c.difficile.pptx

Antibiotic Associated Diarrhoea And
Clostridioides difficile Infection
Dr Umashankar
DM Resident, DDHD

Objectives
• Antibiotic associated Diarrhoea
• Clostridioides Difficile
--Microbiology
-Risk Factors
-Clinical Features
-Diagnosis
-Management

Antibiotic Associated Diarrhoea
• Complicates 2 % to 25 % of antibiotic treatment
• Commonest antibiotics implicated
• Ampicillin (5 to 10%)
• Amoxicillin-clavulanate (10 to 25%)
• Cefixime
• Fluoroquinolones and trimethoprim-uncommon

Pathogenesis
Intestinal Flora Alteration Alteration in fermentation of complex
carbohydrates –osmotic diarrhoea
Unconjugated bile salts stimulate fluid
secretion
Stimulation of intestinal motility Erythromycin
Allergic Reaction
Pathogenic Microorganisms Clostridium Perfringes type A, Staph
Aureus, Klebsiella oxytoca
Clostridioides dificile (10%)

Clinical Features and Treatment
• Mild and self limited
• No fever
• No pseudomembraneous colitis
• Discontinue the inciting antibiotic
• Antiperistaltic agents are not contraindicated
• Probiotics such as S.boulardi and lactobacilli when used
prophylactically in combination with antibiotics reduce the risk of
AAD especially with a history of susceptibility

Clostridioides difficile infection

Clostridioides Difficile
• Anaerobic
• Gram Positive
• Spore forming
• Toxinogenic
• Primary cause of nosocomial infectious
diarrhoea in developed nations

A History of C. difficile
1893 -
pseudomembranous
colitis first described
1935 - isolated in
stool
1978 - C. difficile
responsible for
antibiotic associated
diarrhea
1996-2003 CDC
reports rate of CDI
increased from 31
cases per 100,000
persons to 61 cases
per 100,000 persons
1. Heinlen L, Ballard JD. Clostridium difficile Infection. The American journal of the medical sciences. 2010;340(3):247-252.
2. The Clostridium difficile PCR ribotype 027 lineage: a pathogen on the move Valiente, E. et al. Clinical Microbiology and Infection , Volume 20
2005 – US continues to report
increased CDI
2016 reclassified into
Clostridiodies difficle

• Intestinal carriage rates of C. difficile in healthy adults-0% to 3%
• Inpatients treated with antibiotics - 10% to 21%
• Acquisition from the hospital environment is a major source of CDI
• Highly resistant spores of C. difficile persist for many months in the
hospital environment
• Asymptomatic carriers - important reservoir of nosocomial infection
• Infective dose - low as 2spores
C. difficile

C difficile infection(CDI)
• CDI may be hospital or community acquired.
• Hospital acquired - have their onset of symptoms and signs of colitis
develop in the hospital or after discharge to the community.
• Community-acquired CDI - diagnosed in patients who lack typical
risk factors for the disease (e.g., recent antibiotic exposure)

Predisposing Antibiotics
Frequently Sometimes Rarely
Amoxicillin Macrolides Aminoglycosides
Ampicillin Other Penicilllins Bacitracin
Cephalosporins sulfonamides Carbapenems
clindamycin trimethoprim chloramphenicol
Fluroquinolones Trimethoprim +sulfamethoxazole Daptomycin
Metronidazole
Rifampicin
Rifaximine
Teicoplanin
Tetracycline
Tigecycline

Concept of ‘’colonisation resistance’’

• Toxins A (308 kd) and Toxin B (220 kd )
• Toxin B 10 times more potent than toxin A
• Toxin encoding gene reside in a 19.6-kb chromosomal region,
• Contains
1. tcdA
2. tcdB
3. tcdC
4. tcdD
5. tcdE
TcdR

Toxins of C difficle
• N-terminal enzymatic domain - toxic effects
• Central hydrophobic region -a transmembrane domain to facilitate entry into the
cytoplasm
• C-terminal domain - mediate toxin binding
• Fourth domain -encodes intrinsic peptidase that releases enzymatic domain
• Uridine diphosphate glucose hydrolases and glucosyltransferases
• Glucosylation of rho proteins by the toxins leads to disordered cell signaling,
disorganization of the cytoskeleton, disruption of protein synthesis, cell rounding,
and cell death.
• Activate nuclear factor-κB, mitogen-activated protein kinases, and COX-2 -> IL-
1β, TNF-α, and IL-8

Immune Response to C. Difficile
• Serum IgG and IgA antibodies against C.
difficile toxins
• Mucosal IgA antitoxin antibodies
• High concentrations of antitoxin
antibody - protection against CDI,
recurrence
• Low concentration of serum antitoxin -
48-fold greater risk of recurrent disease
after initial successful treatment

Spectrum of Disease
• Asymptomatic carriage
• Mild to moderate diarrhoea
• Life Threatening pseudomembraneous colitis with Toxic Megacolon

Carrier State
• 10-21% of Hospital inpatients receiving anti biotics in high risk units
• Asymptomatic due to adaptive protective immunity

• Frequent passage of loose or watery bowel movements.
• Fever, leukocytosis, and cramping abdominal pain.
• Mucus or occult blood may be present
• Melena or hematochezia is uncommon
• C. difficile is not an invasive pathogen, extraintestinal manifestations of
CDI such as septic arthritis, bacteremia, or tissue abscess are extremely
rare
• Oligoarticular, asymmetrical, nondeforming large-joint arthropathy
rarely seen
C.difficile Diarrhoea

Severe disease
• Colonic ileus
• Toxic Megacolon
• Minimal or even No diarrhoea
• Clues
• -High grade fever, polymorphonuclear leucocytosis ,lower or diffuse
abdominal pain
• -Abdominal Distension

Complications
• Dehydration
• Hypoalbuminemia
• Ascites
• AKI
• Toxic Mega colon
• SIRS
• Bowel Perforation

Whom to Test?
• Patient with new onset
diarrhoea (3 or more unformed
stools in 24 hours), especially if
they had antibiotic exposure
within the previous 2 to 3
months
Whom Not to Test?
• Testing of solid or formed stools
• Follow-up stool testing to
confirm cure
IDSA & SHEA 2017 guidelines

Sample collection
• Freshly passed stool in a clean water tight container
• Rectal swab in patients with ileus
• Anaerobic media or transport media is not needed
• Storage at ambient temperature can lead on to denaturation of fecal toxin
or bacterial DNA
• If there is delay REFRIGERATE

Test Advantage Disadvantage
Testing Toxins Enzyme immuno-
assay (EIA)
• Detects toxin A or both A & B
• Rapid (same day)
•Inexpensive, high specificity
Less sensitive
63-94%
Tissue culture
cytotoxicity assay
Provides specific and sensitive results for C. diff
67-100%
-Detect toxin B
-Technical expertise
-Expensive
-Slow,24-48 hours
Organism ID Glutamate
Dehydrogenase
(GDH)
Rapid, sensitive, may
prove useful as a triage or
screening tool
Not specific, toxin testing required
to verify diagnosis
Do not differentiate between
toxigenic and non-toxigenic
strains
PCR Rapid, sensitive and
specific , detects presence of toxin gene
Expensive
Special equipment
Highly sensitive
Stool culture Most sensitive test
available when performed
appropriately
False-positive results if isolate is
not tested for toxin production;
labor-intensive; requires 48–96
hours 31
Testing

Colleen R. Kelly et al; ACG CDI 2021guidelines; Am J Gastroenterol 2021

Sigmoidoscopy and colonoscopy
• Not Always indicated
• Helpful when the diagnosis is in doubt or in severe cases
• Normal - mild diarrhea
• Nonspecific colitis, erosions- moderate cases.
• Pseudo membranes - virtually pathognomonic for C. difficile colitis
• Yellow, gray, or white plaques 2 to 5mm in diameter
• Pseudo membranes in the more proximal areas in15-20%

Pseudomembraneous enterocolitis
• Intestinal surgeries
• Intestinal Ischemia
• Shigella
• NEC
• Intestinal obstruction
• Colonic Ca
• Staph. Aureus
• Severe Systemic insults (shock , HUS, extensive burns ,AKI)

Abdominal X ray
• Dilated colon > 7 mm
• Small bowel ileus with multiple
Fluid levels

CT findings of Pseudomembranous colitis
• Bowel wall thickening (m/c)
• Accordion sign
• Shaggy mucosal outline
• Peritoneal free fluid : seen in up to
40% of cases
• Typically the whole colon is
involved
• Right colon and transverse colon
affected in isolation in up to 5% of
cases
• Rectal involvement - majority of
cases (90-95%)

Summit sign /Volcano sign
Focal Ulceration of the colonic mucosa with exudation of pseudomembrane made up of inflammatory cells,
fibrin,necrotic debris .
Adjoining mucosa is intact

General Principles of Management
• Minimise use of concomitant antibiotics
• Discontinue all other antimicrobials whenever possible
• If necessary chose the antibiotic least likely to exacerbate C.difficile
infection
• If all antibiotics are discontinued ,diarrhoea resolves in approximately 15 to
25 %patients over 2 to 6 weeks without specific therapy
• Avoid Antimotility agents and narcotics for fear of impaired toxin
clearance, ileus and megacolon

Non severe CDI
• Leukocytosis, WBC of
≤15,000cells/mL and Cr <1.5 mg/dL
• Oral vancomycin 125 mg QID* 10
days
• Oral fidaxomicin 200 mg BD*10 days
• Oral metronidazole 500 mg TID *10
days
• Leukocytosis, WBC of >15,000
cells/mL OR Cr >1.5 mg/dL
• Oral vancomycin 125 mg QID* 10
days
• Oral fidaxomicin 200 mg BD*10 days
Severe CDI

Vancomycin
• Glycopeptide antibiotic
• First line drug
• Not absorbed orally
• High concentrations are achieved in the colonic lumen-> Systemic side
effects are rare.
• Can be used in pregnancy and children <10 years
• Improvement in diarrhea is usually evident within 72 hours of initiating
therapy, and complete resolution of symptoms occurs in most patients by
the end of a 10-day treatment course

Vancomycin
• Dosage -125 mg 4 times a day in mild to moderate cases
- 500 mg 4 times a day in severe cases
-Pulsed/tapering regimen : 125 mg QID 10-14 days, BD for a wk,
OD for a wk and then every 2 or 3 days for 2-8 wk
• Vancomycin therapy is recommended now for patients with mild,
moderate or severe CDI, including patients who fail to respond to
metronidazole, are intolerant of metronidazole
• Dose of 125 mg 4 times a day is as effective as vancomycin 500 mg 4
times a day.

Vancomycin125mg vs 500 mg
Gonzales et al. BMC Infectious Diseases 2010, 10:363

Fidaxomicin
• Macrocyclic antibiotic
• Mechanism of action: Inhibits bacterial RNA polymerase
• Little systemic absorption, achieves high fecal concentrations
• Limited activity against other members of the intestinal microbiota
• Selective therapy against C. difficile and lead to fewer post-treatment recurrences
• Dosage :200 mg twice daily for10 days
• Advantage : - low recurrence rate compared with vancomycin and in patients treated for
first recurrence
• Less effective for NAP-1 strain
• For patients with an initial CDI episode and CDI recurrence, use fidaxomicin rather than a
standard course of vancomycin ( IDSA & SHEA 2021)

VAN vs FDX
Cornely et al, Lancet; 2012; 12.281-289

Others
• Teicoplanin 100 mg bd for 10 days ; expensive, not available in oral form
• Nitazoxanide
• Rifaximin 400 tid for 10 days for primary theray
• Rifaximin 400 tid for 20 days after standard CDI therapy in which recurrent
CDI rates decreased from 31% to 15% ( Rifaximine chaser regimen )
• Bacitracin 25,000 units 4 times daily for 7 to 10 days
• Binding Resins (Colestepol, cholestyramine and tolevamer) which bind to
the toxins in the bowel; disappointing results

• Severe CDI plus presence of hypotension or shock or ileus or megacolon
• Diarrhoea may be minimal or absent
• Abdominal pain, peritoneal signs, colonic dilatation, marked
leucocytosis
• Clinical picture of progressive sepsis with hypotension (possibly
requiring the use of a vasopressor)
• Mental status changes, elevated serum lactate, and end-organ failure
(e.g., renal, pulmonary).
Initial episode- fulminant

Initial episode- fulminant
• Discontinue non–C. difficile antibiotics
• Adequate volume resuscitation
• Oral vancomycin 500mg 6th hourly for the first 48–72hours.
• Presence of ileus, vancomycin (500 mg every 6 hours) administered via
NG tube, with intermittent clamping of the tube.
• Addition of vancomycin enemas (500 mg every 6 hours) is beneficial
• Combination therapy with parenteral metronidazole 500mg 8th hourly
can be considered
• Fidaxomicin role in the management of fulminant disease has not yet
been established

Salvage therapy
• Not responding to combined treatment with vancomycin and
metronidazole
1. IV tigecycline (loading dose of 100 mg IV followed by 50 mg 2 times
per day)
2. Human immunoglobulin (400 mg/kg body weight)
• Failure of response to vancomycin is not related to acquisition of
antibiotic resistance
• Rather due to host factors such as age, immune deficiency,
comorbidity, or lack of compliance.

Surgical therapy
Surgeries:
1. Total colectomy with end
ileostomy and a stapled rectal
stump
2. Diverting loop ileostomy with
colonic lavage and intraluminal
vancomycin
Choice depending on clinical
circumstances, the patient’s
estimated tolerance to surgery, and
the surgeon’s best judgment

Diverting loop ileostomy with colonic lavage
and intraluminal vancomycin
Neal et al; Ann Surg 2011;254:423–429

• Multiple or sequential FMTs in combination with anti-CDI antibiotics(vancomycin
or fidaxomicin)
• FMT can be safely administered through careful colonoscopy with gentle CO2
insufflation and careful advancement of the scope beyond the splenic flexure.
• Repeated every 3–5 days until resolution of pseudomembrane.
• Concomitantly, administration of oral vancomycin (125 mg every 6 hours) or
fidaxomicin (200 mg every 12 hours) should be continued as long as
pseudomembrane is present.
• When a complete resolution of pseudomembrane is ascertained by colonoscopy,
a final FMT should be delivered completing the sequential therapy.
Fecal microbiota transplantation for severe
and fulminant CDI

Fecal microbiota transplantation for severe
and fulminant CDI
• Considered for patients with severe and fulminant CDI refractory to
antibiotic therapy, in particular, when patients are deemed poor
surgical candidates

• Defined as the recurrence of diarrhea and a confirmatory positive test (NAAT
orEIA) within 8 weeks after treatment of an initial episode of CDI
• Rule out Post infectious IBS , Microscopic colitis ,celiac disease and lactose
intolerance

Risk Factors for Recurrent CDI
• Increasing age
• Prior CDI (risk increases with each episode)
• Medications (antibiotics, gastric acid suppression, immunosuppression,
chemotherapy)
• Decreased serum antitoxin antibodies
• Comorbidities such as renal insufficiency, IBD or malignancy
• Prolonged length of hospital stay
• Long-term care facility residence
• Contact with actively infected individuals or carriers

Treatment of First & second Recurrent CDI
• Tapering/pulsed-dose VAN for patients experiencing a first recurrence
after an initial course of FDX, VAN, or metronidazole
• FDX 200 mg given twice daily for 10 days if VAN was used for the initial
episode ( FDX> VAN a/c IDSA & SHEA 2021)
• Rationale of pulse therapy: Toxin production by C.difficile usually does
not occur during the early exponential growth phase of the bacterium,
but rather in the subsequent stationary phase

• Extended pulsed regimen of FDX
• Pulsed/tapered regimen of VAN
• VAN followed by rifaximin( Rifaximin chaser)

Principle
• CDI result from a perturbed ecologic imbalance in the microbiota of
intestinal tract dysbiosis and the reintroduction of normal flora via donor
faeces corrects the imbalance and restore the phylogenetic richness
Indications
• Recurrent CDI- two or more rCDI
• Refractory CDI
Mullish BH, et al. BSG FMT Guidelines Gut 2018;0:1–22.

Donor screeing
Mullish BH, et al. BSG FMT in CDI Guidelines Gut 2018;0:1–22.

Routes
• Colonoscopy
• Retention enema
• Capsules
• Upper GI- nasogastric,
nasoduodenal or nasojejunal
tube/ upper GI endoscopy.
Resolution Rates
• Stomach (81%)
• Duodenum/jejunum(86%)
• Cecum/ascending colon(93%)
• Distal colon (84%)
Mullish BH, et al. BSG FMT Iin CDI Guidelines Gut 2018;0:1–22.

• ≥18 and≤60 years old and have a BMI of ≥18 and ≤30 kg/m2
• Stool collection should follow a standard protocol
• Donor stool should be processed within 6 hours of defaecation
• Using ≥50 g of stool in each FMT preparation
• Stool should be mixed 1:5 with diluent to make the initial faecal
emulsion
• Banked frozen(-80o C) FMT material should be considered preferable
to fresh preparations for CDI
Mullish BH, et al. BSG FMT in CDI Guidelines Gut 2018;0:1–22.

Safety profile of FMT
• Minor transient symptoms : bloating, cramps, abdominal pain, nausea, gas,
diarrhea, irregular bowel movements, constipation, and low-grade fevers
• Serious adverse events rarely among immunocompromised patients
• Risk of infection with ESBL- Escherichia coli bacteremia
• The methods used to administer FMT may present increased risk such as
perforation, bleeding, and sedation related complications
• Fatal aspiration pneumonia has been reported with administration through
nasoenteric tube because of regurgitation of donor stool particularly when the
patient is lying flat or may have an ileus.

Suppressive and Prophylactic Vancomycin
INDICATIONS:
1. rCDI who are not candidates for FMT
2. Who relapsed after FMT
3. Who require ongoing or frequent courses of antibiotics
• Long-term suppressive oral vancomycin may be used to prevent further
recurrences
• Oral vancomycin prophylaxis (OVP) may be considered during subsequent
systemic antibiotic use in patients with a history of CDI who are at high risk
of recurrence to prevent further recurrence

OVP
• This high-risk group includes patients aged 65 years, or older or with
significant immunocompromise who were hospitalized for severe CDI
within the past 3 months.
• NNT to prevent 1 CDI is 7
• Low-dose vancomycin 125 mg once daily, which is typically continued
until 5 days after completion of systemic antibiotics.
• No significant increase in VRE infection rate

Antitoxins- Bezlotoxumab
• Antitoxin A- Actoxumab
• Antitoxin B - Bezlotoxumab
• Actoxumab was not effective in reducing CDI recurrence.
• Bezlotoxumab neutralizes C. difficile toxin B by binding to its putative
receptor-binding domain.
• Bezlotoxumab (10mg/kg) associated with fewer CDI recurrences
during the subsequent 12 weeks (16.5% compared with 26.6% for
placebo).
• High cost, CHF

Gerding DN et al. Clin Infect Dis 2018;67(5):649–56

IDSA & SHEA 2021 update
• For patients with a recurrent CDI episode within the last six months-
use bezlotoxumab as a co-intervention along with SOC antibiotics
rather than SOC antibiotics alone
• In patients with a primary CDI episode and other risk factors for CDI
recurrence (such as age >65 years, immunocompromised host and
severe CDI on presentation) may particularly benefit from receiving
bezlotoxumab.

Probiotics
• NOT recommended for the prevention of CDI in patients being treated
with antibiotics (primary prevention)
• NOT recommended for the prevention of CDI recurrence .

CDI and IBD
• IBD pts have 4.8 fold increased risk of CDI (UC=CD)
• Community-onset CDI, younger and recurrent CDI
• Considered as severe disease
• Mortality risk is about 4-fold higher than patients admitted for IBD alone
(UC>CD)
• C. difficile testing is recommended in patients with IBD presenting with an
acute flare associated with diarrhea
• Vancomycin 125 mg p.o. 4 times a day for a minimum of 14 d
• Serum albumin below 3 g/dL was identified as an independent predictor of
surgery and death

Sequential vs concomitant anti-CDI antibiotic &
immunosuppressive therapy
• Distinguishing CDI in quiescent IBD from C. difficile colonization in
active IBD
• Endoscopic evaluation, stool testing can help distinguish between
these 2 scenarios.
• Inactive IBD patients with CDI: anti-CDI antibiotic therapy should be
initiated and maintenance therapy for IBD continued.
• Inadequately controlled IBD, may develop CDI d/t inflammation and
disturbed microbiota, which then contributes to symptoms of disease
flare.

• Immunosuppressive therapy should be escalated to treat the flare
• Therefore when CDI is diagnosed, anti-C. difficile antimicrobial therapy
is initiated while the maintenance IBD therapy is continued.
• If no improvement in clinical symptoms is observed after 3 days,
immunosuppressive therapy should be optimized or escalated to
address the underlying active IBD.( NO NEED TO WITHDRAW/STOP
THERAPY)
• FMT should be considered for recurrent CDI in patients with IBD

Pregnancy and lactation
• Vancomycin to treat pregnant and peripartum patients with CDI.
• Vancomycin is recommended to treat breastfeeding patients with CDI.
• Fidaxomicin is not recommended due to lack of studies

C. difficile Vaccines
• Chemically inactivated toxoids A and B
• Early clinical trials, vaccine was immunogenic
• A Phase 3 vaccine trial for CDI prevention was initiated but
was closed in 2017 after an interim review of the study data
indicated that the study was unlikely to reach its objectives
de Bruyn G, Saleh et al. Vaccine 2016;34(19):2170–8.

Prevention
• Avoiding unnecessary use of broad spectrum antibiotics
• Hand Hygiene
• Environmental cleaning
• Antibiotic stewardship

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