[Fwd: PRO/EDR> Clostridium difficile, increased virulence - USA (multistate)]

[Guest guest]

I thought that the group might be interested in this article. For

myself, I found that I was carrying C. difficile after a

culture yielded its presence even though I was asymptomatic. Ended up

with a two week regimen of Vancomycin.

Philip

---

PRO/EDR> Clostridium difficile, increased virulence - USA

(multistate)

Date:

Fri, 02 Dec 2005 20:47:17 -0500 (EST)

From:

ProMED-mail

Reply-To:

promedNOREPLY@...

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promed-edr@...

CLOSTRIDIUM DIFFICILE, INCREASED VIRULENCE - USA (MULTISTATE)

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Travel Medicine and Infectious Disease

<http://thelancet.url123.com/av327>

Date: Thu, 1 Dec 2005

Source: MMWR 2 Dec 2005; 54:1201-1205 [edited]

<http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5447a1.htm?s_cid=mm5447a1_e>

_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 Reports

--------------

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,

and metronidazole.

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 , MD, Philadelphia Dept of

Public Health; A Weltman, MD, Pennsylvania Dept of Health. LC

Mc, MD, L Wiggs, G Killgore, DrPH, A , MSSc, Div of

Healthcare Quality Promotion, National Center for Infectious

Diseases; M LeMaile-, MD, E Tan, MBBS, FM , 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. Mc 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. Mc LC, Killgore GE, 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, 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. A, Katz V, Dotters D, R: _Clostridium difficile_

infection in obstetric and gynecologic patients. South Med J 1997; 90:889-92.

--

ProMED-mail

[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 Bartlett and Tish Perl of s 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. Mc LC, Killgore GE, 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, 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.

- Mod.LL]

[see also:

Clostridium difficile, ribotype 027 - Belgium 20051021.3071

Clostridium difficile, increased virulence - Netherlands 20050706.1912

Clostridium difficile, increased virulence - UK (England) (05) 20050630.1843

Clostridium difficile, increased virulence - UK (England) 20050606.1572

Clostridium difficile, increased virulence, 2004 - USA, Canada 20050412.1055

2004

----

Clostridium difficile, increased virulence - USA 20041004.2735

Clostridium difficile, fatal - Canada (QC) 20040808.2191]

.........................mpp/ll/pg/mpp

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