Published Date: 2005-12-02 23:50:00
Subject: PRO/EDR> Clostridium difficile, increased virulence - USA (multistate)
Archive Number: 20051202.3472
CLOSTRIDIUM DIFFICILE, INCREASED VIRULENCE - USA (MULTISTATE)
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Travel Medicine and Infectious Disease
Date: Thu, 1 Dec 2005
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Source: MMWR 2 Dec 2005; 54:1201-1205 [edited]
_Clostridium difficile_ is a spore-forming, gram-positive bacillus
that produces exotoxins that are pathogenic to humans. _C.
difficile_-associated disease (CDAD) ranges in severity from mild
diarrhea to fulminant colitis and death. Antimicrobial use is the
primary risk factor for development of CDAD because it disrupts
normal bowel flora and promotes _C. difficile_ overgrowth. _C.
difficile_ typically has affected older or severely ill patients who
are hospital inpatients or residents of long-term-care facilities.
Recently, however, both the frequency and severity of
health-care-associated CDAD has increased; from 2000 to 2001, the
rate of USA hospital discharge diagnoses of CDAD increased by 26
percent (1). A possible explanation for these increases is the
emergence of a previously uncommon strain of _C. difficile_
responsible for severe hospital outbreaks (2). Although individual
cases of CDAD are not nationally reportable, in 2005, the
Pennsylvania Department of Health (PADOH) and CDC received several
case reports of serious CDAD in otherwise healthy patients with
minimal or no exposure to a health-care setting. An investigation was
initiated by the Philadelphia Department of Public Health (PDPH),
PADOH, and CDC to determine the scope of the problem and explore a
possible change in CDAD epidemiology.
This report summarizes the results of the investigation in
Pennsylvania and 3 other states, which indicated the presence of
severe CDAD [both] in healthy persons living in the community and
[in] peripartum women, populations previously thought to be at low
risk. The findings underscore the importance of judicious
antimicrobial use, the need for community clinicians to maintain a
higher index of suspicion for CDAD, and the need for surveillance to
better understand the changing epidemiology of CDAD.
Case 1. A woman aged 31 years who was 14 weeks pregnant with twins
went to a local emergency department (ED) after 3 weeks of
intermittent diarrhea, followed by 3 days of cramping and watery,
black stools 4-5 times daily. Stools specimens tested positive for
_C. difficile_ toxin, and the patient was admitted. Her only
antimicrobial exposure during the preceding year was
trimethoprim-sulfamethoxazole (for a urinary tract infection)
approximately 3 months before admission.
She was treated with metronidazole and discharged but was readmitted
the next day for 18 days with severe colitis, receiving
metronidazole, cholestyramine, and oral vancomycin. She improved on
vancomycin and was allowed to return home. However, 4 days later she
was readmitted with diarrhea and hypotension. She spontaneously
aborted her fetuses. Despite aggressive treatment including a
subtotal colectomy, intubation, and inotropic medication, the patient
died on the 3rd hospital day. Histopathologic examination of the
colon demonstrated megacolon with evidence of pseudomembranous colitis.
Case 2. A girl aged 10 years (unrelated and without contact with case
1) went to a children's hospital ED because of intractable diarrhea,
projectile vomiting, and abdominal pain. She had not taken
antimicrobials during the preceding year. Stool specimens were
positive for _C. difficile_ toxin. The child had been healthy until 2
weeks before the ED visit, when she became symptomatic within days of
her younger brother having a febrile diarrheal illness. The boy was
not on antimicrobials when he became ill. His symptoms resolved
within 2-3 days without medical treatment, but his sister had fever
as high as 102 degrees F (39 degrees C), abdominal pain, and diarrhea.
One week into her illness, she was examined by a clinician, who
performed a rapid streptococcal antigen test on a swab from her
oropharynx; the result was positive. The patient was prescribed
amoxicillin but was unable to take it because of her stomach cramps
and diarrhea; her symptoms worsened until she was having liquid
stools up to 14 times daily. Symptoms resolved with hospital
admission and the administration of intravenous fluids, electrolytes,
Epidemiologic and Laboratory Investigations
In May and Jun 2005, a request for voluntary reports of peripartum
CDAD (i.e., 4 weeks before and after delivery) was initiated by PDPH;
case definitions for peripartum CDAD were developed and distributed
nationally through the Epidemic Information Exchange (Epi-X) and
locally through the PDPH Health Alert Network (HAN). The New Jersey
Department of Health and Senior Services also distributed the alert
statewide through its HAN system. A separate request for reporting of
community-associated CDAD (CA-CDAD) along with a case definition was
developed and distributed in Jun 2005 in Philadelphia and 4
surrounding Pennsylvania counties (Bucks, Chester, Delaware, and
Montgomery) through local and statewide HANs.
Detailed, open-ended interviews were conducted with patients who were
reported by hospital personnel to state and local health departments
after distribution of the notices. Medical details, such as type of
antimicrobial agent and duration, were confirmed with treating
clinicians whenever possible.
To determine the minimum population rate and rate per antimicrobial
prescription of CA-CDAD, the number of cases reported from
Philadelphia and 4 surrounding counties were divided by 2004 USA
census population estimates for these 5 areas. The number of
antimicrobial prescriptions were calculated on the basis of census
estimates of the population surveyed, multiplied by national
prescribing rate estimates (3). Available toxin-positive stool
samples were cultured for _C. difficile_ using standard methods.
Isolates underwent pulsed-field gel electrophoresis (PFGE),
toxinotyping, and detection of binary toxin and deletions in tcdC, a
putative negative regulator of toxin production (2, 4).
10 peripartum and 23 CA-CDAD cases were reported from 4 states during
May-Jun 2005 (Table 1, for tables see original URL), with onset dates
ranging from 26 Feb 2003 to 28 Jun 2005. All but 1 of the cases
occurred during 2004-2005. Age of nonperipartum cases ranged from 6
months to 72 years (mean: 26 years; median: 23 years). Peripartum
cases occurred in patients from New Hampshire, New Jersey, Ohio, and
Pennsylvania; because CA-CDAD surveillance was conducted only in the
greater Philadelphia area, these cases were only from this area.
Transmission to close contacts was evident for 4 cases: 2 were in
children of CDAD patients with peripartum exposures, 1 was in an
adult caring for a hospitalized parent with confirmed CDAD, and 1 was
in an adult who visited a parent with confirmed CDAD in a nursing
home. One peripartum mother who transmitted _C. difficile_ to her
child also transmitted CDAD to a family friend.
8 (24 percent) of 33 patients reported no exposure to antimicrobial
agents within 3 months before CDAD onset. 5 of these were children, 3
of whom required hospitalization. 3 of the 8 cases without exposure
to antimicrobial agents occurred in patients who had close contact
with a person with diarrheal illness; 2 of these persons had
confirmed CDAD. An additional 3 (9 percent) of 33 patients contracted
CDAD after receiving less than 3 doses of antimicrobials; 2 received
only 1 dose of clindamycin for group B streptococcus prophylaxis
before CDAD onset. Clindamycin was the most common antimicrobial
exposure noted; overall, 10 (30 percent) of 33 cases were in patients
who reported exposure to the drug before disease onset; these 10
patients included the 2 who had less than 3 doses of antimicrobials.
15 (46 percent) patients required hospitalization or an ED visit. 13
(39 percent) patients had a relapse of disease and required antimicrobials.
The estimated minimum annual incidence of CA-CDAD in Philadelphia and
its surrounding 4 counties during Jul 2004-Jun 2005 was 7.6 cases per
100 000 population, with 1 case of CDAD for every 5549 outpatient
antimicrobial prescriptions; this figure is based on national
estimates of antimicrobial prescribing in ambulatory settings applied
to the Philadelphia area. 2 patient isolates were available for
characterization and were compared with the recently described
"epidemic strain" that has been detected as the cause of either
severe hospital outbreaks or hospital-endemic cases of CDAD in 16
states (2; CDC, unpublished data, 2005). Neither shared the same
toxinotype as the epidemic strain, but both were binary toxin
positive; 1 isolate, from an Ohio peripartum CDAD case, was greater
than 80 percent related by PFGE to the epidemic strain, and the
other, from a Philadelphia-area CA-CDAD case, had an 18-bp deletion
in tcdC (Table 2).
[Reported by E Chernak, MD, CC Johnson, MD, Philadelphia Dept of
Public Health; A Weltman, MD, Pennsylvania Dept of Health. LC
McDonald, MD, L Wiggs, G Killgore, DrPH, A Thompson, MSSc, Div of
Healthcare Quality Promotion, National Center for Infectious
Diseases; M LeMaile-Williams, MD, E Tan, MBBS, FM Lewis, MD, EIS officers, CDC]
MMWR editorial note:
Considered in the context of recent high-morbidity,
hospital-associated outbreaks in North America, Great Britain, and
the Netherlands (5), these cases of severe CDAD disease in
populations previously thought to be at low risk might further
reflect the changing epidemiology of CDAD. Certain features of CDAD
that have been uncommon in the past, such as close-contact
transmission, high recurrence rate, young patient age, bloody
diarrhea, and lack of antimicrobial exposure, might be changing.
_C. difficile_ exotoxins A and B cause colonic dysfunction and cell
death. The epidemic strain produces 16 times more toxin A and 23
times more toxin B compared with other common strains (5). The
increased severity of epidemic CDAD might result from this level of
toxin production; however, the actual role of tcdC deletions in
increased toxin production has not been determined. _C. difficile_
toxinotype 0 is the historical standard type; variant toxinotypes
have previously accounted for less than 20 percent of USA hospital
isolates (6). Although the role of this binary toxin in human disease
is unknown, it was previously detected in only 6 percent of clinical
isolates but now is found uniformly in the epidemic strain (6). The
isolates recovered during this investigation were both variant
toxinotypes and carried the gene for binary toxin; 1 also carried the
same 18-bp deletion in tcdC as the epidemic strain.
Virulent strains, which cause more severe disease in populations at
high risk, might also cause more frequent, severe disease in
populations previously at low risk (e.g., otherwise healthy persons
with little or no exposure to health-care settings or antimicrobial
use). Although the minimum annual incidence cited in this report is
similar to previous estimates in ambulatory populations (8 to 12
cases per 100 000 population), the CA-CDAD case definition more
stringently excluded hospital-acquired CDAD (7, 8). The estimated
case rate per antimicrobial prescription is twice as high as the less
than 1 case per 10 000 incidence cited in these earlier studies (7,
8). Because reporting in this investigation was voluntary, the true
incidence of community CDAD is probably higher. Because historic
surveillance data are not available, determining whether CDAD rates
in peripartum women are changing is not possible; however, the only
available report suggests a low baseline incidence, with only 3
obstetric cases identified among 74 120 obstetrics and gynecology
admissions to a North Carolina hospital during 1985-1995 (9).
The findings in this report are subject to at least 2 limitations.
First, because the report describes a convenience sample, the results
are subject to reporting and selection biases. Second, because this
sample was collected in a limited geographic region, results might
not be generalizable to other regions. Moreover, although a single
national estimate for ambulatory prescribing rates was applied to
this region, substantial variation in these rates might exist.
Further investigation into the scope of CA-CDAD acquisition and
related risk factors is warranted. Nonetheless, the cases described
in this report demonstrate the need for clinicians to consider the
diagnosis of CDAD in patients with severe diarrhea even if the
patients do not necessarily have traditional risk factors such as
recent hospitalization or antimicrobial use.
Patients should seek medical attention for diarrhea lasting longer
than 3 days or accompanied by blood or high fever. The findings
underscore the fact that antimicrobial exposure is not benign and
that judicious antimicrobial use in all health-care settings should
continue to be emphasized.
1. McDonald CL, Banerjee S, Jernigan DB: Increasing incidence of
_Clostridium difficile_-associated disease in U.S. acute care
hospitals, 1992-2001 [Abstract]. In: Proceedings of the 14th Annual
Scientific Meeting of the Society for Healthcare Epidemiology of
America, Philadelphia, PA; 17-20 Apr 2004.
2. McDonald LC, Killgore GE, Thompson A, et al: Emergence of an
epidemic, toxin gene variant strain of _Clostridium difficile_
responsible for outbreaks in the United States between 2000 and 2004.
N Engl J Med 2005 (in press).
3. McCaig LF, Besser RE, Hughes JM: Antimicrobial drug prescriptions
in ambulatory care settings, United States, 1992-2000. Emerg Infect
Dis 2003; 9:432-37.
4. Rupnik M, Avesani V, Janc M: A novel toxinotyping scheme and
correlation of toxinotypes with serogroups of _Clostridium
difficile_. J Clin Microbiol 1998; 36:2240-47.
5. Warny M, Pepin J, Fang A, et al: Increased toxins A and B
production by an emerging strain of _Clostridium difficile_
associated with outbreaks of severe disease in North America and
Europe. Lancet 2005; 366:1079-84.
6. Geric B, Rupnik M, Gerding DN, et al: Distribution of
_Clostridium difficile_ variant toxinotypes and strains with binary
toxin genes among clinical isolates in an American hospital. J Med
Microbiol 2004; 53:887-94.
7. Levy DG, Stergachis A, McFarland LV, et al: Antibiotics and
_Clostridium difficile_ diarrhea in the ambulatory care setting. Clin
Ther 2000; 22:91-102.
8. Hirschhorn L, Trnka Y, Onderdonk A, et al: Epidemiology of
community-acquired _Clostridium difficile_-associated diarrhea. J
Infect Dis 1994; 169:127-33.
9. James A, Katz V, Dotters D, Rogers R: _Clostridium difficile_
infection in obstetric and gynecologic patients. South Med J 1997; 90:889-92.
[This worrisome report clearly describes rare _C. difficile_ illness:
severe disease in individuals not thought to be at high risk
(children and peripartum women) who have little or no direct
antimicrobial exposure. Some of the cases were in household contacts
of cases who had received antimicrobial agents. Of note, the
antimicrobial agent most closely linked to the cases was clindamycin,
the drug first linked by Dave Alpers' group in St. Louis to
pseudomembranous enterocolitis in the early 1970s (1).
The epidemic strain referred to the the posting is a ribotype 027,
toxinotype III organism which is a hyperproducer of toxin(s). Here,
only 2 strains have been characterized and neither were toxinotype
III. They do, however, produce a binary toxin (CDT) similar to the
iota toxin of _Clostridium perfringes_ which is also a characteristic
of the epidemic strain. It is not clear if the binary toxin has a
role in pathogenicity.
Additionally, one of the strains from this posting had an 18-bp
deletion in the _tcdC_ reading frame also found in the toxinotype III
epidemic strain. This gene is felt to be a negative regulator of the
production of toxins A and B and may be responsible for the
recognized enhanced toxin production of the epidemic strain (2). The
amount of toxin produced from the mutant TcdC strain in this posting
is not specifically noted.
TcdC is part of the pathogenicity locus (PaLoc) of _C. difficile_
(3). This 19.6-kb locus also contains the genes for toxins A
(_tcdA_) and B (_tcdB_) and for TcdB, a positive regulator of the
toxins as well as genetic information for several insertion sequences.
In response to the MMWR publication, the New England Journal of
Medicine yesterday released 2 early articles (4, 5) and a
corresponding editorial (6) -- to be published in the 8 Dec 2005
issue -- which are concerned with the epidemic strain outbreaks in
the USA (4) and Canada
(5). Additionally, these epidemic strains were resistant to
fluoroquinolones, which was one risk factor for disease. Resistance
to fluoroquinolones was not mentioned in the 2 strains in this posting.
The editorial by John Bartlett and Tish Perl of Johns Hopkins again
stresses the prevention of _C. difficile_ disease, primarily by
aggressive infection control maneuvers including the fastidious use
of both barrier precautions and hand washing as well as increased
restraint in the use of epidemiologically implicated antimicrobial agents.
1. Tedesco FJ, Barton RW, Alpers DH: Clindamycin-associated colitis:
a prospective study. Ann Intern Med 1974; 81:429-33.
2. Warny M, Pepin J, Fang A, et al: Toxin production by an emerging
strain of _Clostridium difficile_ associated with outbreaks of severe
disease in North America and Europe. Lancet 2005; 366:1079-86.
3. Spigaglia P, Mastrantonio P: Molecular analysis of the
pathogenicity locus and polymorphism in the putative negative
regulator of toxin production (TcdC) among _Clostridium difficile_
clinical isolates. J Clin Microbiol 2002; 40:3470-75.
4. McDonald LC, Killgore GE, Thompson A, et al: An epidemic, toxin
gene-variant strain of _Clostridium difficile_. N Engl J Med 2005; 353:2433-41.
5. Loo VG, Poirier L, Miller MA, et al: A predominantly clonal
multi-institutional outbreak of _Clostridium difficile_-associated
diarrhea with high morbidity and mortality. N Engl J Med 2005; 353:2442-49.
6. Bartlett JG, Perl TM: The new _Clostridium difficile_ - what does
it mean? N Engl J Med 2005; 353:2503-505.