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Pathology: ID & Micro

Pathology of Bacterial Infections ............................................................................................................................................ 2


Streptococci (I & II) ................................................................................................................................................................. 5
Enterococci.............................................................................................................................................................................. 9
Listeria & Other Gram-Positive Rods .................................................................................................................................... 10
Introduction to Gram-negative Bacilli................................................................................................................................... 14
Fastidious Gram Negative Rods ............................................................................................................................................ 17
Non-fermentative Gram Negative Bacteria .......................................................................................................................... 20
Neisseria Species ................................................................................................................................................................... 23
Anaerobic Gram Positive Bacteria ........................................................................................................................................ 25
Emerging and Re-emerging Bacterial Zoonoses ................................................................................................................... 28
Pathology of Mycobacteria Infection.................................................................................................................................... 31
Vector-Borne Zoonoses ........................................................................................................................................................ 34

1
Pathology of Bacterial Infections
Final outcome determined by host & bacterial pathogen: can direct Tx towards both
Examples: think about what bacteria has to overcome to get in!
 Respiratory entry: eyes (blinking, tears, lysozyme, secreted IgA, lactoferrin sequesters iron); nasopharynx
(microflora, secretions); lungs (resident macrophages)
 GI tract entry: mouth (sloughing cells, flow of saliva, lysozyme, sIgA, microflora, lactoferrin); stomach (low pH,
proteolytic enzymes), small intestine (fast flow, mucous, sloughing cells); colon (slow flow, sloughing cells,
mucus, lots of resident microflora)

Pathologic & histopathologic correlates of bacterial infection


Acute inflammation:
 PMNs (purulent): marginate & extravasate, eventually followed by mononuclear cells (48h: Mφ & plasma cells)
 Can have necrosis (suppuration)

Chronic inflammation:
 Key: Lymphocytes & Macrophages (= histiocytes)
1. Granulomas: aggregates of lymphocytes & histiocytes; often with fibroblasts & giant cells
2. Granulomatas: poorly aggregated infiltrates of lymphocytes / histiocytes
3. Chronic nonspecific inflammation: mostly infiltrates of lymphocytes, fewer histiocytes

Major types of histopathologic inflammatory responses to bacterial pathogen infections

1. Exudative +/- necrosis


o Usually localized
o Vascular permeability ↑; recruitment of PMN & other WBC ↑
o Non-necrotizing: examples
 S. pyogenes
 Pharyngitis (“strep throat”): pus on tonsils; swollen (edema) – lots of PMNs
 S. pneumonia
 Pneumonia: lobar, generally resolves well (not necrosis, just fill up alveoli with exudate
& PMNs. Turn firm because filled up = consolidation)
 Meningitis: meninges / septae too wide (inflammatory cells); inflammation can cause
bystander damage (neurological sequelae). Gross pathology: meninges cloudy (filled
with leukocytes)
o Necrotizing
 Exudative with necrosis = suppuration
 Host damage: can be from bacterial virulence factors
 P. aeruginosa
o Pneumonia: consolidation with infiltrate; makes lots of toxins (cell damage &
death); lots of hemorrhage and necrosis
 Clostridium perfringens
 Myonecrosis (gas gangrene): big gas bubbles produced; inflammation & necrosis

2. Chronic inflammation +/- granulomas


o Granulomas & granulomatous inflammation
 activated epitheliod Mφ, lymphocytes, etc.
 Response to bacteria that withstand PMN phagocytosis
o Granulomas:
 M. tuberculosis: granulomas (nodular) with giant cells; caseous necrosis in center
 Little red bacilli with acid fast stain within or outside cells
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o Granulomatous inflammation (more diffuse; same cells but less organized)
 M. leprae: foamy Mφ; more diffuse organization; acid-fast rods inside cells
o Interstitial Inflammation
 Nonspecific morphology (chronic, nonspecific inflammation)
 Virus, Mycoplasma, Rickettsia, spirochete infections (if in infectious clinical setting)
 Mycoplasma pneumonia: Interstitial pneumonitis
 Thickening of alveolar spaces, lots of cells & fluid in interstitium (hurts O2 exchange)

o When do granulomas form and when does general chronic inflammation happen?
 Cytokines IL-1B, IFN-γ, CXCL, CCL  granuloma forms
 Different cytokines IL-4, IL-10  chronic inflammation
 Each type of cytokine suppresses the other response

3. Cytopathic
o Most typical of viral infections
o Can be seen with intracellular bacterial infections
 Chlaymydia trachomatis – U/G infections
 Cervix red, swollen; purulent mucoid exudates
 Chlamydia grows within vacuoles intracellularly
4. Cytoproliferative inflammation
o Bartonella spp. (henslae) – angioproliferative responses (cause blood vessels to overgrow)
 Esp. in HIV patients, causes dermis to be replaced by vascular structures
 From cats (also causes cat scratch fever)
5. “Null reaction”
o Absence of inflammatory, necrotizing, or cytopathic responses
o Rare in bacterial infections
o Can occur with neutropenia, immune compromise (HIV, cancer chemo, genetic defects) or by rapid,
unrestricted bacterial growth
o Vibrio vulinficus with neutropenia: tons of Gram (-) bacteria but just a few inflammatory cells
o Bacillus anthracis (anthrax): skin, meninges, inhalational. Bacteria grows faster than immune response
is mounted (also suppress immune response)

Extracellular vs Intracellular bacteria: differences in response


Extracellular:
 Acute inflammation (PMNs) +/- necrosis (depends on virulence factors)
1. Acute inflammation with edema
2. Necrosis  pus formation (suppuration) or abscess formation
 Eventually gives way to mixed acute & chronic inflammation
 Examples: S. pneumonia, S. aureus, P. aeruginosa, most other bacteria

Intracellular: both facultative & obligate


 Chronic nonspecific or granulomatous inflammation
1. Granulomas (e.g. M. tuberculosis)
2. Chronic nonspecific or lymphohistiocitic inflammation (e.g. mycoplasma, rickettsiae, chlamydiae,
spirochetes)
 Initially chronic inflammation +/- acute inflammation (chronic or mixed)
 Can cause necrosis
1. Caseous (e.g. granulomas)
2. Microabscesses (granulomatous inflammation)
3. Host-cell-specific necrosis or apoptosis
 Examples: M. tuberculosis, R. rickettsii (Rocky Mountain Spotted Fever), C. trachomatis (U/G infections)

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Effects of alterations in host defense, inflammation, immunity

1. Physiologic defects
 Cystic fibrosis (no appropriate mucous production = ↑ lung infiltrates)
 Achlorhydria (can’t generate acid in stomach = ↑ lower GI infections)
2. Host can’t make inflammatory cells: no inflammatory infiltrates (congenital neutropenia, etc.)
3. Host inflammatory cells can’t accumulate: no inflammatory infiltrates
 Leukocyte adhesion molecule deficiency (don’t see WBC at site of infection)
4. Host immune suppressed (HIV, Rxs): modified inflammatory response
 Chronic granulomatous disease (↓ superoxide radicals in phagocytes: see bacteria ingested but not
destroyed)
 Complement deficiency, asplenia = ↑ susceptibility to encapsulated bacteria (need C’ to opsonize)
 Hypogammaglobulinemia = ↓ opsonization
 HIV, cancer therapy, corticosteroid, immune suppressive therapy = ↓ T-cell responses
 Interferon-γ receptor deficiencies = recurrent Mycobacteria and Salmonella infections

Hosts that lack inflammatory response = not well protected against effects of infection

Laboratory tests to identify bacterial infections

I. During active infection: Finding Organism


1. Nonspecific morphological PMNs in gastric mucosa H. pylori
identification (Gram stains, tissue Abscesses with “sulfur granules” Actinomyces spp
sections) Caseating granulomas M. tuberculosis
o Initial inflammatory response Lymphocytic vasculitis R. rickettsii
usually stereotypical and (Rocky Mountain Spotted Fever)
nonspecific
o Can use inflammation type, special stains, anatomic location, other clues
 H. pylori: seagull-shaped; on surface of mucosal epithelium; can use silver stain. PMNs in pits of
gastric epithelium
 Actinomycosis: huge GPR collecting in abscesses with fibrous appearance; sulfur granules
 M. tuberculosis: acid-fast stain, or can use fluorochrome
 R. rickettsii: petichae, lymphocytic vasculitis (lots of lymphocytes around / in vessels & walls; R.
rickettsii in endothelial cells
2. Culture
3. Direct detection in clinical samples (fluorescent Ab, in situ hybridization, PCR)

II. Examining host immune response


 Serological (Ab detection): antibody present, seroconversion – looking at humoral immunity
o Ab titer increase: usually want to look @ onset of illness & follow titer level. Compare acute phase (low
titer) to chronic phase (higher titer) to confirm Dx.
o Fluorescence tests for Abs too (indirect)
o Agglutination (mix serum with antigen & look for agglutination)
o Western blots (HIV, Lyme disease)
 Cellular immunity tests (e.g. PPD)
 Lymphocyte proliferation test
 IFNγ production test

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Streptococci (I & II)
General Features of Streptococci:
Structure Streptococci: Major Pathogens
 Gram (+) cocci (GPC) in very nice Str. pyogenes Group A Most frequent cause of bacterial
chains and pairs (division in 1 plane). infection globally
Remain attached via thin cell wall Str. agalactiae Group B Peri-natal & opportunistic
bridges Str. pneumoniae Primary cause of pneumonia &
 Non-motile, non-spore bearing meningitis globally
 Gram (+) cell wall +/- capsule (major Viridans group Relative wimps
pathogens do have capsule)
Physiology Organism Normal flora in…
 Fastidious: enriched media, narrow pH/temp ranges Viridans #1 aerobic colonizer of upper
 Aerobic & facultative anaerobes resp tract (#2 aerobic on skin)
 Fermentative metabolism (glucose  lactic acid, not Group A Small #s of individuals
Krebs cycle) Group B Normal below the belt
 Catalase NEGATIVE Str. pneumoniae Depends on country & season
o No cytochrome oxidative system (Gram
negatives, S. aureus, etc. do have)
Classification
 Hemolytic reaction
Hemolysis Examples Blood agar
Beta (produce H2O2, lyse RBC) Groups A & B (also C,D,F,G) Clear
Alpha (degrade Hb to met-Hb) Viridans group Green
Str. pneumoniae
Non-hemolytic (“gamma”) Red
 Immunologic
o Grouping: based on C-polysaccharide antigen on cell wall
o Typing (for Group A): based on M-protein
 Genetic: 45+ strains known

Str. pyogenes
Group A strep virulence factors: Cytolysis and spreading factors

Cell-associated:
 Hyaluronic acid capsule (unusual – most just complex
polysaccharide) – INHIBITS PHAGOCYTOSIS
 M-protein (typing)
1. Inhibits C’ fixation
2. Major adherence factor: binds with LTA so cells can adhere
to pharynx, skin & not be washed away
 Protein F: binds to fibronectin, adherence factor
 Lipoteichoic acid (LTA): binds with M-protein; adherence factor
 Cell-bound peptidase: inhibits C’
 Peptidoglycan layer
 Has fimbrae (M-protein + LTA) to help adhere

Extracellular:
 Hemolysins O (oxygen labile) and S (oxygen stable)
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o Large zone of beta-hemolysis; most strains have both but if they’ve only got one, it’s O
o O: very antigenic (make Ab)
 Endonucleases: digest nucleic acids, nuclei of leukocytes.
o Fewer WBC around than Staph infections, etc. because of endonucleases
 Streptokinase: liquefies material around cells; dissolves clots
 Pyrogenic exotoxins (A, B, C)
 Toxic shock toxin (like S. aureus toxin)
 Many others (so organism can diffuse throughout body)

Clinical features: Local manifestations: edema, heat, erythema, pain, spreads with extreme rapidity, few PMN-rich
abscesses, systemic manifestations too

Toxigenic strains: toxic shock, scarlet fever

Disease presentations:
 Pharyngitis (also other URI: otitis, sinusitis). Pus; grayish-white discharge; edematous tonsils. Complications:
clotting / obstruction / jugular vv infections. Common in children, closed populations (college, military). 3-5
days: transmissibility decreases
 Skin / soft tissue: erythema, edema, pain
o Impetigo: frequently staph/strep mix; painful, swelling, little clear fluid-filled vesicles if strep only.
Different M-protein types than pharyngitis types
o Celulitis: superficial skin infection. rapid spread, advances up lympathics (reddish streaks). Huge
vesicles with clear fluid later
o Necrotizing fasciitis / myositis (killing skin / muscle cells). Abx don’t reverse damage – need surgical
intervention. Path: dead mm cells, no PMNs
 Puerperal (post-delivery) sepsis – more historically no.
 Scarlet fever
o Str. pyogenes strain producing pyrogenic toxin (plasmid-mediated). Usually pharyngitis-associated
o Scarlatiniform sandpaper rash (upper chest to trunk, extremities); strawberry tongue
o Desquamation follows
 Toxic shock syndrome: strep TSS parallels S. aureus’
 Post-streptococcal diseases (immunologic cross-reactions between strep antigens & heart or kidney)
o Rheumatic fever (9-10d post-infection)
 Any M-protein type; reinfection has same latency
 Heart (myocarditis, valves); joints (arthraligias, arthritis), skin (erythema marginatum), CNS
(Sydenham’s chorea)
o Glomerulonephritis (few days post-infection)
 Specific M-types implicated
 Proliferative disorder of renal glomerulus
 Edema, hypertension, hematuria, proteinuria
 Can have no sequellae or progress to end-stage renal disease

More likely to transmit if high amount, in nose/throat; less likely if you’ve been a carrier for a while.

Str. agalactiae
Regular polysaccharide capsule (inhibits phagocytosis & C’)
 9 serotypes (M-proteins) with different capsule composition
CAMP factor (hemolysin)
Small zone of B-hemolysis
Found in normal GI flora; vaginal tract of 5-30% sexually active women

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Can be primary or co-pathogen in immunocompromised

Clinical presentation: causes neonatal sepsis and meningitis (early & late forms)
 Associated with prolonged rupture of membranes in colonized mother
 Early onset: 1st 6 days. Septicemia (60%), also pneumonia (30%), meningitis (10%). 10% mortality
 Late onset: 7d-3mo. Majority due to type III; may be fulminant with septic shock & severe meningitis
 Neurologic sequellae: 25-50% children
Prevention:
 Maternal screening
 Prophylactic antibiotics (if colonized mother or any mother with prolonged membrane rupture)
Str. viridians Group
General characteristics:
 Alpha-hemolytic (green pigment)
 Relatively non-virulent
 Normal flora of respiratory tract, vaginal tract, skin, other

Pathogenicity
 Endocarditis: relatively indolent, really needs damaged setting (e.g. IV drugs, then lands on already damaged
heart valve)
 Abcesses(most common cause of liver abscesses. Complications: rupture  hemorrhage, high mortality rate.)
o Str. anginosis, Str. intermedius, Str. constillatus
 Dental caries: Str. mutans (part of gingival flora, clings to enamel)
o To get caries: need right microflora, diet, and host/teeth situation.
o Str. viridians is most common aerobe in oral flora
o Virulence: from high acid production
 Septicimia in immunocompromised patients
 Co-pathogens in mixed flora infections (e.g. Gram + and – together)
 Non-infectious events: chronic gingivitis  atherosclerotic plaques?

Str. pneumonia (“the pneumococcus”)


 Gram positive, in pairs & chains like others (prominent pairs)
 Physiology: fastidious, narrow pH/temp ranges, fermentative Lab diagnosis:
metabolism, catalase negative (like other strep), prefer 5% CO2  GPC in pairs (& chains)
 Alpha hemolytic
Polysaccharide capsule: high MW, complex polysaccharides  inhibited by optochin
 Types defined by capsule antigens  Bile soluble
 Different types have different virulence, C’ and cytokine reactivity,  Quellung reaction (add anti-
Abx resistance, and preferred sites of pathogenicity pneumococcal Ab, see swelling)
 Lots of cross-reactions (other microbial capsules, blood group
antigens, other foreign polysaccharides)
o Can get antibodies very early in life via cross-reactivity
o Capsule very antigenic; repeat infection with same type is rare

Genetic features
 Transfer of DNA via transformation, phages, conjugation
o Transformation ability varies with capsule type, inflammation (cytokine activation), other types of
stress, antibiotics, starvation, chemical exposure. E.g. Abx can induce ability to acquire resistance!

Virulence factors: major one is the capsule (blocks phagocytosis if specific antibody not present).
 Need capsule for virulence (capsule + rest of pneumococcus too)

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 Cell-surface-associated:
o pili (adherence)
o cell wall polysaccharides (induce inflammation, activate C’)
o surface protein A: inhibits activation of C’,
o autolysin (how pneumococci commit suicide when they don’t like where they are)
 Cytoplasmic (release of these as cells lyse are primary cause of death within 48 hours despite abx):
o Autolysin: releases pnemolysin & cell wall products
o Pneumolysin: cytotoxin, activates C’/cytokines
o Neurominidase: exposes host cell receptor sites
o Peptide permeases: enhance adhesion
o Others (hemolysin, hydrogen peroxide, etc.)

Pathogenicity:#1 cause worldwide of pneumonia, meningitis, otitis, sinusitis

 Normal flora in 20-100% individuals (colonization: normally host makes protective Ab preventing blood-based
spread, from this normal exposure)
o Direct infections (otitis, sinusitis) can still occur
 Facultative pathogen; produces intense inflammatory response without necrosis
 Major cause of death at age extremes

Pneumonia
 Occurs with newly acquired type that patient doesn’t have Ab to
 Typical case: respiratory viral infection, fever recurs 4-7d post viral infection, pneumonia sets in
o Virus damages ability to clear tracheobronchitic tree, destroys ciliary epithelial cells, produces excess
mucus & fluid, blocking normal clearance
 Often begins with aspiration of oropharyngeal contents (alcoholism, neurologic impairment, etc.)
 Purulent nasal discharge, lobar pneumonia, intact alveolar structure, inside of alveoli jammed with
inflammatory cells. Radiology: alveolar infiltrate
 Little residual morbidity – can resolve well (not destroying alveoli)

Meningitis: Meninges jammed with PMNs, not in brain tissue


 3x mortality of N. meningitis; more frequent, more sequelae (CNS, deafness)

Pneumococcal septicemia: especially common in sickle cell children (give PCN prophy until vaccination possible)

Management:
1. Antibiotics (Penicillins, others).
a. Rapidly emerging resistance
i. PBP mutations: “intermediate” resistance, can overcome with ↑ dose sometimes. Increasing
doses doesn’t help for endocarditis or meningitis (just can’t get *drug+ high enough in there)
ii. B-lactamase development
b. Less active: cephalosporins (used to be 2nd line, now resistance emerging too)
c. Varies with location
2. Prevention (vaccines)
a. 23-component vaccines (23 different types / polysaccharides)
b. Different kinds: peds vs adults
c. Vaccine works less well in older patients (although mandated to offer to all pts > 55yo on discharge
from hospital & document reasons for refusal)

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Enterococci
General features:
 Look like strep (GPC in chains); metabolism like strep (facultative anaerobes, fermentative metabolism)
 Catalase negative (but can make a little bit if they receive DNA from other spp)
 Not fastidious (permissive pH range, no enriched media required, etc.).
o Survive heating, dessication, resistant to disinfectant products (good at health care spread)
o Not damaged by gastric pH
 Part of normal gut flora (E. faecalis & E. faecium are most prevelant)
 Mostly non-hemolytic (some spp alpha-hemolytic; very rare strains beta-hemolytic)
 Grow as small grayish colonies on blood agar

Structure: normal gram+ cell wall, no flagellae, +/- capsule

Infectivity:
 Commensals (below diaphragm – colonic flora, vaginal flora, external genitalia)
 Facultative pathogens

Virulence factors (importance unknown): adherence factors, cytolysins, permeability factor, gelatinase, aggregation
factor (clumping), superoxide production
 LTA: can exhibit endotoxin-like features of septic toxicity (incl. hypotensive shock) in large amounts
 Biofilm formation (especially hearty)

Diseases:
 E. faecalis (60-70%) & E. faecium (10-20%)
 Most commonly: mixed infections (e.g. abscesses below the diaphragm)
o Intra-abdominal abscesses, colonic diverticulitis, urinary tract, gall bladder
 Enterococcal endocarditis
o Classic presentation: elderly male with obstructive uropathy
o Unlike S. aureus, symptoms commonly indolent; low grade fever often ignored
o (especially big abx diffusion problem)
 Septicemia (predominantly in debilitated / immunocompromised; mortality 42-68%)

Resistance:
 VRE: vancomycin-resistant enterococci (esp. E. faecium). Hospitals, nursing homes (where abx are used
commonly); hand-spread; 50%+ mortality
o Some strains have developed resistance to all new alternatives – no effective antimicrobial choices
 Can transmit resistance genes to S. aureus: MAJOR CONCERN

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Listeria & Other Gram-Positive Rods

Listeria Monocytogenes
Characteristics:
 Short, gram-positive rods, can live intracellularly
 Survives & grows at low temp (fridge), low pH (stomach acid), high [salt]: overcomes food prep barriers
Colonizes: animals, humans, soil, vegetative matter
 Food-borne illness (listeriosis): contaminated meat, dairy, fruits, vegetables (rinse!)

Pathogenesis:
 GI tract  blood  meninges
 Invades, survives in variety of cell types

 Intestine: provokes active endocytosis (“internalins”) to cross mucosal barrier; survives intracellularly
o Escapes death in lysozome: formes pores to get out of phagolysosomes
o Replicates in cytoplasm (molecular mimicry: proteins look like host proteins)
o Promotes actin polymerization, makes “comet’s tail” that pushes organism out into adjacent cell
o Covered by host cell membrane (more molecular mimicry) in
next cell Lab diagnosis of Listeria:
 Spread hematogenously  Culture: grows well (30-37 °C best)
 Virulence factors: many; survival & invasion. Internalin helps  Blood agar:
internalize, listeriolysin O (LLO) helps organism escape from o small white colonies
phagocytic vacuoles (inserts pore), Act A induces actin polymerization o beta-hemolytic
 Catalase positive
Epidemiology: major cause of bacteremia & meningitis
 Characteristic tumbling motility
 Immunocompromised (especially cell-mediated immunity) and
elderly patients
 Colonized mothers (can be asymptomatic)  can pass to fetus
 High mortality (500-600 deaths; 2500 cases in US/yr)

Clinical presentation:
 Febrile gastroenteritis (6-48h incubation) in healthy persons. Self-limited. Many asymptomatic.
o Fever/chills, abdominal pain, diarrhea, nausea/vomiting, myalgias
 Bactermia: (pregnancy or immunocompromise)
o “bactermia without an obvious source”
o Fever/arthalgias, headache, GI symptoms, backache: or asymptomatic.
 Meningitis: 2nd most common cause of bactermia in adults > 50 yo; 5th overall
o Usual presentation of meningitis (stiff neck, headache) but:
 CSF glucose not low
 Mononuclear cells can predominate (intracellular; others = PMNs)
 Pregnancy: somewhat immunocompromised (predisposition)
o Can be infected in last ½ 2nd trimester & 3rd trimester
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o Listeria can proliferate in placenta (infect child in utero)
o Stillborn / neonatal death: up to 20%
 Neonatal infection
o Disseminated form of disease: granulomatosis infantisepticum
o Late onset up to 2 wks post-partum; meningitis
o Hepatomegaly

Treatment: Ampicillin; TMP+SMX for PCN allergic (but watch out for kernicterus!?)
Bacillius spp.
General Characteristics:
 Aerobic, Gram positive rod
 Spore forming; ubiquitous
 Major pathogens: B. anthracis (anthrax), B. cereus (bacteremia, wound / eye infections, food poisoning)

Bacillus anthracis
Acquisition: Soilherbivoreshumans acquire via inoculation with spores:
 Inhalation*, ingestion*, or trauma (*=more lethal)
 Mostly in agrarian societies
 Category A biological terrorism agent (easy dissemination, high mortality, social disruption)

Pathogenesis
 Spores  skin, GI tract, lung  germinate in Mφ to regional lymph nodes  local production of
toxinsedema, necrosis  bacteremia, toxemia
 Virulence factors:
o Capsule: inhibit phagocytosis
o Protective antigen: binds to cell membranes (better binding/transport of edema factor & lethal factor)
o Edema factor:
 ↑ cellular cAMP; ↑membrane permeability (↑edema)
 ↓PMN function, ↓cytokine pathways (↑ proliferation, bacteremia, systemic infection)
o Lethal factor: Zn-dependent protease. Cleaves MAP kinases, oxygen radicals released
 Leads to Mφ lysis and cell death
Pruritic: itchy
Eschar: scab
Clinical presentations: Papule: circumscribed, solid elevation
 Cutaneous anthrax: of skin with no visible fluid, varying in
o Pruritic papule  enlarges (round ulcer)  painless, black size from a pinhead to 1 cm
eschar (dries, falls off); regional lymphadenitis FYI: Anthracis = “coal” (black eschar)

 Inhalational anthrax: mortality close to 100%


o 1-6d incubation; initial Sx flu-like (non-specific:
Anthrax Dx:
malaise, fever, non-productive cough, chest
 Hx of exposure; appropriate presentation
discomfort)
 Gram stain
o Rapid progression: dyspnea, cyanosis, shock
o Large, gram(+) rods in chains
o Hemorrhagic mediastinitis
 Culture:
o Meningitis can occur
o Blood, CSF, pleural fluid
o Radiography: mediastinal enlargement (hilar,
o 6-24h growth on 5% sheep’s blood
mediastinal lymphadenopathy  hemorrhage)
o Medium gray irregular colonies, swirling
o Pathology: tons / sheets of purple anthrax bacilli, tons
projections
of hemorrhage
o Non-hemolytic & non-motile
o PCN susceptible
 Gastrointestinal anthrax: 25-60% mortality

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o Ingestion of vegetative bacteria (not spores) from poorly cooked, contaminated meat  ulcers in all
areas of GI tract  regional lymphadenopathy  nausea, vomiting, bloody diarrhea, sepsis
(excruciating pain)
o Pathology: intense submucosal hemorrhage

Treatment:
 EARLY administration of antibiotics is crucial
 Penicillin, doxycycline, ciprofloxacin
 Vaccine: military use only unless exposed to spores (lots of side effects; anthrax is rare)

Bacillus cereus
Soil organism; broad range of clinical syndromes
B. cereus Dx:
 Gram’s stain: GPR in chains
Clinical presentations:
 Culture
 Food-borne illness (especially rice that was left sitting out)
o Grows well on 5% sheep’s blood
o Diarrheal type: heat-labile enterotoxin; 8-16h post exposure
o Large, feathery, spreading colonies
o Emetic type: heat-stable enterotoxin; 1-5h post-exposure
o Beta-hemolytic (not anthrax)
 Ocular disease (penetrating trauma: bacteria in soil; almost always
o Organisms are motile, lecthinase
lose eye) & Wound infections (healthy persons): extensive damage,
(+) (not anthrax)
liquefactive necrosis
 Bacteremia, endocarditis, abscesses in immunocompromised pts & IV drug users

Treatment:
 Food poisoning: usually self-limited
 Produces broad-spectrum β-lactamase: resistant to PCNs & cephalosporins
 Vancomycin, clindamycin are active

Cornyebacterium diptheriae
General characteristics of Cornyebacterium spp.
 Aerobic bacteria, non-spore forming, Gram-positive bacilli
 Curved or club-shaped (corney = club)
 Catalase positive
 Normal flora of skin, mucous membranes of mammals; hard to distinguish colonization/contamination/infection
 Need to ID to species level when isolated from normally sterile sites, urine (if lots), clinical material

Cornyebacterium diptheriae: most important pathogen


 Humans = only known reservoir; Asx carriers = important for epidemics
 Spread: airborne respiratory droplets, direct contact with resp. secretions or exudates from skin lesions,
contaminated milk
 Most cases: colder months
 N. America: mostly disadvantaged groups (skin infections)
 Vaccine-preventable

Pathogenesis
 Non-invasive
 Exotoxin: major virulence factor
o 2-segment polypeptide
 B-segment (binding): bind to receptors on susceptible cells
 A-segment (active): inhibits protein synthesis in mammalian cells

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o Can affect all cells in body (heart, nerves, kidney most common)
o Also contributes to pseudomembrane production

Clinical presentation:
 Respiratory tract disease: 2-4d incubation period; can have local inflammation at various sites
o Pharyngeal (most common)
1. Abrupt onset (fever, malaise, sore throat)
2. Pseudomembrane forms & spreads
 one or both tonsils  oropharynx, nasopharynx, soft palate
 white then dirty gray with black necrosis
 Can compromise & distort lower airway: “bull’s neck”
o Systemic complications from toxin: myocarditis, neurotoxicity (cranial neuropathies)
 Cutaneous:
o Non-healing ulcers, dirty gray membranes, C. diptheriae Dx:
superinfected with other bacteria  Presumptive dx: clinical
o Outbreaks among alcoholic homeless, impoverished
 Definitive dx: isolate, ID organism
(no boosters, poor sanitation)
 Notify state lab (reportable) & send
o Rarely associated with toxigenic illness
material
 Others: can have invasive disease (e.g. endocarditis) with
 Lab dx: sheep’s blood & selective medium
non-toxigenic C. diptheriae

Treatment & prevention


 Strict isolation
 Antibiotics: PCN or erythromycin for 14 days
 Supportive care
 Vaccine: part of childhood DTaP series (4 doses total); booster at school entry, every 10 years with tetanus

13
Introduction to Gram-negative Bacilli
Gram negative bacilli: rods that stain red by Gram’s stain;
 large, diverse group
 Classification: growth requirements, phenotypic or genotypic characteristics, disease associations

Major categories of GNRs:


 Enterobacteriaceae – fermenters. Enteric pathogens & non-enteric infections
 Glucose non-fermenting GNRs
 Oxidase positive fermenters (cause diarrhea)
 Fastidious GNRs: require specialized media / growth conditions
 Anaerobic GNRs
 GNRs associated with zoonoses

Can use selective material which is inhibitory to Gram (+), e.g. MacConkey agar, to isolate Gram (-)
 Red/pink: acid produced, lowers pH, lactose fermenter
 Clear: non-lactose fermenter; diarrheal pathogens
 No growth: not Gram (-)

Enterobacteriaceae (this lecture)


General characteristics:
 Tons of diversity, found in GI tracts of humans, animals, fish, etc. Some Enterobacteriaceae:
also in environment: soil, water, plants. Certain kinds (Salmonella,  Ferment glucose (often with
Shigella, Yersinia) shouldn’t be in humans ever. gas production)
 Facultative anaerobes (rapid growth with or without O2)  Reduce nitrates to nitrites
 Grow readily on simple material (12-8h incubation).  Catalase: positive
 Diseases: all major categories except STDs  Cytochrome oxidase: negative
Morphology: large, parallel sides, rounded ends
 Some strains: peritrichous flagella (go around whole circumference)
 Some: encapsulated
 Many: surface pili for adherence
 Do NOT form spores

Antigenic structure (serotyping):


 O (somatic) antigen (= LPS = endotoxin): cell-wall LPS, heat-stable (IgM response)
 K or Vi (capsular) antigens: cell surface polysaccharide (Vi = virulence, for salmonella)
 H antigens: externally located flagellar proteins (IgG response)

Remember the gram (-) cell wall: has porins in OM; antimicrobial resistance: mutate porin so drugs can’t get in

Urinary tract infections


Community-acquired:
Types of UTIs
 80% from uropathogenic E. coli, then Klebsiella and Proteus
 Urethritis (urethra)
 Predisposition: anatomy, density of mucosal receptors, sexual activity
 Cystitis (bladder)
Hospital-acquired  Pyelonephritis (kidney)
 Frequently in patients with indwelling bladder catheters
Usually ascending; can be
 E. coli still main cause; also other resistant Gram (-)s
descending (from kidneys)
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E. coli: Need uropathogenic strains: low pH in urine, lots of antimicrobial compounds in urine
 Specific fimbriae (type 1, good for colon/vagina colonization), pili (P pili:
E. coli: Lab Dx
adherence to urinary tract)
 β-hemolytic on sheep’s blood
 Toxins: endotoxin and α-hemolysin (pore forming cytotoxin; explains
 Lactose fermenter
hemolysis, causes toxicity to uroepithelial cells too)
 Rapid indole positive
 Aerobactin – siderophore (chelates iron)

Proteus spp.
 Associated with UTIs, urolithiasis (stones) Proteus: Lab Dx
 Proteus mirabilis, Proteus vulgaris  Non-lactose fermenter
 Cycle: Proteus produces urease, hydrolyzes urea to CO2 + NH3   Very motile (swarming over
neutralize/alkalinize urine  inorganic compounds fall out of solution & agar plate)
crystallize  stones  become embedded & reinfected

Klebsiella pneumoniae
 UTIs, pneumonia; hospital-acquired infections with multidrug resistance Klebsiella pneumoniae: Lab Dx
 Mucoid capsule (important for virulence)  Non-lactose fermenter
 Get in lungs/urine; huge inflammatory response  Non-motile
 Disgusting mucoid colonies

Gram-Negative Pneumonia
Predisposing factors: Gram (-) pneumonia Pneumonia
NON-HOSPITALIZED HOSPITALIZED 1. Rapid growth
 Underlying cirrhosis (↑ encapsulated infections)  Diminished cough reflex, anesthesia 2. Inflammation (intense,
 Loss of consciousness, alcoholism, drug abuse  Mechanical ventilation PMNs)
 Elderly, immunocompromised  Immunocompromised 3. Inefficient killing of organism
(varies with host)
Klebsiella pneumoniae 4. Obstruction, obliteration of
 Pneumonia: necrotizing, develop cavitation in areas of consolidation lung tissue
o If you survive: chronic lung disease (pulmonary fibrosis) 5. Death (tissue / host)

Aerobic Gram-Negative Rod Meningitis


0-4 wks Grp B strep, E. coli, L. monocytogenes, Salmonella
Aerobic GNR meningitis
4-12 wks Grp B strep, E. coli, H. influenza, S. pneumoniae, N. meningitidis
3mo – 50 yrs S. pneumoniae, N. meningitides (H. influenza in adolescents)  E. coli (75% capsular type K1)
> 50 yrs S. pneumoniae, N. meningitides, L. monocytogenes, aerobic GNR  Klebsiella sp
 Predominantly neonates, elderly, neurosurgery pts  Salmonella sp
 Don’t let your babies play with snakes & iguanas! (salmonella)  Pseudomonas aeruginosa
 Other factors: immunocompromise, head trauma/neurosurgery, CNS
shunt (↑ aerobic GNR meningitis)
Bacterial meningitis: Lab Dx:
Neonatal meningitis: Exposure/colonization (Asx?) during birth + poor immune
LP: response  bactermia  meningitis
Other agents:  ↑: pressure, WBC, PMNs, protein, lactate
 Citrobacter koseri (sporadic cases, utilize citrate);  ↓: glucose
 Enterobacter sp (yellow pigmented, highly virulent, MDR) Gram stain & culture: GNRs & PMNs
Gross path: cloudy, pus in meninges
High mortality with GNR meningitis

15
Intestinal infections
Salmonella (S. enterica = most pathogens; also S. bongori)
 Various virulence factors (Vi = salmonella typhi) Salmonella: Lab Dx
 Exposure: poultry or products (eggs)  Gram (-), non-motile
 Stays in vacuoles inside cells; enters submucosa, basal membrane; goes to  Produces H2S (black colonies)
mesenteric lymphocytes  blood stream  Use selective media to
 Clinical presentations: recover from stool
o Gastroenteritis (S. typhimurium mostly)
 6-24h post-exposure: nausea, vomiting, abd. pain, diarrhea; 50% have fever
o Bacteremia (non-typhoidal): much more frequently found in blood than Shigella
o Typhoid fever (S. typhi, S. paratyphi)
 1-4wk incubation; fever, multi-organ system infection, may or may not have diarrhea
 Multiplication in spleen, liver  gall bladder during infection

Shigella
 Four serotypes: S. sonnei (major in US), S. flexneri, S. boydii, S. dysenteriae (epidemic dysentery, produces
Shiga toxin),
 Presentation: fever, severe, cramping abd. pain, bloody diarrhea Shigella: Lab Dx
 Virulence factors plasmid associated; LPS in all  Gram (-), non-motile
 More severe pain than Salmonella, lower abd. (colon)
 Pathogenesis:
o Through stomach acid & small bowel  terminal ileum/colon
o Engineers own phagocytosis
o Escapes from vacuole! Stays in mucosa(fecal WBC confined to mucosal layer)
o Non-motile; cause invasive infection by spreading cell-cell via actin polymerization.
o Destroys colonic epithelial cells in process (blood, pus in stool); self-limiting 2-5d

E. coli
 EnteroToxigenicEC (traveler’s diarrhea), EnteroInvasiveEC
(uncommon, invasive) EnteroPathogenicEC (infantile, ST E. coli: Lab Dx
childhood diarrhea), EnteroAggregativeEC (traveler’s  Gram (-)
diarrhea): from previous lecture  Hand-deliver quickly!
 Direct detection of SLT in STEC pts’ stool
 Shiga-toxin-producing E. coli: STEC  Culture: grows well on standard lab material;
o Hemorrhagic Colitis selective material can be usd
o Hemolytic-Uremic Syndrome (thrombocytopenia,  PMNs + GNRs: think this family!
renal failure, hemolytic uremia) – associated with production of Stx-2 (Stx-1 only: EPEC)

Yersinia can cause diarrhea too


Antibiotics & GNRs

 Order susceptibility testing on organisms from


clinical material (disk diffusion / microbroth
dilution)
o Look for MIC
 MDR control: hand hygiene, contact
precautions, antimicrobial stewardship
 Klebsiella can be especially bad (resistant to
almost everything!)

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Fastidious Gram Negative Rods
Haemophilus sp
Characteristics: normal resp flora of humans & animals
 Pleomorphic, GNRs
 Invasive strains = encapsulated
 Requires special growth factors in vitro: X factor, V factor. Optimal growth on chocolate agar

Lots of different kinds. No capsule = not invasive (H. influenza non-typeable for instance)
 H. influenzae type b (a-f are other types).
o Type b causes epiglottitis, sinusitis, meningitis, pneumonia, septic arthritis, etc.
 H. influenzae non-typeable (unencapsulated): now #1 cause pediatric acute otitis media; sinusitis too
o Replaced S. pneumoniae

H. influenzae type B (HiB)


 Fallen 99% post-vaccine area (22 cases 2007, unvaccinated/incompletely vaccinated children)
Haemophilus: Lab Dx
Epidemiology/pathogenesis
 Gram Stain (pleomorphic GNR)
 Nasopharynx of 3-5% healthy people colonized with Hib
 Culture (chocolate agar)
 Pathogenesis: penetrates submucosa of nasopharynx  o Look for X, V factor requirements
bloodstream  CNS  meningitis o Hemolysis?
 Virulence factors: capsular polysaccharide, fimbriae, IgA protease,
OM proteins, ciliostatic glycopeptides (paralyzes cilia to make colonization easier)

Treatment/prevention:
 33% produce plasmid-mediated beta-lactamase (PCN resistant)
 Invasive disease: 3rd gen cephalosporin
 Non-invasive disease: amoxicillin + clavulanate
 HiB Vaccine x 4: 2,4,6,12-15 mo of age

Bordetella pertussis
 Gram (-) coccobacilli (single or pairs; faintly-staining); strict aerobe; needs special media (have to ask for it)

Epidemiology: B. pertussis: Lab Dx


 Can’t survive in environment: requires direct, person-person  Gram Stain (single/pairs, Gram (-)
spread via airborne droplets coccobacillus)
 Adults can be reservoir for infection  Strict aerobe
o (unexplained cough = avoid babies!)  Best specimens: NP aspirates/swabs
 Children < 1yo: most severe disease (immune system not at peak)  *Culture (special media)
 Vaccine preventable! o Can require up to 10d to recover
(way too long for Dx)
Pathogenesis: Non-invasive (secretes toxins)  *Nucleic acid detection: faster &
1. Adheres to non-ciliated resp. epithelium (fimbrae) most sensitive
2. Produces local damage; disrupts host defenses
 Serology = only retrospective
3. Systemic disease
Key virulence factor: pertussis toxin (all stages)
* = recommended by CDC
Clinical presentation: Pertussis syndrome (more atypical presentation in adult)
0. Incubation period (1-3 weeks)
1. Catarrhal stage (1-2 weeks): Most contagious; rhinorrhea, malaise, sneezing, low-grade fever
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2. Paroxysmal stage (2-4 weeks): paroxysmal coughing with inspiratory whoops; post-cough vomiting, air hunger /
apnea / cyanosis, peripheral lymphocytosis (hallmark: tens of thousands!)
a. Basically can’t get air! Whooping = trying to inspire against closed glottis. Really sucks to have.
b. Radiography: Peri-hilar infiltrates, distal airways spared,
3. Complications: secondary bacterial pneumonia (damaged resp. epithelium), pulmonary hemorrhage (exertion
of coughing), encephalopathy (toxin to brain), seizures (hypoxemia), coma/sudden infant death

Treatment / Prevention
 Supportive care (vent, ICU, fluids, etc.)
 Erythromycin: doesn’t alter course but decreases bacterial load (less infective)
 Vaccine:
o used to use whole cell (DTP); high reactogenicity, 50-90% efficacy, wanes in adolescents/adults
o Discontinued in some countries  pertussis outbreaks
o Acellular vaccine now in use: DTaP (diphtheria, tetanus, aceullular pertussis)
 Immunogens of B. pertussis, no endotoxins (less side effects) with equal efficacy
 5 doses (2mo-5yr); one-time booster for adults (Tdap)

Legionella
General characteristics:
 thin, poorly-staining GNRs
 Require L-cysteine for growth; use AA for growth (non-fermenters)
 Biochemically inert (weak oxidase rxn; catalse positive, liquefy gelatin)
 Motility: polar flagella

Epidemiology: tons of species; L. pneumophila is responsible for >90% disease (rest named by where they’re from)
 Ubiquitous, widely distributed in environment (aquatic settings: natural or man-made)
 Wide temperature range (0-63C)
 Parasitize & survive in free-living amoebae!
 Form biofilms in water systems
Transmission: inhalation of droplets; aspiration of water; wound infection (more rare) by contaminated water

Pathogenesis:
1. Adhere to resp epithelium Risk factors for Legionella infections
2. Phagocytosed  Cigarette smoking, chronic lung
3. Intracellular survival / multiplication disease, alcoholism
a. Inhibits acidification of lysosome  Immunosuppresion (corticosteroids,
b. No fusion of lysosome with phagosome malignancies, HIV, transplantations)
c. Lysosome associates with rER (molecular mimicry; lined  Diabetes, end-stage renal dz, CV dz,
with ribosomes); bacteria replicates here advanced age
4. Cell rupture & release
24 kD protein macrophage infectivity potentiator (mip): target of many Legionella: Lab Dx
molecular tests  Culture: need special medium
(request!) to inhibit normal flora (abx,
Clinical presentations: etc). Can take up to 7 days (slow
 Legionella pneumonia: 2-15% cases of CAP growing)
 Legionnaire’s disease: systemic illness with pulmonary and  Legionella urinary antigen: only
extrapulmonary manifestations (rare to have extrapulmonary serotype 1, but that causes most dz
alone)  Nucleic acid amplification (no FDA but
o Radiologically indistinguishable from other some in-house depending on lab)
pneumonias
 Direct fluorescent antibody
 unilateral, lower-lobe alveolar infiltrates; some

18
pleural effusion
 cavities/abscesses can occur if immunocompromised
o Slight, non-productive cough (no PMNs because intracellular)
o GI: watery diarrhea; abd. pain
o CNS: mental confusion, headache
o Bradycardia; hyponatremia, hypophosphatemia, elevated CK, increased transaminases
o Doesn’t respond to beta-lactams
Getting a sample: no special transport, room temp OK, refrigeration if delayed.
 Send sputum, aspirates, BAL fluids, pleural, lung tissue.

Legionella urinary antigen detection


 Detects LPS of cell wall
 Serotype 1 only (80% of dz though)
 Antigen shows up day 1-3 of Sx; can persist for weeks/months

Treatment: 10-14d
 Newer macrolides (azithromycin, clarithromycin); quinolones (levofloxacin)
 Can also use tetracyclines or TMP+SMX

Prevention:
 Routine culture surveillance of hospital water distribution systems
 Treat If pathogenic legionella found (hard to get biofilm out). Chemicals, heating, etc.

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Non-fermentative Gram Negative Bacteria
General features:
 White on MacConkey agar = non-fermenter (pink=fermenter)
 Complex mix (opportunistic pathogens of plants, animals, (most) Non-Fermentive Gram (-)s:
humans)  Aerobic, Non-spore forming, Bacilli
 75% in clinical specimens are one of these four  Cytochrome oxidase positive
1. Psudomonas aeruginosa  Catalase positive
2. Acinetobacter baumanii  Don’t ferment CHOs; may oxidatively
3. Burkholderi cepecia metabolize some sugars
4. Stenotrophomonas maltophilia  Motile, nutritionally versatile
 Opportunistic pathogens: most often hospital-acquired  Grown on MacConkey Aga

Pseudomonas spp

 Ubiquitious (soil, water, decaying organic matter, vegetation)


 Found throughout hospital environment (moist reservoirs, incl. dialysis equipment, mops, toilets, etc.)
 Simple growth requirements: wide temp range; can use lots of nutrients for C&N source
o Can even grow in distilled water and disinfectant solutions!
 Lab classification: fluorescent (make pyoverdin green under UV) & non-fluorescent
o Fluorescent group includes P. aeruginosa and P. fluorescens, most important for clinical
o P. aeruginosa also makes pyocyanin
 Important for invasiveness & characteristic of aeruginosa on plate

Pseudomonas aeruginosa
 Aerobic, straight/slightly curved, non-spore forming, Gram(-) rod
 Motile (1+ polar flagella)
 Grows well on SBA, chocolate, MacConkey; wide temp range; Pseudomonas aeruginosa: definitive Lab Dx
 Catalase positive  Gram (-) rod
 Makes both pyoverdin & pyocyanin  Oxidase positive (rapid oxidase test)
 Grape-like or corn-tortilla odor
Virulence: multifactorial (structural components, toxins, enzymes)  Recognizable colony morphology
 Structural: o SBA/chocolate: large colonies, metallic
sheen, mucoid/rough/pigmented
o LPS (endotoxin), Pili (adhesion; neuraminidase to remove
o MacConkey: lactose negative; green
sialic acid from pili receptor); capsule (adhesion &
pigmentation or metallic sheen
suppression of phagocytosis / immune response);
pyocyanin (tissue damage: hydroxyl radical products; IL-8 stimulus)
 Toxins/enzymes:
o Exotoxin A & S(inhibits protein synthesis); cytotoxin (leukocydin) (cytotoxic for eukaryotic membranes;
microvascular injury); Elastase (disrupts elastin-containing tissues, collagen)

Clinical presentation:
 Bacteremia, pneumonia top 2
 Others: pretty much all sites of body but particularly adapted to respiratory tract
o CF patients; chronic colonizer of pts with chronic lung P. aeruginosa: Predisposing factors
disease
 Chronic debilitating illness (lots of hosp)
o #1-2 cause of Ventilator-Associated Pneumonia (VAP)
 Prior therapy with broad-spectrum abx
 Can produce disease far away from initial site of tropism
 Breach of airway (tracheostomy,
 Intact host defenses: not at much risk (opportunist) endotracheal tube)
 Imparied host immunity (primary disease
Pulmonary infections in CF patients: colonization  tracheobronchitis or iatrogenic)

20
 necrotizing bronchopneumonia
 Tropism for CF epithelial cells; actually switches to a CF phenotype (rough LPS, mucoid, less motility)
o Increased Abx resistance because of prior broad-spectrum abx in CF pts

Skin infections from P. aeruginosa:


 Ecthyma gangrenosum secondary to P. aeruginosa bacteremia (pretty classic for P.aerug)
 Folliculitis (e.g. after hot-tub)
 Burn wounds: P. aeruginosa very important!
o Colonization  local vascular damage / necrosis  bacteremia
o Risk correlates to extent of burned surface
o Commonly <1wk from burn injury

“Community-acquired” P. aeruginosa infections: can happen in outpatient setting


 Corneal ulcers, keratitis (extended wear contact lenses / abrasions / scratches)
 Endopthalmitis (deeper eye infection; after eye trauma or surgery)
 Exposure to moist environment (hot tub, whirlpool, swimming pool)
 Otitis externa : “swimmer’s ear”; malignant external otitis can extend to cartilage & bones (pts with diabetes,
elderly, etc.)
 Puncture wounds (through tennis shoes, etc.)  osteochondritis
 Endocarditis (IV drug users)

Treatment, prevention, control: recognize high level antimicrobial resistance worldwide; carbapenems may be driving
emerging resistance; lots of MDR Pseudomonas.
 Might be able to use old drug (colistin) despite bad side effect profile
 Can’t eliminate from hospital environment: need infection control (safeguard patients)
o Keep equipment sterile; prevent health care worker  pt transfer; responsible ABx use

Acinetobacter spp
 Widely distributed (nature & hospital)
 2nd most common non-fermenter found in humans after P. aeruginosa Acinetobacter spp
 Can survive on moist & dry surfaces; present in food & on skin  Gram(-) coccobacillary rods
 Increased frequency: immunocompromised, debilitated pts  Strictly aerobic
 Grow on MacConkey (colorless)
Acinteobacter baumanii:  Non-motile, non-fermentative
 Most frequently isolated from human specimens  >> Oxidase negative << (key)
 Most often responsible: hospital-acquired infections  Usually nitrate negative

Clinical presentations: Risk factors: Acinetobacter


 Hospital acquired:  Stay in ICU
o Respiratory tract infection  Abx treatment
o UTI, Wound infection, Bacteremia
 Surgery
o Nosocomial pneumonia / VAP
 Mechanical ventilation
o Digestive tract of ICU patients can be reservoir for MDR strains
 Community-acquired:
o CA-Pneumonia with fatal outcome (initially misdiagnosed; wrong Tx)
o Wound infections & osteomyelitis (e.g. battlefield infections)

Tx & prevention: Need Abx susceptibility testing for every clinically significant isolate!
 Intrinsic resistance to cephalosporins; carbapenem resistance ~ 20%; high frequency of MDR
 Ampicillin-sulbactim, ticarillin-clavulanate or imipenem are most effective
 Also: TMP-SMX, quinolones, doxycycline. Can add aminoglycoside if severe infection; colistin possible if MDR
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Stenotrophomonas maltophilia
 Similar profile to Burkholderia cepacia
 Widely distributed: nature & hospital S. maltophilia
 Can colonize resp tract in pts. with prolonged hospitalization (e.g.  Gram(-) rod
immunocompromised)  Motile, non-fermentative
 Virulence factors unknown, opportunistic human pathogen  Grows well on MacConkey
 Oxidase negative
Clinical presentation:
 Nosocomial; high morbidity/mortality
o Bacteremia, pneumonia, UTI, wound infctions
o Increasing incidence: resp tract infections in CF patients
Treatment:
 Intrinsic resistance to almost every antimicrobial commonly used (B-lactams, AGs, others)
 TMP+SMX is primary choice for treatment

Burkholderia cepacia complex


B. cepacia: most commonly isolated Burkholderia sp. in clinical specimens; consists of 9 complex genovars
 Plants, soil, water as reservoir
 NOT part of normal human flora; can colonize resp tract
 Nosocomial: associated with contaminated hosp equipment, medications, and disinfectants
o (even iodine & chloride solutions! Albuterol! Sterile blood culture systems!)
Clinical presentation: opportunistic pathogen, variety of infections
 Bacteremia, UTI, septic arthritis, peritonitis, pneumonia
 Risk factor: chronic granulomatous disease or CF pts

B. cepacia and cystic fibrosis


 Emerged in 1980s; require special infection control practices
 Approx 3% CF pts in US infected with B. cepacia, 6-7% adults
 Most strains inherently resistant (broad spectrum abx)
 May be absolute contraindication for lung transplant
 20% develop cepacia syndrome: bacteremia, fatal outcome

Treatment: resistant to most antimicrobials (B-lactams, AGs, others)


 Susceptible: TMP+SMX, ceftazime, imipenem, meropenem, some fluroquinolones

Burkholderia pseudomalli
 Found in soil, water, vegetation: SE Asia, Northern Australia (watch out for travelers)
 Wrinkled colonies on plate
 Acquisition: inhalation or inoculation (trauma/wounds); Potential bioterrorism agent

Clinical presentation:Causes melioidosis


 Can be acute, subacute, or chronic (chronic can mimic TB)
 Pneumonia = most common clinical presentation (abscess formation, cavitation)
 Protean manifestation (assumes many forms)
o Asx, cutaneous, pulmonary dz
o High propensity for bacteremia
o Diabetes, renal dz, cirrhosis, thalassemia, alcoholism (& immunocompromise) predispose

Treatment: TMP+SMX and broad-spectrum cephalosporin


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Neisseria Species
General characteristics:
 Gram (-) diplococci, inhabit mucous membrane surfaces Features of Neisseria
 Group contains:  Aerobic
o Non-pathogens (upper resp tract dwellers)
 Non-motile, non-spore forming
o Strict pathogens:
 Oxidase, catalse positive
 N. gonorrhoeae (STI: gonorrhea);
 Chocolate agar (best)
 N. meningitidis (epidemic/endemic meningitis)
 Use CHO oxidatively

Neisseria gonorrhoeae
Same characteristics as other Neisseria
Nutritionally: more fastidious
 Requires cysteine for growth; other requirements too

Epidemiology: STI except in newborns


 humans are only host; huge incidence (355,000/yr), mostly in sexually active teens & young adults
 Women (men too) can be asymptomatic and transmit infection
 Risk factors:
o Social: lower SES, urban, lack of education, unmarried, STD history)
o Behavioral: unprotected intercourse, multiple / high risk partners, drug use, MSM

Pathogenesis: adherence  cell entry/transport  evade  stimulate PMN host response (pyogenic)
 Special features of surface structure:
o Oligosaccharide endotoxin (smaller than LPS)
o Pili (attachment), peptidoglycan (toxic to fallopian tubes), membrane proteins (survival & invasion)
 Adheres to non-ciliated cells (e.g. fallopian tubes); adjacent ciliated cells damaged, slough off, more can attach
o Loss of ciliated cells  obstruction, infertility, ectopic pregnancy, etc.

Clinical presentation N. gonorrhoeae: Lab Dx


 Women: Mucopurulent cervicitis is typical, also urethral  Gram stain (better in male urethral samples)
syndrome (distal urethra), pelvic inflammatory disease  Culture-based: sexual abuse, treatment
(ascending disease; scarring, etc.). failures, test of cure
 Neonates: perinatal transmission; Ophthalmia neonatorum o Multiple methods (need 2nd to confirm:
(purulent conjunctivitis); also gonococcal scalp abscesses or important to be right, esp. child abuse)
systemic infections.  Nucleic acid amplification (PCR) – very
 Men: Urethritis, epididymitis, rectal infections (if MSM) sensitive (can’t use for test of cure)
 Common features: purulent exudates, inflammation,
erythema (penis/os). Burning on urination (men)
o Unusual adult manifestations: conjunctivitis, disseminated gonococcal infection (vesicle  purulent papule,
erythema, central necrosis)

Culture: selective media; supplemented with growth factors; 72h, small, glistening, raised.
 Glucose metabolizer(not maltose or sucrose)

Treatment:
 Uncomplicated: Ceftriaxone IM or Cefixime PO
o Treat for CHLAMYDIA TRACHOMATIS (lots of coinfection): AZI PO x1 dose or doxycycline PO bid x 7d)
 Report & contact-trace infected persons
Prevention: sex ed, abstinence, condoms, no vaccine
 use 1% silver nitrate or macrolide antibiotic prophylax for newborns
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Neisseria meningitidis (“meningococcus”)
All age groups, both individual (sporadic) & epidemic
Multiple serotypes: B,C,Y most severe in US
Immunization possible (esp. closed populations)

Epidemiology
 All age groups, both individual (sporadic) & epidemic
 Multiple serotypes: B,C,Y most severe in US
 Asymptomatic nasopharyngeal carriage (8-25%), precedes infection
o Colonization ↑ in closed populations (college, military)  need vaccination
 Terminal C’ deficiency (C5-9): recurrent, severe infections
 Worldwide: Epidemics in some countries (at end of rainy season)
 USA: Vast majority sporadic with localized outbreaks
o Case fatality: 10-14% !!

Pathogenesis
 Virulence factors: Pili, engulfment, transport in host cells; Polysaccharide capsule (↓ phagocytosis, C’); Lipo-
oligosaccharide endotoxin (very toxic!)
 Process: HAPPENS REALLY FAST
1. Pili adhere to non-ciliated resp epithelium invades submucosa
2. Capsule prevents phagocytosis
3. Replicates in submucosa; evades
4. Spreads into bloodstream
5. Endotoxin in blood: cytokine & alternative C’ activation

Clinical presentations: N. meningitidis Lab Dx:


1. Bacteremia without sepsis (rare)  Direct exam of CSF (presumptive, quick)
2. meningitis with neurologic sequelae  Culture: CSF, blood, other
3. meningococcemia (overwhelming sepsis & DIC) o Chocolate agar
a. with adrenal insufficiency: Waterhouse-Frederichsen  Definitive ID: glucose & maltose use
Syndrome

Meningitis  Meningococcemia
 Like other meningitis but faster.
 Sudden onset: Fever, chills, myalgias, arthralgias, headache, confusion, nuchal rigidity
 CSF: 1200 WBC/mL, Glc↓, protein ↑
 Meningococcemia
o Rash: palpable purpura (infection of endothelial cells  DIC, small hemorrhages)
o Can get peripheral gangrene; lose digits
 Adrenal hemorrhage can cause insufficiency (W-F syndrome)

Treatment:
 Meningitis/meningococcemia: Penicillin (alternatives: ceftriaxone, chloramphenicol in other countries)
o Not PCN resistant!
 Prophylaxis (close contacts) – trace! Rifampin, cipro, ceftriaxone
Vaccines:
 Old: polysaccharide tetravalent (poor immunogenicity, not long-lasting, no reduction in NP carriage)
 New: tetravalent conjugate vaccine (Menactra) for 2-55yo (give 11-12 or entry to HS; should have for college)
o Capsular polysaccharide conjugated to diphtheria toxin; induces T-cell dep response (good for infants)
o Reduces Asx carriage
o Indications: asplenia, C’ deficient, traveling to endemic areas, closed pops, prevention, lab workers
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Anaerobic Gram Positive Bacteria
General characteristics:
 Don’t grow in presence of oxygen
Anaerobic infections (Clinical Dx)
 Two groups:
 Foul-smelling discharge
o Obligate anaerobes (strict or moderate)
 Proximity to mucosal surface
o Aerotolerant anaerobes
 Gas in tissues
 Tons of different kinds (many part of normal microflora, protective)
 Negative aerobic cultures
 Classification (pathogenic): shape, gram, spore formation, toxin
production
 Widespread: environment (soil, sewage, foods, etc.)
o animals & humans: oral cavity around teeth, GI tract, skin (some), G/U tract
o habitats with low oxygen tension & reduced oxidation reduction potential

Pathogenesis:
 Disruption of normal mucosal barriers
 Anaerobic infections often mixed (synergy with aerobes, other anaerobes)
 Virulence factors: capsules, adhesions, enzyme production, toxin production (some very potent toxins)

Presentations:
 brain abscess (usually anaerobes or microaerophilic strep)
 bacteremia (need virulence factors to get into bloodstream)
 lots of others (mixed) – e.g. empyema (pus in pleural cavity)

Lab Dx:
 Get a good specimen (not anything where anaerobes would be in normal flora; Exception: C. diff & feces)
o gastric washings, urine, vagina/cervix, feces, upper resp. secretions, etc. are bad
 Swabs are bad specimens, aspirates & tissue biopsies are best (transport immediately)
o Inject into anaerobe transport media
 Semi-solid, 5% CO2, reducing agent  shows anaerobiosis
o Culture in complex media: supplemented; chopped meat glucose; use anaerobe chamber

The following are GRAM POSITIVE ANAEROBES


Peptostreptococcus
 Anaerobic, Gram (+) cocci; variable shape & size
 Found on skin, mucous membranes
 Importance: Causes bacteremia & mixed infections

Propionibacterium spp
(Major metabolic product = propionic acid)
 Anaerobic, Gram (+) rods, highly pleomorphic (curved, clubbed, pointed ends)
 Normal flora of skin, mucous membranes; major contaminant of blood cultures
 Non-spore forming
 Importance: acne, also opportunist with medical devices(shunts, caths, prosthetic valves)

Actinomyces
Anaerobic, Gram (+) rods, pleomorphic (short/club shaped, long/thin/beaded rods, branching)
Slow-growing – makes a “ molar tooth” colony. Reason why labs hold AnO2 cultures for up to 1 wk

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Actinomycosis
 Indolent, progressive infection that progresses across tissue boundaries
 Purulent foci with dense fibrotic tissue around
 Can look like neoplasia/tumor (mass)
 Later: sinus tract; drainage with “sulfur granules” (yellowish)
 E.g. cervical actinomycosis (cervicofacial is most common)

Clostridium species: overview


 Obligate anaerobes, Gram (+) bacilli
 spore-forming, pleomorphic, most motile
 Large group; ubiquitous in nature (GI tract of humans/animals; soil)

Clostridium perfringens
Clostridial myonecrosis (“gas gangrene”)
 Pathogenesis: production of phospholipase C (very potent alpha toxin)tissue destruction
 Diagnosis: clinical: septic appearance, gas in tissues (palpable bubbles),
o Necrosis with gas & no inflammatory cells: phospholipase C kills them too quickly!
 Treatment: need extensive surgical debridement! (can’t contain with abx & host immune system)
o Supportive care
o Abx: penicillin G + clindamycin
o Hyperbaric oxygen for some locations
Food poisoning: toxin made after food ingested
Necrotizing enterocolitis: beta-toxin production after poorly cooked pork, rare in US

Clostridium difficile
Pseudomembranous colitis & antibiotic associated diarrhea;
 Pathogenesis: Toxin A (enterotoxin), Toxin B (cytotoxin)
o Extra toxins: epidemic strain
 Clinical presentation: bloody diarrhea; can include toxic megacolon (distended)
 Diagnosis: DIRECT DETECTION OF TOXIN IN STOOL is major way to diagnose
 Treatment:
o Withdraw offending antibiotic
o Metronidazole PO or vancomycin
o Surgery if toxic megacolon, intestinal perforation, severe illness

Clostridium botulinum
Botulinum toxin: most potent neurotoxin known; bioterrorism agent
Botulism: three types
1. Foodborne: typically adults; from ingestion of preformed toxin in contaminated food (poorly-made jams, etc)
2. Infant: organism in GI tract; toxin produced in vivo, most common form of disease
3. (Wound) – rare

Pathogenesis: toxin production; potent neurotoxin that blocks Ach release at neuromuscular junctions

Clinical presentation:
1. Incubation: 18-36h, dose dependent
2. Afebrile, alert, oriented, normal sensory exam; early nausea/vomiting, diarrhea
3. Cranial nerve symptoms (ptosis, blurry/double vision, trouble swallowing/talking, ↓ salivation)
4. Progressive motor symptoms: BILATERAL DESCENDING FLACCID PARALYSIS  resp paralysis
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5. Death in 60% (untreated; 5% with Tx)

Lab Dx: toxin in serum, gastric fluid, stool

Treatment:
1. Supportive care (airway support)
2. Administer antitoxin (equine serum for adults – 9-20% hypersensitivity – or human botulism Ig for infants)
3. (if wound: debride too)

Clostridium tetani
VACCINE PREVENTABLE!
Widespread distribution of spores in soil & aquatic environments
Pathogenesis:
1. Spores contaminate puncture wounds, etc.
2. Spores germinate (low oxidation-reduction from poor vascular flow)
3. Vegetative cells multiply; release tetanospasmin (attaches to peripheral nerve endings; travels up to CNS)
4. Toxin: binds gangliosides in CNS and blocks inhibitory impulses (PROLONGED MUSCLE SPASMS)

Clinical presentation
 Spastic muscle contractions
 Difficulty opening the jaw (“lock-jaw”)
 Characteristic smile (“risus sardonicus”)
 Contractions of back muscles can result in arching – can actually snap spine!

Treatment:
1. Supportive care (airway maintenance, antispasmodics)
2. Antitoxins: human tetanus Ig, tetanus toxoid
3. Antibiotics: metronidazole

Prevention: vaccine!

Clostridium septicum
Bacteremia associated with malignancy
 Pathogenesis: high dose chemo damages GI; organisms translocate at site of mucosal damage
 Blood cultures positive
 Treatment: Penicillin G, supportive care, sometimes surgery

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Emerging and Re-emerging Bacterial Zoonoses
 Zoonosis: any infectious disease that may be transmitted from other animals (wild & domestic) to humans or
from humans to animals
 Vector: any animal that transmits an agent of human disease or plays an essential role in the agent’s life cycle
o E.g. mosquitos / malaria; snail hosts / schistosomiasis; rodents / leishmaniasis
o Typically arthropod vectors (mosquitos, ticks, flies, lice, fleas)
 Emerging infections: diseases that have recently appeared or are growing in incidence. Lots!
o Zoonotic, vector-borne, bacterial  high RR for disease to emerge

Transmission of bacterial zoonoses


Direct contact: animals/infected materials Leptospirosis (Leptospira); Brucellosis (Brucella)
Animal bites / scratches Cat scratch disease / bacillary angiomatosis (Bartonella henselae)
Arthropod vectors Plague (Yersinia pestis)
Contaminated food Lyme disease (Borrelia burgdorferi), Rocky Mountain Spotted Fever
(Rickettsia rickettsi)

Leptospirosis
Leptospira: spirochete (spiral-shaped); Enormous taxonomic group

Leptospirosis:
 Estimated >10M cases worldwide, uncommon in US
(Hawaii, Wisconsin?), more common in tropics
 Acquisition: contaminated animal or rodent urine: lives in
bladder, urinary tract of asymptomatic animals
o Water/soil
o Skin abrasions; conjunctivae
o Domestic pets (dogs) / livestock too
Clinical presentation:
 Fever, headache, myalgia, abdominal pain, conjunctival suffusion (inflammation / red eyes)
 5-10%: Icteric form (Weil’s disease)
o Can precede worse outcomes: renal failure, pulmonary hemorrhage, cardiac arryhmias
 Uveitis (late manifestation, can lead to blindness)
 Death in 5-15% (esp old age)
Histopathology:
 Cholestasis: brown pigment in liver (jaundice too)
 Pulmonary hemorrhage(mechanism not known)
 Interstitial nephritis: chronic inflammatory cells in interstitial around tubules

Pathogenesis:
 urine contaminated water  mucous membrane / skin abrasion  liver, CNS, kidney, all organs  localized in
kidneys  patient sheds Leptospira in urine
 Virulence factors: motility, hemolysins, adhesions / invasions (bind & localize), hemostasis & coagulation genes
 Immunologic pathogenesis:
o Proinflammatory response to LPS (via TLR2); activates host inflammation
o Multi organ-system failure due to DIC
o Pulmonary hemorrhage (Ig, C’ fixation on host cells; more common with high Ab titers)
o Ocular disease: uveitis during “immune phase” – Ig & C’? uvea = iris, choroid, ciliary body

Dx: can culture during acute phase (1st week); IHC / microscopy / PCR not great.

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 Microagglutination test (MAT): detect Abs as early as 5-7d post-onset;
o single high titer acceptable; seroconversion preffered
Tx: doxycycline, penicillin, cefotaxime.
 Jarisch-Herxheimer reaction (proinflammatory cytokine cascade; like sepsis, should anticipate possibility)

Brucellosis (Brucella spp)


α-2 proteobacteria
Gram (-) coccobacillus; facultative intracellular
 B. melitensis is key organism. Not sure if 1 or 3 species

Epidemiology: worldwide distribution (Eurasia, Africa, S. America most) ;


domestic wild populations coexisting
 Human transmission:
o Oral contamination (domestic farm animals)
o Consumption of unpasteurized dairy products
o Inhalation of aerosolized contaminated animal products

Pathogenesis:
1. Enters via mucosa, endocytosed by phagocytes
2. Survives in acidified phagolysosome; enters into ER (abx resistant), delays apoptosis
3. Regulates TNFα by translocating a protein into cell’s cytoplasm

Granulomas everywhere = characteristic of intracellulars like brucella

Clinical presentations

Classic febrile brucellosis: acute infection


 insidious onset (fever, sweating, malaise, headache, weight loss; aches/pains  frank arthritis)

Relapsing / undulant brucellosis (Malta fever)


 > 2mo after classical febrile brucellosis if un/der treated
 Liver involvement, arthritis, uveitis, orchiepididymitis
 Can be chronic; > 1 yr

Complications:
 Osteoarticular disease
o Peripheral arthritis (acute infection, non-erosive, knees, hips, ankles, wrists)
o Sacroilitis (acute infection)
o Spondylitis (lumbar spine; often irreparable damage)
 Epididymoorchitis (granulomatous inflammation with lots of lymphocytes in epididymis; enlarged testicles)
 Abortion in pregnant females, liver, CNS (meningitis, etc  grave prognosis)
 ENDOCARDITIS: main cause of mortality, usually aortic valve, generally requires surgery
 Relapse: inadequate treatment; usually 1st year

Diagnosis:
 Blood or bone marrow culture: need Biosafety level 3 (easily aerosolized)
 Detect Abs (serum agglutination test: draw pt serum, add antigens for Brucella). Safer, for presumptive Dx

Treatment:
 Doxycycline + rifampin (or streptomycin/netilomycin) for 4-6 weeks

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Bartonella spp
 Small, Gram (-) rods; facultative intracellular bacterium; α-2 proteobacteria, related to Brucella
 Mammalian, arthropod reservoirs (rodents, felids, lice, fleas, ticks)
 Infects erythrocytes & endothelial cells

Bartonella henselae: Cat-scratch disease

Epidemiology:
 ↑risk: kitten exposure, ownership, bites/scratches
 Cats: often seropositive; persistently infected with B.
henselae (“normal blood flora”-ish)
 Fleas: vector between cats, not humans (except maybe
immunocompromised?)

Clinical diagnosis:
 Regional lymphadeopathy with or without fever
 Cat/kitten scratch/bite
 Papule at inoculation site (small, red, elevated lesion)
 Characteristic histopathological features
o Stellate microabscess in granuloma (in lymph nodes)
 Apoptotic cells, macrophages, PMNs, epitheliod histiocytes, etc.
o Clusters of bartonella inside lesions

Pathogenesis:
 Fleas on infected cats defecate; cats clean, flea feces under claws
 Inoculation of bacteria in cat scratch
 Spread: draining lymph nodes  infection
 Occasional: systemic spread but resolves spontaneously in most cases

Clinical manifestations:
 Cat-scratch episcleritis (Parinaud’s oculoglandular syndrome)
o Inoculation in/around eye; drains to post-auricular node
o Neuroretinitis: CNS involved; fluffy infiltrates (bacteria in retina)
 Usually in immunocompromised pts:
o Bacillary angiomatosis / peliosis
 Proliferation of blood vessels & capillaries in skin (angiomatosis) or liver/spleen (peliosis)
 Inflammatory cells in interstitium; bacteria cluster there
o Endocarditis – very important
 Thrombus-like material forms; most of necrotic lesion filled with Bartonella

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Pathology of Mycobacteria Infection
M. leprae: Leprosy
 Caused by M. leprae (acid-fast; obligate aerobe)
 Prefers cooler parts of body (lesions on skin prominences, nose, URT, peripheral nerves, testes)
o Neuropathy secondary damage to fingers, etc – secondary infection; loss of digits.
 2 types: tuberculoid (nothing to do with TB) & lepromatous
LEPROMATOUS TUBERCULOID
 Weak host immune response  Strong host immune response
 Numerous bacilli (MB: multibacillary)  Few bacilli (PB: paucibacillary)
 Sheets of macrophages, not granulomas  Granulomatous reaction
 Non-reactive lepromin (skin) test  Reactive lepromin (skin) test
o Note how immune reaction is responsible for other differences
 Extremely rare in USA; more common in other countries (esp. Africa, Nepal) – usually travelers if in US

M. tuberculosis: TB
 Epidemic waves of morbidity/mortality: sharp rise; peak, gradual decline over 100s of years
 Worldwide: #2 ID killer (HIV, 2.7M; TB: 2.2M; Malaria: 1.1M)
o 2 billion infected with M. tb; 8M new cases/yr, 1 death every 10 seconds; 500k infected with HIV too
o One untreated pt infects 10-15 new pts / yr
 Epidemiology: poverty, overcrowded housing, undernourishment (airborne)
o Slums of US, etc. where poor, elderly together

Mycobacterium tuberculosis:
 Acid-fast bacteria (high lipid content of cell walls; Ziehl-Neelsen stain)
o Red dye, washed away from other cells by acid alcohol, counterstain blue
 Obligate aerobes, hard to detect in tissue, slow to grow in culture
 Can survive intracellularly

Transmission:
 Person-person (small airborne droplet nuclei)
o Have to be small to avoid mucociliary apparatus
o Produced when coughing/sneezing/speaking/singing
o Remain airborne; disperse uniformly throughout enclosed space (can’t use regular surgical mask)
 Expt: guinea pigs in cages on roof infected via aerosolization; distance didn’t matter
 MDR-TB is more easily spread!

Primary TB:
Initial spread & development of Ghon focus / complex
1. Goes to middle, lower lung fields (in periphery) – greatest
volume of air goes there
2. Nuclei implant on respiratory bronchioles/ alveoli (past
mucociliary system, way out into lungs)
3. Initially: non-specific PMN response (usually not observed)
4. Alveolar Mφ engulf mycobacteria  multiply within Mφ
5. Some mycobacteria are killed by Mφ  process/present
antigen to T-helper lymphocytes  release lymphokines to
attract more Mφ & activate  monocytes infiltrate;
activated histiocytes  granuloma forms
o Caseous center, etc. If you hear caseous or AFB,
think TB!
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6. Some Mφ with M. TB transported to regional lymph nodes, then throughout body
o Ghon focus: initial site of implantation
o Ghon complex: Ghon focus + lymph node (classic for primary TB)
Simon foci: some bacteria  lung apacies (higher oxygenation, lower blood flow so lymphostasis)
 Apical scars: common in tuberculin + pts; harbor more bacilli (dormant) than other areas of lung
 1st part driven by anatomy/physiology; this is driven by metabolic character of the organism

Outcomes of this part:


 >90% heal; have positive PPD; viable bacilli remain! (calcified granule in lung can harbor dormant M. TB)
 5% go on to develop progressive primary TB

Progressive Primary TB
 5-10% of patients (especially lowered immunity, kids, elderly) progress to primary progressive TB
 If granulomata erode, can discharge into different spaces
1. Miliary TB: erode into vessel
 Characteristics:
 tons of evenly-sized, tiny foci throughout lung (bacteria well mixed in blood)
 larger foci towards apex (better oxygenation)
 Worst prognosis
 Pulmonary vein: left heart; to rest of body: new lesions in both lungs
 Pulmonary artery: back into that lung; new lesions in one lung
2. TB Bronchopneumonia: erode into airway
 Characteristics: larger pieces of granuloma breaking off  unevenly sized, clustered nodules
3. TB empyema: erode into pleural space
 Characteristics: can see granulomatous change, caseation in former pleural space

Post-primary TB
Infections which develop in individuals with immunity to bacillus.
1. Reactivation of previously healed TB (Simon foci)
a. Begins in posterior segment of upper lobe
b. About 1-2% untreated PPD + pts will reactivate <
5yrs
2. Reinfection of previously infected individual (with
different strain)
a. Not totally prevented; suggests BCG vaccine not
effective

CAVITATION IS HALLMARK OF POST-PRIMARY TB:


 Granulomata eroding, eventually leave cavitation where
they were before (especially near apex)
 Can manifest as TB bronchopneumonia (airway), Miliary
TB (vein), TB empyema (pleura) like before or…
o Massive hemorrhage (erode into artery)  specific for post-primary TB
o Leads to hemoptysis
 Cavity can also heal (risk of aspergilloma – fungal - infection)

Preventing post-primary TB: treat PPD+ even if asymptomatic!


 Cuts risk of developing active disease; can treat while still healthy!

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Non-Tuberculous Mycobacteria
 A.k.a. “atypical” mycobacteria, “anonymous” mycobacteria, “pseudotubercule bacilli”
 Classified into 4 groups, don’t produce disease in guinea pigs
 Acquired from ENVIRONMENT (soil, water) – not person-person like M. tb
 Opportunists: usually infect people with underlying lung dz or decreased immunity

HIV & Mycobacterium tuberculosis


 HIV: depletes CD4+ cells; decreases monocyte/macrophage function
 HIV+ & +PPD: very high active disease rate
 Highest AIDS demographic groups: blacks/Hispanics 22-44 = greatest increase in TB
 Reversal of downward TB trend (1985-6: AIDS)

HIV patients & TB: TB usually diagnosed 6mo before opportunistic infections (more virulent); now an AIDS-defining dz
 More often extrapulmonary TB
 TB in lungs often non-apical, non-cavitary; poorly-developed granuloma (no good immune response)
 Drug-resistance higher; PPDs more often negative
 Complications: crushing spine (Pott’s disease); ocular involvement
 Rest of world: TB is leading cause of death in HIV+ individuals

Worrisome: TB form in Africa resistant all known drugs; usually fatal.

HIV & NTM


 NTM (e.g. mycobacterium avium complex) common in pts with AIDS (need low CD4 count)
 Enter via GI tract; occur late (less virulent), no person-person transmission
 No granulomas, histiocytes packed with bacilli (look pale blue & striated)

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Vector-Borne Zoonoses
Vector: any animal that transmits an agent of human disease or plays an essential role in the agent’s life cycle
 typically refers to arthropod vectors (mosquitos, ticks, fleas, flies, lice, etc.)
 Vector transmission only: Lyme disease, RMSF
 Direct-contact and vector transmission: plague
Yersinia pestis (Plague)
Gram-negative coccobacillus; stains in a bipolar pattern; facultative intracellular bacterium
Ecology: endemic foci maintained; persistant rodent hosts; flea vector active year round
 Epizootic hosts; low resistance to infection (squirrels / chipmunks), high mortality/population density
 Rural rats  fleas  urban rats  fleas  humans(bubonic)  humans(pneumonic)
Potential bioterrorism agent (pneumonic)

Transmission:
 Flea bite: bubonic plague
1. Rat flea bites patient
2. Inoculate flea material into wound  drain to local lymph nodes  bubo (hyperplasia & necrosis of LN)
3. Fever, headache, chills, malaise, painful lymphadenopathy (2-6d later)
4. With Tx: cure in 3-5 days
 Aerosol: pneumonic plague
 Pulmonary infection  rapid spread & septicemia
 Either: septicemic plague
 Invade blood without buboes; high frequency of death
 Endotoxin / cytokine release / Gram (-) sepsis; resp. distress syndrome (ARDS); SIRS
 Complications: endophthalmitis, mmeningitis, tissue abscesses

Epidemiology: endemic in Africa, Asia, N/S America; >2,000 cases / yr in world, high case fatality rate
 Human transmission: depends on environment, host mammals, arthropods

Pathophysiology: rapid spread & growth in tissue & blood


 PMN: engulf & kill Yersinia
 Mφ: just get infected; Yersinia propogates inside, kills Mφ
 Bacteria suppresses leukocyte function
o Yops: suppress inflammation
o LcrV: stimulates TLR-CD14 on MφIL-10(anti-inflammatory )
 LPS activates systemic inflammatory responses, coagulation, fibrinolytic pathways (SEPSIS)
 Pla protease (plasmid)  tissue destruction & C’degradation (required for bubo)

Pathology: Extensive tissue necrosis without extensive inflammation

Diagnosis: clinical suspicion, blood culture, bipolar staining


Treatment: streptomycin, doxycycline, sulfonamides

Borrelia burgdorferi (Lyme Disease)


Borrelia burgdorferi:
 Spiral-shaped (corkscrew / twisting motility); small, obligate parasite found with mammals, birds, ticks
 Transmitted exclusively through tick bites
 Maintained in small mammal via Ixodes species tick cycle (mammal reservoir, tick vector varies with location)
o Tick: larvae  nymph  adult; nymphs do most of the biting (small tick = immature)
o Larvae needs to acquire borrellia from mammal reservoir (last season’s nymphs did the infecting!)
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Tick-bite (ixodes scapularis, “deer tick”) transmitted
 Tick life cycle:
 Tick bite: inserts through epidermis into dermis; both insert/secrete saliva & aspirate tissue (infects & can be
infected); spirochete to tick midgut
o Mild inflammatory lesion where bite occurs

Epidemiology: N. America (northeast, Wisconsin/Michigan area, etc.), Europe, Asia


 Seasonality: bimodal distribution (most May-July: nymphal deer ticks; secondary peak in late fall: adult ticks)
 Incidence increasing

Clinical presentation:
 Early localized infection: erythema migrans (“bull’s eye”)
o EM +/- draining lymphadenopathy; usually 1st week post-tick bite. EM not always present!
o Nonspecific inflammation; perivascular lymphocytes: looks like chronic inflammation
 Early disseminated infection: systemic manifestation (disseminates to lymphatics, blood vessels, capillaries)
o Fever (infrequent in early-localized)
o Multiple erythema migrans
o CN VII palsy, Carditis (arrhythmias), Oligoarticular arthritis, Meningitis
 Late infection: oligoarticular, chronic arthritis, encephalopathy (very rare), chronic pain/memory loss/etc.
 Post-Lyme disease syndrome: no response to antibiotics, not present in vaccine placebo group from trial,
independent of serological results, no resistance to Abx: NO EVIDENCE FOR LONG TERM ABX and this cluster of
symptoms really seems unrelated to Borrelia!

Pathogenesis: inflammatory response to spirochetal lipoproteins in specific anatomical sites


 OpsA (adhesion for borreliae in tick midgut)
 OpsC (transmission from tick salivary gland; infection in mammal)
 Dissemination: spirochetes blind plaminogen; converted to plasmin, helps in interstitial / cell invasion
o Host plasmin + spirochete: better movement through ECM (degrade); activate matrix metalloproteases
to cleave ECM more
 Lots of lipoproteins (interact with TLRs host proinflammatory cytokine & chemokine production)
o Joints: arthritis; heart: carditis; neural structures: neuritis

Diagnosis: Clinical (Hx exposure; endemic region, erythema migrans), culture, SEROLOGY
 Serology: enyzme immunoassay (sensitive, not specific) first, then western blot to confirm
Treatment: amoxicillin, doxycycline, ceftriaxone (CNS infections)
Prevention:
 Vaccine no longer available
 Prophylatic doxycycline for tick bites in highly endemic areas (85-90% effective < 24 hrs)
 Remove attached ticks, avoid areas, etc.

Rickettsia rickettsii (Rocky Mountain Spotted Fever)


Gram (-), Obligate intracellular bacteria (Rickettsia = intracytoplasmic; Erlichia & Anaplasma = intravacuolar)
True bacteria (debated at first: DNA, RNA, ribosomes, binary fission)
Close relative to mitochondria (ATP transporter to steal ATP from cell: opposite of mito, etc.)
Tick-bite transmitted

Epidemiology: SE USA, emerging in Southwest. North, Central, South America


 Case-fatality rate: up to 8% overall, higher in children & elderly.
 Lyme disease: non-fatal; RSMF: can be deadly!
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Pathogenesis:
 attach & enter endothelial cells  escape from phagosome & inhibit phagolysosome fusion  escape, cell dies
 Causes lymphocytic vasculitis

Clinical presentation: SUDDEN ONSET Rash progression in RSMF
 High fever, severe headache, severe myalgias  Macular: flat, pink-red
 Maculopapular-petechial rash after 3-5d  Maculopapular: raised; blanches
 Normal WBC with left shift; thrombocytopenia  Petichiae: blood extravasated
 Lymphocytic vasculitis  loss of intravascular fluid (won’t blanch)
o Hypotension; shock, end-organ ischemic injury
 GI system, renal system (acute tubular necrosis secondary to hypotension)
o Cerebral edema; meningoencephalitis
 E.g. herniated brainstem through foramen magnum, crush respiratory centers
o Non-cardiogenic pulmonary edema
 Pathology: inflammation, damage to endothelium, damage to dermis, not epidermis (around endothelial cells)

Diagnosis: clinical (h/o tick bite, fever, headache); SEROLOGY


 5x risk death after 5d of illness
 Most not treated until after 5d: “hallmark” rash comes in late!
o Presentation during non-peak tick activity, early presentation (1st 3 days) higher risk for missed Dx
 Culture not advocated: VERY HAZARDOUS (use PCR or skin biopsy with antigen)
o Serology not useful in first 7-14 days

Treatment: doxycycline (or tetracycline; doxy has better outcome than chloramphenicol; tooth-staining uncommon
with these doses in kids)

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