Professional Documents
Culture Documents
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Introduction to Infectious Diseases
Infectious Disease: When an interaction with a microbe causes damage to the host, Steps in microbial
resulting in clinical signs and symptoms of disease pathogenesis
1. Contact
Pathogen: Any organism that has the capacity to cause disease 2. Attachment
3. Invasion
Factors that affect pathogenicity: Host, Agent, and Environment 4. Evasion
5. Cell Damage
I. Host: WHO IS THE PATIENT? (must develop a specific plan for that pt) 6. Spread
a. Age: According to P. Murphy, all organ functions decline at about 1% per year.
Immunologic parameters which decline with age Immunologic parameters which increase with age
Thymus atrophies (by age 40) Variability of response to a new antigen ↑
Primary antibody responses ↓ Incidence of monoclonal immunoglobulins ↑
Skin reactivity ↓ Incidence of auto-Ab against DNA (anti-nuclear),
T cell proliferation to mitogens ↓ immunoglobulins (rheumatoid factor), and organs
# naïve T cells ↓ (thyroid) ↑
T cells make less IL-12 (immunostimulatory) # memory T cells ↑
T cells make more IL-10 (immunosuppressive)
b. Nutritional status
Need mixed protein (40g/day, all 20 amino acids in correct proportions) for protein synthesis
Can’t store amino acids – unused ones used as energy
Protein deficiency & immunity: T-cell function ↓ (main problem); PMN production also ↓ but less obvious.
Liver makes less albumin
Lots of hospital pts. malnourished (esp in ICU, etc.) Can be a big predictor of outcome
c. Host genetics
E.g. breed susceptible/resistant animals, N. Europe may have been selected for TB, measles, smallpox
resistance, certain human mutations lower resistance to certain organisms, genetic basis for some HIV
resistance in certain patients.
d. Host co-morbidities
Most clinical infections are situational: reason exists for why pt. became infected
o Chronic medical illnesses (diabetes, etc); immunosuppressive
drugs (steroids, transplants, chemo, rheumatoid arthritis tx); Types of Pathogens:
IV access for many reasons Prions (single protein molecule,
II. Pathogen PrP)
a. Endogenous vs. Exogenous Flora Viruses (Nucleic acid –RNA or DNA
Endogenous flora: organisms which are long-term residents of - & proteins)
body surfaces (“commensals”) Bacteria (prokaryotes; nucleic acid
o Colonization by endogenous flora happens right after birth - DNA & RNA – not separated from
o Good for nutrient acquisition, differentiation of mucosal sites, rest of cell by membrane)
stimulates immune system, provides accessory growth factors Fungi (eukaryotes)
o Harder for pathogenic organisms to establish residence on Parasites (eukaryotes)
body surface or multiply & cause problems
Exogenous flora: organisms which can’t survive indefinitely in a single individual but depend on transmission
from one person to the next
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b. Better classification scheme
Commensals: Very normal to have; rarely cause disease
Facultative Pathogens: some patients get sick, others don’t (who’s the patient?)
Obligate pathogens: never should be there; is essentially always causing disease if present
c. Human microbiome: effort to categorize what kinds of flora live where in / on humans
Inoculum size:
If you brush teeth, some bacterial always entering your blood, but you’re ok (small size so neutrophils take care
of it).
If you have an abscess burst of the same bacteria, you’re in trouble (tons entering blood stream at once)
About 1011 Gram-negative bacilli (1 mL stool), 1012 Gram-positive bacilli can kill you
Growth rate:
Doubling time varies among organisms
Bacteria = minutes (exceptions: mycobacteria, chlamydia, etc. are slower)
Virus = hours (poliovirus @ 5hrs is fastest)
Fungi, parasites = slower
Virulence factors: properties that enable a microorganism to establish itself on or within a host & enhance its potential
to cause disease (resist host defenses, multiply from small inoculum to concentration that causes disease)
Growth @ 37 C, for instance; toxicity, etc).
Host resistance
Non-immunological: HOST RESISTANCE
o Skin impermeable to most bacteria Immunological
Nonimmunological
o Mucous membranes allow small #s bacteria Innate (“Natural”) Acquired
to pass through (induce immunity) Skin Macrophages B-cells
o Constant flow in body tubes washes out Mucous membranes Neutrophils (PMNs) T-cells
bacteria (saliva, bile, urine) Constant flow in NK cells
o Lungs protected by cilia and cough reflex body tubes Complement
o Breaking these barriers (e.g. central lines, IV Clilia, cough in lungs Interferon
drugs, Foley cath) is a great way to cause infection
Innate (“Natural”)
o Macrophages & Dendritic cells
Roles: Phagocytosis, antigen presentation, secrete cytokines to drive acquired immune
response differentiation,
use pattern recognition receptors (CD14, Toll-like Receptors) to recognize molecules from
pathogens (e.g. LPS in Gram (-), peptidoglycan in Gram (+))
o Polymophonuclear cells (PMNs = neutrophils)
Roles: phagocytosis (opsonic, PAMPs, etc.)
Microbes can escape phagocytosis:
o have a capsule to protect
o inhibit fusion of phagolysosome
o escape into cytoplasm & replicate there
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o resist killing (e.g. catalase)
Reach infection site via chemotaxis (chemicals from initial host-pathogen interaction) and
adhesion interactions (sticking & migration from vessel)
o NK Cells: large, low-density, granular cells without T-cell receptors or surface IgG
Don’t require activation before function
Triggered by cells that do not display self class I MHC
Mostly antiviral activity
Acquired immunity
o T-cells (cell-mediated immunity)
Roles: directly kill infected cells, generate DTH responses, promote Ab formation
TH (CD4+) cells: work with MHC class II molecules
facilitate immune response by T-cells & B-cells
secrete products that promote antiphagocytic activity
TCTL (CD8+) cells: work with MHC class I molecules
Lyse infected cells
o B-cells (humoral immunity)
Produce immunoglobulins which recognize unique antigenic structures
NB: Good review slides for the end of the block at the end of this “Healthy people who are well-fed,
lecture: defect in ____, increased susceptibility to_____. reasonably separated from each other, and have
access to pure water
seldom have serious infectious illnesses”
– P. Murphy
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Prokaryotic Structure & Physiology
Prokaryotes vs. Eukaryotes PROKARYOTE EUKARYOTE
SIZE OF CELL Small Bigger
NUCLEUS No nuclear membrane / nucleoli Nuclear membrane / nucleoli
Important things: differences between MEMBRANE-ENCLOSED Nope Yep
prokaryotes and eukaryotes are good ORGANELLES
targets for antibiotics (cell wall, ribosomes, FLAGELLA Simple (2 building blocks) Complex (microtubules)
etc.) GLYCOCALYX Capsule / slime layer Present in some cells (if no
cell wall)
CELL WALL Usually present; complex When present, simple
Bacterial shape & size PLASMA MEMBRANE No CHO; mostly lacks sterols Sterols & CHO as receptors
CYTOPLASM No cytoskeleton Cytoskeleton
Cocci (round) RIBOSOMES Smaller (70S) Bigger (80S); smaller (70S) in
Bacilli (rods) organelles
CHROMOSOME (DNA) Single circular chromosome Multiple linear chromosomes
Pleomorphic (shape is variable or shape No histones Histones
is “in-between”, e.g. “coccobacilli”) CELL DIVISION Binary fission Mitosis
Also vibrio (=commas), spirochetes SEXUAL REPRODUCTION Transfer of DNA fragments only Meiosis
(=spirals), etc.
Size: about 0.2-5 μm
Gram’s Stain
Process:
Get sample, fix by air drying (don’t heat – could hurt cell wall)
Crystal violet (all purple) iodine (stabilizes) alcohol (decolorizes G- ) Safranin (counterstains G- red)
End result: Gram (+) = purple, Gram (-) = red
Gram stain adheres to gram+ peptidoglycan layer & resists decolorization
Exception:
Acid-fast bacteria cannot be Gram-stained
Resist decolorziation with alchol because of a high lipid concentration in cell walls)
Mycobacteria, etc: have to use an acid-fast stain (show up red)
Uses:
1. Bacterial identification (especially in low resource areas, or quick ID)
2. Early identification of an appropriate antibiotic (e.g. could start empiric treatment to cover Gram (+) )
Tips:
Try to minimize epithelial cells (would take up safranin, so would be red)
Neutrophils usually show up but are much bigger than your bacteria
o Can use neutrophils to judge the decoloration (pale red = too declored, too blue = not declored enough)
o If you leave alcohol on too long, could decolor even Gram (-) bacteria
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Important features of bacterial cell walls:
Bacterial capsule:
Gelatinous layer, covers bacterium, found in some spp, usually polysaccharide
o Sugars vary spp to spp; can use to do serological typing
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o Virulence: prevents phagocytosis
o Swells if homologous Ab around: QUELLUNG REACTION
Example: think you have strep; mix with an anti-strep-capsule Ab, get Quellung reaction to
confirm that you’re right (organism has that capsule)
o Can be used as antigen with some vaccines
Spore formation:
Clostridium and Bacillus produce them (e.g. recurrence of C. diff, etc.)
Response to adverse conditions
Form inside the cell (DNA, cytoplasm, cell membrane, peptidoglycan, thick keratin-like structure around it)
No metabolic activity (can be dormant for years)
When environment more favorable, enzyme degradation of coat, germination into bacterium
Highly resistant to heat and chemicals
Obligate aerobes cannot grow without oxygen (ATP-generating system needs oxygen as hydrogen acceptor)
Faculative anaerobes can use oxygen for respiration if it’s around, but they can also go anaerobic
Obligate anaerobes lack one or both of these enzymes so they can’t generate ATP via respiratory pathway
Bacterial genetics: bacteria are haploid with a single chromosome (usually circular, ~2000 proteins; can transfer to
other bacteria, e.g. as plasmid); fission results in identical progeny.
Mutations are changes in base sequence of DNA that results in altered phenotype
Substitutions (missense, nonsense); frame shift, transposons / insertion sequences.
Can occur randomly & may be caused by chemicals, radiation, viruses – but genetic diversity not generated
during reproduction like in eukaryotes
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These are two ways that inducible resistance can arise, or production of a toxin which wasn’t previously
produced, for example.
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Bacterial Toxins
Toxins: molecules produced by microbes that can produce disease
Toxoids: detoxified toxins that retain antigenicity / immunogenicity) vaccinations (diphtheria, tetanus)
EXOTOXIN ENDOTOXIN
molecule (usually protein) produced and released by a intracellular / cell-associated structural component
microorganism to affect target cells at a distance of Gram (-) bacteria (e.g. LPS)
Act enzymatically or directly with host cells; stimulate Most located in cell envelope & act locally
variety of host responses
Exotoxins
Toxin genes:
chromosomes (cholera), bacteriophage (diphtheria),
plasmids (E. coli heat-labile), combination (Staph enterotoxin)
Mechanisms of action of A-B exotoxins (organism can have more than 1 toxin too)
1. ADP-ribosylating toxins. Remove ADP ribosyl group from NAD & stick it on host-protein, inactivating or
modifying function
2. Adenylate cyclase toxins. Synthesize cAMP after binding host cell calmodulin
3. RNA glycosidase toxins. Cleave host cell rRNA, stopping protein synthesis cell death
4. Metalloprotease toxins. Proteolytic disrupt cell function
Membrane-damaging toxins: release of host cell nutrients (cell death) & better direct injection of bacterial components
Pore-forming toxins: trans-membrane pores into phospholipid bilayer; disrupt selective ion movement.
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o B. anthracis edema factor, S. aureus α-toxin (abscesses), streptolysin O of S. pyogenes (strep throat)
Cytotoxins: hydrolyze / solubilize phosopholipid bilayer
o (α-toxin of C. perfringens)
Exotoxin examples:
Anthrax: uncommon, risk factors: animals & hides, industrial activities, bioterrorism. Cutaneous/inhalational/GI; any
can be associated with hemorrhagic meningitis. Radiography: widened mediastium (hemorrhagic lymphadenitis).
Substantial edema (around lesions on skin).
Diptheria: uncommon (universal vaccination with diphtheria toxoid); endemic in Latin America / Carribean, immunity
does not prevent carriage, adult immunity wanes without booster.
Endotoxins
Endotoxin: LPS, located in outer membrane of Gram (-) bacteria.
Released from lysed bacteria (host defense and/or Abx)
Generally acts locally.
Structure:
o O-antigen: variable among Gram (-) bacilli. Facilitates tissue adherence, carrier for lipid A, antigenic
variation, phagocyte resistance, protection from Ab & C’
o Core (R) polysaccharide: conserved within / distinct between genera
o Lipid A: highly conserved
Generates febrile response (direct: hypothalamus; induces endogenous pyrogens like IL-1,
prostaglandins)
Directly activates Mφ, coagulation cascade
Activates C’: histamine release PMN chemotaxis
Induces interferon production, TNFα (↑capillary endothelial cell permeability shock)
↑colony stimulating factor production; polyclonal B-cell production, immunoglobulin secretion
Inject LPS: fever, leukocytosis, disseminated intravascular coagulation (DIC), hypotension, shock, death.
Mechanism of action:
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1. Lysis release of LPS binds to circulating LPS-binding protein; complex then binds to CD14 on Mφ cell
membranes (associates with other proteins)
2. Triggers secretion of pro-inflammatory cytokines (IL-1, IL-6, IL-8, TNFα, PAF) from Mφ.
3. Cytokines bind cytokine receptors on target cells (inflammation, C’ activation, coagulation pathway)
4. Leads to endotoxic shock, multi-organ systemic failure
High fevers, severe back pain, pain on urination; CVA tenderness (costovertebral angle kidneys);
PMNs in urine, Gram (-) on gram stain
Hypotension, tachycardia, dyspnea
Superantigens
Biological activities: overstimulation of immune system, pyrogenicity, shock
Mechanism:
Superantigen mediates non-specific interaction between class II MHC on APCs and specific Vβ chains of TCR on
T-lymphocytes
Massive stimulation of T-cells (20% activated massive cytokine release)
Toxic shock syndrome: Hypotension, fever, diffuse erythematous rash
Scarlet fever:
Pharyngitis from Group A Streptococcus usually self-limited (2-5d); Tx: prevent complications
Scarlet fever: pyrogenic exotoxin (Group A strep): complication from pharyngitis
“Sandpaper rash”: 1-2d after onset; upper chest rest of body, texture key in Dx
o Rash fades desquamation
“Strawberry tongue”: bright red tongue
Toxins as friends:
1. Immunogens in vaccines directed against toxin (toxoid)
2. Direct targeting of cells with receptor can exploit toxin B subunits (e.g. fusion proteins in cancer chemo)
3. Botulinum toxin (Botox ®)
a. Control of disorders with uncontrolled muscle spasms
i. Blepharospasm (uncontrollable blinking)
ii. Torticollis (relentless turning of neck to one side)
b. Chronic anal fissures
c. Temporary reduction of skin wrinkles
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Fever & Sepsis
Fever: “a state of elevated core temperature which is often, but not necessarily, part of the defensive response of a
multicellular organism (host) to the invasion of live or inanimate matter recognized as pathogenic or alien by the host.”
Drugs, cancers, etc. can also cause fever – not just infection
Variability of temperature:
1. observer (calibration, etc.)
2. anatomic (oral is best – easily accessible & responds promptly to core changes; also rectal & tympanic)
3. physiological: ↓(age, in morning), ↑(ovulation, exercise, at night)
a. No set “normal body temperature”: normally distributed among individuals
b. Varies : 96°F 101.3°F (> 101.3 usually defined as fever)
Thermoregulation:
Heat derived from internal work (peristalsis, myocardial contraction), biochemical reactions, external work
(exercise, shivering)
Core heat distributed via circulatory system (e.g. ↑core temp, ↑cutaneous blood flow to dissipate via skin)
o Turn red with fever (dilating vessels)
Pre-optic area controls body temp
o If over set point: activate heat loss responses (lower body temp)
Pyrogens affect temperature regulation (drugs too!)
o Endogenous: PGE2 (from COX-2, PGE2 synthase via arachadonic acid pathway) to preoptic area
o Pyrogenic cytokines: IL-1 (most commonly associated, also TNF, IL-6, IFN)
Source: Mφ (response to endotoxin, peptidoglycan, fungal cell walls, bacterial toxins, drugs)
Example: LPS + LPS-binding protein Mφ CD14 reeptor cytokines PGE2 production from
endothelial cells pre-optic area increase body temperature (feeds back on cytokine
expression)
o Non-infectious pyrogens: non-infectious febrile disease from pyrogens produced in immune response
Fever in malignancy: generally infection or body’s attempts to reject tumor
Certain tumors (e.g. Hodgkin’s disease): malignant cells can produce endogenous pyrogens
Treatment:
Antipyretics: if you’re going to give, GIVE CONSISTENTLY AND CONTINUOUSLY
o nontoxic, analgesic effects, reduces metabolic demands & fever-induced alterations in mentation
People feel worse when temperatures are changing (e.g. chills & sweats)
No definitive studies to show benefits or harmful effects for moderate fever
Temperature > 106°F: enzymatic processes start to break down (big trouble)
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Stimuli: infections, trauma, cancer, burns, exercise, childbirth
Body trying to limit actions of what it perceives to be invader:
o IL-6: changes in hepatic protein synthesis
↓ albumin
↑ fibrinogen, haptoglobins (increased amounts);
↑ C reactive protein and serum amyloid A associated protein (not present in normal plasma)
o IL-1: ↓ serum iron/zinc (withhold from bacteria), ↑ PMNs & bands
C-reactive protein:
o binds phosphocholine on microorganism, damaged host cells;
o activates C’ & ↑phagocyte adherence (better clearance)
o Good marker for following Tx of chronic infection (e.g. osteomyelitis). (Can also look at anemia of
chronic disease: Iron increased)
Serum amyloid A: ↑adhesiveness, chemotaxis of phagocytic cells & lymphocytes
SEPSIS
Definitions:
SIRS: systemic inflammatory response syndrome:
o “abnormal, generalized inflammatory reaction in organs remote from the initial insult
o (fever, tachycardia, leukocytosis / PMNs)
o Could also be from drug rxn, tumor, etc.
Sepsis: when SIRS occurs in pt with suspected or proven infection, then SIRS = sepsis
Severe sepsis: sepsis + hypotension
Septic shock: severe sepsis + organ dysfunction that cannot be reversed by fluids (usually liver, kidney)
Sepsis: (85% SIRS have bacterial causes = sepsis): Caused by host reaction to agents (all good things but too magnified)
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Diarrheal Disease Caused by Bacteria
Diarrhea: #2 cause child death worldwide (#1 = acute respiratory disease)
5 million /yr in 1980 1.5-1/7 million today because of ORS)
Most cases: 1st 2 years of life; mortality highest in < 1yo.
Frequency of bowel movements: most 1-2 per day (varies in general population, not impossible for 3/day to be normal)
Diagnosis: clinical symptoms, microscope exam, culturing stool (primary), ELISA, PCR.
Looking at Ab can be used only retrospectively (takes too long)
Normal GI function: 2L fluid in, 200mL out in stool (98% absorbed, most in small bowel).
Villus cells absorb, crypt cells secrete.
Continuous removal of intestinal epithelial cells (shed in stool ~2-3d)
o Divide @ crypt, travel up & sloughed at top. Normal: # cells entering villus = # cells dying
Normal microbial flora: few in small intestine; abundant in large bowel (also in mouth)
o Mostly anaerobes (99%); facultative anaerobes (e.g. E. coli) ~1%
o Provide protection against enteric pathogen colonization (Salmonella, C. difficile)
o Non-immunologic control: gastric acid, normal peristalsis, bile
o Immunologic control: sIgA from mucosal immune system, cell-mediated immunity in gut
FYI: lactating mammary gland makes these Ab too; important for newborns
Fecal-oral transmission
Developing countries: contaminated water supply, inadequate latrines, poor sanitation
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Developed countries: contamination of processed foods
Virulence factors
Inoculum size: variable (Shigella, EHEC: 10-100 organisms for; cholera, ETEC: 105-8)
o Person-person requires small inoculum size; food/water requires large inoculum size
Enterotoxigenic vs Invasive
o Enterotoxigenic: V. cholerae, ETEC. Attach to mucosal
cells in intestine by pili, other mechanism; sit on border
& secrete toxins
o Enteropathogenic: attatch & efface microvilli; cause
some damage to the border (EPEC, EHEC)
o Invasive: Shigella, Campylobacter, Salmonella, Yersinia,
Listeria. Enter cells & replicate there
Enterotoxins:
Cholera toxin (CT); E. coli heat-labile toxin (LT): large MW toxins,
5B:1A, arranged like donut
Heat stable (ST) E.coli toxin is Enterotoxigenic Invasive
smaller (E. coli, Cholera) (Campylobacter, Shigella)
Shiga and Shiga-like toxins (S. Diarrhea Severe Moderate
dysenteriae, EHEC) also large MW , Major site of disease Small bowel Colon
different action Major defect Increased secretion Decreased absorption,
Bacteriophage control (horizontal Increased secretion
gene transfer): CT & Shiga-like Character of fecal loss Isotonic electrolyte Same + mucus, ±blood,
Plasmid control: LT & ST E. coli solution ± pus
toxins Primary Rx Fluid-electrolyte Fluid-electrolyte + Abx
Incubation period generally 1-3 days, rarely 4-5 days; very rare 30d+
V. cholerae:
O1, O139 only serogroups that cause epidemic cholera
Most severe of all diarrheas (60-70% mortality untreated; 12-24h death, > 1L/hr)
Result of the cholera toxin
Clinical course: exposed, 1d incubation, vomiting at first / “rice water” diarrhea, low BP, tachycardic
Findings: “washerwoman’s hands”, skin turgor, sunken eyes (severe dehydration), no real histological changes
May see metabolic acidosis (losing bicarbonate): huffing & puffing
Potassium lost may lead to hypotension & even renal failure
Stool: NO RBC, NO PROTEIN (similar to serum: isoelectric!)
ETEC: most common bacterial cause of diarrhea in developing world; most frequent cause of traveler’s diarrhea. Very
similar to V. cholerae.
Both V. cholerae & ETEC: similar mechanisms of pathogenesis (CT & ETEC LT are very similar)
Large inoculum size (105-8 organisms); achlorhydria can predispose
Colonize small bowel via fimbriae attaching to mucosal receptors
Produce enterotoxins while sitting on surface
o B subunits of CT/LT attach to GM1 ganglioside receptors; ST attaches to different one)
o A subunits of CT/LT activate adenylate cyclase: ↑cAMP
↑ Cl secretion from crypt cells
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↓ NaCl absorption from villus cells
o ST: activates guanylate cyclase; ↑cGMP, same changes
o Coupled Na/glucose absorption NOT affected: important for ORS
Lab diagnosis:
Treatment: FLUID REPLACEMENT (IV or oral)
If cholera, antibiotics help decrease stool output & shorten disease. Tetracycline, Cholera: use special
erythromycin, cipro. media to culture
Oral rehydration therapy (ORS): Na, Cl, K, Citrate + carbohydrate. Does not (TCBS agar)
decrease severity/duration of diarrhea. Uses coupled Na/glucose transport to
efficiently absorb sodium. Universal therapy for all dehydrating diarrhea. ETEC: need
o Keep osmolarity lower than normal serum (don’t want to suck fluid out) molecular methods
o Use citrate because it’s more stable than bicarbonate (no easy culture)
With good treatment: mortality <1%
Vibrio parahaemolyticus
Gram (-) rod, halophilic (thrives on high salt); normal inhabitant of costal waters
Common cause of diarrheal disease after eating undercooked shellfish (especially oysters)
Major cause of diarrheal illness in Asia (esp. Japan) eating raw fish
Mechanism of action not well understood (heat-stable toxin?)
One serotype “pandemic”: O5:K6 (Asia Europe, US)
Clinical presentation:
Seasonal: summer months predominate (warmer water)
24h incubation, mild diarrhea (±nausea, vomiting, low-grade fever)
Vibrio vulnificus
Gram(-) rod, lives in sea water (mostly in summer along Gulf Coast)
Blood stream infections (ingestion in seafood like raw oysters, wounds after exposure to salt water)
Pts with liver disease or severe immunocompromise almost exclusively affected (very rare in normal pts)
Sepsis results
Treatment: infections very difficult to treat; mortality very high in spite of Abx & surgery
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o Nutritional therapy can be important (not absorbing nutrients from damaged bowel)
Campylobacter jejuni
Gram (-), slightly curved rod
Common in small children of developing world, young adults of developed world
Present in >50% supermarket chicken packages (prevalent in poultry and other mammals too)
o Transmission: food preparation; on outside of meat (easily cooked away)
Mechanism for diarrhea production not known
Requires 42C incubation, microaerophilic conditions to grow
Treatment: antimicrobial therapy useful (azithromycin is drug of choice; erythromycin, fluroquinolones too).
Often cipro-resistant
Dx can take several days, pt may recover by then.
Oral therapy not too helpful
Source: food industry failures. Healthy young cows are reservoir; contamination from stool
Low inoculum size so big mixtures of hamburger meat can still be infectious
Irradiation can control but not widely used
Pathogenesis: colonize large bowel mucosa; attach & efface microvilli of mucosal cells
Produce two shiga-like enterotoxins (SLT-1, SLT-2) controlled by bacteriophages
o 5B:1A toxins; A subunit inhibits 60S ribosomal subunit (kills cells)
Clinical presentation: 1-2d incubation hemorrhagic colitis (blood in stool); HUS can develop in 10% pts after 6 days
(diarrhea has already disappeared)
HUS: hemolysis, renal failure, thrombocytopenia. 3-5% HUS pts die, 3-5% get chronic renal dz
Dx: stool cultures on special media (Sorbitol MacConkey agar); otherwise look like normal E. coli
ID toxin in stool; look for serological responses to toxin & O antigens too
Tx: supportive
ANTIMICROBIALS ARE CONTRAINDICATED (can increase the production/release of the toxins!)
Prevention:
Avoid undercooked hamburger, unpasteurized milk / apple cider (steaks=OK because not a big mixture).
Wash hands after petting zoos
Food industry: improve methods, culture all hamburger prior to shipping, irradiate to sterilize meat
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Enteropathogenic E. coli (EPEC)
Gram (-) rod
Limited to children < 2yo; previously big cause of nursery diarrhea
Mild illness; can use ORS as tx (no evidence for Abx)
Not as frequent as ETEC; particularly common in Brazil
Pathophys: attach to small intestine (attach & efface microvilli), do not produce enterotoxins
doesn’t cause too much damage
Dx: serotype E. coli in stool
Non-typhoid Salmonella
Gram (-), non-lactose-fermenting rods Non-typhoid Salmonella:
Fecal-oral transmission; generally through prepared foods in developed world S. typhimurium
Chickens thought to be primary reservoirs (eating contaminated chicken or S. enteritidis
infected eggs via shell contamination or transovarial passage)
S. Heidelberg
o Also: amphibians, reptiles (turtles!)
S. Newport
One of the most common causes of large food-borne illnesses in USA
Clinical presentation:
Inflammatory changes in small bowel
Generally mild disease except in children, elderly, immunocompromised (sepsis, mortality↑)
Strains can differ in virulence (some produce enterotoxins)
Typhoid fever: a.k.a. enteric fever, also caused by Salmonella paratyphi A & B
Primarily in the developing world, rare in developed world except for travelers
Found in all age groups, normally mild in young children
Clinical presentation: prolonged fever, constipation, hepatomegally, occasionally rose spots on abdomen/chest
Mortality 10-20% w/o tx; 1% with good tx
Complications: intestinal hemorrhage, intestinal perforation, cholecystitis (can affect any organ system)
Tx:
Antimicrobials (fluoroquinolones, AZI, ceftriaxone = 1st line; chloramphical, ampicillin, TMP+SMX = 2nd line if
susceptible). Increasing resistance.
Vaccines: two effective ones now
o Live vaccine: oral, 70% protection for 5 yrs
o Injectible vaccine: 70% protection, 2 years, not for kids
Clostridium difficile
Gram (+), spore-forming, anaerobic rod
Part of normal flora of large bowel (3% normal stools, 25% hosp pts); cause disease infrequently
Seen after use of broad-spectrum Abx (grow to high concentrations)
Produce toxins leading to illness
o TxA, TxB – mechanism not known
Clinical presentation:
Diarrhea, colitis (fever, pain, cramping), ↑ WBC, hypoalbuminemia
Advanced form: pseudomembranous enterocolitis
Mostly hospitals & medical institutions; responsible for ~25% antibiotic-related diarrheal illness
Dx: toxins A/A+B in stool (enzyme immunoassay or tissue culture), also endoscopy for pseudomembranes
Stool culture not useful (high frequency of normal colonization)
Tx: Stopping/changing antimicrobial therapy, metronidazole (250 mg po qid x 10d) or vancomycin (po) if failure
Relapses are common (spore-forming) – can treat with same drugs, longer duration
Also: cholestyramine, probiotics
Listeria monocytogenes
Small, Gram (+), intracellular rods
Can be part of normal bowel flora in adults
Soil / animals
Transmission: contaminated foods (cheese, pork, milk) can be outbreaks (esp. soft-cheese related)
Epidemiology:
Long incubation period (~30d)
Can be asymptomatic
Can cause disseminated infections (e.g. acute meningitis) especially in immunocompromised
Pregnant women: especially susceptible (spontaneous abortion)
Diagnosis: culture of normally sterile body fluids (CSF, blood). Difficult to culture from stool; not diagnostic if found
Serology can be useful (outbreaks)
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Treatment: ampicillin +/- gentamicin (gentamicin accumulates in Mφ, Listeria killed when they escape cytoplasm)
Prevention: avoid contaminated foods (soft cheese, pork products, esp. for immunocompromised / pregnant)
TMP+SMX prophylaxis for AIDs patients
Yersinia enterocolitica
Gram (-) coccobacillus; intracellular
Clinical presentation:
self-limited, mild gastroenteritis;
can provoke mesenteric adenitis which can present as “pseudo-appendicitis”
Helicobacter pylori
Small microaerophilic Gram (-) rods; colonize stomach
Don’t cause diarrhea (dyspepsia)
Can be Asx for life, very common in developing countries
Major cause of peptic ulcer disease; major contributor to gastric cancer
Summary of treatment:
1. Rehydration (IV/oral) most important in secretory diarrheas, where stool output is great
2. Antimicrobials critical for tx of shigellosis & invasive diarrheas but should be withheld if EHEC is suspected
3. Nutritional therapy important in children in developing countries (Zn therapy if zinc deficiency common)
Control by vaccines:
1. Typhoid: two vaccines on market
2. V. cholerae & ETEC: live, killed oral vaccines being tested
3. Shigella/Campylobacter: live, killed oral vaccines being tested in military
4. EHEC, Helicobacter: vaccines being developed
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Staphylococci
General characteristics:
Staphyle = “a bunch of grapes”, kokkus = “berry” Medically important Staphylococci
Gram (+) cocci 1. Staph. aureus (most virulent)
Divide randomly in 3 planes; daughter cells don’t Most important
separate completely: grape-like clusters Healthy & hospitalized (“staph infections”)
2. Staph. epidermidis (less virulent)
Distinguishing staph: Opportunist, oncology pts, implanted
Blood agar: medical equipment (biofilm), neonates
o S. epidermidis: white colonies, no hemolysis 3. Staph. saphrophyticus (less virulent)
o S. aureus: golden yellow colonies, beta- UTI in young women
hemolysis
Coagulase test (rabbit plasma + staph: does it coagulate?)
o S. aureus: coagulase positive
o All other staph: coagulase negative
Virulence factors:
Polysaccharide capsule (some species)
o Most S. aureus infections caused by 2 types (5+8)
Peptidoglycan: minor differences between Staph species (major scaffold anchoring surface adhesions)
Teichoic acids: water soluble polymers, linked covalently to peptidoglycan backbone, site of attachment of cell-
wall active enzymes / proteins (not virulence factor; may be important in adhesion to nasal epithelium)
NO LPS (Gram positive!)
Pathogenesis: e.g. attach during insertion and/or migrate down cath (sterile technique important!)
Virtually non-pathogenic in normal people
Resistant to many antibiotics
Clinical presentation: variety of clinical disease; usually indolent, rarely fulminant or life-threatening
Risk factors: hardware/foreign material (IV cath, dialysis access, implants/implanted devices)
Pre-term infants at risk (fragile skin, low integrity)
Can lead to:
o neonatal septicemia (NEC = neonatal necrotizing enterocolitis, bowel wall injury / necrotizing infection)
o endocarditis
S. aureus
Extremely common in N. America
Can acquire/integrate accessory genetic elements (↑pathogenicity)
Evolves to elude antimicrobials
Clinical presentation: TONS of clinical presentations (see below) Toxic shock syndrome
1. Impetigo (infected eczema, etc.) E.g. following introduction of high-
2. Cellulitis (deeper than impetigo) absorbency tampons (overgrowth of
3. Cutaneous abscesses (MRSA most common cause of staph)
skin/soft tissue infection in US EDs) Fever, profound hypotension,
o Boils (= furuncle; skin infection involving entire hair erythematous rash
follicle & nearby skin tissue) Vomiting/diarrhea common
o Carbuncles (involves group of hair follicles) Multisystem organ dysfunction
4. Wound infections Usually no bacteremia
5. Deep abscesses TSST-1 and other superantigen toxins to
o Abdominal, neck/sinus blame (Ab against TSST-1 = protective)
o E.g. pyomyositis: bacterial infection of skeletal
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muscle leading to pus-filled abcess
6. Osteomyelitis (bone infection)
7. Septic arthritis
8. Septicemia
9. Endocarditis
10. Toxin-mediated
o Toxic-shock syndrome
o Scalded skin syndrome (esp. children & neonates)
Basement membrane destroyed, skin sloughing off, follows cellulitis
o Food poisoning
o Necrotizing fasciitis
NOTE: S. aureus usually causes non-severe infection (celulitis, boils, etc.) but fulminant infections make the headlines
Antibiotic resistance:
Abx pressure acquisition / transfer of resistance genes (between and within species)
Penicillinase: plasmid-encoded; opens beta-lactam penicillin ring, no cephalosporin action
o Inhibited by most beta-lactamase inhibitors
o Present in 95%+ of S.aureus isolates: never choose PCN for empiric S.aureus treatment!
Vancomycin-resistant S. aureus
o Has been mainstay of treatment for serious MRSA
o MIC levels for vancomycin keep rising (some isolates have popped up with high MICs); now MIC of 4 is
no longer “susceptible” (4-8mcg/mL from “susceptible” to “intermediate”)
o Limited right now but will likely change
o Worry: Staph are good at horizontal gene transfer – could pick up VanA from VRE?
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Prion Disease
Prion: a proteinaceous infectious particle which is resistant to inactivation by most procedures that modify nucleic acids
Scrapie: ataxic sheep; wasting, cerebellar dysfunction, commonest fatal genetic disease of sheep
Studied agent:
o Resistant to things that inactivate nucleic acids: formaldehyde, ethanol, proteases, nucleases, UV/ionizing radiation, etc.
o Inactivated by things that inactivate proteins: autoclaving, pH extremes, inorganic salts, detergents
o Isolated the protein: had same sequence as naturally occurring proteins
PrPC is normal form (α-helical, monomeric, on cell surface, soluble)
PrPSC is changed form (β-sheets, big aggregates, insoluble amyloid fibrils/rods, found in
intracellular vesicles / extracellular space)
Misfolded: nobody knows how it starts
CJD
Transmitted, rare (1:1,000,000/yr), no regional pattern, varied presentation
Vacuolization in neurons; like pathology of scrapie & kuru
Presentation: myoclonic jerking dementia death
o No recovery, rapid progressive decline (~5 months on average, no good days), 90% dead < 1yr
NATURAL SPREAD OF CJD
LACK OF COMMUNICABILITY EVIDENCE OF TRANSMISSIBILITY
Absence of temporal/geographical Transmission to experimental host (brain, viscera, CSF inoculation)
clustering Transmission by physician (corneal transplantations, cerebral
Lack of conjugal cases corticography, dural grafts)
Lack of predominance by occupation Transmission to children (growth hormone injection from human
pituitary glands)
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Growth hormone: 1985: from human pituitary, combined many sources, some children infected. Resulted in
development of recombinant GH
Lack of transmission by blood products: case control studies (transfusion ≠ higher vCJD risk), no CJD in 342
recipients from donors who developed CJD, 12,000 hemophiliacs & no CJD
vCJD
Colloquially “mad cow” but not technically BSE; only 2 cases in US
Different from CJD: younger patients, psychiatric abnormalities (not myoclonic movements & dementia)
o CAN be transmitted by transfusion: 2 cases in UK
New: BSE diagnosed in cow in Washington, transfusion cases of vCJD, reports of possible BSE strains
Response to BSE in US: increased cattle testing, prohibited non-ambulatory cattle for human consumption, SRM &
mechanically separated meat prohibited from human food, carcasses of tested animals not passed until negative test
Deterrents to risk assessment: unknown mode of natural transmission, species barriers, dose/route of entry, strains,
differences in pathogenesis
Needs:
Blood test for humans & animals
Better understanding of pathogenesis (transmission, species barriers, strains, etc)
Neuropathological exams on all degenerative diseases
Worldwide surveillance of TSEs (humans & animals)
Current situation:
Kuru gone (incubation > 50 yr)
Iatrogenic CJD (hGH & dural graphs) ↓ but will continue for decades
BSE / vCJD outbreaks ↓ in UK but isolated cases worldwide
Chronic wasting disease: no spread to cattle or humans but spreading in N. America; wide host range in lab
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Academy Awards of Infectious Diseases
New diseases: 58% from animals (zoonosis)
Most important ID events in 20th century (survey):
smallpox eradication, penicillin, HIV, 1918 influenza, childhood immunization, clean water
Most likely to be eradicated: probably guinea worm (Jimmy Carter’s campaign!), but talked about polio.
Poliovaccine: 1000 children paralyzed per day (1988) herd immunity in US (early 90s)
Down to 6 countries / 575 cases/yr
New vaccine: Hepatitis B. 60% hepatocellular carcinoma; 300,00 cases / 5,000 deaths/yr
1st: anti-STD vaccine, anti-cancer vaccine. Can’t cultivate virus in artificial media (impressive)
Big drop in HBV in USA, Taiwain (decided to vaccinate in 80s). HBV endemic in Asia (lots of perinatal trans)
New bacterium: H. pylori. Role in Type B gastritis, achlorhydria, peptic ulcers, gastric carcinoma & lymphoma, others?
Some crazy guy drank a glass of it & got sick (achlorhydria, etc.) Non-invasive; tons of polys.
Abx shown to have better prevention of recurrence than ranitidine
More and more chronic diseases shown to have microbial components
unpredicted, projected US toll: 50% infected, 1.8 mil Surge capacity (biggest US challenge)
hospitalized, 30-90,000 deaths; will be tracked in real time! Global sharing unlikely
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Anaerobic Infections
Anaerobes: dominant form of life on/in people
“Organisms of neglect”- important but not much known about them Most anaerobic infections:
Mixed (polymicrobial)
History: Pasteur (Clostridum butyricum); Veillon & Zuber: intraabdominal sepsis Endogenous (host flora)
(IAS) & B. fragilis, “classical studies”(1889 – 1938) looking at genitourinary tract Microbial dx rare
flora, lung abscesses, IAS; “renaissance” (1965-1980) – clinical studies, culture, Empiric tx with abx
taxonomy, antibiotic development
Classification of anaerobes
Growing anaerobes: commonly use a chopped meat glucose EOS (extremely O2 sensitive): tolerates
broth seconds/minutes of O2 exposure
Strict anaerobe: tolerates > 0.4% O2
Much less anaerobic bacteremia now than in past (people
Moderate anaerobe: tolerates 0.8-2.5% O2
learned how / when to treat anaerobic infections)
Microaerophilic: tolerates >2.5% O2
Facultative anaerobes: tolerates anaerobic
Major pathogens:
condition but also grows in air or 10% CO2
Gram negative bacilli (Bacteroides, Prevotella)
Gram positive cocci (Peptostreptococci, a.k.a. “peptococci”)
Gram positive bacilli (Clostridia) – pretty much the only anaerobe transmitted human-human because it’s
spore-forming; the spores can exist aerobically)
SITE RATIO ANO2 : O2
Hopless (Lactobacillus, Bifidobacteria, Veillonella)
Saliva, tooth 1:1
How to diagnose anaerobes: Stomach, Ileum
Gingiva 1000:1
Microbiologic diagnosis: get specimen from a normally sterile site;
Colon
transport while protecting from too much O2, think if it makes sense / from
an anaerobic site Vagina 5:1
Clinical diagnosis: think of site of infection (not pharyngitis, etc. but maybe a peritonsilar abscess); putrid
discharge, polymicrobial flora Gram Stain.
Growing anaerobes: get anaerobic transport media; often grow in anaerobic chamber, etc.
Is it pratical?
o Specimens are hard to obtain; microbiology is polymicrobial, tedious; the process is expensive &
prolonged, treatment is empiric anyway because susceptibilities are high; patients are often discharged
before report comes in
o Antibiotic sensitivities are of poor quality and not recommended, clinical clues are good
o One exception: blood infections (usually take a sample & put in both aerobic and anaerobic bottles)
If E. coli, would grow in both; if Bacteroides Fragilis, would grow just in AnO2
Recognizing anaerobes:
Often see polymicrobial mix
AnO2 GNRs have an unique morphology (e.g. long & fusiform); AnO2 GPCs just look like cocci
Abscesses & IAS (Intra-abdominal sepsis): often E. coli & B. fragilis (if polymicrobial, probably anaerobes involved!)
If you perforate your colon, tons of anaerobes headed inside
Flow is slower in colon so anaerobes can grow; by the time stool gets out, it’s almost purely anaerobes (just
about as much as could fit in the space that the stool occupies!)
Often E. coli early (peritonitis stage; recovery); B. fragilis late (abscess stage, higher mortality).
o Different roles: E. coli causes bacteremia & shock; B. fragilis causes abscess
o Not synergestic: each has its own role
Remember that other organisms (e.g. S. aureus) can cause abscesses commonly too!
B. fragilis
bacteremia without septic shock (no active endotoxins)
capsular polysaccharide: need capsule for sepsis (capsule itself can actually cause an abscess!)
In vitro resistance to abx: very little
o Metronidazole is best against B. fragilis
o Imepenem or Pip-Tazo work too
Clostridial syndromes
Clostridium sp. Syndrome
C. botulinum Botulism
C. tetanus Tetanus
C. perfringens Gas gangrene
C. perfringens enterotoxigenis Food poisoning
C. difficile Antibiotic-associated colitis
C. sordellii Septic absorption
C. septicum Neutropenic colitis
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Chlamydia & Mycoplasma
Chlamydia
Obligate intracellular organism; tiny
Thought to be a virus for a time: DNA, RNA, ribosomes; make own proteins & nucleic acid (true bacteria)
Inner & Outer membrane (like gram neg) but no peptidoglycan layer (don’t Gram stain at all: too small)
Energy parasite (can’t make own ATP)
Chlamydiaceae:
Chlamydia trachomatis: trachoma, oculogenital, LGV: STIs & conjunctivitis
Chlamydia pneumoniae: atypical pneumonias
Chlamydia psittaci: psittacosis (from birds)
Chlamydia trachomatis
Infects non-ciliated, columnar epithelial cells; infection doesn’t confer much resistance to reinfection
Doesn’t grow on normal lab media: need to use tissue culture (like a virus)
Culture isn’t great for Dx: use PCR for LGV & D-K (more sensitive)
o Trachoma: clinical diagnosis
Serovars D-K:
Common genital infections, conjunctivitis (neonates)
Presentations
o Men: urethritis epididymitis (70% due to CT!)
Serosanguinous penile discharge (gonorrhea more purulent)
o Women: urethritis, cervicitis, (PID, ectopic pregnancy, chronic pelvic pain if untreated)
Majority asymptomatic
Cervicitis: mucopurulent discharge (can use swab to test)
o Both: pharyngitis, pneumonia, proctitis (anal sex), conjunctivitis
Proctitis: direct inoculation from anal sex; rectal bleeding, pain, mucous discharge, diarrhea
o Neonatal conjunctivitis (30-50% exposed babies)
Highest in women, blacks, ages 15-25; most frequently reported STD & ID in US (2-4M new cases/yr)
high partner co-infection rate
Remember: notifiable disease; must treat all sex partners from previous 60 days or reinfection is likely
High reinfection rate
Screen: all women <25yo yearly; re-screen 2-4 months after Tx
Serovars L1-L3:
Lymphogranuloma venereum (LGV)
Worldwide; higher in tropical/subtropical; MSM mostly in US
More invasive strains; cause thrombolymphangitis
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Stages:
1. Primary: genital lesion (painless) – transient ulcer
Ulcer most often undetected; 30d incubation
Heal without scarring; can get anal/rectal reinfection with anal intercourse/contaminations
2. Secondary: regional lymphadenopathy; systemic Sx
2-6wks later: buboes (swelling of lymph node); painful!
“Groove sign” – groove between two LNs
Rupture or harden, then resolve
Inguinal LAD is most common (less in Treating Chlamydia
women so go undiagnosed) Tetracyclines (doxycycline)
Rectal involvement: MSM, anal sex macrolides (azithromycin: only need one dose)
3. Tertiary: genital elephantiasis; strictures, Resistance: extremely uncommon
fistulas, abscesses, frozen pelvis
More common in women (lack of Sx in 1st 2 stages)
Elephantiasis! Nasty!
Serovars A-C:
Trachoma: leading cause of preventable (infectious) blindness worldwide
A chronic keratoconjunctivitis endemic to Africa, Asia, Middle East, Australia (aboriginal groups)
Transmission: children & women who care for them; Via hand-eye, fomites, flies
Developing world only
Pathogenesis:
o repeated reinfection chronic follicular conjunctival inflammation (active trachoma)
o tarsal conjunctival scarring distorts tarsal plate
o entropion (turning in of edges of eyelid so that lashes rub against eye surface) & trichiasis (cicatricial
trachoma)
o corneal abrasions, scarring, opacification: blindness
Chlamydia pneumoniae
Chlamydia psittaci
Birds (parrots pigeons, hens, turkeys pet owners, pet shop employees, poultry farmers)
Severe Atypical Pneumonia, also typhoidal-form fevers, splenomegaly, malaise possible
Culture is DANGEROUS – use serology or PCR
Mycoplasma
Tiny prokaryotes, lack a cell wall; Cell membrane bound: contain sterols; has RNA, DNA; hard to grow (special agar)
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Non-Tuberculous Mycobacteria (NTM) & Nocardia
NTM & Nocardia: both in same order (Actinomycetales); both found in environment and only cause disease if
immune system compromised somehow
NTM vs Nocardia
Mycobacteria Nocardia
Route of Infection Inhaled Inhaled, direct inoculation
Source/Reservoir NTM-soil,water; leprosy-human Soil
Host range MOTT-large; leprosy-narrow Large
Clinical 1o lung or skin (GI?), can 1o lung or skin, can disseminate
disseminate
Cell Wall PG, AG, mycolates (C60-C90: long!) PG, AG, mycolates (C44-C66: shorter!)
Microbiology Acid fast, aerobic, rod Weakly acid fast, aerobic,
filamentous rod
Host Defense Cell mediated immunity Cell mediated immunity
Evasion Phagosome-lysosome non-fusion Phagosome-lysosome non-fusion
Decontaminating specimens:
Mycobacteria grow slowly (1x/day vs. E. coli ~20m); can be overgrown by other bacteria/fungi
o Sterile specimens: blood, CSF inoculate directly onto media
o Non-sterile specimens: sputum chemical decontamination to remove normal flora/contaminants
Abx to inhibit other bacteria; decontaminate with pH
Suppresses both mycobacteria & others but less for myco (suppression can be problem)
Culture: more sensitive than smear, TAKES WEEKS to grow, may require special conditions (low temp, etc.)
Importance: species ID, drug susceptibility, monitoring response to Tx
Need low temp (environmental organism needs environmental temperatures): need to notify lab for NTM
Liquid media faster (1-3wks vs 4-6 for solid)
Can’t grow M. leprae!
Speciation: traditionally growth characteristics; biochemical tests (slow) DNA probes, other methods
M. tuberculosis, M. avium complex, M. kansasii = important pathogens
M. gordonae: not a pathogen but common lab contaminant
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Mycobacterium leprae & Leprosy
A.k.a. Hanson’s disease, big historical significance (& >500K new cases/yr), mostly Brazil & India
M. leprae
Obligate intracellular parasite; cannot be cultivated in lab
50% genes “pseudogenes” (evolutionary reduction: from environment to humans, had excess genes left over)
Armadillos are a natural reservoir (SE US) & tool for research
Pathogenesis:
URT transmission (inefficient) multiples in tissue Mφ & Schwann cells around nerves mostly skin,
peripheral nerves disease: local effects of multiplication / host cell-mediated immune response; lose sensory
input around lesions, etc,
Neuropathic effects: neuropathy trauma/burns autoamputation of digits
Sunken nose: bacillary multiplication (low temp) destroys bone & cartilage
Leprosy spectrum:
Tuberculoid (TT) BB: Lepromatous (LL)
Paucibacillary (few bacteria) borderline Multibacillary (lots of bacteria)
BT: BL:
↑ peripheral nerve thickness Unstable:
borderline borderline
Flat granules, well-defined usually go
tuberculoid lepromatous Leonine facies (lesions heaped up wth
granulomatous lesions one way skin cells; filled with mycobacteriae)
Good TH-1 mediated immunity or other Mostly TH-2 mediated response
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Lymphadenitis (cervical lymphadenitis: MAC is most common entity; need to excise LN)
Pulmonary MAC: underlying lung disease is common (e.g. COPD,
emphysema, CF: prevent clearance) Diagnostic criteria: NTM lung dz
o Patterns: Solitary pulmonary nodule, fibrocavitary, nodular Clinical (need 2)
bronciectatic (small nodules, esp. in periphery larger 1. Typical Sx & radiology
bronchi) 2. Exclusion of other Dx
o Hot tub lung: hypersensitivity pneumonitis caused by reaction
to MAC in hot tub water Microbiologic (need 1)
Subacute SOB, cough, fever 1. + culture x2 (sputa)
+ MAC culture in hot tub & lung 2. + culture x1 (bronchoscopy)
May not require Abx 3. Biopsy evidence of granulomas
Disseminated (AIDS pts) + culture x1
o CD4 VERY LOW (<50), Incidence way down (HAART)
o Entry: GI tract; Subactute presentation: fever/abd pain/diarrhea/wt loss; hepatosplenomegaly,
pancytopenia, adenopathy
o Dx: blood culture (can grow from blood = tons of organism)/biopsy
o Path: phagocytes jammed with MAC
M. kansasii
TB mimic: most likely to present like TB (upper lobe cavitary dz)
Strictly transmitted via water supply (midwest, SE)
Risk factor: underlying lung disease (COPD, smoker)
M. marinum
Aquatic/marine environments; natural pathogen of fish
Human dz: inoculated into skin post-trauma (fishermen, watermen, aquarium hobbyists)
Chronic ulceronodular skin disease: “Fish tank granuloma”
o Chronic: dx often after weeks/months
Grows best at low temp: 28-30 C (notify lab)
M. ulcerans
Close relative of M. marinum; presumed aquatic
ONLY TOXIN PRODUCING MYCOBACTERIUM (has a huge PLASMID that encodes)
Buruli ulcer: emerging dz of sub-saharan Africa; chronic painless cutaneous ulcer
Major cause of disability (esp. children – aquatic environment) because of scarring, fibrosis (e.g. over joint!)
Tx: streptomycin + rifampin x 8wks
Rapidly-growing Mycobacteria
Colonies in ≤ 7days (relatively fast next to others; still pretty
slow) – can be longer for primary isolate RGM: Diagnosis
M. abscessus, M. chelonae, M. fortuitum: 90% clinical Grow on mycobacterial media (may also
isolates grow on normal blood agar/culture systems)
Ubiquitous in home & hospital; common contaminants of Need to notify lab if suspect RGM:
fluids & devices 1. More readily decolorized in AFB stain
Pseudo-outbreak of M. fortuitum pulmonary dz at JHH: from 2. More susceptible to decontamination
ice machine! 3. Require cooler temperatures for growth
Opportunistic pathogens: surgical site infections, implant-associated, pulmonary infection of diseased lungs (M.
abscesses), disseminated in immunocompromised pts.
Example: surgeon’s dye to mark incision sites contaminated; inoculated pt when cuts made
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Nocardia
Aerobic, Gram (+), filamentous rod
o Require modified acid-fast stain (weaker decolorization)
o Various spp with varying Abx susceptibility
Ubiquitous in soil, decaying vegetation
Infection: inoculation or inhalation
o NO PERSON TO PERSON TRANSMISSION
M. TUBERCULOSIS NOCARDIA
Order: Actinomycetales
SIMILARITIES
Ubiquitous in environment
Latent infection; gives +
tuberculin skin test
Slower generation time
Longer mycolates
(more resistant to
decolorization; more acid-fast)
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Antimicrobial Stewardship
Why is this important?
200-300M abx annually, 45% outpatient
25-40% hosp pts get abx; 10-70% unnecessary or suboptimal; 5% adverse reaction
Abx unlike other drugs: use in one pt can compromise use in another!
Resistance (up), really expensive ($30B annually)
# new abx (down), and mostly just modifications of existing classes
o Timeline for development:9 -10yrs, really hard
Definitions
Prophylaxis: use of antimicrobial agents to prevent the development of an infection
o Pre-exposure: e.g. surgical prophylaxis
o Post-exposure: e.g N. meningitidis prophylaxis
Empiric treatment: use of antimicrobial agents when infection is suspected and patient is ill enough to require
treatment
o e.g. tx of pt with possible sepsis
Pathogen-directed treatment: use of antimicrobial agents to treat a proven infection
o e.g. tx of pt with blood cultures growing S. aureus
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o Avoid "antibiotics for every fever"
Fever is not an illness: it's a sign of illness
Non-specific, host response to inflammation, not always an infectious cause, don't
always need abx even if infectious
Same goes for "antibiotics for increased WBC"
3. Choose an antibiotic
o Empiric therapy: when we don’t know what’s causing the disease, but we need to start something
What bacteria are likely to be involved & what antibiotics cover these bacteria?
Common error: try to cover every possible organism
Cover most likely & tailor to sickness of patient
o Pathogen-directed therapy: ID’d organism & have antibiotic susceptibilities
Choose antibiotic with narrowest coverage that will treat organism.
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Urine cultures
4 questions
1. What is source of urine? (clean catch good; cath/foley bag not good)
2. Does patient have symptoms of a UTI? ( dysuria, frequency, suprapubic pain, fever: don’t culture if none!)
3. What does urinalysis show? (should be sterile & uncontaminated. Suggestive of UTI: > 5-10 WBC/µL, no
epithelial cells – don’t rely on dipstick only)
4. What does the culture show? (positive ≥ 105 colonies; common UTI pathogens = E. coli, K. pneumoniae)
Wound cultures
Superficial cultures of chronic ulcers & cultures from drains: usually polymocribial; contaminated/colonized
More reliable: cultures from newly incised / drained abscesses
o Can be polymicrobial too; significant pathogens = heavy growth (S. aureus, GNR)
o Organisms like coag neg staph, enterococcus, strep viridans: if light growth, don’t need abx coverage
unless they’re only organism present
o Think of anaerobes in abdominal infections (might not grow in culture)
Sputum cultures
Lab classification of quality of sputum sample: PMNs = good, epithelial cells = bad (want lower resp secretions)
o Type 1: discarded; lots of squamous cells, problem in specimen collection
o Type 2: adequate; PMNs=epithelial
o Type 3: good! PMNs > epithelial (rare or none)
o Type 4: just spit (bad)
From endotracheal tubes: often colonized (look out) – should have clinical evidence of pneumonia to start abx
Cases:
1. 68 yo diabetic male; osteomyelitis, no systemic sx – don’t start abx right away (wait & check it out – stable pt)
2. 35 yo male, no comorbidity, picture of CA-pneumonia: want to start abx right away (pneumonia), thinking of S.
pneumoniae, HiB, (M. catarralis)+ atypical (legionella, Chlamydia, etc.) as common, give ceftriaxone (GPC) + azithromycin
(atypical) as empiric coverage. Find out susceptible to PCN! Give PCN (actually amoxicillin – easier PO because you don’t
have to give it as often) as pathogen-directed therapy.
3. 45 yo woman, severe Crohn’s disease, on TPN via central venous cath, fever 101 F & fatigue. Start abx (has cath!); probably
want to cover staph (vanco empirically for MRSA possibility), get a blood culture. Comes back MSSA; give oxicillin for
definitive Tx.
4. 50 yo man; central venous cath, took blood culture for no clinical reason, doing fine at home, culture comes back GPCC
(don’t start abx! Asymptomatic)
5
5. 55yo woman HT/high cholesterol; has acute MI; U/A & Cx show >10 colonies of E. coli. Find out if she has Sx, check U/A
results, think about source before starting abx.
Pharmaceutical representatives: varying perception about appropriateness of gifts; people think that it only affects
other doctors & not me, etc.
38
Syphilis (& other STIs)
NB: Most STIs are ASYMPTOMATIC ask about BEHAVIOR, not Genital ulcer diseases:
just symptoms! Syphilis (Treponema pallidum)
Herpes (HSV 1&2)
Syndromes & causes:
Chancroid (Haemophilus ducreyi) – mostly in
Genital ulcer diseases: syphilis & herpes are the big
the south; uncommon
ones
Lymphogranuloma venereum (Chlamydia
“Drips” (discharges): gonorrhea, chlamydia,
trachomatis L1-L3)
trichonomiasis are main ones
o Possible presentation esp in developing
o Pt presents with a drip: treat for gonorrhea &
world; usually causes proctitis (MSM, etc.)
chlamydia empirically & then trich if sx don’t
Granuloma inguinale or donovanosis
resolve
(Klebsiella granulomatiosis)
Urethral/vaginal/cervical inflammation; proctitis (receptive anal sex), pediculosis pubis too.
Treponema pallidum
Spirochete (slender, tightly coiled, unicellular, helical)
Can’t culture in vitro (hard to study – inject into bunny testicles)
Has very few proteins on outer membrane – relatively inert; has very little genetic diversity
Pathogenesis:
1. Penetrates skin through little microabscesses common with intercourse
disseminates quickly (hours/days) via lymphatics/blood to any organ Stages of syphilis:
(especially CNS: in 1st few days!) divides ~30h
2. T. palladium gets to deep tissues (induces matrix metalloprotease-1 “early syphilis”
production) quickly, induces endothelial cells to express ICAM-1/VCAM- 1. Primary syphilis
1/E-selectin inflammatory cells migrate to tissues 2. Secondary syphilis
a. PMNs respond first 3. Latent syphilis
b. Dendritic cells stimulated (TLR2 recognizes T. pallidum PAMPs) a. Early latent
phagocytosis taken to regional LNs T-cells activated (slow
process b/c T. pallidum outer membrane is relatively inert) “late syphilis”
3. [CD4] & [CD8] peak 13-18d post-exposure (ulcers resolve); T. pallidum b. Late latent
survives in an unknown reservoir 4. Late syphilis
4. Incubation period: ~3wks 5. (Neurosyphilis: early &
5. Very low inoculum size (~10 spirochetes = infection!) late)
ii. Meningovascular: endarteritis of small blood vessels (meninges, brain, spinal cord)
1. Strokes, seizures
2. MCA STROKE is especially common site
iii. Parenchymatous: actual destruction of nerve cells “Argyll Robertson (AR) pupil”
1. Tabes dorsalis: affects spinal cord a.k.a. “Prostitute’s Pupil”, although
(shooting pains down leg, ataxia, cranial that’s probably not too PC these days
nerve abnormalities) small pupils, accommodate (to near
2. General Paresis: affects brain (dementia, objects) but don’t react (to bright light)
psychosis, slurring speech, “Argyll Wikipedia notes this fun mnemonic:
Robertson” pupil). Schizophrenia-type “like a prostitute, they ‘accommodate
but do not react.’”
symptoms of general paresis are big in
literature, Law & Order: SVU
Transmissibility
Sexual transmission: only possible prior to late-latent syphilis
In utero transmission: possible at any time
o All pregnant women need a syphilis test at their 1st visit
Congenital syphilis
In utero infection can occur at any stage of syphilis; tends to happen after 4th month of gestation
Baltimore has a number of cases each year (marker of public health quality)
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Perinatal manifestations: rhinitis (“snuffles”) followed by diffuse rash (esp. soles of feet), splenomegaly,
anemia, jaundice, thrombocytopenia; osteochondritis not uncommon (predilection for long bones & cartilage in
nasal area; causes deformity)
Later manifestations: neurosyphilis, deafness, keratitis, recurrent arthropathy, Hutchinson’s teeth (widely-
spread incisors; look kind of like Dracula)
Diagnosis
Dark-field microscopy: gold standard test for primary syphilis (serology negative in ~ 30% cases); not often
used (unavailable), can’t use for oral /GI lesions (lots of oral/GI nonpathogenic spirochetes)
Serology: primary tests used, not sensitive in primary syphilis (prior to Ab formation); pt can become non-
reactive in secondary, early latent, early-late-latent syphilis
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STI DDx: urethral / vaginal / cervical inflammation
N. gonorrhoeae, Chlamydia trachomatis, Trichomonas vaginalis
Symptoms: dysuria (pain with urination), increased urinary frequency, urethral/cervical/vaginal discharge,
occasionally epididymitis / orchitis (testicular pain) in men
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