In adults, oral ciprofloxacin 500 mg twice daily for 3 to 5 days is effective against
multidrug-resistant S. dysenteriae type 1 infection in the setting where all isolates are
susceptible to ciprofloxacin and nalidixic acid.
10 With the widespread introduction of
fluoroquinolones as the drugs of choice for the treatment of shigellosis, not
unexpectedly, quinolone-resistant shigellae have emerged.
i n Shigella species from Asia and Africa has progressively increased from 0.6%
prior to 2000 to 29.1% during 2007 to 2009.
ciprofloxacin-resistant Shigella remains low (less than 5%) in Europe and
international travel is strongly associated with the importation and
subsequent circulation, within the United States, of ciprofloxacin-resistant Shigella
78 and other multi-drug resistant Enterobacteriacae.
In the setting of epidemic dysentery caused by S. dysenteriae type 1, similar clinical
outcomes were observed in adults treated with a single 1 g oral dose of azithromycin
or multiple doses of ciprofloxacin (500 mg orally twice daily for 3 days). In this
study, the mean number of days until resolution of symptoms after starting therapy
was similar (2.5 days for azithromycin vs. 2.3 days of ciprofloxacin) but only 17% of
isolates were nalidixic acid–resistant.
In adults with moderate-to-severe shigellosis caused by multidrug-resistant
Shigella species, clinical efficacy is similar with oral azithromycin (500 mg on day
1, then 250 mg daily for 4 days) or oral ciprofloxacin (500 mg every 12 hours for 5
days), 89% versus 82%, respectively (P > 0.2).
In a subgroup analysis, a greater
proportion of patients infected with S. dysenteriae type 1 failed therapy with either
azithromycin (29%) or ciprofloxacin (17%), compared with patients infected with
other Shigella species (failure rate of 6% for either antibiotic).
the S. dysenteriae type 1 isolates were nalidixic acid–resistant (median ciprofloxacin
MIC of 0.125 mcg/mL) whereas only 6% of other Shigella species were nalidixic
acid–resistant (median ciprofloxacin MIC of 0.016 mcg/mL).
Concerning is the intercontinental spread through sexual transmission of
azithromycin-resistant shigellosis and treatment failure following azithromycin
82 S. sonnei with reduced susceptibility to azithromycin remains susceptible
The oral third-generation cephalosporin cefixime is unreliable for the treatment of
shigellosis, with failures reported in 11% to 47% of patients.
and cefotaxime have excellent in vitro activity against Shigella species and have
for patients failing ciprofloxacin therapy.
Though uncommon, ceftriaxone-resistant Shigella have been reported in Asia.
Ongoing surveillance to detect changes in antimicrobial susceptibility among
Shigella species is needed to direct local empiric treatment recommendations.
CASE 69-12, QUESTION 4: Should loperamide be started in patients with dysentery?
The role of antimotility drugs in patients with dysentery has been debated, the
concern being that prolonging the clearance of pathogens from the intestinal tract
could worsen the severity of illness. However, loperamide (in combination of
ciprofloxacin) has been safely used in non-critically ill adults with bacillary
dysentery primarily caused by Shigella species, decreasing the number of unformed
stools and shortening the duration of diarrhea; fever was not prolonged in these
9 However, the authors stress that all Shigella isolates in the study were
susceptible to the antimicrobial used (i.e., all isolates were susceptible to
ciprofloxacin and nalidixic acid) and none of the patients were critically ill; thus, it
would not be prudent to extrapolate the findings from this study to critically ill
severe dysentery, likely caused by Shigella species?
Ciprofloxacin, azithromycin, and ceftriaxone are the primary agents used for the
though resistance to all of these agents has been reported.
In the setting of severe dysentery associated with nausea and vomiting, parenteral
ceftriaxone is a reasonable empiric option.
71 Fluoroquinolones are a less desirable
option given the widespread prevalence of fluoroquinolone-resistant Shigella
species in areas including the Indian subcontinent
CLINICAL PRESENTATION TREATMENT
antimicrobials for her presumed, mild case of shigellosis?
Compared to M.T., F.F. is experiencing a much milder, and likely self-limiting case
of shigellosis. In industrialized countries, risk factors for shigellosis include settings
where individuals are in close contact such as in child-care centers, military
barracks, and institutional housing.
82 are other means of spreading shigellosis. Secondary
attack rates as high as 40% occur within 1 to 4 days after exposure to the primary
case; infected persons may continue to asymptomatically shed Shigella in stool
following recovery from their illness.
S. sonnei accounts for 90% of shigellosis in developed countries. As most patients
have a mild and self-limiting illness, antimicrobials are not generally required.
However, from a public health standpoint they are often prescribed to shorten the
duration of illness to reduce the infectious period.
86 On the other hand, with the
emergence of multidrug-resistant Shigella species, some experts favor reserving
antimicrobials for only severely ill persons.
Empiric antimicrobial options include a 3-day course of either ciprofloxacin 500
mg orally twice daily or azithromycin 500 mg orally once daily; ceftriaxone can also
87 Clinical improvement may be evident within 24 hours.
Prevention of shigellosis requires good hygiene including proper hand washing and
reducing fecal–oral exposure during sexual
88 Development of an effective vaccine has been limited by poor vaccine
immunogenicity, decreased vaccine protection because of the changing prevalence of
infection caused by non-vaccine serotypes and adverse effects.
history of present illness and clinical presentation consistent with Campylobacter gastroenteritis?
M.U.’s presumptive diagnosis of Campylobacter gastroenteritis is consistent with
her recent history of eating undercooked chicken at a restaurant associated with an
ongoing outbreak of Campylobacter gastroenteritis. In industrialized nations, the most
important risk factor for acquiring Campylobacter infection is the consumption of
contaminated undercooked poultry, dairy products, unpasteurized foods, or
89 Prevention of Campylobacter infection involves careful food
preparation and cooking practices.
Beginning 24 to 72 hours after consumption of contaminated foods, clinical
manifestations of Campylobacter gastroenteritis typically include diarrhea, fever, and
abdominal cramps with either loose and watery or bloody stools.
complications of C. jejuni gastroenteritis include Guillain–Barré syndrome, reactive
arthritis, and postinfectious irritable bowel syndrome; the latter associated with
diarrhea lasting more than 7 days.
CASE 69-14, QUESTION 2: Would M.U. benefit from antimicrobial therapy to treat her Campylobacter
Because C. jejuni gastroenteritis is typically an acute, self-limiting illness
91 antibiotic therapy is usually not necessary.
Antibiotics are recommended for patients with symptoms lasting longer than 1 week,
high fevers, bloody stools, pregnant women, or immunocompromised hosts.
M.U.’s clinical presentation includes fever with bloody stools, antimicrobial therapy
is warranted. Effective antimicrobial therapy shortens the duration and the severity of
illness by a mean of 1.3 days, and it is most beneficial when started with 3 days of
CASE 69-14, QUESTION 3: What empiric antimicrobial therapies could be initiated to treat M.U.’s
presumed case of C. jejuni gastroenteritis?
Macrolides (or an azalide) remain the drugs of choice for the treatment of
Campylobacter gastroenteritis.
3 Macrolide resistance has remained relatively stable
89 but depending on geographic location, higher macrolide resistance has
been reported from Eastern Europe and China (5%–11%)
Once considered the drugs of choice for Campylobacter infection, fluoroquinolones
are no longer first-line options as a consequence of widespread fluoroquinolone
resistance, largely attributed to their use in veterinary medicine and food animals
(e.g., poultry); the latter practice has since been banned in the United States.
Fluoroquinolone-resistant C. jejuni exceeds 80% in Spain, Thailand, and Hong Kong,
and it is about 50% in selected European Union States.
prevalence of ciprofloxacin-resistant C. jejuni remained between 20% and 30% from
96 However, higher quinolone-resistance among Campylobacter
93 underscores the need to consider local
resistance patterns from where infection was acquired, when selecting empiric
antimicrobial therapy for returning travelers.
Recommended oral treatments for C. jejuni gastroenteritis for adults are
azithromycin 500 mg once daily for 3 days or erythromycin 500 mg 4 times daily for
3 Children may be treated with azithromycin 10 mg/kg/day once daily for 3 to
5 days or erythromycin 30 mg/kg in two to four divided doses for 3 to 5 days.
basis of M.U.’s medical history and clinical presentation, empiric therapy with oral
Of the nearly one billion people traveling each year from industrialized countries to
developing areas of the world, approximately 10% to 60% will experience an acute
self-limiting episode of travelers’ diarrhea (TD).
complications occur in a small proportion of returning travelers.
recommend pretravel education focusing on the prevention of TD and instructions for
the self-treatment of TD at the onset of illness.
vegetables, prepared foods, and unbottled beverages.
why are their clinical presentations consistent with this diagnosis?
Both travelers have several risk factors for acquiring TD. First, their travel to Latin
America, a destination considered “high-risk” for TD (i.e., ≥20% risk within the first
high-risk destinations include South Asia and West/Central Africa.
the highest risk for TD is during the first 2 weeks of travel, their recent arrival to an
at-risk destination increases the likelihood for infection; the risk for TD lessens
during the second (9.9% risk) and third (3.3% risk) weeks of travel.
travel style of eating foods with a high-risk for contamination with enteropathogens
such as foods from local street vendors and drinking unbottled beverages. Additional
high-risk foods include ice cubes, raw milk, unpeeled fruits and vegetables,
uncooked foods, moist foods; foods remaining at room temperature for prolonged
periods of time, allowing bacteria to multiply or release their enterotoxins
acid-inhibiting medications allowing acid-susceptible enteropathogens to pass
through to the intestines; and genetic predisposition.
TD is defined as three or more loose, unformed stools per day plus at least one
symptom of enteric infection such as abdominal cramps, nausea, vomiting, fever,
fecal urgency, tenesmus, or the passage of bloody or mucoid stools. Like in these
travelers, illness typically begins within 24 to 48 hours after consuming fecally
contaminated foods. Left untreated, TD is generally a self-limiting illness lasting 4 to
CASE 69-15, QUESTION 2: What general approach should W.D. and B.D. take to manage their diarrheal
Realizing that their symptoms are consistent with TD, both travelers review their
pretravel information for the self-management of TD.
To replace fluid and electrolyte losses they should continue to drink only bottled or
boiled liquids such as tea, broth, carbonated beverages, and fruit juices.
Electrolytes can be replaced by eating salted crackers or similar sources of sodium
chloride. For travelers able to drink fluids ad libitum, a modified World Health
Organization oral rehydration solution offers no additional benefit over the
administration of loperamide alone.
100 Neither traveler has symptoms indicative of
significant dehydration such as thirst, dizziness, or altered mental status.
SAFE FOODS—“PEEL IT, BOIL IT, OR FORGET IT”
Travelers should avoid consuming foods with a high risk for contamination with
enteropathogens such as raw vegetables, fruit they have not peeled themselves,
cooked food not served steaming hot, and tap water.
fruits that they have peeled themselves or that have been adequately washed, and
well-cooked foods served steaming hot. Enteropathogens are killed at 100°C and
foods served piping hot at 60°C are generally safe.
Despite adherence to dietary restrictions and precautions, prevention of TD is not
always possible, likely reflecting the difficulty with adhering to sanitary standards
for the preparation and serving of foods, the lack of facilities for employees to wash
their hands after going to the bathroom, or the lack of screens or windows to prevent
flies from contaminating foods.
SELF-TREATMENT OF TRAVELERS’ DIARRHEA
Antimotility agents alone provide rapid relief of symptoms but do not cure the
infection, whereas antimicrobials alone will cure the infection but symptoms may
In the appropriate setting, antimotility drugs plus
antibiotics provide the fastest relief of diarrheal symptoms.
99 Selection of a selftreatment plan is, in part, based on the traveler’s severity of illness and
manifestations of their diarrheal illness.
Microbial Etiology, Clinical Manifestations, and
CASE 69-15, QUESTION 3: For travelers with the following manifestations of TD, (a) watery diarrhea
the common microbial etiologies, and what treatment options are available to manage these diarrheal
The microbial etiology of TD is recognized in 50% to 94% of patients, with
bacteria most commonly identified; viruses and parasites are less frequently
14 For travelers to developing countries, the most common enteropathogen is
enterotoxigenic E. coli (ETEC), followed by enteroaggregative E. coli (EAEC),
diffusely adherent E. coli, noroviruses, rotaviruses, Salmonella species, C. jejuni,
14 The likely enteropathogen afflicting individual travelers can
in part be predicted by the clinical manifestations of the diarrheal illness and the
travel destination (information which is helpful for selecting an appropriate selftreatment plan).
WATERY DIARRHEA WITHOUT FEVER OR BLOODY DIARRHEA
ETEC is suspected in the setting of acute watery diarrhea, especially in travelers to
Latin America and the Caribbean (≥35% of reported pathogens), Africa (25%–35%
of reported pathogens), and South Asia (15%–25% of reported pathogens).
produce enterotoxins that stimulate the intestinal mucosa to secrete fluid into the gut
lumen, leading to diarrheal stools.
Loperamide, Diphenoxylate/Atropine, Bismuth Preparations
Loperamide alone can be considered in patients with a mild diarrheal illness, e.g.,
two loose stools and mild symptoms,
103 without fever or bloody stools.
Loperamide rapidly relieves diarrheal symptoms, often within <24 hours
better tolerated than diphenoxylate/atropine. Mild diarrheal illness may be less likely
to be infectious in etiology, but instead because of noninfectious causes such as
anxiety, diet changes, and stress.
103 Bismuth subsalicylate is moderately effective in
Alternatively, travelers on a short and critical trip (e.g., business) might consider
the addition of an antibiotic. However, the potential adverse consequences of
antimicrobial therapy such as the risk for adverse drug events, additional cost, and
antimicrobial resistance should also be considered. A recent prospective study
reported that depending on the travel destination, the risk for a traveler with diarrhea
becoming colonized with extended-spectrum beta-lactamase producing
Enterobacteriacae was greatest (28%–80%) if an antimicrobial was taken versus if
no antibiotic was taken (8%–47%).
79 After returning home up to 24% of travelers
remain colonized at 6 months and 10% remain colonized at 3 years.
some experts do not recommend antimicrobials for mild-to-moderate disease nor for
Rifaximin, ciprofloxacin or levofloxacin, or azithromycin
travelers with watery diarrhea without fever or dysentery
106 where ETEC is a frequent cause of TD, a
single dose of ciprofloxacin 500 mg, azithromycin 1 g, or levofloxacin 500 mg
decreased the median time to passage of the last unformed stool to 22 to 33 hours
versus 54 to 66 hours for travelers given placebo.
107 For travelers to Mexico or
India, oral rifaximin 200 mg 3 times daily or ciprofloxacin 500 mg twice daily for 3
days significantly reduced the median time to passage of the last unformed stool to 32
hours and 29 hours, respectively, versus 66 hours for travelers taking placebo.
Rifaximin is not systemically absorbed, is well tolerated and has a low potential for
the development of antibiotic resistance.
Therapy for Travelers’ Diarrhea in Adults
Ciprofloxacin 500 mg twice daily for 1–3 days
Levofloxacin 500 mg daily for 1–3 days
Azithromycin 1,000 mg in a single dose or 500 mg once daily × 3 days
Rifaximin 200 mg 3 times daily for 3 days
otherwise, may continue antibiotic for up to 3 days.
review of the evidence base for self-therapy of travelers’ diarrhea. J Travel Med. 2009;16:161.
Antimotility Drugs Plus Antimicrobials
The combination of antimotility drugs plus antimicrobials provide the fastest relief of
diarrheal symptoms. The antimotility drug quickly acts to reduce the number of
stools, whereas the antimicrobial cures the infection.
stationed in Turkey with TD primarily caused by ETEC, the median time to the
passage of the last unformed stool was shortened to as little as 3 hours in recruits
taking oral loperamide (4 mg initially, then 2 mg as needed; maximum 16 mg/day)
plus either levofloxacin (single 500-mg dose) or azithromycin (single 1-g dose).
otherwise healthy US students at least 18 years old attending school in Mexico, the
combination of rifaximin (200 mg orally 3 times daily for 3 days) plus loperamide (4
mg initially, then 2 mg after each unformed stool) relieved diarrheal symptoms faster
(27 ± 4.13 hours) than rifaximin alone (32.5 ± 4.14 hours) or loperamide alone (69 ±
BLOODY DIARRHEA WITH OR WITHOUT FEVER, OR DIARRHEA
Invasive pathogens including Shigella, Campylobacter, and less commonly
Salmonella, non-cholera Vibrios and Aeromonas species are suspected in the setting
of acute bloody diarrhea with fever. Campylobacter species are frequent causes of
TD in travelers to Southeast Asia (25%–35% of reported pathogens) and South Asia
(15%–25% of reported pathogens).
A comparative study reported the highest cure rate with a single dose of azithromycin
1 g (96%), followed by 3 days of either azithromycin 500 mg daily (85%) or
levofloxacin 500 mg daily (71%).
110 The lower cure rate with levofloxacin was
because of infection with levofloxacin-resistant Campylobacter species. Nausea
during the 30 minutes after receipt of the first antimicrobial dose was more common
in persons given 1 g of azithromycin versus the other regimens (14% vs. <6%,
Rifaximin should not be used in patients with diarrhea complicated by fever and
bloody stools, being ineffective against invasive enteropathogens, e.g., Salmonella,
Shigella, and Campylobacter species.
CASE 69-15, QUESTION 4: Based on the symptoms each traveler is experiencing, what drug therapies are
available for W.D. and B.D. that can be considered to reduce the duration and severity of their TD?
For travelers with mild watery diarrhea without fever or bloody stools (like
W.D.), loperamide can be used, often relieving symptoms in less than 24 hours.
improvement is not evident within 12 hours, an antimicrobial could be started.
For travelers with moderate-to-severe diarrhea with fever or bloody stools (like
B.D.), antimicrobial therapy is recommended to shorten the duration and severity of
101 Treatment options include a fluoroquinolone or azithromycin
(Table 69-3). Azithromycin is recommended for travelers to areas with a high
prevalence of fluoroquinolone-resistant Campylobacter species,
Thailand (93%), Nepal (71%), Asia (70%), Latin America (61%), and Africa
102 or for travelers not responding within 48 hours to a fluoroquinolone.
Rifaximin is not effective for TD caused by invasive enteropathogens
POSTINFECTIOUS COMPLICATIONS OF TD
CASE 69-15, QUESTION 5: Three weeks after returning from their trip, unlike W.D. who is free of
be recommended to manage her symptoms?
Clinical Presentation and Risk Factors
Postinfectious complications of TD include reactive arthritis and Guillain–Barré
syndrome which are associated with C. jejuni infection and PI-IBS which may occur
in 3% to 17% of travelers following a diarrheal episode
including Campylobacter, Salmonella, and Shigella species.
include a severe episode of TD (like B.D.), the number of episodes, pretravel
diarrhea, pretravel adverse life events, and infection with heat-labile toxin-producing
Treatment of PI-IBS is aimed at providing symptomatic relief; antimicrobials have
not been proven to be beneficial and may be harmful.
managed with loperamide; if postprandial fecal urgency is problematic, taking
loperamide 30 minutes before meals is recommended. Bloating and abdominal
discomfort can be managed with simethicone or antispasmodic agents
abdominal symptoms can be managed with low doses of amitriptyline and selective
serotonin reuptake inhibitors.
111 About 50% of patients with PI-IBS recover within 6
years, although recovery is less likely in the setting of persistent depression or
Prevention of PI-IBS with chemoprophylaxis of TD has not been proven. A recent
randomized, double-blind, placebo-controlled study evaluating prophylactic
rifaximin for the prevention of diarrhea in travelers to South and Southeast Asia did
not find rifaximin to reduce the occurrence of new-onset IBS. The absence of a
benefit could be attributed to inadequate power of the study to detect a true
difference; more studies are needed to address this issue.
CASE 69-15, QUESTION 6: On hearing of the travels of W.D. and B.D., friends J.G. and T.M. begin
What drug therapies can be recommended for the chemoprophylaxis of TD?
CANDIDATES FOR ANTIMICROBIAL PROPHYLAXIS AND SPECIFIC
Antimicrobial prophylaxis for TD is recommended when the benefit of prophylaxis
outweighs the risks of drug therapy including adverse drug reactions such as
photosensitivity with fluoroquinolones, bacterial resistance, and expense.
otherwise healthy persons, TD is typically a self-limiting illness lasting several days,
and should it occur, traveler’s self-management of TD reduces the time to the last
unformed stool to within 24 hours of the onset of illness.
113 For these reasons, routine
chemoprophylaxis for TD is not recommended.
Chemoprophylaxis could be considered for travelers at greatest risk for infection
or its complications, including persons in whom a short-term illness could ruin the
purpose of the trip (e.g., athletes, politicians, lecturers, others); persons in whom a
bowel disease, advanced cancer, or HIV infection); and persons with conditions
which increase the risk for enteric infection (e.g., genetic predisposition, gastric
disease or surgery, or use of acid-reducing medications).
chemoprophylaxis should not extend beyond 2 to 3 weeks.
are not candidates to receive antimicrobial prophylaxis for TD. Instead, at the onset
of illness, they should follow their self-treatment plan for TD they received from
For travelers who are candidates for chemoprophylaxis of TD, the following
Chemoprophylaxis with a fluoroquinolone (ciprofloxacin 500 mg or levofloxacin
500 mg given daily during travel but not exceeding 2–3 weeks and for 2 days after
return) is recommended to reduce the incidence of diarrheal illness.
the current efficacy of fluoroquinolones should be viewed with caution, given rising
fluoroquinolone resistance in common enteropathogens
in India, and Campylobacter species in Asia and Latin America.
mg daily is an alternative chemoprophylactic agent and preferred for travel to
destinations where Campylobacter species is a common cause of TD, e.g., South and
Rifaximin is not FDA approved for the prophylaxis of TD, but it has been effective
for the prevention of TD in students traveling from the United States to Mexico where
ETEC is a common enteropathogen.
114 A more recent randomized, double-blind,
placebo-controlled study showed only a modest (48% protection) benefit of
rifaximin compared to placebo in otherwise healthy travelers to South and Southeast
Asia—areas where enteroinvasive pathogens are frequent causes of TD.
Bismuth subsalicylate, two tablets (526 mg/dose) 4 times daily for a maximum of 3
weeks has a protective efficacy of 65% against TD.
because of inconvenient dosing, salicylate content, and unpleasant adverse effects as
mentioned before need to be considered.
Probiotics have been studied on the basis of their ability to prevent enteropathogen
colonization. The effectiveness of probiotics has not been determined and more
studies are needed before these agents can be routinely recommended.
QUESTION 1: P.J., a 3-year-old girl, is brought to the ED because of “stomach pains” and non-bloody
STEC as the cause of P.J.’s illness?
E. coli O157:H7 is a strain of E. coli that produces Shiga toxins as one of its
mechanisms of causing GI illness. A second virulence factor of STEC strains is their
ability to attach to and damage the intestinal mucosa.
116 These E. coli bacteria cause a
wide spectrum of illness, including asymptomatic carriage, mild and non-bloody
diarrhea, bloody diarrhea (hemorrhagic colitis), HUS, and thrombotic
diarrhea associated with Shigella species or Campylobacter species, fever is often
absent or of low grade because this pathogen is not invasive.
illness are more likely to have fever, however.
STEC is most commonly spread by consumption of undercooked beef products that
are contaminated with E. coli O157:H7, although other modes of acquiring this
infection have been reported. The incubation period for this infection is usually 3 to 4
days, which is consistent with P.J.’s recent history of eating undercooked hamburger.
In most instances, the illness resolves in 5 to 8 days.
121 Fecal leukocytes may or may
not be found in stool samples.
CASE 69-16, QUESTION 2: How can P.J.’s diagnosis of E. coli O157:H7 infection be confirmed?
In the United States, E. coli O157:H7 is the most common STEC serotype
associated with this infection.
122 Unlike other E. coli, O157:H7 does not rapidly
this media. Because of other sorbitol-fermenting organisms and non-O157 STEC,
further testing for Shiga toxins or the genes encoding them is increasingly
mg/dL; serum potassium (K), 6.8 mEq/L; WBC count, 20,000 cells/mm
; hemoglobin (Hgb), 5 g/dL; platelets,
; and urinalysis is positive for blood and protein. The stool specimen sent on admission is
positive for E. coli O157:H7. What complication of E. coli O157:H7 infection does P.J. now display?
thrombocytopenia, microangiopathic hemolytic anemia, and acute renal failure with
124 On physical examination, P.J.’s “bruises” on her extremities are
consistent with thrombocytopenia, which is confirmed by the low platelet count. Her
pale appearance is consistent with anemia and is confirmed by the low Hgb. The
dark urine is caused by the color imparted from bilirubin because of red cell lysis
(hemolytic anemia). Finally, P.J.’s decreased urine output and increased serum
creatinine and BUN concentrations are consistent with renal failure.
several risk factors for HUS: her age (i.e., children aged <5–15 years, median age 4–
8 years), fever, increased peripheral WBC count, and the season of the year (i.e.,
126–129 Although not present in this case, other possible risk factors for
developing HUS are age >65 years
122 and treatment with antimotility or antidiarrheal
130 although this has not been universally confirmed.
E. coli O157:H7 gastroenteritis to HUS typically becomes apparent about 1 week
126 Of children, 3% to 7%130 may develop HUS, with
a mortality rate ranging from 3% to 5%.
In adults, E. coli O157:H7 infection progresses to HUS in as many as 27% of
patients, with a higher rate in patients >65 years of age.
reached 42% in patients >15 years of age
; elderly nursing home patients have a
Other than supportive measures to manage the complications associated with
illness caused by E. coli O157:H7, no specific drug therapy for this infection
In retrospective and prospective studies, antibiotics have not influenced the
severity of illness, or the duration of diarrhea or other GI symptoms.
SMX was started a mean of 7 days after the onset of diarrhea, the duration of E. coli
O157:H7 excretion was not altered.
The effect of antibiotic administration on the risk of E. coli O157:H7
complications (e.g., HUS) remains controversial. A prospective cohort study of 71
children with diarrhea caused by E. coli O157:H7 found that antibiotic treatment
increased the risk of progression to HUS.
129 Previous publications have supported
134 whereas others have reported that antibiotics do not increase
the risk of progression to HUS.
135 A systematic review of these and other studies
revealed no association between antibiotic administration and development of
136 Antibiotic selection, dosing, timing of administration, small sample sizes,
and a lack of placebo use in the selected studies complicate the analysis. Thus, the
role of antibiotics in the treatment of E. coli O157:H7 infection remains
controversial. Currently, clinicians do not recommend antibiotic treatment for STEC,
though active US surveillance reports nearly 2/3 of patients with this diagnosis
receive antimicrobial therapy, including 29% of patients receiving therapy after
137 Despite these numbers, P.J. should not receive antibiotic
therapy at this time. Clinicians must carefully weigh empiric antibiotic treatment
before an organism has been identified.
Antimotility drugs are not recommended for patients with E. coli O157:H7
infection because they have been variably associated with an increased risk of
135 although other studies have failed to find an
129 Despite these concerns, recent reports suggest up to 31% of
patients continue to receive antimotility agents for this infection.
explanation for the increased risk is unknown, the reduction of bowel motility may
decrease the clearance of organisms from the GI tract, thereby increasing the
absorption of toxins. Administration of antimotility drugs within the first 3 days of
illness has been associated with a longer duration of bloody diarrhea.
CASE 69-16, QUESTION 5: P.J.’s family members want to know what they could have done to prevent this
infection. On discharge from the hospital, is it safe for P.J. to return to her day-care center?
STEC is often spread to humans by consumption of contaminated beef products
that are not thoroughly cooked.
117 Because thorough cooking kills this organism, meat
should be well cooked (i.e., juices from meat should be clear, not pink). In addition,
this infection can be acquired by consuming other contaminated foods, including
water, unpasteurized milk, apple cider, lettuce, and sprouts.
Finally, because contact with infected persons commonly results in transmission of
134 P.J. should not return to day care until at least 48
hours after her diarrhea has ceased.
CLOSTRIDIUM DIFFICILE INFECTION
CLINICAL PRESENTATION AND DIAGNOSIS
QUESTION 1: B.W., a 35-year-old woman, is admitted to a 10-bed medical ward for the treatment of
likely caused by C. difficile. What is the most likely mechanism for this patient’s AAD?
ADD is a common complication of antimicrobial therapy.
which antibiotics cause diarrhea include direct allergic and toxic effects on intestinal
mucosa, and alterations of GI motility (e.g., erythromycin) and of normal intestinal
Changes in the normal bowel flora can lead to changes in carbohydrate or bile
acid metabolism by intestinal bacteria or to overgrowth of pathogenic bacteria, either
of which may be followed by diarrhea.
139 Bacteria known to be associated with AAD
include C. perfringens, S. aureus, Klebsiella oxytoca, Candida species, and C.
difficile. C. difficile infection (CDI) is the most clinically relevant microbial cause
and the focus of this section.
A spore-forming, gram-positive anaerobic bacillus, C. difficile can cause a wide
spectrum of syndromes, including asymptomatic carriage, diarrhea of varying
severity, colitis with or without formation of pseudomembranes, toxic megacolon,
colonic perforation, and death.
The pathogenesis of CDI involves disruption of the normal colonic flora, most
commonly by antibiotics (Table 69-4). An increasing number of cases in the
outpatient setting have been identified without any antibiotic exposure, making
additional risk factors difficult to find.
141 Recent data suggest that proton-pump
inhibitors may be responsible for CDI.
143 Alteration of the colonic microflora is
followed by overgrowth of toxin-producing strains of C. difficile.
primarily toxins A and B, are responsible for causing colonic inflammation and the
clinical manifestations of this infection.
A highly pathogenic strain of C. difficile has been described in outbreaks in the
United States and around the world.
144 This strain, labeled BI/NAP1 (or ribotype
027), generally causes more severe disease. Among its increased virulence factors
are an increased production of both toxins A and B and a binary toxin. This ribotype
has become endemic in some facilities and appears to cause more severe disease
even in non-outbreak situations.
Medications Implicated in Clostridium difficile–Associated Diarrhea
Society for Healthcare Epidemiology of America (SHEA) and the Infectious Diseases Society of America
(IDSA). Infect Control Hosp Epidemiol. 2010;31:431.
CASE 69-17, QUESTION 2: Why is B.W.’s history and presentation consistent with AAD caused by C.
B.W.’s major risk factor for acquiring CDI is her receipt of an antibiotic within the
last 2 weeks. C. difficile is a common cause of nosocomial diarrhea. The clinical and
laboratory findings consistent with CDI include mucoid, greenish, foul-smelling
watery stools and crampy abdominal pain. Patients usually present with low-grade
fevers, but temperature may be >104°F.
146 Peripheral leukocytosis is common with
CDI, sometimes with WBC >30,000 cells/mm3
147 Fecal leukocytes are variably
present in CDI and are not clinically useful for diagnosis.
The onset of symptoms of CDI varies widely from a few days after the start of
antibiotic therapy to 8 weeks after the agent is discontinued.
acquiring CDI are admission to a hospital in which C. difficile is endemic or in
which there is an ongoing outbreak of CDI.
CASE 69-17, QUESTION 3: How can B.W.’s diagnosis of CDI be confirmed?
Finding toxins in unformed stool of symptomatic patients is the gold standard for
diagnosis. Older enzyme immunoassays detecting toxins A/B have largely been
replaced by polymerase chain reaction (PCR) tests, because PCR is much more
149 An advanced two-step diagnostic method is increasingly recommended.
The two-step test first looks for the presence of glutamate dehydrogenase (GDH)
antigen as a quick and inexpensive screening test. GDH is produced by all C.
difficile strains, so positive GDH tests are then followed by toxin-detecting PCR.
Samples negative for GDH are considered negative and not tested further. Culture,
though helpful, is complicated by the fact that of the C. difficile strains isolated from
various populations, 5% to 25% do not produce toxins (non-toxigenic) and do not
146 Routine testing for specific C. difficile strains such as
ribotype 027 is not typically available in most settings.
Colonoscopy with biopsy is used to make the diagnosis of C. difficile colitis
characteristic pseudomembranes may be scattered throughout the colon, the diagnosis
of pseudomembranous colitis can be missed with colonoscopy.
CASE 69-17, QUESTION 4: How can B.W.’s CDI be differentiated from enigmatic AAD?
Only 10% to 20% of cases of AAD are positive for toxigenic C. difficile; the
remaining cases have an unknown cause and are referred to as simple, benign, or
139 The clinical resolution of benign diarrhea is a self-limited
illness that resolves with nonspecific supportive measures and discontinuation of
antibiotics. These clinical entities can be differentiated from one another by several
objective measures. In hospitalized patients, watery diarrhea, low functional
capacity, acid suppression, low albumin, and a WBC >13,000 cells/mm3 were
significant predictors of CDI.
151 Other clinical features that suggest CDI rather than
enigmatic diarrhea are constitutional symptoms, lack of an antibiotic dose
relationship to the illness, and hospital-wide epidemics of diarrhea.
general plan to treat B.W.’s CDI?
After replacement of fluids and electrolytes, there are several steps to most
effectively manage B.W.’s CDI. The first is to discontinue the offending drug (if
possible), which in B.W.’s case is probably the antibiotic ceftriaxone. While some
data suggest that withdrawal of the precipitating antibiotic and supportive care may
be sufficient for mild disease, all available guidelines suggest specific antimicrobial
Because B.W. is being treated for bacterial meningitis, a life-threatening infection,
discontinuing antibiotics is not an option. A second option is to change her
antimicrobial therapy to an agent less likely to cause CDI. B.W. is taking a
cephalosporin, which, as with ampicillin, amoxicillin, and clindamycin, is frequently
implicated as a cause of C. difficile diarrhea (Table 62-4). In contrast, antibiotics,
such as TMP–SMX, and aminoglyclosides, are less commonly associated with
154–156 None of these antimicrobials, however, is a suitable alternative for
treating S. pneumoniae meningitis.
B.W. should also receive therapy directed against C. difficile while continuing to
take ceftriaxone for the treatment of her bacterial meningitis.
Specific C. difficile–directed Antimicrobials
CASE 69-17, QUESTION 6: What antibiotic should be selected to treat B.W.’s CDI?
The oral agents most commonly used to treat CDI are metronidazole and
vancomycin. The differentiation between these two agents is complex and evolving,
but it is guided in part by severity of illness
(Table 69-5). The most optimal
definition of severe disease is not well established, but general markers of instability
of vital signs with high white counts and changes in albumin and serum creatinine are
In patients categorized as having mild-to-moderate disease severity,
metronidazole is generally recommended as the preferred initial agent.
randomized trial that enrolled patients with CDI and colitis, no significant difference
was found in the efficacy of these drugs after 10 days of treatment.
of patients treated for a first episode of CDI with oral metronidazole or vancomycin
are expected to respond to therapy.
161 Recent reports have shown increases in C.
difficile resistance to metronidazole and vancomycin, but the clinical significance in
treatment selection is unknown.
163 Antibiotic sensitivities, therefore, are not routinely
Metronidazole is well absorbed after oral administration and is excreted through
the biliary tract before reaching the colon. Common adverse reactions include
nausea, vomiting, diarrhea, dizziness, confusion, and an unpleasant metallic taste.
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