Chapter 43 - Miscellaneous Bacterial Infections of GIT

Miscellaneous Bacterial
Infections
of Gastrointestinal System
Learning objectives
At the end of the session, the students will be able to understand:
▰ Campylobacter infections
▰ Helicobacter infections and their treatment
▰ Clostridioides difficile infection and infection prevention measures
3
Essentials of Medical Microbiology by Apurba S Sastry © Jaypee Brothers Medical Publishers
CAMPYLOBACTERIOSI
S
4
CAMPYLOBACTERIOSIS
▰ Campylobacter species cause both diarrheal and systemic diseases.
▰ They are motile, nonsporing, microaerophilic, curved gram-negative rods.
▰ Human pathogens fall into two major groups:

 1. Primarily diarrheal disease - Caused by C. jejuni (accounting for 80–
90% of total cases), and others - C. coli, C. upsaliensis, C. lari, C.
hyointestinalis, C. fetus
 2. Extraintestinal infection: Caused by C. fetus.
5
Epidemiology
▰ Source: Zoonotic, found in the intestine of many animals (poultry, cattle,

sheep and swine) and household pets (including birds, dogs and cats).
▰ Mode of transmission:
 By raw or undercooked food products: Ingestion of contaminated
poultry (most common), raw (unpasteurized) milk or untreated water
 Direct contact with the infected household pets
 Oral-anal sexual contact.
6
Epidemiology (Cont..)
▰ Infective dose: Small; <500 organisms can cause disease
▰ Age: Persons of all ages are affected; however:

 C. jejuni infection - common among children
 C. fetus infection - highest in extremes of age.
7
Pathogenesis
▰ Motility of the strain (possesses single polar flagellum and exhibits darting
motility)
▰ Capacity to adhere to host tissues
▰ Produce toxins, which play a minor role:
 Enterotoxin (heat-labile, similar to cholera toxin)
 Cytotoxins (cytolethal distending toxin, or CDT).
▰ Proteinaceous capsule-like structure (S-layer) expressed by C. fetus.
8
Clinical Manifestations
▰ Incubation period of campylobacteriosis varies from 2–4 days.
▰ Intestinal infection: Inflammatory diarrhea, abdominal pain and fever.
▰ Complications: Mainly due to C. fetus - in immunocompromised hosts

and at the extremes of age. Common manifestations - bacteremia, sepsis,
meningitis, vascular infections.
9
Clinical Manifestations (Cont..)
▰ Campylobacter can precipitate the pathogenesis of various other diseases
such as:
 Guillain–Barre syndrome (mainly by C. jejuni serotype O19)
 Irritable bowel syndrome
 Alpha chain disease, a form of lymphoma that originates in small
intestinal mucosa-associated lymphoid tissue.
 Reactive arthritis and other rheumatologic manifestations, in persons
with the HLA-B27 phenotype.
10
Laboratory Diagnosis
▰ Freshly collected stool specimen and rectal swab are the preferred
specimens.
11
Direct Microscopy
▰ Gram stained smear of feces - curved

gramnegative bacilli, comma or S-
shaped or spiral (gull wing) shaped.
▰ Dark ground microscopy

demonstrates the darting motility of
the bacilli.
12
Culture
▰ Transport medium: If delay is expected - Cary-Blair medium can be used
▰ Selective media: Feces or rectal swabs are plated onto selective media
such as:
 Skirrow’s selective medium - figure
 Butzler’s selective medium
 Campy BAP selective medium.
13
Culture (Cont..)
▰ Culture conditions: Incubated at - Microaerophilic condition (5% oxygen)
▰ Growth at 42°C: Thermophilic Campylobacter species (C. jejuni, C. coli

and C. lari) – differentiated from C. fetus, which is nonthermophilic.
14
Culture (Cont..)
▰ After 2–5 days of incubation, characteristic effuse droplet-like colonies

are produced - further subjected to conventional biochemical tests or
automated systems such as MALDI-TOF or VITEK for species
identification
15
Molecular Method
▰ Automated multiplexed PCR assay - BioFire FilmArray is available.
▰ Its gastrointestinal (GI) panel - simultaneously detect 22 different enteric

pathogens directly from stool specimens, including Campylobacter.
16
Treatment of Campylobacteriosis
▰ Fluid and electrolyte replacement - mainstay of treatment.
▰ Specific antimicrobial therapy - indicated only for severe infection or for
immunocompromised patients.
▰ Antibiotics used for treatment are:
▰ Diarrheal disease: Oral macrolides - drug of choice (erythromycin or
azithromycin). Ciprofloxacin or doxycycline can be used alternatively
17
Treatment of Campylobacteriosis
(Cont..)
▰ Systemic/life threatening infection (by C. fetus): Parenteral imipenem or

meropenem plus gentamicin – started empirically but susceptibility testing
then be performed.
18
HELICOBACTER
INFECTIONS 19
HELICOBACTER INFECTIONS
▰ Helicobacter pylori - curved gram-negative rod that colonizes stomach and
is associated with peptic ulcer disease and gastric carcinoma.
20
Pathogenesis
▰ Colonization of the Gastric Mucosa - 50% of the world’s population
(30% in developed & nearly 80% in developing countries)
▰ Colonization favored by :
 Acid-resistance
 Urease enzyme, Amidase and arginase
 Adhesins
 Resistance to oxidative stress
21
Pathogenesis (Cont..)
▰ Induces Pathological Changes:
 Vacuolating cytotoxin (VacA)
 Cytotoxin-associated gene A (CagA)
 Molecular mimicry
 Alteration in gastric mucus
 Host factors
 Environmental risk factors
22
▰ Acute gastritis
▰ Peptic ulcer disease
▰ Chronic atrophic gastritis
▰ Autoimmune gastritis
▰ Pernicious anemia
▰ Adenocarcinoma of stomach
▰ Gastric mucosa associated lymphoid tissue (MALT) lymphomas.
23
Protective Role for H. pylori
▰ Colonization of H. pylori–induced hypochlorhydria has an inverse relation

with the occurrence of:
 Gastroesophageal reflux disease (GERD)
 Barrett’s esophagus
 Adenocarcinoma of esophagus
 Allergic disorders including asthma.
24
Laboratory Diagnosis – Invasive tests
▰ Endoscopy-guided multiple
biopsies (antrum and corpus)
▰ Histopathology with Warthin

Starry silver staining -
immunostaining to improve
sensitivity
25
(Cont..)
Microbiological methods
▰ Gram-staining: Curved gram-negative bacilli with seagull-shaped

morphology
▰ Culture: Most specific test for H. pylori - it is not sensitive

 Skirrow’s media and chocolate agar
 Plates are incubated at 37°C under microaerophilic condition (5%
oxygen). 26
(Cont..)
Biopsy urease test (also called rapid urease test):
▰ Detects the presence of urease activity in gastric biopsies by using a broth

that contains urea and a pH indicator.
▰ Rapid, sensitive and cheap.
27
Laboratory Diagnosis – Non-invasive
tests
▰ Urea breath test:
 Most consistent and accurate test
 Most sensitive, quick and simple
 Used to monitor treatment response
▰ Fecal antigen (coproantigen) assay
 Used to monitor treatment response
 Useful for screening of children.
28
Laboratory Diagnosis – Non-invasive
tests (Cont..)
▰ Antibody (IgG) detection by ELISA:
 Screening before endoscopy,
 Seroepidemiological study.
29
Treatment of H. pylori infection
Treatment of H. pylori infection is indicated for:
▰ (i) active or past history of peptic ulcer disease,
▰ (ii) atrophic gastritis,
▰ (iii) MALT lymphoma,
▰ (iv) following endoscopic resection of early gastric cancer
30
Treatment of H. pylori infection (Cont..)
▰ Treatment - not recommended for asymptomatic colonizers or primary

prophylaxis for gastric cancer.
▰ Usually multidrug regimens are used.
▰ Monotherapy is not useful because of inadequate antibiotic delivery to the
colonization niche
▰ Success of treatment depends on: (i) Patient’s close compliance with the
regimen, and (ii) Use of susceptible antibiotics
31
Treatment of H. pylori infection (Cont..)
Treatment regimen:
▰ OBTM quadruple therapy: Omeprazole + bismuth subsalicylate +

metronidazole + tetracycline; given for 14 days
▰ OCM or OCA triple therapy: Omeprazole + clarithromycin +

metronidazole or amoxicillin for 14 days - only if H. pylori clarithromycin
resistance is low (<15%).
32
Monitoring Patients during Treatment
▰ Perform urea breath test after completion of treatment regimen.
▰ If tests positive, repeat the treatment course with the same quadruple
regimen
▰ If urea breath test still remains positive, treatment is instituted based on

culture of endoscopy guided biopsy, followed by antimicrobial
susceptibility report.
33
CLOSTRIDIOIDES
DIFFICILE
INFECTION
34
CLOSTRIDIOIDES DIFFICILE
INFECTION
▰ Obligate anaerobic, gram-positive, spore-forming bacillus, responsible for
a unique colonic disease—pseudomembranous colitis - occurs almost
exclusively in association with prolonged antimicrobial use.
▰ So named due to unusual difficulties involved in the isolation of C.

difficile.
▰ Taxonomically, it is recently placed into a separate genera, Clostridioides

difficile.
35
Pathogenesis
▰ Major cause of hospital-acquired infection mainly in the Western world
▰ Risk factors:
▰ Prolonged hospital stay: Spores in hospital environment colonize colon of
patients
▰ Prolonged antimicrobial use: Disruption of normal colonic flora 
enhances C. difficile infection
 Cephalosporins (e.g. Ceftriaxone) – More common
 Others - Clindamycin, Ampicillin and fluoroquinolones
36
▰ Toxin production: Pathogenesis is toxin-mediated.
▰ Only the toxigenic strains can cause pseudomembranous colitis.
▰ Two powerful exotoxins—toxin A (enterotoxin) & toxin B (cytotoxin)
 Both toxins secreted in intestine → glycosylate GTP binding proteins
that regulate the cellular actin cytoskeleton → disruption of the
cytoskeleton  loss of cell shape, adherence, and disruption of
epithelial cell barrier → diarrhea & pseudomembrane formation
▰ Infants - asymptomatic infection as they lack suitable mucosal toxin
receptors
37
▰ Host immune response determine the outcome
 Strong IgG response to toxin A— become asymptomatic carriers
 Inadequate IgG response to toxin A— develop disease
38
▰ Other risk factors:
 Suppression of normal flora, Advanced age (>65 years)
 Immunosuppression & malignancy, Gastric acid suppressant
medications
 Use of electronic rectal thermometer
 Hypervirulent epidemic strain: BI/NAP1/027 - produces higher
levels of toxins and causes severe infection
39
▰ Diarrhea – MC manifestation
 Others - abdominal pain and leukocytosis, Blood in stool rare
▰ Pseudomembrane:
 Composition: necrotic leukocytes, fibrin, mucus & cellular debris
 Attaches to the underlying mucosa
 whitish-yellow plaque , 1–2 mm to large enough to spread over the
entire colonic mucosa
 Relapse after treatment - 15–30% of cases.
40
Laboratory Diagnosis
▰ Case definition of C. difficile infection comprises of ≥3 unformed stool per
day and isolation of the bacilli followed by toxigenicity testing
41
Laboratory Diagnosis (Cont..)
▰ Stool culture: Anaerobic culture on selective media
 CCFA (cefoxitin cycloserine fructose agar)
 CCYA (cefoxitin cycloserine egg yolk agar)
 Sensitive and specific
 Since C.difficile can be a GIT colonizer the GIT, only isolation is not
enough to establish the infection. Toxin demonstration is more
meaningful
42
▰ Cell culture cytotoxin neutralization assay: Highly specific but not as
sensitive
▰ Antigen detection: Rapid tests or enzyme immunoassay are available for

the detection of C. difficile specific antigens in stool specimen
 Toxin A/B: Detection in stool indicates presence of toxigenic strains of
C. difficile
 Glutamate dehydrogenase (GDH): Present in both toxigenic and
non-toxigenic strains.
43
▰ Molecular methods:
 PCR, real time PCR, gene Xpert - targeting genes coding for C.
difficile - tcd A (toxin A), tcd B (toxin B) and tpi (triose phosphate
isomerase) in stool.
 Highly sensitive and specific with faster turnaround time
▰ Colonoscopy: Highly specific if pseudomembranes are seen - sensitivity is

low, when compared with other tests
44
▰ Histopathology:
 Histopathology of colonic pseudomembrane (obtained by

colonoscopy) can be performed by hematoxylin and eosin stain.
 Highly specific; but the sensitivity is very low.
45
Treatment of C. difficile infection
▰ Mild to moderate cases (Initial episode): Oral vancomycin or
fidaxomicin - DOC (given for 10 days). Oral metronidazole can be given
alternatively - less effective.
▰ Fulminant cases: Oral vancomycin plus IV metronidazole plus rectal

instillation of vancomycin is recommended.
46
Treatment of C. difficile infection (Cont..)
▰ Recurrent cases: The treatment options are:
 For first recurrence: Oral vancomycin or fidaxomicin (10 days)
 For multiple recurrences: Taper-and-pulse regimen—after the 10 days

therapy of oral vancomycin (125 mg four times day) - tapered over 2-8
weeks.
47
▰ Intravenous immunoglobulin: Passively provide antibodies to neutralize
the C. difficile toxins, primarily toxin A
▰ Fecal microbiota transplant (FMT) - considered for multiple recurrent

cases - involves replenishing of the gut flora with donated feces from a
screened healthy donor
48
▰ Fidaxomicin: Macrolide antibiotic - used in initial and recurrent cases, and
also against hypervirulent strains.
▰ Note: IV vancomycin is not effective for C. difficile infection.
49
Prevention (Infection Control
Measures)
▰ Broad spectrum antimicrobials - stopped at the earliest.
▰ Contact precaution should be followed such as:
 Strict hand hygiene
 Isolation: Patient - placed at isolation room and transfer should be
restricted
 Ensure proper disinfection of floor, surfaces, toilets and other soiled
areas - 1% freshly prepared hypochlorite solution.
50
Questions:
▰ Q1. Most sensitive method of diagnosis of Helicobacter pylori is:
a. Culture
b. Biopsy urease test
c. Histopathology
d. Urea breath test
51
Questions:
▰ Q2. All the following drugs are indicated in C. difficile infection, except:
a. Oral vancomycin
b. Fidaxomicin
c. Oral metronidazole
d. IV vancomycin
52

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Miscellaneous Bacterial

At the end of the session, the students will be able to understand:

▰ Helicobacter infections and their treatment

▰ Clostridioides difficile infection and infection prevention measures

▰ Campylobacter species cause both diarrheal and systemic diseases.

▰ They are motile, nonsporing, microaerophilic, curved gram-negative rods.

▰ Human pathogens fall into two major groups:

▰ Source: Zoonotic, found in the intestine of many animals (poultry, cattle,

▰ Infective dose: Small; <500 organisms can cause disease

▰ Age: Persons of all ages are affected; however:

▰ Incubation period of campylobacteriosis varies from 2–4 days.

▰ Intestinal infection: Inflammatory diarrhea, abdominal pain and fever.

▰ Complications: Mainly due to C. fetus - in immunocompromised hosts

▰ Gram stained smear of feces - curved

▰ Dark ground microscopy

▰ Culture conditions: Incubated at - Microaerophilic condition (5% oxygen)

▰ Growth at 42°C: Thermophilic Campylobacter species (C. jejuni, C. coli

▰ After 2–5 days of incubation, characteristic effuse droplet-like colonies

▰ Automated multiplexed PCR assay - BioFire FilmArray is available.

▰ Its gastrointestinal (GI) panel - simultaneously detect 22 different enteric

▰ Systemic/life threatening infection (by C. fetus): Parenteral imipenem or

▰ Colonization of H. pylori–induced hypochlorhydria has an inverse relation

▰ Histopathology with Warthin

▰ Gram-staining: Curved gram-negative bacilli with seagull-shaped

▰ Culture: Most specific test for H. pylori - it is not sensitive

Biopsy urease test (also called rapid urease test):

▰ Detects the presence of urease activity in gastric biopsies by using a broth

▰ Rapid, sensitive and cheap.

 Screening before endoscopy,

Treatment of H. pylori infection is indicated for:

▰ (i) active or past history of peptic ulcer disease,

▰ (ii) atrophic gastritis,

▰ (iii) MALT lymphoma,

▰ (iv) following endoscopic resection of early gastric cancer

▰ Treatment - not recommended for asymptomatic colonizers or primary

▰ OBTM quadruple therapy: Omeprazole + bismuth subsalicylate +

▰ OCM or OCA triple therapy: Omeprazole + clarithromycin +

▰ If urea breath test still remains positive, treatment is instituted based on

▰ So named due to unusual difficulties involved in the isolation of C.

▰ Taxonomically, it is recently placed into a separate genera, Clostridioides

 Strong IgG response to toxin A— become asymptomatic carriers

 Inadequate IgG response to toxin A— develop disease

▰ Antigen detection: Rapid tests or enzyme immunoassay are available for

▰ Colonoscopy: Highly specific if pseudomembranes are seen - sensitivity is

 Histopathology of colonic pseudomembrane (obtained by

 Highly specific; but the sensitivity is very low.

▰ Fulminant cases: Oral vancomycin plus IV metronidazole plus rectal

 For first recurrence: Oral vancomycin or fidaxomicin (10 days)

 For multiple recurrences: Taper-and-pulse regimen—after the 10 days

▰ Fecal microbiota transplant (FMT) - considered for multiple recurrent

▰ Note: IV vancomycin is not effective for C. difficile infection.

b. Biopsy urease test

d. Urea breath test

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