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Cis 551
Cis 551
Diarrhea is common among hospitalized patients but the causes are distinct from those of diarrhea in the
community. We review existing data about the epidemiology of nosocomial diarrhea and summarize recent
progress in understanding the mechanisms of diarrhea. Clinicians should recognize that most cases of noso-
comial diarrhea have a noninfectious etiology, including medications, underlying illness, and enteral feeding.
Apart from Clostridium difficile, the frequency of infectious causes such as norovirus and toxigenic strains of
Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus, and Bacteroides fragilis remains largely
undefined and test availability is limited. Here we provide a practical approach to the evaluation and manage-
ment of nosocomial diarrhea when tests for C. difficile are negative.
Nosocomial diarrhea is a common complication in countries, and provide an algorithm for diagnosing
hospitalized patients but its causes and significance and managing patients with nosocomial diarrhea
are underappreciated. Diarrhea predisposes patients to when C. difficile tests are negative.
infections, contributes to morbidity and mortality, and
increases hospital length of stay and costs [1–6]. Physi- BACKGROUND AND
cians frequently focus on Clostridium difficile infection PATHOPHYSIOLOGY
(CDI) as the primary cause of diarrhea but most cases
are due to medications, enteral feeding, and underly- Definitions
ing illness [5–15]. In fact, clinical studies indicate that Diarrhea is defined as at least 1 day with ≥3 unformed
12%–32% of hospitalized patients develop diarrhea stools or a significant increase in stool frequency above
but ≤20% of cases are attributable to CDI [7, 12, 13]. baseline [18, 20, 21]. Nosocomial diarrhea is an acute
Other infectious causes are uncommon, but altera- episode of diarrhea in a hospitalized patient that was
tions in the intestinal microbiome appear to play a not present on admission and arises after ≥3 days
role in many patients [16–19]. Here we review the in- of hospitalization [7, 22]. Clinically, this definition is
fectious and noninfectious causes of nosocomial diar- useful because the likelihood of community-acquired
rhea, focusing primarily on adults in industrialized viral, bacterial, or parasitic gastroenteritis developing
after the third hospital day is low enough that testing
and evaluation can be focused on causes that are more
Received 2 February 2012; accepted 30 May 2012; electronically published 14 likely in hospitalized patients [22].
June 2012.
Correspondence: Christopher R. Polage, MD, Clinical Microbiology Laboratory, Clinical Spectrum of Disease
UC Davis School of Medicine, STC Bldg, Rm 1712, 3740 Business Dr, Sacramento,
CA 95820 (christopher.polage@ucdmc.ucdavis.edu).
Most nosocomial diarrhea not due to CDI is mild
Clinical Infectious Diseases 2012;55(7):982–9 or moderate and resolves after a few days, though
© The Author 2012. Published by Oxford University Press on behalf of the Infectious there are exceptions [7]. For example, toxin-producing
Diseases Society of America. All rights reserved. For Permissions, please e-mail:
journals.permissions@oup.com.
strains of Clostridium perfringens and Klebsiella
DOI: 10.1093/cid/cis551 oxytoca can cause severe symptoms or colitis [23, 24].
Infectious Causes Associated With Antibiotics prevalence and bacterial counts of C. perfringens in sympto-
Clostridium difficile is the most common infectious cause of matic patients vs controls, and from outbreaks of nosocomial
nosocomial diarrhea, representing 10%–20% of cases [12, 13, diarrhea associated with C. perfringens and no other patho-
19, 21, 23, 35]. CDI is typically associated with prior antibiotics gens [23, 37]. Others have observed high carriage rates and
but may follow other exposures that also disrupt the microbio- similar concentrations of C. perfringens in asymptomatic pa-
ta. (See recent guidelines and reviews for further discussion of tients [37]. Regardless, large studies suggest that only 1%–3%
CDI [21, 27, 32].) Other toxin-producing bacteria that have of diarrheal samples have C. perfringens as a potential cause;
been associated with diarrhea following antibiotics are dis- occasional studies report up to 8% as positive [19, 23, 35, 38].
cussed next. Clinically, the median duration is 7 days, 1 in 5 patients have
≥10 stools per day, and patients respond to metronidazole [23].
Klebsiella oxytoca Pseudomembranes have not been reported [23, 37].
Pathogenic strains of Klebsiella oxytoca produce a toxin that Diagnostic testing is not widely available and <5% of wild-
inhibits DNA synthesis [33]. Such strains cause 50%–80% of type C. perfringens strains are toxigenic, making culture
cases of C. difficile negative, hemorrhagic colitis after antibiot- impractical [35]. A research immunoassay has been developed
ics but are probably not a significant cause of nonbloody to detect the enterotoxin (CPEnt) and polymerase chain
AAD [24, 36]. A prospective study of hospitalized patients reaction (PCR) for the cpe gene has also been used [19, 35].
with AAD identified cytotoxic K. oxytoca in 3 of 18 (16.7%)
patients with bloody diarrhea but none of 89 patients with Others
nonbloody diarrhea [36]. More recently, a laboratory study Staphylococcus aureus has been questioned as a cause of AAD
identified cytotoxic K. oxytoca in only 2.3% of 429 stool but it can occur rarely (0.2%–4%), especially with methicillin-
specimens submitted for C. difficile testing, confirming that resistant strains that produce toxins [19, 39, 40]. Salmonella
K. oxytoca is relatively rare in routine stool samples [33]. Most species are a rare cause of AAD and pseudomembranous
patients are adults and present with acute onset of abdominal colitis [18].
pain, bloody diarrhea, and leukocytosis after exposure to peni-
cillins or other antibiotics [24]. Symptoms resolve upon antibi- Infectious Causes not Associated With Antibiotics
otic discontinuation, and therapy directed at K. oxytoca is not Norovirus is the predominant cause of infectious gastroenteri-
necessary [24]. Diagnosis is supported by recovery of pure or tis in the community, accounting for up to 90% of outbreaks
predominant K. oxytoca from stool or colon aspirate, but few and 5%–30% of patients presenting to clinics and hospitals
wild-type strains produce toxins and tests for toxin-producing with diarrhea during active seasons [41]. In hospitals, norovi-
K. oxytoca are not available clinically [33, 36]. rus is an important cause of outbreaks but the extent of spora-
dic infections is unknown [25, 42]. Lopman et al conducted
Clostridium perfringens a 1-year study of diarrheal outbreaks in hospitals in
Enterotoxin-producing type A C. perfringens is an established England [25]. Using an outbreak definition of ≥2 cases from
cause of food poisoning and infrequent cause of AAD [23, 37]. the same unit within 7 days, norovirus was detected in ≥1
The majority of data supporting a role for C. perfringens specimens from 63% of outbreaks with samples collected [25].
in AAD come from cross-sectional studies showing a higher Interestingly, the median duration of symptoms was 3 days
Table 2. Relative Frequency of Clostridium difficile and Other Causes of Nosocomial Diarrhea in High-Risk Patient Subgroups
References: [1, 3, 5–8, 10–15, 18, 19, 21, 23, 27, 29, 31, 33, 35–40, 46, 47].
Abbreviations: HSCT, hematopoietic stem cell transplant; N/S, not significant; SOT, solid organ transplant.
a
Proportion of patients developing diarrhea in each risk group.
b
Proportion of total diarrheal episodes in risk group attributable to an infectious cause or individual infectious agent.
c
Data not available for intensive care population. Specified percentages are for antibiotic-associated diarrhea.
d
Estimated percentage; data not available for chemotherapy patients.
e
Antibiotic-associated: Clostridium perfringens, Klebsiella oxytoca, Staphylococcus aureus (does not include Bacteroides fragilis).
f
Most often adenovirus, astrovirus, or rotavirus; likely includes a mix of nosocomial and community infections.
g
Proportion of total diarrheal episodes with no infectious cause identified. Most common noninfectious causes by group are as follows: Antibiotics—antibiotic
effect on microbiota or gut, laxatives; Intensive care—laxatives, antibiotics, sorbitol-containing medications, enteral feeding; Chemotherapy—laxatives,
antineoplastic agents, antibiotics, radiotherapy; SOT—immunosuppressants, bacterial overgrowth; HSCT—chemotherapy, immunosuppressants, antibiotics,
radiotherapy, laxatives, graft-vs-host disease.
performed routinely [49]. Tests for fecal lactoferrin and other due to medications or graft-vs-host disease [8, 10, 11, 31].
inflammatory markers are potentially useful in selected cases In human immunodeficiency virus–infected patients or trans-
but there are inadequate data in patients with nosocomial diar- plant patients with risk factors for community-acquired bacte-
rhea to support their routine use at this time. Testing for other ria or parasites or a history of diarrhea prior to admission,
infectious causes has a low yield except possibly in transplant stool culture and tests for parasites may be considered but
patients [22]. In these patients, active cytomegalovirus infec- should not be performed routinely [22]. Testing a single
tion and other gastrointestinal viruses such as norovirus, ade- sample is sufficient unless the patient is from a parasite-
novirus, and rotavirus should be excluded but most cases are endemic region. Patients with significant, persistent diarrhea,