Diareea cu

Clostridium difficile
Colita pseudomembranoasa
Dr. Irina Dumitru
 The New Epidemic
 Quebec, Canada – raporteaza pentru prima data o frecventa si
severitate crescuta
 Raportari similare in SUA in 2003

 1991 vs 2003,
 crestere de 4 x a incidentei
 10 x la pers > 65 ani)
 Complicatii: megacolon toxic ce necesita colectomie, soc toxicoseptic,
deces
 Mortalitate crescuta (16%)
 Risc mare de recurente
 Risc mare de rezistenta la tratament
CMAJ 2004; 171 NEJM 2005;353 Ann Intern Med
2006; 145 Gastro 2009; 136:1913–1924
 SUA

Gerding, et al. GASTRO 2009;

136:1913–1924
Prevalenta diareei cu C. difficile
The spread of O27
started in 2003-2004
CINE MAI ARE NEVOIE DE MÂINE?
Trăim într-o lume dedicată zeului Azi.

Prof Dr. Gabriel Adrian Popescu

 Clostridium difficile
 bacil Gram pozitiv, anaerob, sporulat
 produce 2 toxine
 Toxina A,
 enterotoxina, determina inflamatie si cresterea secretiei de fluide la
nivelul mucoasei intestinale.
 Toxina B
 prezinta in vitro o actiune citotoxica de aproximativ 1000 ori mai
puternica decat toxina A, actioneaza sinergic cu aceasta.

 Tulpina NAP-1 sau 027 produce o toxină binară, care

nu este prezentă la celelalte tulpini de Clostridium
difficile  VIRULENTA CRESCUTA
 Aceste toxine
 distrug celulele epiteliului intestinal,
 denudarea mucoasei intestinale
 apariția pseudomembranelor
caracteristice
Colon normal

 responsabile de producerea colitei

pseudomembranoase
 plăci discret alb-gălbui care se
detașează cu ușurință.

hemoragie
necroza
C. diff microvilli
 Clostridium difficile

 1935 - Bacillus difficilis, flora normala la

nou nascut
 1978 – C. difficile identificat ca si cauza
primara a colitei pseudomembranoase
 Portaj de C difficile

Perioada neonatala 70%

3 ani 3-10%

Adult – comunitate 3% (1.5-15.4)

Adult – spital 10-25% (37-40% vor dezvolta diaree)

Distributia infunctie de varsta
 Cum apare?
 Colita indusa de C.difficile rezulta ca urmare a
 unui dezechilibru a florei bacteriene a colonului,
 colonizarii cu C.difficile si
 producerii de toxine.

 Tratamentul antibiotic este responsabil de alterarea

florei

 Tinta principala a infectiei o reprezinta persoanele

spitalizate.
 Cum apare?
 Colonizarea se produce pe cale fecal-orala.

 C. difficile formeaza spori termorezistenti care

pot persista in mediul inconjurator de la cateva
luni pana la cativa ani.

 Flora intestinala normala se opune

colonizarii, insa tratamentul antibiotic, prin
suprimarea florei, faciliteaza proliferarea
C.difficile
 Exogenous
infection

Endogenous
infection ?

Schroeder et al. AFP (2005) 71: 921-928

 Pathogenesis of CDI
1. CDI spores
survive in the 3. Altered lower intestine flora
environment for (due to antimicrobial use) allows
long periods of proliferation of C. difficile in colon.
time. Following
ingestion, they 4. Toxin A & B Production
traverse the leads to colon damage
acidic +/- pseudomembrane.
environment of
the stomach.

2. Spores
germinate
within the
intestine.

Sunenshine & McDonald Cleve Clin J Med 2006; 73(2):187-197.

17
 Histology
 Type I - patchy epithelial
necrosis with fibrin /polys
exudate

 Type II - prominent exudate as

“summit lesion” from ulcer

 Type III - diffuse

necrosis/ulceration with
pseudomembranes composed of
neutrophils, fibrin, mucin,
cellular debris
 Ce trebuie sa mai stim?
 160 ribotypuri de C. difficile

 Tip 010 cel mai fredcvent intalnit

 027
 Virulenta crescuta
 Secreta ambele toxine (A si B)
 Apare in general dupa administrarea de Quinolone
 Poate genera epidemii in spitale
 Rezistenta la tratament
 Mortalitate crescuta
 Romania
 The spread of the hypervirulent C. difficile strain in
Europe (PCR ribotype 027)
- one case in 2007 June (Budapest)
- we confirmed in December that it was 027
- it was added to this Europe-wide data-base
M 1 2 3 4 5 M 6 7 8 9 10 M

Control PCR ribotype 027

Eurosurveillance (2008)
Terhes et al: CMI 2009
Web-based surveillance 2009
November; 29 European countries /10 000
patients day
 Factori de risc

 1. Expunerea la antibiotice
 Boala a fost descrisa initial la pacientii care au primit tratament cu
clindamicina

 2. Varsta avansata
 Riscul creste 20 x

 3. Spitalizarea
 Riscul creste 20-40%

Clin Infec Dis 1998;26 NEJM 1989;320

Very commonly related Less commonly related Uncommonly related

Clindamycin Sulfamides Aminoglycosides

Ampicillin Macrolides Tetracycline
Amoxicillin Carbapenems Chloramphincol
Cephalosporins Other penicillins Linezolid
Fluoroquinolons Tigecyclin

 Among symptomatic patients with CDI:

• 96% received antimicrobials within the 14 days before onset
•100% received an antimicrobial within the previous 3 months
 20% of hospitalized patients are colonized with C. diff

24
 Factori de risc
 4. Chirurgia GI sau procedurile GI.

 5. Boli Inflamatorii intestinale (3.6 X)

 6. Agenti inhibitori de aciditate gastrica

 Blocanti - H2 (2.0 X)
 Inhibitori pompa de protoni -PPIs (2.9 X)

 7. Immunosupresia/chemotherapia

JAMA 2005; 294:2989-2995

Gastro 2009; 136:1913–1924
 Manifestari clinice
Forme usoare/ moderate Forme severe

 Diaree apoasa > 3 scaune/zi  Diaree apoasa > 10

 Crampe abdominale scaune/zi
 Crampe abdominale de
intensitate crescuta
 Febra
 Tahicardie
 Greata
 Abdomen meteorizat
 Deshidratare
 IRA
 !!!!!!!!!!!!!!!!!!!!!!!!!!!!!
 Diagnosticul de colita indusa de C. difficile
trebuie suspectat la orice pacient cu diaree
 care a primit tratament antibiotic in ultimele 2 luni
si/sau
 diareea a debutat dupa 72 ore (sau mai mult) de la
spitalizare.

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!
 Complicatii

Frecvente Rare

 Deshidratare  Megacolon toxic

 Insuficienta renala acuta  Perforatie intestinala 
 Dezechilibre electrolitice peritonita
 Hipoalbuminemie severa   Soc toxic
Ascita  Deces
 Paraclinic

 Analize de laborator
 Reactie leucemoida (leucocitoza cu neutrofilie)
 Hipoalbuminemie severa (ascita)

 Deshidratare severa (IRA)

 Dezechilibre hidroelectrolotice

Gastro 2009; 136:1913–1924

Ann Intern Med 2006;245
Megacoln toxic
 Scor ATLAS
Parametru 0 puncte 1 punct 2 puncte

Vârsta < 60 ani 60 - 79 ani > 80 ani

Temperatura < 37.5oC 37.6 – 38.5oC > 38.6oC

Leucocite < 16 000 16 – 25 000 > 25 000

(cel/mm3)
Albumină (g/dL) > 3,5 2,6 – 3,5 < 2,5

antibiotic sistemic nu - da
simultan terapiei
ICD(> 1 zi)
 Diagnostic: Lab

 Detectia de toxine ramane cea mai utilizata

metoda
 ELISA (poate detecta toxine A si B)
 Spec 95-100% Sens 65-85%

 PCR (detectie toxine A si B)

 Spec 100% Sens 92-97%

Gastroenterol 2009; 136:1913–1924

J Clin Micro 2006;44
Test Advantage Disadvantage
Testing Enzyme • Detects toxin A or both A & B Less sensitive
Toxins immuno-assay • Rapid (same day) 63-94%
(EIA)

PCR Rapid, sensitive, detects Expensive

presence of toxin gene Special equipment

Tissue culture Provides specific and sensitive results -Detect toxin B

cytotoxicity for C. diff -Technical expertise
assay 67-100% -Expensive
-24-48 hours
Organism Glutamate Rapid, sensitive, may Not specific, toxin
ID Dehydrogenase prove useful as a triage or testing required to
(GDH) screening tool, detects the presence verify diagnosis
of glutamate dehydrogenase
produced by C difficile
Stool culture Most sensitive test False-positive
available when performed results if isolate is not
appropriately tested for toxin
labor-intensive;
requires 48–96 hours 34
 Investigatii imagistice
 Rg abdominala pe gol – megacolon toxic

 Echografie abdominala – ascita, ingrosarea

peretelui colonic

 CT, RMN – ascita, perforatie

 Rectosigmoidoscopie – colita
pseudomembranoasa
 !!!!!!! NU in colita fulminanta, risc de perforatie
Megacolon
Toxic
Echo CT
CT
“Thumbprinting”
Endoscopic
C diff megacolon
 Tratament
 STOP – antibiotic (ampi, amoxi, clinda,
cefalosporine, quinolone)
 STOP – agenti antiperistaltici – evolutie spre
megacolon toxic

 Tratament suportiv (hidratare, electroliti)

 Tratament specific antimicrobian:
 Metronidazol oral: 500 mg x3/zi - 10 zile;
 Vancomicina oral : 125-250 mg x4/zi - 10 zile
 Asocierea cu Rifaximina si continuarea > 10 zile,
impiedica aparitia recurentelor!
 Tratament forme usoare/
moderate/severe
 If a patient has strong a pre-test suspicion for CDI, empiric
therapy for CDI should be considered regardless of the laboratory
testing result, as the negative predictive values for CDI are
insufficiently high to exclude disease in these patients. (Strong
recommendation, moderate-quality evidence)

 Any inciting antimicrobial agent(s) should be discontinued, if

possible. (Strong recommendation, high-quality evidence)

 Patients with mild-to-moderate CDI should be treated with

metronidazole 500 mg orally three times per day for 10 days.
(Strong recommendation, high-quality evidence)
American Guidelines 2016
 Patients with severe CDI should be treated with vancomycin
125 mg four times daily for 10 days (Conditional
recommendation, moderate-quality evidence)

 Failure to respond to metronidazole therapy within 5–7 days

should prompt consideration of a change in therapy to
vancomycin at standard dosing. (Strong recommendation,
moderate-quality evidence)

 For mild-to-moderate CDI in patients who are

intolerant/allergic to metronidazole and for
pregnant/breastfeeding women, vancomycin should be
used at standard dosing. (Strong recommendation, high-
quality evidence)
 In patients in whom oral antibiotics cannot reach a segment
of the colon, such as with Hartman’s pouch, ileostomy, or colon
diversion, vancomycin therapy delivered via enema should
be added to treatments above until the patient improves.
(Conditional recommendation, low-quality evidence)

 The use of anti-peristaltic agents to control diarrhea from

confirmed or suspected CDI should be limited or avoided,
as they may obscure symptoms and precipitate complicated
disease. Use of anti-peristaltic agents in the setting of CDI must
always be accompanied by medical therapy for CDI. (Strong
recommendation, low-quality evidence)
 Forme severe/complicate
 Supportive care should be delivered to all patients and includes
 intravenous fluid resuscitation,
 electrolyte replacement, and

 pharmacological venous thromboembolism prophylaxis.

Furthermore, in the absence of ileus or significant abdominal distention, oral

or enteral feeding should be continued. (Conditional recommendation, low-
quality evidence)

 CT scanning of the abdomen and pelvis is recommended in

patients with complicated CDI. (Conditional
recommendation, low-quality evidence)
 Vancomycin delivered orally (125 mg four times per day)
plus Metronidazole intravenous (500 mg three times a day)
is the treatment of choice in patients with severe and
complicated CDI who have no significant abdominal distention.
(Strong recommendation, low-quality evidence)

 Vancomycin
 orally (500 mg four times per day) and
 per rectum (500 mg in a volume of 500 ml four times a day)

plus
 Metronidazole
 intravenous (500 mg three times a day)

is the treatment of choice for patients with complicated CDI

with ileus or toxic colon and/or significant abdominal
distention. (Strong recommendation, low-quality evidence)
 Surgical consult should be obtained in all patients with
complicated CDI.

 Surgical therapy should be considered in patients with any one

of the following attributed to CDI:
 hypotension requiring vasopressor therapy;
 clinical signs of sepsis and organ dysfunction (renal and pulmonary);
 mental status changes;
 white blood cell count ≥50,000 cells/μl, lactate ≥5 mmol/l; or failure to
improve on medical therapy after 5 days. (Strong recommendation,
moderate-quality evidence)
 Mortality 45%
Leffler and Lamont in GASTRO 2009;136:1899–1912
 Recaderi

Leffler and Lamont in GASTRO 2009;136:1899–1912

 Recurente
 15-30% dintre pacienti (20% in medie)
 La aproximativ 1 s de la primul episod (1-8 s)
 Apar aceleasi simptome

 50% date de re-infectie (noi tulpini)

 50% date de recadere
 Rezistenta antibiotica este destul de mica
 Spori reziduali care nu sunt

Gastro 2006;130
Ann Intern Med 2006; 145
 Recurente

 Factori Risc :
 Varsta >65,
 Comorbiditati,

 Raspuns imun scazut la toxina A

 Concentratii scazute de IgG la toxina A poate fi un
important factor de risc

Gastro 2006;130 Ann Intern Med 2006; 145

 Management of recurrent CDI
 The first recurrence of CDI can be treated with the same regimen
that was used for the initial episode. If severe, however vancomycin
should be used.

 The second recurrence should be treated with a pulsed vancomycin

regimen. (Conditional recommendation, low-quality evidence)

 If there is a third recurrence after a pulsed vancomycin regimen,

fecal microbiota transplant (FMT) should be considered.
(Conditional recommendation, moderate-quality evidence)
 C Diff
Recurente

Leffler and Lamont

in GASTRO 2009;
136:1899–1912
 There is limited evidence for the use of adjunct
probiotics to decrease recurrences in patients with
RCDI. (Moderate recommendation, moderate-quality
evidence)

 No effective immunotherapy is currently available.

Intravenous immune globulin (IVIG) does not
have a role as sole therapy in treatment of RCDI.
However, it may be helpful in patients with
hypogammaglobulinemia. (Strong recommendation,
low-quality evidence)
 Alte antibiotice
 Fidaxomicin,
 was not inferior to vancomycin for initial cure for CDI, but no data are
available on the efficacy of this drug in severe or complicated disease.

 Tigecycline
 is a novel analog of minocycline that exhibits broad antimicrobial activity
against Gram-negative and Gram-positive organisms.
 Several published case reports suggest open-label benefit of intravenously
administered tigecycline as a rescue strategy for the treatment of patients
with severe CDI, in whom therapy with vancomycin and metronidazole
has failed.
 Rifaximin
 Nu se abdoarbe din intestin
 Nu este distrusa de sucul gastric
 Spectru larg, anaerobi si aerobi
 Putem asocia la terapia cu Vanco si metronidazol
 Eficienta discutabila in prevenirea recurentelor
 Incidenta scazuta a rezistentei

Chemotherapy 2000;46 Ann Intern Med 2006; 145

Gastro 2009; 136:1899-1912
 Recurente: Tratament

 Probiotice
 Saccharomyces boulardii: 500 mg bid 4-6 s
 Lactobacilli: 1 g qid for 4-6 s

Gastro 2006;130 Ann Intern Med 2006;145

Leffler and Lamont in Gastro 2009; 136:1899–12
 Recurente: Tratament
 Transplant de fecale:
 Se administreaza fecale “prelucrate” prin colonoscopie
 De obicei de la un membru de familie (sanatos); 30-50 g
materie proaspata

Gastro 2006;130 Clin Infect Dis 2003;36

 Coyle’s Corollary

It is better to be
a stool donor
than a recipient.
 Alternative

Freeze Fecal Microbiota

Freeze-dried, Capsulized Fecal Microbiota

 Bezlotoxumab (Zinplava)
 injection (Merck & Company, Inc) for the
prevention of Clostridium difficile infection (CDI)
recurrence
 in patients aged 18 years or older.

 fully human monoclonal immmunoobulin G1/kappa

antibody that binds to and neutralizes C difficile
toxin B
 intravenously (IV) as a single dose of 10 mg/kg over
1 hour.
 Management of patients with CDI and
co-morbid conditions
 All patients with IBD hospitalized with a disease flare should
undergo testing for CDI. (Strong recommendation, high-quality
evidence)

 Underlying immunosuppression (including malignancy,

chemotherapy, corticosteroid therapy, organ transplantation, and
cirrhosis) increases the risk of CDI, and such patients should be
tested if they have a diarrheal illness. (Strong recommendation,
moderate-quality evidence)

 Any diarrheal illness in women who are pregnant or periparturient

should prompt testing for C. difficile. (Conditional
recommendation, low-quality evidence)
 Noi orizonturi
 Tolevamer:
 Mimeaza receptori de toxine (A si B)
 Phase III
 Eficienta moderata

 Vaccinare: toxoid vaccine

 Raspuns foarte bun la pacientii
imunocompetenti
 Studii clinice Gastro 2005;128 Gastro 2006;130
Gastro 2009; 136:1839-1912
 Control infectie
 Camere cu baie
 Spalatul mainilor cu apa si sapun
 Dezinfectarea periodica a saloanelor
 Summary
 In crestere
 Ribotipul 027 (f virulent) in crestere, poate
declansa epidemii in spitale
 Forme severe de boala, mortalitate crescuta
 Necesitate chirurgie.
 Vancomycina in clisma eficacitate crescuta in
formele severe
 Preventia este cea mai buna rezolvare