1297CHAPTER 165 Salmonellosis

among infants, the elderly, and immunocompromised patients, especially those with HIV infection. NTS endovascular infection should be

suspected in high-grade or persistent bacteremia, especially with preexisting valvular heart disease, atherosclerotic vascular disease, prosthetic vascular graft, or aortic aneurysm. Arteritis should be suspected

in elderly patients with prolonged fever and back, chest, or abdominal

pain developing after an episode of gastroenteritis. Endocarditis and

arteritis are rare (<1% of cases) but are associated with potentially fatal

complications, including valve perforation, endomyocardial abscess,

infected mural thrombus, pericarditis, mycotic aneurysms, aneurysm

rupture, aortoenteric fistula, and vertebral osteomyelitis.

Invasive NTS disease is among the most common causes of bacteremia in children and in HIV-infected adults in sub-Saharan Africa

and Southeast Asia, causing 39% of community-acquired bloodstream

infection in one study. NTS bacteremia among these children is not

associated with diarrhea and has been associated with poor nutritional

status, malaria, sickle cell disease, and HIV infection. S. Typhimurium

ST 131, the most common cause of invasive NTS disease in sub-Saharan

Africa, forms a specific clade that is associated with genome reduction

and loss of traits required for environmental stress resistance, likely

contributing to making this strain more human adapted, perhaps as a

result of carriage by immunosuppressed individuals with HIV.

Localized Infections •  INTRAABDOMINAL INFECTIONS

Intraabdominal infections due to NTS are rare and usually manifest

as hepatic or splenic abscesses or as cholecystitis. Risk factors include

hepatobiliary anatomic abnormalities (e.g., gallstones), abdominal

malignancy, and sickle cell disease (especially with splenic abscesses).

Eradication of the infection often requires surgical correction of abnormalities and percutaneous drainage of abscesses.

CENTRAL NERVOUS SYSTEM INFECTIONS NTS meningitis most commonly develops in infants 1–4 months of age and in adults with HIV

infection. It often results in severe sequelae (including seizures, hydrocephalus, brain infarction, and mental retardation), with death in up

to 60% of cases. Other rare central nervous system infections include

ventriculitis, subdural empyema, and brain abscesses.

PULMONARY INFECTIONS NTS pulmonary infections usually present

as lobar pneumonia, and complications include lung abscess, empyema, and bronchopleural fistula formation. The majority of cases occur

in patients with lung cancer, structural lung disease, sickle cell disease,

or glucocorticoid use.

URINARY AND GENITAL TRACT INFECTIONS Urinary tract infections

caused by NTS present as either cystitis or pyelonephritis. Risk factors

include malignancy, urolithiasis, structural abnormalities, HIV infection, and renal transplantation. NTS genital infections are rare and

include ovarian and testicular abscesses, prostatitis, and epididymitis.

Like other focal infections, both genital and urinary tract infections can

be complicated by abscess formation.

BONE, JOINT, AND SOFT TISSUE INFECTIONS Salmonella osteomyelitis

most commonly affects the femur, tibia, humerus, or lumbar vertebrae

and is most often seen in association with sickle cell disease, hemoglobinopathies, or preexisting bone disease (e.g., fractures). Prolonged

antibiotic treatment is recommended to decrease the risk of relapse

and chronic osteomyelitis. Septic arthritis occurs in the same patient

population as osteomyelitis and usually involves the knee, hip, or

shoulder joints. Reactive arthritis can follow NTS gastroenteritis and is

seen most frequently in persons with the HLA-B27 histocompatibility

antigen. NTS rarely can cause soft tissue infections, usually at sites of

local trauma in immunosuppressed patients.

■ DIAGNOSIS

The diagnosis of NTS infection is based on isolation of the organism from freshly passed stool or from blood or another ordinarily

sterile body fluid. Salmonella is increasingly identified by cultureindependent diagnostic tests due to increased sensitivity, rapid turnaround, and ability to detect multiple enteric pathogens in one

test. Culture-independent positive specimens should have primary

isolation performed to replicate results and recover NTS isolates. All

NTS isolates should be referred to local public health departments for

serotyping. Blood cultures should be obtained whenever a patient has

prolonged or recurrent fever. Endovascular infection should be suspected if there is high-grade bacteremia (>50% of three or more blood

cultures positive). Echocardiography, CT, and indium-labeled white

cell scanning are used to identify localized infection. When another

localized infection is suspected, joint fluid, abscess drainage, or cerebrospinal fluid should be cultured, as clinically indicated.

TREATMENT

Nontyphoidal Salmonellosis

Antibiotics should not be used routinely to treat uncomplicated

NTS gastroenteritis. The symptoms are usually self-limited, and the

duration of fever and diarrhea is not significantly decreased by antibiotic therapy. In addition, antibiotic treatment has been associated

with increased rates of relapse, prolonged gastrointestinal carriage,

and adverse drug reactions. Dehydration secondary to diarrhea

should be treated with fluid and electrolyte replacement.

Preemptive antibiotic treatment (Table 165-2) should be considered for patients at increased risk for invasive NTS infection,

including neonates (probably up to 3 months of age); persons

>50 years of age with known or suspected atherosclerosis; and

patients with immunosuppression, cardiac valvular or endovascular abnormalities, or significant joint disease. Treatment should

consist of an oral or IV antibiotic administered for 48–72 h or

TABLE 165-2 Antibiotic Therapy for Nontyphoidal Salmonella

Infection in Adults

INDICATION AGENT DOSAGE (ROUTE) DURATION, DAYS

Preemptive Treatmenta

Ciprofloxacinb 500 mg bid (PO) 2–3

Severe Gastroenteritisc

Ciprofloxacin

Azithromycin

500 mg bid (PO) or

400 mg q12h (IV)

500 mg once daily

7

5

Trimethoprimsulfamethoxazole

160/800 mg bid (PO) 7

Amoxicillin 1 g tid (PO) 7

Ceftriaxone 1–2 g/d (IV) 7

Bacteremia

Ceftriaxoned 2 g/d (IV) 7–14

Ciprofloxacin 400 mg q12h (IV), then

500 mg bid (PO)

Endocarditis or Arteritis

Ceftriaxone 2 g/d (IV) 42

Ciprofloxacin 400 mg q8h (IV), then

750 mg bid (PO)

Ampicillin 2 g q4h (IV)

Meningitis

Ceftriaxone 2 g q12h (IV) 14–21

Ampicillin 2 g q4h (IV)

Other Localized Infection

Ceftriaxone 2 g/d (IV) 14–28

Ciprofloxacin 500 mg bid (PO) or

400 mg q12h (IV)

Ampicillin 2 g q6h (IV)

a

Consider for neonates; persons >50 years of age with possible atherosclerotic

vascular disease; and patients with immunosuppression, endovascular graft, or

joint prosthesis. b

Or ofloxacin, 400 mg bid (PO). c

Consider on an individualized basis

for patients with severe diarrhea and high fever who require hospitalization. d

Or

cefotaxime, 2 g q8h (IV).

1298 PART 5 Infectious Diseases

until the patient becomes afebrile. Immunocompromised persons

may require up to 7–14 days of therapy. The <1% of persons who

develop chronic carriage of NTS should receive a prolonged antibiotic course, as described above for chronic carriage of S. Typhi.

Because of the increasing prevalence of antibiotic resistance,

empirical therapy for life-threatening NTS bacteremia or focal

NTS infection should include a third-generation cephalosporin or

a fluoroquinolone (Table 165-2). If the bacteremia is low-grade

(<50% of blood cultures positive), the patient should be treated for

7–14 days. Patients with HIV/AIDS and NTS bacteremia should

receive 1–2 weeks of IV antibiotic therapy followed by 4 weeks of oral

therapy with a fluoroquinolone. Patients whose infections relapse

after this regimen should receive long-term suppressive therapy with a

fluoroquinolone or TMP-SMX, as indicated by bacterial sensitivities.

If the patient has endocarditis or arteritis, treatment for 6 weeks

with an IV β-lactam antibiotic (such as ceftriaxone or ampicillin)

is indicated. IV ciprofloxacin followed by prolonged oral therapy is

an option. Early surgical resection of infected aneurysms or other

infected endovascular sites is recommended. Patients with infected

prosthetic vascular grafts that cannot be resected have been maintained successfully on chronic suppressive oral therapy. For extraintestinal nonvascular infections, a 2- to 4-week course of antibiotic

therapy (depending on the infection site) is usually recommended.

In chronic osteomyelitis, abscess, or urinary or hepatobiliary infection associated with anatomic abnormalities, surgical resection or

drainage may be required in addition to prolonged antibiotic therapy for eradication of infection.

■ PREVENTION AND CONTROL

Despite widespread efforts to prevent or reduce bacterial contamination

of animal-derived food products and to improve food-safety education

and training, recent declines in the incidence of NTS in the United States

have been modest compared with those of other food-borne pathogens.

This observation probably reflects the complex epidemiology of NTS.

Identifying effective risk-reduction strategies requires monitoring of

every step of the food supply chain, including farm sources, slaughter

and processing of raw animal or plant products, storage and transport,

and preparation of finished foods. Contaminated food can be made safe

for consumption by pasteurization, irradiation, or proper cooking. All

cases of NTS infection should be reported to local public health departments because tracking and monitoring of these cases can identify the

source(s) of infection and help authorities anticipate large outbreaks.

Prudent use of antimicrobial agents in both humans and animals is

needed to limit the emergence of MDR Salmonella. In developing

countries, immunogenic conjugated vaccines against NTS and rapid,

point-of-care diagnostics are critically needed to reduce the morbidity

and mortality associated with invasive NTS infection.

■ FURTHER READING

Cruz Espinoza LM et al: Occurrence of typhoid fever complications

and their relation to duration of illness preceding hospitalization:

A systematic literature review and meta-analysis. Clin Infect Dis

69(Suppl 6):S435, 2019.

GBD 2017 Non-Typhoidal Salmonella Invasive Disease Collaborators: The global burden of non-typhoidal salmonella invasive

disease: A systematic analysis for the Global Burden of Disease Study

2017. Lancet Infect Dis 19:1312, 2019.

Milligan R et al: Vaccines for preventing typhoid fever. Cochrane

Database Syst Rev 5:CD001261, 2018.

Onwuezobe IA et al: Antimicrobials for treating symptomatic

non-typhoidal Salmonella infection. Cochrane Database Syst Rev

CD001167, 2012.

Shakya M et al: Phase 3 efficacy analysis of a typhoid conjugate vaccine trial in Nepal. N Engl J Med 381:2209, 2019.

Singeltary LA et al: Loss of multicellular behavior in epidemic African

nontyphoidal Salmonella enterica serovar Typhimurium ST313 strain

D23580. mBio 7:e02265, 2015.

Wain J et al: Typhoid fever. Lancet 385:1136, 2015.

The discovery of Shigella as the etiologic agent of dysentery—a clinical

syndrome of fever, intestinal cramps, and frequent passage of small,

bloody, mucopurulent stools—is attributed to the Japanese microbiologist Kiyoshi Shiga, who isolated the Shiga bacillus (now known as

Shigella dysenteriae type 1) from patients’ stools in 1897 during a large

and devastating dysentery epidemic. Shigella cannot be distinguished

from Escherichia coli by DNA hybridization and remains a separate

species only on historical and clinical grounds.

■ ETIOLOGIC AGENT

Shigella is a non-spore-forming, gram-negative bacterium that, unlike

E. coli, is nonmotile and does not produce gas from sugars, decarboxylate lysine, or hydrolyze arginine. Some serovars produce indole, and

occasional strains utilize sodium acetate. Shigella dysenteriae, Shigella

flexneri, Shigella boydii, and Shigella sonnei (serogroups A, B, C, and

D, respectively) can be differentiated on the basis of biochemical and

serologic characteristics.

Genome sequencing of E. coli K12, S. flexneri 2a, S. sonnei, S.

dysenteriae type 1, and S. boydii has revealed that these species

have ~93% of genes in common. The three major genomic “signatures” of Shigella are (1) a 215-kb virulence plasmid that carries most of

the genes required for pathogenicity (particularly invasive capacity);

(2) the lack or alteration of genetic sequences encoding products (e.g.,

lysine decarboxylase) that, if expressed, would attenuate pathogenicity;

and (3) in S. dysenteriae type 1, the presence of genes encoding Shiga

toxin, a potent cytotoxin.

■ EPIDEMIOLOGY

The human intestinal tract represents the major reservoir of Shigella,

which is also found (albeit rarely) in the higher primates. Because

excretion of shigellae is greatest in the acute phase of disease, the bacteria are transmitted most efficiently by the fecal–oral route via hand

carriage; however, some outbreaks reflect foodborne or waterborne

transmission. In impoverished areas, Shigella can be transmitted by

flies. The high-level infectivity of Shigella is reflected by the very

small inoculum required for experimental infection of volunteers

(100 colony-forming units [CFU]), by the very high attack rates during outbreaks in day-care centers (33–73%), and by the high rates of

secondary cases among family members of sick children (26–33%).

Shigellosis can also be transmitted sexually.

Throughout history, Shigella epidemics have often occurred in

settings of human crowding under conditions of poor hygiene—e.g.,

among soldiers in campaigning armies, inhabitants of besieged cities,

groups on pilgrimages, and refugees in camps. Epidemics follow a cyclical pattern in areas such as the Indian subcontinent and sub-Saharan

Africa. These devastating epidemics, which are most often caused by

S. dysenteriae type 1, are characterized by high attack and mortality

rates. In Bangladesh, for instance, an epidemic caused by S. dysenteriae

type 1 was associated with a 42% increase in mortality rate among

children 1–4 years of age. Apart from these epidemics, shigellosis is

mostly an endemic disease, with 99% of cases occurring in the developing world and the highest prevalences in the most impoverished

areas, where personal and general hygiene is below standard. S. flexneri

isolates predominate in the least developed areas, whereas S. sonnei is

more prevalent in economically emerging countries and in the industrialized world.

Prevalence in the Developing World In a review published

under the auspices of the World Health Organization (WHO), the total

annual number of cases in 1966–1997 was estimated at 165 million,

and 69% of these cases occurred in children <5 years of age. In this

review, the annual number of deaths was calculated to range between

500,000 and 1.1 million. Data (2000–2004) from six Asian countries

166 Shigellosis

Philippe J. Sansonetti, Jean Bergounioux

1299CHAPTER 166 Shigellosis

cell membrane come into contact, cellular protrusions form and are

engulfed by neighboring cells. This series of events permits bacterial

cell-to-cell spread.

Cytokines released by a growing number of infected intestinal epithelial cells attract increased numbers of immune cells (particularly

polymorphonuclear leukocytes [PMNs]) to the infected site, thus

further destabilizing the epithelial barrier, exacerbating inflammation, and leading to the acute colitis that characterizes shigellosis.

Evidence indicates that some type III secretion system–injected effectors can control the extent of inflammation, thus facilitating bacterial

survival.

Shiga toxin produced by S. dysenteriae type 1 increases disease

severity. This toxin belongs to a group of A1-B5 protein toxins whose

B subunit binds to the receptor globotriaosylceramide on the target

cell surface and whose catalytic A subunit is internalized by receptormediated endocytosis and interacts with the subcellular machinery to

inhibit protein synthesis by expressing RNA N-glycosidase activity on

28S ribosomal RNA. This process leads to inhibition of binding of the

amino-acyl-tRNA to the 60S ribosomal subunit and thus to a general

shutoff of cell protein biosynthesis. Shiga toxins are translocated from

the bowel into the circulation. After binding of the toxins to target cells

in the kidney, pathophysiologic alterations may result in hemolyticuremic syndrome (HUS; see below).

■ CLINICAL MANIFESTATIONS

The presentation and severity of shigellosis depend to some extent

on the infecting serotype but even more on the age and the immunologic and nutritional status of the host. Poverty and poor standards of

hygiene are strongly related to the number and severity of diarrheal

episodes, especially in children <5 years old who have been weaned.

Shigellosis typically evolves through four phases: incubation, watery

diarrhea, dysentery, and the postinfectious phase. The incubation

period usually lasts 1–4 days but may be as long as 8 days. Typical initial manifestations are transient fever, limited watery diarrhea, malaise,

and anorexia. Signs and symptoms may range from mild abdominal

discomfort to severe cramps, diarrhea, fever, vomiting, and tenesmus.

The manifestations are usually exacerbated in children, with temperatures up to 40°–41°C (104.0°–105.8°F) and more severe anorexia

and watery diarrhea. This initial phase may represent the only clinical

manifestation of shigellosis, especially in developed countries. Otherwise, dysentery follows within hours or days and is characterized by

uninterrupted excretion of small volumes of bloody mucopurulent stools

with increased tenesmus and abdominal cramps. At this stage, Shigella

produces acute colitis involving mainly the distal colon and the rectum.

Unlike most diarrheal syndromes, dysenteric syndromes rarely present

with dehydration as a major feature. Endoscopy shows an edematous and

indicate that, even though the incidence of shigellosis remains stable,

mortality rates associated with this disease may have decreased significantly, possibly as a result of improved nutritional status. However,

extensive and essentially uncontrolled use of antibiotics, which may

also account for declining mortality rates, has increased the rate of

emergence of multidrug-resistant Shigella strains. A 2013 prospective

matched case-control study of children <5 years of age emphasizes the

importance of Shigella in the burden and etiology of diarrheal diseases

in developing countries. Shigella is one of the top four pathogens associated with moderate to severe diarrhea and is now ranked first among

children 12–59 months of age. These moderate to severe cases account

for an 8.5-fold increase in mortality incidence over the average diarrheal disease-related mortality. The study’s authors conclude that Shigella remains a major pathogen to be targeted by health care programs.

An often-overlooked complication of shigellosis is the short- and

long-term impairment of the nutritional status of infected children in

endemic areas. Combined with anorexia, the exudative enteropathy

resulting from mucosal abrasions contributes to rapid deterioration of

the patient’s nutritional status. Shigellosis is thus a major contributor to

stunted growth among children in developing countries.

Peaking in incidence in the pediatric population, endemic shigellosis is rare among young and middle-aged adults, probably because

of naturally acquired immunity. Incidence then increases again in the

elderly population.

Prevalence in the Industrialized World In pediatric populations,

local outbreaks occur when proper and adapted hygiene policies are not

implemented in group facilities such as day-care centers and institutions

for the mentally retarded. In adults, as in children, sporadic cases occur

among travelers returning from endemic areas, and rare outbreaks of

varying size can follow waterborne or foodborne infections.

■ PATHOGENESIS AND PATHOLOGY

Shigella infection occurs essentially through oral contamination via

direct fecal–oral transmission, the organism being poorly adapted to

survive in the environment. Resistance to low-pH conditions allows

Shigella to survive passage through the gastric barrier, an ability that

may explain in part why a small inoculum (as few as 100 CFU) is sufficient to cause infection.

The watery diarrhea that usually precedes the dysenteric syndrome

is attributable to active secretion and abnormal water reabsorption—a

secretory effect at the jejunal level described in experimentally infected

rhesus monkeys. This initial purge is probably due to the combined

action of an enterotoxin (ShET-1) and mucosal inflammation. The

dysenteric syndrome, manifested by bloody and mucopurulent stools,

reflects invasion of the mucosa.

The pathogenesis of Shigella is essentially

determined by a large virulence plasmid of

214 kb comprising ~100 genes, of which 25

encode a type III secretion system that inserts into

the membrane of the host cell to allow effectors to

transit from the bacterial cytoplasm to the host cell

cytoplasm (Fig. 166-1). Bacteria are thereby able to

invade intestinal epithelial cells by inducing their

own uptake either directly at the opening of colonic

crypts, or following the initial crossing of the epithelial barrier through M cells (the specialized

translocating epithelial cells in the follicle-associated epithelium that covers mucosal lymphoid

nodules). Shigella induces apoptosis of subepithelial resident macrophages. Once inside the cytoplasm of intestinal epithelial cells, Shigella effectors

trigger the cytoskeletal rearrangements necessary

to direct uptake of the organism into the epithelial

cell. The Shigella-containing vacuole is then quickly

lysed, releasing bacteria into the cytosol.

Intracellular shigellae next use cytoskeletal components to propel themselves inside the infected

cell; when the moving organism and the host

Shigella

M cell

Epithelial cells

IcsA

IpaB

Macrophage apoptosis

Caspase-I activation by IpaB

Bacterial survival

Initiation of inflammation

IpaC type III

secretion

Cell-to-cell

spread

+

IpaA

IL-8 Macrophages

IL-18

IL-1β

Activation of

NF-κB caused by

IL-1β and

intracellular

NLR activation

Disruption of epithelial

permeability barrier by PMNs

Massive invasion of

epithelium

FIGURE 166-1 Invasive strategy of Shigella flexneri. IL, interleukin; NF-κB, nuclear factor κB; NLR, NODlike receptor; PMN, polymorphonuclear leukocyte.

1300 PART 5 Infectious Diseases

hemorrhagic mucosa, with ulcerations and possibly overlying exudates

resembling pseudomembranes. The extent of the lesions correlates with

the number and frequency of stools and with the degree of protein loss

by exudative mechanisms. Most episodes are self-limited and resolve

without treatment in 1 week. With appropriate treatment, recovery takes

place within a few days to a week, with no sequelae.

Acute life-threatening complications are seen most often in children <5 years of age (particularly those who are malnourished) and in

elderly patients. Risk factors for death in a clinically severe case include

nonbloody diarrhea, moderate to severe dehydration, bacteremia,

absence of fever, abdominal tenderness, and rectal prolapse. Major

complications are predominantly intestinal (e.g., toxic megacolon,

intestinal perforations, rectal prolapse) or metabolic (e.g., hypoglycemia, hyponatremia, dehydration). Bacteremia is rare and is reported

most frequently in severely malnourished and HIV-infected patients.

Alterations of consciousness, including seizures, delirium, and coma,

may occur, especially in children <5 years old, and are associated with

a poor prognosis; fever and severe metabolic alterations are more often

the major causes of altered consciousness than is meningitis or the

Ekiri syndrome (toxic encephalopathy associated with bizarre posturing, cerebral edema, and fatty degeneration of viscera), which has been

reported mostly in Japanese children. Pneumonia, vaginitis, and keratoconjunctivitis due to Shigella are rarely reported. In the absence of

serious malnutrition, severe and very unusual clinical manifestations,

such as meningitis, may be linked to genetic defects in innate immune

functions (i.e., deficiency in interleukin 1 receptor–associated kinase 4

[IRAK-4]) and may require genetic investigation.

Two complications of particular importance are toxic megacolon

and HUS. Toxic megacolon is a consequence of severe inflammation

extending to the colonic smooth-muscle layer and causing paralysis

and dilation. The patient presents with abdominal distention and tenderness, with or without signs of localized or generalized peritonitis.

The abdominal x-ray characteristically shows marked dilation of the

transverse colon (with the greatest distention in the ascending and

descending segments); thumbprinting caused by mucosal inflammatory edema; and loss of the normal haustral pattern associated with

pseudopolyps, often extending into the lumen. Pneumatosis coli is an

occasional finding. If perforation occurs, radiographic signs of pneumoperitoneum may be apparent. Predisposing factors (e.g., hypokalemia and use of opioids, anticholinergics, loperamide, psyllium seeds,

and antidepressants) should be investigated.

Shiga toxin produced by S. dysenteriae type 1 has been linked to

HUS in developing countries but rarely in industrialized countries,

where enterohemorrhagic E. coli (EHEC) predominates as the etiologic

agent of this syndrome. HUS is an early complication that most often

develops after several days of diarrhea. Clinical examination shows

pallor, asthenia, and irritability and, in some cases, bleeding of the

nose and gums, oliguria, and increasing edema. HUS is a nonimmune

(Coombs-negative) hemolytic anemia defined by a diagnostic triad:

microangiopathic hemolytic anemia (hemoglobin level typically <80 g/L

[<8 g/dL]), thrombocytopenia (mild to moderate in severity; typically

<60,000 platelets/μL), and acute renal failure due to thrombosis of

the glomerular capillaries (with markedly elevated creatinine levels).

Anemia is severe, with fragmented red blood cells (schizocytes) in the

peripheral smear, high serum concentrations of lactate dehydrogenase

and free circulating hemoglobin, and elevated reticulocyte counts.

Acute renal failure occurs in 55–70% of cases; however, renal function

recovers in most of these cases (up to 70% in various series). Leukemoid reactions, with leukocyte counts of 50,000/μL, are sometimes

noted in association with HUS.

The postinfectious immunologic complication known as reactive

arthritis can develop weeks or months after shigellosis, especially in

patients expressing the histocompatibility antigen HLA-B27. About

3% of patients infected with S. flexneri later develop this syndrome,

with arthritis, ocular inflammation, and urethritis—a condition that

can last for months or years and can progress to difficult-to-treat

chronic arthritis. Postinfectious arthritis occurs only after infection with S. flexneri and not after infection with the other Shigella

serotypes.

■ LABORATORY DIAGNOSIS

The differential diagnosis in patients with a dysenteric syndrome

depends on the clinical and environmental context. In developing

areas, infectious diarrhea caused by other invasive pathogenic bacteria

(Salmonella, Campylobacter jejuni, Clostridium difficile, Yersinia enterocolitica) or parasites (Entamoeba histolytica) should be considered.

Only bacteriologic and parasitologic examinations of stool can truly

differentiate among these pathogens. A first flare of inflammatory

bowel disease, such as Crohn’s disease or ulcerative colitis (Chap. 326),

should be considered in patients in industrialized countries. Despite

the similarity in symptoms, anamnesis discriminates between shigellosis, which usually follows recent travel in an endemic zone, and these

other conditions.

Microscopic examination of stool smears shows erythrophagocytic

trophozoites with very few PMNs in E. histolytica infection, whereas

bacterial enteroinvasive infections (particularly shigellosis) are characterized by high PMN counts in each microscopic field. However,

because shigellosis often manifests only as watery diarrhea, systematic

attempts to isolate Shigella are necessary.

The “gold standard” for the diagnosis of Shigella infection remains

the isolation and identification of the pathogen from fecal material.

One major difficulty, particularly in endemic areas where laboratory

facilities are not immediately available, is the fragility of Shigella and

its common disappearance during transport, especially with rapid

changes in temperature and pH. In the absence of a reliable enrichment

medium, buffered glycerol saline or Cary-Blair medium can be used

as a holding medium, but prompt inoculation onto isolation medium

is essential. The probability of isolation is higher if the portion of

stools that contains bloody and/or mucopurulent material is directly

sampled. Rectal swabs can be used, as they offer the highest rate of successful isolation during the acute phase of disease. Blood cultures are

positive in fewer than 5% of cases but should be done when a patient

presents with a clinical picture of severe sepsis.

In addition to quick processing, the use of several media increases

the likelihood of successful isolation: a nonselective medium such as

bromocresol-purple agar lactose; a low-selectivity medium such as

MacConkey or eosin-methylene blue; and a high-selectivity medium

such as Hektoen, Salmonella-Shigella, or xylose-lysine-deoxycholate

agar. After incubation on these media for 12–18 h at 37°C (98.6°F), shigellae appear as non-lactose-fermenting colonies that measure 0.5–1 mm

in diameter and have a convex, translucent, smooth surface. Suspected

colonies on nonselective or low-selectivity medium can be subcultured

on a high-selectivity medium before being specifically identified or can

be identified directly by standard commercial systems on the basis of

four major characteristics: glucose positivity (usually without production of gas), lactose negativity, H2

S negativity, and lack of motility. The

four Shigella serogroups (A–D) can then be differentiated by additional

characteristics. This approach adds time and difficulty to the identification process; however, after presumptive diagnosis, the use of serologic

methods (e.g., slide agglutination, with group- and then type-specific

antisera) should be considered. Group-specific antisera are widely

available; in contrast, because of the large number of serotypes and

subserotypes, type-specific antisera are rare and more expensive and

thus are often restricted to reference laboratories.

TREATMENT

Shigellosis

ANTIBIOTIC SUSCEPTIBILITY OF SHIGELLA

As an enteroinvasive disease, shigellosis requires antibiotic treatment. Since the mid-1960s, however, increasing resistance to multiple drugs has been a dominant factor in treatment decisions.

Resistance rates are highly dependent on the geographic area.

Clonal spread of particular strains and horizontal transfer of resistance determinants, particularly via plasmids and transposons,

contribute to multidrug resistance. The current global status—i.e.,

high rates of resistance to classic first-line antibiotics such as

amoxicillin—has led to a rapid switch to quinolones such as

1301CHAPTER 166 Shigellosis

nalidixic acid. However, resistance to such early-generation quinolones has also emerged and spread quickly as a result of chromosomal mutations affecting DNA gyrase and topoisomerase IV; this

resistance has necessitated the use of later-generation quinolones

as first-line antibiotics in many areas. For instance, a review of

the antibiotic resistance history of Shigella in India found that,

after their introduction in the late 1980s, the second-generation

quinolones norfloxacin, ciprofloxacin, and ofloxacin were highly

effective in the treatment of shigellosis, including cases caused

by multidrug-resistant strains of S. dysenteriae type 1. However,

investigations of subsequent outbreaks in India and Bangladesh

detected resistance to norfloxacin, ciprofloxacin, and ofloxacin in

5% of isolates. In the United States, the resistance rate of Shigella to

fluoroquinolones reached 87% during 2014−2015. The incidence of

multidrug resistance parallels the widespread, uncontrolled use of

antibiotics and calls for the rational use of effective drugs. Despite

the alarming proportion of resistant Shigella, there is a lack of studies assessing the resistance of community-acquired strains.

ANTIBIOTIC TREATMENT OF SHIGELLOSIS (TABLE 166-1)

With effective antibiotic therapy clinical improvement occurs

within 48 h, resulting in a decreased risk of complications and

death, shorter duration of symptoms, and elimination of Shigella

from the stool. Because of the ready transmissibility of Shigella,

current public health recommendations in the United States are that

every case be treated with antibiotics. The use of fluoroquinolones

(first-line, preferably ciprofloxacin), and cephalosporins and β-lactams

(second-line) for 7−10 days is recommended for the treatment of

shigellosis. Whereas infections caused by non-dysenteriae Shigella

in immunocompetent individuals are routinely treated with a 3-day

course of antibiotics, it is recommended that S. dysenteriae type 1

infections be treated for 5 days and that Shigella infections in immunocompromised patients be treated for 7–10 days.

Treatment for shigellosis must be adapted to the clinical context,

with the recognition that the most fragile patients are children

<5 years old, who represent two-thirds of all cases worldwide. There are

few data on the use of quinolones in children, but Shigella-induced

dysentery is a well-recognized indication for their use. The half-life

of ciprofloxacin is longer in infants than in older individuals. The

ciprofloxacin dose generally recommended for children is 30 mg/kg

TABLE 166-1 Recommended Antimicrobial Therapy for Shigellosis

ANTIMICROBIAL

AGENT

TREATMENT SCHEDULE

CHILDREN ADULTS LIMITATIONS

First-Line

Ciprofloxacin 15 mg/kg 500 mg

2 times per day for 3 days, PO

Second-Line

Pivmecillinam 20 mg/kg 100 mg Cost

4 times per day for 5 days PO No pediatric formulation

Frequent administration

Emerging resistance

Ceftriaxone 50–100 mg/kg – Efficacy not validated

Must be injected

Once a day IM for 2–5 days

Azithromycin 6–20 mg/kg 1–1.5 g Cost

Once a day for 1–5 days PO Efficacy not validated

Minimum inhibitory

concentration near serum

concentration

Rapid emergence of

resistance and spread to

other bacteria

Source: Reproduced with permission from World Health Organization: Guidelines for

the control of shigellosis, including epidemics due to Shigella dysenteriae type 1.

per day in two divided doses. Adults living in areas with high

standards of hygiene are likely to develop milder, shorter-duration

disease, whereas infants in endemic areas can develop severe, sometimes fatal, dysentery. In the former setting, treatment will remain

minimal and bacteriologic proof of infection will often come after

symptoms have resolved; in the latter setting, antibiotic treatment

and more aggressive measures, possibly including resuscitation, are

often required.

Vaccine studies for S. flexneri have been impaired by the lack of

optimal animal models. New findings document the immunogenicity and preclinical efficacy effects of S. flexneri vaccine in mice

and suggest that further work can help elucidate relevant immune

responses and, ultimately, its clinical efficacy in humans.

REHYDRATION AND NUTRITION

Shigella infection rarely causes significant dehydration. Cases

requiring aggressive rehydration (particularly in industrialized

countries) are uncommon. In developing countries, malnutrition

remains the primary indicator for diarrhea-related death, highlighting the importance of nutrition in early management. Rehydration should be oral unless the patient is comatose or presents

in shock. Because of the improved effectiveness of reduced-osmolarity oral rehydration solution (especially for children with acute

noncholera diarrhea), the WHO and UNICEF now recommend a

standard solution of 245 mOsm/L (sodium, 75 mmol/L; chloride,

65 mmol/L; glucose [anhydrous], 75 mmol/L; potassium, 20 mmol/L;

citrate, 10 mmol/L). In shigellosis, the coupled transport of sodium

and glucose may be variably affected, but oral rehydration therapy

remains the easiest and most efficient form of rehydration, especially in severe cases.

Nutrition should be started as soon as possible after completion

of initial rehydration. Early refeeding is safe, well tolerated, and

clinically beneficial. Because breast-feeding reduces diarrheal losses

and the need for oral rehydration in infants, it should be maintained

in the absence of contraindications (e.g., maternal HIV infection).

NONSPECIFIC, SYMPTOM-BASED THERAPY

Antimotility agents have been implicated in prolonged fever in

volunteers with shigellosis. These agents are suspected of increasing

the risk of toxic megacolon and are thought to have been responsible for HUS in children infected by EHEC strains. For safety

reasons, it is better to avoid antimotility agents in bloody diarrhea.

TREATMENT OF COMPLICATIONS

There is no consensus regarding the best treatment for toxic megacolon. The patient should be assessed frequently by both medical

and surgical teams. Anemia, dehydration, and electrolyte deficits

(particularly hypokalemia) may aggravate colonic atony and should

be actively treated. Nasogastric aspiration helps to deflate the colon.

Parenteral nutrition has not been proven to be beneficial. Fever

persisting beyond 48–72 h raises the possibility of local perforation

or abscess. Most studies recommend colectomy if, after 48–72 h,

colonic distention persists. However, some physicians recommend

continuation of medical therapy for up to 7 days if the patient seems

to be improving clinically despite persistent megacolon without free

perforation. Intestinal perforation, either isolated or complicating

toxic megacolon, requires surgical treatment and intensive medical

support.

Rectal prolapse must be treated as soon as possible. With the

health care provider using surgical gloves or a soft warm wet cloth

and the patient in the knee-chest position, the prolapsed rectum

is gently pushed back into place. If edema of the rectal mucosa is

evident (rendering reintegration difficult), it can be osmotically

reduced by the application of gauze impregnated with a warm solution of saturated magnesium sulfate. Rectal prolapse often relapses

but usually resolves along with the resolution of dysentery.

HUS must be treated by water restriction, including discontinuation of oral rehydration solution and potassium-rich alimentation.

Hemofiltration is usually required.

1302 PART 5 Infectious Diseases

■ DEFINITION

Bacteria of the genus Campylobacter and of the related genera Arcobacter and Helicobacter (Chap. 163) cause a variety of inflammatory

conditions. Although acute diarrheal illnesses are most common,

these organisms may cause infections in virtually all parts of the body,

especially in compromised hosts, and these infections may have late

nonsuppurative sequelae. The designation Campylobacter comes from

the Greek for “curved rod” and refers to the organism’s vibrio-like

morphology.

■ ETIOLOGY

Campylobacters are motile, non-spore-forming, curved, gram-negative

rods. Originally known as Vibrio fetus, these bacilli were reclassified as

a new genus in 1973 after their dissimilarity to other vibrios was recognized. More than 20 species have since been identified. These species

are currently divided into three genera: Campylobacter, Arcobacter,

167 Infections Due to

Campylobacter and Related

Organisms

Martin J. Blaser

■ PREVENTION

Hand washing after defecation or handling of children’s feces and

before handling of food is recommended. Stool decontamination

(e.g., with sodium hypochlorite), together with a cleaning protocol for

medical staff as well as for patients, has proven useful in limiting the

spread of infection during Shigella outbreaks. Ideally, patients should

have a negative stool culture before their infection is considered cured.

Recurrences are rare if therapeutic and preventive measures are correctly implemented.

Although several live attenuated oral and subunit parenteral vaccine

candidates have been produced and are undergoing clinical trials,

no vaccine against shigellosis is currently available. Especially given

the rapid progression of antibiotic resistance in Shigella, a vaccine is

urgently needed.

■ FURTHER READING

Arena ET et al: Bioimage analysis of Shigella infection reveals targeting

of colonic crypts. Proc Natl Acad Sci USA 112:E3282, 2015.

Bennish ML, Wojtyniak BJ: Mortality due to shigellosis: Community

and hospital data. Rev Infect Dis 13(Suppl 4):S245, 1991.

Cossart P, Sansonetti PJ: Bacterial invasion: The paradigms of

enteroinvasive pathogens. Science 304:242, 2004.

Kotloff KL et al: The incidence, aetiology, and adverse clinical

consequences of less severe diarrhoeal episodes among infants and

children residing in low-income and middle-income countries: A

12-month case-control study as a follow-on to the Global Enteric

Multicenter Study (GEMS). Lancet Glob Health 7:E568, 2019.

Mani S et al: Status of vaccine research and development for Shigella.

Vaccine 34:2887, 2016.

Niyogi SK: Shigellosis. J Microbiol 43:133, 2005.

Phalipon A, Sansonetti PJ: Shigella’s ways of manipulating the host

intestinal innate and adaptive immune system: A tool box for survival? Immunol Cell Biol 85:119, 2007.

Traa BS et al: Antibiotics for the treatment of dysentery in children.

Int J Epidemiol 39(Suppl 1):i70, 2010.

World Health Organization: Guidelines for the control of shigellosis, including epidemics due to Shigella dysenteriae type 1. WHO

Library Cataloguing-in-Publication Data. www.who.int/cholera/

publications/shigellosis/en/.

and Helicobacter. Not all of the species are pathogens of humans. The

human pathogens fall into two major groups: those that primarily cause

diarrheal disease and those that cause extraintestinal infection. The

principal diarrheal pathogen is Campylobacter jejuni, which accounts

for 80–90% of all cases of recognized illness due to campylobacters

and related genera. Other organisms that can cause diarrheal disease

include Campylobacter coli, Campylobacter upsaliensis, Campylobacter

lari, Campylobacter hyointestinalis, Campylobacter fetus, Arcobacter

butzleri, Arcobacter cryaerophilus, Helicobacter cinaedi, and Helicobacter fennelliae. The two Helicobacter species causing diarrheal disease,

H. cinaedi and H. fennelliae, are intestinal rather than gastric organisms; in terms of the clinical features of the illnesses they cause, these

species most closely resemble Campylobacter rather than Helicobacter

pylori (Chap. 163) and thus are considered in this chapter. The pathogenic roles of Campylobacter concisus, Campylobacter ureolyticus, and

Campylobacter troglodytis are uncertain. A new subspecies—C. fetus

subspecies testudinum—has been described, chiefly in Asian patients;

the very close resemblance of human isolates to strains isolated from

reptiles suggests a food source.

The major species causing extraintestinal illnesses is C. fetus.

However, any of the diarrheal agents listed above may cause systemic

or localized infection as well, especially in compromised hosts. Neither aerobes nor strict anaerobes, these microaerophilic organisms

are adapted for survival in the gastrointestinal mucous layer. This

chapter focuses on C. jejuni and C. fetus as the major pathogens and

prototypes for their groups. The key features of infection are listed by

species (excluding C. jejuni, described in detail in the text below) in

Table 167-1.

■ EPIDEMIOLOGY

Campylobacters are found in the gastrointestinal tract of many animals

used for food (including poultry, cattle, sheep, and swine) and many

household pets (including birds, dogs, and cats). These microorganisms often do not cause illness in their animal hosts, but occasionally

this can occur (especially in puppies). In most cases, campylobacters

are transmitted to humans in raw or undercooked food products or

through direct contact with infected animals. In the United States and

other developed countries, ingestion of contaminated poultry that has

not been sufficiently cooked is the most common mode of acquisition

(30–70% of cases). Other modes include ingestion of raw (unpasteurized) milk or untreated water, contact with infected household pets,

ingestion of contaminated seafood, travel to developing countries

(campylobacters being a leading cause of traveler’s diarrhea; Chaps.

124 and 133), oral–anal sexual contact, cross-contamination from any

of these sources, and (occasionally) contact with an index case who is

incontinent of stool.

Campylobacter infections are common. Active surveillance of foodborne infections in the United States estimates the incidence of

diarrheal disease due to campylobacters at ~20 cases per 100,000

persons—similar in incidence to Salmonella and more common than

Shigella. Infections occur throughout the year, but the incidence peaks

during summer and early autumn. Persons of all ages are affected;

however, attack rates for C. jejuni are highest among young children

and young adults, whereas those for C. fetus are highest at the extremes

of age. Systemic infections due to C. fetus (and to other Campylobacter

and related species) are most common among compromised hosts.

Persons at increased risk include those with AIDS, immunoglobulin

deficiencies, neoplasia, liver disease, diabetes mellitus, and generalized

atherosclerosis as well as neonates and pregnant women; proton pump

inhibitor use also increases risk. However, apparently healthy nonpregnant persons occasionally develop transient Campylobacter bacteremia

as part of a gastrointestinal illness (0.1–1% of cases).

In contrast, in many developing countries where sanitation is poor,

C. jejuni infections are hyperendemic, with the highest rates among

children <2 years old. According to large prospective cohort studies

in low- to middle-income countries, Campylobacter infections—even

when asymptomatic—are associated with short stature (stunting).

Rates of clinically apparent infection fall with age, as does the illnessto-infection ratio, consistent with development of immunity.