Shigella species
Authors: Shai Ashkenazi, M.D., M.Sc.
Shigellosis is the clinical illness caused by bacteria of the genus Shigella. The disease is characterized by acute diarrhea (with or without blood or mucus), high fever and general toxicity (31).
MICROBIOLOGY
Shigellae are small nonmotile Gram-negative rods which belong to the family Enterobacteriaceae (11). They do not ferment lactose, or do so slowly. The genus Shigella includes four species or serogroups: Shigella dysenteriae, group A; Shigella flexner, group B; Shigella boydii, group C; and Shigella sonnei, group D. Species classification is important regarding the treatment of shigellosis because the species differ in geographic distribution and antimicrobial susceptibility. In developed countries S. sonnei is the most common species and its relative prevalence is increasing (9, 36); in 2012 it accounted for 75% of all Shigella isolates in the United States. (55). In developing countries, S. flexneri is most frequent; with outbreaks that are often caused by S. dysenteriae, which are often resistant to multiple antimicrobial agents (50, 51, 72).
EPIDEMIOLOGY
Shigellae spread through the fecal-oral route. Because of the low infectious dose (10-100 organisms), person-to-person transmission is common and typical for shigellosis, is seen mainly in children (6, 29).Transmission by contaminated food, drinking water, swimming pools and flies has also been documented. The highest incidence is in young children, usually 1-4 years old.
CLINICAL MANIFESTATIONS
The incubation period of shigellosis is usually 12 to 48 hours. Onset of the disease is often abrupt, with high fever, general toxicity and crampy abdominal pain. Typically, there is initially high-volume watery diarrhea that may be followed after about a day with small-volume, bloody and mucous diarrhea (6, 31); urgency and tenesmus are prominent. About half of the patients do not develop bloody or mucous diarrhea. Without therapy, fever and diarrhea persist for about a week. In immunocompromised patients, especially those with the acquired immunodeficiency syndrome (AIDS) - relapsing or chronic symptomatic infection has been reported (44).
LABORATORY DIAGNOSIS
Definitive diagnosis of shigellosis depends on isolation of the organism from stool specimens or rectal swabs. Because the organisms do not survive well in the environment, a transport medium is needed if there is a delay in transfer or processing of the specimen. Serology is usually based on lipopolysaccharide antibodies and is of limited help in clinical practice; it is used mainly for epidemiologic studies. Diagnosis by DNA probes or by the polymerase chain reaction (PCR) is possible but still mainly limited to the research setting.
PATHOGENESIS
Invasiveness is the major pathogenic mechanism of shigellae, causing the severe toxicity of the infection. It is mediated mainly by a 140 Md invasion plasmid, which encodes several protein necessary for invasion. Several toxins are produced the organism; Shiga toxin is produced mainly by S. dysenteriae type 1 and relates to the complication of hemolytic-uremic syndrome. The role of the other toxins in the pathogenesis has not yet been clarified.
SUSCEPTIBILITY IN VITRO AND IN VIVO
The major problem in treating shigellosis is the increasing antimicrobial resistance of Shigella species (5, 18, 54). Although initially susceptible to most antimicrobial agents, including sulfonamides, nowadays most isolates are resistant to the classically recommended antibiotics (Table 1) and even multiple resistance is frequent (10, 17, 28, 45, 46, 54). High resistance rates were first reported in developing countries, but they have rapidly spread to developed countries, initially among travelers, day care centers and Native American reservations (2, 34, 71, 76). Seasonality in antimicrobial resistance of Shigellae has been reported, with winter isolates significantly more resistant than summer isolates to ampicillin, trimethoprim-sulfamethoxazole (TMP-SMX), or both (10). The frequent use of antibiotics during winter months may play a role.
Not all antimicrobial agents are active against Shigella species in vitro are also efficacious in vivo, clinically or bacteriologically (38, 66). Although the reasons for this disparity are not always clear, it mandates that recommendations for antimicrobial therapy be based not only on in vitro susceptibility but also on clinical studies, preferably randomized and double blind.
Sulfonamides and Trimethoprim-Sulfamethoxazole (TMP-SMX):
Sulfonamides have been the primary agents of choice against shigellosis for many years. Today, however, most Shigella isolates are resistant to sulfonamides.
Controlled studies have documented the efficacy of TMP-SMX (8), TMP-SMX yields a clinical response (absence of fever and appearance of formed stool without blood or mucus after 48 hours of therapy) in about 97%, and a bacteriologic response (eradication of shigellae from the stool by day 3 of therapy) in about 94%. TMP-SMX is still recommended as a treatment against shigellosis in several textbooks, though many isolates of Shigella species have shown increasing resistance to this agent in more and more locations, particularly in Asia, Africa and South America. Resistance has been documented in Bangladesh (45, 62), India (19, 22), Thailand (51, 74), Saudi Arabia (43), Israel (5, 10, 52), Kenya (47, 81), Somalia (24), China (59), Mexico (69), Iran (65) and Brazil (49). Studies in the United States (54, 70, 71, 80), Germany (2), Belgium (78) and Spain (76) have emphasized high TMP-SMX esistance among travelers with shigellosis and in the United States, a high resistance rate of 21% was noted in Native American populations (34).
Resistance is now spreading to developed countries as well (36, 45, 77). In Canada, TMP-SMX resistance of Shigella increased from 3% in 1978 to about 30% in 1990 (36). A random sampling of Shigella isolates in 1995, performed by the U.S. Centers for Disease Control and Prevention (CDC), showed 37% resistance to TMP-SMX (28) as compared to only 7% in 1985-6 (71). In 1990 an outbreak of shigellosis occurred in the United States that was multiply-resistant to ampicillin, tetracycline, and TMP-SMX. TMP-SMX resistance is now high for all Shigella species, with a particularly alarming increase for S. sonnei, the most common species seen in developed countries (10).
Aminopenicillins:
Studies in the 1960s and 1970s showed good results with ampicillin against shigellosis, both in vitro and in vivo. Controlled studies comparing ampicillin to either placebo or ineffective therapy such as unabsorbed neomycin, confirmed its therapeutic benefit, with clinical efficacy ranging between 87% and 100% and bacteriologic efficacy between 83% and 94% (66).
As with TMP-SMX, however, most Shigella isolates are currently resistant to ampicillin (Table 1). High resistant rates have been noted in both developing and developed countries. In the United States, the report of ampicillin resistance of Shigella isolates increased from 32% in 1985-6 to 73% in 1995 (45, 71), although it was 26% according to the Antimicrobial Resistance Monitoring System in 2012 (54). Therefore, ampicillin can no longer be recommended as appropriate empiric antibiotic treatment against shigellosis. Although the resistance of Shigella species to ampicillin is usually mediated by beta-lactamase, the efficacy of combining aminopenicillins with beta-lactamase inhibitors remains to be proven.
Amoxicillin is similar to ampicillin in its in vitro activity against Shigella strains. A single open study has compared the efficacy of amoxicillin (25 or 50 mg/Kg/d) and ampicillin (50 mg/Kg/d) for shigellosis; amoxicillin was inferior in terms of longer diarrhea and persistence of Shigellae in stool cultures. It was concluded that amoxicillin is ineffective against shigellosis.
Cephalosporins:
Controlled studies have shown that first and second generation cephalosporins, including cephalexin, cefamandole and cefaclor, are ineffective against shigellosis, often despite in vitro susceptibility of the pathogen (66). Their main limitation is the delayed eradication of shigellae from stool specimens.
The third generation cephalosporins hold promise. Most Shigella isolates have shown susceptibility in vitro (10, 75). Among this group, ceftriaxone has been the most extensively investigated. A comparative study in children showed that parenteral ceftriaxone (50 mg/Kg/d) yielded a good clinical response and 100% eradication of the pathogen after five days (75). A single dose of ceftriaxone, though clinically efficacious, showed a high rate of bacteriologic failure; two doses were comparable to five doses, both clinically and bacteriologically (32). Ceftriaxone has been suggested as the treatment of choice for children with severe shigellosis in need of parenteral therapy, especially those who are hospitalized (56). Its high efficacy may be related to the excretion of the active agent in the bile with an enterohepatic circulation, leading to high levels of the drug within the lumen of the gastrointestinal tract. S. flexneri serotype 2a resistant to ceftriaxone has been reported (26).
Less definitive conclusions have been drawn for other third generation cephalosporins. Clinical and bacteriological failure of cefotaxime therapy in a child with S. flexneri, despite in vitro susceptibility (MIC 0.0098 µg/ml) has been reported (38). Of the two oral agents studied, ceftibuten showed promising results, despite the small number of patients investigated (12 study patients vs. 8 treated with TMP-SMX) (58), and cefixime was proven effective for relatively mild shigellosis, caused mostly by S. sonnei (7). Indeed, 82% of the control group who received TMP-SMX, had TMP-SMX-resistant Shigella isolates. Cefixime was ineffective in patients with severe shigellosis, caused mostly by S. dysenteriae and S. flexneri (68). Resistance to third-generation cephalosporins, mediated by extended- spectrum beta lactamase, has been reported in several locations, including developed countries (33, 54, 61, 62).
Quinolones:
Until the end of the 1980s nearly all Shigella isolates were susceptible to quinolones. A double-blind trial in Bangladesh showed that five days of therapy with nalidixic acid yielded rapid clinical improvement, although bacteriologic eradication was somewhat slower (67). Because of its low cost and availability in suspension for children, and the high ampicillin and TMP-SMX resistance ofShigella species, nalidixic acid was introduced for the treatment of shigellosis in developing countries.
Unfortunately, resistance to nalidixic acid appeared relatively quickly . Already in 1990, 20% of Shigella isolates in Bangladesh were resistant to nalidixic acid, as compared to only 0.8% in 1986, before it came into widespread use (16). Resistance was particularly high (58%) for S. dysenteriae type 1. Nalidixic acid resistance has since been reported in other developing countries, including India (22, 74), Pakistan, and Taiwan (50), but resistance is relatively rare in developed countries (64). A high-level nalidixic acid resistance has been reported from China (59).
Most Shigella isolates, including those resistant to nalidixic acid, are susceptible to the newer fluoroquinolones. Clinical studies have shown that ciprofloxacin, norfloxacin, enoxacin and pefloxacin are clinically and bacteriologically effective against shigellosis (15, 20, 21, 35). Because of the relatively long half-lives of the fluoroquinolones and their high activity against shigellae in vitro, they were evaluated for short courses of therapy. Single doses of ciprofloxacin or norfloxacin were effective in the treatment of infections caused by species other than S. dysenteriae tpye 1 (12, 17). The relative resistance of this serotype to a single dose regimen may be related to its tendency to cause more severe symptoms or to its lower in vitro susceptibility. Ciprofloxacin has been recommended as the first-line treatment of shigellosis in adults (29).
Recently, however, of reduced susceptibility and even resistance of Shigella isolates to the newer fluoroquinolones, have appeared (54, 62). In India, six Shigella strains resistant to nalicixic acid, ciprofloxacin, pefloxacin and enoxacin were noted (73). Japanese investigators studied seven clinical isolates of S. sonnei with reduced susceptibility (MICs 16 to 32 times higher than susceptible strains) to ciprofloxacin, ofloxacin and sparfloxacin; resistance was likely due to a mutation of the DNA gyrase subunit A gene of these strains (39), as shown also by Rahman et al (63). Five nalidixic acid-resistant Shigella strains isolated in the Netherlands showed reduced susceptibility to norfloxacin (77). John et al (42) studied the activities of six fluoroquinolones against 117 S. sonnei isolates. Excluding enoxacin, which had a relatively high MIC (0.25 ), all the other agents had good in vitro activity (MIC 0.008 to 0.032g/ml).
Other Antimicrobial Agents:
Despite their good in vitro activity against shigellae and high fecal concentrations, nonabsorbable oral antimicrobial agents are usually ineffective against shigellosis, both clinically and bacteriologically. They include streptomycin, neomycin, kanamycin, gentamicin and furazolidone (41, 66). Oral, poorly absorbed aztreonam (100 mg three times a day for five days) was shown to be effective in travelers to Mexico suffering from bacterial diarrhea (30). As compared to placebo, aztreonam reduced the duration of both diarrhea and fecal excretion of the bacteria. However, only seven patients with Shigella gastroenteritis were included in the study.
Pivmecillinam is a penicillin that binds selectively to penicillin-binding protein-2 and therefore has high activity against Gram-negative bacteria, including Enterobacteriaceae. It has been proven effective clinically against infections with Shigella when compared to TMP-SMX (57) or to nalidixic acid (1). This antimicrobial agent is not available in the United States and in other locations. Resistance of Shigella strains to pivmecillinam has been reported in Bangladesh and Guatemala (57).
Azithromycin, with a broad spectrum of antimicrobial activity, was compared to ciprofloxacin for the treatment of shigellosis (45). Five-day treatment gave comparable results in terms of clinical efficacy of 82% and bacteriologic efficacy of 100% after 2 days (46). A randomized controlled study has shown that oral azithromycin in more efficacious than cefixime for shigellosis in children (13). Shigellae with reduced susceptibility(25, 37, 40) or resistance to azithromycin have been reported (23).
ANTIMICROBIAL THERAPY
Benefits of Antimicrobial Therapy
The clinical and bacteriologic benefits of effective antimicrobial therapy against shigellosis have been proven in controlled studies by comparison to placebo or ineffective therapy (8, 66). Clinically, effective therapy shortens the duration of diarrhea and fever, resulting in a higher proportion of patients who are free of symptoms by the end of the treatment period. Concomitantly, excretion of shigellae in stools is notably shortened and usually ceases after two days. This is important epidemiologically, because infected patients are the major reservoir of shigellae, and person-to-person spread is the major mode of transmission of this infection. A meta-analysis of 16 studies, which included 1,748 children and adults with Shigella dysentery (a subset of Shigella gastroenteritis), concluded that appropriate antibiotic therapy shortened significantly the duration of the disease (27).
Theimpact of antibiotic therapy on the complications of Shigella infections, including hemolysis, hemolytic-uremic syndrome, bacteremia and toxic megacolon, is less clear. Complications rates are low, and it is therefore nearly impossible to study them in prospective treatment trials. A summary of several studies in Bangladesh has shown that antibiotic treatment might reduce the risk of hemolytic-uremic syndrome after S. dysenteriae type 1 infection (14). In developing countries, appropriate antibiotic treatment may have a significant benefit on the nutritional status and growth of children with shigellosis, because it shortens the duration of diarrhea, thereby enabling early feeding with adequate intestinal absorption.
Because of the increasing antibiotic resistance of Shigella spp, the treatment of choice depends on the specific geographic location and on epidemiologic data of local susceptibility patterns. Shigella strains susceptible to TMP-SMX or to ampicillin should be so treated. Susceptibility can be predicted according to up-to-date microbiologic data of isolates in the community, according to results of contact patients or during outbreaks.
Fluoroquinolones, such as ciprofloxacin, norfloxacin, ofloxacin and pefloxacin, are now the usual treatment of choice for suspected shigellosis in adults, especially in developing countries and in travelers (29). Fluoroquinolones are also effective against most other causes of bacterial gastroenteritis, which may be indistinguishable from shigellosis clinically, when empiric therapy is started.
Alternative Therapy
Quinolones are not approved for use in children less than 17 years of age because of possible damage to the growing cartilage, as seen in animal studies. In children with severe shigellosis, parenteral ceftriaxone (IV or IM), 50 mg/Kg/day, is the treatment of choice. For milder cases, and when parenteral therapy is impossible, oral azithromycin is recommended. Although nalidixic acid is a quinolone, it is approved for children older than two months - a consequence of a historical rather than a scientific precedent, as nalidixic acid was introduced and approved for use in children before the possible skeletal damage of the quinolones was known - but resistance to this agent has been increased worldwide (Table 1).
Duration of Treatment
The usual duration of antimicrobial treatment of shigellosis is five days. This is the only recommendation when TMP-SMX ampicillin, nalidixic acid or azithromycin is used. Shorter durations have been studied with parenteral third-generation cephalosporins and the fluoroquinolones. Two days of treatment with ceftriaxone (50 mg/Kg/day in a single daily dose) in children showed very good clinical and bacteriologic efficacy (32). Since a single dose of ceftriaxone failed to effectively eradicate shigellae from stools, it was concluded that two-day treatment with ceftriaxone was safe in children. Regarding oral cephalosporins, two days' therapy with cefixime was clinically as effective as five days of treatment, but there was a higher rate of bacteriologic failure with the shorter course of therapy (53).
Nevertheless, a 3-day course of quinolones is usually recommended (29). As mentioned, a single dose of ciprofloxacin (1 gm) or norfloxacin (800 mg) was effective in controlled studies in adults. During an outbreak of multi-resistant Shigella infection in Madagascar, nalidixic acid was not available, so pefloxacin was used to treat the affected children (35). A single dose (20 mg/Kg) in 13 children resulted in rapid resolution of the diarrhea; stool cultures performed after five to eight days were negative. A single fluoroquinolone dose should not be used for infections caused by S. dysenteriae type 1.
Special Situations
Patients with underlying immune deficiency disorder or neutropenia, especially those with the acquired immunodeficiency syndrome (AIDS), may have a more complicated course of shigellosis (44). These patients may have a prolonged or recurrent course of diarrhea and systemic complications, such as septicemia; a high mortality rate has been reported. In addition, as reported in African AIDS patients, they may have infections with multi-resistant Shigella strains. In these patients we recommend a full course (at least five days, pending resolution of fever and other symptoms) of parenteral antibiotic therapy, preferably with ceftriaxone in children or adults, or with fluoroquinolones ciprofloxacin or norfloxacin), in adults only.
Treatment of Mild Cases
Shigella infections may cause only mild symptoms, such as mild watery diarrhea and low-grade fever, which resolve spontaneously within a few days. Asymptomatic infections have also been reported. The treatment of mild cases is controversial. Early treatment may enhance recovery, but its main benefit is early eradication of shigellae from stools and, thereby, prevention of secondary cases and spread of infection. Treatment of mild cases is of particular importance in patients in hospitals, day care centers and institutions, where spread of the infection is likely. The main disadvantage of the treatment of mild cases is the spread of resistant strains, and cost may also be a factor in some locations. Practically, shigellosis is usually not suspected in mild cases of diarrhea unless relevant epidemiologic data are available.
Quinolones in Children
The new fluoroquinolones are not approved for use in children because of their potential cartilaginous toxicity. This finding, however, was noted in young animals when relatively high doses were used. Because of the frequent resistance to other antimicrobial agents and the relatively short treatment course, quinolone treatment in children may be useful. After limited uncontrolled experience with pefloxacin for shigellosis in children (35), controlled blinded studies are currently being done. A double-blind study in children has shown that a short course (three days) of ciprofloxacin was safe in children (6 months to 10 years) with shigellosis, although the follow-up was only for three weeks (48).
ADJUNCTIVE THERAPY
Replacement of fluid and electrolyte losses is essential in treating patients with shigellosis. Dehydration may be caused by the high-volume watery diarrhea during the early course of the disease, or later, by the low-volume bloody diarrhea, when the generalized toxicity and vomiting preclude sufficient fluid intake. Oral rehydration solutions containing glucose and electrolytes are usually efficacious, though intravenous fluids may be necessary. In certain patients, especially young children, nutritional support is also important.
Antimotility agents, such as diphenoxylate (Lomotil), prolong the duration of fever, diarrhea and excretion of the organism in patients with Shigella infections and should therefore not be used when shigellosis is suspected. Intestinal motility and the constant fluid flow may actually be an important host defense mechanism for rapid clearance of the infection. In a randomized double-blind study, green banana has reduced the clinical severity of shigellosis in children (60).
ENDPOINTS FOR MONITORING THERAPY
With effective antimicrobial therapy, clinical improvement, i.e. resolution of fever, diarrhea and dysentery, is usually seen within two days. After five days the patient is usually afebrile, with less than three stools a day, which are non-watery. Bacteriologically, the eradication of shigellae from the stool culture is usually seen after two days of effective treatment. Clinical failure is defined as the presence of fever or watery diarrhea after five days of therapy, and bacterial failure, as a positive stool culture after two days.
VACCINES
Although oral vaccines have been developed and some have demonstrated efficacy in clinical trials, none are commercially available (11). Research is continuing in this area.
PREVENTION
At the community level, safe drinking water is the single most important factor in preventing shigellosis. Effective sewage disposal and improvement in sanitation are important. Person to person transmission can be prevented by personal hygiene, effective handwashing, removal of food handlers with diarrhea from their duties, refrigeration, and cooking of potentially infected foods. In developing countries, vector control with insecticides helps prevent spread of disease.
Hospital Infection Control
Strict adherence to universal precautions and contact precautions are recommended.
Prophylactic Antibiotics
Prophylactic antibiotics are not useful in preventing shigellosis.
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Tables
Table 1:In Vitro Antimicrobial Resistance of Shigella Isolates In Various
| Publication | Country | Year isolates obtained | Percent resistance to:a | ||
|---|---|---|---|---|---|
| AMP | TMP-SMX | NAL | |||
| Center for Disease Control and Prevention- 2014 | USA (NARMS)b | 2012 | 26 | 43 | 4.5 |
| Qu- 2014 | China | 2004-2011 | 87 | 82 | 91 |
| Sudeghabadi - 2014 | Iran | 2013 | - | 100 | 30 |
| Bhattacharya - 2014 | India | 2006-2011 | 100 | 80 | - |
| Zaidi - 2013 | Mexico | 2010-2011 | 35 | 59 | 0 |
| Shiferaw - 2012 | USA | 2000-2010 | 74 | 36 | 2 |
| Wong - 2010 | USA (NY) | 2006-2009 | 68 | 66 | 5 |
| Vrints - 2009 | Belgium | 1990-2007 | 19 | 86 | 3.8 |
| Rahman - 2007 | Bangladesh | 2001-2002 | 56 | 72 | 51 |
| Ashkenazi - 2003 | Israel | 1998-2000 | 85 | 94 | 0.5 |
| Shapiro - 2001 | Kenya | 1997-1998 | 88 | 94 | 2 |
| Lima - 1995 | Brazil | 1988-93 | 90 | 84 | 8 |
| Lin - 1992 | Taiwan | 1982-87 | 52 | 10 | 25 |
| Kagalwalla - 1992 | Saudi Arabia | 1985-90 | 54 | 72 | --- |
| Thisyakorn - 1992 | Thailand | 1990 | 90 | 81 | --- |
aAMP, ampicillin; TMP-SMX, trimethoprim-sulfamethoxazole; N, nalidixic acid.
bNARMS,National Antimicrobial Resistance Monitoring SystemWhat's New
Butler T. Loperamide for the Treatment of Traveler's Diarrhea: Broad or Narrow Usefulness? Clin Infect Dis 2008; 47:1015-6
Picking WL, Picking WD. Early Steps in Inducing Type III Secretion in Shigella. Microbe. 2009;4(12):554-559.
Traveler's Diarrhea: Broad or Narrow Usefulness? Clin Infect Dis 2008; 47:1015-6GUIDED MEDLINE SEARCH FOR:
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Baron EJ. Flow chart for identification of enteric fecal pathogens
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