288 CLOSTRIDIUM DIFFICILE

• High-dose penicillin G (250 000–400 000 U/kg per day; maximum daily dose: 24 mil-
lion units) should be administered intravenously. Clindamycin, metronidazole, mero-
penem, ertapenem, and chloramphenicol can be considered as alternative drugs for
patients with a serious penicillin allergy or for treatment of polymicrobial infections.
The combination of penicillin G and clindamycin may be superior to penicillin alone
because of the theoretical benefit of clindamycin inhibiting toxin synthesis.
• Hyperbaric oxygen may be beneficial, but efficacy data from adequately controlled
clinical studies are not available.
ISOLATION OF THE HOSPITALIZED PATIENT: Standard precautions are recommended.
CONTROL MEASURES: Prompt and careful débridement, flushing of contaminated
wounds, and removal of foreign material should be performed.
Penicillin G (50 000 U/kg per day) or clindamycin (20–30 mg/kg per day) has been
used for prophylaxis in patients with grossly contaminated wounds, but efficacy is un-
known.

Clostridium difficile
CLINICAL MANIFESTATIONS: Clostridium difficile is associated with a spectrum of gastroin-
testinal illness, as well as with asymptomatic colonization that is common, especially in
young infants. Mild to moderate illness is characterized by watery diarrhea, low-grade fe-
ver, and mild abdominal pain. Symptoms often begin while the child is hospitalized re-
ceiving antimicrobial therapy but can occur up to 10 weeks after therapy cessation. Pseu-
domembranous colitis is characterized by diarrhea with mucus in feces, abdominal
cramps and pain, fever, and systemic toxicity. Toxic megacolon (acute dilatation of the
colon) should be considered in children who develop marked abdominal tenderness and
distension with minimal diarrhea and may be associated with hemodynamic instability.
Other complications of C difficile disease include intestinal perforation, hypotension,
shock, and death. Complicated infections are less common in children than adults. Severe
or fatal disease is more likely to occur in neutropenic children with leukemia, infants with
Hirschsprung disease, and patients with inflammatory bowel disease. Clinical illness at-
tributable to C difficile is rare in children younger than 12 months. Extraintestinal manifes-
tations of C difficile infection can include bacteremia, wound infections, and reactive ar-
thritis.
ETIOLOGY: C difficile is a spore-forming, obligate anaerobic, gram-positive bacillus. Some
strains produce exotoxins (toxins A and B), which are responsible for the clinical manifes-
tations of disease when there is overgrowth of C difficile in the large intestine.
EPIDEMIOLOGY: C difficile is shed in feces. People can acquire infection from the stool of
other colonized or infected people through the fecal-oral route. Any surface (including
hands), device, or material that has become contaminated with feces may also transmit C
difficile spores. Hospitals, nursing homes, and child care facilities are major reservoirs for
C difficile. Risk factors for acquisition of the bacterium include prolonged hospitalization
and exposure to an infected person either in the hospital or the community. Risk factors
for C difficile disease include antimicrobial therapy, repeated enemas, proton pump inhibi-
tor therapy, prolonged nasogastric tube placement, gastrostomy and jejunostomy tube
placement, underlying bowel disease, gastrointestinal tract surgery, renal insufficiency,
and immunocompromised state. C difficile colitis has been associated with exposure to al-
most every antimicrobial agent; cephalosporins and fluoroquinolones are considered to be
 CLOSTRIDIUM DIFFICILE 289

the highest-risk antibiotic agents, particularly for recurrent C difficile disease and infections
with epidemic strains. The NAP-1 strain is a virulent strain of C difficile because of in-
creased toxin production and is associated with an increased risk of severe disease. NAP-1
strains of C difficile have emerged as a cause of outbreaks among adults and are reported
sporadically in children.
Community-associated C difficile disease is occurring with increasing frequency in re-
cent years. Although the rates of both community- and health care-associated C difficile
disease are increasing in children, recent data suggest the incidence of pediatric commu-
nity-associated C difficile disease may be twice as frequent as health care-associated dis-
ease.
Asymptomatic intestinal colonization with C difficile (including toxin-producing
strains) is common in children younger than 5 years and is most common in infants
younger than 1 year. Epidemiologic studies show that up to 50% of healthy infants have
colonization. Colonization rates drop to less than 5% in healthy children older than 5
years and adults. Asymptomatic colonization with C difficile is common in recently hospi-
talized patients, with rates upward of 20%.
The incubation period is unknown; colitis usually develops 5 to 10 days after initi-
ation of antimicrobial therapy but can occur on the first day of treatment and up to 10
weeks after therapy cessation.
DIAGNOSTIC TESTS: Endoscopic findings of pseudomembranes (2- to 5-mm, raised yel-
lowish plaques) and hyperemic, friable rectal mucosa suggesting pseudomembranous coli-
tis is highly correlated with C difficile disease. More commonly, the diagnosis of C difficile
disease is based on laboratory methods including the detection of C difficile toxin(s) or
toxin gene(s) in a diarrheal stool specimen. In general, laboratory tests for C difficile should
not be ordered on a patient who is having formed stools unless ileus or toxic megacolon is
suspected. Notwithstanding the availability of several test methods, there presently is no
generally agreed on gold standard laboratory test method for the diagnosis of C difficile
disease.
Molecular assays using nucleic acid amplification tests (NAATs) now are commonly
used testing methods for toxigenic strains of C difficile toxins in both adult and pediatric
hospitals. NAATs detect genes responsible for the production of toxins A and B, rather
than free toxins A and B in the stool that are detected by enzyme immunoassay (EIA).
EIAs are rapid, performed easily, and highly specific for diagnosis of C difficile infection,
but their sensitivity is relatively low. The cell culture cytotoxicity assay, which also tests
for toxin in stool, is more sensitive than the EIA but is labor intensive and has a long turn-
around time, limiting its usefulness in the clinical setting. NAATs combine excellent sensi-
tivity and analytic specificity, and provide results to clinicians in times comparable to
EIAs. However, detecting toxin gene(s) in patients who are only colonized by C difficile is
common and likely contributes to misdiagnosis of C difficile infection in children with
other causes of diarrhea, leading to unnecessary antibiotic treatment for C difficile. Several
steps can be taken to reduce the likelihood of misdiagnosis of C difficile infection related to
use of highly sensitive NAATs. For example, because colonization with C difficile in infants
is common and symptomatic infection in this age group is not thought to occur, C difficile
diagnostic testing on samples from children under 12 months of age should be discour-
aged. Because sensitivity is nearly 100%, repeat NAAT testing for the same episode of di-
arrhea is discouraged because it is more likely to result in subsequent false positive tests.
Furthermore, testing should be avoided or deferred in children with other more likely
290 CLOSTRIDIUM DIFFICILE

causes of diarrhea, such as concomitant laxative use and in children with symptoms more
consistent of viral or noninfectious etiologies. Finally, because shedding of C difficile in the
stool can persist for several months after symptoms resolution, tests of cure are impracti-
cal and should not be performed.
TREATMENT: A central tenet to control C difficile infection is the discontinuation of pre-
cipitating antimicrobial therapy; stopping these agents will allow competing gut flora to
reemerge and, thus, crowd out C difficile within the intestine. A variety of therapies are
available; use of a particular treatment modality is dependent on severity of illness, the
number of recurrences of infection, tolerability of adverse effects, and cost. Recom-
mended therapies for first occurrence, first recurrence, and second recurrence are pro-
vided in Table 3.3 (p 482). Drugs that decrease intestinal motility should not be adminis-
tered. Follow-up testing for toxin is not recommended. Asymptomatic patients should not
be treated.
When vancomycin is being used orally, as a cost-saving measure, vancomycin for in-
travenous use can be administered orally. The intravenous formulation is less expensive
than the product available for oral use. Intravenously administered vancomycin is not ef-
fective for C difficile infection.
Fidaxomicin is approved for treatment of C difficile-associated diarrhea in adults.
Studies have demonstrated equivalent efficacy to oral vancomycin, although subjects with
life-threatening and fulminant infection, hypotension, septic shock, peritoneal signs, sig-
nificant dehydration, or toxic megacolon were excluded. No comparative data of fidax-
omicin to metronidazole are available. There are anecdotal reports of fidaxomicin use in
children, although it is not approved for use in patients younger than 18 years.
There are limited data on the use of nitazoxanide in the treatment of recurrent C dif-
ficile infection in adults, but it has not been approved for this indication and no pediatric
data are available.
Up to 20% of patients experience a recurrence after discontinuing therapy, but infec-
tion usually responds to a second course of the same treatment. Metronidazole should not
be used for treatment of a second recurrence or for prolonged therapy, because neurotox-
icity is possible. Tapered or pulse regimens of vancomycin may be considered for recur-
rent disease, often as 3 times a day for several days followed by twice a day for several
days. Data are limited for the following vancomycin regimens:
• Vancomycin, orally, 10 mg/kg/dose (maximum 125 mg/dose), 4 times a day for 7
days, then 3 times a day for 7 days, then twice a day for 7 days, then once daily for 7
days, then once every other day for 7 days, then every 72 h for 7 days.
• Vancomycin, orally, 10 mg/kg/dose (maximum 125 mg/dose) 4 times a day for 14
days, then twice a day for 7 to 14 days, then once daily for 7 to 14 days, then every 2
to 3 days for 2 to 8 weeks.
• Vancomycin, orally, 10 mg/kg/dose (maximum 125 mg/dose) 4 times a day for 14
days, then either:
♦ Rifaximin, orally, 400 mg, 3 times a day for 14 days (note that rifaximin dosing in
pediatric patients is not well described, but it is poorly water-soluble and mini-
mally absorbed; it should be avoided if the patient recently has received rifaximin
for C difficile infection or another indication).
OR
♦ Nitazoxanide, orally, 100 mg, twice a day (1–3 years of age), 200 mg, twice a day
(4–11 years of age), or 500 mg, twice a day (≥12 years of age) for 10 days.
 CLOSTRIDIUM DIFFICILE 291

Table 3.3. Treatments for Clostridium difficile Infection

Severity Recommendation
First Occurrence
Mild-moderate Metronidazole, 30 mg/kg/day, PO, every 6 h (preferred), or IV, every 6 h
for 10 days (maximum 500 mg/dose)

If failure to respond in 5–7 days:

Consider switch to vancomycin, 40 mg/kg/day, PO, every 6 h for 10 days
(maximum 125 mg/dose)

For pregnant/breastfeeding or metronidazole-intolerant patients:

Vancomycin, 40 mg/kg/day, PO, every 6 h for 10 days (maximum 125
mg/dose)

In patients for whom oral therapy cannot reach colon:

To above regimen, ADD vancomycin, 500 mg/100 mL normal saline, en-
ema, as needed every 8 h until improvement
Severea Vancomycin, 40 mg/kg/day, PO, every 6 h for 10 days (maximum 125
mg/dose)

Severe and If no abdominal distension (use both for 10 days):

complicatedb Vancomycin, 40 mg/kg/day, PO, every 6 h (maximum 125 mg/dose)
PLUS metronidazole, 30 mg/kg/day, IV, every 6 h (maximum 500
mg/dose)

If complicated with ileus or toxic colitis and/or significant abdominal disten-

sion (use all for 10 days):
Vancomycin, 40 mg/kg/day, PO, every 6 h (maximum 500 mg/dose)
PLUS metronidazole, 30 mg/kg/day, IV, every 6h (maximum 500 mg/dose)
PLUS vancomycin, 500 mg/100 mL normal saline enema, as needed every 8
h until improvement
Severity Recommendation
First Recurrence
Mild-moderate Same regimen as for first occurrence (see above)
Severe Vancomycin, 40 mg/kg/day, PO, every 6 h (maximum 125 mg/dose)
Second Recurrence
All DO NOT USE METRONIDAZOLE
Vancomycin, PO, as pulsed or prolonged tapered dose (see text for options)
PO indicates orally; IV, intravenously.
a
Severe: not well defined in children, but should be considered in the presence of leukocytosis, leukopenia, or worsening renal
function.
b
Severe and complicated: intensive care unit admission, hypotension or shock, pseudomembranous colitis by endoscopy, ileus,
toxic megacolon.

Fecal transplant (intestinal microbiota transplantation) appears to be effective in

adults, but there are limited data in pediatrics. No pediatric data are available evaluating
use of human monoclonal antibodies (against toxin A and B); a lower rate of recurrent
292 CLOSTRIDIUM PERFRINGENS FOOD POISONING

disease in adult patients receiving antibiotic therapy for primary or recurrent C difficile in-
fection is reported in those receiving human monoclonal antibodies. Cholestyramine is
not recommended. Other potential adjunctive therapies of unclear efficacy include Im-
mune Globulin therapy and probiotics (particularly Saccharomyces boulardii and kefir).
ISOLATION OF THE HOSPITALIZED PATIENT: In addition to standard precautions, con-
tact precautions and a private room (if feasible) are recommended at the time that disease
is suspected through resolution of diarrhea.
CONTROL MEASURES: Exercising meticulous hand hygiene, properly handling contami-
nated waste (including diapers), disinfecting fomites, and limiting use of antimicrobial
agents are the best available methods for control of C difficile infection. Gloves should be
worn for all in-room care to prevent hand contamination and hand hygiene should be
performed immediately after glove removal. Alcohol-based hand hygiene products do not
inactivate C difficile spores. Washing hands with soap and water is considered to be more
effective in removing C difficile spores from contaminated hands. There is disagreement
among experts about when and whether soap-and-water hand hygiene should be used
preferentially over alcohol hand gel in nonoutbreak settings. However, in outbreak set-
tings or an increased C difficile infection rate, 1 washing hands with soap and water is the
preferred method of hand hygiene after each contact with a C difficile-infected patient.
Thorough cleaning of hospital rooms and bathrooms of patients with C difficile dis-
ease, as well as reusable equipment with which infected patients had contact, is essential.
Because C difficile spores are difficult to kill with standard hospital disinfectants approved
by the US Environmental Protection Agency, many health care facilities have instituted
the use of disinfectants with sporicidal activity (eg, hypochlorite).
Children with C difficile diarrhea should be excluded from child care settings until
stools are contained in the diaper or the child is continent, and stool frequency is no more
than 2 stools above that child’s normal frequency for the time the child is in the program,
and infection-control measures should be enforced (see Children in Out-of-Home Child
Care, p 122).

Clostridium perfringens Food Poisoning

CLINICAL MANIFESTATIONS: Clostridium perfringens foodborne illness is characterized by a
sudden onset of watery diarrhea and moderate-to-severe crampy, mid-epigastric pain.
Symptoms usually resolve within 24 hours. The shorter incubation period, shorter dura-
tion of illness, and absence of fever in most patients differentiate C perfringens foodborne
disease from shigellosis and salmonellosis. As compared with foodborne illnesses associ-
ated with heavy metals, Staphylococcus aureus enterotoxins, Bacillus cereus emetic toxin, and
fish and shellfish toxins, C perfringens foodborne illness is infrequently associated with vom-
iting. Diarrheal illness caused by B cereus diarrheal enterotoxins can be indistinguishable
from that caused by C perfringens (see Appendix VII, Clinical Syndromes Associated with
Foodborne Diseases, p 1086). Necrotizing colitis and death have been described in pa-
tients with disease attributable to type A C perfringens who received antidiarrheal

1McDonald
LC, Gerding DN, Johnson S, et al. Clinical practice guidelines for Clostridium difficile infection in
adults and children: 2017 update by the Infectious Diseases Society of America (IDSA) and Society for
Healthcare Epidemiology of America (SHEA). Clin Infect Dis. Published online February 15, 2018. Available at:
https://doi.org/10.1093/cid/cix1085