09/04/2019

9:30-12:00 W Introduction to Infectious Disease

7:30-10:00 F Medicine II
LDT Juan Ismael Sumagaysay, M.D.

OUTLINE o Increase antibiotic use increases risk of

infection by killing the normal flora
I. AnatB1 Introduction to Infectious Disease  Treatment with immunosuppressive drug:
II. Enteric Gram-negative Rods important especially in fungal and immunocompromised patients
(Enterobacteriaceae)
III. Diseases Caused by Escherichia coli Host-Factor Interactions

INTRODUCTION TO INFECTIOUS DISEASE  Geography: Dengue and Malaria are common in tropics
 Environment
 Not a system or part of the body  Behavior
 Broad, composes different disciplines
 Anything caused by a microbe  Specific factors that influence likelihood of infections:
1. Age: extreme of ages
 Multi system involvement: outmost (skin) to innermost (bone)
2. Immunization history: common in children
 Top most diseases
3. Prior illness
o Tuberculosis
4. Level of nutrition
o Diarrhea o Malnourished (prone to disease)
 Second leading cause of death worldwide o More nourished (more prone to dengue)
5. Pregnancy: prone to disease
Host-Pathogen Interactions 6. Coexisting illnesses: diabetes, COPD, hepatitis, renal problem
7. Emotional state
 Infectious disease: major cause of death and debility around the world o Emotionally stressed
 Common in 3rd world due to: o Lack of sleep
o Poverty o Always starving
o Overcrowding
o Cultural differences
 Tripod The Immune Response
o Etiologic agent
o Host  Innate immunity
o Immune system o Defensins
 Antibiotic resistance occurs at an alarming rate: microbes develop the o Simple peptide on the skin
ability to elude the best antimicrobials and develop new survival o Macrophages
strategies  Adaptive immunity
 There is resurgence of disease long thought to be eradicated o Cellular immunity
o Factor: migration from area of high incidence of disease to area of  T lymphocytes
low incidence  Macrophage
o Disease resurgence in recent times  Natural killer cells
 Tuberculosis: increased incidence in developing countries
 Cholera
 RA Approach to the Patient
 West Nile Virus Encephalitis
 Careful history taking
o Recently emerging newer disease pathogens o Paramount in the evaluation of a patient with a possible infectious
 Ebola virus disease
 Human metapneumovirus o Guides PE and initial diagnostic testing
 Anaplasma phagocytophila infection o Focus on 2 areas
 Retroviruses / HIV  An exposure history that may identify microorganisms with
 Helicobacter pylori infection which the patient may have come into contact
 Zika virus infection  Host-specific factors that may predispose to the development of
an infection
 Infectious diseases don’t often occur in isolation (e.g. contaminated
H2O respiratory droplets) o History of infections or exposure to drug-resistant microbes
 May alter the choice of antibiotics
Medical Care Factors
o Social history
 Hospitalization  Unsafe sexual behaviors (IV drug use)
o Prone to develop hospital acquired infection  Hobby-associated exposures (avid gardening)
o Increase hospitalization, increase risk  Occupational exposures (increased risk for MTB exposure in
 Breach in the skin / mucosal membrane funeral service workers)
 Introduction of foreign bodies: implant, valve o Dietary habits
 Alteration of natural flora (antibiotic use)  Shiga toxin-producing strains of E. coli and T. gondii:
o Chemotherapy consumption of raw or undercooked meat or raw seafood

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  S. typhimurium, L. monocytogenes, and M. bovis: unpasteurized
milk
 Leptospira spp., parasites, and enteric bacteria: unpurified water
 Vibrio spp., norovirus, helminthes and protozoa: raw seafood
o Animal exposures: often vectors of infectious diseases
o Travel history
 Both international and domestic travel
 Fever in a patient who has recently returned from abroad
significantly broadens the differential diagnosis
 Careful review of systems
 Thorough Physical Examination
o Vital signs: temperature, HR, PR, RR
o Lymphatics
 Infections are an important cause of lymphadenopathy
 Evaluation of lymph nodes in multiple regions
 Location
 Size
 Consistency
 Presence or absence of tenderness
 Whether the nodes are matted (connected and moving
together)
 Determining whether the patient has generalized versus localized
lymphadenopathy
o Skin: specific rashes are extremely helpful in narrowing the
diagnosis of an infection
o Foreign bodies
 Maintenance of epithelial barriers is one of the most important
mechanisms in protection against infection
 Hospitalization of patient is often associated with branches of
barriers: IV lines, surgical drains or tubes
 Allow microorganisms to localize in sites to which they
normally would not have access
Laboratory Investigations
 Must be directed towards establishing an etiologic diagnosis
 Shortest possible time, lowest possible cost, least possible cost and least
possible discomfort to the patient
 Specimens must be appropriate and handled carefully
o Must be based directly on the patient’s history and physical exam
findings
o Limited to those conditions that are reasonably likely and treatable,
important in terms of public health considerations, and/or capable of
providing a definitive diagnosis that will consequently limit other
testing
 WBC count
o Elevations in the WBC count are often associated with infection,
though many viral infections are associated with leukopenia
o Important to access the WBC differential count
 Bacteria: increase in polymorphonuclear neutrophils
 Viruses: increase in lymphocytes
 Certain parasites: increase in eosinophils
 Inflammatory markers
o Erythrocyte Sedimentation Rate
o C-reactive Protein
 Analysis of CSF
o Critical for patient with suspected meningitis or encephalitis
o Opening pressure should always be recorded, and fluid should
routinely be sent for cell counts, Gram’s stain and culture and
determination of glucose and protein levels
 Cultures
o Mainstay of infectious disease diagnosis
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o Specimens are collected before the administration of antimicrobial
therapy (blood, urine, sputum, pus from a wound)
o Allows identification of the etiologic agent, determination of the
antimicrobial susceptibility profile and isolate typing
 Pathogen-specific testing
o Serology, Antigen testing, PCR testing
o Facilitate rapid turnaround that ultimately enhances patient care
o PCRs identify organisms that currently are not cultivable and have
unclear relationships to disease
 Radiology
o Allows evaluation for lymphadenopathy in regions that are not
externally accessible, assessment of internal organs for evidence of
infection, and facilitation of image-guided percutaneous sampling of
deep spaces
o CT scan, MRI, Ultrasound, Nuclear medicine
Treatment
 “Primum non nocere”: do no harm
 Obtain relevant samples for culture prior to the administration of
antibiotics
 Although a general maxim for antibiotic treatment is to use a regimen
with as narrow a spectrum as possible, empirical regimens are
necessarily somewhat broad, given that a specific diagnosis has not yet
been made
Laboratory Diagnosis of Infectious Diseases
 Requires demonstration, either direct or indirect, of viral, bacterial,
mycotic, or parasitic agents in tissues, fluids or excreta of the host
o Direct: microscopy, pathology (biopsy)
o Indirect: PCR, serologic test
 Detection of pathogenic agents by culture
o Specimen collection and transport
o Isolation of bacterial pathogens
o Isolation of viral agents: cultured cell for cytopathic effect,
immunofluorescent detection of viral antigen
 Detection methods
o Biologic signals: a material that can be reproducibly differentiated
from other substances present in the same physical environment
 Structural components of bacteria, fungi
 Detection system: trained eye of the technologist
o Sensitive electronic instruments: immunofluorescence,
chemiluminescence
 Amplification: culture of bacterium on an agar plate, PCR, enzyme
immunoassays
 Direct detection
o Microscopy
o Staining: Gram’s stain, Acid fast stain, Fluorochrome stains,
Immunofluorescent stains
o Macroscopic antigen detection: Latex agglutination assays, Enzyme
Immunoassays
 Identification methods
o Classic Phenotyping
o Gas-liquid chromatography
o Nucleic acid probes
 Susceptibility testing
o Paper disk method
o Broth tube method
o Minimum Inhibitory Concentration (MIC)
Principles of Immunization and Vaccination
 Universal immunization has invariably remained an unattained goal
 Vaccination (Polio: only disease that it totally eradicated)
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  Immunization  Immunocompromised persons (HIV+, hematologic/generalized
o Process of inducing or providing immunity malignancy)
 Passive: given as immunoglobulins o Should be immunized in the same manner as individuals with
 Human tetanus Immunoglobulin normal immune system
 Transplacental transfer of antibodies o Live attenuated vaccine is contraindicated, may lead to disseminated
 Active: as toxoids promoting production of antibodies directly infection with the vaccine virus
(will take some time for the body to produce its own antibody)
ENTERIC GRAM-NEGATIVE RODS (ENTEROBACTERIACEAE)
 Factors that can give rise to increase in vaccine-preventable disease
o Low rates of immunization that result in an accumulation of  Large and heterogenous
susceptible people  Facultative anaerobes and aerobes
o Changes in the infectious agent that permit it to escape vaccine-  Often called Coliforms
induced protection  Many produce toxins and virulence factors
o Waning of vaccine-induces immunity
 Found in the intestinal tract of humans and animals
o Point-source introductions of large inoculate o Escherichia
o Shigella
Approaches to Immunization and Vaccination
o Salmonella
o Enterobacter
 Vaccine: attenuated or live microorganisms/antigenic portion
o Klebsiella
 Toxoid: modified bacterial toxin
o Serratia
 Immune globulin: antibody containing protein
o Proteus
 Antitoxin: antibody derived from serum of animals
o Citrobacter
 Active immunization
o Morganella
o Live, attenuated: generally long-lasting immunity
o Providencia
o Inactivated: multiple doses or periodic boosters
o Cronobacter
 Passive Immunization
o Edwardsiella
o Generally used to provide temporary immunity
o Treatment of certain diseases associated with toxins  Among the most commonly cultured in laboratory and disease bacteria
 Classifications
 Route of administration
o Classified as to shape, growth, colony form, biochemical properties
o Determine the rapidity and nature of the vaccine
o Gram-negative rods
o Must determine the licensed route to ensure immunogenicity
o Motile or nonmotile
 Orally
 Intranasally o Grow on peptone and MacConkey’s agar
 Intramuscular o Ferments glucose
o Catalase (+), Oxidase (-)
o Temperature and transport are factors that can affect the o Reduce nitrate to nitrite
effectiveness of vaccines o Typically short, gram-negative rods
 Primary Response o Some have capsules: Klebsiella
o Measurable circulating antibody do not appear for 7-10 days o Most have convex, smooth, circular colonies
o Characterized by early appearing IgM antibodies
 Secondary Response Escherichia coli
o Elicited by second exposure to the same antigen
o Usually occur within 4-5 days  Indole +
o Characterized by marked proliferation of IgG antibodies  Lysine decarboxylases
o Hypersensitivity reaction  Produce gas from glucose
o Herd immunity  Ferments mannitol
 Constituents of Vaccines  Hemolyzes blood agar
o Preservatives, stabilizers, antibiotics  Iridescent sheen on culture media (Greenish-metallic Sheen)
o Adjuvants: enhance immune response
o Suspending fluids Klebsiella – Enterobacter - Serratia

Target Population and Timing of Immunization  Mucoid growth

 Large polysaccharide capsule
 Demographic features of the populations at risk  Lacks motility
 Duration and character of the immunologic response
 Influenza pandemic preparedness Proteus – Morganella – Providentia
 Breast feeding: neither killed nor live vaccine affect the safety of breast
feeding for either mother or infant  Deaminate phenylalanine
 Pregnancy  Motile: swarming on solid media
o Routine immunization should be avoided  Grow on potassium cyanide medium
o Tetanus and diphtheria toxoid can be safely given  Ferments xylose
o MMR, varicella should be withheld (has teratogenic effects Citrobacter
especially in the first trimester)
 Hepatitis B vaccine: workers  Citrate +
 Rubella, Measles, varicella – Health caregivers  Do not decarboxylase lysine

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 Shigella 6 Distinct Types of Intestinal E. coli
1. Enterohemorrhagic E. coli (EHEC) / Shiga-toxin producing E. coli
 Non-motile (STEC)
 Do not ferment lactose 2. Enterotoxigenic E. coli (ETEC)
 Produce acid but not gas 3. Enteropathogenic E. coli (EPEC)
 Do not produce H2S 4. Enteroinvasive E. coli (EIEC)
5. Enteroaggregative E. coli (EAEC)
Salmonella 6. Diffusely adherent E. coli (DAEC)

 Motile Enteropathogenic E. coli (EPEC)

 Ferment glucose and mannose  Primarily affecting young children
 Most produce H2S: associated with typhoid fever  Infants, Nurseries: Infantile diarrhea
 Breastfeeding decreases its incidence
Antigenic Structure of Enterics  Stools often contain mucus rather than blood
 Rapid person-to-person spread
 O Antigen (Somatic Antigen)  Colonization of the bowel
o Most external part of the cell wall o Initial localized adherence to enterocytes via Type IV bundle-
o Resistant to host and alcohol forming pili
 K Antigen (Capsular Antigen)  Effacement of microvilli
o External to O antigen on some  Cup-like actin-rich pedestals
o Associated with virulence
o Can be identified by capsular swelling in some  Incubation period: 1 or 2 days (often self-limited, lasting 5-15 days)
 H Antigen (Flagellar Antigen)  Host cell modulation by Type III secretion system
o Located in flagella  Diarrhea: accompanied by vomiting and fever
o Denatured by heat or alcohol  Atypical EPEC
o Strains lacking bundle-forming pili
o Pathogens in all age groups
Colicins
o Can affects immunocompromised patients
 Bacteriocins o Diarrheal stool contains mucus
 Produce by certain enterics
Enterotoxigenic E. coli (ETEC)
 Virus-like bactericidal substances which act against certain strain of
closely related species  Traveler’s diarrhea and very important cause of diarrhea in infants
 Used in typing of organisms  Major cause of endemic diarrhea
o Children after weaning commonly experiences several episodes of
DISEASES CAUSED BY ESCHERICHIA COLI infection during first 3 years of life
 Adherence of ETEC via colonization factors that causes net fluid
Escherichia coli: UTI
secretion in jejunum and ileum
o Heat-labile toxin (LT-1) activates adenylate cyclase
 Escherichia coli  Structurally and functionally similar to Cholera toxin
o Most common cause of UTI  A and B subunit
o Accounts for approximately 90% of 1st UTI in young women  Binding of B subunit to GM1 ganglioside leads to intracellular
translocation of A subunit
 Signs and Symptoms
 A Subunit: functions as ADP-ribosyltransferase
o Uncomplicated Cystitis: most common acute UTI syndrome
o Dysuria o Heat-stable toxin (STa) activates guanylate cyclase: increased
 Initial intracellular secretions of CGMP
 Terminal  Usually self-limited: a large inoculum (106-1010 CFU) is needed to
 Caused by cystitis, inflamed urinary bladder produce disease
 Urethritis  Incubation period: 12-72 hours
o Hematuria  Although symptoms are usually self-limited (3-5 days), infection may
result in significant morbidity and mortality
o Pyuria
o Watery diarrhea accompanied by cramps
o Flank pain
o Mucus, blood and inflammatory cells in stool
 Together with fever
o Fever
 Suggests progression to pyelonephritis
o Disease spectrum ranges from a mild illness to a life-threatening
o Fever cholera-like syndrome
 May take 5-7 days to resolve completely
 Persistent or increasing fever and neutrophil counts should Enterohemorrhagic (EHEC) / Shiga toxin-producing E. coli (STEC)
prompt evaluation for intrarenal or perinephric abscess and/or
obstruction  More common in developed countries where the consumption of
 Prostatic infection is a potential complication of UTI in men processed food is more common
 Symptom may suggest progression to pyelonephritis  Several large outbreaks resulting from the consumption of fresh
produce (lettuce, spinach, sprouts) and of undercooked ground beef
E. coli Associated Diarrheal Disease  O157:H7 strains are the fourth most commonly reported cause of
bacterial diarrhea in the US

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  Less than 102 CFU can cause disease  Diarrhea of more than 10 days: Giardia or Cryptosporidium
 Incubation period: 3-4 days  O157 STEC/EHEC: identified via culture
o Self-limited (5-10 days) o Screening for E. coli strains not fermenting sorbitol
 Mode of transmission:
o Environmental contamination
o Person to person transmission Treatment
 Produces verotoxin (Shiga toxin), associated with hemorrhagic colitis
with hemolytic uremic syndrome  Appropriate fluid and electrolyte replacement: mainstay treatment
o Stx gene: present on chromosomally integrated prophages for all diarrheal syndromes
o Uncommon but feared complication is HUS, which occurs 2-14  Self-limited use of prophylactic antibiotic should be discouraged
 Stool free of mucus and blood
days after diarrhea in 2-8% of cases
o Early patient initiation of treatment of traveler’s diarrhea with
o This complication is mediated by the systemic translocation of
fluoroquinolone or azithromycin to decrease duration of illness
Shiga toxins
 Colonic edema and an initial non-bloody secretory diarrhea may
SOURCES
develop into the STEC/EHEC hallmark syndrome of grossly bloody
diarrhea
o Grossly bloody diarrhea: 90% of cases  Upclass trans
o Absence of fever  Doc’s ppt
o Significant abdominal pain: 70% of cases  Recordings
o Fecal leukocytes: 70% of cases  Harrison’s
 HUS: 2 to 14 days after diarrhea
APPENDIX
o Most often in very young or elderly patients (STEC/EHEC)
o Non-elderly adults especially young women (ST-EAEC)
o Mediated by systemic translocation of Shiga toxin

Enteroaggregative (EAEC) and Diffusely Adherent E. coli (DAEC)

 Acute and chronic diarrhea in children (>14 days)

 Can cause traveler’s diarrhea
 Associated with prolonged watery diarrhea
 DAEC: diarrheal disease in children 2-6 years old
 Large inoculum is required for infection
 In vitro, the organisms exhibit a diffuse or “stacked-brick” pattern
of adherence to small intestine epithelial cells
 Pathogenesis begins with intestinal adherence
o Stimulation of epithelial mucus production and bacterial biofilm
formation
o Inflammation from epithelial cell exfoliation

Enteroinvasive E. coli (EIEC)

 Children and travelers

 Uncommon cause of diarrhea
 Produces diseases similar to shigellosis
 Unlike shigella, it produces disease only at a large inoculum
o 108-1010 CFU
 Incubation period: 1-3 days
 Symptoms are usually self-limited (7-10 days)
o Colonization and invasion of the colonic mucosa -> replication
therein and cell-to-cell spread -> development of inflammatory
colitis
 Fever
 Abdominal pain
 Tenesmus
 Scant stool containing mucus, blood, and inflammatory cells

 Can cause sepsis and meningitis

Diagnosis

 Differentiation between inflammatory and non-inflammatory diarrhea

o Non-inflammatory: most commonly viral
o Inflammatory: usually bacterial
 ETEC, EPEC, EAEC and DAEC are uncommon cause of non-
inflammatory diarrhea
 ETEC causes majority of causes of non-inflammatory traveler’s diarrhea

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 Recommended Immunization Schedule (Adult)
Vaccine 19-21 22-26 years 27-49 50-64 ≥65
years years years years
Influenza 1 dose annually
Tdap/Td 1 dose Tdap, then Td booster every 10 yrs
MMR 1 or 2 doses depending on indication (if
born in 1957 or later)
VAR 2 doses
RZV 2 doses
ZVL 1 dose
HPV- 2 or 3 doses depending
Female on age at series
initiation
HPV- 2 or 3 Depending
Male doses on age at
series
initiation
PCV13 1 dose
PPSV23 1 or 2 doses depending on indication 1 dose
HepA 2 or 3 doses depending on vaccine
HepB 3 doses
Men 1 or 2 doses depending on indication, then booster every 5
ACWY yrs if risk remains
MenB 2 or 3 doses depending on vaccine
Hib 1 or 3 doses depending on indication

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