INTRODUCTION — Shigella infections are a major cause of morbidity and mortality in resource-limited settings. They are the most common cause of moderate to severe diarrhea among children in Asia and Africa [1]. In the United States, the incidence of Shigella infections is approximately 4 to 8 per 100,000 [2]. The mortality in resource-rich countries is less than 1 percent [3].
The treatment and prevention Shigella infection in adults will be reviewed here. The epidemiology, microbiology, clinical manifestations, and diagnosis of Shigella, as well as the management of Shigella infection in children, are discussed separately. (See "Shigella infection: Epidemiology, microbiology, and pathogenesis" and "Shigella infection: Clinical manifestations and diagnosis" and "Shigella infection: Treatment and prevention in children".)
NATURAL HISTORY OF INFECTION — Infection with Shigella is generally self-limited; the average duration of symptoms associated with untreated Shigella gastroenteritis is seven days [4]. In the absence of specific antibiotic treatment, patients with Shigella gastroenteritis may shed the organism for up to six weeks after the resolution of symptoms; risk factors for asymptomatic shedding are not known.
Complications of Shigella gastroenteritis, including bacteremia and severe colonic disease that results in obstruction or perforation, are uncommon in adults. However, individuals with underlying immunodeficiency (including human immunodeficiency virus [HIV] infection) or malnutrition are at increased risk for complications of and worse outcomes with Shigella infection [5-8]. (See "Shigella infection: Clinical manifestations and diagnosis", section on 'Intestinal complications' and "Shigella infection: Clinical manifestations and diagnosis", section on 'Systemic complications'.)
ANTIMICROBIAL RESISTANCE — The increasing antimicrobial resistance of Shigella species is a major problem in the treatment of Shigella gastroenteritis. Thus, antibiotic susceptibility testing is essential for management of all patients with Shigella infection. This is particularly important in patients who are at risk of infection with a resistant isolate, including patients with infections in Asia and Africa, those who report international travel, HIV-infected individuals, and men who have sex with men (MSM).
High rates of antimicrobial resistance were first reported in Asia, Africa, and South America, and antimicrobial resistance has spread rapidly to resource-rich countries [9-11]. In Asia and Africa, 65 to 85 percent of isolates are resistant to nalidixic acid (a quinolone) and trimethoprim-sulfamethoxazole, and 20 to 30 percent are resistant to fluoroquinolones [12,13]. Resistance to azithromycin, the drug of choice for treatment of Shigella, has been reported in Asia [14-16] and Europe [17,18]. Resistance to nalidixic acid has also been reported in England [19]. A clone that has spread through parts of Vietnam displays resistance to third generation cephalosporins and fluoroquinolones [20].
In the United States, antimicrobial resistance is an increasing problem. Resistance to azithromycin was reported in Shigella sonnei in an outbreak at a retirement community in Vermont [21] and in several outbreaks and sporadic cases elsewhere, predominantly among MSM [22-26]. Clusters of ciprofloxacin-resistant S. sonnei have been reported throughout the United States, likely introduced by international travelers with subsequent domestic spread [27]. Due to an increasing proportion of Shigella isolates in the United States with ciprofloxacin minimum inhibitory concentration (MIC) >0.12 mcg/mL, associated in some cases with clinical and microbiological failure [21], the Clinical and Laboratory Standards Institute changed the breakpoints for ciprofloxacin to the following: susceptible, MIC ≤0.25 mcg/mL; intermediate, MIC 0.5 mcg/mL; and resistant ≥1 mcg/mL [28].
Scattered infections with extremely drug-resistant isolates that are ciprofloxacin resistant and have decreased susceptibility to azithromycin have also been reported [29-31]. These isolates retain susceptibility to third generation cephalosporins (cefixime and ceftriaxone) [27]. There had been earlier reports of Shigella flexneri strains resistant to ceftriaxone and ciprofloxacin [32].
Since 1999, the National Antimicrobial Resistance Monitoring System (NARMS) for Enteric Bacteria has tested every 10th (through 2002) or 20th (since 2003) Shigella isolate submitted from public health laboratories across the United States for antimicrobial susceptibility [33]. Among the 465 isolates tested during 2018 (mainly S. flexneri and S. sonnei), the following proportions of resistant isolates were reported:
●Ciprofloxacin – 14.2 percent resistant (of note, this does not include those isolates that have suspected decreased susceptibility to ciprofloxacin [ie, MIC 0.12 to 1 mcg/mL]).
●Ceftriaxone – 3.9 percent resistant.
●Azithromycin – 34 percent with MIC ≥16 mcg/mL for S. flexneri or MIC ≥32 mcg/mL for all other Shigella species.
●Trimethoprim-sulfamethoxazole (TMP-SMX) – 64 percent resistant.
●Ampicillin – 53 percent resistant.
●Resistance to ≥3 antimicrobial classes – 70 percent.
As above, some cases of drug-resistant Shigella in the United States have been associated with international travel or adoption. As an example, in an analysis of data on 1118 Shigella isolates reported to the Foodborne Diseases Active Surveillance Network (FoodNet) of the Centers for Disease Control and Prevention, and tested through NARMS between 2000 and 2010, strains isolated from individuals with a history of international travel within the preceding week were more likely to be resistant to trimethoprim-sulfamethoxazole (75 versus 39 percent of isolates from those without such travel) or resistant to at least five antibiotic classes (13 versus 4 percent) [34].
Decreased susceptibility to azithromycin in the United States has been associated with infections among individuals who live in a retirement community, are HIV infected, or are MSM. In an analysis of cases of Shigella infection with decreased susceptibility to azithromycin identified through NARMS or public health reporting, among those adults for whom information was available, 13 of 16 were HIV infected, 11 of 14 were MSM, and none of 29 had reported international travel [22].
The major route for dissemination of resistance to multiple agents is horizontal transfer of plasmids carrying antibiotic resistance genes (R-plasmids). A commonly isolated plasmid carries resistance against ampicillin, chloramphenicol, tetracycline, sulfonamides, streptomycin, and trimethoprim [35]. Plasmid-mediated fluoroquinolone resistance genes have been implicated in cases of multidrug-resistant Shigella [36,37]. Epidemic spread of Shigella among men who have sex with men (MSM) has been facilitated by horizontal transfer of a plasmid carrying azithromycin resistance genes [38]. In a retirement community outbreak, azithromycin resistance was conferred by mphA, which encodes a phosphotransferase that inactivates azithromycin, and ermB, which encodes a methylase that modifies the target site [21]. Ampicillin resistance is mediated by beta-lactamases, most frequently OXA-1 and TEM-1.
MANAGEMENT
Supportive therapy — Hydration is important to compensate for fluid loss from the gastrointestinal tract; oral rehydration is sufficient in most cases. Intestinal antimotility drugs such as paregoric, diphenoxylate (Lomotil), or loperamide (Imodium) should be avoided because of concerns about prolongation of fever, diarrhea, and bacterial shedding [39]. (See "Oral rehydration therapy" and "Maintenance and replacement fluid therapy in adults".)
Antibiotic treatment
Indications — For symptomatic adult patients with documented Shigella infection, we suggest antibiotic therapy. Antibiotics are effective in shortening the duration of fever and diarrhea caused by Shigella infection by about two days [40]. Antibiotic treatment also shortens the duration of pathogen shedding in stool, which is expected to reduce the risk of person-to-person spread, although this secondary outcome has not been definitively demonstrated. However, because most individuals will clear the infection spontaneously [40], antibiotic treatment is not essential. We do not give antibiotics to patients with documented Shigella who become asymptomatic without treatment (eg, while awaiting susceptibility testing) unless there are public health issues (ie, if the patient is a food handler and may asymptomatically shed Shigella organisms for a prolonged period). (See 'Natural history of infection' above.)
In response to increasing minimum inhibitory concentrations (MICs) to fluoroquinolones among Shigella isolates in the United States (see 'Antimicrobial resistance' above), the Centers for Disease Control and Prevention has recommended reserving antibiotic treatment for individuals with more severe symptoms, abnormal hosts, and special circumstances, including the following [36]:
●Patients who are immunocompromised (including HIV-infected patients).
●Patients who have severe disease characterized by bacteremia, intestinal or extraintestinal complications, or the need for hospitalization.
●Individuals who are food handlers, childcare providers, residents of nursing homes, or otherwise in settings that have the potential to spread the disease.
Nevertheless, we continue to suggest antibiotic therapy for most symptomatic adults for the following reasons:
●The secondary household attack rate for Shigella infection is approximately 20 percent [41]; thus, although data are limited, there may be public health benefit to Shigella treatment. By shortening the duration of diarrhea, antibiotic therapy may reduce spread. Small randomized, placebo-controlled trials in adults and children with Shigella infection demonstrate reductions in diarrhea frequency and duration (by approximately 50 percent and two days, respectively), fever duration (by approximately one day), and bacterial shedding (two to five days versus up to four weeks with placebo) [40,42-45].
Shigella dysenteriae type 1 produces a Shiga toxin that is structurally identical to one of the Shiga toxins produced by enterohemorrhagic Escherichia coli (EHEC) and is associated with hemolytic uremic syndrome (HUS). Unlike EHEC-associated HUS, antibiotic treatment of S. dysenteriae infection has not been observed to increase the incidence of HUS [46], potentially because the mechanism that controls Shiga toxin production in S. dysenteriae is distinct from that in EHEC. Thus, risk of precipitating HUS should not be a consideration when deciding whether to initiate antibiotic therapy in a patient with S. dysenteriae infection.
While culture data are pending, the choice to initiate empiric antibiotic therapy in the setting of diarrheal illness depends on the severity of illness and the presence of host factors that predispose to severe infection. This is discussed in detail elsewhere. (See "Approach to the adult with acute diarrhea in resource-limited countries", section on 'Antibiotic therapy' and "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Empiric antibiotic therapy'.)
Antibiotic selection
Empiric therapy — Because of rising rates of antimicrobial resistance (see 'Antimicrobial resistance' above), drug selection should be guided, if possible, by results of antimicrobial susceptibility testing. (See 'Directed therapy' below.)
If initiation of antibiotic therapy is warranted prior to receipt of antimicrobial susceptibility testing results or if susceptibility testing is not available, the choice among agents typically active against Shigella (table 1) should be informed by the risk of resistance based on patient demographics and the local prevalence of resistance. As an example, there is widespread resistance to ciprofloxacin, trimethoprim-sulfamethoxazole, and azithromycin in the Asian subcontinent and Africa, so infections acquired in these regions have a high risk of multidrug resistance [14,20]. There is also a pocket of resistance to third generation cephalosporins in Vietnam. Additionally, in the United States, infections with isolates that are resistant to ciprofloxacin and/or have reduced susceptibility to azithromycin have been mainly reported among HIV-infected individuals and men who have sex with men (MSM) [22,24,29].
For patients who have no clear risk factors for drug resistance, a fluoroquinolone is a reasonable empiric option. Empiric treatment for individuals at high risk of having a multidrug-resistant isolate can include a third generation cephalosporin (cefixime or ceftriaxone) until susceptibilities are available. (See 'Antimicrobial resistance' above.)
For management of infections suspected to be due to multidrug-resistant Shigella, infectious disease consultation is advised.
Directed therapy — Results of antimicrobial susceptibility testing should guide antibiotic regimen selection. Treatment options generally include a fluoroquinolone, azithromycin, and a third generation cephalosporin (cefixime or ceftriaxone). Trimethoprim-sulfamethoxazole and ampicillin are also options if susceptibility is documented. Doses and durations are included in the table (table 1).
Ciprofloxacin susceptibility, in particular, should be assessed by the MIC value, and fluoroquinolones should be avoided when the ciprofloxacin MIC is ≥0.12 mcg/mL [36]. Although MICs in the 0.12 to 0.25 mcg/mL range will be reported as susceptible, 2 of 15 patients with S. sonnei isolates with ciprofloxacin MICs of 0.12 mcg/mL experienced clinical and/or microbiological failure with ciprofloxacin treatment [21]. Moreover, treatment of enteric fever due to Salmonella Typhi and Salmonella Paratyphi isolates with MICs in this range has been associated with an increased rate of clinical failure with fluoroquinolone treatment [47,48]. However, in a large study of pediatric diarrhea due to Shigella, which included isolates that had elevated fluoroquinolone MICs, the failure rate with fluoroquinolone treatment was only 7.6 percent, and failure was not associated with an elevated MIC [49]. Given the possibility of impaired responses with an elevated MIC, when an alternative antibiotic is an option, it should be used instead.
Azithromycin is an additional treatment option, but many clinical laboratories do not routinely test Shigella isolates for azithromycin susceptibility because there is no standardized testing for this. However, some laboratories can perform azithromycin susceptibility testing when specifically requested, and if available, this should be done, especially for isolates from patients who are MSM. For Shigella species, MIC breakpoints for azithromycin are ≤8 mcg/mL for susceptible, 16 mcg/mL for intermediate, and ≥32 mcg/mL for resistant. Disc diffusion breakpoints for azithromycin are ≥16 mm for susceptible, 11 to 15 mm for intermediate, and ≤10 mm for resistant [28]. The zone of inhibition for azithromycin can be hazy and therefore difficult to interpret; when this is the case, we recommend requesting that MICs be performed.
For management of infections due to multidrug-resistant Shigella, infectious disease consultation is advised.
Fluoroquinolones, macrolides, beta-lactams, and trimethoprim-sulfamethoxazole all have established efficacy for Shigella when isolates are susceptible. In a systematic review of 16 trials evaluating these different antibiotic regimens, there was no consistent evidence that one particular agent was superior to the others, although the overall quality of the data was low [40].
Duration — The duration of antibiotic therapy for Shigella infection depends on the agent used and certain patient factors (table 1). In general, fluoroquinolones and azithromycin are given for three days; beta-lactams are given for five days. However, for patients with infection due to S. dysenteriae type 1 or with HIV coinfection, five to seven days of therapy are warranted [50-52]. Longer durations (eg, 14 days) are reasonable in the rare event of bacteremia.
Follow-up — 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 [53,54]. Patients who are treated with antibiotics should be evaluated for improvement of symptoms soon after this time frame. For patients empirically treated with antibiotics, if symptoms persist or worsen despite three days of antibiotic therapy, stool culture and susceptibility testing should be performed to evaluate for microbiologic failure and resistance. The antibiotic regimen should be adjusted to these susceptibility testing results.
In the unusual circumstance that symptoms persist despite treatment with an antibiotic to which the isolate has demonstrated in vitro susceptibility, other potential causes of the symptoms (eg, inflammatory bowel disease) should be considered, and switching to another antibiotic is reasonable. (See "Approach to the adult with acute diarrhea in resource-rich settings", section on 'Persistent diarrhea'.)
Counseling — Patients diagnosed with Shigella infection should be advised on measures to prevent transmitting infection to others. If antibiotics are not prescribed, the patient should be advised to employ diligent hand hygiene (washing hands with soap and water for at least 20 seconds), to avoid sex until two weeks after the resolution of diarrhea and practice safe sex for several additional weeks, to avoid public swimming facilities, and to avoid preparing food for others. These precautions should be continued for several weeks after diarrheal symptoms have improved because of the possibility of asymptomatic bacterial shedding. If antibiotics are prescribed, the patient should be advised to follow these same precautions for 48 hours of antibiotic therapy, after which time stool cultures are typically negative.
Food handlers should not be involved in food preparation as long as they are experiencing diarrhea or their stool cultures are positive; conversion to negative stool cultures generally occurs after 48 hours of antibiotic therapy.
In most states, Shigella is a reportable infection.
PREVENTION — Control measures to prevent spread of infection are an important component of management, and all patients with diarrheal disease and documented Shigella infection should be counseled on practices to reduce the risk of transmission. (See 'Counseling' above.)
Uninfected individuals should also be made aware of measures to prevent acquisition of infection. Hygiene measures include frequent handwashing with soap and water, particularly after using the restroom or changing a child's diaper [55]. Given the outbreaks of Shigella among men who have sex with men, such men should be particularly aware to avoid sex if they or their partners have or are recovering from diarrhea; to wash hands, genitals, and anus before and after sex; and to use barriers such as condoms and gloves during anal or oral sex [56]. In childcare centers, separate staff should be assigned to food preparation and diapering.
In resource-limited settings, access to safe drinking water is a critical component of prevention.
There is no effective vaccine against Shigella; potential vaccines are in clinical trials. Rifaximin is effective in preventing infection if given prior to an oral Shigella challenge [57]. The use of prophylactic antibiotics, including rifaximin, to prevent diarrhea in patients traveling to locations where enteric infections such as Shigella are endemic is discussed elsewhere. (See "Travelers' diarrhea: Treatment and prevention".)
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 adults".)
SUMMARY AND RECOMMENDATIONS
●Infection with Shigella is generally self-limited; the average duration of diarrhea from untreated Shigella infection is seven days. (See 'Natural history of infection' above and "Shigella infection: Clinical manifestations and diagnosis".)
●For adults with documented symptomatic Shigella infection, we suggest antibiotic therapy (Grade 2C). We do not give antibiotics to patients who become asymptomatic without treatment (eg, while awaiting susceptibility testing) unless there are public health issues, such as in food handlers. Antibiotics have been shown to decrease the duration of fever and diarrhea by about two days. Shortening the duration of bacterial shedding with antibiotic treatment is also expected to reduce the risk of person-to-person spread. (See 'Indications' above.)
●The increasing antimicrobial resistance of Shigella species is a major problem worldwide. Stool culture with antibiotic susceptibility testing is essential for management of all patients with suspected or documented Shigella infection. (See 'Antimicrobial resistance' above and "Shigella infection: Clinical manifestations and diagnosis", section on 'Susceptibility testing'.)
●Antibiotic selection should be guided, if possible, by results of antimicrobial susceptibility testing. Options generally include a fluoroquinolone, azithromycin, and a third generation cephalosporin (cefixime or ceftriaxone) (table 1). Trimethoprim-sulfamethoxazole and ampicillin are also options if susceptibility is documented. (See 'Antibiotic selection' above.)
●If initiation of therapy is warranted prior to receipt of antimicrobial susceptibility testing results or if susceptibility testing is not available, the choice among these agents should be informed by the risk of resistance based on patient demographics and the local prevalence of resistance. For patients without risk factors for resistant infection, we suggest a fluoroquinolone (Grade 2C). For patients with risk factors for multidrug-resistant infection (such as infection acquired in Asia or Africa, in HIV-infected individuals, and in men who have sex with men), we suggest a third generation cephalosporin (Grade 2C). (See 'Antibiotic selection' above.)
●Hydration is important to compensate for fluid loss from the gastrointestinal tract; oral rehydration is sufficient in most cases. We suggest not using intestinal antimotility agents for symptomatic therapy (Grade 2C). (See 'Supportive therapy' above and "Oral rehydration therapy".)
●Frequent handwashing with soap and water is important for prevention, particularly after using the restroom and prior to food preparation. Patients who are not treated should continue these precautions for several weeks after diarrheal symptoms have improved. They should also avoid sex until two weeks after the resolution of diarrhea and practice safe sex for several additional weeks because of the possibility of asymptomatic bacterial shedding. (See 'Prevention' above.)
●Food handlers should not be involved in food preparation as long as their stool cultures are positive; conversion to negative stool cultures generally occurs after 48 hours of antibiotic therapy. (See 'Prevention' above.)
