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C. perfringens or B. cereus (long-incubation disease) produce heat-labile toxins

after the ingestion of contaminated foods, explaining the longer incubation period

compared with illness caused by the ingestion of preformed toxins. Foods implicated

in C. perfringens food poisoning include improperly stored beef, fish, poultry dishes,

pasta salads, and dairy products, whereas foods implicated in long-incubation B.

cereus food poisoning include meats, vanilla sauce, cream-filled baked goods, and

salads.

26

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p. 1453

Foodborne illnesses caused by these toxin-producing bacteria usually resolve

within 24 hours; therefore, antibiotic therapy is not indicated for either student.

CRYPTOSPORIDIUM PARVUM

The protozoan parasite C. parvum is an important cause of human intestinal illness in

both healthy and immunocompromised persons. The role of antiprotozoal agents and

the clinical response to antiprotozoal therapy depends on the competence of the

host’s immune system.

Clinical Presentation

CASE 69-6

QUESTION 1: C.K. is a 35-year-old, previously healthy man presenting to his physician with complaints of 15

days of watery diarrhea and a 5-pound weight loss. He is concerned that his illness is related to the

announcement by the Board of Health notifying the community of an outbreak of cryptosporidiosis from

contaminated water supplies. Why is C.K.’s history of present illness and clinical presentation consistent with

cryptosporidiosis? Should antiprotozoal agents be prescribed to treat cryptosporidiosis in otherwise healthy

persons such as C.K.?

A key finding from C.K.’s history is his exposure to water supplies known to be

contaminated with cryptosporidium oocysts; other modes of spreading

cryptosporidiosis include animal contact (cattle and sheep) and person-to-person

contact.

27

C.K. is presenting with persistent diarrhea, i.e., diarrhea lasting longer than 14

days. Common microbial causes of persistent watery diarrhea include parasites, such

a s Isospora belli, Microsporidia, G. lamblia, and C. parvum. The spectrum of

infection with C. parvum ranges from asymptomatic carriage to a persistent,

noninflammatory diarrheal illness; vomiting, abdominal cramps, weight loss, and

fever may also occur.

27

Immunocompetent patients like C.K. can generally expect a

self-limiting illness lasting approximately 2 weeks.

27

In contrast, in immunocompromised patients cryptosporidiosis can be a chronic,

debilitating, diarrheal illness associated with malnutrition, increased mortality, and

in children, long-term cognitive impairment.

28

Treatment

For immunocompetent hosts with cryptosporidiosis, other than replacement of fluids

and electrolytes no specific therapy directed at the organism is generally required.

However, nitazoxanide is an FDA-approved treatment for diarrhea caused by C.

parvum. A randomized, double-blind, placebo-controlled trial in immunocompetent

adults and children found that diarrhea resolved in 80% of those treated with

nitazoxanide versus 41% of patients given placebo; oocyst shedding was also

significantly reduced in the treatment group. Diarrhea generally resolved within 3 to

4 days of starting treatment.

29 Nitazoxanide 500 mg orally twice daily for 3 to 14

days is recommended for the treatment of cryptosporidiosis.

3

In contrast, in immunocompromised persons a meta-analysis of treatments for

cryptosporidiosis found no evidence to support the role of chemotherapy.

30 These

findings are consistent with randomized trials concluding that neither a short, 3-day

course of nitazoxanide nor a more intensive regimen of nitazoxanide (200–400 mg

orally twice daily for 28 days) provided any benefit to HIV-positive children. For

HIV-infected persons, reconstitution of the immune system with effective

antiretroviral therapies is the mainstay of treatment for cryptosporidiosis.

SALMONELLA

Salmonellae are enteric gram-negative bacilli belonging to the Enterobacteriacae

family. Widely found in nature colonizing animal hosts including mammals, reptiles,

and birds,

31

they are major causes of foodborne illness as a consequence of

consuming contaminated foods including poultry or poultry products and dairy

products. Worldwide, the annual incidence of salmonellosis is about 1.3 billion

cases, and of the nearly 3 million persons who die,

32 most live in developing areas of

the world.

The role of antimicrobials in the management of salmonellosis depends on the

clinical syndrome, its severity, and underlying health problems of infected persons.

Non-typhoidal salmonellae (e.g., Salmonella typhimurium, Salmonella enteritidis,

Salmonella choleraesuis, and many others) cause the clinical syndromes of

gastroenteritis, asymptomatic carriage in the stool, bacteremia, and localized

infection.

33 Typhoidal salmonellae (Salmonella typhi and Salmonella paratyphi A, B,

and C) cause the syndromes of enteric fever (also referred to as typhoid or

paratyphoid fever) and chronic carriage.

31

Non-typhoidal Salmonellosis

CASE 69-7

QUESTION 1: An outbreak of Salmonella gastroenteritis being investigated by the Department of Public

Health has traced the source of the outbreak to Restaurant A, specifically the popular turkey dinner special.

Anticipating that infected diners with specific clinical syndromes associated with Salmonella infection will

benefit from antimicrobial treatment, and that antimicrobial resistant Salmonella species are increasingly

problematic, the Department of Health has asked you to address the following question of what antimicrobials

are available for the treatment of non-typhoidalsalmonellosis.

CHLORAMPHENICOL, TRIMETHOPRIM–SULFAMETHOXAZOLE (TMP–

SMX), OR AMPICILLIN

Until the late 1980s, standard treatments for non-typhoidal Salmonella were

chloramphenicol, TMP/SMX, or ampicillin. By the early 1990s, widespread

multidrug-resistance (MDR) defined as simultaneous resistance to ampicillin,

chloramphenicol, streptomycin, tetracyclines, and sulfonamides precluded their use

as empiric therapies for the treatment of salmonellosis.

31 Depending on the

geographic area, rates of MDR Salmonella species are as high as 80% in East Asia

and southern Europe and 30% to 40% in the United States.

32 As MDR-resistant

Salmonella species remained susceptible to the fluoroquinolones, these

antimicrobials became the agents of choice for the treatment of salmonellosis.

Interestingly, since the early 2000s there has been a decline in the prevalence of

MDR-non-typhoidal Salmonella in some areas of the world.

32

FLUOROQUINOLONES

With the advent of MDR-non-typhoidal Salmonella, fluoroquinolones were widely

prescribed for the empiric treatment of non-typhoidal salmonellosis.

31 During the

1990s, suboptimal clinical responses following treatment with fluoroquinolones

were noted when isolates were resistant to nalidixic acid. Both nalidixic acid and the

fluoroquinolones are related compounds belonging to the quinolone family of

antimicrobials. As these isolates also displayed elevated ciprofloxacin MICs

compared to

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p. 1454

nalidixic acid–susceptible strains (i.e., 0.12–1 mcg/mL vs. ≤0.06 mcg/mL), they

were referred to as having decreased ciprofloxacin susceptibility (DCS).

34

Consequently, nalidixic acid resistance became a surrogate marker for isolates with

DCS, for which ciprofloxacin was not an optimal antimicrobial choice.

In subsequent years, additional fluoroquinolone-resistance mechanisms in

Salmonella species emerged which were not detected by nalidixic acid screening

(i.e., isolates were nalidixic acid susceptible but had elevated ciprofloxacin MICs);

thus, nalidixic acid resistance was no longer a reliable surrogate marker to detect

Salmonella with DCS.

34 Consequently, in 2012 the Clinical Laboratory Standards

Institute (CLSI) lowered for Salmonella species the breakpoint for susceptibility to

ciprofloxacin from <1 to <0.06 mcg/mL, a change which would reliably detect

Salmonella with DCS. The CLSI also recognized that not all laboratories (e.g.,

resource-limited settings) would be able to institute these new ciprofloxacin

breakpoints, and because nalidixic acid–susceptible isolates with concurrent

decreased susceptibility to ciprofloxacin are still uncommon, CLSI allowed for the

continued use of nalidixic acid screening,

34

though prescribers should be made aware

of its limitations as a marker for isolates with DCS.

Currently, nalidixic acid–resistant non-typhoidal Salmonella are prevalent in Asia

and increasingly more common in the United States, reportedly 0.4% in 1996 and

2.3% in 2003. Antimicrobial treatment options for nalidixic acid–resistant

Salmonella include azithromycin and selected third-generation cephalosporins.

34

β-LACTAMS

Non-typhoidal salmonella resistance to ceftriaxone is currently uncommon, but it has

been reported worldwide, including in Africa, Europe, Asia, the Philippines, and the

United States

31

; some isolates are also simultaneously resistant to

fluoroquinolones.

32

,

35 Carbapenems

35 have been successfully used for the treatment of

invasive infection caused by ceftriaxone- and ciprofloxacin-resistant Salmonella

enterica serotype choleraesuis,

36

though carbapenem-resistant Salmonella have also

been reported.

31

AZITHROMYCIN

Azithromycin displays good in vitro activity against non-typhoidal S. enterica

37 and

is a recommended treatment for non-typhoidal salmonellosis requiring antimicrobial

treatment,

3

including the treatment of nalidixic acid–resistant isolates.

Anticipating the need for recommendations to guide prescribers regarding which

diners with salmonellosis should receive antimicrobial therapy, the Department of

Health has asked you to address the following question: “Considering a diner’s

severity of illness and underlying health problems, should antimicrobials be

prescribed for diners with the following clinical syndromes: (a) uncomplicated

gastroenteritis in the immunocompetent host, (b) asymptomatic stool carriage, or (c)

extraintestinal Salmonella infection? If appropriate, what specific antimicrobial

therapies would you recommend?”

UNCOMPLICATED GASTROENTERITIS IN THE IMMUNOCOMPETENT

HOST

Clinical Presentation and Treatment

CASE 69-8

QUESTION 1: B.B., a 35-year-old, otherwise healthy man presents with a 1-day history of fever, abdominal

pain, nausea, vomiting, and non-bloody stools. B.B. has no significant medical history. Physical examination is

significant for a non-ill appearing, febrile male; his presumptive diagnosis is mild, uncomplicated non-typhoidal

Salmonella gastroenteritis. Should he receive antimicrobial therapy?

Like B.B., within 6 to 72 hours of ingesting contaminated foods patients begin

experiencing the clinical manifestations of Salmonella gastroenteritis including acute

onset of fever, diarrhea, and abdominal cramping; in more severe illness, bloody

diarrhea and dehydration may occur.

In otherwise healthy individuals with uncomplicated non- typhoidal Salmonella

gastroenteritis, antimicrobials are not recommended as salmonellosis is typically a

self-limiting illness lasting for 2 to 5 days. Antimicrobials do not reduce the duration

or severity of illness and may be harmful, by placing patients at risk for adverse drug

reactions, prolonging the asymptomatic carriage of salmonellae, and promoting the

emergence of antimicrobial-resistant bacteria.

33

,

38 Most individuals like B.B. will

only require replacement of lost fluids and electrolytes.

ASYMPTOMATIC STOOL CARRIAGE

Clinical Presentation and Treatment

CASE 69-8, QUESTION 2: Three weeks after resolution of B.B.’s episode of Salmonella gastroenteritis, he

continues to excrete Salmonella bacteria from his stool, despite remaining asymptomatic. Should antimicrobials

be prescribed to eliminate B.B.’s intestinal carriage of non-typhoidal Salmonella?

Antimicrobials should not be prescribed to eliminate asymptomatic intestinal

carriage of non-typhoidal Salmonella.

18 A randomized, double-blind trial in healthy,

asymptomatic adults from areas where non-typhoidal Salmonella infection is

endemic found that neither norfloxacin nor azithromycin were better than placebo in

eradicating intestinal carriage of Salmonella species.

18 The median duration of fecal

shedding of non-typhoidal Salmonella is about 1 month in adults and 7 weeks in

children younger than 5 years of age.

39

GASTROENTERITIS IN PATIENTS AT RISK FOR EXTRAINTESTINAL

SALMONELLA INFECTION

Clinical Presentation and Treatment

CASE 69-9

QUESTION 1: W.M., a 50-year-old male with a past medical history significant for a recently diagnosed

malignancy, presents with a 1-day history of fever, severe abdominal pain, nausea, vomiting, and non-bloody

stools. One day prior to the onset of these symptoms, he ate cream-filled pastries from a bakery that has since

been closed by the Department of Health because of its association with an ongoing outbreak of Salmonella

gastroenteritis. Should antimicrobials be prescribed for his presumed diagnosis of Salmonella gastroenteritis, and

if so, what would you recommend?

Antimicrobials are indicated for patients at risk for developing extraintestinal

Salmonella infection such as persons with malignancy (like W.M.), diabetes,

rheumatologic disorders, HIV infection,

32 persons receiving immunosuppressive

therapies, very young age, low gastric pH (e.g., as in infancy, pernicious anemia, or

medication-induced), severe infection,

33 and persons older than 50 years of age who

may have atherosclerotic lesions which could become hematogenously infected.

40

Overall, less than 5% of patients with non-typhoidal Salmonella gastroenteritis

become bacteremic, though infection with some serotypes, e.g., S. choleraesuis and

Salmonella dublin are more likely to cause bloodstream infection.

33 Once in the

bloodstream extraintestinal complications include osteomyelitis, septic arthritis,

meningitis, or infectious endarteritis. Lastly, antimicrobials have been used when

rapid interruption of fecal excretion of organisms is needed to control outbreaks of

salmonellosis in institutionalized persons.

40

p. 1454

p. 1455

For patients at risk for extraintestinal infection or with severe diarrhea,

antimicrobial options include an oral fluoroquinolone (e.g., levofloxacin 500 mg

once daily) for 7 to 10 days, azithromycin 500 mg once daily for 7 days, or

parenteral ceftriaxone 1 to 2 grams daily for 7 to 10 days (14 days is recommended

for patients with immunosuppression).

3 For HIV-infected persons with a CD4 ≥200

cells/μL, the recommended duration of therapy for gastroenteritis without bacteremia

is 7 to 14 days, and for patients with a CD4 <200 cells/μL, 2 to 6 weeks is often

recommended.

41

EXTRAINTESTINAL SALMONELLA INFECTION

Clinical Presentation and Treatment

CASE 69-10

QUESTION 1: B.T., an “ill-appearing” 70-year-old man with a history significant for the same cream-filled

pastries as B.T. (Case 659-9, Question 1), who is hospitalized for severe abdominal pain, bloody diarrhea, newonset right hip pain, high fever, and low blood pressure. His past surgical history is significant for a right hip

prosthesis. Would B.T. benefit from antibiotic therapy, and if so, what would you recommend?

B.T. is presenting with signs and symptoms of Salmonella gastroenteritis,

bacteremia (fever, low blood pressure) and possible localized infection of his right

hip prosthesis (new onset hip pain).

Treatment of Salmonella bacteremia without localized infection is generally

successful after 10 to 14 days of antimicrobial therapy.

3

,

32 For HIV-infected persons,

a longer course of therapy (2–6 weeks) is recommended.

35

,

41

If infection of B.T.’s hip

prosthesis is confirmed, surgery may be required to cure his infection.

39

Recommended treatment durations for extraintestinal non-typhoidal salmonellosis are

available.

40

Considering the antimicrobial resistance patterns from where the Salmonella

infection was acquired (e.g., travel history), prior antimicrobial therapy, and site of

infection, until susceptibilities are available empiric therapy options include selected

IV third generation cephalosporins (e.g., ceftriaxone 1 g IV q24, cefotaxime 1 g IV

q8),

41 an IV or oral fluoroquinolone (e.g., ciprofloxacin 400 mg IV q12h,

ciprofloxacin 500–750 mg PO q12h, levofloxacin 750 mg IV or PO q24h), or the

combination of a third-generation cephalosporin with a fluoroquinolone.

40 For

bacteremic patients, some experts prefer the IV route of administration,

40 particularly

until the patient has stabilized,

32 while other experts recommend either the IV or oral

route of administration.

41

Typhoidal Salmonellosis—Typhoid Fever (Enteric

Fever)

CLINICAL PRESENTATION

CASE 69-11

QUESTION 1: B.C. is a 49-year-old obese woman, presenting to the emergency department with a 1-week

history of fever, confusion and delirium, severe abdominal pain, headache, anorexia, and diarrhea and, for the

past 1 day, a red rash on her chest. Her history of present illness is significant for returning 10 days ago from

travel to the Indian subcontinent where she stayed with relatives, some of whom were recovering from typhoid

fever. B.C.’s medical history is significant for gallstones. She lives in California with her husband. Admission

vital signs show a temperature of 101°F, a heart rate of 60 beats/minute and a stable blood pressure. Physical

examination is significant for a “toxic appearing” female with a red rash on her chest, splenomegaly, and

hepatomegaly. Laboratory tests include the following: WBC is 3.0 × 10

6

/μL, liver function tests are mildly

elevated, and the results of two sets of blood cultures are pending. B.C. is given the presumptive diagnosis of

severe enteric fever and encephalopathy most likely attributable to S. typhi. Why is her history of present

illness, clinical presentation, and laboratory results consistent with this diagnosis?

A key piece of information from B.C.’s history of present illness supporting the

diagnosis of typhoid fever is her recent travel to the Indian subcontinent where

typhoid fever is endemic, and her contact with relatives recovering from this

infection. Other developing countries with endemic typhoid fever include Southeast

Asia, Africa, and Latin America.

42

In developed countries, enteric fever is a sporadic

disease occurring mainly in travelers returning from areas where the disease is

endemic; in the United States 85% of cases of typhoid fever are travel-related.

43

B.C.’s clinical presentation and laboratory findings are classic for enteric fever.

During the 7- to 14-day incubation period,

42 salmonellae multiply within

macrophages and monocytes, and systemic manifestations of infection appear after

the release of bacteria into the bloodstream. Patients usually present with fever,

abdominal pain, anorexia, diarrhea or constipation, headache, dry cough,

splenomegaly, and hepatomegaly, while severe illness is characterized by

concomitant GI bleeding, encephalopathy, and shock. Bacteremia may be followed

by localized infection to the liver, spleen, bone marrow, gallbladder, and Peyer’s

patches of the terminal ileum.

42 Laboratory abnormalities consistent with typhoid

fever include B.C.’s low WBC count and mildly elevated liver function tests.

31

TREATMENT

CASE 69-11, QUESTION 2: Would B.C. benefit from a course of antimicrobials to treat her presumptive

diagnosis of typhoid fever? If so, what options are available?

B.C. would benefit from effective antimicrobial treatment for typhoid fever in the

following ways: (1) shortening the resolution of fever from 3 to 4 weeks to 3 to 5

days,

44 with clearing of all symptoms within 7 to 10 days,

45

(2) decreasing mortality

from usually 5% to 10% to less than 1%,

31

(3) eradicating fecal shedding of S. typhi,

thereby limiting further spread of infection,

45 and (4) preventing relapse of infection.

Most cases of typhoid fever are effectively treated with oral antimicrobials; IV

therapy is reserved for severely ill patients or patients with persistent vomiting and

severe diarrhea.

42

Chloramphenicol, TMP–SMX, or Ampicillin

Until the late 1980s, typhoid fever was cured in more than 90% of patients treated

with 14 to 21 days of chloramphenicol, TMP–SMX, or ampicillin.

46 By the early

1990s multidrug-resistant (i.e., simultaneous resistance to chloramphenicol,

ampicillin, and TMP-SMX) S. typhi caused outbreaks of typhoid fever in Asia and

Africa. Fortunately, these multidrug-resistant isolates remained susceptible to the

fluoroquinolones, which then became the antimicrobials of choice. Interestingly,

there has been a reduction in multidrug- resistant S. typhi to as low as 12% in some

areas of the world.

Fluoroquinolones

Short-treatment courses (less than 5 days) of oral fluoroquinolones were once as

effective or better than previously used treatments (e.g., TMP–SMX, ampicillin, or

chloramphenicol).

46 By the late 1990s, short-course fluoroquinolone therapies used

in parts of Asia were associated with clinical failures in up to 50% of patients.

43

Microbiologic evaluation revealed these isolates were resistant

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p. 1456

to nalidixic acid and had higher ciprofloxacin MICs (0.125–1 mcg/mL) compared to

Salmonella that was fully susceptible to ciprofloxacin (MICs of <0.03 mcg/mL).

47

Gatifloxacin, a newer generation fluoroquinolone (no longer marketed in the United

States) with lower MICs compared to ciprofloxacin (0.19 vs. 0.5 mcg/mL,

respectively) cured greater than 95% of children with typhoid fever, most of whom

were infected with nalidixic acid–resistant S. typhi.

15

In areas with a high prevalence

of nalidixic acid–resistant S. typhi, alternatives to fluoroquinolones include

azithromycin and selected third-generation cephalosporins.

Azithromycin

Azithromycin is effective for patients with mild-to-moderate typhoid fever.

48

Azithromycin (20 mg/kg/day) for 7 days cured greater than 95% of children with

uncomplicated typhoid fever in Vietnam where 96% of S. typhi are nalidixic acid–

resistant; fever clearance time was 106 hours and there were no relapses.

15

In

contrast, lower azithromycin doses (10 mg/kg/day) in the setting of nalidixic acid–

resistance are associated with lower cure rates (82%).

49 Concerning is the

identification of azithromycin-resistant S. typhi

50 and non-response to azithromycin.

51

α-lactams and Tigecycline

Cefixime, an oral third-generation cephalosporin, is variably effective for the

treatment of typhoid fever. Failure rates range from 4% to 27%50 and some experts

do not recommend its use for the treatment of typhoid fever.

43 The lower clinical

response to cefixime may be related to the poor intracellular penetration of the βlactam because the intracellular compartment is the primary site of S. typhi

colonization.

52

Ceftriaxone, an intravenous third-generation cephalosporin, is recommended for

the treatment of severe typhoid fever

44 with the caveat that longer treatment courses

are recommended to prevent relapse of infection. In patients with bacteremia caused

by ceftriaxone-susceptible isolates, relapse of infection was higher among patients

treated with a 7-day course of ceftriaxone versus azithromycin, 14% versus 0%,

respectively.

53 No relapses were reported when a longer course (14 days) of

ceftriaxone was used for infection caused by multidrug-resistant S. typhi.

54 Patients

treated with ceftriaxone may remain febrile for as long as 10 days.

55 Ceftriaxoneresistant S. typhi have been reported in India, the Philippines, China, the United

States, and elsewhere.

56 Potential alternatives to ceftriaxone include carbapenems

(imipenem, meropenem, and ertapenem) and tigecycline, though clinical data are

lacking.

48

TREATMENT—SEVERE VERSUS UNCOMPLICATED TYPHOID FEVER

CASE 69-11, QUESTION 3: What specific empiric antibiotic regimen would you recommend for the

treatment of B.C.’s complicated (severe) typhoid fever? How would her treatment differ if she had

uncomplicated typhoid fever?

For complicated typhoid fever, empiric therapy with ceftriaxone is

recommended.

57 Once susceptibility data are available, treatment options include 10

to 14 days of ceftriaxone (1–2 grams IV once daily) continued for at least 7 days after

defervescence to minimize the risk for relapse,

48 or a fluoroquinolone for 10 to 14

days.

44

Uncomplicated typhoid fever is typically treated in the outpatient setting.

44 Empiric

oral regimens include azithromycin 500 mg daily × 5 to 7 days,

44 or a

fluoroquinolone (e.g., levofloxacin 500 mg once daily or ciprofloxacin 500 mg twice

daily).

3 For children, azithromycin or ceftriaxone is recommended.

3

Interestingly,

with the reduction in MDR S. typhi in some areas, ampicillin, amoxicillin, TMP–

SMX, or chloramphenicol are again options for susceptible isolates.

44

ADJUNCTIVE TREATMENT

CASE 69-11, QUESTION 4: Besides the administration of antibiotics, what adjunctive therapies could

benefit B.C. for the treatment of severe typhoid fever?

Enteric encephalopathy, i.e., altered mental status, is associated with a mortality

rate as high as 56% if effective treatment is not promptly administered.

58

In patients

with enteric encephalopathy, retrospective data report improved survival when

appropriate antimicrobial therapy is combined with high-dose dexamethasone (3

mg/kg IV followed by 1 mg/kg every 6 hours IV for eight doses).

58 The mechanism of

action of dexamethasone in enteric encephalopathy is not known.

58

CASE 69-11, QUESTION 5: Fourteen months after discharge from the hospital, B.C. remains free of

symptoms associated with typhoid fever, but follow-up testing reveals she continues to excrete S. typhi in her

stools. Additionally, their adult son who has dinner with them every Sunday, presents to his clinic doctor with

fever, headache and chills, and is confirmed to have uncomplicated typhoid fever. He has no significant past

medical history and has no recent travel history. How might her son have acquired typhoid fever? What

treatment recommendations can be provided to this family?

Unlike his mother B.C., her son has no travel history to an area where typhoid

fever is endemic. Instead, he is likely to have contracted typhoid fever from

consuming foods prepared by his mother who is now a chronic carrier of S. typhi.

Most patients with typhoid fever continue to excrete S. typhi in their stools for 3 to 4

weeks after recovery from their illness. However, 1% to 3% of persons like B.C.

become chronic carriers who continue to excrete Salmonella from stool or urine for

more than 1 year after infection and serve as reservoirs for spreading infection.

Unlike for non-typhoidal salmonellae, humans are the only natural host and reservoir

for S. typhi.

55 B.C.’s risk factor for becoming a chronic carrier is her history of

gallstones which allows the sequestration of organisms within her abnormal biliary

tract.

CHRONIC TYPHOID CARRIERS

Treatment

CASE 69-11, QUESTION 6: What therapeutic options are available to cure B.C.’s chronic carrier state?

Treatment options for chronic S. typhi carriers like B.C. include a prolonged

course of antibiotics, cholecystectomy, or suppressive antimicrobial therapy.

42 Fifty

to ninety percent of chronic carriers may be cured after prolonged courses of

antibiotics,

59–62 although efficacy may be lessened when anatomic abnormalities (e.g.,

cholelithiasis) are present.

59 Relapse is usually detected within the first several

months after completing antimicrobial therapy

63 but can occur up to 24 months after

completing therapy.

64 For susceptible S. typhi, curative oral antimicrobial regimens

include amoxicillin 2 g 3 times daily for 28 days,

61 ampicillin 1 g 4 times daily for

90 days,

60 ampicillin 1.5 g 4 times daily plus probenecid for 6 weeks,

59 TMP–SMX

160/800 mg twice a day for 3 months,

62 ciprofloxacin 500 to 750 mg twice a day for

3 to 4 weeks,

65–67 or norfloxacin 400 mg twice daily for 4 weeks.

68

Prevention

CASE 69-11, QUESTION 7: B.C.’s sister is planning a trip to the Indian subcontinent and is concerned

about acquiring typhoid fever. What can she do to reduce her risk for becoming infected?

p. 1456

p. 1457

The U.S. Centers for Disease Control and Prevention recommends vaccination for

travel to areas where the risk for S. tyhi is increased including many Asian, African,

and Latin American countries.

69

In the United States, two licensed vaccines are

available to protect against S. typhi but not against S. paratyphi. The intramuscular

vaccine for persons older than 2 years of age is 55% effective in preventing typhoid

fever; adverse effects include local pain and swelling, fever, and headache.

69 The

oral live-attenuated vaccine Ty21a vaccine (series of 4 doses) for persons older than

6 years of age is well tolerated, and it affords a protective efficacy rate around

55%.

69 Since the oral vaccine is a live-attenuated vaccine, it should not be

administered to immunocompromised persons. Additionally, to ensure full vaccine

activity, the live-attenuated vaccine should not be given until at least 3 days after the

last dose of an antimicrobial, and if possible, antimicrobials should not be initiated

within 3 days of the last dose of the oral vaccine; longer intervals should be

considered for long-acting agents such as azithromycin.

69

Finally, because the protective efficacy of available vaccines against S. typhi is

not 100%, and because neither vaccine is licensed to protect against S. paratyphi

which in some Asian countries accounts for up to 50% of blood isolates from

patients with enteric fever,

70

it is still necessary to reinforce the importance of good

hygiene and the avoidance of foods with a high risk for being contaminated with

enteropathogens.

SHIGELLA SPECIES

Shigella are gram-negative intracellular bacterial pathogens belonging to the

Enterobacteriacae family. They are the most frequent cause of dysentery, which is an

inflammatory diarrheal illness characterized by bloody or mucoid stools with

abdominal cramps. Of the four Shigella species, severe dysentery is most commonly

caused by Shigella dysenteriae followed by Shigella flexneri, whereas milder illness

characterized by watery diarrhea with or without blood is typically caused by

Shigella sonnei and Shigella boydii.

71

Shigellosis—Severe Illness

CLINICAL PRESENTATION

CASE 69-12

QUESTION 1: M.T. is a 60-year-old, ill-appearing man hospitalized for bloody diarrhea and fever. Two days

before admission he noted the onset of fever, abdominal cramps, and six to seven non-bloody, watery stools.

His diarrhea has since worsened to 10 to 12 small-volume stools with blood and mucus, and he now complains

of painful straining while passing his stools. His history of present illness is significant for returning 3 days ago

from a business trip to Indian subcontinent. During the business portion of the trip, he remained at the hotel

where all his meals were prepared by hotel staff well trained in the sanitary preparation of foods. However, on

the day of his departure he opted to mingle with local residents to get a first-hand taste of native foods and

beverages from street vendors. M.T. lives alone in Florida, has no significant medical history or drug allergies,

and takes no medications. On admission, his temperature is 101°F and physical examination reveals a critically

ill man with severe abdominal tenderness. Why is M.T.’s history of present illness and clinical presentation

consistent with the diagnosis of dysentery, most likely caused by S. dysenteriae type 1.

M.T.’s diagnosis of dysentery, likely caused by S. dysenteriae type 1 is consistent

with his recent travel to the Indian subcontinent where S. dysenteriae type 1 is both

epidemic and endemic,

71 primarily as a consequence of inadequate systems for

disposal of sewage.

71 M.T. likely became infected from the consumption of

contaminated foods or beverages prepared by local street vendors, by person-toperson contact with symptomatic persons with diarrhea, or from asymptomatic

persons continuing to excrete shigellae from their stool.

72 As few as 10 to 100

shigellae can cause illness

71

in healthy hosts, explaining why shigellosis is a very

contagious infection.

Once ingested virulence factors allow shigellae to evade detection by the immune

system and invade colonic and rectal epithelium. Enterotoxin production causes fluid

secretion into the intestinal lumen and cytotoxin production causes cell death; both

toxins lead to the severe clinical manifestations of shigellosis.

71

As with M.T., within 24 to 48 hours after ingestion of Shigella bacteria symptoms

of dysentery begin and include fever, fatigue, malaise, and anorexia.

72 Watery

diarrhea generally precedes dysentery, and frequently is the only manifestation of

mild infection.

72 Progression to dysentery may follow within hours to days and is

characterized by frequent, small-volume, bloody, and mucoid stools; abdominal

cramps; and tenesmus which is described as painful straining when passing stools.

72

Hemolytic uremic syndrome (HUS) is a serious complication of shigellosis,

occurring in up to 13% of patients with dysentery caused by S. dysenteriae type 1.

HUS is a consequence of the production of shiga-toxin 1, most commonly produced

by S. dysenteriae but also rarely by S. flexneri.

71 Longer-term health complications of

diarrheal illness caused by invasive pathogens like Shigella species, as well as

Salmonella and Campylobacter species, include postinfectious irritable bowel

syndrome

73 or reactive arthritis.

74

TREATMENT

CASE 69-12, QUESTION 2: Would M.T. benefit from antimicrobials to treat the bloody diarrhea and fever

(dysentery), presumably caused by S. dysenteriae type 1?

For several reasons, M.T. would benefit from antimicrobial therapy for dysentery

presumably caused by S. dysenteriae type 1. First, effective antimicrobial therapy

reduces the average duration of illness from 5 to 7 days to about 3 days

72 and reduces

the risk of death and serious infection-related complications. Within 48 hours of

starting treatment M.T. should notice a reduction in stool frequency, volume of

bloody stools, and fever. Second, effective antimicrobial therapy quickly reduces the

carriage and excretion of shigellae, thus limiting the spread of infection. Despite the

aforementioned benefits of antimicrobial therapy, there has been concern that

antimicrobials could increase the risk for developing HUS. However, Bennish et al.

75

reported that early administration of effective antimicrobials (i.e., within 3–4 days of

the onset of dysentery) is associated with a low risk for developing HUS.

CASE 69-12, QUESTION 3: What empiric antimicrobial regimens are available for the treatment of

shigellosis?

Shigella species are well known for rapidly developing resistance following

exposure to antimicrobials; therefore, selection of empiric therapy should be based

on local antimicrobial susceptibility patterns.

71

Ampicillin, TMP–SMX, and Nalidixic Acid

During the 1960s to 1980s, ampicillin, TMP–SMX, or nalidixic acid were the

standard treatments for shigellosis. During the 1990s, multidrug-resistant (i.e.,

resistance to ampicillin, TMP–SMX, and chloramphenicol) Shigella precluded their

empiric use for shigellosis, but as these multidrug-resistant isolates remained

susceptible to fluoroquinolones, these agents became the drugs of choice for this

infection.

71

p. 1457

p. 1458