In a systematic review, during 2010 to 2012, <1 percent of isolates from Europe-America were resistant to ceftriaxone, cefotaxime, and ceftazidime [40].

•New Zealand – In a 2015 to 2016 nationwide survey of Shigella isolates in New Zealand, 23 percent of isolates were resistant to fluoroquinolones and 11 percent were resistant to azithromycin [41].

•Asia and Africa – In India and Bangladesh, 20 percent or more of isolates are resistant to nalidixic acid [42-44]. Increasing levels of resistance to ceftriaxone and azithromycin have also been reported in Asia [45-47]. In a systematic review, during 2010 to 2012, 14 percent of isolates from Asia-Africa were resistant to ceftriaxone, 23 percent to cefotaxime, and 6 percent to ceftazidime [40]. Resistance to third-generation cephalosporins was especially high in Vietnam, China, and Iran.

ANTIBIOTIC THERAPY

Rationale — The goals of antibiotic therapy for Shigella include improvement in symptoms and eradication of the organism, which may result in decreased spread of infection.

In randomized trials, appropriate antimicrobial treatment of Shigella gastroenteritis improves diarrhea (by approximately three days), fever (by approximately one day) and reduces shedding (two to five days versus up to four weeks if untreated) [48-52]. It is uncertain whether antibiotic therapy prevents relapse [52]. Appropriate antimicrobial treatment also may reduce the risk of developing complications [49,53]. (See 'Natural history' above and "Shigella infection: Epidemiology, clinical manifestations, and diagnosis", section on 'Intestinal complications' and "Shigella infection: Epidemiology, clinical manifestations, and diagnosis", section on 'Systemic complications'.)

These benefits outweigh the potential risk of promoting the development of resistant organisms. Serious adverse effects may occur with antibiotics used to treat Shigella (eg, anaphylaxis, hypersensitivity, Stevens-Johnson syndrome). However, in a 2010 meta-analysis of 16 trials (1748 pediatric and adult participants), all of the antibiotics were found to be safe; no serious adverse effects were reported. Antimicrobial therapy does not appear to increase the risk of Shigella dysenteriae-related hemolytic-uremic syndrome [54]. (See "Shigella infection: Epidemiology, clinical manifestations, and diagnosis", section on 'Hemolytic-uremic syndrome (HUS)'.)

Indications — Decisions regarding initiation of antimicrobial therapy must consider the clinical condition of the patient, host factors that predispose to more severe infection, and public health considerations. Shigella is highly contagious – ingestion of as few as 10 organisms can produce disease [55]. Thus, eradication of the organism from children and adolescents at risk to transmit the disease to others (eg, a daycare attendee, hospitalized patient) is particularly compelling.

●Immunocompromised or ill patients – We recommend empiric antimicrobial therapy for shigellosis in children and adolescents who present with suspected shigellosis (eg, bloody/mucous diarrhea, abdominal cramping, high fever, polymorphonuclear leukocytes on a methylene blue stain of the stool) and [6,56]:

•Are immunocompromised

•Have clinical features that may suggest bacteremia (leukocytosis, hypothermia, temperature >39°C [102.2°F], lethargy)

For these patients, antibiotics should be started empirically – after obtaining stool, and, if needed, also blood culture – and then modified as needed based upon susceptibility testing. (See 'Choice of regimen' below.)

●Symptomatic patients with culture-proven Shigella – We recommend antimicrobial therapy for children and adolescents with symptomatic culture-proven Shigella who:

•Have documented bacteremia

•Require hospitalization

•Attend daycare

•Live in institutions

•Are involved in food handling

For other symptomatic patients, antimicrobial therapy also may be warranted, but the decision depends upon the severity of illness and risk of transmitting infection to others.

●Suspected Shigella – We suggest antimicrobial therapy for symptomatic children and adolescents who do not fall into one of the above categories and have one of the following:

•Suspected shigellosis according to epidemiologic data (eg, outbreak setting, positive culture in household or daycare contact, etc)

•Suspected shigellosis on clinical basis (bloody/mucous diarrhea, high fever)

●Mild disease or recently recovered – We do not recommend antimicrobial therapy for most children with mild disease or spontaneous recovery. We suggest antimicrobial therapy for children with mild disease or children who have recovered from Shigella by the time the report of positive Shigella culture is available if they are hospitalized, attend daycare centers, or live in institutions. However, such treatment is controversial. Antimicrobial treatment is unlikely to significantly affect the clinical course but will shorten fecal excretion and thus possibly reduce the spread of this highly contagious bacterium.

Choice of regimen — The empiric antibiotic regimen is determined by host factors, severity of illness, local resistance patterns, and history of travel to an area with increased resistance [57,58]. Empiric therapy is changed as necessary based upon the results of susceptibility testing (which should be performed on all isolates) or if the patient remains symptomatic after ≥3 days of therapy. (See 'Antibiotic resistance' above and 'Treatment failure' below.)

Parenteral versus oral therapy — Parenteral antibiotic therapy is indicated for children with proven or suspected shigellosis who:

●Have underlying immune deficiency; shigellosis in children with immune deficiency, including acquired immunodeficiency syndrome (AIDS), is associated with a prolonged course, increased risk of complications, and prolonged shedding

●Have severe toxemia or suspected bacteremia (signs of suspected bacteremia include leukocytosis, hypothermia, temperature >39°C [102.2°F], and lethargy [6]); bacteremia is associated with increased mortality (see "Shigella infection: Epidemiology, clinical manifestations, and diagnosis", section on 'Systemic complications')

●Are unable to take oral medications (vomiting, stupor, etc)

Parenteral therapy

●Susceptibility results available – Children whose susceptibility testing results are available should be treated with an antibiotic to which their isolate is susceptible.

●Susceptibility of isolate unknown and extensively drug resistant shigellosis is not suspected – For children and adolescents with proven or suspected shigellosis, in whom the antibiotic susceptibility of the isolate is unknown and extensively drug-resistant Shigella is not suspected, the preferred parenteral therapy varies with age.

•For children <18 years of age, we prefer ceftriaxone [56]. Fluoroquinolones are an alternative for children in whom there is no other safe and effective alternative [59]. (See "Fluoroquinolones", section on 'Children'.)

•For children ≥18 years of age, we prefer ceftriaxone or ciprofloxacin [8,60,61].

The regimens are as follows:

•Ceftriaxone 50 mg/kg per day intravenously (IV) in a single daily dose (maximum 1.5 g) for five days.

Patients who do not have immune deficiency or bacteremia and are afebrile after two days may be treated for two rather than five days [62]. In comparative studies, two days of ceftriaxone was as effective as five days [62,63]. However, a single dose of ceftriaxone did not eradicate Shigella from the stool in adult patients [63].

•Ciprofloxacin 10 mg/kg IV (maximum 400 mg/dose) every 12 hours for three to five days [8,60,61].

Both ceftriaxone and ciprofloxacin achieve high concentrations in the serum and stool and have activity against Shigella and usually against some other bacterial causes of diarrhea (eg, ceftriaxone against Salmonella; ciprofloxacin against Salmonella and Campylobacter) [64,65].

The benefits of ceftriaxone were demonstrated in an open trial in which 40 children (mean age 4.5 years) with severe Shigella dysentery were randomly assigned to IV ceftriaxone 50 mg/kg per day or ampicillin 100 mg/kg per day for one to two days followed by intramuscular or oral therapy, respectively [66]. All of the Shigella isolates were sensitive to ceftriaxone, whereas 28 percent were resistant to ampicillin. Children treated with ceftriaxone had shorter mean duration of diarrhea (2.5 versus 6.8 days), greater rates of eradication from the stool after five days (100 versus 60 percent), and fewer bacteriologic relapses (0 versus 40 percent) than those treated with ampicillin.

●Confirmed or suspected extensively drug-resistant shigellosis – For children with confirmed or suspected extensively drug-resistant shigellosis, consultation with an expert in infectious diseases may be warranted. Parenteral therapy options for extensively drug-resistant Shigella are limited. Some experts suggest intravenous carbapenem therapy (eg, meropenem), although carbapenems should be reserved for children with severe Shigella infection or Shigella infection in an immunocompromised child [67]. Extensively drug-resistant Shigella isolates in the United States generally do not carry resistance mechanisms for carbapenems [24].

Oral therapy — Oral treatment of shigellosis depends upon local resistance patterns. Susceptibility testing should be performed on all isolates and empiric therapy changed as necessary based upon the results, as well as on clinical response because the breakpoints for susceptibility to azithromycin have not been established [8,39,56]. Recommended doses and durations are provided in the table (table 2).

Children <18 years

●Preferred initial oral therapy

•Susceptibility results available – Children whose susceptibility testing results are available should be treated with an antibiotic to which their isolate is susceptible.

•Susceptibility unknown and extensively drug-resistant shigellosis is not suspected – Azithromycin is the preferred initial oral treatment of shigellosis in children <18 years of age if the antibiotic susceptibility of the isolate is unknown and extensively drug-resistant Shigella is not suspected.

In a randomized trial in hospitalized adults with shigellosis, azithromycin was clinically and bacteriologically successful in 82 and 94 percent of recipients, respectively [64]. However, resistance to azithromycin is increasing in many parts of the world [23,30,36,41,68] and in certain populations, such as adolescent men who have sex with men [29,33]. Children and adolescents who do not respond to azithromycin may require an alternative agent, guided by susceptibility testing to other antibiotics. (See 'Antibiotic resistance' above.)

For children who acquire shigella in South Asia (eg, India, Pakistan, Bangladesh), cefixime or ceftibuten may be used as the initial oral agent. In South Asia there is widespread resistance to other commonly used drugs, including ciprofloxacin, trimethoprim-sulfamethoxazole, and azithromycin [45].

•Confirmed or suspected extensively drug-resistant shigellosis – For children with confirmed or suspected extensively drug-resistant shigellosis, consultation with an expert in infectious diseases may be warranted. Some experts suggest a regimen of pivmecillinam (not available in the United States) for 5 to 7 days with fosfomycin on days 1, 3, and 5 [67]. Extensively drug-resistant Shigella isolates in the United States generally do not carry resistance mechanisms for fosfomycin [24].

●Oral therapy alternatives – Alternative oral treatment options for children <18 years of age include:

•Fluoroquinolones (eg, ciprofloxacin, norfloxacin [not available in the United States]) are an alternative to azithromycin; in children <18 years of age they are reserved for Shigella caused by isolates resistant to other oral antibiotics [59]. (See "Fluoroquinolones", section on 'Children'.)

•Cefixime or ceftibuten is an alternative to azithromycin [69-71], although experience with these agents is limited and their efficacy is unclear [56]. In an open randomized trial, azithromycin was more effective than cefixime in bacterial eradication [72].

•Nalidixic acid (not available in the United States) is an alternative in regions with low levels of resistance. However, nalidixic acid must be given four times per day. In addition, in studies in children and adults, nalidixic acid was inferior to fluoroquinolones and azithromycin in reducing duration of diarrhea and/or eradication of the organism from the stool [73-76].

•Pivmecillinam (an extended spectrum penicillin, also not available in the United States) is another alternative. In randomized trials and systematic reviews, it was effective in reducing duration of diarrhea and eradication of the organism from the stool [57,61,77]. However, pivmecillinam must be given four times per day [57].

•Trimethoprim-sulfamethoxazole or ampicillin should be used only if the isolated strain is known to be susceptible given the high worldwide resistance.

Adolescents ≥18 years — The approach to the treatment of Shigella in adolescents ≥18 years is the same as that for adults. (See "Shigella infection: Treatment and prevention in adults".)

FOLLOW-UP

Treatment response — Improvement (eg, fewer stools, less blood in the stools, lower fever, improved appetite) is expected within one to two days if Shigella infection is treated with an antibiotic to which the isolate is susceptible [57,78].

Treatment failure — Treatment failure is defined by persistent or worsening fever, grossly bloody stools, or unchanged stool frequency by Day 3 of therapy [78]. Treatment failure suggests a resistant organism or other/additional pathogen. Stool cultures should be obtained in patients with treatment failure [27,37]. Antibiotic therapy should be changed accordingly, based upon culture and susceptibility results. Consultation with an expert in infectious diseases may be warranted. Morbidity and mortality are increased in patients in whom the isolate is not susceptible to the initial antimicrobial agent [79,80].

Test of cure — It is not routinely necessary to obtain stool cultures after appropriate antibiotic therapy in patients who recovered clinically. However, follow-up cultures may be necessary to prevent spread of infection in specific settings (eg, among food-handlers, child care attendees or staff members).

PREVENTION

General measures — General recommendations for the prevention of Shigella infections include the use of safe drinking water, chlorination of unreliable water sources, strict hand washing, and refrigeration and proper cooking of food. A meta-analysis of clinical studies suggested that hand washing with soap reduces the risk of shigellosis by 59 percent [81].

Breast feeding is strongly encouraged in young infants living in less-developed settings because it confers considerable protection against shigellosis, especially against moderate-to-severe disease [82,83].

Food handlers infected with Shigella must be treated with antibiotics and should not be involved in the preparation of food until their stool cultures are negative, which generally requires at least 48 hours of antibiotic treatment. (See 'Indications' above.)

Persons infected with Shigella should stay out of recreational water (eg, swimming pools, water playgrounds, ponds, lakes) during diarrhea and for two weeks after it ends [24].

Isolation — In addition to standard precautions, contact precautions are indicated for the duration of illness or hospitalization for Shigella infection [56]. (See "Infection prevention: Precautions for preventing transmission of infection", section on 'Standard precautions' and "Infection prevention: Precautions for preventing transmission of infection", section on 'Contact precautions'.)

School or daycare — If Shigella infection occurs in a child attending daycare or in a staff member, stool cultures or polymerase chain reaction (PCR) tests should be obtained from other symptomatic daycare attendees, staff members, and household contacts [56]. The local health department should be contacted to assess and manage potential outbreaks.

Symptomatic persons with positive stool cultures or PCR tests should be excluded from the child care center until appropriate antibiotic therapy is initiated and ≥24 hours after diarrhea has resolved and, depending upon local regulations, until one or more stool cultures or PCR tests are negative for Shigella. In an observational study that used published data to calculate the effectiveness of various policies for exclusion from childcare in the setting of a Shigella outbreak, requiring a single negative PCR test before returning to childcare was associated with the lowest probability of transmission [84].

Additional control measures for day schools and daycare centers include [36,85-87]:

●Appropriate hand washing and diapering practices

●Scheduling hand washing sessions on arrival at the daycare center, before meals, or after playing outdoors

●Supervised hand washing for young children

●Eliminating water play areas

Vaccine — A vaccine against shigellosis is not yet available, though this is an area of active investigation, based mainly on observations that serum antibodies against Shigella lipopolysaccharide antigens correlate with serotype-specific protection against shigellosis [88-91].

Antibiotic prophylaxis — We generally do not suggest prophylactic antibiotics to prevent Shigella gastroenteritis in travelers unless the child has an underlying medical illness that predisposes them to severe consequences of shigellosis. The use of antibiotics, including rifaximin (which is not absorbed), to prevent traveler's diarrhea is discussed separately. (See "Travelers' diarrhea: Treatment and prevention".)

MANDATED REPORTING — In the United States, laboratory-confirmed cases of shigellosis should be reported to the Centers for Disease Control and Prevention through local and state health departments [92].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acute diarrhea in children".)

SUMMARY AND RECOMMENDATIONS

●Supportive care – Correction of fluid and electrolyte losses is the mainstay of treatment for acute gastroenteritis in children, no matter the cause. (See "Oral rehydration therapy" and "Treatment of hypovolemia (dehydration) in children in resource-abundant settings".)

Avoid antimotility drugs (eg, paregoric, diphenoxylate, loperamide) in children with suspected shigellosis because they may prolong symptoms and excretion of the organism. (See 'Supportive therapy' above.)

●Goals of antibiotic therapy – The goals of antibiotic therapy for Shigella include improvement in symptoms and eradication of the organism, which may decrease the spread of infection to contacts. (See 'Rationale' above.)

●Indications for antibiotic therapy – Decisions regarding initiation of antimicrobial therapy must consider the clinical condition of the patient, host factors that predispose to more severe infection, and public health considerations. (See 'Indications' above.)

•Suspected shigellosis – Shigellosis should be suspected in children who present with bloody/mucous diarrhea, abdominal cramping, high fever, and polymorphonuclear leukocytes on a methylene blue stain of the stool.

For children and adolescents with suspected shigellosis who are immunocompromised or who have clinical features suggestive of bacteremia (eg, leukocytosis, hypothermia, temperature >39°C [102.2°F], lethargy), we recommend empiric antimicrobial therapy (Grade 1B). (See 'Indications' above.)

•Culture-proven Shigella

-For children and adolescents with symptomatic culture-proven Shigella who have bacteremia, require hospitalization, attend daycare, live in institutions, or are involved in food handling, we recommend antimicrobial therapy (Grade 1A). (See 'Indications' above.)

-For symptomatic children and adolescents with culture-proven shigellosis or suspected shigellosis according to epidemiologic data or clinical presentation, we suggest antimicrobial therapy (Grade 2A). (See 'Indications' above.)

●Choice of regimen – The empiric antimicrobial regimen is determined by host factors, severity of illness, local resistance patterns, and history of travel to an area of frequent resistance. Susceptibility testing guides changes in empiric therapy and should be performed on all isolates. (See 'Choice of regimen' above.)

•We provide parenteral antimicrobial therapy for children with proven or suspected shigellosis and one or more of the following:

-Severe toxemia or suspected bacteremia

-Underlying immune deficiency

-Inability to take oral medications

We typically use ceftriaxone as the first-line parenteral therapy for shigellosis in children <18 years of age if the susceptibility of the isolate is unknown and extensively drug-resistant shigellosis is not suspected (table 2). (See 'Parenteral versus oral therapy' above and 'Parenteral therapy' above.)

•Oral treatment of shigellosis depends upon local resistance patterns.

We typically use azithromycin as the first-line oral treatment of shigellosis in children <18 years of age if the antibiotic susceptibility of the isolate is unknown and extensively drug-resistant shigellosis is not suspected (table 2). (See 'Oral therapy' above.)

The approach to the treatment of Shigella in adolescents ≥18 years is the same as that for adults. (See "Shigella infection: Treatment and prevention in adults".)

●Treatment failure – Treatment failure is defined by Persistent fever, grossly bloody stools, or unchanged stool frequency by day 3 of therapy. Treatment failure suggests a resistant organism or other/additional pathogen, and antibiotic therapy should be changed accordingly. (See 'Treatment failure' above.)

●School and child care precautions – Symptomatic persons with stool cultures positive for Shigella should be excluded from daycare until treatment is initiated, the diarrhea has resolved, and, depending on local regulations, until stool cultures are negative for Shigella. (See 'School or daycare' above.)