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Antimicrobial Therapy of Acute Diarrhoea A Clinical Review

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Antimicrobial therapy of acute diarrhoea: a clinical

review

Christoph Lübbert

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 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY, 2016
VOL. 14, NO. 2, 193–206
http://dx.doi.org/10.1586/14787210.2016.1128824

REVIEW

Antimicrobial therapy of acute diarrhoea: a clinical review

Christoph Lübbert
Division of Infectious Diseases and Tropical Medicine, Department of Gastroenterology and Rheumatology, Leipzig University Hospital,
Leipzig, Germany

ABSTRACT ARTICLE HISTORY

Diarrhoea is one of the most commonly occurring diseases. This article presents a review of the current Received 10 October 2015
state of the treatment of acute infectious diarrhoea, as well as of the most important pathogens. The Accepted 2 December 2015
general principles of the therapy of diarrhoea are exemplified, followed by a description of the targeted Published online
29 December 2015
antimicrobial therapy of the most important bacterial gastrointestinal infections, including salmonel-
losis, shigellosis and Campylobacter infections, as well as infections with pathogenic Escherichia coli KEYWORDS
strains, yersiniosis and cholera. Diarrhoea caused by toxigenic Clostridium difficile strains has increased Antimicrobial therapy;
in incidence and in severity. These infections will therefore be described in detail, including important GI tract; diarrhoea;
new aspects of treatment. Symptomatic therapy is still the most important component of the treat- gastroenteritis; Clostridium
Downloaded by [Christoph Lübbert] at 10:19 07 February 2016

ment of infectious diarrhoea. However, empirical antibiotic therapy should be considered for severely difficile; colonisation;
ill patients with a high frequency of stools, fever, bloody diarrhoea, underlying immune deficiency, infection; resistance
advanced age or significant comorbidities. Increasing resistance, in particular against fluoroquinolones,
must be taken into consideration. Therapy with motility inhibitors is not recommended for Shiga toxin-
producing Escherichia coli (STEC) infections, Clostridium difficile infections (CDI), and severe colitis. The
macrocyclic antibiotic fidaxomicin can reduce the rate of recurrent disease in CDI. Furthermore,
evidence for the benefits of faecal microbiota transplantation as a treatment option for multiple
recurrences of CDI is increasing. In conclusion, the treatment of acute diarrhoea is still primarily
supportive. General empirical antibiotic therapy for acute diarrhoea is not evidence-based.

Introduction symptoms. The normal stool range extends from three

The human gastrointestinal tract (GI tract) comprises a
mucosal surface of about 250 to 400 m2 (approximately
the area of a tennis court), thus providing the largest
contact zone between the body and the environment.
[1] Due to the low pH in the stomach and the effects of
bile and pancreatic enzymes, infections are relatively
rare in the upper GI tract, despite the exposed position.
Lower acid concentrations in the small intestine and
colon allow the survival of both physiological intestinal
flora and pathogens. Due to the significantly longer
transit time in the colon, the density of bacteria here
(1012 colony forming units [CFU] per gram wet weight)
is much higher than in the jejunum (104 CFU per gram
wet weight), or in the ileum (106 CFU per gram wet
weight).[1] The present review discusses the current
state of the antimicrobial treatment of acute infectious
diarrhea, as well as the most important pathogens.
Definitions and importance
Diarrhea (see box for definition) is classified as acute,
chronic, or persistent, depending on the duration of
bowel movements a day to three a week.
Definition
The word ‘diarrhea’ is derived from the ancient
Greek word ‘diárrhoia’, which is made up of the
words ‘diá’ for through and ‘rhéō’ for ‘flow’. This is
defined as defecation of liquid stool more than
three times a day. A less practical scientific defini-
tion of diarrhea in adults gives a stool weight of
more than 250 g per day, with excessive frequency
and excessive water fraction.
There is an established clinical distinction between
acute and chronic diarrhea. If acute diarrhea lasts for
up to 2 weeks, the etiology not only is almost always
infectious, but also includes ischemia, toxins, and medi-
cations. In chronic diarrhea, the symptoms last for more
than 4 weeks. This is usually caused by local diseases of
the GI tract, vascular, and functional disorders, and meta-
bolic disorders; it is much more rarely caused by patho-
gens. The term ‘persistent diarrhea’ is used when the

CONTACT Christoph Lübbert christoph.luebbert@medizin.uni-leipzig.de

© 2015 Taylor & Francis
 194 C. LÜBBERT

symptoms last for 2–4 weeks. Gastroenteritis is defined
as inflammation (‘-itis’) of the GI tract that involves both
the stomach and the small intestine. Enteritis is inflam-
mation of the small intestine, and colitis refers to inflam-
mation of the colon. Enterocolitis involves both the small
intestine and the colon.
Infectious diarrhea is one of the most common dis-
eases in the world; according to the World Health
Organization (WHO), it is one of the five most important
causes of death.[2] The pathogens may be viral, bacter-
ial, or parasitic. Recent data from Germany and the USA
indicate that in developed countries approximately one
episode of acute gastroenteritis occurs per person per
year in adults.[3,4]
General therapeutic principles in diarrhea
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body weight, circulatory shock, or impaired con-
sciousness) or with continuing severe vomiting, the
patient must be rehydrated in hospital by intrave-
nous infusion, preferably with full electrolyte solu-
tions.[1,5]
Therapy with motility inhibitors such as loperamide
is not generally recommended, as there is a principal
risk of excessive pathogen densities or toxin enrich-
ment in the intestine, with protracted disease and addi-
tional complications.[1,5,6] Therefore, the use of
motility inhibitors is strictly contraindicated in hemor-
rhagic diarrhea or suspected Clostridium difficile infec-
tions (CDIs), as they are associated with protracted fever
in severe shigellosis, with enhanced hemolytic uremic
syndrome (HUS) in Shiga toxin-producing Escherichia
coli (STEC) infections, and with the development of
toxic megacolon in CDI.[1,5,6,9] Moreover, motility inhi-

Primary therapy for diarrhea consists of oral rehydra-
tion with solutions containing sugar and salt, e.g.
sweetened tea with salted biscuits.[1,5,6] Possible
alternatives include diluted fruit juice with added
sugar and salt, or by mixing a special rehydration
solution. Rice gruel is best for infants with massive
dehydration.[7] The World Health Organization
(WHO) recommends the mixture known as oral rehy-
dration salts (ORS) solution (Table 1).[8] Finished
products – either ORS and solutions or rice-based
solutions – are globally available on the pharmaceu-
tical market.[1,5,6] Oral rehydration is always prefer-
able to intravenous fluid replacement. Antiemetic
therapy (e.g. with metoclopramide) may be neces-
sary for patients who have vomited. If the attacks of
diarrhea are accompanied by abdominal cramps,
analgesia with metamizole can be used (although it
is rarely applied in clinical practice), as this drug
possesses spasmolytic activity.[1] Although therapy
with N-butylscopolamine is also active, patients
often suffer unpleasant but reversible anticholinergic
side effects, such as dry mouth, palpitations, and
mydriasis.[1] In severe cases (dehydration of >10%
Table 1. Composition of the current ORS formulation of the
World Health Organization (WHO), modified from [8] (permis-
sion to reuse this table was granted from the WHO Head Office,
Geneva, Switzerland).
grams/
ORS (WHO) liter % ORS (WHO)
Sodium chloride 2.6 12.7 Sodium
Glucose, anhydrous 13.5 65.9 Chloride
Potassium chloride 1.5 7.3 Glucose,
anhydrous
Trisodium citrate 2.9 14.1 Potassium
dihydrate
Citrate
Total 20.5 100 Total osmolarity
bition does not automatically lead to decreased secre-
tion, so that the patient may suffer severe exsiccosis in
spite of reduced bowel movements.[1] Short-term
symptomatic therapy with loperamide for only 2 days
may be considered in patients with nonhemorrhagic
diarrhea and without fever. Bismuth subsalicylate
(Pepto-BismolTM) is a drug with anti-inflammatory and
antibacterial activity. It is popular in North America, but
is not often used in Europe.[5,6]
Diagnostic panel before the initiation of
antimicrobial therapy
The vast majority of patients with infectious diarrhea
have a self-limiting course of disease and do not
seek medical attention. In severely ill patients with
significant dehydration, fever, bloody diarrhea,
underlying immune deficiency, recent use of antibio-
tics, advanced age, significant comorbidities, or hos-
pitalization, primary evaluation of stool specimen for
bacterial agents (Salmonella, Campylobacter, and
Shigella species), STEC, and CDI should be per-
formed.[1,5,6] In the majority of cases, the bacterial
pathogen is detected in the first or second sample
that is submitted, so performance of multiple cul-
tures is not useful.[6] Targeted tests for ova and
parasites (O&P exam) are required in symptomatic
patients with suspected enteric parasitic infection
mmol/
liter such as persons who have resided in areas of the
75 world where enteric parasites are endemic, returning
65 travelers with intestinal and/or extraintestinal com-
75
plaints, symptomatic patients with high-risk expo-
20 sure (e.g. daycare, outbreaks, wilderness camping,
10
sexual risk exposures), and symptomatic patients
245 with underlying immune deficiency.

Empirical antimicrobial therapy of acute
diarrhea
It has not been demonstrated that general empirical
antibiotic therapy is of benefit in acute diarrhea.[1,5,6]
Admittedly norfloxacin caused a slight reduction in the
duration of Campylobacter enteritis in a Swedish study.
[10] However, antimicrobial therapy had no demon-
strable effect in patients with salmonellosis.[11] In addi-
tion, possible adverse effects of antibiotic treatment
must be considered (HUS in STEC infection; increased
frequency of asymptomatic carriers in salmonellosis; risk
of CDI).[5,6,9,12] A disturbing consequence of antibiotic
treatment has been the long-term persistence of anti-
biotic resistance genes in the human gut.[13]
However, empirical antibiotic therapy can be con-
sidered for severely ill patients with a high frequency
of bowel movements (arbitrarily >6/day), symptoms
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persisting for >1 week, fever, bloody diarrhea, under-
lying immune deficiency, advanced age, or significant
comorbidities.[1,5,6] The current drug of choice is
ciprofloxacin, although its use is being increasingly
restricted by growing resistance, particularly in
imported cases (especially India).[1,14–16] One alter-
native is azithromycin (1 × 500 mg p.o. for 3 days).
[1,5,6] A single dose of fluoroquinolones or macro-
lides has also been found to be active in the empirical
treatment of noninvasive acute diarrhea.[5,6,17] In
milder cases, it is also possible to use the nonabsorb-
able antibiotic rifaximin, at a dose of 2–3 × 200 mg p.
o.[18] Specific therapy of severe infectious diarrhea
requires a differentiated microbiological examination
of the stool.
Effects of antibiotics on the human microbiome
The normal microflora of the skin and mucous mem-
branes acts as a barrier against colonization by poten-
tially pathogenic microorganisms and against excessive
growth by opportunistic microorganisms. This physio-
logical control of the growth of opportunistic microor-
ganisms is known as colonization resistance.[19]
Administration of antimicrobially active substances
causes clinically relevant disturbances in the ecological
equilibrium between the host and the normal micro-
flora, particularly the intestinal flora.[19] Alterations in
the physiological intestinal flora then develop, depend-
ing on the biological properties of the antibiotic used
(pharmacodynamics), its absorption and elimination
and possible enzymatic inactivation and/or binding to
the feces. The most frequent disorders are antibiotic-
associated diarrhea (AAD), fungal overgrowth (particu-
larly Candida species), and, increasingly, CDI. While AAD
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 195
and fungal overgrowth normally end after the end of
treatment [13], CDI usually requires targeted therapy.
Balanced composition of the intestinal microflora
and broad diversity help to stop resistant bacteria
from becoming established.[19] If antibiotics with a
narrow spectrum of action are used, it will not severely
impair colonization resistance. The risk that resistant
bacterial strains will develop and get transferred
between patients will then be reduced. Moreover, the
spread of resistant clones among microorganisms is
markedly reduced. Therefore, the benefits of an empiri-
cal antibiotic therapy must always be balanced against
the disadvantages of short and long-term interference
with the human intestinal microbiome.[13,19]
Epidemiology of individual disease entities and
their specific therapy
In Europe, the leading causes of acute bacterial gastro-
enteritis include Campylobacter, enteropathogenic E.
coli, and enteroaggregative E. coli (EAEC).[6,20,21] For
some years, Campylobacter infections have been
reported more frequently than infections caused by
non-typhoidal Salmonella (68 per 100,000 versus 22
per 100,000 population in 2012).[20] The number of
salmonellosis cases has continuously decreased in
Europe over the past 10 years, most likely because of
the implementation of veterinary control programs
against Salmonella species, especially in poultry.[1,6]
EAEC has also been recognized as an important patho-
gen for community-acquired diarrhea in developed
countries.[6,22] In addition, CDIs have emerged as a
cause of community-acquired enterocolitis, with many
patients lacking typical risk factors.[6,12,23] Foodborne
transmission of C. difficile has been hypothesized as a
possible source of community-associated infections
[24]; however, the evidence needed to confirm or refute
this hypothesis is incomplete.[6] Other less common
pathogens include Shigella species, Yersinia species,
non-cholera Vibrio species, and STEC strains.[6] In
2012, according to the European Centre for Disease
Prevention and Control (ECDC), STEC cases were
reported at a rate of 1.5 cases per 100,000 popula-
tion.[20]
The incidence of acute viral gastroenteritis in Europe
is higher than that of bacterial entities.[1,20,21]
Particularly, norovirus infections are a common problem
in the European Union (EU) and worldwide. Estimates
suggest that norovirus accounts for 12% of severe gas-
troenteritis cases among children <5 years of age, and
that each year norovirus causes 64,000 episodes of
diarrhea requiring hospitalization, and 900,000 clinic
visits among children in industrialized countries.[25]
 196 C. LÜBBERT
Norovirus outbreaks commonly occur in nurseries and
schools, mainly during the winter months. For all rele-
vant viral etiologies, particularly noroviruses, rota-
viruses, astroviruses, and adenoviruses, purely
symptomatic therapies are required, as the course of
the disease is short and self-limiting.[1] Only in single
patients with immune suppression, there may be pro-
tracted disease and delayed elimination of the patho-
gen.[26]
Between 15% and 50% of travellers from industria-
lized countries to developing nations experience travel-
ler’s diarrhea (TD), depending on the destination.[6,27]
TD is most often acquired in the first 2–3 weeks of
travel, through the ingestion of contaminated foods
and, less often, drinks.[6,27] A meta-analysis concluded
that the incidence of acute diarrheal disease was very
similar in travellers who followed the traditional advice,
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‘boil it, cook it, peel it, or forget it’, and those who
engaged in more adventurous nutritional habits.[28]
Specific antimicrobial therapy of the most important
bacterial infections will now be discussed, together with
a detailed discussion of the current treatment of CDIs.
Table 2 summarizes the specific therapies and indica-
tions for each pathogen causing acute diarrheal
disease.
Salmonellosis
In 2012, approximately 94,000 cases of human salmo-
nellosis were reported in the EU (notification rate of 22
cases per 100,000 population), but the real number of
cases is expected to be much higher.[20] Infections
from non-typhoidal Salmonella normally exhibit a self-
limiting course and do not require antibiotic therapy, as
this can prolong pathogen elimination.[11,29] Specific
antimicrobial therapy is indicated for severe invasive
courses or for sepsis.[11] Antimicrobial therapy should
be considered for patients in the first year of life, for
very aged patients, patients with inborn or acquired
immune defects, and patients with known anomalies
or prosthetic replacement to heart valves or vessels,
even when the disease is purely gastroenteritic, as
there is always a risk of complication in such patients.
[1,11,29]
As there is increasing development of resistance in
Salmonella, it is advisable in principle to determine the
resistance in culture, particularly if the disease is
imported from high-prevalence regions for multidrug
resistance such as India.[1,6,14,18] Depending on the
results of the resistance testing, fluoroquinolones such
as ciprofloxacin, or alternatively ampicillin, azithromy-
cin, or third-generation cephalosporins (e.g. cefotaxime)
can be used. Recent data from the EU showed that only
5–13% of human non-typhoidal Salmonella isolates
were resistant to ciprofloxacin in 2011.[30] In contrast,
fluoroquinolone-resistant and carbapenem-resistant
Salmonella strains producing New Delhi metallo-beta-
lactamase 1 (NDM-1) have emerged in the Indian sub-
continent and have spread from there as individual
cases to neighboring countries, China, Europe, and
North America.[31] Antimicrobial treatment is for
7–10 days or for 14 days with immunosuppressed
patients. These antibiotics are also suitable for the treat-
ment of chronic carriers (Salmonella carriage for more
than 1 year), which are very rare in non-typhoidal sal-
monelloses. However, in such cases, possible predispos-
ing factors (particularly gallstones) should be clarified
and specifically treated (e.g. by cholecystectomy). At
the follow-up to the 4–6 week antimicrobial therapy,
the success of the treatment must be checked by ade-
quate microbiological controls.[1]
Shigellosis
Less than 8000 cases of shigellosis are reported
annually in the EU, but the real number of cases is
expected to be higher due to inadequate diagnostic
procedures.[20] As shigellosis is highly infectious, anti-
biotic therapy is generally recommended.[15] This
reduces bacterial elimination and shortens the duration
of the disease.[32] It is advisable to test the resistance
of the pathogen, as there is increasing resistance devel-
opment.[15,32–34] In principle, it is recommended to
administer azithromycin 1 × 500 mg p.o. for 3 days or
ciprofloxacin 2 × 500 mg p.o. for 3–5 days.[32]
Depending on the resistance profile, it is also possible
to use third-generation cephalosporins (such as cefo-
taxime 3 × 2 g i.v. for 3–5 days). For patients in good
general condition, symptomatic therapy with oral fluid
replacement can be adequate.[1] Motility inhibitors may
be used in the treatment of shigellosis and have proven
to be safe when restricted to mild and moderate cases
without invasive disease.[33]
Campylobacteriosis
In 2012, approximately 220,000 cases of human campy-
lobacteriosis were reported in the EU (notification rate of
68 cases per 100,000 population), three times more fre-
quent than non-typhoidal salmonellosis.[20] Infections
with Campylobacter jejuni are most frequent.[35] The
disease is mostly self-limiting. Symptomatic therapy
with volume and electrolyte replacement is almost
always adequate. Antibiotic therapy is indicated for
patients with signs of an invasive disease (hemorrhagic
diarrhea, fever), with suspected septic dissemination or
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 197

Table 2. Important pathogen profiles and therapeutic principles in infectious diarrhea, modified from [1] (permission to reuse this
table was granted from Springer Medizin, Heidelberg, Germany).
Incubation Duration of
Pathogen period Clinical symptoms disease Therapya
Viruses
Norovirus Approximately Vomiting, diarrhea, myalgias, cephalgia, rarely with 1–2 days Symptomatic
1 day fever
Astrovirus Watery diarrhea 2–3 days Symptomatic
Rotavirus Watery diarrhea, vomiting, rarely with fever 5–7 days Symptomatic
Adenovirus Diarrhea, vomiting, rarely with fever Up to 12 days Symptomatic
Bacteria
Salmonella spp. 1–3 days Gastroenteritis (75%), fever (50%), bacteremia (5–10%), 1–3 weeks Only in case of invasive disease:
bloody diarrhea (occasionally); complication: reactive ciprofloxacin, azithromycin
arthritis
Shigella spp. 1–8 days Fever, intense abdominal cramp, initially watery 3 days up to 1 Ciprofloxacin,
diarrhea, later bloody-mucoid diarrhea; complication: week (rarely up to azithromycin
reactive arthritis 4 weeks)
Yersinia spp. 1–3 days Fever, abdominal cramps, diarrhea; complication: 1–3 weeks In severe cases:
reactive arthritis ciprofloxacin, doxycycline
Campylobacter spp. 1–4 days Abdominal cramps, watery diarrhea (occasionally Up to 1 week In severe cases:
bloody diarrhea); complication: reactive arthritis, azithromycin, ciprofloxacin
occasionally Guillain Barré syndrome (GBS)
Enterotoxic/ 1–2 days Watery diarrhea, in severe cases cholera-like (rice water 3–7 days In severe cases:
enteropathogenic stool) ciprofloxacin, azithromycin,
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E. coli (ETEC, EPEC) rifaximin

Enteroinvasive/ 1–14 days Watery or bloody diarrhea, vomiting, fever, abdominal 3–7 days Symptomatic,
enterohemorrhagic cramps, hemolytic-uramic syndrome (EHEC) no antibiotic therapy
E. coli (EIEC, EHEC) (azithromycin may be considered
to reduce the duration of bacterial
shedding)
Listeria 1–6 days Watery diarrhea, vomiting, fever, myalgias, abdominal Up to 1 week Only in case of invasive disease:
monocytogenes cramps; Ampicillin, gentamicin
complications (immunodeficient patients): sepsis,
meningitis, encephalitis
Bacterial toxins of Hours Nausea, vomiting, watery diarrhea 1–2 days No antibiotic therapy
Staphylococcus
aureus
Bacterial toxins of Hours Nausea, vomiting, watery diarrhea 1–2 days No antibiotic therapy
Bacillus cereus
Bacterial toxins of Hours Nausea, vomiting, watery diarrhea, abdominal cramps, 1–2 days No antibiotic therapy
Clostridium dehydration
perfringens
Vibrio cholerae 1–3 days Rice water stool, vomiting, severe dehydration, shock, Individually Ciprofloxacin, azithromycin
coma variable
Clostridium difficile Very variable Usually in direct temporal association with previous Individually Metronidazole, vancomycin,
antibiotic use: variable, up to fidaxomicin
1. watery, self-limiting diarrhea several months
2. pseudomembranous colitis, potentially life-
threatening
Protozoal parasites
Cryptosporidium 3–12 days Watery diarrhea, abdominal cramps, occasionally fever Usually self- In human immunodeficiency virus
parvum limiting in (HIV)-positive patients: initiation of
immuno- antiretroviral therapy (ART)
competent
patients
Giardia lamblia 7–10 days Giardiasis/lambliasis If untreated, up to Metronidazole, albendazole
several months or
years
Entamoeba histolytica 11–21 days, Amoebiasis (amoebic dysentery): bloody diarrhea, If untreated, up to Metronidazole (in case of invasive
sometimes vomiting, fever, abdominal pain; most common several months infection), paromomycin (for
longer extraintestinal manifestation: amoebic liver abscess intraluminal cyst eradication)
a
The occurrence of antimicrobial resistance has to be considered

severe clinical courses (e.g. in immunosuppressed gradually developed to ciprofloxacin and has reached
patients or when the symptoms persist for more than >90% in countries such as Thailand [36] and >40% in
1 week).[35,36] Macrolides (azithromycin, clarithromycin) Europe.[20] Unfortunately, macrolide-resistant
are the drugs of choice, with fluoroquinolones (ciproflox- Campylobacter strains are also being increasingly recog-
acin) as second-line drugs. The duration of treatment is nized [37], but macrolide resistance in Europe is still
3–5 days. For about the last 20 years, resistance has below 5%.[6,20]
 198 C. LÜBBERT

Diarrheagenic Escherichia coli strains 3 × 2 g i.v.) or combination therapy with doxycycline

2 × 100 mg i.v. and gentamicin 5–7 mg/kg body
Enterohemorrhagic E. coli (EHEC), enteropathogenic E.
weight i.v. may be used.[1,40]
coli (EPEC), enterotoxin-producing E. coli (ETEC), enter-
oinvasive E. coli (EIEC), EAEC, and diffuse adherent E. coli
(DAEC) must be considered.[5,6,27] While EPEC, ETEC, Listeriosis
and DAEC interact with surface structures in the small
Listeria monocytogenes is an uncommon cause of gas-
intestine, EHEC and EIEC target colonic epithelial cells.
troenteritis, but probably it is underestimated because
EAEC adhere to both small and large bowel epithelia.
of a lack of clinical awareness and microbiological diag-
ETEC is the principle pathogen of TD. ETEC adhere to
nostics.[41] Thus, outbreaks caused by L. monocyto-
small bowel enterocytes and induce watery diarrhea by
genes experience most likely substantial under-
the secretion of heat-labile and/or heat-stable entero-
reporting. Overall, 1676 confirmed cases of listeriosis
toxins.[27] Antibiotic therapy with rifaximin, ciprofloxa-
were reported in the EU in 2012 (including five major
cin, or azithromycin is restricted to moderate to severe
foodborne outbreaks), giving a case rate of 0.35 per
courses and should be started even if on the first day of
100,000 population with a minimum case-fatality ratio
illness. This can effectively reduce bacterial elimination
of 12.1%.[20] Infections associated with L. monocyto-
and shorten the course of the disease.[27]
genes usually present as acute diarrhea followed by
EHEC exhibit several special features that enhance
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invasive disease in immunocompromised individuals.

their virulence: By means of special coating proteins
Contaminated ready-to-eat foods such as soft cheeses,
(bacterial adhesins), they can attach to the epithelial
milk, seafood, and raw meats are usually the major
cells of the human colonic wall. As a consequence of
sources of listeriosis, as their long shelf life is conducive
bacteriophage infection with gene transfer, they are
to bacterial growth.[41] Old-aged adults, immunocom-
capable of producing Shiga toxin or verocytotoxin
promised individuals, pregnant women, and newborns
(STEC/VTEC). Finally, EHEC strains produce plasmid-
have an increased risk of invasive listeriosis, character-
coded hemolysins. Almost 60% of detected pathogens
ized by bacteremia, sepsis, meningitis, encephalitis,
belong to the three most common serogroups – O157,
fetal loss, and death. Antimicrobial therapy is required
O103, and O26.[9,20] The greatest outbreak yet of
in invasive listeriosis and comprises ampicillin as the
EHEC/STEC in the world was in Germany in mid-2011,
drug of choice in a dose of 4 × 2–3 g i.v. for at least
but was caused by a Shiga toxin producing EAEC/EHEC
2–3 weeks, accompanied by gentamicin as a synergistic
hybrid strain (STEC O104:H4).[38,39] Antimicrobial ther-
partner in severe cases at a dose of 5–7 mg/kg body
apy of patients with EHEC/STEC is not recommended. In
weight i.v. for 1–2 weeks.[42] Several outbreaks have
this case, the risk of unfavorable effects (especially with
highlighted the importance of preventing produce con-
already established infections), particularly HUS, clearly
tamination within farm and processing environments
outweighs the effects of rapid pathogen reduction –
[20,41], and therefore, centralized surveillance of
which may anyway only be achieved if the drug is used
human Listeria cases seems to be essential for the
at a very early stage.[1,9] This restriction to use may not
early detection of outbreaks and for the organization
apply to the same extent with carbapenems and the
of an immediate and appropriate response, as was
newer macrolides, such as azithromycin, or to rifampi-
demonstrated in a report describing an outbreak of 12
cin/rifaximin.[38,39] Therapy with azithromycin
patients with invasive listeriosis in Belgium in 2011.[43]
1 × 500 mg p.o. for 3 days appears to have a favorable
effect on the long-term EHEC/STEC carrier status.[39]
Cholera
Cholera causes severe acute secretory diarrhea, with the
Yersiniosis
infectious pathogen Vibrio cholerae, serogroups O1 or
Approximately 6500 cases of yersiniosis were reported O139. This disease is endemic in more than 50 countries
in the EU in 2012 (notification rate of approximately and regularly causes epidemic outbreaks, for example,
two cases per 100,000 population).[20] Infections with in Haiti in 2010.[44] Adequate parenteral rehydration
Yersinia enterocolitica are generally self-limiting and do therapy is of central therapeutic importance. Cases
not require antibiotic therapy. Only severe courses imported to Europe are very rare (18 confirmed cases
should be treated with the antibiotics ciprofloxacin, in the EU in 2012).[20] Because of increasing resistance
2 × 500 mg p.o., or alternatively doxycycline, to standard treatment with co-trimoxazole, tetracycline,
2 × 100 mg [1,40] for 3–5 days. If there is sepsis, or doxycycline in epidemics, the preferred antimicrobial
third-generation cephalosporins (e.g. cefotaxime therapies are ciprofloxacin at a dose of 15 mg/kg body

weight i.v. for 3 days or a single azithromycin dose of
20 mg/kg body weight i.v.[45]
Clostridium difficile infections
The number and severity of cases of CDIs are increasing
throughout the world, both in hospital and among out-
patients.[6,12] The incidence in most European countries
is thought to be at least 5–20 cases per 100,000 popula-
tion per year, and in North America even more than
100–140 cases per 100,000.[12] C. difficile was responsi-
ble for almost half a million infections and was asso-
ciated with approximately 29,000 deaths in 2011 in the
United States.[46] The maximum risk for CDI is during
the first month after antibiotic therapy.[47]
The most important issue is the rational use of anti-
biotics for primary prophylaxis. It has been convincingly
Downloaded by [Christoph Lübbert] at 10:19 07 February 2016
shown that reducing antibiotics can significantly reduce
the incidence of CDI.[47,48] In cases of mild disease, the
symptoms may vanish after the antibiotic causing them
is discontinued.[49,50] Motility inhibitors should be
avoided, and proton pump inhibitor (PPI) treatment
should be discontinued if possible.[12] First-line therapy
for mild CDI is oral metronidazole.[49,50] For the initial
treatment of moderately severe or severe disease (for
which there is, however, no standard clinical definition),
oral vancomycin is the first-line drug [49,50]; alterna-
tively, oral fidaxomicin can be used.[49,50] It has been
shown that the clinical risk stratification proposed by
Zar et al. [51] is effective, according to which
3 × 500 mg metronidazole p.o. and 4 × 125 mg vanco-
mycin p.o. are equally effective in treating patients with
mild CDI. However, the response to treatment with
vancomycin was better in severe cases (73% versus
81%).[51] A suitable dosage for daily practice is
4 × 125–250 mg vancomycin as drinking solution from
ampoules at affordable costs. Enterocapsules contain-
ing 250 mg vancomycin can also be used, although the
daily therapy costs are then higher.[12] There have
been no controlled studies on the treatment of mild
cases with metronidazole versus placebo. Thus, there is
no evidence-based answer to whether mild cases of CDI
should be treated at all, or whether simply discontinu-
ing the antibiotic is enough.[12,52] It should be borne
in mind that metronidazole is completely absorbed in
the upper small intestine and that active antimicrobial
concentrations of the drug are only possible through
secretion into the inflamed colon.[52] In contrast, at a
dosage of 4 × 125 mg, oral vancomycin gives colon
concentrations that are more than 1000-fold greater
than the minimal inhibitory concentration (MIC).[52]
The European Guidelines for the treatment of CDI
recommend the administration of intravenous
EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 199
metronidazole, if oral uptake is not possible, or in com-
bination with vancomycin in severe cases with compli-
cations (see Table 3).[49,50] The therapeutic success is
evaluated on the basis of the clinical course. It is not
sensible to reexamine the stool when there has been
clinical improvement.
Current research and drug development are addres-
sing the prophylactic efficacy of probiotics through
modulation of the intestinal flora and influencing the
function of the intestinal mucous membrane. However,
there are as yet hardly any convincing data from large
controlled studies.[53] Nevertheless, a Canadian group
have performed a meta-analysis of 20 clinical studies
with more than 3800 patients who had been given
various probiotics in parallel to antibiotic treatment.
The pooled values demonstrated a reduction of up to
66% in the risk of suffering CDI.[54] A recent rando-
mized, double-blind, placebo-controlled, multicenter
trial performed in the UK, however, clearly revealed no
evidence that a multistrain preparation of lactobacilli
and bifidobacteria was effective in the prevention of
AAD or CDI.[55]
In spite of clinically successful primary therapy,
15–20% of CDI patients suffer a recurrence of the dis-
ease.[12,48] Some of these cases may be new infec-
tions, and these cannot be distinguished from
genuine recurrences without precise identification of
pathogen typing. On the basis of specific PCR used to
sequence the toxin-coding genes, it could be shown
that 10–50% of the cases are reinfections.[12,48] The
risk factors for a recurrence are similar to those for a
primary infection. The current recommendations of the
European Society for Clinical Microbiology and
Infectious Diseases (ESCMID) (see Table 3) lay down
that the first recurrence should be treated with vanco-
mycin or fidaxomicin.[49,50] If there are multiple recur-
rences, it is possible to perform a vancomycin reduction
scheme intended to prevent the germination of resi-
dual C. difficile spores.[12] For the same purpose, a
simple cost-effective pulse regimen proposed by the
American College of Gastroenterology (ACG) may be
used: a standard 10-day course of oral vancomycin at
a dose of 125 mg given four times daily, followed by
125 mg daily pulsed every 3 days for 10 doses.[48]
The nonabsorbable macrocyclic antibiotic fidaxomi-
cin was approved in the USA and Canada in 2011 and in
Europe at the end of 2012. This promises a marked
reduction in the rate of recurrences, together with the
same primary efficacy as vancomycin. Extensive use of
this antibiotic is certainly restricted by the high price of
ca. 1600 to 2200 Euro for a 10-day treatment course
(dose: 2 × 200 mg p.o.).[12] Although fidaxomicin
reduces relapses and therefore the subsequent cost of
 200 C. LÜBBERT
treating relapses, first-line prescription would certainly
lead to an increase in total treatment costs and is
therefore considered to be not cost-effective.[56]
Fidaxomicin exhibits much higher in vitro activity
against C. difficile than does vancomycin.[12,48] In con-
trast to vancomycin, it has bactericidal activity with a
better post-antibiotic effect. This drug’s minimal
absorption and lower activity against physiological
intestinal flora than with metronidazole or vancomycin
make it a very promising candidate to improve and
extend the therapeutic options. The approval study of
Louie et al. showed for the first time that fidaxomicin
has an efficacy and side effect profile similar to standard
therapy with vancomycin, but with a statistically signif-
icant reduction in the rate of recurrence (7.8% versus
25.5%) within 4 weeks after treatment.[57] However, if
the infection was with the hypervirulent ribotype 027
Downloaded by [Christoph Lübbert] at 10:19 07 February 2016
strain (NAP-1), which is dominant in North America, the
rate of recurrence remained high.[57] The reason that
fidaxomicin has a lower rate of recurrence is presum-
ably that it has a narrower antibiotic spectrum, as, for
example, it does not suppress the Bacteroides group in
the intestine. As a result, there is less overall effect on
the intestinal microflora than with oral vancomycin
treatment.[12] Even though fidaxomicin is hardly
absorbed from the intestine, the side effects include
nausea (11%), vomiting (7%), abdominal pain (6%), gas-
trointestinal bleeding (4%), anemia (2%) and neutrope-
nia (2%).[12,52,57]
A highly active alternative to drug therapy for multi-
ple recurrence of CDI that is also recommended in the
European Guidelines is the so-called fecal microbiota
transplantation (FMT, or fecal bacteriotherapy, or ‘stool
transplantation’). Analysis of the results with approxi-
mately 600 patients has shown that this gives very
good results with multiple CDI recurrences.[12] The
interim analysis of a randomized controlled single-site
study from the Netherlands [58] has confirmed that the
long-term success rate is ca. 80–90%. This study
employed controlled administration of donor stool
over a nasoduodenal tube to 16 patients. The compar-
ison with standard therapy with vancomycin was 81%
versus 31%.[58] Not-for-profit ‘stool banks’ such as
OpenBiome (www.openbiome.org) in North America
show that the application of and the access to micro-
biome transfer can be simplified and standardized.
[12,59] The long-term goal is oral application of stan-
dardized bacterial preparations.[60]
There are as yet only case series on the use of
rifaximin p.o. and tigecycline i.v. in recurrent CDI.
[61,62] Another therapeutic option for the prophylaxis
of recurrences is the intravenous administration of
monoclonal antibodies to toxins A and B. This has
already been successfully studied in a phase II trial
(the results of a phase III trial are expected to be
published soon). In this trial, a single infusion reduced
the proportion of recurrences from 25% to 7%.[63] As
with the administration of fidaxomicin, this approach is
limited by high treatment costs.[12] Approval in Europe
is expected by 2016.
Pathogens that cause chronic diarrhea
There are many differential diagnoses for chronic diar-
rhea, including the chronic inflammatory bowel dis-
eases (CEDs) ulcerative colitis and Crohn’s disease,
gastrointestinal tumors, exocrine pancreatic insuffi-
ciency, vascular and functional enteropathies, collage-
nous and lymphocytic colitis, celiac disease, lactose or
fructose intolerance, autonomic neuropathy in diabetes
mellitus, disorders in thyroid function, disorders in
intestinal absorption (e.g. short bowel syndrome), and
drug-induced or radiation-associated enteropathies
(e.g. radiogenic colitis).[64,65]
Infectious clinical pictures are generally rare; the
most important are lambliasis/giardiasis, followed by
amoebic colitis, cryptosporidiosis, or microsporidiosis
in immunosuppressed patients and the very rare
Whipple’s disease.[64] In principle, pathogens detected
in chronic diarrhea can also lead to shorter clinical
courses, which are in accordance with the definition
of acute diarrhea.[65] For example, Cryptosporidium par-
vum is an important pathogen of acute diarrhea in
children and older people.[66] However, the converse
does not apply; pathogens for acute diarrhea are gen-
erally not found in chronic diarrhea.
Cryptosporidiosis
Cryptosporidium hominis and C. parvum are the most
frequent pathogens of human cryptosporidiosis, a dis-
ease that causes up to 7% of cases of acute diarrhea.
[66,67] In immunocompetent patients, cryptosporidiosis
causes self-limiting watery diarrhea accompanied by
nausea and abdominal pain. This mainly affects children
and older adults. However, in immunocompromised
patients, a Cryptosporidium infection may be life-threa-
tening or chronic.[66] As with giardiasis, uptake of only
10 oocysts can cause an infection.[67] Infections are
normally transmitted through contaminated drinking
water.[66]
Pathogen-specific therapy of cryptosporidiosis is dif-
ficult. Although the authors of a 2007 meta-analysis
identified seven studies with a total of 169 immuno-
compromised patients, they were forced to conclude
that there was no evidence for effective drug treatment
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 201

Table 3. Recommended treatment of Clostridium difficile infections by clinical presentation (modified from [12,49,50]) (permission
to reuse this table was granted from Deutscher Ärzte-Verlag, Cologne, Germany).
Clinical Level of Grade of
classification Therapy Duration evidence recommendation
Mild Metronidazole, 3 × 500 mg orally 10 days I A
Vancomycin, 4 × 125 mg orally 10 days I A
Interruption of antibiotic treatment that triggered infection, clinical observation, no specific II C
treatment
Severe Vancomycin, 4 × 125 mg orally 10 days I A
Fidaxomicin, 2 × 200 mg orally 10 days I B
Severe with If possible, vancomycin, 4 × 125 to 500 mg orally (rationale for dose escalation purely 10 days I A
complications empirical)
(plus) metronidazole, 3 × 500 mg IV 10 days II A
(plus) vancomycin retention enemas 4 × daily, intracolonically 500 mg (in 100 mL saline) 10 days III B
(plus) tigecyclin 2 × 50 mg IV 10 days III C
First recurrence Vancomycin, 4 × 125 mg orally 10 days I B
Fidaxomicin, 2 × 200 mg orally 10 days I B
Multiple Vancomycin, 4 × 125 mg orally (10 days) followed by pulse schedule for at least 3 weeks (125 5 weeks II B
recurrences to 500 mg orally every 2 to 3 days)
Vancomycin, 4 × 125 mg orally (10 days) followed by tapering schedule (approx. 5 weeks) or a 7 weeks II B
pulsed regimen (e.g. 125 mg daily pulsed every 3 days for 10 doses)
Fidaxomicin, 2 × 200 mg orally 10 days II B
Rescue therapy: stool transplantation in an experienced center following preliminary <1 week I A
vancomycin treatment, 4 × 500 mg orally (4 days)
Downloaded by [Christoph Lübbert] at 10:19 07 February 2016

under these conditions.[67] Nitazoxanide can be suc-
cessfully used in immunocompromised patients.[65]
The combination of paromomycin and azithromycin
also appears to be possible, although the supporting
evidence is not adequate.[67–69]
Lambliasis/giardiasis
Lambliasis/giardiasis is one of the most frequent intest-
inal protozoal diseases in man.[70] The reporting rate of
giardiasis in Europe was 5.43 cases per 100,000 popula-
tion in 2012.[20] The pathogen Giardia lamblia is also
known as G. intestinalis or G. duodenalis and can have
two different forms, neither of which causes invasive
tissue disease. While the cyst form is invasive, the actual
disease is triggered by trophozoites. An infection can be
caused by as few as 10 cysts.[65,70] After a mean period
of 8 days, the patient develops foul-smelling, watery
diarrhea, with flatulence, and (very rarely) fever.[71] The
pathogen can be detected with the fecal Giardia antigen
assay, or with procedures based on PCR techniques or,
conventionally, with stool microscopy.[71]
First-line treatment is with metronidazole or other
nitroimidazole preparations, such as tinidazole or sec-
nidazole, which is often used in South America.[65]
The recommended metronidazole dose for adults is
3 × 500 mg p.o. for 5–10 days.[70–74] A possible
alternative is to administer 2 g metronidazole per
day on three consecutive days.[73] Recent observa-
tions, particularly in the Indian subcontinent, indicate
that human pathogenic lambliae are becoming
increasingly resistant to metronidazole; this is not
the case with amoebiasis.[65,72] There is, however,
no immediate prospect of routine systematic resis-
tance testing, unlike bacteria. One of the precondi-
tions for this, namely culture of the pathogens, is not
fulfilled; this is only done in a few international cen-
ters for tropical medicine, such as Hamburg,
Liverpool, and London, in the context of scientific
studies. Therefore, if treatment is unsuccessful, it is
recommended to switch to alternative drugs, such as
albendazole, paromomycin, or nitazoxanide.[70–74]
Nitazoxanide is not commercially available in Europe
and is apparently no more active than the other drugs
mentioned.[65] The recommended dosages for adults
are 1 × 400 mg p.o. albendazole, or 25–30 mg/kg
body weight p.o. paromomycin split into three daily
doses for 7–10 days, or 2 × 500 mg p.o. nitazoxanide
over 3 days.[73,74]
Amoebic colitis
Entamoeba histolytica is the only protozoon that causes
amoebic colitis. The diagnosis must distinguish this
from E. dispar and E. moshkovskii; this cannot be reliably
achieved by microscopy alone and necessitates the use
of PCR procedures or specific antigen assays.[65,75]
Amoebic colitis is transmitted by the intake of cysts
from contaminated water or food.[71,76] This is the
reason that developing countries bear the main burden
 202 C. LÜBBERT
of the infections.[76,77] Although infections with E.
histolytica mainly give rise to asymptomatic courses,
they may trigger sometimes intense diarrhea and colitis
in about 10% of infected subjects.[76,77] These severe
courses are correlated with the occurrence of tissue-
invasive trophozoites (erythrophagic so-called ‘magna
forms’). These possess intense cytotoxic activity and
lead to the invasive clinical course, which can lead to
colon perforation or liver abscesses.[78,79]
Apart from a few exceptions, an intestinal infection
with E. histolytica is treated medically and conserva-
tively. Metronidazole is the drug of choice and is very
active against the tissue-invasive forms.[79] However,
the activity is inadequate for exclusive infections of
the intestinal lumen.[76,77] For this reason, additional
treatment is needed with nonabsorbable ‘contact
amoebicides’, such as diloxanide furoate or paromomy-
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cin.[76,77] There is no known resistance to any of these
drugs. Occasional patients who suffer severe dysenteric
disease should be given antibiotics for bacterial super-
infections.[65,76,77] Pure infections of the intestinal
lumen are much more frequent and, for these, treat-
ment with paromomycin or another drug that is active
in the intestinal lumen is adequate. As, however, tissue
invasion by individual amoebas cannot always be reli-
ably excluded, additional treatment with metronidazole
is often performed.[65] Depending on the clinical sever-
ity – ranging from mild diarrhea to the acute dysenteric
stage or colonic amebomas – the daily adult dose of
metronidazole may range from 3 × 500 mg p.o. for
7–10 days to 3 × 10 mg/kg body weight i.v. for
10 days. This is followed by a daily dose of 25–30 mg/
kg body weight paromomycin split into three daily
doses over 7–10 days.[65,76,77]
Special features in the treatment of TD
It is important to remember that patients with TD
usually experience self-limiting disease, and that <1%
require hospitalization.[6] Thus, the same basic thera-
peutic rules apply as in other cases with infectious
diarrhea. Empirical antibiotic therapy should be consid-
ered for severely ill patients and should be started early
in order to effectively shorten the duration of ill-
ness.[27]
The choice of the antimicrobial agent depends on
the geographic location of travel. In Latin America and
the Caribbean, ETEC is the dominating pathogen (≥35%
of all cases) in TD, followed by EAEC (25–35%),
Norovirus and Rotavirus (both 15–25%), Shigella (5–
15%), Campylobacter (<5%), Salmonella (<5%), and
Giardia lamblia (<5%).[27] In Africa, ETEC is the most
important pathogen as well (25–35% of all cases),
followed by Norovirus (15–25%), Rotavirus (5–15%),
Shigella (5–15%), Salmonella (<5%), Campylobacter
(<5%), EAEC (<5%), and Giardia lamblia (<5%).[27] In
South Asia, ETEC, EAEC, and Campylobacter cause
15–25% of TD cases, respectively, followed by
Norovirus and Rotavirus (both 5–15%), Shigella (5–
15%), Giardia lamblia (5–15%), and Salmonella (<5%).
[27] In South East Asia, Campylobacter is the most com-
mon pathogen (25–35% of all cases), followed by ETEC
(15–25%), EAEC (10–20%), Salmonella (5–15%), Giardia
lamblia (5–15%), Shigella (<5%), Norovirus, and
Rotavirus (both <5%).[5,17,27] For most destinations, a
fluoroquinolone (ciprofloxacin or levofloxacin) is still
the drug of choice.[27] However, where Campylobacter
species are a common etiology, such as in South and
South East Asia, azithromycin is a better choice, as most
Campylobacter species are resistant to fluoroquino-
lones.[17,80] For all antibiotics, single-dose therapy or
treatment for up to 3 days is usually sufficient to cure
disease.[27] Rifaximin is noninferior to ciprofloxacin
when noninvasive enteric bacteria are considered [18],
but it should not be used when there are signs of
invasive disease accompanied by fever, and when
Shigella, Campylobacter, or invasive Salmonella species
are suspected.[27] Campylobacter species are routinely
resistant to rifaximin.[18] A combination of loperamide
and an antibiotic may be taken when prompt reversal
of symptoms is necessary in uncomplicated TD.[27]
In a recent study from Finland, empirical antibiotic
therapy for TD proved to be independent risk factors,
with up to 80% of symptomatic travellers contracting
extended-spectrum beta-lactamases (ESBL)-producing
Enterobacteriaceae [81], and in another recent study
from Germany that was conducted by the author, it
was demonstrated that even strict hygiene measures
during travel offered no effective protection against
colonization with ESBL producers.[16] In modern pre-
travel counseling for those visiting high-risk regions,
travellers should therefore be advised against taking
antibiotics for mild or moderate TD.[81] The use of
bismuth subsalicylate (Pepto-BismolTM), which has
good anti-inflammatory and antibacterial activity
[5,6,27], appears to be less problematic regarding devel-
opment of resistance than antibiotics.
Expert commentary
Acute infectious diarrhea is one of the most com-
monly occurring diseases, even in industrialized
countries. Symptomatic therapy focusing on oral
rehydration is still the most important form of treat-
ment for self-limiting disease. Thus, antimicrobial
therapy is not required in most patients. For severely
 EXPERT REVIEW OF ANTI-INFECTIVE THERAPY 203

Key issues
● Infectious diarrhea is one of the most common diseases in the world; according to the World Health Organization (WHO), it is one of the five
most important causes of death, especially in children under 5 years of age.
● Symptomatic therapy is still the most important component of the treatment of infectious diarrhea. However, empirical antibiotic therapy should
be considered for severely ill patients with a high frequency of stools (arbitrarily >6/day), symptoms persisting for >1 week, fever, bloody
diarrhea, underlying immune deficiency, advanced age or significant comorbidities.
● Increasing resistance, in particular against fluoroquinolones, must be taken into consideration and profound knowledge of local resistance
patterns is required, especially in patients with TD. In a recent study, empirical antibiotic therapy for TD proved to be independent risk factors,
with up to 80% of symptomatic travellers contracting ESBL-producing Enterobacteriaceae.
● Antimicrobial therapy of patients with STEC infection is not recommended. In this case, the risk of unfavorable effects, particularly HUS, clearly
outweighs the effects of rapid pathogen reduction, which may anyway only be achieved if the drug is used at a very early stage. However,
therapy with azithromycin appears to have a favorable effect on the long-term EHEC/STEC carrier status.
● Infections from non-typhoidal Salmonella normally exhibit a self-limiting course and do not require antibiotic therapy, as this can prolong
pathogen elimination. Specific antimicrobial therapy is indicated for severe invasive courses, sepsis, and patients in the first year of life, very aged
patients, patients with inborn or acquired immune defects and patients with known anomalies or prosthetic replacement to heart valves or
vessels, even when the disease is purely gastroenteritic.
● Diarrhea caused by toxigenic Clostridium difficile strains has increased in incidence and in severity. The macrocyclic antibiotic fidaxomicin can
reduce the rate of recurrent disease in CDIs. Furthermore, evidence for the benefits of FMT as a treatment option for multiple recurrences of CDI
is increasing, and establishment of oral, capsulized, frozen fecal microbiota transfer has already successfully passed pilot studies.
● Therapy with motility inhibitors is not recommended for STEC infections, CDI, and severe colitis.
● A major clinical challenge in assessing patients with acute diarrhea is the decision of when to test for causative pathogens, which then should
lead to targeted antimicrobial therapy. In severely ill patients with significant dehydration, fever, bloody diarrhea, underlying immune deficiency,
recent use of antibiotics, advanced age, significant comorbidities or hospitalization, primary evaluation of stool specimen for bacterial agents
Downloaded by [Christoph Lübbert] at 10:19 07 February 2016

(Salmonella, Campylobacter, and Shigella species), STEC, and CDI should be performed.

ill patients with a high frequency of bowel move-
ments (arbitrarily >6/day), symptoms persisting for
>1 week, fever, bloody diarrhea, underlying immune
deficiency, advanced age, or significant comorbid-
ities, empirical antibiotic therapy should be consid-
ered. Increasing resistance, in particular against
fluoroquinolones, must be taken into consideration
and profound knowledge of local resistance patterns
is required, especially in patients with TD. Therapy
with motility inhibitors is not recommended for STEC
infections, CDI, and severe colitis. A major challenge
in assessing patients with acute diarrhea is the deci-
sion when to test for causative pathogens, which
then should lead to targeted antimicrobial therapy.
the development and approval of new classes of
antibiotics.
Acknowledgements
Native language support was provided by Rodney Yeates, M.A.
Financial & competing interests disclosure
The author received financial support for consulting, lecture
fees, and travel costs from Astellas, InfectoPharm, MSD,
Novartis, and Pfizer. The author has no other relevant affilia-
tions or financial involvement with any organization or entity
with a financial interest in or financial conflict with the subject
matter or materials discussed in the manuscript apart from
those disclosed.

Five-year view
Looking forward over the next 5 years, significant
advances are expected in the nonantibiotic therapy
of CDIs involving both treatment with monoclonal
antibodies against C. difficile toxins and establishment
of oral, capsulized, frozen fecal microbiota transfer for
relapsing infection. Further increase of antimicrobial
resistance in typical enteritis pathogens such as E.
coli, Campylobacter, Salmonella, and Shigella has to
be expected, especially in developing countries with
widely uncontrolled use of antibiotics. Nevertheless,
fluoroquinolones and macrolides will remain the most
important cornerstones of antibiotic therapy for the
time being, but a slow rise in extreme resistance
involving even carbapenem-resistant strains (particu-
larly in the Indian subcontinent) has to be consid-
ered. An effective response to this challenge must be
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